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28 DRINKING WATER AND HEALTH 1,2-DICHLOROETHANE ethylene dichloride; ethane, 1,2~ichIor~ CAS No. 107{~2 ClH2 CCH2 Cl 1,2-Dichloroethane was evaluated in the first and third volumes of Drink- ing Water and Health (National Research Council, 1977, pp. 723-725; 1980, p. 104~. Because of its commercial availability as an intermediate in the production of vinyl chloride and 1, 1,1-trichloroethane, it merits con- tinued surveillance. In the United States approximately 10 billion pounds are consumed annually, and some 2 million workers are exposed to the chemical (Fishbein, 1979~. Ten percent of those are exposed to high con- centrations of 1,2-dichloroethane when used as a solvent in textile clean- ing, metal decreasing, and adhesives. At least 45 fumigant formulations are now in use, and 36 U.S. gasoline formulations contain 1,2-dichloro- ethane as an additive (Fishbein, 1979~. Consequently, it is likely to enter the water supply from a variety of activities. Drury and Hammons (1979) surveyed a number of reports on the occur- rence of 1,2-dichloroethane in water. They concluded that its presence in municipal drinking water is infrequent, probably because it is relatively volatile and unstable in the atmosphere through photooxidation (Drury and Hammons, 1979~. The following material, which became available after the 1980 report was prepared, updates and, in some instances, reevaluates the information in the previous reviews. Also included are some references not discussed in the earlier reports. IdETAB OLISM Significant progress has been made in our understanding of the metabo- lism of 1,2-dichloroethane (Anders and Livesey, 1980~. The metabolic pathways that account for the known metabolites of this compound and other 1,2-dihaloethanes are shown in Figure II-1. 1,2-Dichloroethane is metabolized to ethylene by cytosolic hepatic en- zymes dependent upon glutathione. Most likely the same enzymes involved in the metabolism of halogenated methanes also participate in the conver- sion of 1,2-dichloroethane to ethylene. The enzymatic formation of S-~2- chloroethyl~glutathione probably involves glutathione S-transferase (An- ders and Livesey, 1980), based on similarities reported for this enzyme by Jakoby et al. (19761. Anders and Livesey (1980) theorized that 1,2-dichlo-

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Toxicity ot Selected Corkaminants 29 OH X-CH2-CH2-X ~ [X-CH2-CH-X] GT GSH GS~ H2CH2 -X GSH~ CH2 = CH2 + GSSG -X exe [:S~ H2O GSH GS-CH2CH2 -SG o X-CH2-C-H D _ X-CH2COOH GT | GSH,-Xe . , O GS-C H2-C-H DH _ GS~H2 ~OOH 1 Peptidase - GS-CH2-CH2-OH- ~ GS-CH2-CH2-OH NH2 ~ ~ HOOC -CH-CH2 -S -CH2 -COOH Peptidase NH~ o 1 ' HOOC-CH-CH2 -S-CH2 ~H2 -OH Acetyl CoA ~ N-Acetyl transferase O 11 NHC-CH3 1 HOOCCHCH2 -SCH2 -CH2 -OH / ,' HOOC-CH2-S-CH2COOH o 11 P450 NH-C-CH3 O HOOC'H-CH2SCH2 ~H2OH o HOOCCH2NHC GS = NH2 O CHCH2S- ~ 11 HOOCCHCH2 -CH2CNH FIGURE II-1 Metabolic pathways of 1,2-dichloroethane and other 1,2-dihaloethanes. GT = reduced glutathione (GSH) transferase; DH = debydrogenase; P450 = cytochrome P450; X = a halogen; and CoA = coenzyme A. From Anders and Li~resey, 1980, with per- mission. roethane is metabolized through an initial enyme-catalyzed nucleophilic (SN2, i.e., bimolecular) attack of glutathione on the electron-deficient car- bon of 1,2-dichloroethane to form S-~2-chloroethyl)-glutathione. A subse- quent reaction of glutathione with the sulfur atom of S-~2-chloroethyl)-glu- tathione is followed by ,6-elimination of halide to fonn ethylene. Loss of chloride ion from S-~2-chloroethyl)-GSH results in the formation of an epi- sulfonium ion, which is highly reactive. This ion is believed to be the reac-

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30 DRINKING WATER AND HEALTH five intermediate that results in covalent reaction with biopolymers (An- ders and Livesey, 1980~. Sipes and Gandolfi (1980) reported the covalent reaction of 1,2-dichlo- roethane with proteins, lipid, and DNA in vitro following activation by rat hepatic microsomes supplied with a system generating reduced nicotina- mide adenine dinucleotide phosphate (NADPH). Oxygen was required for a covalent reaction with 1,2-dichloroethane, which was one of the least re- active aliphatic halogenated hydrocarbons tested. Since microsomes free of cytosolic enzymes were used in this study, the reaction measured by this assay was probably the formation of chloracetaldehyde, rather than the pathway leading to ethylene via the episulfonium ion. Glutathione greatly inhibited the covalent reaction. We do not yet know which pathway is most important in determining the metabolic events that lead to the toxicity of 1,2-dichloroethane. The muta- genic activity of 1,2-dichloroethane is probably associated with the forma- tion of the episulfonium ion (Anders and Livesey, 1980~. Observations in Humans No new data were found by the committee. Observations in Other Species New data found by the committee are summarized below. Mutagenicity 1,2-dichloroethane was found to be nonmutagenic in the standard Ames Salmonella plate incorporation assay, but was reported to be mutagenic when the plates were placed in desiccators at doses of 3, 6, and 9 mg/plate. Mutagenicity was detected with strains TAlS35 (2-fold increase) and TA100 (20-fold increase), both in the presence and absence of an Aroclor 1254-induced rat liver S9 metabolic activation system (Nest- mann et al., 1980; Stolzenberg and Hine, 1980~. Isolated, perfused liver from male Wistar rats was used as a metabolizing system to study the mu- tagenicity of 1,2-dichloroethane in the Salmonella assay. At the beginning of the test and 90 minutes later, 360 AM of 1,2-dichloroethane was added to the perfused liver. Within 15 to 30 minutes, the extracted bile, which was diluted 10-fold, induced a strong mutagenic effect in strain TA1535 (800 and 600 colonies after 0 and 90 minutes, respectively). The perfusate produced only slight increases in the number of revertants in TA1535. A weak response was obtained with undiluted bile after the addition of only 24 AM of 1,2-dichloroethane to the perfusion system obtained from male Wistar and Sprague-Dawley rats (90 and 70 colonies, respectively). In vivo

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Toxicity of Selected Contaminants 31 experiments with CBA mice given a single intraperitoneal 80 mg/kg injec- tion of 1,2-dichloroethane resulted in the production of bile that, after a 10-fold dilution, gave rise to approximately double the number of sponta- neously produced revertant colonies in TA153S (Rannug and Beije, 1979~. Negative results were obtained in a micronucleus test in CBA male mice at a concentration of 100 mg/kg bw after 30 hours of exposure (Jenssen and Ramel, 1980~. In summary, the data suggest that 1,2-dichloroethane is mutagenic in microbial mutagenicity assays. Carcinogenicity Van Duuren et al. (1979) examined the carcinogenicity of 1,2-dichloroethane bythe mouse skin bioassay. When 126 mg of 1 ,2-dichlo- roethane was administered once dermally to 30 female Sch:HA(ICR) Swiss mice, followed by 5 fig of phorbol myristate acetate (PMA) 14 days later, all the mice had papillomas after 357 days. However, the authors attributed little significance to this result, which was supported by the failure of re- peated applications of 1,2-dichloroethane to induce skin tumors. When 126 mg of 1 ,2-dichloroethane in 0.2 ml of acetone was administered topically for 440 to S94 days to 30 female mice, 26 mice developed lung tumors (P ~ .0005), and three had stomach tumors. The authors did not consider the papillomas significant in the two-stage skin bioassay, noting that no skin tumors appeared after repeated skin exposure. However, the lung tumors observed after repeated skin applications were regarded as significant. Teratogenicity Rao et al. (1980) exposed rats to vapor at 100 and 300 ppm (409 and 1,227 mg/m3) for 7 hours daily during days 6 to 15 of gesta- tion. Ten of the 16 rats exposed to 300 ppm died, and only one rat with an implanted pregnancy had total resorption. At 100 ppm, there was neither increased resorption nor decreased fetal weight. Lane et al. (1982) adminis- tered 1,2-dichloroethane at concentrations up to 1,000 mg/kg/day in the drinking water of mice and found no adverse reproductive effects. In studies of maternal exposures to 1,2-dichloroethane, Vozovaya (1976) and Vozovaya and Malyarova (1975) reported preimplantation reproductive failure and accumulation of the compound in fetal rat liver. The limited studies available for review indicate that 1,2-dichloroethane is not teratogenic to mice or rats. CONCLUSIONS AND RECOMMENDATIONS The information that has become available since the 1980 review of 1,2- dichloroethane in Drinking Water and Health does not permit any more realistic assessment of no-adverse-response levels than the data previously

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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