Document e5kkoB7YN1OJr9E2d7nmL9mGm

HEXACHLOROBUTADIENE CAS: 87-68-3 HCBD; Hexachloro-1,3-butadiene C4CI6 Cl2C=CCI-CCI=CCl2 Skin TLV-TWA, 0.02 ppm (0.21 mg/m3) A2 - Suspected Human Carcinogen 1980: TLV-TWA, 0.02 ppm, A2 Carcinogen, proposed 1982-present: TLV-TWA, 0.02 ppm, A2 Carcinogen 1984-present: Skin notation 1992: Documentation revised Chemical and Physical Properties Hexachlorobutadiene (HCBD) is a heavy, clear liq uid. Chemical and physical properties include:01 Molecular weight: 260.76 Melting point: -21C Boiling point: 212C Solubility: insoluble in water; soluble in alcohol and diethyl ether Major Uses or Sources of Occupational Exposure Although HCBD has been employed as a pesticide with limited applications, it is primarily encountered as a by-product of certain processes associated with the chlorination of hydrocarbons. It is used as a solvent for elastomers, heat transfer liquid, transformer and hydrau lic fluid, and a wash liquor for removing C* and higher hydrocarbons.01 Animal Studies Acute The acute oral toxicity of HCBD is rated by various investigators as moderate to high; LD values have been reported as 90 mg/kg for guinea pigs; 87-116 mg/kg for mice;13'41 and 200-350 mg/kg for rats.41 The lethality of HCBD following single, oral doses indicated that young rats are more sensitive than adults. The LD50 in 21-dayold male and female mice was 64 and 46 mg/kg, respec tively. Some deaths were delayed as long as 17 days after dosing, but the majority of these mice died on the second or third day post-treatment. The material is absorbed through the skin of rabbits according to Kociba et al.(5) The dosages causing death by dermal absorption are in the same range as by oral administration. The mortality following single exposures to HCBD vapors has been described. Some or all of the rats exposed for 4 to 7 hours at 133 to 500 ppm died. All rats survived 161 ppm for 0.88 hour or 34 ppm for 3.3 hours. Most guinea pigs and cats died subsequent to inhalation of 161 ppm for 0.88 hours or 34 ppm for 7.5 hours. Subchronic Gage described short-term repeated inhalation studies of HCBD using groups of four male and four female rats and summarized the findings as follows: 250 ppm: 2 x 4-hour exposures -- ocular and upper respiratory tract irritation; respiratory difficulty, females affected more than males, apparent recovery after exposure; histopathologic study showed degeneration of the middle renal proximal tubules and of the adrenal cortex. 100 ppm: 12 x 6-hour exposures -- ocular and upper respiratory tract irritation; respiratory difficulty; poor condition; weight loss; slight anemia in females; urine tests normal, two females died; gross inspection showed kidneys pale and enlarged, adrenals en larged; degeneration of renal cortical tubules with epithelial regeneration were documented with his topathologic study. 25 ppm: 15 x 6-hour exposures -- poor condition; diminished weight gain in females; respiratory diffi culty; blopd and urine tests normal; at gross necropsy, the kidneys were pale and enlarged; microscopic evaluation revealed damage to the renal proximal tubules. 10 ppm: 15 x 6-hour exposures -- retarded weight gain in females; at gross autopsy, all of the organs examined were reported to be normal. 5 ppm: 15 x 6-hour exposures -- no signs of toxicity, and upon gross inspection of these rats, all of the organs were reported to be normal. Gulko et al.(4> reported that repeated inhalation expo sure at 24 mg HCBD/m3 (about 2.3 ppm) for 7 months caused no alterations in mice or rats. The duration and frequency of the repeated exposures were not stated. No deleterious effects were reported by Schwetz et al. in adult Japanese quail maintained for 90 days on diets containing up to 30 ppm HCBD by weight (about 5 mg/kg/day). Feeding HCBD in the diet of rats at daily doses ranging from 1 to 100 mg/kg for 30 days was reported to increase the kidney-to-body weight ratio and induce renal tubular degeneration, necrosis, and-regenerative hyper plasia in the rats fed 30, 65, or 100 mg HCBD/kg/day. Other adverse effects observed included decreased food consumption and body weight gain at 10,30,65, and 100 mg/kg/day; minimal hepatocellular swelling at 100 mg/kg/day; and hemoconcentrations at 10, 30, 65, and 100 mg/kg/day. No adverse effects were observed among those receiving 3 mg/kg/day. The kidney was the organ most sensitive to the deleterious effects of HCBD. DO 073656 736 CONFIDFNTTAl Chronic/Cardnogenidty Detailed data on the results of the lifetime dietary study of HCBD in rats are available in a report by Kociba et al.'8' Kodba et al. have summarized these data as follows:'5' Lifetime ingestion of the highest dose level of 20 mg/kg-day of HCBD caused multiple toxi cologic effects. This included increased mortality (males), decreased body weight gain (males and females), increased urinary excretion of coproporphyrin (males and females), and increased terminal weights of kidneys (males and females). Pathologic examinations revealed changes in the kidneys, including hyperplasia and neoplasia of renal tubular epithelium. Some of the neo plasms were noted grossly as nodules in the kidneys. These nodules in the kidneys were microscopically diagnosed as renal tubular ade nomas or adenocarcinomas, some of which me tastasized to the lungs. Approximately 23% of the males and 25% of the females from the 20 mg/kg/day dose level had renal tubular neo plasms. At the intermediate dose level of 2.0 mg/kgday of HCBD, findings considered related to treatment were limited to an increased urinary excretion of coproporphyrin (females only) and increased hyperplasia of renal tubular epithe lium. This intermediate dose level of 2 mg/kg-day of HCBD caused no neoplasms considered re lated to treatment. Lifetime ingestion of the low est dose level of 0.2 mg/kg-day of HCBD caused no discernible ill effects in any of the parameters monitored in this study.'5' Kociba and associates'5' concluded that '... these data indicate a clear-cut dose-response relationship for HCBD-induced toxicity affecting primarily the kidney. HCBD-induced renal neoplasms occurred only at a dose level higher than that causing discernible renal injury." Reproductive/Developmental Kodba'5' reviewed the reproductive and develop mental toxidty studies carried out by Schwetz et al.(9) as follows: Adult male and female rats ingesting the high dose level of 20 mg/kg-day of HCBD showed multiple toxicological effects, induding de creases in food consumption and body weight gain. Terminal kidney weights of these males and females were increased, as were the liver weights of the males. Pathologic examination revealed renal tubular epithelial degeneration and regeneration in both males and females ingesting 20 mg/kg-day of HCBD. Adult rats ingesting the intermediate dose level of 2 mg/kg- day of HCBD were comparable to controls ex cept for a much lower inddence of the renal tubular histopathologic changes noted at the high dose level. Adult rats ingesting 0.2 mg/kgday of HCBD had no observations considered related to treatment. The ingestion of 20, 2, or 0.2 mg/kg-day of HCBD had no effect on the percent pregnancy, gestated survival, neonatal survival, neonatal sex ratio or morphologic alterations in neonates. Neonatal body weights were unaffected except for a decreased body weight on day 21 for the neonates of the high dose level, 20 mg/kg-day of HCBD. TLV Recommendation Based on a no-effect level of 0.2 mg/kg/day after continuous ingestion of HCBD by rats for 2 years, a TLV-TWA of 0.02 ppm is recommended. At this time, no STEL is recommended until additional toxicological data and industrial hygiene experience become available to provide a better base for quantifying on a toxicological basis what the STEL should be. The reader is encour aged to review the section on Excursion Limits in the "Introduction to the Chemical Substances" of the current TLV/BEI Booklet for guidance and control of excursions above the TLV-TWA, even when the 8-hour TWA is within the recommended limits. Since Kociba et al.<5> reported that HCBD is absorbed through rabbit skin in amounts comparable to those absorbed following oral administration, this substance merits the skin notation. Since a significant carcinogenic response resulted from ingestion of less than 50 mg/kg/day,'7' HCBD can be considered a rodent carcinogen of intermediate po tency, Accordingly, HCBD has been given the A2 desig nation, suspected human carcinogen. Other Recommendations OSHA PEL: OSHA established a PEL-TWA of 0.02 ppm for HCBD (with no skin notation). OSHA concluded that the PEL would protect workers exposed to this substance from the significant risks of kidney damage; eye, skin, and pulmonary irritation; and renal neo plasms.'10' NIOSH REUIDLH. NIOSH [Ex 8-47, Table N6A] established a REL-TWA of 0.02 ppm with a skin notation by concurrence with the original OSHA proposed PEL and recommended that OSHA consider HCBD as a potential occupational carcinogen.'10' NIOSH has not es tablished an IDLH value for this substance. ACGIH Rationale for TLVs that Differ from the PEL orREL: The TLV, PEL, and REL values are identical save for the skin designation. Although no quantitative data are cited, Kociba et al.(5> reported that HCBD is absorbed in toxicologically significant amounts through the skin of OO 073657 CONFIDENTIAL 737 rabbits. Based on the low TLV, even small quantities of HCBD absorbed through the skin would contribute sig nificantly to the body burden. The fact that HCBD is currently classified as A2 (suspected human carcinogen) also merits attention. Based on the above, ACGIH be lieves HCBD merits a skin notation. NTP Studies: NTP has conducted a prechronic feed ing study in mice at 0,1,3,10,30, or 100 ppm of HCBD. A July 1992 NTP status report on this study does not indicate a carcinogen designation at this time. This sub stance has also been selected for study by inhalation. Chemical disposition and pharmacokinetic studies have been completed by NTP. The chemical was negative in the Salmonella assay, the Drosophila test for sex-linked recessive lethal mutations, and for the induction of chro mosomal aberrations in cultured Chinese hamster ovary (CHO) cells. HCBD was positive for the induction of sister-chromatid exchanges in the CHO assay and was tested in the mouse lymphoma assay. Carcinogenic Classification IARC: Group 3, not classifiable as to its carcinogenicity to humans. MAK: Group B, justifiably suspected of having carcino genic potential. NIOSH: Carcinogen, with no further categorization. TLV: A2, suspected human carcinogen. Other Nations Australia: 0.02 ppm, skin, Category 3, suspected of having carcinogenic potential (1990); Federal Republic of Germany: no MAK, skin, Group B, justifiably suspected of having carcinogenic potential (1991). References 1. Sax, N.I.; Lewis, Sr., RJ.: Hawley's Condensed Chemical Dictionary, 11th ed., p. 596. Van Nostrand Reinhold Co., New York (1987). 2. Murzakaev, F.G.: Toxicity Data for Hexachlorobutadiene and Its Intermediate. Fannakol. Toksikol 26:750 (1963); Chem. Abstr. 60:13776b (1964). 3. Gehring, PJ.; MacDougall, D.: Review of the Toxicity of Hexachlorobenzene and Hexachlorobutadiene. Toxicology Research Labora tory, Dow Chemical Company, Midland. Ml (1971). 4. Gulko, A.G.; Zimina, N.I.; Shroit, I.G.: Toxicological Study of the insecticide Hexachlorobutadiene. Vopr. Gig. SaniL Ozdorovt Vneshn. Sredy. Kishinev. Sb. 128 (1964); Chem. Abstr. 62:13753c (1965). 5. Kodba, RJ.; Schwetz, B.A.; Keyes, D.G.; et a!.: Chronic Toxicity and Reproduction Studies of Hexachlorobutadiene in Rats. Environ. Health PerspecL 21:49-53 (1977). 6. Gage, J.C.: The Subacute Inhalation Toxicity of 109 Industrial Chemi cals. Br. J. Ind. Med. 27:1-16(1970). 7. Schwetz, B.A.; Norris, J.M.; Kodba, RJ.; et al.: Reproduction Study ofJapanese Quail Fed Hexachlorobutadiene for 90 Days. Toxicol. Appl. Pharmacol. 30255-265 (1974). 8. Kodba, R.J.; Keyes, D.G.; Jersey, G.C.: et al.: Results of a Two-year Chronic Toxidty Study with Hexachlorobutadiene in Rats. Am. Ind. Hyg. Assoc. J. 38:589-602 (1977). 9. Schwetz. B.A.; Smith, FA; Humiston, C.G.; et al.: Results of a Reproduction Study in Rats Fed Diets Containing Hexachlorobutadi ene. Toxicol. Appl. Pharmacol. 42:387-398 (1977). 10. U.S. Department of Labor, Occupational Safety and Health Admini stration: 29 CFR Part 1910, Air Contaminants; Final Rule. Fed. Reg. 54(12)2489-2490 (January 19,1989). DO 073658 CONFIDENTIAL 738