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32 DRINKING WATER AND HEALTH assessed. The additional studies recommended in the last review are still needed. Despite extensive knowledge concerning the metabolism of 1,2-dichlo- roethane, there is still a need to know the comparative pharmacokinetics in different species, including humans. The knowledge that 1,2-dichloroe- thane has been shown to have both mutagenic and carcinogenic properties in animals provides further reason to obtain these kinds of data following oral exposure in order to develop better estimates of the risk to humans exposed to low levels. 1, 1-DICHLOROETHYLENE ethene, 1,l~ichior~ CAS No. 75-35-4 H2 C = CC12 1,1-Dichloroethylene is commonly called vinylidene chloride. This sub- stance is used primarily as an intermediate in the synthesis of copolymers slated for food-packaging films and coatings. It is also used in the synthe- sis of 1,1,1-trichloroethane. This volatile liquid has a boiling point of 31.7C, and it is practically insoluble in water, having a solubility of only 0.04 w/v (400 mg/liter) at 20C (Hardie, 1964~. It has been found in drinking water in concentrations as high as 0.1 ~g/liter (U.S. Environ- mental Protection Agency, 1975b). In 1976, 120 million kg were produced in the United States; 50 million kg were used as an unisolated intermediate (International Agency for Research on Cancer, 1979a). The threshold limit value is 10 ppm (40 mg/m3) (American Conference of Governmental In- dustrial Hygienists, 1981~. METAB OLI SM Orally administered 1,1-dichloroethylene is rapidly and completely ab- sorbed in rats (Jones and Hathway, 1978a; Putcha et al., 1982; Reichart et al., 1979~. Following distribution, the highest concentrations are found primarily in the liver and kidneys (Jones and Hathway, 1978a~b; McKenna et al., 1978~. At low doses a major route of elimination is exhalation of the parent compound (Chieco et al., 1981; Jones and Hathway, 1978b; Rei- chert et al., 1979~. lithe exhaled metabolic product is carbon dioxide. At higher doses, the parent compound predominates (Jones and Hathway, 1978a,b; McKenna et al., 1978~. The compound is metabolized to a number of metabolites, presumably

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Toxicity of Selected Contaminants 33 through the formation of an epoxide (Greim et al., 1975; Henschler, 1977; Henschler and Bonse, 1978; Leibman and Ortiz, 19771. Jones and Hathway (1978a) reported that 80~o of an intragastrically administered 0.5 mg/kg dose appeared as urinary metabolites, whereas only 33% of a 350 mg/kg dose was metabolized. At the higher dose, 375to of the urinary metabolites were identified as thiodiglycolic acid and 48% as an N-acetyl- S-cysteinyl derivative. McKenna et al. (1978) observed that 78% of a single oral 1 mg/kg dose was accounted for in metabolites found in the urine and feces, that 21 To was exhaled as carbon dioxide, and that from 1~0 to 3~0 was exhaled as unchanged 1,1-dichloroethylene. After the administration of a 50 mg/kg dose, 19% was exhaled unchanged by fed rats and 29% by fasted rats. The two major urinary metabolites excreted within 25 hours following the ad- ministration of 1 mg/kg to fed rats were identified as thiodiglycolic acid (22~o of the metabolites) and 5-~2-hydroxyethyl)-N-acetylcysteine (13% of the metabolites). Reichert et al. (1979) observed dose-dependent metabo- lism: 1.3% was exhaled unchanged following an oral dose of 0.S mg/kg, but 16.5% was exhaled after 50 mg/kg. Renal excretion was approxi- mately 43% in both cases, but biliary excretion amounted to 16~o after the low dose and 8% after the high dose. Thiodiglycolic acid was the main urinary metabolite, accounting for approximately Who. Other metabo- lites, including chloroacetic acid, dithioglycolic acid, thioglycolic acid (Jones and Hathway, 1978a), N-acetyl-5-~2-carboxymethyl) cysteine, and methylthio-acetylaminoethanol (Reichert et al., 1979) have also been iden- tified in rat urine. In in vitro studies with rat liver microsomes, monochlo- roacetate and dichloroacetaldehyde were identified as metabolites (Costa and Ivanetich, 1982a,b). Mice given an oral dose of 50 mg/kg metabolized the compound to a greater extent than did rats; they exhaled to un- changed in contrast to the 28~o exhaled by rats (Jones and Hathway, 1978b). Dithioglycolic acid (23~o of the dose) and the N-acetyl-S-cysteinyl acetyl derivative (Woo of dose) were the primary metabolites. HEALTlI ASPE CTS Observations in Humans No definitive studies in humans have been reported. Early studies of work- ers exposed to traces of 1~1-dichloroethylene cannot readily be evaluated since the major compound to which the workers were exposed was vinyl chloride (Kramer and Mutchler, 1972~. Ott et al. (1976) examined the health of 138 employees exposed to 1,1-dichloroethylene where vinyl chlo- ride was not a copolymer. Time-weighted averages for exposure ranged

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34 DRINKING WATER AND HEALTH from less than 10 ppm to greater than 50 ppm (40-198 mg/m31. The inves- tigators observed no alterations in results of clinical laboratory tests, in- cluding hematological tests, urinalyses, and tests for respiratory functions, performed on these workers. There are no data on long-term exposures of large numbers of human beings. Observations in Other Species Acute Effects The most commonly reported toxic effect of 1 ,1-dichlo- roethylene is hepatotoxicity. Jenkins et al. (1972) reported that a single oral 100 mg/kg dose of 1,1-dichloroethylene in corn oil given to rats caused a decrease in liver glucose-6-phosphatase and an increase in alkaline phos- phatase activity but did not cause elevations in plasma alkaline phospha- tase and alanine aminotransferase. These plasma enzymes were elevated following doses of 300 mg/kg and 500 mg/kg. Establishing a dose-response relationship for the oral lethality of 1,1- dichloroethylene in rats has presented some difficulties (Andersen et al., 1979~. For large ~ ~ 200 g) male rats, the dose-response reached a plateau at about 400 mg/kg. Immature rats (73 g) were more sensitive: there was an almost 1005to lethality at doses of 200 mg/kg, but there was an apparent decrease in lethality when dose levels greater than 200 mg/kg of the com- pound were administered. Smaller rats also responded with a greater in- crease in hepatotoxicity, as assessed by serum enzymes following a 50 ma/ kg dose of 1,1-dichloroethylene in corn oil (Andersen and Jenkins, 1977~. Plasma aspartate aminotransferase in these animals (100-110 g) was ele- vated at a dose of 25 mg/kg but not at 12.5 mg/kg. In one study, female rats were observed to be less sensitive to injury than were males (Andersen and Jenkins, 1977), but in another, female rats were reported to be more sensitive (Jenkins et al., 1972~. A confounding factor in the studies of 1 ,1-dichloroethylene has been the influence of fasting prior to administration of the compound. Jaeger et al. (1974) exposed rats by inhalation to various concentrations of 1,1-dichlo- roethylene and estimated that the minimum lethal concentration was 200 ppm (794 mg/m3) for fasted rats and 10,000 ppm (39,700 mg/m3) for fed rats. Serum alanine aminotransferase levels were elevated at 150 ppm (595 mg/m3) in fasted rats, but a level of at least 2,000 ppm (7,940 mg/m3) was needed for the same effect in fed rats. This striking difference was related to the effect of fasting on hepatic glutathione concentrations. The importance of fasting was also observed histologically (Reynolds and Moslen, 1977; Reynolds et al., 1975~. Hepatic lesions occurred earlier and were more extensive in fasted rats exposed to 200 ppm (794 mg/m3) of 1,1-

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Toxicity of Selected Contaminants 35 dichloroethylene for 4 hours than were observed in fed rats subjected to the same exposures. These lesions included nuclear changes, swollen and rup- tured mitochondria, and midzonal necrosis. Other effects have been reported. Harms et al. (1976)observed in rats that a 0.5 ml/kg dose administered intraperitoneally caused an increase in bile-duct pancreatic fluid flow but had little or no influence on hepatic bile flow. Jenkins and Andersen (1978) reported the occurrence of nephrotoxicity in rats, based on elevations in blood urea nitrogen (BUN), which generally parallel hepato- toxic responses. The doses needed to elicit this response were higher than those needed to induce hepatotoxicity; a dose of 400 mg/kg caused elevations in BUN in fasted but not in fed rats. Chronic Effects Prendergast et al. (1967) exposed rats, guinea pigs, dogs, rabbits, and monkeys by inhalation to 5, 15, 20, and 45 ppm (20, 60, 80, and 180 mg/m3) 1,1-dichloroethylene for 90 days. At the highest level, 7 of 15 guinea pigs and 3 of 9 monkeys died. Dogs and monkeys lost weight, and rats gained less weight than did the controls. In the livers, there was fatty metamorphosis, focal necrosis, hemosiderin deposition, bile duct proliferation, and fibrosis. These signs were most severe in the dog. The morphologic changes were accompanied by elevations in liver al- kaline phosphatase and serum aspartate aminotransferase, but serum urea nitrogen levels were not elevated. In the rat kidneys there was nuclear hypertrophy of the tubular epithelium. At 20 ppm, weight losses were ob- served in rabbits, dogs, and monkeys, and 3 of IS guinea pigs and 2 of 3 monkeys died, but no defined histopathological changes were observed. At 15 ppm, 3 of 5 guinea pigs died, and the monkeys and rats had poor weight gain. At.5 ppm, 2 of 45 rats, 2 of 4S guinea pigs, and 1 of 21 monkeys died, but no signs of toxicity were observed. No histopathological lesions were found in the liver, and serum enzyme levels were normal. In the control group, 7 of 304 rats, 2 of 314 guinea pigs, none of 34 dogs, and 1 of 57 monkeys died. Quast et al. (1977) exposed male and female Sprague-Daw- ley rats to 60, 100, or 200 ppm (6, 10, or 19 mg/kg) daily for 90 days. No changes were obser~red in body weight gain, hematological indices, urine analysis, BUN, serum alkaline phosphatase, serum alanine aminotrans- ferase, gross patholog~y, or organ weights. Hepatocellular vacuolization was seen in the animals receiving 200 ppm. Norris (1977) reported that no adverse effects were observed in dogs given 1,1-dichloroethylene in doses of 6.25, 12.5, or 25 mg/kg for 90 days. This assessment was based on clinical observation, body weights, and gross and histopathological examination. Rampy et al. (1977) exposed male and female Sprague-Dawley rats to 1,1-dichloroethyJene at concentrations of 68, 106, and 220 mg/liter in drinking water. They examined the groups at 6, 12, 18, and 24 months of

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36 DRINKING WATER AND HEAlTH exposure. There were no consistent changes in body weight gain, hemato- logical indices, urinalysis, and nonprotein sulfhydryl groups in the liver and kidneys. There was slightly higher mortality than in the controls for the males in all three treatment groups, but this was not related to dose and was not observed in the females. No differences were observed in organ weights except for a decreased kidney to body weight ratio in the males at the lowest dose levels at the 90-day sacrifice. The only histopathological change noted was a vacuolization of hepatocytes at the 220 mg/liter expo- sure. 1,1-Dichloroethylene was administered by gavage in corn oil to Fischer 344 rats and B6C3~ mice S times per week for 13 weeks at levels of 0, S. IS, 40, 100, or 250 mg/kg bw (National Toxicology Program, 1982b). Cen- trilobular necrosis was observed in three rats, which died at the highest level of exposure. Cellular Apia, characterized as altered nuclear/cytoplas- mic ratios, megalocytosis, basophilia, clear cells, and an increase in binu- cleated cells, was seen in the rats given the turo highest dose levels. Foci of cellular alteration were observed in rats receiving the 5 and IS mg/kg doses, but not in those at the higher doses. In the mice, there was considerable mortality at the higher doses, and a dose-related decrease in body weight was observed in the males. Dose-related hepatic lesions were observed but were minimal at 5 mg/kg. In the same study, 1,1-dichloroethylene was administered for 104 weeks by garage in corn oil at levels of 1 orS mg/kg bw (to rats) and 2 or 10 mg/kg bw (to mice) (National Toxicology Program, 1982b). There were no adverse effects on body weight or sundial of the rats, and no compound-related clinical signs were observed. The only lesion of possible significance reported was a dose- dependent increase in chronic inflammation of the kidney, but this lesion was also present in the controls. In mice, the body weights of the treated males were lower than those of the controls, but in both males and females there were no clinical signs of toxicity or significant differences in survival. Mutagenicity 1,1-Dichloroethylene was found to be mutagenic In the Ames Salmonella assay by the following investigators: Bartsch et al. (1975, 1979), Jones and Hathway (1978c), and Simmon et al. (1977~. These assays were performed in desiccators. A variety of mammalian metabolic acti~ra- tion systems elicited or enhanced mutations in one or more of the Salmo- nella base~pair substitution mutants. Activating systems were: uninduced kidney and liver S9 fractions from male albino mice; Aroclor 1254-induced kidney and liver S9 fractions from male Sprague-Dawley rats; a presumed phenobarbital-induced S9 liver fraction from humans; phenobarbital-in- duced liver S9 fractions and phenobarbital-induced and uninduced kidney and lung S9 fractions from OF-1 mice; and uninduced S9 fractions from

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Toxicity of Selected Contaminants 37 the liver, kidney, and lung of female BD VI rats. Preparations that failed to induce mutations were uninduced liver S9 fractions from marmosets, humans, and male rats. 1,1-Dichloroethylene did not induce chromosome breakage in Chinese hamster DON-6 cells when tested at concentrations of 3 X 10-3 and 3 X 10-2 mM. It could not be determined from the data whether or not the compound induced toxic effects (Sasaki et al., 1980~. No increase in 8-azaguanine- and ouabain-resistant colonies was observed when Chinese hamster V79 cells were exposed in desiccators to to and loo 1,1-dichlo- roethylene vapor in air for 5 hours (Drevon and Kuroki, 1979~. Anderson et al. (1977) exposed male mice by inhalation to 50 ppm (198 mg/m3) for 6 hours per day for 5 days prior to mating and found no evi- dence of dominant lethality. Short et al. (1977) reported similar findings in rats. Mutagenic activity was observed in the multiple end point E. cold K12 strain when assayed in suspension at a concentration of 2.5 mM in the presence only of liver S9 fraction derived from phenobarbital-pretreated male mice (Greim et al., 1975~. Both point mutation and mitotic gene con- version were observed in Saccharomyces cerevisiae D7 in the presence of liver S10 fraction obtained from male mice pretreated with Aroclor 1254 (Bronzetti et al., 1981~. They also observed mutagenic activity in a mouse host-mediated assay with S. cerevisiae D7 after the animals were Savaged with 1,1-dichloroethylene in corn oil. The data indicate that 1,1-dichloroethylene is mutagenic in several mi- crobial mutagenicity assays and in a mouse host-mediated microbial assay. Negative results were obtained in an in vitro mammalian mutagenicity as- say and in a mouse dominant lethal study. No chromosome breakage was observed in an in vitro study with Chinese hamster cells. Carcinogenicity Evidence for a carcinogenic effect of 1,1-dichloroeth- ylene was obtained in studies of mice (Maltoni, 1977~. Of the 300 male and female Swiss mice exposed to 25 ppm (100 mg/m3) of the compound 4 hours/day, 5 days/week for 52 weeks, 25 (8.3~o) had developed kidney adenocarcinomas at the end of the experiment (98 weeks). No such tumors were found in controls. No tumors were found in rats or hamsters exposed to higher concentrations of 1,1-dichloroethylene for the same length of time. In another study, mice and rats were exposed to 1,1-dichloroethylene at 55 ppm (220 mg/m3), 6 hours/day, 5 days/week. The experiment was ter- minated after 12 months (Lee et al., 19781. Among the 70 male and female exposed mice, six bronchial lung tumors were found; the earliest of the tumors appeared between 4 and 6 months, and the latest after 12 months.

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38 DRINKING WATER AND HEALTH Three of the 70 mice had hepatic hemangiosarcomas. Because of the small number of tumors and the low incidence, it was questionable whether these findings were related to 1,1-dichloroethylene exposure. In 2 of 35 male rats, hemangiosarcomas were found in the mesenteric lymph nodes or in subcutaneous tissues. Despite the low incidence, the investigators believed that these tumors were related to the 1,1-dichlorethylene. 1,1-Dichloroethylene was found to produce skin tumors when applied once to mouse skin, followed by repeated treatments with phorbol myris- tate acetate. When given alone, it did not produce tumors when applied topically or by subcutaneous injection. Thus, 1~1-dichloroethylene can be regarded as an initiating agent for mouse skin (Van Duuren et al., 1979~. Several studies failed to demonstrate significant carcinogenic activity of 1,1-dichloroethylene. In a study by Viola and Caputo (1977), Wistar rats were exposed to 1,1-dichloroethylene by inhalation to 200 ppm (792 mg/m3) for 5 months. The exposure was then reduced to 100 ppm (396 mg/m31. Both exposures were administered 4 hours/day, 5 days/ week. The second exposure was continued for the lifetime of the animals. There was no difference in the incidence of tumors between the exposed and control rats. The experiment was repeated with Sprague-Dawley rats, which were exposed to 1,1-dichloroethylene in concentrations of 100 or 75 ppm (396 or 297 mg/m3~. At the time of reporting, Viola and Caputo (1977) could not conclude that 1,1-dichloroethylene was carcinogenic. Male and female Sprague-Dawley rats were also exposed for their lifetime to concentrations of 1,1-dichloroethylene ranging from 60 to 200 mg/liter in drinking water. The authors reported no increase in tumor incidence, a conclusion based on gross tumor count only. The same laboratory con- firmed that exposure to 1,1-dichloroethylene at 10 to 40 ppm (40-160 ma/ m3) in air (6 hours/day, 5 day/week for 18 months) was not carcinogenic to Sprague-Dawley rats (Rampy et al., 1977~. 1,1-Dichloroethylene monomer was dissolved in olive oil and given orally to 24 pregnant female BD IV rats at a dose of 150 mg/kg on the 17th day of gestation. Their offspring (89 males and 90 females) then received weekly 50 mg/kg doses of 1,1-dichloroethylene, which was administered in olive oil by stomach tube. Animals were killed when moribund, and approxi- mately one-half of the animals survived for 130 weeks. In the treated ani- mals, there was an increased incidence of liver tumors. In treated males, there were more meningiomas than in the controls. However, the total number of tumor-bearing animals was the same for exposed animals and controls. There was some question whether the dose used in this experi- ment was the maximum tolerated dose (Ponomarkov and Tomatis, 1980~. A similar problem was encountered in a study commissioned by the Na- tional Toxicology Program (1982b). In a 104-week study, Fischer 344 rats were given 1 or 5 mg/kg doses of 1,1-dichloroethylene 5 times per week;

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Toxicity of Selected Contaminants 39 B6C3F~ mice received 2 and 10 mg/kg 5 times per week. In this bioassay, there was no evidence that 1,1-dichloroethylene was carcinogenic for either the rats or the mice. However, there was some doubt as to whether a maxi- mum tolerated dose had been used in this study. To date, there has been no evidence that 1,1-dichloroethylene is carcino- genic in humans (Infante, 1977~. However, the only epidemiological study found by the committee was based on a small population of 139 people exposed to measured levels of 1,1-dichloroethylene where vinyl chloride was not used as a copolymer (Ott et al., 1976~. A more recent analysis of the data did not enable investigators to draw definite conclusions (Ap- feldorf and Infante, 1981~. The committee's review indicated that the information on 1,1-dichloro- ethylene is not sufficient for a definite conclusion to be reached about its ability to induce cancer in laboratory animals or humans. Teratogenicity Murray et al. (1979) subjected rats and rabbits to inha- lation exposures of 1,1-dichloroethylene in concentrations as high as 160 ppm (635 mg/m3) for 7-hour periods during days 6 through 18 and 6 through IS of gestation, respectively. Maternal toxicity was observed in both species. No increased general malformation rate was found, but wavy ribs and delayed ossification were more frequent in rat fetuses exposed to 1,1-dichloroethylene at 80 and 160 ppm. Alumot et al. (1976) fed 1,1-di- chloroethylene to pregnant rats at 200 ppm in their diets on days 6 through IS of gestation. They observed no differences between the exposed fetuses and controls. The same investigators also fed rats doses as high as SOO ppm in feed over a 2-year period and found no alteration in fetal mortality or weight when litters were examined after birth. Approximately 60~o to 70% of the substance was estimated to have been consumed. 1,1-Dichloroethylene was reported to be nonteratogenic when given to rats in drinking water at 200 mg/liter or when administered by inhalation to rats and rabbits at 0, 20, 80, or 160 ppm (0, 80, 240, or 580 mg/m3) for 7 hours/day on days 6 to IS of gestation in rats and days 6 to 18 of gestation in rabbits (Norris, 1977~. The data indicate that 1,1-dichlorethylene is not teratogenic to mice, rats, or rabbits. There are no data from which its effects in humans can be judged. CONCLUSIONS AND RECOMMENDATIONS Suggested No-Adverse-Response Level {SNARL} Chronic Exposure The following calculation for a chronic SNARL is based on noncarcinogenic effects only. Rampy et al. (1977) administered

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40 DRINKING WATER AND HEALTH 1,1-dichloroethylene in the drinking water of male and female rats for as long as 2 years. At 220 mg/liter, but not at 106 ppm, vacuolization of the hepatocytes was observed. At 106 mg/liter, the mean daily consumption for males was 10.0 mg/kg and for females it was 12.6 mg/kg. However, a carcinogenesis bioassay of 1,1-dichloroethylene indicated that 10 mg/kg causes slight hepatotoxicity in mice (National Toxicology Program, 1982b). This was not observed at the 2 mg/kg dose. An uncertainty factor of 100 was assumed on the basis of the above study. Assuming that a 70-kg human consumes 2 liters of water daily, that 20~o of the exposure of most individuals would be from drinking water, and a factor of 5/: to correct from a 5- to 7-day weekly exposure, one may calculate the SNARL as: 2mg/kg X70 kg XO.2 5 100 X 2 liters X 7 = 0.10 mg/l~ter. If present in drinking water, 1,1-dichloroethylene would be rapidly and completely absorbed. At the low levels expected to be present, dose-depen- dent kinetics involving saturation of the metabolic pathways would not oc- cur, so that nearly all of the compound would undergo metabolic conver- sion. Studies in animals suggest that the principal target organs in humans would be the liver and, to a lesser extent, the kidney. 1,2-DICHLOROETHYLENE cis (ethene, 1,2~ichlor~(Z)- CAS No. 156-59-2 bans (ethene, 1,2~ichlorm