Document X71yVj1ZZgom8yQnzyxabGjVw

CHEMICAL REVIEW CHEMICAL REVIEW: VINYL CHLORIDE CAS RN 75-01-4 NIOSH # KU 9625000 SAX # VNP000 DOT # 1086 SIC CODE 2813 See N.I. Sax. 1988. Dangerous Properties at Industrial Materials, 7th ed. New York: Van Nostrand Reinhold, p. 3473. SYNS Chlorethylene, chloroethene; chlorethene; chloroethylene; chlorure de '.vinyle (French); cloruro di vinile (Italian); ethyl ne monochloride; Exon 470; monochloroethene; monochloroethylene; Trovidur; vinile (cloruro di) (Italian); vinyl chloride monomer; vinyl chloride, inhibited; vinyl chloride, monomer; vinyl C monomer; vinylchlorid (German); vinylchloride; vinyle(chlorure de) (French); VC; VCM; wihylu chlorek (Polish). MF C2H3C1 MW 62.50 SPECIES IN MIXTURE 99.42% pure. COMMON USES Approximately 96% is used in production of vinyle chloride homopolymer and copolymer resins. It is also used in production of methyl chloroform and as a comonomer with vinylidene chloride in the production of resins. Polyvinyl chloride resins are used in production of plastic piping and conduit. Other uses are in floor covering, consumer goods, electrical applications, and transport applications. Vinyl chloride has been used as refrigerant, an extraction solvent, and as aerosol propellant. (R-63) MARCH,APRIL 1989 STORAGE AND HANDLING TRANSPORT. RAIL (%) 90.0. TRANSPORT. BARGE (%) 2.0. TRANSPORT. PIPE {%) 8.0. CONTAINERS Pressure cylinders, tank cars, tank barges. GENERAL STORAGE PROCEDURE Protect against phys ical damage. Outside or detached storage is prefer able. Inside storage should be in a fire resistive storage room, provided with adequate ventilation and free of sources of ignition and heat. GENERAL HANDLING PROCEDURE Guard against all sources of ignition. PRODUCERS Allied Chemical Corp., Moundsville, WV; American Chemical Corp., Watson, CA; Cum berland Chemical Corp., Calvert City, KY, Charles ton, WV; Dow Chemical Co., Oyster Creek Division, P.O. Box BB, Freeport, TX 77541; Dow Chemical Co., P.O. Box 150, Plaquemine, LA 70764; Ethyl Corp., Gulf States Rd., P.O. Box 341, Baton Rouge, LA 70821; U.S. Tire and Rubber Co., Ashtabula, OH; U.S. Rubber Co., Painesville, OH; Goodyear Tire and Rubber Co., Niagara Falls, NY; Monochem, Inc., Highway 73, Geismar, LA, 70734; Monsanto Co., Texas City, TX; Tenneco Chemical Co., Houston, TX; Union Carbide Corp., Chemicals Div., Texas City, TX; U.S. Rubber Co., Painesville, OH; Goodrich Chemical Co., Louisville, KY, Niagara Falls, NY; Stauffer Chemical Company, Plastics Div., 2112 East 223 St., Carson, CA 90745; Ethyl Corp., La Porte Rd., Pasadena, TX 77501; PPG Industries, Inc., Attn: J.R. Farst, P.O. Box 1000, Lake Charles, LA 70601; PPG Industries, Inc., Aun: K.R. Mesloh, P.O. Box 7572, Ponce, PR 00731; Allied Chemical Corp., Gulf States Rd,, Baton Rouge, LA 70821; Independence Plant, P.O. Box 150, Attn: E.R. Henderson, Deer Park. TX 77536; Union Carbide Corp., Highway 1765, P.O. Box 471, Texas City, TX 77590; BF Goodrich, Chemical Div., Attn: R.K. Hinderer, Highway 1523, Calvert City, KY 42029; Borden Petrochemical, Geis mar, LA 70734; Shell Oil Company, P.O. Box 100, Deer Park, TX 77536; Shell Chemical Co., Norco Manufacturing Complex, P.O. Box 10, Norco, LA 70079; Continental Oil Co., Lake Charles VCM Plant, Box 605, Westlake, LA 70669. (R-47, R-63, R-70) ADDITIVE (%) Phenol. STANDARDCODES NFPA 2,4t,l; ICC Flammable Gas, Red Gas label, 300 lb in an outside container; USCG Bor 006754 7 FEATURES Liquefied Nonflammable Gas; IATA (Inhibited) Flammable Gas, Red label, not acceptable passenger, 140 kg cargo. HAZARDS Flammable gas. (R-I) Severe explosion risk at 30,000 ppm. (R-7) When heated to decom position, it emits highly toxic fumes of phosgene; can react vigorously with oxidizing materials. (R-9) WATER; AGENCY RESTRICTIONS, STANDARDS, OR CRITER IA EPA recommends an ambient water concentration of zero for maximum protection of human health from potential carcinogenic effects due to exposure to vinyl chloride through ingestion of contaminated water and contaminated aquatic organisms. The lev els which may result in incremental increase ofcancer risk over the lifetime are estimated at 1 x 10~s, 1 x 10-6 and 1 x 10-7. The corresponding recom mended criteria are 20 pg/L, 2.0 pg/L, and 0.2 pg/L. (R-l 1) AIR: AGENCY RESTRICTIONS, STANDARDS, OR CRITER IA M.E.C. = 150 mg/m3 if emission > 3 kg/H. (R-6) Clean Air Act designates the concentration of vinyl chloride in all exhaust gases discharged to the atmoshpere during ethylene dichloride purification shall not exceed 10 ppm except as provided for in 40 CFR 61.65(a). (R-107) Clean Air Act emission standards for vinyl chloride producing plants are specified. (R108) FOOD; AGENCY RESTRICTIONS, STANDARDS, OR CRITER IA U.S. Treasury Dept, has banned the use of vinyl chloride polymers in packaging of alcoholic bever ages. (R-63) TRANSPORTATION: AGENCY RESTRICTIONS. STANDARDS, OR CRITERIA HMTA designates vinyl chloride as a hazard ous material for the purpose of transportation in commerce. Hazard class is Flammable Gas. A Flam mable Gas label is required. Material is forbidden for transport on passenger-carrying aircraft or railcar. Maximum net quantity permitted in one package is 300 lb for cargo-only aircraft and package must bear a Cargo Aircraft Only label. Material may be stowed on or below deck and away from living quarters on cargo vessels. For passenger vessels, the material is limited to quantities specified in 49 CFR 173.304 (charging ofcylinders with liquefied compressed gas), 49 CFR 173.314 (requirements for compressed gases in tank cars), and 49 CFR 173.315 (compressed gases in cargo tanks and portable tank containers), and is also subject to the same stowage requirements as for a cargo vessel for the same material. (R-101) CERCLA designates vinyl chloride waste and heavy ends from the distillation of vinyl chloride in vinyl chloride monomer production as hazardous materials under HMTA. (R-101) CWA sections 307(a) and 112 des ignate vinyl chloride as hazardous material under HMTA. (R-101) HMTA also designates inhibited vi nyl chloride as an optional hazardous material for international shipment. IMCO code is Flammable Gases and DOT class is Flammable Gas. A Flammable Gas label is required. Material may be stowed on or below deck and away from living quarters on cargo vessels, but must be stowed on deck and away from living quarters for passenger vessels. (R-l02) OCCUPATIONAL EXPOSURE: AGENCY RESTRICTIONS. STAN DARDS, OH CRITERIA OSHA standard for vinyl chloride is 1 ppm averaged over an 8-H period, with a short term ceiling exposure level of 5 ppm averaged over any period of time not to exceed 15 min. No em ployees may be exposed to vinyl chloride by direct contact with liquid vinyl chloride. (R-l09) ACGIH recommends a TLV of 5 ppm. (R-l06) The NIOSH recommendation for occupational health standard environmental exposure limit is the minimum de tectable level averaged over a 10-H work period, with a short-term ceiling exposure of 1 ppm averaged over any period of time not to exceed 15 min. (R-l 10) Regulated by OSHA as a recognized carcinogen, Ap pendix Ala. (R-111) DISPOSAL: AGENCY RESTRICTIONS. STANDARDS. OR CRITER IA RCRA 3001 -3004 subjects the heavy ends from the distillation of vinyl dichloride in vinyl chloride mon omer production to handling and report/recordkeep ing requirements. (R-l03) The Act also subjects the waste product, off-specification batches, and spill res idues in excess of 1000 kg to handling and report/ recordkeeping requirements. (R-l04) The Act also designates vinyl chloride as an Appendix VIII chem ical. (R-l 05) OTHER AGENCY RESTRICTIONS. STANDARDS. OR CRITERIA OSHA prohibits the use of vinyl chloride in aerosol sprays. (R-7) FLAMMABILITY Very flammable. Extreme hazard. Do not enter. FLAMMABILITY LIMIT (%). LOWER 3.6. FLAMMABILITY LIMIT [%), UPPER 33. TOXIC COMBUSTION PRODUCTS HC1, phosgene, CO. Hazardous. Use self-contained breathing apparatus. EXTINGUISHING METHOD Stop flow of gas. Use water 8 DANGEROUS PROPERTIES OF INDUSTRIAL MATERIALS REPORT BOR 0 0 6 7 5 5 CHEMICAL REVIEW to keep containers cool. Do not extinguish unless nec essary to effect an immediate shutoff of flow. Dry chemical and carbon dioxide can be used to extin guish vinyl chloride fires. FLASH POINT (C) -78. AUTOIGNmON POINT (Q 472. (R-7) 472.22. mTWG CHARACTERISTICS - 153.8C (caution, flash point -- 78C). (MERCK* 83/WIN) BOILING CHAHACTERISTICS -13.37 C; ignites, flash point -78 C. (MERCK* 83/WIN) SOLUBILITY CHAHACTERISTICS Slightly soluble. SPECIFIC GRAVITY 0.9106. VAPOR PRESSURE TEXT 400 mm Hg @ -28 C. STATE Gas. (R-63) COLOR Colorless. (R-6) ODOR Mild, sweetish. (R-6) EXPLOSION LIMITS (\) Lower = 4%; upper = 22%, (R-47) EXPLOSIVENESS Reactive at high temperature or pressure. PolymerIres bv evolution of heat, in the presence of ait. oxygen, sunlight, or heat. SPECIFIC GRAVITY 20 4 D = 0.9106. (R-63) 250/25 D = 0.908. (K-71) SOLUBILITY: OTHER SOLVENTS Soluble in ethanol; very soluble in ether, carbon tetrachloride, and benzene. (R-63) CONVERSION FACTOR 1 ppm in air = 2.6 mg/m' (R63) 1 mg'L = 391 ppm. (R-112) ODOR THRESHOLD: AS .Air = 25,000 ppm; slight odor at 4,000 ppm. Odor index at 20 C = 100. (R-6) OTHER PHYSICALCHEMICAL PROPERTIES Polymerizes in light or in presence of catalyst; on combustion it de grades to MCI. CO. CO; with traces of phosgene; on treatment with strong alkalis at high temperatures it releases HCl. (R'63> Vapor density = 2.2 (air = 1). (R-63) Vinyl chloride is an inert gas which has no AQUEOUS SOLUBILITY Snlulnhly (ppm) 60 Temp (C) 10 Mea\ EsI TEST CONDITIONS No method or test conditions reported. 1.1 2S TEST CONDITIONS No method or test conditions reported. Method Ref R-118 R-119 VAPOR PRESSURE 1 apoi Prfssurr (rum Hg) 2S30 Trtnp (C) 20 TEST CONDITIONS No method or test conditions reported. 2320 20 TEST CONDITIONS No method or test conditions reported. 2660 2$ TEST CONDITIONS No method or test conditions reported. 2320.0 20 TEST CONDITIONS No method or test conditions reported. Mem/E<l Method Ref R-63 R-118 R-120 R-121 N-OCTANOLWATER COEFFICIENT KnU' Ijtg Kow 1.38 E Melhotl Substituro*. c.-crtcr.: estimation Ref R-ll MARCH/APRIL 1989 9 BOR 0 0 6 7 5 6 I FEATURES tendency to escape. When the gas escapes, higli con centrations may accumulate and become very dan gerous. (R-l 14) CHEMICAL SYNTHESIS METHODS Direct chlorination of ethylene to form ethylene dichloride (EDC) and sub sequent purification. Vinyl chloride is produced by thermal cracking of EDC. (R-70) Vinyl chloride gas and vapor is produced during the production of polyvinyl chloride. (R-l 13) PERSISTENCE Polymerizes in presence of air, oxy gen, sunlight, or heat. Volatilizes from water quickly. CARCINOGENICITY: ANIMAL STUDIES Species Route Doses Rot QU 0, 5000 ppm TEST CONDITIONS Alter exposure to 0 ppm (control) or 5000 ppm. 2 male and G2 female Wistar rats were sacri ficed (at 4, 13, 26. and 52 W) and subjected to extensive examinations. Morphological changes were observed in respiratory tract, ceruminous glands, brain, kidney, heart, and spleen. TOXICITY CARCINOGENICITY Studies indicate positive devel opment from occupational exposure. CARCINOGENICITY: IARC DETERMINATION Vinyl chlo ride is a human carcinogen. Vinyl chloride is carcin ogenic in mice, rats, and hamsters by oral and inhalation exposure. (R-63) CARCINOGENICITY: POSITIVE REFERENCES R-l2, R-31, R41, R-63, R-85, R-86, R-89, R-90, R-93, R-97. Dosing Schedule 7 HID, 5 D/W for 52 W Ref R-31 RESULTS Primary tumors were found in the brain (ependyroona). lungs (papillary adenoma and mesenchymal types of tumors), ceruminous glands (mainly keratinized squamous cell tumors), and nasal cavity (carcinomas of the olfactory epithelium, carcino-sarcoma. esthesioneuroepithelioma). Mus Ihl 50, 250, or 1000 ppm TEST CONDITIONS Two-month-old albino CD-I mice were divided into 4 groups, each consisting of 36 males and 36 females. Each group received 0, 50, 250, or 1000 ppm VC. Pour animals of each sex and exposure level were terminated for various laboratory tests and gross and histopathologic examinations at the end of 1, 2, 3, 6, and 9 mos. Surviving animals were terminated at the end of 12 mos. 6 H/D, S D/W R-41 R-86 RESULTS Exposure to VC caused a high incidence of bronchioalveolar adenomas, liver hemangiosarcomas, and mammary gland tumors. The incidence of bronchiolar adenomas was: control group. 1/26 males and 0/36 females; 50 ppm group, 8/20 males and 4/34 females; 250 ppm group, 10/29 males and 12/34 females; 1000 ppm group, 22/33 males and 26/36 females. The incidence of liver he mangiosarcomas was: control group, 0/26 males and 0/36 females: 50 ppm group, 3/29 males and 0/34 females: 250 ppm group. 7/29 males (p < 0.05) and 16/34 females (p < 0.05); 1000 ppm group, 13/33 males Ip < 0.05) and 18/36 females ip < 0.05). Mammary gland tumors consisted of adenocarcinomas and squamous and anaplastic cell car cinomas. There were a total of 0/36. 9/34, 3/34, and 13/36 mammary gland tumors in females exposed to 0, 50, 250 and 1000 ppm, respectively. Metastases in the lung oc curred in 0/36, 2/34, 2/34, and 8/36 females in the 0, 50, 250, and 1000 ppm groups, respectively. BOR 006757 DANGEROUS PROPERTIES OF INDUSTRIAL MATERIALS REPORT CHEMICAL REVIEW CARCINOGENICITY: ANIMAL STUDIES (Continued) Sftenes Houle Doses . Rat Ihl 0, SO, 250. or 1000 ppm TEST CONDITIONS Two-month-old CD rats were divided into 4 groups each consisting of 36 males and 36 temales. Each group received 0. SO, 250, or 1000 ppm VC. Four animals oi each sex and exposure level were terminated at the end of 1, 2, 3. 6. and 9 mos; the surviving animals were terminated at the end of 12 mos. Dosing Schedule 6 H/D, 5 D/W for 1, 2, 3, 6, or 12 mos Ref R-41. R-86 RESULTS The incidence of liver and lung hemangiosarcomas was significantly increased in female rats. An in creased incidence of these tumors was also seen in male rats, but this was not significantly (p < 0.05) increased. None of the male (0/35) or female (0/35) controls, and none of the 50 ppm dose group (0/36 males, 0/36 females) de veloped either liver or lung hemangiosaroomas. The in cidence oi these tumors in the medium- and high-dose groups were as follows: 2/36 males and 10/36 females (p < 0.05) from the 250 ppm group developed hemangiosarcomas in the livers; 0/36 males and 3/34 females from the same group developed hemangiosarcomas in the lungs. A total of 6/34 males and 15/36 females (p < 0.05) from the 1000 ppm group developed hemangiosarcomas in the liver; 4/34 males and 9/36 females (p < 0.05) de veloped hemangiosaroomas in the lungs. VC did not cause any other type of tumor in rats. Rat Ihl 30,000 ppm 4 H/D, 5 D/W for 52 W R-89 TEST CONDITIONS Thirty male and 30 female 17-W-old Sprague-Dawley rats were exposed to 30.000 ppm VC for 1 Y. The animals were then kept under observation until spontaneous death. Rat Ihl 50 ppm RESULTS A total of 31/60 animals had Zymbal gland car cinomas and 17/60 had liver angiosarcomas. No mention of control animals was made. 4 H/D. 5 D/W for l Y R-89 TEST CONDITIONS A total of 300 male and female Spra gue-Dawley rats (11 W old) were exposed to 50 ppm VC for 1 Y (4 H/D, 5 D/W). A control group consisted of 100 untreated rats. The animals were then kept under obser vation until spontaneous death. RESULTS After 100 W there were 55 survivors in the treated group and 28 in the control group. At this time the fol lowing results were observed: Out of 300 animals in the treatment group, 6 had Zymbal gland carcinomas (0/100 controls). 1/100 had a nephroblastoma (1/100 control). 6/ 300 had liver angiosarcomas (0/100 controls), 7/300 had angiosarcomas at other sites (0/100 controls), 43/300 had mammary carcinomas (3/100 controls), 2/300 had mam mary carcinosarcomas (2/100 controls), 45/300 had mam mary fibroadenomas (3/100 controls) and 28/300 had other types of tumors (and/or sites) (7/100 controls). Rat Ihl 1, 5, 10, and 25 ppm TEST CONDITIONS Groups of 120 (males and females combined) Sprague-Dawley rats, age 13 W. were exposed to 0, 1. 5. 10, or 25 ppm VC for 4 H/D, 5 D/W for 1 Y. The animals were then observed until spontaneous death. 4 H/D, 5 D/W for 1 Y R-89 RESULTS After 87 W there were 49. 49. 62. 51. and 45 survivors for the 0, 1, 5, 10, and 25 ppm dose groups, respectively. The numbers of animals with tumors (ex cluding survivors) at this time were as follows: within the 25 ppm group, 3 rats had Zymbal gland carcinomas, 3 had liver angiosarcomas, 10 had mammary carcino mas. and 7 had other type and/or site tumors; within the 10 ppm group. 1 had Zymbal gland carcinoma. 11 had mammary carcinomas, and 5 had other type and/or site tumors; within the 1 ppm group, 8 had mammary carci nomas and 4 had other type and/or site tumors; in the control group, 2 had mammary carcinomas and 4 had other type and/or site tumors. BOR 0 0 6 7 5 8 MARCH/APR1L 1989 I) FEATURES CARCINOGENICITY: ANIMAL STUDIES (Contmwt) Species Routr Rat Ihl 6,000 or 10,000 ppm TEST CONDITIONS A group ot 110 pregnant Sprague- Dawley rate was exposed to 6,000 or 10,000 ppm VC lor 4 H/D for 7 D, from the 12th to the 18th D of pregnancy. Offspring were examined for tumors to see if VC was transported transplacentally. The animals were exam ined 143 W posttreatment. Four groups were used: Group 1 consisted of 30 who received 10,000 ppm VC; Group H of 30 dams who received 6,000 ppm VC; Group 01 of 54 offspring whose mothem received 10,000 ppm VC; Group IV of 32 offspring whose mothers received 6,000 ppm VC. No controls were used. basing Schedule Rtf 4 H/D, 7 D R-89 RESULTS Group 1: 1 animal had a Zymbal gland carci noma, 1 an intraabdominal angiosarcoma, 1 a liver fibroangioma, and 1 a liver angioma. Group II; No tumors were found. Group III: 3 animals had Zymbal gland car cinomas. 1 a nephroblastoma, 1 a liver fibroangioma, 1 a liver angioma, 1 a Zymbal gland fibrosarcoma, and 1 an ovarian leiomyosarcoma. Group IV: I animal had a Zymbal gland carcinoma, 1 a subcutaneous angiosar coma, 1 an intraabdominal angiosarcoma, 1 a Zymbal gland adenoma, 1 a skin carcinoma, 1 a subcutaneous fibroangioma. and 1 a mammary carcinoma. Rat Ihl 6,000 or 10,000 ppm TEST CONDITIONS A group of 45 female and 44 male Sprague-Dawley rats began treatment at 1 D of age. An imals received 6,000 or 10.000 ppm VC 4 HID, 5 D/W for 5 W. The animals were then observed until spontaneous death. 4 H/D, 5 D/W for 5 W R-89 RESULTS Of the 46 animals receiving 10.000 ppm VC. there were 10 angiosarcomas and 15 hepatomas (total of 19 rats with tumors). Exposure to 6,000 ppm VC to 43 rats resulted in 10 angiosarcomas and 13 hepatomas (total of 17 rats with liver tumors). At W 104 (from start of treat ment) there were 5 and 8 survivors in the 6,000 and 10,000 ppm exposure groups, respectively. Ham Ihl 50. 250. 500. 2.500, 6.000 or 10,000 ppm 4 H/D, 5 D/W for 30 W R-89 TEST CONDITIONS A total of 268 male Golden hamsters were exposed to 0, 50, 250, 500, 2.500, 6,000 or 10.000 ppm VC, 4 H/D, 5 D/W for 30 W. After treatment animals were observed until spontaneous death. Surviving animals were examined after 109 W of treatment. RESULTS Group I (10,000 ppm): 6/35 had skin trichoepi theliomas and basaliomas: 4/35 had forestomach epithe lial tumors, 1 subcutaneous angioma, and 1 gall bladder adenocarcinoma: Group II (6.000 ppm): 1/32 had a liver angiosarcoma. 2/32 skin trichoepitheliomas and basa liomas, 2/32 melanomas, 7/32 forestomach epithelial tu mors, 2/32 hepatomas, 2/32 livr fibroangiomas. 2/32 liver angiomas, and 1/32 a biliducts adenocarcinoma. Group III (2,500 ppm): out of 33 hamsters, 1 had skin trichoepi theliomas and basaliomas, 1 had melanomas, 1 had lym phomas. 11 had forestomach epithelial tumors, 1 had hepatoma, 1 had a liver fibroangioma. and 1 had a liver angioma. Group IV (500 ppm): out of 33 hamsters, 2 had liver angiosarcomas. 4 had skin trichoepitheliomas and basaliomas, some had lymphomas, 7 had forestomach epithelial tumors, 1 had a subcutaneous angioma, and 1 had a bronchial carcinoma. Group V (250 ppm): out of 32 hamsters, 3 had skin trichoepitheliomas and basa liomas, 1 had lymphomas, and 2 had forestomach epi thelial tumors. Group VI (50 ppm): out of 33 hamsters, 6 had skin trichoepitheliomas and basaliomas, 1 had a melanoma. 1 had lymphoma, and 4 had foiestomach ep ithelial tumors. Group VII (0 ppm): out of 70 animals, 2 had skin trichoepitheliomas and basaliomas, 2 had lym phomas, and 2 had iorestomach epithelial tumors. B0* oo,,Ss 12 DANGEROUS PROPERTIES OF INDUSTRIAL MATERIALS REPORT CHEMICAL REVIEW CARCINOGENICITY: ANIMAL STUDIES (Continued) Species Route Doses Dosing Schedule Ref Rat Ihl SO. 2S0, 500, 2,500. 6,000 or 10,000 ppm 4 H/D. S D/W for 52 W R-89 TEST CONDITIONS Groups of 64-74 Sprague-Dawleyrats (mala and female combined), age 13 Weeks, were ex posed to the above VC concentrations for 52 W. Controls consisted of 68 untreated rats. After exposure the animals were observed until spontaneous death. RESULTS After 135 weeks (end of experiment) increased incidences of liver angiosarcomas. Zymbal gland carci nomas, and nephroblastomas were observed in the treated rats. The following incidences of these tumors were ob served in rats that survived until at least 26 W. when the first tumor was observed (for the controls. 50. 250, 500, 2,500, 6,000, and 10,000 ppm dose groups, respectively): liver angiosarcoma, 0/58, 1/59, 4/59, 7/59, 13/59, 13/60, and 9/61: Zymbal gland carcinoma, 0/58, 0/59. 0/59, 4/59 . 2/59, 7/60, and 16/61; nephroblastoma. 0/58, 1/59. 6/59, 4/59, 6/ 59. 4/60, and 5/61. Rat Ihl 100, 150, and 200 ppm TEST CONDITIONS Groups of 120 (male and female com bined) Sprague-Dawley rats, age 13 W, were exposed to the above VC concentrations for 52 W. Controls consisted of 165 untreated rats. After exposure the animals were observed until spontaneous death. 4 H/D. 5 D/W for 52 W R-89 RESULTS The results after 143 W (end of experiment) were given. Liver angiosarcomas and nephroblastomas were observed in the treated but not control animals. The fol lowing number of animals with these tumors tor the con trol, low-, medium-, and high-dose groups, respectively, were observed; liver angiosarcoma, 0, 1, 5. and 12; ne phroblastomas, 0. 10. 7, and 3. Rat Ihl 50. 250, 500, 2,500, 6,000, and 10,000 ppm TEST CONDITIONS Groups of 60 (male and female com bined) Sprague-Dawley rats, age 17 W, were exposed to the above concentrations of VC. Controls consisted of 190 untreated rats. After exposure the animals were ob served until spontaneous death. 4 H/D, 5 D/W for 17 W R-89 RESULTS The results after 155 W (end of experiment) were given. The incidence of Zymbal gland carcinomas and brain euroblastomas were increased in the treated rats. Hie number of animals with these tumors for the control 50, 250, 500, 2,500, 6.000, and 10.000 ppm dose groups, respectively, were as follows: Zymbal gland carcinoma. 1,0, 1, 3. 6, and 7; brain neuroblastoma. 0, 0, 0, 0, 2. 2. and 6. Nephroblastomas and liver angiosarcomas were observed in 0-2 animals per each exposed group, but none were seen in the control animals. Mus Ihl 50. 250. 500, 2.500. 6.000 and 10,000 ppm TEST CONDITIONS Groups of 30 male and 30 female Swiss mice, age 11 W. were exposed to the above VC concen trations tor 30 W. Controls consisted of 80 untreated males and 70 untreated females. After exposure the animals were observed until their spontaneous death. 4 H/D, 5 D/W for 30 W R-89 RESULTS The experiment was terminated after 81 W. Lung tumors, mammary carcinomas, liver angiosarcomas, and epithelial tumors of the skin were increased in the treated mice. The following incidences (males and females com bined) of these tumors were noted in animals alive after 16 W, when the first tumor was observed (the control group, followed by lowest through highest dose group): lung tu mors. 8/141, 2/57, 33/58, 38/58. 30/53, 8/54, and 35/50; mam mary carcinomas. 0/141, 12/57. 11/58, 7/S8, 9/53, 8/S4, and 13/50; liver angiosarcomas, 0/141. 1/57, 11/58, 1/58, 11/53. 5/54, and 8/50; and skin epithelial tumors, 0/141. 0/57, 2/ 58, 1/58, 3/53. 6/54, and 3/50. BOR 0 0 6 7 6 0 MARCH/APRIL 1989 13 FEATURES CARCINOGENICITY: ANIMAL STUDIES (Continu'd) Species Route Doses Dosing Schedule Ref Rat Ihl SO. 250. S00, 2,500, 6.000, and 10,000 ppm TEST CONDITIONS Groups of 30 Wistar rats (malm and females combined) were exposed to VC by inhalation for 52 W. Controls consisted of 40 untreated tats. After treat ment the animals were observed until spontaneous death. 4 H/D, 5 D/W for 52 W R-89 RESULTS After 136 W there were 3 animals still alive in the control group and none in the treated groups. Treat ment with VC caused an increased incidence of liver an giosarcomas. The numbers of rats with this tumor were 0, 0, 1, 4, 3, 2, and 6 for the controls, 50, 250, 500, 2,500, 6,000 and 10,000 ppm dose groups, respectively. Rat Orl 3.33, 16.65, and 50 mg/kg TEST CONDITIONS Groups of 80 Sprague-Dawley rats were administered VC by gavage, 4-5 D/W tor 52 W. A control group of rats received the olive oil vehicle only. After treatment the animals were observed until spon taneous death. 4-5 D/W for 52 W R-89 RESULTS After 120 W there were 4. 4, 2. and 2 animals still alive in the control, low-, medium-, and high-dose groups, respectively. Treatment with VC was associated with an increased incidence of liver angiosarcomas. The numbers of animals with this tumor at 120 W were 0, 0. 9, and 16 for the control, low-, medium-, and high-dose groups, respectively. Rat Orl 0.03, 0.3. and 1 mg/kg TEST CONDITIONS Groups of 156-163 Sprague-Dawley rats were to be given VC by gavage for 104 W. This ex periment was still underway at the time of the report. The control group received the olive oil vehicle only. 4-5 D/W for 104 W R-89 RESULTS Since this experiment was still underway, con clusions were not made. However, the tumors found in animals that died at the time of the report (57 W) are given in the report. Mus Ihl 50 ppm 500 ppm TEST CONDITIONS Albino NMR1 mice. 12 W old, were used. Twelve male and 12 females were exposed to 50 ppm VC for 6 HID, 5 D/W for 52 W. The same number of rats were exposed at the same schedule for 26 W to 500 ppm VC. Each experimental group had a control series that ran parallel to it. Pour animals of each sex from all groups were sacrificed and examined for pathology 26 W after start of exposure. Additionally. 4 control animals were sacrificed 1 Y after the start of the experiment. Re maining animals were allowed to live until spontaneous death, or were sacrificed when moribund. 6 H/D. 5 D/W for 52 W 6 H/D. 5 D/W for 26 W R-90 RESULTS Results of the control animals were pooled since no difference between the 2 groups was found. Out of a total of 48 control animals. 3 were found with tumors (1 mammary adenocarcinoma, 1 ovarian disgerminoma. and 1 reticulum cell sarcoma). In the 50 ppm group. 18/24 an imals developed tumors. Alveologenic adenomas were observed in 13/24 animals. Subperitoneal hemangiosarcomas were found in 14/24 animals, and subcutaneous hemangiosarcomas in 5/24 animals. In the 500 ppm group exposure was stopped at 26 W due to the bad condition of most of the animals. All (24/24) exposed animals in this group developed alveologenic adenomas. Subperitoneal hemangiosarcomas were found in 8/24 animals, and mammary carcinomas were observed in 4/24 animals. The primary subcutaneous and subperitoneal hemangiosar comas found in both the 50 and 500 ppm groups were all located in fat tissue. BOR 006761 14 DANGEROUS PROPERTIES OF INDUSTRIAL MATERIALS REPORT CHEMICAL REVIEW CARCINOGENICITY: ANIMAL STUDIES (Continued) Species Route Doses Mus Ihl SO, 200, or 2,500 ppm TEST CONDITIONS Groups of 100 male and 100 female CDI Swiss ChR mice (age NG) were exposed to 50. 200, or 2,500 ppm VC in air for 7 H/D, 5 D/W for 9 mos and were observed for an additional 9 mos. Dn\mg Srhrdute Krf 7 H/D, 5 D/W for 9 mos R-63 RESULTS After 8 mos of exposure, 49 treated animals died with tumors. A total of 42 pulmonary adenomas. 41 liver angiosarcomas, and 11 mammary gland adenocar cinomas were observed. Distribution of these tumors were as follows: pulmonary adenomas, 2 in the 50 ppm group, 12 in the 200 ppm group, 28 in the 2500 ppm group, and 0 in the control group; liver angiosarcomas, 3 in the 50 ppm group. 11 in the 200 ppm group, 28 in the high-dose group, and 0 in the controls; and mammary adenocarci nomas, 2 in the low-dose group, 3 in the mid-dose group, 6 in the high-dose group, and 0 in the controls. Rat Ihl 30,000 ppm TEST CONDITIONS Male Wistar rats, 3 mos old, were exposed to 30,000 ppm VC (99% purity) vapors for 4 H/D. 5 D/W for 12 mos. There were 25 rats in the control group. At the end of treatment surviving animals were sacrificed at 20 D intervals. 4 H/D, 5 D/W for 12 mos R-12, R-S5 RESULTS Of 26 treated rats, 17 developed skin carcino mas (predominately epidermoid carcinomas). No tumors were found in the control animals. Treated animals with lesions of the lungs: 1 adenocanthoma, 3 adenocarcino mas. 1 squamous cell carcinoma, and 1 mucous produc ing adenocarcinoma. Treated animals with lesions of the bone: 5 osteochondromas. Hat Ihl 600 ppm or 600 ppm plus 4 H/D. 5 D/W for 1 Y 5% ethanol in drinking water R-40 TEST CONDITIONS Groups of 80 Sprague-Dawley male rats were used. One group was exposed to 600 ppm VC vapors; a second group received 5% ethanol in the drink ing water ad libitum 4 W before the beginning of VC inhalation and continued to receive ethanol-water until death; the control group received only the ethanol-treated drinking water and a fourth group received no treatmerit. RESULTS At the time of this preliminary report, 17% of the animals had been autopsied. Histological evidence showed the latent period for angiosarcoma of the liver to appear was 53 W in rats exposed to vinyl chloride alone and 38 W in rats exposed to VC and 5% ethanol. Prelim inary results of this long-term study indicated synergism between inhaled VC and ingested ethanol in the induc tion of tumors. Rat Ihl 50, 500, 2.00:, 5,000, 10,000. and 20.000 ppm 4 H/D. 5 D/W for 12 mos R-98 TEST CONDITIONS Groups of 150-200 male and female Wistar Ar/IRE rats, 3 mos old, were exposed to the above VC concentrations for 12 mos. Controls consisted of 200 rats not exposed to VC and kept under the same condi tions for 13 mos. RESULTS Exposure to VC was associated with an in creased incidence of liver angiosarcomas, skin squa mous cell carcinomas, and lung adenocarcinomas. The following incidence of these tumors were observed in the control group, followed by lowest- to highest-dose groups, respectively: liver angiosarcoma. 0/200. 0/200, 4/150. 10/ 200. 12/200, 16/200, and 18/150; skin squamous cell carci noma, 0/200, 0/200, 3/150, 0/200 (6/200 sldn cecanlhomas, however, at 2000 ppm), 20/200. 34/200, and 67/150; and lung adenocarcinomas. 0/200. 0/200, 0/150, 8/200.4/200. 14/ 200. and 21/150. Rbt Ihl 10.000 ppm TEST CONDITIONS Forty rabbits were exposed to 10,000 ppm VC. Controls consisted of 20 rabbits not exposed to VC and kept under similar conditions for 15 mos. NG R-98 RESULTS Skin acanthomas were observed in 12/40 ex posed rabbits and 0/20 controls. Lung adenocarcinomas were observed in 6/40 exposed rabbits and 0/20 controls. MARCH/APRIL 1969 lb BOR 006762 FEATURES CARCINOGENICITY: HUMANS Rnulr Dost NG NG TEST CONDITIONS A retrospective cohort study of work ers at 4 VC facilities (that had been engaged in the po lymerization of VC for at least 15 Y and had a sizable work force) was conducted. Employment records initially were obtained of every individual who had ever worked at any of the 4 VC plants. Individuals for study were selected from the records of individuals having 5 or more Y of employment and 10 Y since initial employment. A modified life-table technique was used to obtain the 12.720 person-years at risk of dying, according to 5 Y age group. 5 Y calendar period, years of work experience, and time since onset of exposure to VC. Comparison was made between the observed number of deaths among the study cohort members and that expected on the basis of the U.S. white male death rates specific for age and calendar year and cause. Dosing Srhedult Occupational exposure K'l R-93 RESULTS A total of 13G deaths occurred among workers exposed to VC as contrasted with 12G.3 deaths expected. Only 2 causes of death were in excess among workers exposed to VC: nonmalignant respiratory disease, and all malignant neoplasms (6 observed vs 3.4 expected and 35 observed vs 23.5 expected, respectively). The latter excess was statistically significant at p < 0.05. When cancer mortality was analyzed by site, excesses were found for 4 organ systems: brain and central nervous sys tem (3 observed vs 0.9 expected), respiratory system (12 vs 7.7 expected), hepatic system (7 vs 0.6 expected, p < 0.01), and lymphatic and hematopoietic systems (4 vs 2.5 expected). Of the 14 histologically confirmed cases of bil iary and liver cancer, 11 cases of angiosarcoma of the liver were diagnosed (this includes 4 cases still alive at the time of the report). NG NG TEST CONDITIONS Identification particulars were ob tained for over 7,000 men who were at some time between 1940 and 1974 exposed to VC monomer in the manufac ture of PVC in Great Britain. Approximately 99% of these men have been traced and their mortality experience studied. The number of deaths observed was compared to that expected using sex and age standardized death rates for England and Wales. Occupational exposure R-95 RESULTS The overall standardized mortality ratio, 75.4, shows a significant reduction compared with the na tional rates. Four cases of liver cancer were found. Two of these have been confirmed by a panel of liver pathol ogists as angiosarcoma and 2 as not angiosarcoma. There is no evidence to support the hypothesis that cancers other than those of the liver are associated with exposure to VC monomer. The 2 cases of angiosarcoma were found in men who had been exposed to high concentrations of the monomer although the 2nd man died only 8 Y after first exposure. NG 5-240 ppm TWA TEST CONDITIONS A retrospective cohort study of the mortality experience of individuals occupationally ex posed to VC between 1942 and 1960 was conducted. Em ployees were grouped into 4 exposure categories according to the highest levels of VC exposure experiences for at least 1 mo. Departmental census lists were reviewed over the specified years (1942 and 1960) lor 5 production units: unit 1, copolymer plant, 1942-1960; unit II, PVC and co polymer plant, 1953-1960: unit m, VC monomer plant, 19471954; unit IV, copolymer semiplant, 1946-1955; and unit V, vinyl latexes and polymer plant, 1946-1960. Exposure measurements were available of units I and D but not lor the 3 smaller units. To investigate dose-response rela tionships with respect to VC, industrial hygiene data were reviewed for each job classification and each job was assayed on exposure level of low, intermediate, or high. The 3 categories primarily were based on estimated TWA concentrations for an 8 H day. The low level was defined as TWA concentrations below 25 ppm VC, the interme diate level as 25-200 ppm. and the high level as 200 plus ppm VC. A subjective evaluation of the other 3 units by industrial hygienists indicated that exposures were in the low to intermediate range, with occasional excur sions to high levels. The observed mortality of the study population was compared to that of the U.S. white male population. Occupational exposure R-97 RESULTS The distribution ol the malignant neoplasms with respect to exposure category suggests a possible dose-response relationship. Although the numbers of deaths were small, 9 of the 13 malignancies were ob served in the high-exposure group. An approximate sta tistical evaluation of the difference between observed and expected malignancy deaths in the high-exposure group compared with all other exposure groups combined was performed, based on the conditional distribution of in dependent Poisson random variables. A Chi-square value of 6.1 Ip < 0.025) was obtained after adjusting the total expected deaths to the observed number of deaths (high exposure 9 vs 4.64 expected; all other groups 5 vs 9.36 expected). Mortality experienced 15 or more Y after initial exposure was examined. Eight of the 9 malignancies oc curred in the high-exposure groups. Again, the Chi-square comparison of the distribution of malignancy deaths be tween the high- and all other exposure groups was sig nificant (p < 0.01). A comparison within the high-exposure group between those individuals with less than 1 Y of high exposure versus those with more than 1 Y of high exposure was not significant. BOR 006763 16 DANGEROUS PROPERTIES OF INDUSTRIAL MATERIALS REPORT CHEMICAL REVIEW CARCINOGENICITY: HUMANS (Continued) !.\.out,r Dose NG NG TEST CONDITIONS A retrospective mortality study was conducted of 8.384 men from ,33 plants who had worked lor at least 1 Y in a job involving exposure to VC before December 31, 1972. The observed mortality was com pared to that of the U.S. male population. Vital status could not be determined for 15% of the study population. Analysis was restricted to the 7,128 workers on whom follow-up was complete. Dosing Schedule Occupational exposure Ref R-96 RESULTS No specific cause of death (cancer or otherwise) was (statistically) significantly greater than expected in the total group. When the group was analyzed according to duration or level of exposure, again no significant in creases in cancer mortality were observed. However, some cancer mortality increased, although not significantly, and may have been related to exposure. According to the authors, mortality from digestive cancer, respiratory can cer, cancer of other unspecified sites, and lymphomas appeared to be related to exposure. CARCINOGENICITY: OTHER STUDIES 'Phis study investi^ucd die possibility that changes in nuclear size of 1 U-Ui S3 cells, exposed in vitro, might be used as an index of the carcinogenicity of compounds. VC, along with oilier tested carcinogens, caused an increased nuclear size in exposed cells. These effects were not seen with noncarcinogens. (R-4) Bln this study, 1,047 workers exposed to VC monomer from 3 different VC/I'VC plants and 289 workers from a polyvinylchloride (PVC) extrusion plant manufacturing a PVC textile product (exposed to much lower concentra- tions of VC) were examined. Carcinoembryonic an tigen (CEA) titers were determined. The investigation demonstrated that occupational exposure in VC/PVC . plants can cause elevations in the CEA titers of oth erwise healthy individuals. (R-35) MUTAGENICITY: GENE MUTATION-POSITIVE REFEREN- CES R-2, R-20, R-22, R-27, R-58, R-59. MUTAGENICITY: GENE MUTATION-NEGATIVE REFEREN CES R-56. MUTAGENICITY: GENE MUTATION STUDIES I'wn t ype Bacterial mutation assay Species/Cell Type Escherichia coli K12 TEST CONDITIONS Mutagenicity of VC was evaluated in E. coli K12 at 4 different loci, consisting of three back mutation systems (gal +, arg +, and nad +) and one for ward mutation (MTR). The test was performed using liver microsomes from male mice pretreated for 10 D with 0.1 % phenobarbital in the drinking water. VC gas (> 99.9% purity) was bubbled through the liquid medium to give a concentration of 10.6 mM. Yoast mutation assay Schizosacchctromyces pombe TEST CONDITIONS This haploid strain of S. pombe con tains a missense mutation in the ade6 locus. Treatment with a mutagen causes forward mutation at 5 genetic loci for the biosynthesis of adenine. These mutations produce a change in the phenotype of the colonies, which can be scored. VC was bubbled through liquid cell suspensions, producing concentrations of 18 and 48 mM. Host-mediated microbial mutation mus-Schieosaccharomyces pombe TEST CONDITIONS Swiss albino mice weighing 25 g each were treated orally with J.85% vinyl chloride monomer (VCM) in 1 mL of olive oil (700 mg/kg body weight). Yeast cells of S. pombe (P. strain) were injected into the peritoneium and incubated for various times to measure the forward mutation frequency. Route Doses 10.6 mM Ref R-100 RESULTS Mutagenicity was expressed as number of col ony forming units (efu) on selective medio per number of efu on complete media. VC was mutagenic in the pres ence of a metabolic activation system. The percentages of spontaneous mutation rate at the different loci were as follows: gal + 231%; arg + 663%; MTR 172%; and nad + 148%. 16 or 48 mM R-20 RESULTS Mutagenic activity was found in S. pombe only when microsomal preparations (105,000 g) from mouse liver were included with the treatment solution. A doseeffect relationship was linear with mMolar concentra tions in treatments of 30 min. The vinyl chloride monomer (VCM) treatment did not produce any detectable decrease in the survival of cells. Orl 700 mg/kg R-20 RESULTS VCM was found active at a dose of 700 mg/kg during 12 H of treatment. Data from regression analysis were significant at the 1% level. This demonstrated VCM was genetically active, in vivo. MARCH/APFlIL 1989 17 BOR 0 0 6 7 6 4 FEATURES MUTAGENICITY: GENE MUTATION STUDIES (Continued) Assay Type Species/Crlt Type HouleDoses_______ ^ff Ames assay Salmonella typhimurium TA1S30, TA1S35, G4S 0.2, 2, or 20% R-22 RESULTS Exposure of S. typhimurium strains to VC in creased the number of His-I- revertants/plate, 16. 12. or 5 times over the spontaneous mutation rate. After 6 H of exposure to 20% vinyl chloride monomer (VCM) in air, the mutagenic response for TA1530 strain was enhanced 7-, 4-, or 5-fold when fortified postmitochondrial liver frac tions from humans, rats, or mice were added. VC en zyme-mediated mutagenicity was dependent on an NADPH generating system. Highest mutagenic response was seen with TA1530. Exposure of this strain to 20% VC in air. in the absence of any metabolic activation system caused a linear increasing mutagenic response as a function of incubation time, which was 20 times the spontaneous rate, at 48 H. Phenobarbitone pretreatment of rats and mice increased the mutagenic response by up to 15-40% as compared to untreated controls. Sex-linked recessive lethal Drosophila melanogaster Ihl 10.000. 100,000, 200.000 ppm R-27 TEST CONDITIONS Male D. malanogaster, wild type strain Kansas 60, 0 to 2 D old, were used tor treatment with VC. Males were mated individually with 2-3 Muller $ iemales tor D 6-12 alter treatment without any brooding. Heterozygous daughters were individually mated to 2-3 Muller 5 males and the progeny was tested for recessive lethals. In induction experiments, males were treated with sodium phenobarbiturate and/or VC (1% solution sodium phenobarbiturate dissolved in sucrose water lor 24 HI. RESULTS VC increased mutagenicity at the lowest ex posure tested. There was no indication of an increased effect with higher concentrations. Experiments with so dium phenobarbiturate (one with 1% VC and one with 10% VC) produced a pronounced effect. The total number of recessive lethals (when 1% VC was used) with sodium phenobarbiturate pretreatment was different from con trol at 0.1% significance level (using Chi-square and Yates Correction). Mammalian spot test Mus Oil 4,600 ppm R-56 TEST CONDITIONS Female mice of inbred C57BL/6J Han (a/a; wild type) were mated to Han rotated-bred males of T-stock strain. On the 10th D of gestation females were exposed to 12,000 mg/m3 (4,600 ppm) of VCM in air for 3 H. FI offspring were examined at 3-5 W of age for mosaic coat colon. An experiment using cyclophosphamide to test the ability to induce colored spots in the FI hybrids served as a positive control. Statistical evaluations of the data were done by Chi-square test. RESULTS The mammalian spot test did not provide evi dence that VC induces somatic gene mutations in mam mals in vivo. No offspring with abnormal morphology were found in the vinyl chloride monomer (VCM) expo sure group. Treatment with 10 mg (scu) CP/kg produced significant differences in the number of white and col ored spots in the offspring in comparison with the control or VCM-treated group. Ames assay Salmonella typhimurium TA1530 20% R-58 TEST CONDITIONS Liver S-9 fractions from adult female BD-V1 rats and from human patients were used as met abolic activation systems. RESULTS VC was mutagenic in the presence of both rat and human liver S-9 fractions. The number of his - revertants in S. typhimurium mediated by human and ro dent liver S-9 exposed to 20% VC (v/v) in air for 4 H and incubated for 48 H at 37 C was 85 and 100 revertants/ plate, respectively. The number of revertants/plate after exposure to VC in the absence of cofactors NADP-, G 6P) was subtracted. BOR 006765 18 DANGEROUS PROPERTIES OF INDUSTRIAL MATERIALS REPORT CHEMICAL REVIEW MUTAGENICITY: GENE MUTATION STUDIES (Continued) Assay Tyfie Speaes/Cell Typt Route Doses Ref Na/K ATPase assay Chinese ham-V79 TEST CONDITIONS The mutagenicity oi VC was tested in V79 Chinese hamster cells in the presence and ab sence of a S-1S liver fraction from phenobarbitone-pretreated rats. The cells were exposed to a vapor concentration of S-30% (v/v) for S H. Mutagenicity was measured by the induction of B-azaguanine and oubain resistance. Ames assay Salmonella typhimuiium TA1530 TEST CONDITIONS The mutagenicity of VC in S. typhimurium TA1530 without metabolic activation at the above concentrations was evaluated. In tests to evaluate the effect of a metabolic activation system, a 2% VC concen tration was used. The metabolic activation system con sisted of S-9 liver fraction from adult male NMR1 mice either left untreated or treated with Aroclor 1254. 5. 10. 20. and 30% R-2 RESULTS VC induced both 8-azaguanine and oubain re sistant dose-related mutants at 5-30% VC in air in the presence of the S-15 fraction. At a concentration of 30%, mutation frequencies were 10-20 times those of sponta neous reversions. At this concentration there were 51 azaguanine and 4 oubain resistant colonies per 100,000 survivors. Neither toxicity nor mutation was induced in the absence of the metabolic activation system. 2, 7, 12. and 20% R-59 RESULTS In the absence of a metabolic activation sys tem, VC increased the number of his- revertants in a dose-related manner. At the highest concentration (20%) there were 101 revertants in the treated plate compound to 10 in the controls. The addition of the S-9 fraction en hanced the mutagenicity of VC. This effect was even more pronounced when liver S-9 from pretreated mice was used. MUTAGENICITY: CHROMOSOMAL EFFECTS STUDIES Assay Type Species/Cell Type Route Doses Ref In vivo cytogenetics Chinese hamster-bone marrow Human lymphocytes TEST CONDITIONS Bone marrow cells from Chinese hamsters treated with VC in the above doses and routes were studied to determine whether chromosomal aber rations in the bone marrow cells were significantly higher in comparison to control groups. A similar analysis of workers from a PVC plant was undertaken, using lym phocytes from 20 workers with symptoms of VC illness, from 10 workers with no symptoms of VC illness, and from 10 controls matched according to age. A total of 100 cells per individual were scored for gaps, breaks, frag ments, dicentrics, rings, chromatid and chromosome translocations, and deletions. Dominant lethal CD-I mus In vivo cytogenetics Hron-peripheral blood lymphocytes TEST CONDITIONS Seven occupationally exposed male workers and 3 nonexposed control subjects, all employed in the same PVC factory, were studied for chromosomal effects of VC exposure. In weeks prior to blood sample collection, air concentration was approximately 20-30 ppm. Workers who were studied had been exposed to VC for periods ranging from 9 to 29 Y. Ihl, ipr Ihl 2.500 or 5.000 ppm by ihl followed by 600 and 300 mg/kg ipr NG R-3 RESULTS In humans, only the group consisting of work ers with VC illness showed a significant increase in the rate of aberrations in comparison to the control group (statistical information and exact data not given). In the hamsters, chromosomal aberrations were also signifi cantly higher in the treated animals as compared to con trols. Ihl 3,000, 10.000. 30.000 ppm R-S5 RESULTS No mutagenic effects were seen on any matu ration stage of spermatogenesis in male CD-I mice ex posed by inhalation to 7.8, 26, or 78 g/m3 VC in air for 6 HID for 5 D as compared to controls. Ihl 20-30 ppm R-28 RESULTS Investigators found that the average frequency of chromosomal aberrations in this group (9.52%) was significantly ip < 0.001) greater than in the controls (1.94%). This was true for chromatid and isochromatid breaks. MARCH/APRIL 1989 19 BOR Q *766 FEATURES MUTAGENICITY: CHROMOSOMAL EFFECTS STUDIES (Continued) Assay Type Speaes/Cell Type Route Doses In vivo cytogenetics Chinese hamster-bone marrow TEST CONDITIONS Groups of 4 adult (10-15 W old) Chinese hamsters, weighing 30 g, were exposed to 2.5% VC in air for S, 12, or 24 H. The male-female ratio was 1:1. Another group of 10 hamsters was exposed to 5% VC for 24 H only. Hamsters received intraperitoneal infection of 8 mg col chicine/kg body weight 24 H after beginning VC expo sure. Bone marrow chromosomes were analyzed for gaps, breaks, fragments, deletions, and exchanges 2 H later. Micronucleus test CBA mus TEST CONDITION Three CBA male mice were exposed to S% VC for 4 H. Controls consisted of 3 untreated mice. In vivo cytogenetics Hmn-peripheral blood lymphocyte TEST CONDITIONS The 11 subjects were male workers who had received repeated exposure to VC in an upstate NY polyvinyl chloride polymerization plant. Duration of recurrent occupational exposure in the 11 men ranged from 4 to 28 Y, with an average of 15 Y. Of the 10 healthy male controls. 4 were from within the same factory pop ulation without known VC exposure; E controls were also selected from outside the factory environment. The chro mosome studies were performed on cultures of periph eral blood lymphocytes. Fifty metaphases from each individual were evaluated. In vivo cytogenetics Hmn-lymphocytes TEST CONDITIONS Lymphocytes from humans who were exposed occupationally to VC for periods ranging from 10 to 27 Y to concentrations most frequently between 20 and 150 ppm were examined. Ihi 2.5% or 5.0% R*49 RESULTS The frequency of chromosome aberrations de pended on dose and exposure time. After G and 12 H of exposure at the 2.5% level, aberrations (breaks and frag ments) were induced in 0.8% of the metaphase. After 24 H the frequency of induced breaks and fragments in creased to 4.5%. In 1.400 metaphases of 14 control ham sters only 1 break (0.1%) was found. Gaps included chromosome aberrations increased from 0.6% in controls to 7.3% in group exposed 24 H to 2.5% VC. The highest measured effect was 25.7% metaphases with aberrations when hamsters were exposed to 5% VC for 24 H (p < 0.02). Significance of differences in the number of metaphases with aberrations was verified using the Chi-square test. Ihl 5% R-64 RESULTS Exposure to VC caused a significant increase in the number of polychromatic micronucleated cells as compared to controls. Statistical evaluation was per formed with t-tests and combined probability analysis according to Fisher. Occupational NG R-60, R-94 RESULTS Exposure to VC increased the frequency of chromosomal aberrations. Much of this increased dam age was due to cells with unstable chromosome changes such as fragments, dicentrics, and rings. Ihl 20-150 ppm R-66 RESULTS Of the examined lymphocytes from exposed workers. 5.2% had chromosomal aberrations as com pared with 1.8% in the control workers. The aberrations included chromatid and chromatin breaks; chromatid and chromosome exchanges were frequent. MUTAGENICITY: CHROMOSOMAL EFFECTS-POSITIVE REFER ENCES R-3, R-28, R-49, R-60, R-64. MUTAGENICITY: DNA DAMAGE/REPAIR-POSITIVE REFEREN CES R-20, R-49. MUTAGENICITY: CHROMOSOMAL EFFECTS-NEGATIVE RE FERENCES R-55. BOR 006767 20 DANGEROUS PROPERTIES OF INDUSTRIAL MATERIALS REPOR" CHEMICAL REVIEW MUTAO*NICITY: DNA damage/repair studies v V/"' SCE Specus/Ctll Type Chinese ham TEST CONDITIONS Groups of 4 adult Chinese hamsters (10-15 W old) were used in a 1:1 male to female ratio. Hamster* were exposed to VC 6. 12. and 24 H at concen trations of 1.25 or 2.5% (v/v). The Brd-U-tablet method was used to obtain in vivo induced sister chromatid ex changes (SCE), Hmn-lymphocytes TEST CONDITIONS Lymphocytes from humans who were exposed occupationally to VC for periods of 10-27 Y (to concentrations most frequently between 20 and 150 ppm) were examined. Mitotic gene conversion Saccharomyces cerevisiae TEST CONDITIONS VC eras bubbled through a liquid cell suspension to give concentrations of 16 and 48 mM. The assay was performed in the presence and absence of purified mouse liver microsomes. Induction of gene con version was measured at the ade 2 and tip 5 loci oi this strain oi yeast. Route Ihl Doses 1.25 or 2.5% Ref R-49 RESULTS The number of in vivo induced SCEs depended on dose and length of exposure to VC. Data were ana lyzed statistically using the t-test. The 6 H exposure oi the low dose doubled the SCE frequency with 4.41 SCEs/ cell in controls, and 8.72 in the experimental group. Lengthening of exposure time increased frequency of SCE. After 12 H, 17.51 SCEs/cell were found and 22.33/cell were found after 24 H exposure. SCE frequency increased in all exposure-time-groups after exposure to 2.5% as com pared to the lower dose: 12.66 (6 H), 19.80 (12 H). The highest measured effects were 33.25 SCEs/cell after a 24 H exposure to 2.5% VC. Ihl 20-150 ppm R-66 RESULTS The number of sister chromatid exchanges was increased from 9.41 to 13.80 per lymphocyte. 16 and 48 mM R-20 RESULTS Both gene conversion systems (ade 2 and tip 5) showed a positive response which was dependent on the presence of purified mouse liver microsomes. MUTAGENICITY: OTHER STUDIES A prophage lambda induction test was conducted using 0.1 mL of 20% VC in DMSO/plate. The test used activated micro somal enzymes (S-9) from livers of rats induced with TERATOGENICITY: MAMMALIAN STUDIES Spnirs Route Doses n<H ihl 2,000. 7,000. 12,000 ppm TEST CONDITIONS Groups of 3 pregnant CFY rats were exposed to VC at 2,000, 7,000 or 12,000 ppm in air for 2.5 H on the 18th D of pregnancy. Aroclor. Results were negative (no other data or sta tistical analysis given). (R-21) TERATOGENICITY: MAMMALS-NEGATIVE REFERENCES R-15. R-26. Dosing Schedule 2.5 H on D 18 Ref R-26 RESULTS VC was shown to be present in the fetal and maternal blood as well as in the amniotie fluid, indicat ing the permeability of the placenta to the agent. BOR 0 0 6 7 6 8 m^RC1I/AJ'I<I| litB9 2) FEATURES TERATOGENICITY: MAMMALIAN STUDIES (Continued) Species Route Dose! Dosing Schedule ^ff Rot Ihl 1.500 ppm TEST CONDITIONS Pregnant (first trimester) CFY rats (1328/group) were allocated to experimental groups as fol lows; Groups IA. IC, HA. and IDA inhaled air in an in halation chamber for 24 H/D on days of pregnancy 1-9, 8-14.8-14, and 14-21, respectively: Groups IB, ID, OB, and I1IB were exposed to VC (4,000 mg/m3) or approximately 1,500 ppm, for the same length of time during the same periods of gestation as their respective controls. The rats in groups 1C and ID were given, subcutaneously, 2 in jections (SO mg/kg bw) of trypan blue (1% solution) on the 7th and 8th D of gestation. Group IV was another control. On the 21st D of gestation, the position of fetuses living, dead, or resorfaed was noted. Fetuses and placentae were excised and weighed, and macroscopic examination was carried out. The t-test was used for statistical comparison of means. The Mann-Whitney U-test was used to compare number affected/total fetuses ratio. Mus Rat Rbt Oil Ihl Ihl 50, 500 ppm 500, 2,500 ppm 500, 2,500 ppm TEST CONDITIONS: Three groups of each species (CF-1 mice, Sprague-Dawley rats. New Zealand rabbits) were tested: control, inhalation of VC only, and inhalation of vinyl chloride and ethanol (15%) in drinking water (ethanol blocks metabolism). 24 H/D R'26 RESULTS The maternal liver weight and liver weight/ body weight ratio increased in response to trypan blue as well as to VC applied in the 1st or 2nd W of pregnancy (p < 0.01 and p < 0.05). The number of resorbed fetuses as well as fetal loss (% total implants) was significantly increased in the group exposed to VC during the first 9 D of pregnancy (p 0,05). Author concluded that VC in itself has no teratogenic effect on CFY rats, but an embryotoxic effect during the early stages of pregnancy (at 1,500 ppm). Fetal losses and induction of central nervous system malformations due to trypan blue administration were not potentiated by a combined exposure of preg nant rats to VC and the dye. 7 H/D 7 H/D, D 6-15 of gestation 7 H/D, D 6-18 of gestation R-15 RESULTS While maternal toxicity was observed, VC alone did not produce any significant anomalies when com pared to controls (p > 0.05). There were significant in creases in the number of fetal anomalies in the group that was given 15% ethanol in their drinking water, while receiving 500 ppm VC (mice). Also among mice exposed to VC in combination with 15% ethanol, several skeletal anomalies occurred at an incidence significantly greater than among mice exposed to VC alone (modified Wilcoxon test, p < 0.05). Authors concluded that exposure of pregnant mice, rats, and rabbits to VC (ihl) at concentra tions high enough to cause maternal toxicity was not teratogenic in any of the 3 species. Exposure of VC alone was not consistently embryotoxic in the 3 species stud ied. Among mice, at 2,500 ppm, the incidence of resorp tions was significantly higher (13%) than among the concurrent controls (7%). Ingestion of 15% ethanol in the drinking water enhanced the toxic effects of the inhaled VC. Maternal toxicity was enhanced to an extent greater than embryotoxicity. TERATOGENICITY: HUMAN STUDIES Route Environmental exposure Doses NG TEST CONDITIONS Three Ohio communities that had polyvinyl production facilities were studied. Since 1968, information for specific congenital malformations in Ohio residents has been recorded on birth certificates. Any information recorded under the congenital anomalies section of the certificate was analyzed. Data for deaths resulting from cancer of the central nervous system, leu kemia. and lymphomas in the adult population aged 45 Y and older were also analyzed. Dosing Schedule NG Ref R-S2 RESULTS The findings suggest that mothers living in communities with PVC production facilities gave birth to an excess number of children with congenital malfor mations as compared to the expected number based on the state average or based on experience in the balance of counties in which these cities are located. With regard to specific malformations, anomalies of the central ner vous system appear to be of the greatest concern. Deaths from central nervous system tumors in adult male resi dents of 2 of the cities were also significantly greater than expected. On a community basis, excess deaths from other cancers were not apparent. pj O 22 DANGEROUS PROPERTIES OF INDUSTRIAL MATERIALS REPORT 006769 CHEMICAL REVIEW PLACENTA!. TRANSFER: POSITIVE REFERENCE R-26. MAJOR SPECIES THREATENED Terrestrial life. INHALATION LIMIT (Value) 300. INHALATION LIMIT (Text) Regulations: OSHA carcino gen (29CFR* 1910); OSHA PEL (TWA) 1 ppm (29CFR* 1910); OSHA peak 5 ppm/15 min (29CFR* 1910). Recommendations'. NIOSH ceiling 2.55 mg/m3/ 15 min; 1 ppm/15 min (CRSOE* PB-246619/NlOSH); ACGIH human carcinogen (TLVADM 83/ACGIH); ACGIH TLV (TWA) 10 mg/m3; 5 ppm (TLVADM 83/ACGIH). DIRECT CONTACT Acts as refrigerant under pro longed contact and as such can cause skin burns. GENERAL SENSATION Sweet-smelling gas. Proposed limits are 1 ppm for 8 H working day, 5 ppm for 15 min average; may be anesthetic above 500 ppm. Han- dling of uninhibited material has caused circulatory and bone changes. (30ZNA5 0001) PERSONAL SAFETY PRECAUTIONS Gas-tight goggles and breathing apparatus are required in fire areas or where closed environment or poor ventilation causes high vapor concentration. Eye goggles and impervious outerwear are recommended for areas where liquid vinyl chloride may be encountered. ACUTE HAZARD LEVEL Irritant. Moderately toxic when inhaled. Should cause no problem in water. Emits toxic vapors when heated to decomposition. CHRONIC HAZARD LEVEL Chronic exposure has shown liver injury in rats and rabbits. Chronic irritant. DEGREE OF HAZARD TO PUBLIC HEALTH Irritant. Mod erately toxic with inhalation. Emits highly toxic va pors when heated to decomposition. CARCINOGENICITY INDICATOR Positive. ANIMAL TOXICITY Value (mg/kg) 20 ppm 500 Time Species Hmn Rat Param TCLo LDjfi Route Oil Orl Ref JWPFAS 0017 TXAPA3 0031 CARCINOGENICITY RESULTS Species SlTam Sex Ham Hmn Golden Hmn Hmn Mus Mus Mus at ;.at Swiss Swiss Swiss Sprague-Dawley r<at Rat Rat Route of Admin Inh Inh Inh Inh Inh Inh Inh PO Inh Inh Inh Inh Tumor Site Liver Liver Brain Lung Liver Lung Mammary glands Liver Liver Lung Kidney Ear (Zymbal gland) Lesion Type Ref IMEMDT 79190377 IMEMDT 74070291. IMEMDT 79190377 IMEMDT 79190377 IMEMDT 79190377 IMEMDT 79190377 IMEMDT 79190377 IMEMDT 79190377 IMEMDT 79190377 IMEMDT 74070291. IMEMDT 79190377 IMEMDT 79190377 IMEMDT 79190377 IMEMDT 79190377 MUTAGENICITY TESTING RESULTS Strain G-46 Indicator Met Act R. L, S-9, PB TA100 R. L. S-9. PB, A TA1530 R. L. S-9. PB TA153S R. L. S-9, PB TA98 R, L. S-9. PB Method Desiccator Desiccator Desiccator Desiccator Desiccator Test System Ames Salmonella typhimurimn Ames S. typhimurium Ames S. typhimurium Ames S. typhimurium Ames $. typhimurium Rel IJCNAW 75150429. BBRCA9 7S6303S3 PNASA6 75725135. DTESD7 77020249 BBRCA9 75630363. ITCNAW 75150429 IJCNAW 75150429. BBRCA9 75630363. PNASA6 75725135 PNASA6 75725135 MARCH/APRIL 1989 23 BOR 0 0 6 7 7 0 FEATURES GENE MUTATION RESULTS* Assay Code CY8 DLT MST PGM RE2 SRL YEC YEH YEY DHT CCG SAL Assay In vivo cytogenic lymphocyteAeucoeyte Dominant lethal test Mouse spot test Plant gene mutation DNA repair-deficient bacteria Sex-linked recessive lethal test Gene conversion test Recombination or gene conversion Forward mutation Heritable (reciprocal) translocation test Gene-Tax Carcinogenicity Panel's list of chemicals Histidine reversion test Species Human Rodents Mouse All tests E. eali polA (&3110-P3478)-all test with S-9 Drosophiha melanogaster Sacchammyces cervisiae 5. cervisiae Schixosaccharomycos pombe D. melanogastni NR Salmonella typhimuiium Endpoint Code C C; G M M N M C C M C I G Result Code Positive Negative Negative Positive, D Positive Positive Positive;M/ Negative.' Positive,'M; Negative) Positive 'J Positive y 'Parameter type: health effects; genetic mutation studies Chemical type: test SUMMARY TABLE Endpoml Code C M N G I Endpoint Chromosomal effect Gene or point mutations DNA-related effects General group; may include several endpoints Unidentified assays Findings > 't 1 ' 2li? 2 Positive; 3 negative; 1 MA (6) ' 3 Positive; 1 negative; 1 MA; 1 D 1 Positive (1) `- 1 Positive; 1 negative (2) ^ 1 Positive (1) MA a metabolic activation system used as part of the experimental protocol ior the given in vitro test. D = a dose eiiect when paired with a positive response. GASTROINTESTINAL ABSORPTION AND TOX ICITY CHEMICAL TYPE Test. PURITY Not reported. CHEMICAL CHARACTERISTICS UC labeled. OTHER CHEMICALS PRESENT No. STUDY PURPOSE Absorption (administration route involves the gastrointestinal tract), distribution (blood and tissues), metabolism (analyses are made up for the unchanged drug or metabolites), excretion (urine, feces, bile, or other excretory products are analyzed for presence of the drug, metabolites, or radiolabel). ORGANISM CLASS Rodent. SPECIES NAME Rat. STRAIN Sprague-Dawley. TEST DURATION 72 H. ROUTE/METHOD Oral. REFERENCE Watanabe, P.G., G.R. McGowan, ar P.J. Gehring. 1976. Fate of uC-vinyl chloride aft single oral administration in rats. Toxicol Appl Plu. macol 36(2): 339-352. CHEMICAL TYPE Test. * PURITY 95% or greater purity. CHEMICAL CHARACTERISTICS Solution, 99.9% purt OTHER CHEMICALS PRESENT No. STUDY PURPOSE Distribution (blood only' ORGANISM CLASS Rodent. SPECIES NAME Rat. STRAIN Wisiar. TEST DURATION 150 min. ROUTE/METHOD Intravenous. rSO o o Pi O m REFERENCE Withey, J.R. 1976. Pharmacodyna ics and uptake of vinyl chloride monomer admit 24 DANGEROUS PROPERTIES OF INDUSTRIAL MATERIALS REPl CHEMICAL REVIEW tered by various routes to rats.J Toxicol Environ Health 1 (3):381--394. CHEMICAL TYPE Test. PURITY 95% or greater purity. CHEMICAL CHARACTERISTICS Solution, 99.9% pure. OTHER CHEMICALS PRESENT No. STUDY PURPOSE Absorption (administration route involves the gastrointestinal tract), distribution (blood only). ORGANISM CLASS Rodent. SPECIES NAME Rat. STRAIN Wistar. TEST DURATION 6 H. ROUTE/METHOD Oral, gavage. REFERENCE Withey, J.R. 1976. Pharmacodynam ics and uptake of vinyl chloride monomer adminis tered by various routes to rats.y Toxicol Environ Health 1 (3):381--394. AQUATIC TOXICITY PARAMETER TYPE Environmental studies; bioconcentration factor data. CHEMICAL TYPE Test. CHEMICAL CHARACTERISTICS ''C label, > 99%. STUDY PURPOSE Bioconcentration factor data. STUDY RELIABILITY 3. Studies assigned a reliability code of 3 do not meet the criteria for quality testing and are generally characterized by; (1) control mor tality unsatisfactory (e.g., greater than 10% and not accounted for statistically); (2) methods section shows weakness in experimental procedures or insufficient description to judge quality of experimental design; (3) static test with unmeasured concentration con ducted improperly (e.g., in the presence of precipi tate or some undisolved chemical, or in an unacceptable container). ORGANISM CLASS Crustacean. SPECIES NAME Daphnia magna; water flea. AGE/UFE STAGE Not reported. ROUTE/METHOD Static. EXPOSURE REGIMEN 72 D. CONTROLS Indeterminate (source document does not provide enough information regarding controls). GENERAL TEST CONDITIONS Freshwater; laboratory study. TEMPERATURE (Q 26.7. HARDNESS Not reported. ALKALINITY Not reported. DISSOLVED O, Not reported. pH Not reported. EFFECT ENDPOINT TYPE Bioconcentration factor data (Calc). EFFECT ENDPOINT VALUE 0.19. OTHER ENDPOINT DATA Partition coefficient, metab olism, photolysis, sediment. MEASURED/UNMEASURED Measured. REMARKS Closed aquatic model ecosystem with mixed species. Nominal cone reported. REFERENCE Lu, P.Y., R.L. Metcalf, N. Plummer, and D. Mandel. 1977. The environmental fate of three carcinogens: Benzo-(alpha)-pyrene, benzidine, and vinyl chloride evaluated in laboratory model ecosys tems. Arch Environ Contam Toxicol 6(2-3); 129-142. PARAMETER TYPE Environmental studies; aquatic toxicity or effects data. CHEMICAL TYPE Test. CHEMICAL CHARACTERISTICS Not reported. STUDY PURPOSE Other. STUDY RELIABILITY 4. Studies assigned a reliability code of 4 are either an abstract or a foreign paper, or they have not been reviewed prior to their inclu sion. MARCH/APRIL 1989 2b BOR 0 0 6 7 7 2 FEATURES ORGANISM CUSS Algae; cyanaphyta. SPECIES NAME Anacystis aeruginosa; blue-gree alga. AGE/UFE STAGE Not reported. ROUTE/METHOD Static. EXPOSURE REGIMEN Not reported. CONTROLS Indeterminate (source document does not provide enough information regarding controls). GENERAL TEST CONDITIONS Not reported; laboratory study. TEMPERATURE <C) 27. HARDNESS Not reported. ALKALINITY Not reported. DISSOLVED o. Not reported. pH 7.0. EFFECT ENDPOINT TYPE Mortality. EFFECT ENDPOINT VALUE 105,000 pg/L. OTHER ENDPOINT DATA Not reported. MEASURED/UNMEASURED Unmeasured. REMARKS Toxicity threshold. REFERENCE Bringmann, G., and R. Kuhn. 1978. Grenzwerte der Schadwirkung Wassergefahrdender StofFe Gegen Blaualgen (Microcystis aeruginosa) und Grunalgen (Scenedesmus quadricuada) lm.. .Von Was set 50:45-60. PARAMETER TYPE Environmental studies; aquatic toxicity, or effects data- CHEMICAL TYPE Test. CHEMICAL CHARACTERISTICS Not reported. STUDY PURPOSE Other. STUDY RELIABILITY 4. Studies assigned a reliability code of 4 are either an abstract or a foreign paper, or they have not been reviewed prior to their inclu sion. ORGANISM CLASS Algae. SPECIES NAME Chilomonas para menu nr. crypto monad flagellate. AGE/UFE STAGE Not reported. ROUTE/METHOD Other. EXPOSURE REGIMEN 48 H. CONTROLS Indeterminate (source document does not provide enough information regarding controls). GENERAL TEST CONDITIONS Not reported; labatory study. TEMPERATURE (O 20. HARDNESS Not reported. ALKALINITY Not reported. DISSOLVED 0 Not reported. pH 6.9. EFFECT ENDPOINT TYPE Population growth, 5% de creased cell count. EFFECT ENDPOINT VALUE 943,000 pg/L. OTHER ENDPOINT DATA Not reported. MEASURED/UNMEASURED Unmeasured. REMARKS Composition described. REFERENCE Bringmann, G., R. Kuhn, and A. Win ter. 1980. Bestimmung der Biologischen Schadwh kung Wasserge-Fahrdender Stoffe Gegen Protozoen III. Saprozoische Flagellaten. Z Wasser Abwasser Forsa 13(5): 170-173. DERMAL ABSORPTION AND TOXICITY PARAMETER TYPE Health effects; absorption, di' tribution, metabolism, excretion. CHEMICAL TYPE Test. PURITY 95% or greater purity. CHEMICAL CHARACTERISTICS 99.9% pure NC Ubeli vapor. BOR 006773 DANGEROUS PROPERTIES OF INDUSTRIAL MATERIALS REPC CHEMICAL REVIEW OTHER CHEMICALS PRESENT No. PURITY 95% or greater purity. STUDY PURPOSE Absorption, distribution, excre tion. CHEMICAL CHARACTERISTICS 99.9% pure l4C labeled vapor. ORGANISM CLASS Primate. OTHER CHEMICALS PRESENT No. SPECIES NAME Monkey. STRAIN Rhesus. AGE/LIFE STAGE Not reported. WEIGHT 4-5 kg. GROUP INFORMATION One group of one member. SEX Male. TEST DURATION 2 H. ROUTE/METHOD Dermal, topical-vapor, isolated, re strained. STUDY PURPOSE Absorption, distribution, excre tion. ORGANISM CLASS Primate. SPECIES NAME Monkey. STRAIN Rhesus. AGE/UFE STAGE Not reported. WEIGHT 4-5 kg. GROUP INFORMATION One group of one member. SEX Male. EXPOSURE REGIMEN 1 X for 2 H. TEST DURATION 2.5 H. SUE/AHEA Whole body. CONTROLS Not reported. CONCENTRATION/DOSE RANGE 3,423 mg. REMARKS Exposure regimen: 2.5 H. REFERENCES Hefner, R.E. Jr., P.G. Watanabe, and P.J. Gehnng. 1975. Percutaneous absorption of vinyl chloride. Toxicol Appl Pharmacol 34:529-532. PARAMETER TYPE Health effects; absorption, dis tribution, metabolism, excretion. CHEMICAL TYPE Test. ROUTE/METHOD Dermal, topical-vapor, isolated, re strained. EXPOSURE REGIMEN Once for 2.5 H. SITE/AREA Whole body. CONTROLS Not reported. CONCENTRATION/DOSE RANGE 391 mg. REMARKS Exposure regimen: 2 H. REFERENCE Hefner, R.E. Jr., P.G. Watanabe, and P.J. Gehring. 1975. Percutaneous absorption of vinyl chloride. Toxicol Appl Pharmacol 34:529-532. ACUTE TOXICITY: TERRESTRIAL LIFE-INHALATION LCW Sptnrf Mus Mus LC,,, (mf'/m') 305.500 68,550 Duration (H) 2 2 Rtf R-1I R-1H TEST CONDITIONS A total of 536 white mice were tested in Pravdin-type gas chambers. Ten concentrations were used. RESULTS The LCM, found using the Behren s method was 27,413 ppm (1 ppm = 2.5 mg/m3 under test conditions). The LCis was 139,975 ppm. MARCH/APRIL 1989 27 FEATURES ACUTE TOXICITY: TERRESTRIAL LIFE-INHALATION LCS0 (Continued) Spears LC,,, (mg/m') Duration (H) Rat 119,100 TEST CONDITIONS A total oi 70 rats were tested at 5 concentrations of VC in a Pravdin-type gas chamber. 2 R-114 RESULTS The LCW. determined using Behren s method, was 47640 ppm (1 ppm * 2.5 mg/m3 under test condi tions). The LC,oo was 208,425 ppm. Gpg 590,000 TEST CONDITIONS A total of 30 guinea pigs were tested at 5 concentrations of VC in a Pravdin-type gas chamber. 2 R-114 RESULTS The LCW, determined using Behren s method, ws 236,215 ppm (1 ppm = 2.5 mg/m* under test condi tions). The LCla) was 277,900 ppm. Rbt 590,000 TEST CONDITIONS A total of 20 rabbits were tested at 5 concentrations of VC in Pravdin-type gas chambers. 2 R-114 RESULTS The LCW, determined using Behren s method, was 236,215 ppm (1 ppm = 2.5 mg/m3 under test condi tions). The LC,,, was 277,900 ppm. Mus Rat Gpg Rbt 293,750 390,000 595,000 595.000 TEST CONDITIONS Experiments were carried out in a 580 L chamber oi the Pravdin type. The animals were ex posed to various concentrations of VC for 2 H. After an imals were placed in the chamber, gas was introduced at the beginning at the lower part of the chamber without any ventilation. Gas was measured volumetrically. A to tal of 536 mice, 70 rats. 30 guinea pigs, and 20 rabbits were used. LDM values were calculated according to the Behrens method. 2 2 2 2 R-J17 ACUTE TOXICITY: TERRESTRIAL LIFE-OTHER STUD IES For mice, the smallest concentration fatal in 10 min is 10-12 mmole/L (about 25-30% volume). The smallest narcotic concentration is about 3.5-5 mmole/ L (8-12% volume). Death occurs due to respiratory paralysis with resultant heart arrest. At a concentra tion of 7 mmols in air, vinyl chloride anesthetizes rab bits and dogs within a minute. Recovery is rapid with no apparent adverse effects, even after prolonged an esthetization. (R-l 15) Single exposure of guinea pigs to vinyl chloride gas at 250 mg/L in air resulted in narcosis and death within 30--60 min. Lower concen trations resulted in ataxia and narcosis. Pathology ex amination revealed congestion and edema of lungs and hyperimia of kidneys and liver. (R-11) Vinyl chloride was considered for use as an anesthetic be cause of its narcotic properties and low acute inha lation toxicity. However, studies with dogs found that vinyl chloride caused cardiac irregularities at ane$- thetic concentrations. (R-l06) EEG's in rats were altered following oral administration of vinyl chlo ride, and the alteration varied with sex. Vinyl chlo ride at 45 and 135 mg/kg altered learning ability. The compound at 12 mg/kg had immunosuppressant ac tivity in rabbits. (R-36) Guinea pigs exposed to 57% concentration of vinyl chloride lived only 1 H following exposure; exposure to 2,5% resulted in an 8 H survival time following exposure. Exposure to 1.5% for 1 H or to 0.5% for 8 H had no effect. (R114) Five mice, 5 rats, and 5 guinea pigs were ex posed to concentrations at 10, 20, and 30% for 30 min. At 10% concentrations, the animals became ag itated, then had unconscious movements, and some fell in a state of narcosis. At 20%, the animal's symp toms were salivary secretion, narcosis, and respiratory failure. At 30%, all these symptoms occurred faster. Dead animals showed lung, hepatic, and renal congestion, lung edema, and hepatic degeneration. 28 DANGEROUS PROPERTIES OF INDUSTRIAL MATERIALS REPORT BOR 006775 CHEMICAL REVIEW {R-114) Mice, rats, guinea pigs, and rabbits were tested to determine acute toxicity levels, symptoms of toxicity, and pathologic effect on the organs. Expo sure was for 2 H in a gas chamber. Animals exposed to vinyl chloride gas without homogenization (no ven tilation) died at concentrauons 3 times lower than when the gas was stirred up continuously. The most com mon symptom in all animals was a state of narcosis, usually attained during the first hour. Narcosis pro ceeded from excitment to tranquility to falling down. These symptoms included muscular contractions, tanico-clonic convulsions, respitory disturbances, bradypnea, Cheyne-Stokes type respiration, and finally death by respiratory failure. Circulatory disturbances were noted also. Animals that survived 2 H exposure rapidly regained a normal appearance. Autopsy re vealed congestion of the lungs, liver, kidneys, brain, and spleen. Some animals also showed pulmonar edema, marmorated liver, and slight tumefaction of the kidneys.(R-l 14) ACUTE TOXICITY: HUMAN STUDIES Two Canadian workers died following acute exposure to vinyl chlo ride gas; autopsies discovered congestion of the liver, spleen, and kidneys. (R-ll) Workers exposed to vinyl chloride reported symptoms of euphoria and intoxication. Irritation of the respiratory tract, chronic bronchitis, headache, irritability, poor memory, and weight loss were also noted. (R-ll) A 3-min ex posure to 2.5% vinyl chloride produced a dizziness and disorientation in humans. (R-113) ACUTE TOXICITY: AQUATIC LIFE-OTHER FRESHWATER STUDIES Spears Northern pike {Esox lucius) Duration (H) 240 Effect Level (ntg/L) 388 Ref R-67 RESULTS The 10 D LD,M Northern Pike (Esox lucius) was 388 ppm. Fifteen fish were exposed to 388 ppm in 15-20 gallon tanks. Within 10 D all had died. First indication of toxicity was loss of scales. This phenomenon was fol lowed by appearance of a gray white ulcerated area sur rounded by indurated borders. A lack of neutrophilic response also was noted. Twenty fish from uncontami nated Illinois Benedictine Lake were used as controls. After 120 D, 1 fish died due to mechanical injury. (R-67) SUBACUTE-CHRONIC EFFECTS: TERRESTRIAL LIFE Species Rat Route Ihl Doses 30.000 ppm Dosing Schedule 4 H/D, 5 D/W for 12 mos Ref R-12 TEST CONDITIONS Twenty-five rats were sacrificed in lots at 20 D intervals after 12 mos of exposure. RESULTS After 10 mos, some animals showed decrease in weight, aggressiveness to outside stimuli, and dis turbed equilibrium. Thirteen animals died from cardi orespiratory complications. Two animals died from hematoperitoneum. Most exposed animals showed path ological degeneration of the brain, liver, kidneys, and thyroid. Six rats showed histopathological alterations of the skeleton. Degeneration of skeleton and connective tissue was similar to that observed in human acroosteolysis of the hands. MARCH/APRIL 1989 3ft 29 BOR 0 0 FEATURES SUBACUTE-CHRONIC EFFECTS: TERRESTRIAL LIFE (Continued) Species Route Doses Dosmg Schedule Re Rbt Ihl 9-10 mg/L 4 H/D for 5.S mos R- BESULTS Aher S.S moe exposure to VC. altered beta-waves (frequency > 80 Hz) appeared on the electroencephalo gram from the anterior hypothalmic nuclei, and poten tials oi the anterior and posterior nuclei increased by 1830% and 70-85%. respectively, over control values. Concommitant changes in the cardiovascular system (brady cardia. arrhythmia. decreased voltage of electrocardiogram peaks or whole complexes, decreased duration of systole, increased arterial pressure, and re tarded blood flow) also occurred. Functional changes in the anterior and posterior hypothalmic nuclei may have a role in pathogenesis of toxic angioneurosis due to VC. Bat Ihl 0.03-0.04 mg/L 5 mos R- RESULTS Chronic exposure of rats to VC disrupted car diac work rhythm, induced bradycardia and arrhythmia, and reduced the relative duration of I-II and T-D sound intervals. The relative duration of the Q-T complex die not change significantly. Within 15 D after terminertior of exposure, the rat cardiac activity rhythm returned tc normal, but the duration of I-II and T-II sound intervals remained below the initial levels for another IS D. The author concluded that the maximal permissible concen trotion of VC is significantly less than 0.03 mg/L. Rat Ihl S.000 ppm TEST CONDITIONS Eighty male and female Wistar rats were used. A control group also was used. 7 H/D. 5 DAV for 52 W I RESULTS After 4, 13, 2G, and 52 W, 10 rats/sex/group wen sacrificed and subjected to extensive examinations as t< growth, mortality, hematology, clinical chemistry, anc organ weights. Slight growth retardation throughout the experimental period and high mortality in the seconc half of the study were observed in the VC-exposed ani mals. Some of the hematological parameters and bic chemical blood parameters were influenced by VC afte an experimental period of 52 W only. Blood clotting tim was shorter in rats exposed to vinyl chloride monome (VCM) than in the controls. There were minor indication of increase potassium contents of the blood serum in VCV exposed animals during the first half of the experimentc period. The kidneys were adversely affected by VCM a indicated by increased blood urea nitrogen levels an relative lridney weights. After 52 W, increased weight of heart and spleen and slight signs of anemia were nc ticed in VCM-exposed rats. Mus NG NG 30 Up to G mos in vitro RESULTS Electron microscopic studies of mouse liver e: posed to vinyl chloride monomer for up to 6 mos reveale changes mainly in and around sinusoids and in sinu: oidal lining cells, particularly with only mild alteratior of hepcttocytes. The angiosarcomas which developed i some mice arose from the sinusoidal lining cells. BOR 006772 DANGEROUS PROPERTIES OF INDUSTRIAL MATERIAL! r-HiECAL Hrrzw SUBACUTE-CHRONIC EFFECTS: TERRESTRIAL LIFE (Continu'd) Sprats Raule Doses Dosing Schedule R'- Rat Ihl S,000 ppm TEST CONDITIONS Alter exposure to 0 ppm (control) or 5,000 ppm, 62 male and 62 female Wistar rats were sac rificed (at 4, 13. 26, and 52 W) and subjected to extensive examinations. Descriptions of morphological changes observed in respiratory tract, ceruminous glands, brain, kidney, heart, and spleen wore noted. Mus, rat Ihl 50. 250, 10,000 ppm 7 HID, 5 D/W for 52 W R-3. RESULTS The VC effect* irwfwW* /cj-s*ra*. ; degree of tubular nephrosis, mild focal of the my- ocardia, and increased "vJxryi - : the <qtleen- 6 H/D, 6 D/W for up to 1 Y R-4! RESULTS Exposure of albino ^^ ^ 2 mas old. to 1.000 ppm of VC VJ=* mte dMths with toxic hepatitis and mwW, **.,*_ ^ the renal cortex. Starting with ti* V, ^ ,Trr^ to 50 or 250 ppm VC became Lew*, -.j.Hy and died. Only a few mice ex*,**- x X pcm survived for 12 mos. Pulmonary macros*^ -,w ^ elevated in some mice. In rats (group* -A % ^ % te;nale CD), exposure to 1.000 ppm V'; de_ pressed body weight of the 1.000 ppm caused a number <A Expofezes of 250 or Rat Ihl SO, 500, 20,000 ppm TEST CONDITIONS The activity of microsomal cyto chrome P-450 monooxygenase and ultrastructure of the liver were studied in rats exposed dynamically to 50. 500. and 20,000 ppm VC over 10 mo$. 10 mos R-45 RESULTS After 1 and 3 mo* of zJS ^ ^ DQ0 ppm VC. the level of cytochrvu* p ^ , bwer than in the control animal* vums-cper: of expo sure, it was restored to the by a sUght increase of acUvr, crtcmpcnied Liver enlargement, develops ,, r was accompamed by ultroetiv;,,^ .....__ begin ning in the 3rd mo of expo*.* -41 Wjl(=ia"^ ol VC. Development of hepatx. -i.-^ i^rophv of smooth and rough endoplswc*. ^ o{ mitochondria, accumulate.'.* v ^ iocci toplasmic degradation! also Rat Ihl 50, 500, 20,000 ppm TEST CONDITIONS A total of 340 male Wistar rats. ISO-- 220 g, were exposed to VC at concentrations of 50, 500. and 20,000 ppm, 5 H/D, 5 D/W for 10 mos. 5 H/D. 5 D/W for 10 mos R-48 RESULTS Morphological lcauus. er sn testes. de tected by light and electron use. awiftri with duration of exposure. After "> -tammu. diifer- ence from controls was statnrv.-ui, p < 0.05) at all levels of VC exposure A t-j- :* aicat weights of spleen, liver, kidneys, bear- v+, >** seas elevated significantly in some group* o w, asoaa. the dil- ierence being most pranaur*** -*U*e=. dose-re- lated for both liver and lacs*?r. 'Jv-iax-rstect level oi VC could not be establish** ~ .* --r.-pntTr--ian of VC (50 ppm) still causes cuv, tcwcs m rats, including slight hematologic-.; . IT.CC.5eS and fluctuations, as well m .i.rj'"rr-n oranges in hepatocytes and a tender*^ /y ... =^rB*c racidence of histological liver altercvyj. raraysis em- ployed the Students' t-tesp BOR 0 0 6 7 7 8 MARCH/APRIL 1989 FEATURES SUBACUTE-CHRONIC EFFECTS: TERRESTRIAL LIFE (Continued) Species Route Doses Doting Schedule Dog Ihl 10%, 20% volume in aii 7 X/3 W. for 3 H each exposure RESULTS At 10% volume, dogs showed no considerable^ changes in liver and kidneys. At 20% volume, there was respiratory paralysis and strong flow of saliva; after nscrosis, vomiting occurred. SUBACUTE-CHRONIC EFFECTS: HUMAN STUDIES Route NG Doses NG TEST CONDITIONS An epidemiological study was per formed covering 5,011 employees with 21,510 man-years experience in various phases of VC and PVC manufac turing in 32 plants throughout the U.S. and Canada. -3 Dosing Schedule Jtej Occupational R4 "3fS RESULTS The total number of definitive cases of acroas^S teolysis (AOL) was 25; IE other individuals were under* suspicion. This condition is clearly associated with the'IS hand cleaning of polymerizers. Workers engaged in other3 phases of VC or PVC manufacturing do not appear to be ? at risk for developing AOL. AOL appears to be a systemic % rather than local disease. At present neither the etiol-'* ogical agent nor its portal of entry is known. NG NG Occupational ,.. ft R-E RESULTS Two cases of acroosteolysis occurring in men' '1' engaged in the polymerization of VC are described. The bones affected were the terminal phalanges of the fin gers and the sacroiliac joints, but in one case the patella and in the other the phalanges of the feet were involved. The condition was accompanied by Raynaud's phenom-' enon and skin lesions. NG NG TEST CONDITIONS The cohort of workers employed in a Swedish VC/PVC plant since its start in the early 1940s has been followed for mortality and cancer morbidity patterns. Only 21 ol the 771 persons could not be traced. Difficulties in establishing exposure levels at different work ares in the past makes an evaluation of dose-effect relationships impossible. Ihl. dermal NG Occupational R-8 RESULTS A four- to five-fold excess of pancreas/liver tu- mors was found, including 2 cases later classified as'| angiosarcomas of the liver. The numbers of brain tumors ' and suicides do not deviate significantly from expected. t Cardiovascular and cerebrovascular diseases, on the other * hand, differ significantly from the expected. ^ 'j V NG 'M RESULTS VC is a sldn irritant, and contact with liquid ; may cause frostbite upon evaporation. VC gas depresses the central nervous system. Lightheadedness, some nau sea. and dulling of visual and auditory responses may develop in acute exposures. Chronic exposure of workers may result in acro-osteolysis. Raynaud's phenomenon, and sclerodermatus skin changes. Chronic exposure also may cause hepatic damage. BOR 006779 32 DANGEROUS PROPERTIES OF INDUSTRIAL MATERIALS MI CHEMICAL REVIEW SUBACUTE-CHRONIC EFFECTS: HUMAN STUDIES (Continued) Doses Dosing Schedule Ref NQ Occupational R-ll RESULTS There are numerous clinical indications that chronic exposure to VC is toxic to humans. Hepatitis-lilce liver changes, angioneurosis of a spastic character, Ray naud's syndrome, scleroderma-like skin changes, lytic lesions of the terminal phalanges in hands and feet, and pseudoclubbing of the fingers have been reported in many workers in the U.S. and Europe. The latter conditions have been termed occupational acro-osteolysis. Other long-term effects include functional disturbances of the CNS with adrenergic sensory polyneuritis, thrombocy topenia, splenomegaly, liver malfunction with marked fibrosis in the portal areas, and pulmonary insufficiency with restrictive changes in the lungs. MG NG thl NG MG NG thl NG Occupational for 1 Y R-H RESULTS Workers exposed to VC for 1 Y showed a decreae of peroxidase, indophenoloxidase, and glutathione levels. Serum levels of gammaglutamic transpeptidase in exposed workers appear to be the best clinical param eter for detecting abnormalities. Alkaline phosphatase, serum glutamic pyruvic transaminase, serum glutamic oxaloacetic transaminase, lactic dehydrogenase, and bi lirubin levels also were increased in many cases. Other data suggest that VC disease is an immune-complex dis order. Immunological and immuno-cheraical investiga tions of workers with the syndrome showed presence of circulating immune complexes in 19 of 28 patients NG R-43 RESULTS Liver function tests showed no difference be tween exposed workers and controls not exposed to VC, and no cases of angiosarcoma or florid-vinyl chloride in duced liver disease. However, of 422 exposed workers, 4 had enlarged spleens, compared with none for 202 con trols. Liver biopsies of selected cases showed no signif icant pathological changes, although there was a minimal increase in portal tract and sinusoidal fibrosis in ex posed workers. Occupational R-44 RESULTS Capillary microscopy study showed that 10% or more of workers exposed to VC have capillary abnor malities which were not found in workers without expo sure to VC. NG R-Gl RESULTS A cytological examination of the sputa of nearly 4,000 Italian workers in the VC/PVC industry has shown a high incidence of changes in bronchial epithelia, among which squamous dysplasia and atypical adenomatious proliferation were observed. fPi. ) 989 33 FEATURES PHARMACOnNETlCS/METABOUSM In rats inhaling 20,000 ppm MC vinyl chloride for 5 min l'1C was found in the liver, bile duct, digestive lumen, and kidneys 10 min from the beginning of the inhalation expo sure. The amount of vinyl chloride and its metabo lites increased up to 3 H postexposure. Additional deposition sites showing MC activity included urinary tract, salivary glands, lacrimal glands, skin, and thy mus. (R-l 1) The tissue deposition of UC vinyl chlo ride has been studied. Immediately after exposure by inhalation of50 ppm vinyl chloride for 5 H in a closed system, the percentage incorporated as UC radioac tivity per gram tissue was highest for kidney (2.13%), liver (1.86%), and spleen (0.73%). Labeled material could still be found in these tissues 48 H after the beginning of exposure. (R-11) Present data indi cate that VC is metabolized to an activated carcinogen electrophile which is capable of covalently reacting with nucleophilic groups or cellular macromolecules. There is also ample evidence that the mixed function oxidase (MFO) system may be involved in the metab olism of vinyl chloride. Rat liver microsomes catalyze the covalent binding of vinyl chloride metabolites to protein and nucleic acids, Chloroethylene oxide is thought to be the primary microsomal metabolite ca pable of alkylating these cellular macromolecules. (R11) The metabolism of vinyl chloride may be in hibited by administering to rats, 320 mg/kg of pyrazole, 1 H prior to inhalation of the gas. Pyrazole is an inhibitor of alcohol dehydrogenase and xanthine oxidase. Pretreatment of rats with ethanol, 5 mg/kg, 95%, also inhibited vinyl chloride metabolism. (R-l 1) When a mixture of vinyl chloride/oxygen (1:1 v/v) was passed through a medium consisting of liver mi crosomes from phenobarbitone-pretreated mice, and an NADPH-generating system, a volatile metabolite was formed; this was trapped by its reaction with 4(4-nitrobenzyl)pyridine, in ethylene glycol. (R-l3) Radioactivity from uC-labeled vinyl chloride was covalently bound to protein and nucleic acids in vivo and m vitro, in the presence of rat liver microsomal fractions of highly purified cytochrome P-450 and NADPH-cytochrome P-450 reductase preparations. The ratio of bound to total nonvolatile metabolites increased from the in vivo to the microsomal to the purified system. In vivo, the total metabolism of UClabeled vinyl chloride was not induced by phenobarbitol pretreatment (0.1% in drinking water for 5 days) in rats exposed to either 10 ppm or 250 ppm of the MC vinyl chloride. However, binding to protein and RNA was enhanced but only at the lower exposure level. In vitro, phenobarbitol pretreatment increased microsomal conversion of HC vinyl chloride to both total and bound metabolites. The metabolites of NC vinyl chloride metabolism in an in vitro liver micro- somal fraction were distributed among many micro somal proteins and not localized to cytochrome P450. (R-25) '"C-labeled vinyl chloride was studied in rats. Rats exposed to 10 ppm VC for 6 H elimi nated 68% of the absorbed radioactivity in their urine and 2% (as VC) in the expired air over 72 H. Six hour exposures to 1,000 ppm resulted in 56% of the dose appearing in the urine with 12% in the expired air as VC. The pulmonary excretion of VC followed first order kinetics with similar half lives at both treat ment levels: 20.4 min at 10 ppm and 22.4 min at 1000 ppm. (R-29) The mechanisms responsible for and protecting against metabolic activation of vinyl chlo ride were investigated in male Sprague-Dawley rats. They inhaled 5% VC for 18 H. When HC vinyl chlo ride was incubated with hepatic microsomes, a MClabeled material became irreversibly bound to micro somal proteins. Binding required NADPH, was de creased by CO, SKF-525A (2-diethylaminoethyl 2,2diphenylvalerate hydrochloride, 75 mg/kg, ipr), or glutathione, and was increased by 1,1,1-trichloropropene-2,3-oxide (TCPO). Inhalation of a 5% vinyl chloride atmosphere decreased hepatic cytochrome P-450 and glutathione. Pretreatment of the animals with DDT or phenobarbital had the following effects: increased in vitro irreversible binding to microsomal proteins measured in the presence but not in the ab sence of TCPO; increased in vivo loss of cytochrome P-450 during inhalation of the vinyl chloride; de creased in vitro irreversible binding to 10,000 g su pernatant proteins; and in vitro loss of glutathiom during inhalation of vinyl chloride. (R-32) In ratexposed to 400 ppm vinyl chloride for 6 H and then treated ipr with 20 mg 3,4-dichlorobenzenethiol, and again exposed to 400 ppm VC for 12 H S-2-(3,4dichlorothiophenyl)acetic acid was detected in tlu urine. Authors concluded that the formation of nu cleophilic carcinogens from nonelectrophilic precur sors can be proven by the use of nucleophilic reagents in vitro as well as in vivo. (R-33) Rats were exposed to 5,000 ppm of vinyl chloride, via inhalation, 6 H, D, 5 D/W for 7 W. This VC was nonlabeled. On the last day of repeated exposure, UC VC was used. The fate of the UC VC was compared in a group of rats exposed repeatedly, to a group exposed simulta neously for a single 6 H period to 5,000 ppm of MC VC. The routes and rates of excretion of HC activity were the same for the two experimental groups. The activity ofmicrosomal enzymes, as reflected by aniliiu hydroxylase and p-nitroanisole-o-demethylase de rived from 9,000 g liver supernatants was essentially the same in rats exposed repeatedly or in nonexposed control rats. Covalent binding to hepatic inacronio lecules was greater in rats repeatedly exposed as com pared to those subjected to a single exposure, 'finis 34 DANGEROUS PROPERTIES OF INDUSTRIAL MATERIALS REPOR BOR 006781 CHEMICAL REVIEW repeated exposure to VC does not induce its biotransformation. However, the increase in hepatic macromolecular binding indicates that repeated exposure augments the reaction of electrophilic metabolites with macromolecules, and this may be expected to en hance potential toxicity including carcinogenicity. (R37) After a 5 H inhalation exposure, rats metabo lized l4C-labeled vinyl chloride much faster than car bon tetrachloride (CC1). The half life was found to be 1.1 H. The 14C vinyl chloride bound covalently to tissue proteins, particularly in the liver. In kidney, small intestine, and other organs much less radioac tivity was observed. (R-39) Vinyl chloride uptake rate and proportion metabolized by isolated perfused rat livers remained constant for VC concentrations of 50-25,000 ppm. The overall VC conversion was 14.6% of the offered concentration. ETOH, pyrazole, and 6-bromobenzothiazole inhibits VC metabolism bv 12.7, 31.6, and 48.9%, respectively. Phenobarbital a: fast ing increases 'C metabolism by 20.9 and 31. .re spectively. Vt has no effect on marker enzym. but slight liver damage occurs after increased metabolic VC transformation. Mixed function oxygenation is apparently involved in VC metabolism. (R-42) The metabolic elimination of vinyl chloride in Rhesus monkeys is a dose-dependent, saturable process, as in rats. Below 200-300 ppm of VC in atm, elimina tion obeys a lst-order law. Clearance rate is much closer to that found in man than that for rats, mice, or gerbils. Maximal velocity of metabolic elimination of VC at high concentrations in Rhesus monkeys is only about half that of rats when related to kg body weight. Thus Rhesus monkeys mimic quantitative as pects of VC metabolism better than do rats or mice. (R-46) In the presence of hepatic microsomes, vinyl chloride produced a type I difference spectrum and stimulated coinhibitable NADPH consumption. A comparison of the binding and Michaeiis parameters for the interaction of VC with uninduced phenobarbitol-, and 3-methylcholanthrene-induced micro somes, indicates that the binding and metabolism of VC was catalyzed by > 1 type P-450 cytochrome, but predominately by cytochrome P-450. Metabolites of VC from this enzyme system decreased the levels of cytochrome P-450 and microsomal heme, but not cy tochrome b5 or NADPH-cytochrome c reductase, in vitro. (R-51) Thiodiacetic acid and S-(carboxy-methyl) cysteine were found in the urine of rats after a 48 H exposure to 1000 ppm vinyl chloride. The structures of both compounds were clarified by means of gaschromatography mass spectroscopy. Chloroethylene oxide, chloroaceialdehyde, and chloroacetic acid are assumed to be intermediates in VC metabolism. Com pounds which can be transformed to one of these alkylating agents hi vivo may also lead to renal excre tion of thiodiacetic acid and S-(carboxymethyl)cysteine. (R-54) Strong evidence has been obtained that the biotransformation of vinyl chloride involves microsomal mixed-function oxidase; i.e., the metabolic activation of VC by a liver microsomal sys tem from rats, mice, or humans, depends on the pres ence of necessary cofactors for a NADPH-generating system and oxygen. Chloroethylene oxide rearranges to 2-chloroacetaldehyde spontaneously. In aqueous solution at pH 7.4 and 37 C, the epoxy compound has a half life of 1.6 min. Chloroethylene oxide is capable of reacting with glutathione and with nucleo philic groups of macromolecules. N-acetyl-S-(2-hydroxyethyl)cysteine (a major metabolite), S(carboxymethyl)cysteine and N-acetyl-S-vinyl cysteine are metabolites of VC after inhalation or oral admin istration in rats. Chloroethylene oxide and chloroacetaldehyde alkylate to 4-(4-nitrobenzyl)pyridine and adenosine. Rat liver microsomes catalyze covalent binding of l4C vinyl chloride to proteins and nucleic acids. (R-57) Ethylene and its analogues (i.e., vinyl chloride, vinyl bromide) are converted to the corre sponding ethylene oxides by cell-free preparations from mature cotyledons of the broad bean (Vida faba). Vinyl chloride acts as a competitive inhibitor in the first order oxidation of ethylene. The measured K, where Kj (gas) = 3.19 x 10-6 M; K, (liquid) = 1.5 x 10~6 M. (R-73) Post-mitochondrial supernatants of liver, kidney, and lung tissue from rats and mice that had been exposed to 20% VCM were assayed for their capacity to generate VCM metabolites muta genic for Salmonella typhimurium TA1530. Data indi cate that the liver tissue efficiently converted VCM into mutagenic metabolites. (R-60) PHYTOTOXICITY: TERRESTRIAL PLANTS Research was designed to study the effect of vinyl chloride on the rate of production of excess hydrogen peroxide (H202), which is toxic to germinating oat seeds. The effect of the increased H202 by VC on the sulfhydryl content in germinating seeds and in potatos was stud ied also. No apparent increase in the H202 level was found when germinated seeds were exposed to 50, 100, or 200 ppm VC gas. Results showed that the amount ofH202 gradually increased from 0.35-0.45, 0.65, 0.92, and 1.15 fig H202/g seed when VC gas was successively increased to 300,400, 500, and 1,000 ppm. The 2,000 ppm VC response was very similar to 1,000 ppm. There was a 10-fold increase in the sulfhydryl content of the seeds after 72 H germina tion without exposure to VC. The sulfhydryl content was decreased gradually by 5.5, 15.2, 21.7, and 30.4% when VC gas was successively increased to 300, 400, 500, and 1000 ppm. The increased production of H202 in the germinating seeds exposed to VC gas de MARCH/APRIL 1989 39 FEATURES creased their sulfhydryl content and thereby pro duced adverse effects and caused abnormalities in growth. The conclusion was that threshold levels of VC are > 200 ppm and that saturation level is 1,000 ppm. (R-34) OTHER ADVERSE EFFECTS Male CD-I mice were exposed to 10, 100, or 1000 ppm vinyl chloride for 2-8 W at 6 H/D, 5 D/W. A slight increase in the spleen weight of mice was noted at the highest level. Spleens were obtained from these animals (4 mice/group after 2, 4, and 8 W exposure) and their lymphocytes cul tured in vitro with or without the presence of phyto mitogens, phytohemagglutinin (PHA), and pokeweed mitogen (PWM). Relative blast formation and the DNA synthesis was measured by the incorporation of SHthymidine in the cultured cells. The response ofsplenic lymphocytes to the phytomitogens was increased sev eral fold by vinyl chloride exposure. The effects were apparent at 1000 ppm VC after 2 W ofexposure and at all levels of VC exposure after 4-8 W. The effects were generally more pronounced at 100 ppm VC ex posure than those at 1,000 ppm. In vitro culture of splenic lymphocytes from control or VC-exposed mice in the VC atmosphere did not show enhancement of blast formation. Alteration of VC metabolism during the VC exposure in vivo yielded results indicating that metabolites of VC may be responsible for the stim ulation of lymphocyte transformation observed in splenic cultures. (R-50) Male, but not female, rats were susceptible to the acute hepatotoxic effects of inhaled vinyl chloride. In phenobarbital-pretreated male rats, pyrazole and SKF-525A, inhibitors ofethanol metabolism and mixed function oxidase svstem (MFO) activity, protected against toxicity. When disulfiram and ethanol were given acutely, a slightly increased toxic effect of vinyl chloride was observed. Ethanol given in drinking water (10% for 7 D or an equivalent dose of 10 ml/kg/D) did not, by itself, enhance vinyl chloride hepatotoxicity in male rats, even though this dose regimen did slightly increase mixed function ox idase system activity. Apparently, inhibition of either liver alcohol dehydrogenase or microsomal oxidase protects rats from acute hepatotoxicity of vinyl chlo ride. Since pyrazole has some inhibitory action on microsomal oxidases, it also is possible that inhibition of reactions catalyzed by the mixed function oxidase system alone could account for protection against vi nyl chloride. (R-52) Single exposure to vinyl chlo ride induced acute liver injury in rats whose mixed function oxidase system was stimulated by pretreat ment with Aroclor 1254 or phenobarbital. The en doplasmic reticulum was involved in the primary morphological injur)', with denaturation of the smooth membranes. The increased hepatotoxicity of vinyl chloride may involve their metabolic activation via free radical or epoxide intermediates. (R-53) Male rats were pretreated by gavage with the PCB mixture Ar oclor 1254 (300 M-mol of PCB/kg) for 3 consecutive days. On D 4, these rats were exposed by inhalation (4 H) to 24,000 ppm vinyl chloride. Animals were sacrificed 24 H later and acute hepatic responses were estimated by measurement of serum-alamine alphaketoglutarate transaminase (SAKT) and by light mi croscopy. Vinyl chloride caused significant elevations of (SAKT) and produced severe degeneration and necrosis of the liver. SAKT elevations (mg pyruvate/ mL serum/H) were: untreated controls, 0.17 : 0.01; PCB pre-treated, not exposed, 0.19 0.02; PCB plus vinyl chloride, 2.58 1.25. (R-5) Absorption through the skin is minor. Calculations based on the percutaneous absorption of vinyl chloride by Rhesus monkeys indicate that a 6 ft, 90 kg man exposed to 7,000 ppm (dermal) for 2 H would absorb the equiv alent of a 0.2 ppm, 8 H inhalation exposure. (R-l 1) Vinyl chloride reacted to a greater extent with den atured than with native herring sperm DNA, in vitro, in aqueous solution. However, vinyl chloride failed to react with previously acylated calf thymus DNA in vitro in citrate buffer. (R-38) Vinyl chloride may be anaesthetic above 500 ppm. Handling of material has caused circulatory and bone changes. (R-47) `*C vinyl chloride, 0.5 mmole/kg in 0.5 mL/kg methanol, was given ipr for 1-6 D to male Sprague-Dawley rats. After administration of the vinyl chloride, hepatic P450 was not significantly decreased after 1 dose, but progressively decreased after repeated doses. Hepatic glutathione and SGPT activity were unchanged and histologic examination ofliver specimens obtained after 1,3, or 6 doses showed no liver necrosis. The amount of l4C material irreversibly bound to proteins in creased in various tissues during administration of the first 3 doses but then tended to decrease in the liver and in the kidney. (R-68) ENVIRONMENTAL IMPACT AIR POLLUTION High. ACTION levels Evacuate area. Enter from upwind after gas levels have subsided. Notify fire and air au thority. Remove ignition sources. IN snv AMELIORATION Use carbon or peat on dis solved portion. Seek professional environmental en gineering assistance through EPA's Environmental Response Team (ERT), Edison, NJ, 24-Hour No. (201) 321-6660. AVAILABILITY OF COUNTERMEASURE MATERIAL Carbon: water treatment plants, sugar refineries. Peat: nur series, floral shops. BQR 006783 36 DANGEROUS PROPEhutk inuu^im/u. maiuwlo ntPORT CHEMICAL REVIEW DISPOSAL METHOD Dilute to 1% solution and re move phenol inhibitor as sodium. (1) Pour onto vermiculite, sodium bicarbonate or a sand-soda ash mixture (90/10). (Add slaked lime if fluoride is pres ent.) Mix in paper boxes, place in incinerator, cover with scrap wood and paper, ignite with excelsior train. Stay upwind. Or, dump in closed incinerator with afterburner. (2) Dissolve in flammalbe solvent and spray in incinerator firebox equipped with afterbur ner and alkali scrubber. DISPOSAL NOTIFICATION Local air authority. MAJOR WATER USE THREATENED Recreational. PROBABLE LOCATION AND STATE OF MATERIAL Colorless gas. Heavy vapors will cling near ground. Some will dissolve. Polymerizes readily in air or sunlight. WATER CHEMISTRY Subject to polymerization. COLOR IN WATER Colorless. ACCIDENT DESCRIPTIONS Discharge of a spray of vapor and liquid under pressure from a cylinder into a fume hood generated static and ignited the vapor. Vinyl chloride tends to self-polymerize explosively if peroxidation occurs, and several industrial explo sions have been recorded. Accidental exposure of the recovered monomer to atmospheric oxygen for a long period caused formation of an unstable poly peroxide which initiated an explosion. An explo sion in a valve in a liquid monomer line was ascribed to traces of oxides of nitrogen remaining after the valve had been passivated by treatment with nitric acid. (Bretherick, L. 1985. Handbook of Reactive Chem ical Hazards, 3rd ed. Butterworth, London, p. 239.) ENVIRONMENTAL FATE; TRANSPORT PROCESSES - SORPTION Sorption measurements of vinyl chloride by 4 basic food constituents (water, corn oil, casein, and sucrose) were conducted. For water, oil/water emulsions, and casein, it was found that the partition coefficient val ues (defined as the equilibrium concentration of VCM sorbed over the equilibrium VCM in headspace) were fairly constant within the sorbate (VCM) concentra tions studied. At 24 C, the partition coefficient values for oil, casein and water were 23.7 x 10s, 11.7 x 10s, and 2.1 x 10s, respectively. Sucrose did not sorb detectable amounts of VCM under the experimental conditions employed. (RTS) ENVIRONMENTAL FATE: MICROBIAL EFFECTS Serum bot tles (125 mL) were used in the anaerobic toxicity assay (A FA). This allowed gas production to be measured periodically with a syringe, and analyzed. The bottles were purged with 70% N2 and 30% C02, and then the following were added: 30 mL of a nutrient and buffer solution (NaHCOs, 5.7 g/L, and FeCL, 0.37 g/ L), 20 mL of sludge from a laboratory digester to serve as a "seed" of anaerobic microorganisms, and 0.100 mL of ethanol to serve as substrate. VC was added to ethanol in various concentrations prior to its addition. The bottles were incubated at 35 C, and a reduction in the rate or extent of gas production in chemical-containing samples in comparison with con trols indicated inhibition. Inhibition was quantified approximately by determining the concentration of VC that causes a 50% reduction in total gas produc tion over a fixed period of time (50% inhibition). Semicontinuous bioassays were conducted using con tinuously stirred, 1.5 L digesters, operated at a 15 D detention time, and a temperature of 35 C 1C. The digesters were initially seeded with digested mu nicipal sludge. Primary sludge was used as feed. Each day 100 mL of digested sludge was removed, and an equal amount of feed sludge was added; 4, 16, or 64 mg/L of VC were added to ethanol and 0.1 mL of the mixture was added each day prior to feeding. Digester performance was evaluated from daily gas production and routine analysis of COD, total and volatile solids, volatile acids, pH, alkalinity, and gas composition. Batch results for VC indicate that 5.4 mg/L was marginally inhibitory and 32 mg/L was strongly inhibitory, although some acclimation did occur. A concentration ofapproximately 40 mg/L was required for 50% inhibition lasting 3.5 D. Semicon tinuous digestion with VC did not result in adverse digester performance, even at the highest concentra tion of 64 mg/L. Volatile acids were slightly higher with VC at 16 and 64 mg/L than in the controls, but no significant signs of stress were apparent. (R-99) ENVIRONMENTAL FATE: OTHER PROCESSES The level of vinyl chloride found in potable water as a result of polyvinyl chloride piping is directly proportional to the level of residual vinyl chloride in the pipe. Pipe containing <1.0 ppm residual showed no vinyl chlo ride in the water with a test sensitive to 2 ppb. CHEMICAL HAZARD RESPONSE INFORMATION NAME ASSESSMENT CODE VCM. DESCRIPTION Gas. Colorless. Sweet odor. Liquid floats and boils on water. Flammable, irritating visible vapor cloud is produced. ACTIONS IN CASE OF EMERGENCY Stop discharge if possible. Keep people away. Shut off ignition sources and call fire department. Stay upwind and use water MARCH/APRIL 1989 37 co vo o nO 1 J <1 ^ (V 4. 1T 1 FEATURES sprav to "knock down" vapor. Evacuate area in case of large discharge. Avoid contact with liquid and vapor. Notifv local health and pollution control agenties. FIRE Flammable. Poisonous gas is produced in fire. Flashbacks along vapor trail may occur. May explode if ignited in an enclosed area. Wear self-contained breathing apparatus. Cool exposed containers and protect personnel effecting shutoff with water. Stop flow of gas if possible. Let fire burn. Extinguish small fires with dry chemical. EXPOSURE Call for medical aid. VAPOR Irritating to eyes, nose, and throat- If inhaled, will cause dizziness or difficult breathing. Move to fresh air. If breathing has stopped, give artificial respiration. If breathing is difficult, give oxygen. LIQUID Will cause frostbite. Flush affected areas with plenty of water. Do not rub affected areas. WATER POLLUTION Not harmful to aquatic life. RESPONSE TO DISCHARGE Issue warning: High Flammability. Evacuate area. LABEL CATEGORY Flammable gas. LABEL CLASS 2. CG COMPATIBILITY CLASS Vinyl halides. IMO"UN DESIGNATION 2.0/1086. DOT ID NUMBER 1086. PHYSICAL STATE Shipped) Liquefied compressed gas. COLOR Colorless. ODOR Pleasant, sweet. PERSONAL PROTECTIVE EQUIPMENT Rubber gloves and shoes; gas-tight goggles; organic vapor canister or selfcontained breathing apparatus. SYMPTOMS FOLLOWING EXPOSURE Inhalation-. High concentrations cause dizziness, anesthesia, lung irri tation. Skin: May cause frostbite; phenol inhibitor may be absorbed through skin if large amounts of liquid evaporate. TREATMENT OF EXPOSURE Inhalation: Remove patient to fresh air and keep him or her quiet and warm; call a doctor; give artificial respiration if breathing stoj Eyes and skin: Flush with plenty of water for at le. 15 min; for eyes, get medical attention; remove c< laminated clothing. THRESHOLD LIMIT VALUE 5 (ppm). SHORT-TERM INHALATION LIMIT 500 ppm for 5 mil LATE TOXICITY Chronic exposure may cause li' damage. VAPOR (Gat) IRRITANT CHARACTERISTICS Vapors cai moderate irritation such that personnel will find hi concentrations unpleasant. The effect is temporal LIQUID OR SOLID IRRITANT CHARACTERISTICS Minimi hazard. If spilled on clothing and allowed to rema may cause smarting and reddening of skin. May ca i frostbite. ODOR THRESHOLD 260 ppm. FLASHPOINT - 110 F (OC). FLAMMABLE LIMITS IN AIR 4-26 %. FIRE-EXTINGUISHING AGENTS For small fires use chemical or carbon dioxide. For large fires stop 1 of gas. Cool exposed containers with water. SPECIAL HAZARDS OF COMBUSTION PRODUCTS Fo highly toxic combustion products such as hydro chloride, phosgenic, and carbon monoxide. BEHAVIOR IN FIRE Container may explode in 1 Gas is heavier than air and may travel consider. distance to a source of ignition and flash back. IGNITION TEMPERATURE 882 F. ELECTRICAL HAZARD Class I, Group D. BURNING RATE 4.3 mm/min. STOICHIOMETRIC AIR TO FUEL RATIO 5.490 (est.). REACTIVITY WITH WATER No reaction. REACTIVITY WITH COMMON MATERIALS No reaction STABILITY DURING TRANSPORT Stable. POLYMERIZATION Polymerizes in presence ol sunlight, or heat unless stabilized by inhibitors. DANGEROUS PROPERTIES OF INDUSTRIAL MATERIALS RE BOR 006785 CHEMICAL REVIEW * INHIBITOR OF POLYMERIZATION Not normally used ex cept when high temperatures are expected. Then, 40-100 ppm of phenol used. REACTIVITY GROUP 35. WATERFOWL TOXICITY None. BIOLOGICAL OXYGEN DEMAND (BOD) None. FOOD CHAIN CONCENTRATION POTENTIAL None. GRADES OR PURITY Commercial or technical 99 + %. STORAGE TEMPERATURE Under pressure; ambient At atm. pressure; low. INERT ATMOSPHERE No requirement. VENTING Under pressure; safety relief At atm. pressure; pressure-vacuum. HAZDARD ASSESSMENT CODE A-B-C-D-E-F-G-Z. CODE OF FEDERAL REGULATIONS Flammable gas. PHYSICAL STATE @ 1 C AND I ATMOSPHERE Gas. BOILING POINT AT I ATMOSPHERE 13.8 C = 259.4 K = 7.2 F. FREEZING POINT -153.8 C = -119.4 K = -244.8 F. CRITICAL TEMPERATURE 158.4 C = 431.6 K = 317.1 F. CRITICAL PRESSURE 52.7 (atm) = 5.34 MN/rrr = 774 psia. SPECIFIC GRAVITY 0.969 @ - 13 C, liquid. LIQUID SURFACE TENSION 16.0 dynes/cm = 0.0160 N/m @ 25 C. LIQUID WATER INTERFACIAL TENSION 30 est., dynes/cm = 0.03 N/m @ 20 C. VAPOR (GAS) SPECIFIC GRAVITY 2.2. RATIO OF SPECIFIC HEATS OF VAPOR (GAS) 1.186. NAS HAZARD RATING FOR BULK WATER TRANSPORTATION Category Fire Health Vapor Irritant Liquid or Solid Irritant Poisons Water Pollution Human Toxicity Aquatic Toxicity Aesthetic Effect Reactivity Other Chemicals Water Self-Reaction Rating A 2 1 2 0 0 0 2 0 2 Comments Flash point < 100 F (CC); boiling point < 100 F Moderate irritation; temporary effect Causes sldn smarting Intermediate toxicity Nontoxic; LDU > IS g/kg Acute threshold limits > 10,000 ppm No significant pollution; gases and odorless liquids React with material rated 3 or 4 No reaction Will undergo self-reaction if contaminated; does not require stabilizer NFPA HAZARD CLASSIFICATION Category Health Hazard (Blue) Flammability (Red) Reactivity (Yellow) Rating 2 4 1 Comment Materials that on intense or continued exposure could cause temporary incapacitation or possible residual injury unless prompt medical treatment is given Materials that will rapidly or completely vaporize at atmospheric pressure and normal ambient temperature, or that are readily dispersed in air and that will bum readily Materials that in themselves are normally stable, but that can become unstable at elevated temperatures and pressures or that may react with water with some release of energy but not violently MARCH/APRIL 1989 39 VO CO bvo- o o m FEATURES LATENT HEAT OF VAPORIZATION 88 cal/g = 3.7 X 10s J/kg = 160 Btu/lb. HEAT OF COMBUSTION -4520 cal/g = -189.1 x 10s J/kg = -8.136 Btu/lb. HEAT OF POLYMERIZATION -405 cal/g = 16,9 x 10s J/kg - - 729 Btu/lb. HEAT OF FUSION 18.14 cal/g. REID VAPOR PRESSURE 75 psia. EPA CHEMICAL ACTIVITY STATUS REPORT AUTHORITY Safety Drinking Water Act of the Public Health Service Act. TYPE EPA. ACTIVITY RPAR or ANPR: includes all stages of Rebuttable Presumption Against Registration under FIFRA; with any other statutory authority, will reflect an Advance Notice of Proposed Rulemaking. STATUS Completed/published; 03/04/82; 47FR P9350. REASON General health effects; general environ mental effects; environmental levels. EXPOSURE Potential. CONTACT DW/CS/Craig Vogt. AUTHORITY Toxic Substances Control Act. TYPE EPA. ACTIVITY Other; FYI-submission. STATUS Referred to; OTS/ECAD/CSB. REASON General health effects; general environ mental effects. EXPOSURE Potential. CONTACT TS/ECA/Terry O'Bryan. AUTHORITY Consumer Product Safety Act. TYPE Non-EPA. ACTIVITY Other; status tracking. 40 m U STATUS Completed/published; 09/81; repoj available. ' REASON Member ofclass of concern; aerosol prt pellants. EXPOSURE Potential. CONTACT CPSC/DHS/Bill Menza. ` If-. - / rtf INDUSTRY FILE INDEX SUBMISSION NUMBER 87. REGULATING AUTHORITY Clean Water Act. r:; SECTION 301; 304; 306; 307; 501. . REGULATION STATUS Proposed. :3m . cal. -- PRECISION QUANTIFICATION Estimated and empir , -m rVi , MEDIA Surface water. c: TYPE OF TECHNOLOGY Best practical technology, be available technology, pretreatment standards for t> isting sources, pretreatment standards for new source new source performance standards. .sr, a REGULATION TITLE Effluent Limitations and Guid lines for the Paint Formulating Point Source Cat gory. *ii. INDUSTRY CODE AND NAME 44; Pigment Base Indu tr>'CHEMICAL STATUS Implicitly regulated. 10*107 A , dY. DESCRIPTOR Toxic pollutant (CWA) of toxic was (rcra). . - T.'. USE INFORMATION Use code, O; use name, othe use, resin constituent; reference, R189:105. SUBMISSION NUMBER 114. REGULATING AUTHORITY Clean Water Act. SECTION 301; 304; 306; 307; 308; 501. REGULATION STATUS Proposed. PRECISION QUANTIFICATION Empirical. p' vo 2 MEDIA Surface Water. K O ffl DANGEROUS PROPERTIES OF INDUSTRIAL MATERIALS RE* CHEMICAL REVIEW TYPE OF TECHNOLOGY Best practical technolog)', best available technolog)', pretreatment standards for new sources, pretreatment standards for existing sources, new source performance standards. REGULATION TITLE Inorganic Chemicals Manufac turing Point Source Category; Effluent Limitations Guidelines, Pretreatment Standards, and New Source Performance Standards. INDUSTRY CODE AND NAME 26; Inorganic Chemicals. CHEMICAL STATUS None. DESCRIPTOR Toxic pollutant (CWA) of toxic waste (RCRA); not treatable by current methods (48FR49408). USE INFORMATION Unknown. CLINICAL TOXICOLOGY OF COMMERCIAL PRODUCTS PRIMARY TRADE NAME Pliovic. MANUFACTURER'S APPROVED USE Vinyl chloride type resins. USE CODE Chloride/Resins/Vinyl. PRODUCER Goodyear, ACTIVITY OF PRODUCT July 1979. CURRENT STATUS OF PRODUCT Replaced. Ingredient Name Vinyl chloride CAS RN 7S-01-4 Loc # 6570 Amount 9S% SUBMISSION NUMBER 115. TOXICOLOGICAL DATA REGULATING AUTHORITY Clean Water Act. SECTION 301; 304; 306; 307; 501. REGULATION STATUS Proposed. PRECISION QUANTIFICATION Emperical. MEDIA Surface water. TYPE OF TECHNOLOGY Best practical technolog)', best available technolog)', best conventional technolog)', new source performance standards, pretreatment stan dards for existing sources, pretreatment standards for new sources. REGULATION TITLE Organic Chemicals and Plastics and Synthetic Fibers Category Effluent Limitations Guidelines, Pretreatment Standards; and New Source Performance Standards. INDUSTRY CODE AND NAME 38; Organic Chemicals and Plastics; Synthetic Fibers. CHEMICAL STATUS Explicitly regulated. DESCRIPTOR Toxic pollutant (CWA) of toxic waste (RCRA). USE INFORMATION Use code, P; use name, product; reference, R216:I5. MUTAGEN DATA mmo-sat 2000 ppm/48H mma-sat 1 pph mma-esc 10600 ^mol/L dnr-esc 100 p.g/plate sln-dmg-ihl 1 pph mre-sme 48 mmol/L/3H mma-ssp 16 mmol/L/30M cyt-hmn:hla 10 mmol/L otr-rat-ihl 2000 ppm/14W-I dnd-rat-orl 18 gm/kg/2Y-C oms-rai:lvr 1 nmol dnd-rai-ihl 205 ppm/5H dns-rat:lvr 2100 nmol/L dni-rat-ivn 9500 p.gAg cyt-rat-ihl 150 p.g/mVI4W-C hma-rat/sme 1 pph/24H-C mnt-mus-ihi 5 pph/4H otr-nms:emb 75 mg/L hma-mus/ssp 700 mg/kg hma-mus/sme 700 mg/kg mma-ham:ing 20 pph/5H cyt-ham-ilil 12500 ppm/6H cyt-ham-mul 600 mg/kg sce-ham-ihl 12500 ppm/6H msc-hanuovr 10 pph CODEN BBRCA9 63,363,75 CBTOE2 1,159,85 BCPCA6 24.2013.75 MUREAV 54.101.78 MUREAV 57.307.78 MUREAV 40,85,76 MUREAV 40,85,76 TXCYAC 9,21,78 ARTODN 47,71,81 CBINA8 22,211,78 NATUAS 257.134.75 CBINA8 37,219,81 CRNGDP 5,1629.84 CBINA8 17,239,77 GISAAA 43(7), 111,78 . MUREAV 91,381,81 MUREAV 75,191,80 CALEDQ 28.85,85 MUREAV 40,85,76 TOERD9 3,131.81 MUREAV 67.173.79 ARTODN 45,1,80 MUREAV 53.187,78 ARTODN 45,1.80 EVSRBT 25,91,82 MARCH/APRIL 1989 41 06788 O m FEATURES TERATOGENIC DATA ihl-man TCLo:30 mg/m'1 (5Y male) ihl-rat TCLo: 1000 ppni/6H (55D male) ihl-rat TCLo: 1500 ppm/24H (1-9D Preg) ihl-rat TCLo:500 ppm/7H (6-15D preg) ihl-rat TCLo:2500 ppm/7H (6-15D preg) ihl-rat TCLo:250 ppm/6H (55D preg) ihl-mus TCLo:30000 ppm/6H (5D male) ihl-mus TCLo:500 ppm/7H (6- I5D preg) ihl-rbt TCLo:500 ppm/7H (6-15D Prg) CODEN GTPZAB 24(3),28,80 JTKHD6 3,905,77 TXCYAC 11,45,78 EVHPAZ 41.171,81 EVHPAZ 41,171,81 JTEHD6 3,965,77 EVHPAZ 21,71,77 EVHPAZ 41.171,81 EVHPAZ 41,171,81 TUMORIGENIC DATA ihl-man TCLo:200 ppm/14Y-I orl-rat TDLo:3463 mg/kg/52W-I ihl-rat TCLo: 1 ppm/4H/52W-I ihl-rat TCLo: 10000 ppm/4H (12- 18D preg) ipr-rat TDLo:21 mg/kg/65W-I scu-rat TDLo:21 mg/kg/67W-I ihl-mus TCLo:50 ppm/30\V-l ihl-ham TCLo:50 ppm/4H/30W-1 ihl-rat TC :50 ppm/7H/26\V-C ihl-rat TC :100 ppm/7H/26\V-C ihl-mus TC :50 ppm/47\V-I orl-rat TD :34 gm/kg/3Y-l ihl-mus TC :50 ppm/6H/4\V-I ihl-mus TC :50 ppm/4H/30\V-I ihl-rat TC :230 ppm/2Y-I ihl-hmn TC :300 mg/mVW-C ihl-rat TC :5 ppm/4H/52W-1 ihl-rat TC :50 ppm/6H/43VV-I CODEN VAPHDQ 372.195.76 EVHPAZ 41,3,81 EVHPAZ 41,3,81 CSHCAL 4,119,77 APDCDT 3,216,76 APDCDT 3,216,76 ANYAA9 271.431.76 APDCDT 3,216,76 TXAPA9 68.120,83 TXAPA9 68.120,83 JTEHD6 4,15,78 EVHPAZ 21,1,77 JTEJD6 7,909.81 CSHCAL 4,119.77 AANLAW 56.1,74 GTPZAB 26(1),28,82 EVHPAZ 41,3,81 JTEHD6 7.909,81 TOXICITY DATA orl-rat LDSO:500 mg/kg CODEN DOWCC* DATA REFERENCES Classification: Agricultural Chemical, Tumorigen, Mutagen, Teratogen ACG1H TLV-Human Carcinogen ACHGIH TLV-TWA 5 ppnt 1ARC Cancer Review: Human Sufficient Evidence IARC Cancer Review: Animal Stifficent Evidence IARC Cancer Review: Human Limited Evidence CODEN 851 NAS 5,623,86 851 NAS 5,623,86 1MEMDT 19,377,79 IMEMDT 7,291,74 IMEMDT 7,291,74 IARC Cancer Review: Animal IMEMDT 19,377 Sufficient Evidence IARC Cancer Review: Group 1 T oxicology Review Toxicology Review Toxicology Review IMSUDL 4.260,8. F.AZMAE 18,365. JTEHD6 1(1).47. CMTVAS 10(3),49.73 Toxicology Review Toxicology Review CHWEAP 70,5.7 CANCAR 39.1792.77 Toxicology Review MUREAV 32(2).93,76 Toxicology Review ZHPMAT 166.113.78 Toxicology Review BNYMAM 54.413.78 Toxicology Review ABMHAM 35,585,77 Toxicology Review Toxicology Review CBINA8 22,117. GTPZAB 20(4),46,76 Toxicology Review Toxicology Review VHTODE 22,31. MUREAV 41,131,76 DOT-Hazard: Flammable Gas; Label: Flammable Gas MSHA Standard-air:TWA 200 CFRGBR 49,172.101.86 DTLWS* 3.31,7; ppm (510 mg/m3) OSHA STANDARD-Air: TWA 1 FEREAC ppm; CL 5 ppm/I5M 40,23073,75 OSHA-Cancer Suspect Agent CFRGBR 29,1910.1017.8 NIOSH REL to Vinyl Chloride- MMWR** Air: Lowest Delectable Level 34(IS),30S,85 EPA Gcnelox Program 1986, Positive: Carcinogenicity-Mouse/ Rat EPA Genetox Program 1986, Positive: In vivo Cytogenetics- Human Lymphocyte; . colt polA with S9 EPA Genetox Program 1986, Positive: Histidine Reversion- Ames Test EPA Genetox Program 1986, Positive: D. melanogasler Sex- Linked Lethal EPA Genetox Program 1986, Positive: S. cerevisiae Gene Conversion; S. Pombe-Forward Mutation EPA Genetox Program 1986, Negative: D. melnnngasta- Reciprocal Translocation EPA Genetox Program 1986, Negative: Rodent Dominant Lethal; Mouse Spot Test EPA Genetox Program 1986, Negative: S. r/>reviswe- homozygosis BOR 006789 42 DANGEROUS PROPERTIES OF INDUSTRIAL MATERIALS RL CHEMICAL REVIEW EPA TSCA Chemical Inventory, 1980 EPA TSCA Sc 'n 8(e) Stains Report SEC 0300345;8EHQ- 32-0457;," LHQ0378-0104 EPA TSCA Section 8(e) Status Report 8EHQ-0986-0629 EPA TSCA Test Submission (TSCAT5) Database, June 1987 NIOSH Current Intelligence Bulletin 28. 1978 NIOSH Analytical Methods; see Vinyl Chloride, 1007 N'TP Fourth Annual Report on Carcinogens, 1984 Meets Criteria for Proposed OSHA Medical Records Rule FEREAC 47,30420,82 FEDERAL REGISTER CITATIONS CITATION NUMBER 47.169.549 (4~FR38462fF, 8-3182) PROPOSED RULE Revision of 40CFR4I3, add 40CFR433, Environmental Protection Agency, Clean Water Act; electroplating and metal finishing point source category; effluent limitation guideline, pretreatment standard. New Stationary Source Perform ance Standard; comments solicited by 11-1-82. CITATION NUMBER 47.173.4 (47FR39168, 9-7-82) FINAL RULE Revision of 40CFR61, Environmental Protection Agency, Clean Air Act; Revision of Test Methods, Quality Assurance Procedures; National Emission Standard For Hazardous Air Pollutants; ef fective date 9-7-82. (45FR26682, 45FR76346, 46FR1318) CITATION NUMBER 47.174.4 (47FR39485, 9-8-82) FINAL RULE Revision of 40CFR61, Environmental Protection Agency, Clean Air Act; revision of Test Method 107A; effective date 9-8-82. (46FR12188) CITATION NUMBER 47.190.249 (47FR43055fF, 930;82) NOTICE OF DELEGATION Revision of 40CFR60.4, 61.04, Environmental Protection Agency, Clean Air Act; New Source Performance Standards and Na tional Emission Standard for Hazardous Air Pollu tants, California. .Arizona, Nevada and Guam; effective date 9-27-82. CITATION NUMBER 48.102.783 (4SFR23552ff, 5-25- 83) PROPOSED RULE Add 40CFR302, Environmental Protection Agency, Comp. Env. Response, Compen sation, and Liability Act; Hazardous Substances, Re portable Quantities; comments solicited by 7-25-83; Resource Conservation and Recovery Act Hazardous Waste No. U043. NOTICE P88-1245, Mitsubishi Chemical for sub stituted vinyl chloride as automobile equipment; source: 53, 102, page 19031, May 26, 1988 NOTICE Civil Action No. 85-C-l 193G, re asbestos emission violations (90-5-2-1-784), in U.S. vs Georgia Pacific Corp, 84-457-B & 85-136-B, requiring NESHAP compliance for vinyl chloride emissions from Plaquemine, LA facilities (90-5-2-1-657), p. 47290. Source: 50, 221, page 47289, November 15, 1985. NOTICE Dainichiseika Color & Chemicals Amer ica, P87-674, substituted vinyl chloride/ethylene pol ymer as paper saturant. Source: 52, 44, page 7019, March 6, 1987. NOTICE EPA receives TSCA premanufacture notices with a comment deadline of June 21, 1984: PMN84-633, BASF System Corp, polymer of vinyl chloride, dimethyl esters as site limited consumer binder in magnetic media coating. Source: 49, 88, page 19110, May 4, 1984. NOTICE EPA delegates authority to Georgia Dept, of Natural Resources' Environmental Protection Di vision to implement NSPS for ferroalloy production facilities and NESHAPS for vinyl chloride. Effective Dec 22, 1977. Source: 42, 246, page 64145, December 22, 1977. PROPOSED 40 CFR Part 61, EPA extends com ment deadline until Aug. 19, 1977 on proposed na tional emission standards for vinyl chloride, published in FR ofJune 2 1977 (42 FR 28154). Makes reference to The Society of Plastics Industry Inc request for extension of comment period. Source: 42, 154, page 40452, August 10, 1977. MEETING EPA and Society of Plastics Industry Inc will meet July 19 at the Society's request to discuss amendments to Natl Emission Standard for vinyl chloride as proposed in Clean Air Act Amendments of 1977. Meeting begins at 10 am. Crystal Mall, Bldg 2, Rm 1112, 1921 Jefferson Davis Hwy, Arlington, VA, 22202; Doc. No. FRL 755-3. Source; 42, 129, page 34532, July 6, 1977. RULE 40 CFR Part 61, EPA corrects typograph ical errors and provides for clarification in certain parts with respect to the vinyl chloride standards; ef- ?`-ARCH'APRIL 19S9 43 BOR 0 0 6 7 9 0 ( i FEATURES fective June 7, 1977. Source: 42, 109, page 29005, June 7, 1977. PROPOSED 40 CFR Pari 61, EPA proposes Na tional Emission Standards for ethylene dichloride, vi nyl chloride and polyvinyl chloride plants. Makes reference to court case involving the Environmental Defense Fund and Society of the Plastics Industry, Inc., Goodyear Tire, Air Products & Chemicals, Inc. EPA proposes amendments which would require sources presently subject to a 10 ppm emission limit to reduce emissions to 5 ppm within 3 years. Amend ments would require more efficient use of existing control technology at existing plants without banning vinyl chloride; describes the more stringent standards for new sources p. 28155; text of regulation p. 28157; comment deadline Aug. 1, 1977. Source: 42, 106, page 28154, June 2, 1977. REFERENCES R-l. Lewis, Richard J., et al., (Ed.). Oct 1980. Registry of Toxic Effects of Chemical Substances (RTECS). Microf iche Edition. DHHS (NIOSH). Publ. No. 8M16-1. R-2. Drevon, C., et al. June 1979. Mutagenicity of vinyl chloride, vinylidiene chloride and chloroprene in V79 Chinese hamster cells. Mut Res 67:173-182. R-3. Fleig, I., et al. April 1978. External chromosome studies undertaken on persons and animals with vinyl chloride illness. Mut Res 53:187. R-4. Agrelo, C. 1978. The effect of carcinogens on the nuclear size of HeLa cells. Toxicol 9:21-27. R-5. Connelly, R.B., et al. 1977. Acute hepatotoxicity of ethylene, vinyl fluoride, vinyl chloride, and vinyl bromide after Aroclor 1254 pretreatment. Toxicol Applied Pharmacol R-6. Verschueren, K. 1977. Handbook of Environmental Data on Organic Chemicals. Van Nostrand Reinhold Co., NY. R-7. Hawley, G.G. 1977. The Condensed Chemical Diction ary, 9th ed. Van Nostrand Reinhold Co., NY. R-8. Key, M. and A. Henschel, et al. (Eds.). June 1977. Occupational Diseases; A Guide to Their Recognition. L'.S. Department of Health, Education and Wel fare. Public Health Service. CDC, NIOSH. DHEW/ NIOSH Publ. No. 77-181. R-9. Sax, N.I. 1988. Dangerous Properties of Industrial Ma terialIs, 7th ed. Van Nostrand Rcinhold Co., NY. R-10. U.S. Dept, of Transportation. Oct. 1978. Chemical Hazard Response Information System (CHRIS). US Coast Guard. Washington, DC. R-l 1. US EPA. Oct 1980. Ambient Water Quality Criteria for Vinyl Chloride. NTIS. Springfield, VA. EPA 440/580-078. R-12. Viola, P. 1970. Pathology of Vinyl Chloride. Medica del Lav 61:174. From CAS:72:85988. R-l3. Barbin, A. Aug 1975. Liver-microsome-mediated formation of alkylating agents from vinyl bromide and vinyl chloride. Biochein Biophys Res Comm 63(2):363-370. R-14. NIOSH. Dec. 1974. Current intelligence bulletin. J Occup Med 16:809. R-15. John, J.A., et al. 1977. The effects of maternally 44 inhaled vinyl chloride on embryonal and fetal de velopment in mice, rats, and rabbits. Toxicol Applied Pharmacol 39:497. R-l6. Suzuki, Y. 1978. Pulmonary tumors induced in mice by vinyl chloride monomer. Env Res 16:285. R-I7. Vazin, AN., et al. 1968. Pathogenic effect of chronic exposure to vinyl chloride or rabbits. Medica del Lavora 31:369-372. From CAS:69:50599. R-18. Vazin, A.N., et al. 1969. Changes in cardiac activity of rats chronically exposed to vinyl chloride vapors. Medica del Lavora 32:220-222. From CAS:70:113464. R-l9. Maltoni, C. 1977. Recent findings on the carcino genicity of chlorinated olefins. Env Health Perspect 21:1-6. R-20. Loprieno, N. 1976. Evaluation ofthe genetic effects induced by vinyl chloride monomer (VCM) under mammalian metabolic activation: Studies in vitro and in vivo. Mut Res 40:85. R-21. Speck, W., et al. 1978. An evaluation of the pro phage induction (inductest) for the detection of po tential carcinogens. Mut Res 54:101-103. R-22. Bartsch, H.,etal. 1975. Human, rat and mouse liver mediated mutagenicity of vinyl chloride in Salmo nella typhimurium strains, lntemat'l J Cancer 15:429. R-23. Feron, V.J., et al. 1979. One year time sequence inhalation toxicity study of vinyl chloride in rats. Toxicol 13:25-28. R-24. Schaffner, F. 1978. Effect of long-term "vinyl chlo ride exposure in mouse liver structures. Falk Symp 25:189-199. R-25. Guengerich, F., et al. 1979. Metabolism of MC- and '"Cl-labeled vinyl chloride in vivo and in vitro. Biochem Pharmacol 28:589-596. R-26. Ungvary, G.Y., et al. 1978. Effects of VC exposure alone and in combination with trypan blue --ap plied systematically during all thirds of pregnancy. Toxicol 11:45-54. R-27. Magnusson, J., et al. 1978. Mutagenic effects of vi nyl chloride on Drosophiha melanogaster with and without pretreatment with sodium phenobarbiturate. Mut Res 57:307-312. R-28. State of California. Dec. 1977. Standard for Vinyl BOR 006791 DANGEROUS PROPERTIES OF INDUSTRIAL MATERIALS REPORT CHEMICAL REVIEW Chloride. Air Resources Board. R-29. Hopkins, J. Aug. 1979. Articles of general interest: vinyl chloride: Metabolism. Food Cosmet Toxicol 17:403. R-30. Feron, V.J., el al. June 1979. One year time se quence inhalation toxicity study of vinyl chloride in rats. III. Morphological changes in the liver. Toxicol 13:143-154. R-31. Feron, V.J., and R. Kroes. June 1979. One year time-sequence inhalation toxicity study of vinyl chloride in rats: Morphological changes in the res piratory tract, ceruminous glands, brain, kidney, heart and spleen. Toxicol 13:131. R-32. Pessayre, D., et al. 1979. Formation and inactivation ofa chemically reactive metabolite ofvinyl chloride. Toxicol Applied Pharmacol 49:505-515. R-33. Mueller, C., el al. 1978. In vivo trapping of a vinyl chloride metabolite by means of S,4-di-chlorobenzenethiol. Int Arch Occup Env Health 42:137. R-34. Ibrahim, F. 1978. Effect of vinyl chloride on me tabolites of germinated seeds. Dissertation Abstr 3282, vol. 39. R-35. Anderson, H.A., el al. 1978. Levels of CEA among vinyl chloride and poly(vinyl chloride) exposed workers. Cancer 42:1560-1567. R-36. Hollo, A-, et al. 1978. Gas chromatographic deter minations of vinyl chloride levels in the blood of treated laboratory animals and the effect of VCM on different toxicological parameters. Proc Hungar ian Ann Mtg for Biochem 18:97-98. From CAS:90:17202. R-37. Watanabe, P.G., et al. 1978. Comparison of the fate of vinyl chloride following single and repeated ex posure in rats. Toxicol Applied Pharmacol 44(2):391399. R-38. Maly, E. 1978. On the reaction of vinyl chloride with DNA. Internal7 Congress Series --Excerpta Medtca 440:270-273. R-39. Bolt, H., and J.G. Filser. 1977. Irreversible binding of chlorinated ethylenes to macromolecules. Env Health Perspect 21:107-112. R-40. Radike, M., et al. 1977. Effect of ethanol and vinyl chloride on the induction of liver tumors: prelim inary report. Env Health Perspect 21:153-155. R-41. Lee, C.C., et al. 1977. Inhalation toxicity of vinyl chloride and vinylidene chloride. Env Health Per spect 21:25-32. R-42. Radwan, Z., and D. Henschler. 1977. Uptake and rate of metabolism of vinyl chloride by the isolated perfused rat liver preparation. Internal! Arch Occup Env Health 40(2):101-110. R-43. Lee, F.I., et al. 1977. Screening for liver disease in vinyl chloride workers. BrJ Indus Med 34(2): 142:147. R-44. Maricq, H.R., et al. 1976. In vivo skin capillary ab normalities in vinyl chloride workers. Microcircula tion [Proc World Congress}, 1st, 1975 2:235-237. R-45. Wisniewska, J., et al. 1980. Mono-oxygenase activity and ultrastructural changes of liver in the course of chronic exposure of rats to vinyl chloride. Inter- nat'l Arch Occup Env Health 46(3):241-249. R-46. Buchter, A., et at. 1980. Pharmacokinetics of vinyl chloride in the Rhesus monkey. Toxicol Letters 6(1):33--36. R-47. NIH-EPA. 1981. Chemical Information System. OHMTADS database. Version 14.5/3.0. R-48. Sokal, J.A., et al. 1980. Experimental studies on the chronic toxic effects of vinyl chloride in rats.J Hyg, Epidem Microbio Immunol 24:285-294. R-49. Basler, A., and G. Rohrborn. 1980. Vinyl chloride: An example for evaluating mutagenic effects in mammals in vivo after exposure to inhalation. Arch. Toxicol. 45:1-7. R-50. Sharma, R.P. 1979. Immunologic effects of vinyl chloride in mice. Annals NY Acad Sciences 320:551563. R-51. Ivanetisch, K., et al. 1977. The interaction of vinyl chloride with rat hepatic microsomal cytochrome P450 in vitro. Biochem Biophys Res Commun 74:14111418. R-52. Jaeger, R., et al. 1976. Vinyl chloride hepatotoxicity and its alteration by modifiers of hepatic biotrans formation in the rat. Proc European Soc Toxicol 17:301-308. R-53. Reynolds, E.S.,etal. 1976. Modulation ofhalothane and vinyl chloride induced acute injury to liver en doplasmic reticulum. Panminerva Medico 18:367-374. R-54. Mueller, G., et al. 1976. Identification of two urine metabolites of vinyl chloride by GC-MS-investigations. Intemat'l Arch Occup Env Health 38:69-75. R-55. Anderson, D.,etal. 1976. Vinyl chloride: Dominant lethal studies in male CD-I mice. Mut Res 40:359370. R-56. Sandor, P., and G. Ungvary. 1980. Lack of muta genic effect of vinyl chloride monomer in the mam malian spot test. Mut Res 77:193-196. R-57. Vaino, Harri. 1978. Vinyl chloride and vinyl ben zene (styrene): Metabolism, mutagenicity and car cinogenicity. Chemico-Biological Interactions 22:117124. R-58. Bartsch, H., et al. 1979. Mutagenic and alkylating metabolites of halo-ethylenes, chlorobutadicnes and dichlorobutenes produced by rodent or human liver tissues. Arch Toxicol 41:249-277. R-59. deMeester, C., et al. 1980. Mutagenicity of vinyl chloride in the Ames test, possible artifacts related to experimental conditions. Mut Res 77:175--179. R-60. Bartsch, H., etal. 1975. Mutagenic and carcinogenic effects of vinyl chloride. Mut. Res. 32:93--114. R-61. Maltoni, C. 1976. Vinyl chloride pathology. Med Biologic Env 4:267-278. R-62. Maltoni, C. 1976. Predictive value of carcinogenesis bioassays. Annals NY Acad Sci 271:431-443. R-G3. 1ARC. 1979. IARC Monograph Series. Evaluation of the Carcinogenic Risk of Chemicals to Man, vol. 19. WHO Publ. Centre, USA. Albany, NY. R-64. Jenssen, D.A.G., and C. Ramel. 1980. The micronuclcus test as part of a short-term mutagenicity test program for the prediction of carcinogenicity eval- MARCH-APRIL 1989 <15 BOR 0 0 t FEATURES uated b\ 143 agents tested. Mut Res 75:191-202. R-65. Malioni, Cesare. 1977. Recent findings on the car cinogenicity of chlorinated olefins. Env Health Peripert 21:1-5. K-6G. Kucerova, M., el al. 1979. Mutagenic and carcino genic effects of vinyl chloride. Prac Lett 31(6-7):249252. (Czech). From CAS:94:25980y. R-67. Brown, E., and T. Sinclair. 1977. Chemical pollu tants in relation to diseases in fish. Ann NY Acad Sci 298:535-546. R-68. Pessayre, D., et al. 1980. Cumulative effects of re peated doses of compounds transformed into re active metabolites. Biochem Pharmacol 29:1041-1047. R-69. Taylor, D.G. 1977, NIOSH Mannual of Analytical Methods, 2nd ed. 1(1): 178. DHEW. R-70. Kent.J.A. 1974. Riegel's Handbook of Industrial Chem istry, 7th ed. Van Nostrand Reinhold Co, NY. R-71. Dean, John, (Ed.). 1979. Lange's Handbook of Chem istry, 12th ed. McGraw-Hill Book Co, NY. R-72. Callahan, Michael A., et al. Dec. 1979. Water-Related Environmental fate of 129 Priority Pollutants, section V, chapter 49. EPA-440/4-79-029b. R-73. 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