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VINYLIDENE CHLORIDE

BACKGROUND INFORMATION

PHYSICAL AND CHEMICAL PROPERTIES

Chemical formula:

CH2=CCl2

Molecular weight:

96.96

Chemical names:

1,1-Dichloroethylene, dichloroacetylene, 1,1-dichloroethane

Synonym:

VDC

Boiling point:

37°C

Flash point:

−10°C

Saturated vapor pressure:

591 torr (20°C)

Solubility:

Sparingly soluble in water; soluble in most organic solvents

General characteristics:

Volatile, colorless liquid that polymerizes readily; mild sweet odor

Conversion factors:

1 ppm=3.97 mg/m3

1 mg/m3 =0.25 ppm

OCCURRENCE AND USE

Vinylidene chloride (VDC) is prepared from ethylene chloride or by passing trichloroethylene over any of several alkaline materials at a temperature above 70°C. It is an intermediate in production of Saran and Velon polymeric plastics for films and coatings. At high concentrations, it may decompose explosively to form CO and phosgene (Stecher et al., 1968). VDC has been reported to be a contaminant of space vehicles and submarines (Saunders, 1967).

SUMMARY OF TOXICITY INFORMATION

EFFECTS ON HUMANS

An uncontrolled 4-d exposure to VDC and many other compounds at a low (but variable and unknown) concentration occurred in a NASA-sponsored Manned Environmental Systems Assessment project involving a five-man crew. Signs and symptoms included loss of appetite, extreme nausea, vomiting, facial-muscle symptoms, and headache. Herpes-like lesions developed on the faces of all participants shortly after the 4-d exposure (Saunders, 1967).

An epidemiologic survey of 138 workers industrially exposed to VDC at 5–70 ppm (TWA) for periods of less than 1 yr and up to over 10 yr revealed no substantial adverse health effects related to exposure (Ott et al., 1976).



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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 VINYLIDENE CHLORIDE BACKGROUND INFORMATION PHYSICAL AND CHEMICAL PROPERTIES Chemical formula: CH2=CCl2 Molecular weight: 96.96 Chemical names: 1,1-Dichloroethylene, dichloroacetylene, 1,1-dichloroethane Synonym: VDC Boiling point: 37°C Flash point: −10°C Saturated vapor pressure: 591 torr (20°C) Solubility: Sparingly soluble in water; soluble in most organic solvents General characteristics: Volatile, colorless liquid that polymerizes readily; mild sweet odor Conversion factors: 1 ppm=3.97 mg/m3 1 mg/m3 =0.25 ppm OCCURRENCE AND USE Vinylidene chloride (VDC) is prepared from ethylene chloride or by passing trichloroethylene over any of several alkaline materials at a temperature above 70°C. It is an intermediate in production of Saran and Velon polymeric plastics for films and coatings. At high concentrations, it may decompose explosively to form CO and phosgene (Stecher et al., 1968). VDC has been reported to be a contaminant of space vehicles and submarines (Saunders, 1967). SUMMARY OF TOXICITY INFORMATION EFFECTS ON HUMANS An uncontrolled 4-d exposure to VDC and many other compounds at a low (but variable and unknown) concentration occurred in a NASA-sponsored Manned Environmental Systems Assessment project involving a five-man crew. Signs and symptoms included loss of appetite, extreme nausea, vomiting, facial-muscle symptoms, and headache. Herpes-like lesions developed on the faces of all participants shortly after the 4-d exposure (Saunders, 1967). An epidemiologic survey of 138 workers industrially exposed to VDC at 5–70 ppm (TWA) for periods of less than 1 yr and up to over 10 yr revealed no substantial adverse health effects related to exposure (Ott et al., 1976).

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 EFFECTS ON ANIMALS LT50s for rats were determined for VDC by Andersen et al. (1979): Concentration, ppm Time, h 100 8.0 200 4.1 500 3.0 1,000 2.4 2,000 1.4 Inhalation of VDC by the rat can result in irritation of the eyes and nose, excessive salivation, respiratory distress, tremors, convulsions, incoordination, prostration, narcosis, and death due to vascular collapse and shock (Carpenter et al., 1949; Jaeger et al., 1973). Exposure to VDC at 200 ppm in air for 4 h produced severe liver damage in rats (Carpenter et al., 1949). Mild liver damage resulted from a 23-h exposure at 60 ppm (Short et al., 1977). Mice exposed at 50 ppm showed progressive renal necrosis in the first 24 h (Reitz et al., 1979); severe tubular necrosis has been reported in mice exposed at 15 ppm for 23 h (Short et al., 1977). Dogs, rats, guinea pigs, rabbits, and monkeys exposed to VDC by inhalation at 99 ppm, 8 h/d, 5 d/wk for 6 wk showed no mortality or evidence of toxicity. However, in continuous exposure at 15 ppm, deaths occurred in 7 of 15 guinea pigs (between days 4 and 9) and 3 of 9 monkeys (days 26, 60, and 64) (Prendergast et al., 1967). Liver damage and kidney damage were seen in most of the animals exposed continuously at 189 mg/m3. Nonspecific lung damage was also seen in most animals (Prendergast et al., 1967). VDC caused epinephrine-induced arrhythmias in rats. Epinephrine in doses as low as 0.5 μg/kg produced a series of premature ventricular contractions in rats exposed to VDC at about 25,000 ppm for 47 min. The cardiac effects were completely reversible on discontinuation of VDC inhalation. Pretreatment of the animals with phenobarbital increased the cardiac effects; that suggests they were due to a metabolite of VDC, in that phenobarbital induces microsomal enzymes (Siletchnik and Carlson, 1974). Rampy et al. (1977) published an interim report of a 2-yr study on VDC toxicity. Sprague Dawley rats that inhaled VDC at 25 or 75 ppm, 6 h/d, 5 d/wk, for 18 mo failed to develop VDC-related tumors, as judged by gross examination 24 mo after the beginning of exposure. Maltoni et al. (1977) exposed Sprague Dawley rats to VDC at 10, 25, 50, 100, and 150 ppm, 4 h/d, 4–5 d/wk, for 12 mo and, under a similar protocol, Swiss mice at 10 and 25 ppm. Early results, 30 wk after the last exposure (animal ages, 91–98 wk), showed an increase in the incidence of mammary tumors in treated groups, but the increase was not dose-related; one Zymbal’s-gland carcinoma was seen in a rat exposed at 100 ppm. VDC did produce renal adenocarcinomas without metastases in

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 mice exposed at 25 ppm, but not at 10 ppm. Oral administration of VDC to rats (25 mg/kg) and inhalation exposure of Chinese hamsters (25 ppm, 4 h/d, for 52 wk) did not result in tumor formation (Maltoni et al., 1977). A carcinogenesis bioassay of VDC conducted on rats (1 or 5 mg/kg) and mice (2 or 10 mg/kg) in which the chemical was given by gavage was negative (National Toxicology Program, 1982). Another carcinogenesis study produced different results (Lee et al., 1978). CD-1 mice were exposed to VDC at 55 ppm, 6 h/d, 5 d/wk, for 12 mo; 3 of 70 mice tested developed hemangiosarcomas of the liver, and 6 of 70 had bronchioalveolar adenomas. Those results are comparable with those of exposure to vinyl chloride. Similar treatment of rats produced a hemangiosarcoma in a lymph node of one animal and another in subcutaneous tissue of a second rat; 71 animals were tested. The VDC was reported to be 99% pure, but analysis was not provided. In the Maltoni et al. study, the material used reportedly contained 99.95% VDC, 0.04% 1,2-dichloroethylene, 0.01% acetone, 0.005% methylene chloride, and 0.002% monochloroacetylene and dichloroacetylene; p-methoxyphenol was added at 200 ppm as a stabilizer. The Lee et al. report commented on gross lesions in several organs in mice, but did not mention any changes in the kidneys; an earlier report from the same laboratory indicated that VDC was renotoxic at 15 ppm in just 23 h. Hong et al. (1981) conducted a 1-yr followup of neoplastic changes after VDC exposure of rats and mice at 50, 250, and 1,000 ppm as a sequel to the work of Lee et al. (1978). Results showed that cumulative tumor incidence in liver, lung, and mammary gland increased with dose and duration of exposure. Evidence of a VDC exposure threshold was presented. Chu and Milman (1981) reviewed carcinogenesis results on VDC and related compounds. Reitz et al. (1980) studied the effects of VDC on DNA synthesis and DNA repair in rats and mice. These animals were exposed to VDC at 10 and 50 ppm for 6 h; for comparison purposes, dimethylnitrosamine was also studied in other animals. DNA alkylation was minimal (one or two orders of magnitude lower than dimethylnitrosamine). However, DNA repair in the mouse kidney was much less than in the liver. Tissue damage and increased DNA repair (by a factor of 25) occurred at 50 ppm in the mouse kidney, but not at 10 ppm. This suggests that the tumors observed in mice exposed to VDC arise primarily through effects of the chemical on nongenetic components of the cells. PHARMACOKINETICS Exposure of rats to [14C]VDC for several hours has demonstrated that most of the label is excreted in the urine, and the balance is expired as 14CO2 and unchanged VDC, excreted in the feces, or retained in the tissues (McKenna et al., 1977). VDC apparently is metabolized to an intermediate that can bind covalently to protein and nucleic acids (McKenna et al., 1977. 1978; Reitz et al., 1979). In a study on the pharmacokinetics of [14C]VDC in rats, McKenna et al. (1978) found that fasting had no effect on its metabolism when rats were exposed to vapor at 10 ppm for 6 h; but fasted rats exposed at 200 ppm for 6 h showed a reduced capacity to metabolize VDC, and liver damage and

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 kidney damage were also noted. The two major urinary metabolites detected—N-acetyl-S-(2-hydroxyethyl)cysteine and thiodiglycolic acid—indicate that a major pathway for detoxification of VDC is conjugation with liver glutathione. Reitz et al. (1979) reported that the extent to which DNA alkylation occurs in VDC-treated rats and mice (10–50 ppm) correlates well with the carcinogenicity results of the Maltoni et al. study: alkylation of rat liver and kidney DNA and mouse liver DNA is low, compared with alkylation of DNA in mouse kidney, the target organ for VDC. These investigators suggested that VDC may act as a carcinogen, not only because its administration can lead to alkylation of mouse kidney DNA, but also because of its frank toxicity to mouse kidney, which forces an increase in the rate of DNA replication as regeneration takes place in the kidney. Hence, the toxicity of VDC to the kidney could promote the initiation effect of DNA alkylation. Such a correlation between toxicity and carcinogenicity is well established with a variety of chemical compounds. The importance of pharmacokinetics needs to be considered. The carcinogenicity of VDC in the mouse kidney can be hypothetically explained by a metabolic transformation of VDC to an alkylating agent that initiates the carcinogenic process by covalent binding to DNA and promotes the process by stimulating cellular regeneration. If such initiation and promotion can occur only when VDC exposures are high enough to deplete tissue stores of glutathione (which detoxifies activated VDC), then it can be argued that there is some degree of exposure to VDC that would result in a low probability of tumor formation. Although not yet substantiated, this is a plausible hypothesis. Therefore, it seems reasonable that, in the case of VDC, EELs can be set if sufficient data are available to permit the Committee to judge what might be an exposure unlikely to result in a toxic effect in humans. INHALATION EXPOSURE LIMITS The ACGIH has recommended a TLV-TWA for VDC of 5 ppm and a 15-min TLV-STEL of 20 ppm (ACGIH, 1983). The TLV-TWA of 5 ppm was considered “low enough to prevent overt toxicity in exposed workers” (ACGIH, 1982). OSHA adopted 10 ppm as the federal workplace standard for VDC (OSHA, 1983). COMMITTEE RECOMMENDATIONS In 1966, the Committee recommended a 24-h EEL and a 90-d CEL for VDC; however, considerable data have since accumulated (Table 12) that indicate that VDC is a potent hepatotoxin and is also a hepatocarcinogen. The data most helpful in recommending an EEL for VDC come from the study of Ott et al. (1976), who examined the mortality and health-examination findings of 138 company employees exposed to VDC at measured concentrations in the absence of vinyl chloride. No occupation-related disorders could be detected among workers exposed to VDC at estimated concentrations of 5–70 ppm (TWA) over several years.

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 The Committee notes that, although the effects of single short-term exposures to carcinogens cannot be predicted, the probability of tumor formation under these conditions would be low—and less than that associated with repeated exposures. Because of the possibility of liver and kidney damage from acute exposure, the Committee recommends a lowering of the 24-h EEL to 10 ppm. The Committee notes that this concentration is approximately 20 times greater than that suggested by the Committee for short-term exposures to VDC as a drinking-water contaminant. However, as pointed out in the introduction to this report, the EELs given here are for a narrowly defined, healthy, adult working population, whereas drinking water containing VDC could be consumed for up to a week by a more heterogeneous population, including young children and other persons with increased sensitivity to the effects of this chemical. The Committee’s recommendation for the 90-d CEL is based on animal studies (continuous and repeated exposure of rats, rabbits, guinea pigs, dogs, and monkeys) and the previously cited (8 h/d) occupational exposure of humans. Continuous exposure at 15 ppm produced mortality among some guinea pigs and monkeys, but surviving animals displayed no organ toxicity. Applying a 100-fold uncertainty factor to the concentration fatal to these species, i.e., guinea pigs and monkeys, the Committee recommends a CEL of 0.15 ppm. The present Committee’s recommended EEL and CEL for VDC and the limits proposed in 1966 are shown below.   1966 1984 24-h EEL 25 ppm 10 ppm 90-d CEL 2 ppm 0.15 ppm

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 TABLE 12 Summary of Results of Recent Inhalation-Toxicology Studies on VDC Species Concentration, ppm Duration of Exposure Toxic Effects Reference Human 5–70 Several years No clinical signs Ott et al., 1976 Monkey 25, 47 24 h/d, 90 d Death Prendergast et al., 1967 Guinea pig 15, 25, 47 24 h/d, 90 d Death Prendergast et al., 1967 Rat 500 6 h/d, 20 d Decreased body weight, liver toxicity Gage, 1970 Rat 150 4 h Increased serum alanine-α-keto-glutarate transaminase 24 h later Jaeger et al., 1975 Rat 100 4 h None Jaeger et al., 1975 Rat 75, 100 4 h/d, 5 d/wk, 12 mo No dose-related tumors Viola and Caputo, 1977 Rat 25, 75 6 h/d, 5 d/wk, 18 mo Cytoplasmic vacuolization in hepatocytes after 1 mo, no gross tumors at 24 mo Rampy et al., 1977 Rat 60 22–23 h/d, 2 d Increased serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase Short et al., 1977 Rat 55 6 h/d, 5 d/wk, 12 mo Hemangiosarcoma in lymph nodes and subcutaneous tissue Lee et al., 1978 Rat 47 24 h/d, 90 d Kidney injury Prendergast et al., 1967 Rat 10, 40 6 h/d, 5 d/wk, 4 wk No vacuolization Rampy et al., 1977

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 Species Concentration, ppm Duration of Exposure Toxic Effects Reference Mouse 100 4 h/d, 2 d Death Maltoni et al., 1977 Mouse 60 22–23 h/d, 2 d Death Short et al., 1977 Mouse 55 6 /d, 5 d/wk, 12 mo Liver hemangiosarcoma and bronchioalveolar adenoma Lee et al., 1978 Mouse 50 4 h/d, 4 d Death Maltoni et al., 1977 Mouse 15 1 d Increased serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase Short et al., 1977 Dog, rat, monkey 47 24 h/d, 90 d Liver injury Prendergast et al., 1967 Not stated 50, 100 8 h/d, 5 d/wk, several months Liver and kidney injury Torkelson and Rove, 1981 Not stated 25 8 h/d, 5 wk, several months “Minimal” liver and kidney injury Torkelson and Rowe, 1981

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 REFERENCES American Conference of Governmental Industrial Hygienists. 1980. Vinylidene chloride. Documentation of the Threshold Limit Values. 4th ed. Cincinnati, Ohio: American Conference of Governmental Industrial Hygienists. p. 433(82)-434(82). American Conference of Governmental Industrial Hygienists. 1983. TLVs(R): Threshold Limit Values for Chemical Substances and Physical Agents in the Work Environment with Intended Changes for 1983–1984. Cincinnati, Ohio: American Conference of Governmental Industrial Hygienists. 93 p. Andersen, M.E., French, J.E., Gargas, M.L., Jones, R.A., and Jenkins, L.J., Jr. 1979. Saturable metabolism and the acute toxicity of 1,1-dichloroethylene. Toxicol. Appl. Pharmacol. 47:385–393. Carpenter, C.P., Smyth, H.F., Jr., and Pozzani, U.C. 1949. The assay of acute vapor toxicity, and the grading and interpretation of results on 96 chemical compounds. J. Ind. Hyg. Toxicol. 31:343–346. Chu, K.C., and Milman, H.A. 1981. Review of experimental carcinogenesis by compounds related to vinyl chloride. Environ. Health Perspect. 41:211–220. Gage, J.C. 1970. The subacute inhalation toxicity of 109 industrial chemicals. Br. J. Ind. Med. 27:1–18. Hong, C.B., Winston, J.M., Thoraburg, L.P., Lee, C.C., and Woods, J.S. 1981. Follow-up study on the carcinogenicity of vinyl chloride and vinylidene chloride in rats and mice: Tumor incidence and mortality subsequent to exposure. J. Toxicol. Environ. Health 7:909–924. Jaeger, R.J., Trabulus, M.J., and Murphy, S.D. 1973. The interaction of adrenalectomy, partial adrenal replacement therapy, and starvation with hepatotoxicity and lethality after 1,1-dichloroethylene intoxication. Toxicol. Appl. Pharmacol. 25:491, Abstr. no. 133. Jaeger, R.J., Conolly, R.B., and Murphy, S.D. 1975. Short term inhalation toxicity of halogenated hydrocarbons. Effects on fasting rats. Arch. Environ. Health 30:26–31. Lee, C.C., Bhandari, J.C., Winston, J.M., House, W.B., Dixon, R.L., and Woods, J.S. 1978. Carcinogenicity of vinyl chloride and vinylidene chloride. J. Toxicol. Environ. Health 4:15–30. Maltoni, C., Cotti, G., Morisi, L., and Chieco, P. 1977. Carcinogenicity bioassays of vinylidene chloride. Research plan and early results. Med. Lav. 68:241–262.

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 McKenna, M.J., Watanabe, P.G., and Gehring, P.J. 1977. Pharmacokinetics of vinylidene chloride in the rat. Environ. Health Perspect. 21:99–105. McKenna, M.J., Zempel, J.A., Madrid, E.G., and Gehring, P.J. 1978. The pharmacokinetics of [14C] vinylidene chloride in rats following inhalation exposure. Toxicol. Appl. Pharmacol. 45:599–610. National Toxicology Program. 1982. Carcinogenesis Bioassay of Vinylidene Chloride in F344 Rats and B6C3F1 Mice (Gavage Study). NTP Tech. Rept. Series No. 228. Bethesda, Maryland: National Toxicology Program, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health. 184 p. [NTP-80–82; NIH Publ. No. 82–1784] Occupational Safety and Health Administration. 1983. Toxic and Hazardous Substances. Air contaminants. 29 CFR 1910.1000. Ott, M.G., Fishbeck, W.A., Townsend, J.C., and Schneider, E.J. 1976. A health study of employees exposed to vinylidene chloride. J. Occup. Med. 18:735–738. Prendergast, J.A., Jones, R.A., Jenkins, L.J., Jr., and Siegel, J. 1967. Effects on experimental animals of long-term inhalation of trichloroethylene, carbon tetrachloride, 1,1,1-trichloroethane, dichlorodifluoromethane, and 1,1-dichloroethylene. Toxicol. Appl. Pharmacol. 10:270–289. Rampy, L.W., Quast, J.F., Humiston, C.G., Balmer, M.F., and Schwetz, B.A. 1977. Interim results of two-year toxicological studies in rats of vinylidene chloride incorporated in the drinking water or administered by repeated inhalation. Environ. Health Perspect. 21:33–43. Reitz, R.H., Watanabe, P.G., McKenna, M.J., Quast, J.F., and Gehring, P.J. 1979. Effects of vinylidene chloride on DNA synthesis and DNA repair in the rat and mouse: A comparative study with dimethylnitrosamine. (Report to Manufacturing Chemists Assoc.) Midland, Michigan: Dow Chemical Co., Toxicology Research Laboratory. 31 p. Reitz, R.H., Watanabe, P.G., McKenna, M.J., Quast, J.F., and Gehring, P.J. 1980. Effects of vinylidene chloride on DNA synthesis and DNA repair in the rat and mouse: A comparative study with dimethylnitrosamine. Toxicol. Appl. Pharmacol. 52:357–370. Saunders, R.A. 1967. A new hazard in closed evironmental atmospheres. Arch. Environ. Health 14:380–384. Short, R.D., Winston, J.M., Minor, J.L., Hong, C.-B., Seifter, J., and Lee, C.-C. 1977. Toxicity of vinylidene chloride in mice and rats and its alteration by various treatments. J. Toxicol. Environ. Health 3:913–921.

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 Siletchnik, L.M., and Carlson, G.P. 1974. Cardiac sensitizing effects of 1,1-dichloroethylene: Enhancement by phenobarbital pretreatment. Arch. Int. Pharmacodyn. Ther. 210:359–364. Stecher, P.G., Windholz, M., and Leahy, D.S., eds. 1968. The Merck Index: An Encyclopedia of Chemicals and Drugs. 8th ed. Rahway, New Jersey: Merck & Co., Inc. p. 1109. Torkelson, T.R., and Rowe, V.K. 1981. Halogenated aliphatic hydrocarbons containing chlorine, bromine, and iodine. Vinylidene chloride. In: Clayton, G.D., and Clayton, F.E., eds. Patty’s Industrial Hygiene and Toxicology. Vol. IIB. Toxicology. 3rd rev. ed. New York: John Wiley & Sons. p. 3545–3550. Viola, P.L., and Caputo, A. 1977. Carcinogenicity studies on vinylidene chloride. Environ. Health Perspect. 21:45–47.