Toxicity Profiles
Formal Toxicity Summary for 1,1-DICHLOROETHANE
NOTE: Although the toxicity values presented in these toxicity profiles were correct at the time they were produced, these values are subject to change. Users should always refer to the Toxicity Value Database for the current toxicity values.
- EXECUTIVE SUMMARY
- 1. INTRODUCTION
- 2. METABOLISM AND DISPOSITION
- 1. INTRODUCTION
- 2.1 ABSORPTION 2.2 DISTRIBUTION 2.3 METABOLISM 2.4 EXCRETION
- 3. NONCARCINOGENIC HEALTH EFFECTS
- 3.1 ORAL EXPOSURES 3.2 INHALATION EXPOSURES 3.3 OTHER ROUTES OF EXPOSURE 3.4 TARGET ORGANS/CRITICAL EFFECTS
- 4. CARCINOGENICITY
- 4.1 ORAL EXPOSURES 4.2 INHALATION EXPOSURES 4.3 OTHER ROUTES OF EXPOSURE 4.4 EPA WEIGHT-OF-EVIDENCE 4.5 CARCINOGENICITY SLOPE FACTORS
- 5. REFERENCES
February 1994
Prepared by: Dennis M. Opresko, Ph.D., Chemical Hazard Evaluation Group, Biomedical and Environmental Information Analysis Section, Health Sciences Research Division, *.
Prepared for: Oak Ridge Reservation Environmental Restoration Program.
*Managed by Martin Marietta Energy Systems, Inc., for the U.S. Department of Energy under Contract No. DE-AC05-84OR21400.
EXECUTIVE SUMMARY
1,1-Dichloroethane is used primarily as an intermediate in manufacturing vinyl chloride and 1,1,1-trichloroethane; it is also used as a cleaning agent and degreaser and as a solvent for plastics, oils, and fats (ATSDR, 1990).
The available evidence indicates that 1,1-dichloroethane can be readily absorbed following inhalation and oral exposures (ATSDR, 1990). The anesthetic effects of 1,1-dichloroethane are evidence that the chemical reaches the central nervous system (CNS). Acetic acid is a major metabolite, and 2,2-dichloroethanol, chloroacetic acid, and dichloroacetic acid are minor metabolites (McCall et al., 1983). In animal studies, orally administered 1,1-dichloroethane was excreted primarily in expired air as the unmetabolized chemical (Mitoma et al., 1985).
No information is available on the oral toxicity of 1,1-dichloroethane to humans. In animals, a drinking water concentration of up to 2500 mg/L for 52 weeks caused no adverse effects in male mice (Klaunig et al., 1986), and maximum gavage doses of 764 mg/kg/day (male Osborne-Mendel rats), 950 mg/kg (female Osborne-Mendel rats), 2885 mg/kg (male B6C3F1 mice), and 3331 mg/kg (female B6C3F1 mice), 5 days/week for 78 weeks (3 weeks on, 1 week off) resulted in no histopathological changes (NCI, 1978). A subchronic oral RfD of 1 mg/kg/day and a chronic oral RfD of 0.1 mg/kg/day (based on an inhalation study in rats and route-to-route extrapolation) are listed in HEAST (EPA, 1993a); however, an oral RfD is currently not found in IRIS. A U.S. Environmental Protection Agency (EPA) reassessment of the oral RfD is pending (EPA, 1993b).
At high vapor concentrations (26,000 ppm), 1,1-dichloroethane induces anesthesia and can cause cardiac arrhythmia in humans, but no fatalities have occurred (ATSDR, 1990). Adverse effects following subchronic or chronic exposures to humans have not been reported. In animal studies, 1,1-dichloroethane did not cause developmental or reproductive effects but did delay rib ossification in rats (Schwetz et al., 1974). Kidney damage was observed in cats exposed to 2025 mg/m3 (6 hours/day, 5 days/week) for 13 weeks followed by 4050 mg/m3 for an additional 13 weeks; however, similar effects were not seen in rats, rabbits, or guinea pigs. A subchronic RfC of 5 mg/m3 and a chronic RfC of 0.5 mg/m3 are listed in HEAST (EPA, 1993a). These RfCs are based on the adverse renal effects in cats following subchronic inhalation exposure. An RfC for 1,1-dichloroethane is not currently on IRIS although an EPA reassessment of the compound is pending (EPA, 1993b).
1,1-Dichloroethane is placed in Group C, possible human carcinogen (EPA, 1993b), based on no human data and limited evidence of carcinogenicity in two animal species (rats and mice), as shown by an increased incidence of mammary gland adenocarcinomas and hemangiosarcomas in female rats and an increased incidence of hepatocellular carcinomas and benign uterine polyps in mice (EPA, 1993b). Slope factors and unit risks have not been calculated.
1. INTRODUCTION
1,1-Dichloroethane is used primarily as an intermediate in the manufacture of vinyl chloride and 1,1,1-trichloroethane; it is also used as a cleaning agent and degreaser and as a solvent for plastics, oils and fats (ATSDR, 1990).
The physicochemical properties of 1,1-dichloroethane, i.e., volatility (vapor pressure 182 mm Hg, Henry's Law Constant, 0.0057 atmm3/mol), water solubility (5500 mg/L), and low soil adsorption coefficient (30-58), suggest that 1,1-dichloroethane would volatilize relatively rapidly from surface waters and soil surfaces, but any soil fraction not subject to volatilization may migrate to groundwater, especially in soils of low organic carbon (U.S. Air Force, 1989). Volatilization of 1,1-dichloroethane from a disposal site could result in inhalation exposures. In addition, exposure through drinking water is possible as a result of groundwater contamination.
2. METABOLISM AND DISPOSITION
2.1. ABSORPTION
Animal studies have shown that 1,1-dichloroethane can be absorbed through the gastrointestinal tract (Mitoma et al., 1985). The anesthetic effects of 1,1-dichloroethane are evidence of its systemic absorption following inhalation exposures (ATSDR, 1990). Dermal absorption has been reported in animals (Browning, 1965).
2.2. DISTRIBUTION
Information on the distribution of 1,1-dichloroethane to tissues and organs following exposure is quite limited. The anesthetic effects of 1,1-dichloroethane indicate that the chemical reaches the CNS and is probably distributed throughout the rest of the body.
2.3. METABOLISM
The metabolism of 1,1-dichloroethane appears to be mediated by the microsomal cytochrome P-450 system (ATSDR, 1990). In vitro studies have shown that acetic acid is a major metabolite of 1,1-dichloroethane and that 2,2-dichloroethanol, chloroacetic acid, and dichloroacetic acid are minor metabolites (McCall et al., 1983). Animal in vivo studies indicate that 1,1-dichloroethane can be metabolized to CO2 (Mitoma et al., 1985).
2.4. EXCRETION
Following oral exposures to rats and mice, 1,1-dichloroethane is excreted primarily in expired air as unmetabolized chemical (70.4% of dose in mice and 86.1% of dose in rats) (Mitoma et al., 1985). A portion of the dose (25.2% in mice and 5.1% in rats) is metabolized to CO2, and only a small fraction (1.6% in mice and 0.9% in rats) is metabolized and excreted in urine and feces (Mitoma et al., 1985).
3. NONCARCINOGENIC HEALTH EFFECTS
3.1. ORAL EXPOSURES
3.1.1. Acute Toxicity
3.1.1.1. Human
Information on the acute oral toxicity of 1,1-dichloroethane to humans was not found in the available literature.
3.1.1.2. Animal
An acute oral LD50 value of 725 mg/kg has been reported for rats (RTECS, 1989).
3.1.2. Subchronic Toxicity
3.1.2.1. Human
Information on the subchronic oral toxicity of 1,1-dichloroethane to humans was not found in the available literature.
3.1.2.2. Animal
A daily oral dose of 5620 mg/kg given to rats 5 days/week for 6 weeks did not result in any lethal effects (NCI, 1978), and similar results were seen in mice dosed with 10,000 mg/kg/day (EPA, 1984).
3.1.3. Chronic Toxicity
3.1.3.1. Human
Information on the chronic oral toxicity of 1,1-dichloroethane to humans was not found in the available literature.
3.1.3.2. Animal
No histopathological lesions occurred in the liver, lungs, or kidneys of male mice that were exposed for 52 weeks to 1,1-dichloroethane in their drinking water at concentrations up to 2500 mg/L (Klaunig et al., 1986). In carcinogenicity studies conducted by the National Cancer Institute (1978), no histopathological lesions were seen in male and female Osborne-Mendel rats and B6C3F1 mice treated by gavage 5 days/week for 78 weeks (3 weeks on, 1 week off) at time-weighted average (TWA) dose levels of 764 and 382 mg/kg/day (male rats), 950 and 475 mg/kg/day (female rats), 2885 and 1442 mg/kg/day (male mice), and 3331 and 1665 mg/kg/day (female mice). The results of the bioassay were complicated by high early mortality (possibly caused by pneumonia) in both treated and control animals.
3.1.4. Developmental and Reproductive Toxicity
Information on the reproductive and developmental toxicity of 1,1-dichloroethane to humans and animals exposed orally was not found in the available literature.
3.1.5. Reference Dose
3.1.5.1. Subchronic
ORAL RfD: 1 mg/kg/day (U.S. EPA, 1993a)
UNCERTAINTY FACTOR: 100
NOAEL: 115 mg/kg/day
PRINCIPAL STUDY: Hofmann et al., 1971
COMMENT: The same study applies to the chronic RfD (see Section 3.1.5.2).
3.1.5.2. Chronic
ORAL RfD: 0.1 mg/kg/day (U.S. EPA, 1993a)
UNCERTAINTY FACTOR: 1000
MODIFYING FACTOR: Not given
NOAEL: 115 mg/kg/day
PRINCIPAL STUDY: Hofmann et al., 1971
COMMENT: Based on a 13-week inhalation study in rats and route-to-route extrapolation. While the oral RfD is listed in HEAST (EPA, 1993a), the IRIS coversheet indicates that an oral RfD assessment for 1,1-dichloroethane is pending (EPA, 1993b).
3.2. INHALATION EXPOSURES
3.2.1. Acute Toxicity
3.2.1.1. Human
At high concentrations (26,000 ppm), 1,1-dichloroethane induces anesthesia and can cause cardiac arrhythmia, but no fatalities have been reported (ATSDR, 1990).
3.2.1.2. Animal
Vapors of 1,1-dichloroethane are relatively low in acute toxicity but can cause narcosis at high concentrations. Rats survived an 8-hour vapor exposure to 4000 ppm but not 16,000 ppm (Clayton and Clayton, 1981). Those exposed to 32,000 ppm survived 30 minutes of exposure but died after 2.5 hours.
3.2.2. Subchronic Toxicity
3.2.2.1. Human
Information on the subchronic inhalation toxicity of 1,1-dichloroethane to humans was not found in the available literature.
3.2.2.2. Animal
In a study conducted by Hofmann et al. (1970; see also Hofmann et al., 1971), rats, guinea pigs, rabbits, and cats exposed to 2025 mg/m3 (500 ppm), 6 hours daily, 5 days a week for 13 weeks exhibited no adverse effects. Rats, guinea pigs, and rabbits tolerated an additional 13 weeks at 4050 mg/m3 (1000 ppm) with no adverse effects. However, cats exposed to 4050 mg/m3 suffered renal damage as evidenced by elevated serum urea and creatinine levels and histopathological signs of renal tubular dilation and degeneration.
3.2.3. Chronic Toxicity
3.2.3.1. Human
Information on the chronic inhalation toxicity of 1,1-dichloroethane to humans or animals was not found in the available literature.
3.2.4. Developmental and Reproductive Toxicity
3.2.4.1. Human
Information on the developmental/reproductive toxicity of 1,1-dichloroethane in humans following inhalation exposures was not found in the available literature.
3.2.4.2. Animal
In studies in which pregnant rats were exposed to 1,1-dichloroethane for 7 hours/day on gestation days 6 through 15, concentrations of 3000 ppm (15,390 mg/m3) or 6000 ppm (24,300 mg/m3) caused no adverse effects on fetal weight or on implants/dam, live fetuses/dam, and resorptions/dam. No teratogenic effects were observed; however, ossification of the ribs was delayed in the fetuses in the high-dose group (Schwetz et al., 1974).
3.2.5. Reference Concentration
3.2.5.1. Subchronic
INHALATION RfC: 5 mg/m3 (EPA, 1993a)
UNCERTAINTY FACTOR: 100
NOAEL: 138 mg/kg/day
PRINCIPAL STUDIES: Hofmann et al., 1971
COMMENT: The same study applies to the chronic RfD (refer to Subsect. 3.2.5.2).
3.2.5.2 Chronic
INHALATION RfC: 0.5 mg/m3 (EPA, 1993a)
UNCERTAINTY FACTOR: 1000
MODIFYING FACTOR: NA
NOAEL: 138 mg/kg/day
PRINCIPAL STUDIES: Hofmann et al., 1971
COMMENT: Based on an inhalation study on cats: critical effect--kidney damage. While the RfC is listed in HEAST (EPA, 1993a), the IRIS coversheet indicates that an EPA RfC assessment for 1,1-dichloroethane is pending (EPA, 1993b). HEAST states that the inhalation RfC values "were derived from methodology that is not current with the interim inhalation methodology used by the RfD/RfC Work Group."
3.3. OTHER ROUTES OF EXPOSURE
3.3.1. Acute Toxicity
3.3.1.1. Human
Information on the acute toxicity of 1,1-dichloroethane to humans or animals by exposure routes other than ingestion or inhalation was not found in the available literature.
3.3.1.2. Animal
Intraperitoneal doses of 1000 mg/kg in mice resulted in some swelling of the renal tubules but no necrosis (Clayton and Clayton, 1981). Repeated applications of 1,1-dichloroethane to the skin of rabbits resulted in slight edema and very slight necrosis after 6 applications (Mackison et al., 1981). When instilled in the eyes of rabbits, the chemical caused immediate but moderate conjunctival irritation and swelling that subsided within one week (Mackison et al., 1981).
3.3.2. Subchronic Toxicity
Information on the subchronic toxicity of 1,1-dichloroethane to humans or animals by exposure routes other than ingestion or inhalation was not found in the available literature.
3.3.3. Chronic Toxicity
Information on the chronic toxicity of 1,1-dichloroethane to humans or animals by exposure routes other than oral or inhalation was not found in the available literature.
3.3.4. Developmental and Reproductive Toxicity
Information on the reproductive and developmental toxicity of 1,1-dichloroethane to humans or animals by exposure routes other than ingestion or inhalation was not found in the available literature.
3.4. TARGET ORGANS/CRITICAL EFFECTS
3.4.1. Oral Exposures
No target organs have been identified for acute, subchronic, or chronic oral exposures to humans or animals.
3.4.2. Inhalation Exposures
3.4.2.1. Primary Target Organ(s)
Kidney: Nephrotoxicity in cats following subchronic exposures.
3.4.2.2. Other Target Organ(s)
1. Nervous system: Anesthetic at high concentrations in humans.
2. Heart: Cardiac arrhythmia has been reported in humans following use as an anesthetic.
3. Developmental: Delayed rib ossification in rats.
4. CARCINOGENICITY
4.1. ORAL EXPOSURES
4.1.1. Human
No information is available on the oral carcinogenicity of 1,1-dichloroethane in humans.
4.1.2. Animal
In a study conducted by the National Cancer Institute (1978), the carcinogenicity of technical grade 1,1-dichloroethane was evaluated in male and female Osborne-Mendel rats and B6C3F1 mice. Test animals were treated by gavage 5 days/week for 78 weeks (3 weeks on, 1 week off) at TWA dose levels of 764 and 382 mg/kg/day (male rats), 950 and 475 mg/kg/day (female rats), 2885 and 1442 mg/kg/day (male mice), and 3331 and 1665 mg/kg/day (female mice). The results of the bioassay were complicated by high early mortality (possibly caused by pneumonia) in both treated and control animals. However, statistically significant increases were observed in the incidence of hemangiosarcomas (0/19 in the controls, 0/50 in the low-dose group, and 4/50 in the high-dose group) and mammary adenocarcinomas (1/20 in the untreated controls, 0/19 in the vehicle controls, 1/50 in the low-dose group, and 5/50 in the high-dose group) among female rats. In male mice surviving 52 weeks, an increased incidence of hepatocellular carcinomas was statistically significant (1/19, 6/72, 8/48, and 8/32 in the matched vehicle control group, pooled vehicle control group, low-dose group, and high-dose group, respectively). In female mice, the incidence of benign endometrial stromal polyps (4/46) was statistically significant in the high-dose group; these polyps were not observed in any other group.
The cancer promoting potential of 1,1-dichloroethane in male B6C3F1 mice was evaluated by Klaunig et al. (1986). Diethyl nitrosamine (DENA) was used as an initiating agent. Groups of test animals were given deionized drinking water or drinking water with DENA (10 mg/L) for 4 weeks followed by 24 or 52 weeks of drinking water containing 0, 835, or 2500 mg/L of 1,1-dichloroethane. Neither the initiated nor the noninitiated groups exhibited a significant increase in the incidence of liver or lung tumors compared with initiated or noninitiated controls. EPA (1993b) notes that the short duration of the study and the high incidence of liver tumors in the controls may have reduced the study's ability to reveal a statistically significant tumor promoting effect.
4.2. INHALATION EXPOSURES
No information is available on the inhalation carcinogenicity of 1,1-dichloroethane in humans or animals.
4.3. OTHER ROUTES OF EXPOSURE
The cancer initiating and promoting potential of 1,1-dichloroethane was evaluated by Story et al. (1986), Herren-Freund and Pereira (1986), and Milman et al. (1988) using the rat liver foci assay. Negative results were obtained in the initiation tests in which phenobarbital was used as the promoting agent, and positive results were seen in the promotion tests in which diethylnitrosamine was used as the initiating agent.
1,1-Dichloroethane did not induce cell transformation in vitro when tested on BALB/c-3T3 mouse cells without an exogenous metabolic activation system (Tu et al., 1985); however, cell transformation was enhanced when the chemical was incubated with cultured Syrian hamster embryo cells prior to exposure to adenovirus SA7 (Hatch et al., 1983).
4.4. EPA WEIGHT-OF-EVIDENCE
4.4.1. Oral
A risk assessment for this substance is under review by an EPA work group (EPA, 1993b).
4.4.2. Inhalation
Classification--C; possible human carcinogen (EPA, 1993b)
Basis--No human data and limited evidence of carcinogenicity in two animal species (rats and mice) as shown by an increased incidence of mammary gland adenocarcinomas and hemangiosarcomas in female rats and an increased incidence of hepatocellular carcinomas and benign uterine polyps in mice (EPA, 1993b).
VERIFICATION DATE: 12/07/89.
4.5. CARCINOGENICITY SLOPE FACTORS
A slope factor has not been calculated for 1,1-dichloroethane (EPA, 1993b).
5. REFERENCES
ATSDR (Agency for Toxic Substances and Disease Registry). 1990. Toxicological Profile for 1,1-Dichloroethane. U.S. Public Health Service, Agency for Toxic Substances and Disease Registry, Atlanta, GA. 103 pp. ATSDR/TP-90-12.
Browning, E. 1965. Toxicity and Metabolism of Industrial Solvents. Elsevier Science Publishing Co., New York., pp. 247-252. (Cited in ATSDR, 1990)
Clayton, G.D. and F.E. Clayton, eds. 1981. Patty's Industrial Hygiene and Toxicology, 3rd rev. ed., Vol. 2A, 2B, Toxicology, John Wiley and Sons, Inc., New York.
Hatch, G.G., et al. 1983. "Chemical enhancement of viral transformation in Syrian hamster embryo cells by gaseous and volatile chlorinated methanes and ethanes." Cancer Res. 43:1945-1950.
Herren-Freund, S.L. and M.A. Pereira. 1986. "Carcinogenicity of by-products of disinfection in mouse and rat liver." Environ. Health Perspect. 69:59-65. (Cited in ATSDR, 1990).
Hofmann, H.T., H. Birnstiel, and P. Jobst. 1970. "Inhalation toxicity of 1,1- and 1,2-dichloroethane." Arch. Pharmakol. 266:360-361. (As cited in ATSDR, 1990; Clayton and Clayton, 1981).
Hofmann, H.T., H. Birnstiel, and P. Jobst. 1971. "On the inhalation toxicity of 1,1- and 1,2-dichloroethane." Arch. Toxikol. 27:248-265. (As cited in EPA, 1993a).
Klaunig, J.E., R.J. Ruch, and M.A. Pereira. 1986. "Carcinogenicity of chlorinated methane and ethane compounds administered in drinking water to mice." Environ. Health Perspect. 69:89-95. (Cited in ATSDR, 1990).
Mackison, F.W., R.S. Stricoff, and L.J. Partridge, Jr. 1981. NIOSH/OSHA Occupational Health Guidelines for Chemical Hazards. U.S. Department of Health and Human Services, Washington, DC. NIOSH Publ. No. 81-123.
McCall, S.N., P. Jurgens, and K.M. Ivanetich. 1983. "Hepatic microsomal metabolism of dichloroethanes." Biochem. Pharmacol. 3:207-213. (Cited in ATSDR, 1990).
Milman, H.A., et al. 1988. "Rat liver foci and in vitro assays to detect initiating and promoting effects of chlorinated ethanes and ethylenes." Ann. N.Y. Acad. Sci. 534:521-530.
Mitoma, C., T. Steeger, S.E. Jackson, et al. 1985. "Metabolic disposition study of chlorinated hydrocarbons in rats and mice." Drug Chem. Toxicol. 8:183-194. (Cited in ATSDR, 1990).
NCI (National Cancer Institute). 1978. Carcinogenesis Bioassay of 1,1-Dichloroethane. NCI Carcinogenesis Technical Report Series Number 66, NCI-CG-TR-66, DHEW Publications No. (NIH) 78-1316.
RTECS (Registry of Toxic Effects of Chemical Substances). 1989. National Institute of Occupational Safety and Health (NIOSH) online database available through the National Library of Medicine's MEDLARS system, Washington, D.C.
Schwetz, B.A.; B.K.G. Leong, and P.J. Gehring. 1974. "Embryo- and fetotoxicity of inhaled carbon tetrachloride, 1,1-dichloroethane, and methyl ethyl ketone in rats." Toxicol. Appl. Pharmacol. 28:452-464. (Cited in U.S. Air Force, 1989).
Story, D.L., E.F. Meierhenry, C.A. Tyson, and H.A. Milman. 1986. "Differences in rat liver enzyme-altered foci produced by chlorinated aliphatics and phenobarbital." Toxicol. Ind. Health 2(4):351-362.
Tu, A.S., T.A. Murray, K.M. Hatch, A. Sivak, and H.A. Milman. 1985. "Transformation of BALB/c-3T3 cells by chlorinated ethanes and ethylenes." Cancer Lett. 25:85-92.
U.S. Air Force. 1989. "1,1-Dichloroethane." In: The Installation Restoration Program Toxicology Guide, vol. 1. Wright-Patterson Air Force Base, OH. pp. 8-1 to 8-27.
U.S. EPA. 1984. Health Effects Assessment for 1,1-Dichloroethane. U.S. Environmental Protection Agency, Environmental Criteria and Assessment Office, Office of Research and Development, Cincinnati, OH. EPA/540/1-86-027.
U.S. EPA. 1993a. Health Effects Assessment Summary Tables. Annual 1993. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Emergency and Remedial Response. Washington, DC.
U.S. EPA. 1993b. Integrated Risk Information System (IRIS). 1,1-Dichloroethane. Online file, updated 01/22/92, retrieved October, 1993. Office of Health and Environmental Assessment, Cincinnati, OH.
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