Advisory Opinion for Cis-I,2-Dichloroethylene Off ice of Drinking Water O.S. Environmental Protection: Agency Washington, D.C» 20460 /AN OFFICE OF DRINKING WATER: HEALTH EFFECTS ADVISOR* The Office of Drinking Water provides advice on health effects upon requestr concerning unregulated contaminants found in drinking water supplies. This information suggests the level of a contaminant in drinking water at which ad- verse health effects would not be anticipated. A margin of safety is factored.in so as to protect the most sensitive members of the general population. The advisories are called Suggested No Adverse Response Levels (SNARLs). SNARLs have been calculated by EPA and by the National Academy of Sciences. (NAS) for selected contaminants in drinking water* An SPA-SNARL and a NAS-SNARL may well differ due to the possible selection of different experimen- tal studies for use as the basis for the calculations. Fur- thermore, NAS-SNARLs are calculated for adults while the EPA-SNARLs are established for a 10 kg body weight child. Normally EPA-SNARLs are provided for one-day, ten-day and longer-term exposure periods where available data exist. A SNARL does not condone the presence of a contaminant in drinking water, but rather provides useful information to assist in the setting of control priorities in cases where contamination occurs. EPA-SNARLs are provided on a case-by- case basis in. emergency situations such as spills, and acci- dents. In the absence of a formal drinking water standard for an .identified drinking water contaminant, the Office of Drink- ing Water develops EPA-SNARLs following the state-of-the-art concepts in toxicology for non-carcinogenic risk for short and longer term exposures. In cases where a substance has been identified as having carcinogenic potential, a range of estimates for carcinogenic risk based upon lifetime exposure as developed by the HAS (1977 or 1980) and/or EPA Carcinogen Assessment Group (EPA, 1980a) is presented. However, the EPA-SNARL calculations for all exposures ignore the possible carcinogenic risk that may result from these exposures* In addition, EPA-SNARLs usually do not consider the health risk resulting from possible synergistic effects of other chemicals; in drinking water, food, and air. EPA-SNARLs are not legally enforceable standards; they are not issued as an official regulation, and they may or may not lead ultimately to the issuance of national standards or Maximum Contaminant Levels (MCLs). The latter must take into account occurrence, relative source contribution factors, treatment technology, monitoring capability, and ------- costs, in addition to health effects* It is quite conceiv- able that the concentration set for EPA-SNARL purposes might. differ from an eventual MCL. The EPA-SNAALs may also change as additional information becomes available. In short, EPA- SNARLs. are offered as advice to assist those such as Region- al and State environmental and health officials, local pub- lic officials, and water treatment facility personnel who are responsible for the protection of public health when dealing with specific contamination situations. General'Information and Properties Cis-l,2-dichloroethylene is one of three isomers of dichloroethylene, all clear, colorless liquids with the molecular formula of C2H2C12 and a molecular weight bf 96.95 (Irish, 1963). It is moderately soluble in water (3.5 g/1 at 25°C) , but soluble in most organic solvents. The cis-isomer has a vapor pressure of 208 Torr ( mm Hg) at 25°C and a boiling point of 60*C. Its vapor density is 3.34, over three times that of air, so that it will settle in low places in a still atmosphere- Its specific gravity is 1.27 at 25°C. Thus, it also would tend to sink in a still body of water. Horsely (1947) lists a binary azeotrope with water (3.35% water by weight, boiling at 55.3°C) and a ternary azeotrope with water and ethanol (2.85% water, 90.5% cis-l,2-dichloro- ethylene and 6.65% ethanol by weight, boiling at 53.8° C). This* isomer also forms an azeotrope with ethanol or methanol alone. In air, one (1) ppm is equivalent to 3.97 mg/m3 and one (1) mg/1 is equivalent to 252 ppm (Irish, 1963). The existing threshold limit value (TLV) for the dichloro- ethylenes in the United States is 200 ppm (794 mg/m3) (ACGIH, 1977). 1,2-Dichloroethylene, as a mixture of the cis- and trans- isomers, is used as a solvent for such substances as fats, rubber, phenol and camphor and for retarding fermentation (Windholz et al., 1976). It also is used as a low tempera- ture extraction solvent for heat sensitive substances and has been employed as a coolant in refrigeration plants (Bardie, 1964). ------- Sources'of Exposure Cis-l,2-dichloroethylene has beea detected in a number of raw and finished drinking waters, principally from ground water sources. During the National Organics Reconnaissance Survey (NORS), this isoraer was detected in Miami drinking water at 16*0 ug/1 (U.S. EPA, 1975)» Concentrations of 0.1 ug/1 were observed in samples from Cincinnati and Philadelphia; none was detected in drinking waters from the other cities. '..,.-..... Cis-l,2-dichloroethylene was detected at an average concen- tration of 0.17 ug/1 in three of 105 raw surface waters examined (2.9%) in a number of surveys (Coniglio, et al, 1980). An average of 0.66 ug/1 was detected in five of 103 samples (4.9%) of finished water from these surface water supplies. Of 13 ground water samples collected in 13 cities during- one or: more of several surveys (NORS, MOMS, or the recent. SRI survey conducted for EPA), four (30.8%) of the samples were positive for cis-l,2-dichloroethylene. Three samples contained less than 1 ug/1; one sample contained 37 ug/1., Pellizzari (1978) found slightly higher levels of 1,2- dichloroethylene (cis- and trans— isomers not distinguished) than 1,1-dichloroethylene during his air sampling survey. The maximum amount of 1,1-dichloroethylene measured was 2500 ng/m^ at Front Royal, Virginia. Maximum concentrations of 1,2-dichloroethylenes detected in various areas of the United States varied from a trace (detection limit » 260 ng/nH or higher) near Magna, Utah, South Charleston, West Virginia, and Grand Canyon, Arizona, to 5263 ng/ra3 at the Kin-Buc Disposal Site in Edison, New Jersey (an industrial site near an urban area). No data are available on the presence of either isomer of 1,2-dichloroethylene in foodstuffs. Pnarmacbkihetics - Cis-l,2-dichloroethylene, as a neutral, low molecular weight, lipid soluble material, should be systemically absorbed following any route of administration. No pharmacokinetic data appear to exist which define the absorption rate of cis-l,2-dichloroethylene after oral exposure. However, pharmacokinetic studies based on urinary and biliary excretion data show that administration of a single oral dose of 1,1-dichloroethylene (1 or 50 mgAg) results in rapid and complete absorption in rats and mice (McKenna, et air 1978b). Rapid absorption and distribution ------- of 1,1-dichloroethylene after intraperitoneal administration to rats also occurs (Jones and Hathway, 1978). For purposes of SNARL development, then, we will assume that cis-1,2- dichloroethylene is absorbed rapidly and completely after oral exposure. Hie absorption of gases from the lung is highly dependent upon the blood:gas partition coefficient. Sato and NaJcajima (1979) showed that cis-l,2-dichioroethylene has a blood:gas partition coefficient of 9.2 in the rat. While it has a high blood solubility, this chemical in air reaches a steady-state within the whole rat in about 2 hours (Filser and Bolt, 1979). Distribution data on cis-l,2-dichloroethylene are not avail- able. However, if this isomer follows the same distribution pattern as that observed for 1,1-dichloroethylene, the highest concentration would be found in the liver and kidney (McKenna, et al, 1978a). These studies were performed in rats, exposed by inhalation to concentrations varying from 10-2000 ppm C-v^40-8000 mg/m3) for 2 or 6 hours. Bonse, et al. (1975) observed that metabolism of cis-1,2- dichloroethylene in perfused rat liver produced detectable amounts of dichloroethanol and dichloroacetic acid, possibly indicating the initial formation of dichloroacetaldehyde. Liebman and Ortiz (1977) have postulated the metabolic pathways for cis-l,2-dichloroethylene. One proposed pathway would be conversion to a reactive epoxide intermediate, then to monochloroacetyl chloride and monochloroacetic acid. The authors also suggested that the production of dichloroace- taldehyde may occur by rearrangement of the glycol or the epoxide with migration of a chloride ion. Their attempts to identify a chromatographic peak as dichloroacetaldehyde were inconclusive. An essential feature of the metabolic pathway is that the compound appears to be metabolized to an epoxide intermedi- ate which is reactive and which may form covalent bonds with tissue macromolecules (Henschler, 1977; Henschler and Bonse, 1977). These authors have synthesized chemically the epox- ides for both isomers of 1,2-dichloroethylene; they believe that these epoxides are formed in vivo during the metabolic process. Each was inactive when tested for mutagenic potential in a modified Ames system (Greim et al, 1975). However, these results only added support to the hypothesis of Henschler and co-workers that the epoxides with symmetri- cal chlorines are more stable and less likely to be mutagen- ic. This does not exclude the possibility that these ------- symmetrical, epoxides may still interact with tissue macro- molecules other than DNA, a process which may result in some form of damage other than autagenesis or carcinogenesis. There apparently are no published studies which test the interaction of the isomers of 1, 2-dichloroethylene with DNA; nor are there any which evaluate the interaction of these two isomers with other tissue macromolecules . No data concerning the excretion of cis-1, 2-dichloroethylene are available. The rate of elimination of 1,1-dichloroethy- lene is relatively rapid, with most of a dose being excreted in the first, 24-72 hours after cessation of exposure* One might assume that cis-1, 2-dichloroethylene would be elimina- ted at a similar rate. Health" fiffects There are no published studies available to us at this time which describe accidental, occupational or controlled expo- sures to cis-1 r 2-dichloroethylene in humans by any route or for any duration of exposure. At high concentrations (4000 ppm) central nervous system effects have been described from unpublished data (Irish, 1963). This concentration was estimated to be sufficient to rapidly produce a state resembling drunkenness and was judged likely to result in unconsciousness if exposure were continued. Data on the toxicity of cis-1, 2-dichloroethylene in animals are severely limited.. No LDso values for the cis- isomer alone have been published. The lowest lethal oral dose for the mixture in the human (70 kg) is estimated to be 500 (McBirney, 1954). Jenkins, et al. (1972) tested the effects of single 400 or 1500 mg/kg oral doses of each isomer of dichloroethylene in corn oil given to adult female Holtzman rats weighing 200-470 g. Liver and plasma enzyme activities were deter- mined 20 hours after dosing. The cis- isomer appeared to exert a more potent effect than did the trans- isomer at the higher dose. No significant difference between the two iso- mers was seen at the lower dose. Each was less potent than 1,1-dichloroethylene. At 400 mg/kg, cis-1, 2-dichloroethylene significantly increased liver alkaline phosphatase to a* level 10% above control (P < 0.05). At 1500 mgAg/ this isomer significantly decreased the level of liver glucose-6- phosphatase to about 88% of control (P < 0.05). Liver tyros ine transaminase was decreased to 80% of control, and plasma alanine transaminase to 14% of control (P < 0.05). Plasma alkaline phosphatase was not altered. x ------- In an animal study reporting on the central nervous system •effect of the cis- isomer, the chemical, did not anesthetize rats in 4 hours at 8000 pom (^-32,000 mg/m3), but at 16,000 ppm (/»^64,000 mg/m3), they were anesthetized in 8 minutes and killed within 4 hours (Irish, 1963). Preundt, and Macholz (1978) showed that single 8-hour inhala- tion exposures to cis-1,2-dichloroethylene at 20Qf 600 or 1000 ppm. (/"-'BOO, 2400 or 4000 mg/m3, respectively) concen- trations resulted in a dose-dependent and significant in- crease in hexobarbital sleeping time, zoxazolamine paralysis time and the metabolic formation of 4-aminoantipyrine (AAP) from aminopyrine in adult female Wistar rats. The effects induced by the cis- isomer were more severe than those induced by the trans- isomer* The authors attributed this difference to the higher uptake of the cis- isomer by liver tissue. The investigators concluded that the inhibition of hepatic drug metabolism, as reflected in the change in AAP levels, was caused by a competitive, reversible interaction of, the chemical with the mixed function: oxidase system. Teratbgehlcity No reports on the teratogenic potential of cis-1,2-dichloro- ethylene are available at the present time. ftutagenicity Both*cis— and trans-1,2-dichloroethylene were non-mutagenic when assayed with E. coli K12 at similar concentrations used for 1,1-dichloroetEylene at which the latter was found to be mutagenic (Greim, et al, 1975). The medium concentration of the cis-isomer was 2.9 mM, that of t-l,2-DCE was 2.3 mM, and that of 1,1-DCE was 2.5 mM. Both 1,1-dichloroethylene and cis-1, 2-dichloroethylene were mutagenic in the host-mediated assay using Salmonella tester strains in- mice (Gerna and Kypenova, 1977). Of the three isomeric dichloroethylenes, only cis-1,2-dichloroethylene produced chromosomal aberrations in bone marrow cells of mice following repeated intraperitoneal injections (daily injections at 1/2 LD$Q for five or ten days). Carcinogenic!ty No studies have been completed which test the carcinogenic potential of cis-1,2-dichloroethylene. It is currently under consideration by the National Toxicology Program. ------- SNARL Development One-day SNARL There are few animal studies available which provide dose- response data on the toxicity of cis-l,2-dichloroethylene (Irish, 1963; Jenkins et al, 1972; Freundt and Macholz, 1973). Only the study by Jenkins and co-workers provides information on what might be identified as a minimal effect level. In measuring levels of three liver enzymes and two plasma enzymes, indicators of liver function, these authors showed that a single 400 mg/kg oral dose to the rat produced a significant change only in liver alkaline phosphatase, while the other enzyme levels were not significantly affec- ted. This slight degree of liver involvement is felt not to be life-threatening; evidence developed for 1,1-dichloro- ethylene points to the fact that this degree of liver effect appears to be quite rapidly and completely reversible once exposure has ceased. The Jenkins et al. results may be used to develop a one-day SNARL. It would be derived thusly: 400 mg/kg x 10 kg x 100% « 4 mg/1 .1000 x 1 Where: 400 mg/kg * minimal effect dose • 10 kg - weight of protected individual (child) 100% • percentage of dose absorbed 1000 * safety factor 1 * volume in liters of drinking water imbibed per day by 10 kg child , Ten-day SNARL A ten-day SNARL can be derived from the one-day SNARL which will adequately protect the sensitive individual from adverse health effects over that duration of exposure. As stated above, any slight alteration in liver function is felt to be quickly and readily reversible after cessation of exposure. A ten-day SNARL would be derived simply by dividing the one- day SNARL by 10 to get 0.4 mg/1. ------- 8 Analysis ^^•MM^H^HM^^B^^B^" , • • Cis-l,2-dichloroethylene and trans-l,2-dichloroethylene can be analyzed by the purge-and-trap gas chromatographic proce- dure used for the determination of volatile organohalides in drinking waters (U.S. EPA, 198Ob; Bellar and Lichtenberg, 1979). In this procedure, volatile components are extracted by an inert gas which is bubbled through the aqueous sample. The compounds are swept from the purging device into a short sorbent trap. After a predetermined period of time, the trapped components are thermally desorbed and backflushed onto the head of a gas chromatographic column where separa- tion takes place. The recommended primary columns for organohalide analysis do not adequately resolve the cis- and trans-l,2-dichloroethy- lene isomersv Therefore, it is suggested that the column recommended for confirmatory analysis be used when these two chemicals are being determined. The recommended chromato- graphic conditions for the analysis are given belowr Column: Six feet long x 0.1 inch ID stainless steel or glass. Packing; n — octane on Porisil - C (100/120 mesh). Temperature; 50°C isothermal for 3 minutes, then program at 6'/minute to 170°C. Carrier"gas? Helium at 40 ml/minute* Detection; Hall model electrolytic conductivity or other halogen specific detector. Sample"volume; 5 ml. The retention time for- the cis- isomer is 726 seconds and for the trans- isomer is 563 seconds under the conditions specified above. Confirmatory analysis of each isomer by a second column or by GC-MS techniques is recommended. Al- though the MS itself will not distinguish between cis- and trans-l,2-dichloroethylene, the difference in GC retention times will allow for proper identification. The purge-and-trap procedure is applicable to the measure- ment of most, organohalides over a concentration range of 0.1 to 1500 ug/1 when the Hall model electrolytic conductivity detector is used. Other halogen specific detectors are generally limited to measurements of 1.0 ug/1 or above. ------- treatment The best options for community systems to remove cis-1,2- dichloroethylene appear to be granular activated carbon (GAC), diffused or packed tower aeration/ and synthetic resins. The preferred treatment needs to be evaluated on a case-by-case basis* Pilot scale testing is essential to estimate cost effectiveness since the quality of water may greatly affect performance for each of the treatments* Pilot scale data indicate that this compound is not as easily removed by aeration (GAC or synthetic resins) as is trichloroethylene or tetrachloroethylene. Counter current diffused aeration, in a 30* diameter 10* deep column, operating with a 10 minute contact time and an air to water ratio of 30:1, removed 85% of cis-1,2-dichloro- ethylene (present in groundwater at concentrations of 18-118 ug/1). At an air to water ratio of 5:1, and the same oper- ating conditions, 58% cis-1,2-dichloroethylene was removed from the same water. Counter current diffused aeration with 1.5 in. diameter columns, a 10 minute contact time and an air to water ratio~of 4:1 removed 80% of the chemical in a different groundwater sample containing 0.5 ug/1 of the chemical. The performance of diffused aeration will be affected by the design of the diffusers and matrix effects (e.g., TOC and dissolved solids content). The extent to which each of these effects performance has not yet been evaluated. Packed column aeration may be a more economical treatment alternative than diffused aeration. However, no empirical data are yet available to compare costs. t GAC with a bed depth of 2.5 ft and an Empty Bed Contact Time (EBCT) of 6 minutes was used to treat a groundwater contain- ing 25 ug/1 cis-1,2-dichloroethylene and 10 mg/1 TOC. Break- through of the chemical (when concentrations in the effluent exceeded .1 ug/1) occurred after 18 days of service or 4,300 bed volumes of throughput. The loading of cis-1,2-dichloro- ethylene on the carbon at breakthrough was 0.3 mg/gm. Amber- sorb XE-340, a synthetic resin, with the same bed depth and EBCT, did not have breakthrough until after 60 days of service or 14,400 bed volumes of throughput; the loading of the chemical on the resin at breakthrough was 0.7 mg/gm. The extent that service life of the adsorbent will be affected by other organic substances competing for adsorption sites is not yet known. ------- 10 In emergency situations,, or where funding is not available for community treatment, boiling can be effectively used to reduce cis-l,2-dichloroethylene concentrations to acceptable levels. Ten minutes of boiling at a water depth of 8 cm. should reduce concentrations of 150 ug/1 to 5 ug/1 or less. Conclusions'and Recommendations , - One-day and ten-day SNARLs of 4 mg/1 and 0.4 mg/1, respec- tively, have been developed for cis-l,2-dichloroethylene. At this time, no satisfactory dose-response, no-effect level data exist from which a longer-term SNARL can be derived. In addition, it would be preferable to have dose-response, no-effect data for the one-day and ten-day SNARLs as well. A grant has been awarded under the EPA Competitive Grants program to study the toxicity of all three dichloroethylenes and compare the percentage absorption via ingestion and inhalation. Data from this study, which will include no- effect, dose-response data, should be available in 1982. At that time, the data will be reviewed and, if found suitable, will form the basis for the revision of the existent SNARLs. If the data are fpund lacking, further research will be requested. ------- 11 REFERENCES American Council of Governmental Industrial Hygienists. 1977. Documentation of the threshold limit value. 3rd ed. Cincinnati, Ohio. Bellar, T. and J.J. Lichtenberg. 1979. Semiautomated headspace analysis of drinking waters and industrial watersfor purgeable organic compounds. In: Measurement of organic pollutants in water and wastewater, ASTM STP 686. C.E. Van Ball, ed.American Society for Testing and Materials, pp. 108-129. Bonse, G., T. Urban, D. Reichert and D."Henschler. 1975. Chemical reactivity, metabolic oxirane formation and bio- logical activity reactivity of chlorinated ethylenes in the isolated perfused rat liver preparation. Biochem. Pharmacol. 24:1829-1834. Cerna, M. and H. Kypenova. 1977. Mutagenic activity of chloroethylenes analysed by screening system tests. Mutat.Res. 46:214: Coniglio, W., K. Miller and D. MacKeever. 1980. The occur- rence of volatile organics in drinking water. Briefing prepared for DAA for Drinking Water. U.S. EPA. 48 pp. Filser, J.G. and H.M. Bolt. 1979. Pharmacokinetics of halogenated ethylenes in rats. Arch. Toxicol. 42:123-136. Preundt, K.J. and J. Macholz. 1978. Inhibition of mixed function oxidases in rat liver by trans- and cis-l,2-di- chloroethylene* Toxicology 10:131-139. Greim, H., G. Bonse, Z. Radwan, D. Reichert, D. Henschler. 1975. Mutagenicity in vitro and potential carcinogenicity of chlorinated ethylenes as a function of metabolic oxi- rane formation. Biochem. Pharmacol. 24:2013-2017. . Bardie, D.W.F. 1964. Dichloroethylene. In: Kirk-Othmer encyclopedia of chemical technology, 2nd edition. Mark, H.F., J.J. McKetta, Jr. and D.F. Othmer, eds. Wiley- Interscience, New York, NY. 5:178-183. Henschler, D. 1977. Metabolism and mutagenicity of halo- genated olefins - a comparison of structure and activity. Environ. Health Perspec. 21:61-64. ------- 12 Henschlerv D» and G» Bonse. 1977» Metabolic activation of chlorinated ethylenes? Dependence of mutagenic effect on electrophilic reactivity of the metabolically formed epox- ides. Arch. Toxicol. 39:8-12. Horsely, L.H. 1947. Table of azeotropes and non-azeotropes. Industrial & Engineering Chemistry, Analytical Chemistry. 19:508-600. Irish, D.D. 1963. Vinylidene chloride. In: Industrial Hygiene and Toxicology, 2nd ed. P.A. Patty, ed. Vol. II. John Wiley and Sons, Inc., New York. pp. 1305-1309. Jenkins, L.J. Jr., M.J. Trabulus and S.D. Murphy. 1972. Biochemical effects of 1,1-dichloroethylene in rats: Comparison with carbon tetrachloride and 1,2-dichloro- ethylene. Toxicol. Appl. Pharmacol. 23:501-510. Jones, B.K. and D.E. Hathway. 1978. The biological fate of vinylidene chloride in rats. Chem. Biol. Interaction. 20: 27-41. Liebman, K.C. and E. Ortiz. 1977. Metabolism of halogena- ted ethylenes. Environ. Health Perspec. 21:91-97. McBirney, R.S. 1954. Trichloroethylene and dichloroethy- lene poisoning. Arch. Ind. Hyg. Occup. Med. 10:130. . » McKenna, M.J., J.A. Zempel, E.O. Madrid, and P.J. Gebring. 1978a. The pharmacokinetics of (14C) vinylidene chloride in rats following inhalation exposure. Toxicol. Appl.. Pharmacol. 45:599-610. McKenna, M.J., J.A. Zempel, E.O. Madrid, W.H. Braun and P.J. Gehring. 1978b. Metabolism and pharmacokinetic profile of vinylidene chloride in rats following oral administra- tion. Toxicol. Appl. Pharmacol. 45:821-835. National Academy of Sciences. 1977. Drinking Water and Health, Volume 1, Safe Drinking Water Committee, Washing- ton, D.C. National Academy of Sciences. 1980. Toxicity of selected drinking water contaminants. In: Drinking Water and Health, Volume 3, Safe Drinking Water Committee, Washing- ton, D.C. National Institute of Occupational Safety and Health. 1978. Registry of toxic effects of chemical substances. Lewis, R.S., Sr. and R.L- Tathen, eds. p. 563.' ------- 13 Pellizzarl, E.D. 1978. Quantification of chlorinated 'hydrocarbons in previously collected air samples. O.S. EPA, Research Triangle Park, NC^ EPA-450/3-78-112. Sato, A. and T. Nakajima. 1979. A structure-activity relationship of some chlorinated hydrocarbons. Arch. Environ. Health. 34:69-75. U.S. EPA. 1975. Preliminary assessment of suspected car- cinogens in drinking water. Report to Congress. Office of Drinking Water, Washington, D.C. U.S. EPA. 1980a. Water Quality Criteria Documents; Avail- ability. Federal Register 45(231):79318-79379. U.S. EPA* 1980b. The determination of halogenated chemical indicators of industrial contamination in water by the purge and trap method, Method 502.1. Environmental Moni- toring and Support Laboratory, Organic Analyses Section, Cincinnati, Ohio 45268. September. Windholz, M., S. Budvari, L.Y. Stroumtsos and M.N. Fertig, eds. 1976. The Merck Index, 9th ed. Merck and Co., Rahway, New Jersey. ------- |