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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 OCR for page 40
Toxicity of Selected Contaminants 41 roacetic acid and dichloroethanol. In this system, the cis isomer was me- tabolized to a greater extent than was the bans isomer. These metabolites are apparently formed via an epoxide intermediate. In studies of rats ex- posed to 1,2-dichloroethylene vapor, trans-1,2-dichloroethylene was found to be metabolized more slowly than was the cis isomer (Filser and Bolt, 1979~. Studies with rat liver microsomes demonstrated a Type 1 difference spectra with these substances, implicating the involvement of cytochrome P450 (Costa and Ivanetich, 1982b). HEALTH ASPECTS Observations in Humans No data were found by the committee. Observations in Other Species Acute Effects The liver is the primary target for 1,2-dichloroethylene toxicity at doses that do not cause narcotic effects (i.e., between l To to to in air). In male rats given single oral 400 mg/kg doses of either the cis or bans isomers, there were only slight changes in liver alkaline phosphatase and liver glucose-6-phosphatase, respectively (Jenkins et al., 1972~. At 1,500 mg/kg, the bans isomer caused only a decrease in liver tyrosine transaminase, whereas the cis isomer caused decreases in liver glucose-6- phosphatase, liver tyrosine transaminase, and plasma glutamic-pyruvic transaminase (alanine aminotransferase), along with an increase in liver alkaline phosphatase. Using an isolated, perfused liver system, Bonse et al. (1975) found that both compounds, after a 2- to 3-hour perfusion pe- riod at a concentration of 55 ~M, caused increases in glutamic-pyruvic transaminase, in glutamic-oxaloacetic transaminase (aspartate amino- transferase), and in the ratio of lactate to pyruvate in the perfusate. An extensive study on trans-1,2-dichloroethylene indicated that the compound's LDso when administered intraperitoneally was 3.2 ml/kg in the mouse and 6.0 ml/kg in the rat (Freundt et al., 1977~. The bans isomer caused a greater lethality when given orally: the oral LDso in the rat was 1.0 ml/kg. Inhalation exposure of rats for 8 hours to trans-1,2-dichloro- ethylene at 1,000 ppm (3,967 mg/m3) resulted in reductions in serum al- bumin, urea nitrogen, and alkaline phosphatase, but these effects were not observed at 200 ppm (793 mg/m3~. Both the leukocyte count and erythro- cyte count were lowered at the higher level, but only the leukocyte count was diminished at the lower exposure. Bromsulfophthalein clearance was not affected. After a single inhalation exposure to 200, 1~000, and 3,000

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42 DRINKING WATER AND HEAl TH ppm (793, 3,967, and 11,901 mg/m3) for 8 hours, there was slight fatty degeneration of the liver lobules in one of six rats exposed to 200 ppm (793 mg/m3~. Pulmonary capillary hyperemia and distention of the alveolar septa were increased. At 1,000 ppm (3,965 mg/m3) two of six rats had fatty degeneration of the liver. The damage was slight in one animal and severe in the other. Changes in the lung were observed in five of the rats. The damage was slight in three rats and severe in two. There was no histo- pathological indication of damage to the kidneys, spleen, brain, striated muscle, or peripheral nerves. Cardiac muscle damage was observed at 3,000 ppm. In an additional study, female rats exposed by inhalation to 200 ppm concentrations of both the cis and bans isomers for ~ hours exhibited in- creases in hexobarbital-induced sleeping times and zoxazolamine-induced paralysis times and decreased metabolism of aminopyrine (Freundt and Macholz, 19781. These effects were shown to be dose dependent and re- versible. Those produced by the cis isomer were greater than those of the bans isomer. This mixed-function oxidase inhibition was shown by in vitro studies using various concentrations of the bans isomer to be competitive, as indicated by a Dixon plot. Nephrotoxicity has been observed in Swiss mice following intraperito- neal exposures to high doses (2 to 4 ml/kg) of both isomers. This effect was demonstrated by an increase in urinary protein. Unlike observations made in studies of 1,1,2-trichloroethane (0.2 ml/kg) or 1,1,2,2-tetrachloro- ethane (1 ml/kg), the changes were not accompanied by an increase in urinary glucose or by histopathological evidence of damage to the proximal convoluted tubules (Plea and Larson, 1965~. In both the kidney and the liver, the cis isomer was more toxic than the bans isomer. Chronic Effects In the study by Fruendt et al. (1977), minimal histo- pathological liver damage was observed after inhalation exposures to 200 ppm (793 mg/m3) for 8 hours. However, after exposure to this level for 5 days/week for 16 weeks, fatty degeneration was absented in the livers of five of six rats, and slight pulmonary capillary hyperemia and alveolar sep- tum distention were observed in all six animals. Mutagenicity c~s-1,2-Dichloroethylene at 2.9 mM and trans-1,2-di- chloroethylene at 2.3 mM concentrations were found to be nonmutagenic when tested in a suspension assay with the multiple end point E. cold K12 strain, which detects reverse mutations at the gal, nad, and arg loci and forward mutation to resistance to S-methyl-DL-tryptophan. The assay was performed both in the presence and absence of a phenobarbital-induced mouse liver activation system. An 88~o survival occurred at the highest

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Toxicity of Selected Contaminants 43 concentration (2.9 mM) of cis-1,2-dichloroethylene; a 90~o survival oc- curred at the highest concentration (2.9 mM) of trans-1,2-dichloroethyl- ene used (Greim et al., 1975~. Under the conditions of these studies neither the cis nor bans isomer of 1,2-dichloroethylene was observed to be mutagenic. Teratogenicity No data were found by the committee. Carcirzogenicity No data were found by the committee. CONCLUSIONS AND RECOMMENDATIONS Both cis- and trans-1,2-dichloroethylene demonstrate a potential for liver and kidney damage. Little information is available on the effects resulting from chronic administration of the materials. Long-term studies, espe- cially those involving oral administration, are needed before a chronic SNARL can be determined. In view of its structural similarity to vinyl chlo- ride, a carcinogenesis bioassay is desirable. In addition, studies are needed to determine the teratogenic and reproductive effects of these isomers, and additional investigations should be conducted to examine their mutagenic properties in mammalian cells. DICHLOROMETHANE methylene chloride; methane, dichIor~ CAS No. 75 09-2 CH2 C12 Dichloromethane was evaluated in the first and third volumes of Drinking Water and Health (National Research Council, 1977, pp. 743-745; 1980, pp. 124-128~. The following material, which became available after the 1980 report was prepared, updates and, in some instances, reevaluates the information contained in the previous reviews. Also included are some ref- erences that were not assessed in the earlier-report. METAB OLI SM DiVincenzo and Kaplan (1981) measured blood carboxyhemoglobin in workers and volunteers exposed as long as 7.5 hours to atmospheric con- centrations of 50, 100, 150, or 200 ppm (174, 347, 522, or 696 mg/m3) for up to 5 consecutive days. As much as 34~o of the absorbed dichlorome- thane was expired as carbon dioxide, and less than 5~o was exhaled as