The Risk Assessment Information System

Toxicity Profiles

Formal Toxicity Summary for 1,2-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
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

May 1994

Prepared by Dennis M. Opresko, Ph.D., Chemical Hazard Evaluation and Communication Program, Biomedical and Environmental Information Analysis Section, Health Sciences Research Division, *, Oak Ridge, Tennessee.

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

1,2-Dichloroethane is used primarily in the manufacture of vinyl chloride, as well as in the synthesis of tetrachloroethylene, trichloroethylene, 1,1,1-trichloroethane, vinylidene chloride, aziridines, and ethylenediamines (U.S. Air Force 1989, ATSDR 1992). It is added to gasoline as a lead-scavenging agent, and, in the past, has been used as a metal degreasing agent; a solvent; and a fumigant for grain, upholstery, and carpets. It has also been used in paints, coatings, adhesives, varnishes, finish removers, soaps, and scouring agents (U.S. Air Force 1989, ATSDR 1992).

1,2-Dichloroethane is expected to be highly mobile in most soils, and consequently, contamination of groundwater is possible. Adsorption to soil particles is low, particularly for soils with a low organic carbon content. Volatilization from soils and surface waters may be an important transport process. Microbial biodegradation is not expected to be significant.

1,2-Dichloroethane is absorbed through the lungs, gastrointestinal system, and skin (ATSDR 1992). It is distributed throughout the body but may be concentrated in adipose tissue. The compound can also accumulate in breast milk (Urusova 1953) and may cross the placenta (Withey and Karpinski 1985, Vozovaya 1977). Metabolism of 1,2-dichloroethane most likely involves conjugation with glutathione (ATSDR 1992). Urinary metabolites are likely to include thiodiglycolic acid, chloroacetic acid, and N-acetyl-S-carboxymethyl-L-cysteine (NTP 1991). Excretion occurs primarily through elimination of soluble urinary metabolites (Reitz et al. 1982, Spreafico et al. 1980).

Bronchitis, hemorrhagic gastritis and colitis, hepatocellular damage, renal tubular necrosis, central nervous system depression, and histopathological changes in the brain have been reported in cases of acute oral poisoning of humans (ATSDR 1992, NIOSH 1976). Animal data indicate that short-term exposures may produce immune system deficiencies (Munson et al. 1982), and subchronic or chronic oral exposures may affect the liver or kidney (NTP 1991, Alumot et al. 1976). Subchronic or chronic oral reference doses for 1,2-dichloroethane have not been adopted by the United States Environmental Protection Agency (EPA) (EPA 1993a); however, a provisional reference dose (RfD) of 0.03 mg/kg/day has been calculated by the Superfund Health Risk Technical Support Center (EPA, 1994) from a no-observed-adverse-effects level (NOAEL) of 26 mg/kg/day for rats tested in a subchronic gavage study (NTP 1991). Use of this value in risk assessment reports for specific sites must be approved by the Support Center.

Acute inhalation exposures to 1,2-dichloroethane (75-125 ppm) can result in irritation of the eyes, nose and throat, dizziness, nausea, vomiting, increasing stupor, cyanosis, rapid pulse, delirium, anesthesia, partial paralysis, loss of tactile sense, degenerative changes in the myocardium, abnormal EEG, liver and kidney damage, pulmonary edema, and hemorrhages throughout the body (NIOSH 1976, CEC 1986, ATSDR 1992, Nouchi et al. 1984). Short-term exposures to animals have resulted in central nervous system depression (inactivity or stupor, tremors, uncertain gait, narcosis); pulmonary congestion; renal tubular degeneration; fatty degeneration of the liver and, less commonly, necrosis and hemorrhage of the adrenal cortex; chronic splenitis; fatty infiltration of the myocardium; and immuno-deficiency (Spencer et al. 1951, Heppel et al. 1946, Storer et al. 1984, Sherwood et al. 1987). Chronic occupational exposure to 1,2-dichloroethane may result in central nervous systems effects including irritability, sleeplessness, and decreased heart rate; loss of appetite; nausea; vomiting; epigastric pain, as well as irritation of the mucous membranes; and liver and kidney impairment (NIOSH 1976). Subchronic or chronic inhalation exposures to animals resulted in pathological lesions in the kidney, liver, heart, lungs, and testes (Heppel et al. 1946, Spencer et al. 1951, Cheever et al. 1990). A subchronic or chronic inhalation reference concentration for 1,2-dichloroethane has not been adopted and verified by EPA (EPA 1993a); however, a provisional RfC of 0.005 mg/m3 has been calculated by the Superfund Health Risk Technical Support Center (EPA 1994) from a LOAEL (gastrointestinal disturbances and liver and gallbladder disease) of 10 mg/m3 for occupationally exposed workers (Kozik 1957). Use of this value in risk assessment reports for specific sites must be approved by the Support Center.

1,2-Dichloroethane is classified by EPA in Group B2 as a probable human carcinogen by both the oral and inhalation exposure routes, based on evidence for the induction of several types of tumors in rats and mice. Male rats treated by gavage with 1,2-dichloroethane exhibited increased incidences of fibromas of the subcutaneous tissue; hemangiosarcomas of the spleen, liver, pancreas, and adrenal gland; and squamous-cell carcinomas of the forestomach. Female rats treated by gavage developed mammary adenocarcinomas. Increased incidences of hepatocellular carcinomas and pulmonary adenomas were observed in male mice treated by gavage, and increased incidences of mammary adenocarcinomas, pulmonary adenocarcinomas, and endometrial polyps and sarcomas were observed in female mice (NCI 1978). Mice treated by topical application of 1,2-dichloroethane exhibited an increased incidence of lung papillomas (Van Duuren et al., 1979). The oral slope factor for 1,2-dichloroethane is 9.1E-2 (ug/kg/day)-1, and the drinking water unit risk is 2.6E-6 (ug/L)-1. The inhalation slope factor is 9.1E-2 (ug/kg/day)-1, and the inhalation unit risk is 2.6E-5 (ug/m3)-1 (EPA 1993a, 1993b).

1. INTRODUCTION

1,2-Dichloroethane is used in the manufacture of vinyl chloride, as well as in the synthesis of tetrachloroethylene, trichloroethylene, 1,1,1-trichloroethane, vinylidene chloride, aziridines, and ethylenediamines (U.S. Air Force 1989, ATSDR 1992). It is added to gasoline as a lead-scavenging agent, and, in the past, has been used as a metal degreasing agent; a solvent; and a fumigant for grain, upholstery, and carpets. It has also been used in paints, coatings, adhesives, varnishes, finish removers, soaps, and scouring agents (U.S. Air Force 1989, ATSDR 1992).

1,2-Dichloroethane is soluble in water (8690 mg/L at 20C) and has a low soil adsorption coefficient (19-83). It has a vapor pressure of 61 mm Hg at 20C and a Henry's Law Constant of 0.045 atmm3/mol at 25C (ATSDR 1992). The available data indicate that 1,2-dichloroethane is likely to volatilize from surface waters and soil surfaces; however, any amount in soils not subject to volatilization may migrate to groundwater, especially in soils of low organic carbon (U.S. Air Force 1989). Volatilization of 1,2-dichloroethane from a disposal site could result in inhalation exposures. In addition, exposure through drinking water is possible as a result of groundwater contamination.

Major review documents on 1,2-dichloroethane include a United States Environmental Protection Agency (EPA) Health Assessment Document (EPA 1985a), an EPA Health and Environmental Effects Profile (EPA 1985b), and an ATSDR Toxicological Profile (ATSDR 1992).

2. METABOLISM AND DISPOSITION

2.1 ABSORPTION

1,2-Dichloroethane is absorbed through the lungs, gastrointestinal system, and skin (ATSDR 1992). The chemical has a high blood serum/air partition coefficient (19.5 in humans and 30.4 in rats), and absorption through the lungs is most likely by passive diffusion across alveolar membranes (ATSDR 1992, EPA 1994). Because of the high lipophilicity of the compound, passive diffusion is likely to also account for the rapid uptake of the chemical across the gastrointestinal mucosa. Studies conducted with radiolabelled 1,2-dichloroethane indicate that absorption following inhalation or oral exposures can equal 90% or more of the administered dose (Reitz et al. 1980). Gastrointestinal absorption is much greater if the chemical is administered in water rather than in corn oil (Withey et al. 1983). Absorption through the skin is substantial both when the chemical is applied in a water solution as well as when it is applied neat (Morgan et al. 1991, Jakobson et al. 1982).

2.2 DISTRIBUTION

1,2-Dichloroethane is lipophilic and distributed throughout the body (EPA 1985a). Following oral or inhalation exposure to animals, the highest concentrations were found in the adipose tissue (7-17 times higher than blood concentrations). The liver and lungs contained lower concentrations than the blood (Spreafico et al. 1980). Studies of women occupationally exposed to 1,2-dichloroethane indicate that the compound can accumulate in breast milk (Urusova 1953), and animal studies have demonstrated its ability to cross the placenta (Withey and Karpinski 1985, Vozovaya 1977).

2.3 METABOLISM

In vivo and in vitro studies in rodents have revealed that the primary metabolic pathway for 1,2-dichloroethane probably involves conjugation with glutathione (ATSDR 1992). Urinary metabolites of 1,2-dichloroethane are likely to include thiodiglycolic acid, chloroacetic acid, and N-acetyl-S-carboxymethyl-L-cysteine (NTP 1991).

2.4 EXCRETION

Excretion of 1,2-dichloroethane is rapid following inhalation or oral exposures and occurs primarily through elimination of soluble urinary metabolites (about 84% of an inhaled dose and 60% of an oral dose) (Reitz et al. 1982, Spreafico et al. 1980). The half-life of whole body elimination is 13-35 minutes after a 5-6-hour inhalation exposure in rats and 6-8 hours after occupational exposure in humans (EPA 1994).

3. NONCARCINOGENIC HEALTH EFFECTS

3.1 ORAL EXPOSURES

3.1.1 Acute Toxicity

3.1.1.1 Human

From case studies of poisoning incidents, the lethal dose of 1,2-dichloroethane has been estimated to be 40-80 mL (ATSDR 1992). Death is usually due to respiratory and circulatory failure. Bronchitis, hemorrhagic gastritis and colitis, hepatocellular damage, renal tubular necrosis, central nervous system depression, and histopathological changes in the brain have been reported in cases of acute poisoning (ATSDR 1992). A latency period of about 1 hour often occurs before the onset of symptoms (NIOSH 1976). Symptoms seen in a 14-year-old boy who had ingested 15 mL included headache, lethargy, vomiting, decreased urination, pulmonary edema, and refractory hypotension. Dizziness, weakness, and vomiting occurred in three individuals, 19-27 years-old, who had ingested 70-80 mL (NIOSH 1976). The acute oral LD50 for 1,2-dichloroethane was estimated to fall in the range of 0.2 to 1.0 g/kg (CEC 1986, Davidson et al. 1982).

3.1.1.2 Animal

Oral LD50 values of 419-489, 670, 860, and 5700 mg/kg have been reported for mice, rats, rabbits, and dogs, respectively (RTECS 1989, ATSDR 1992). Storer et al. (1984) reported that an oral dose of 100 mg/kg resulted in hepatic DNA damage in male B6C3F1 mice. Munson et al. (1982) reported significant reductions in humoral immunity (measured by IgM response to sheep erythrocytes) and cell-mediated immunity (measured by delayed type hypersensitivity response to sheep erythrocytes) in mice treated by gavage with 4.9 or 49 mg/kg/day for 14 days. There was also a 30% decrease in leukocytes at the higher dose.

3.1.2 Subchronic Toxicity

3.1.2.1 Human

Information on the subchronic oral toxicity of 1,2-dichloroethane to humans was not found in the available literature.

3.1.2.2 Animal

The subchronic oral toxicity of 1,2-dichloroethane has been evaluated in mice and rats. In mice, daily gavage doses of 251 mg/kg for 6 weeks resulted in increased mortality, but drinking water concentrations equivalent to doses of 2478 mg/kg/day for females and less than 4207 mg/kg/day for males were not lethal even after 13 weeks of exposure (NCI 1978, NTP 1991). In the 13-week drinking water study, concentrations used were equivalent to daily doses of 249, 448, 781, 2710, and 4207 mg/kg for males and 244, 647, 1187, 2478, and 4926 mg/kg for females. Severe renal effects (karyomegaly, dilation, protein casts, and mineralization) were observed in males at 4207 mg/kg/day, and minimal to moderate renal tubular regeneration occurred at greater than or equal to 2710 mg/kg/day. Decreases in body weight and increases in absolute and relative kidney and liver weights were observed in some of the treatment groups. NTP (1991) reported a NOAEL of 781 mg/kg/day for males and 2478 mg/kg/day for females.

In studies conducted on F344/N rats, gavage doses of greater than or equal to 240 mg/kg/day for 13 weeks increased mortality rates, but drinking water concentrations equivalent to 601 mg/kg/day for females and 515] mg/kg/day for males did not (NTP 1991). Neurological effects (tremors, salivation, abnormal posture, ruffled fur), emaciation, dyspnea, and mild hyperplasia and inflammation of the forestomach were observed at greater than or equal to 240 mg/kg/day in the gavage study, but not in the drinking water study (NTP 1991). In the drinking water study, the only significant dose-related histopathological finding was an increased incidence of mild renal tubular regeneration in females. Decreases in body weight and increases in some relative and absolute organ weights occurred in both the gavage and drinking water studies. Relative liver weight increased at greater than or equal to 37 mg/kg/day in females and at 120 mg/kg/day in males in the gavage study and at 60 mg/kg/day in the drinking water study. Absolute and relative kidney weights were significantly increased at 30-120 mg/kg/day for males and at 75-150 mg/kg/day for females in the gavage study and at greater than or equal to 58 mg/kg/day in the drinking water study (NTP 1991).

Van Esch et al. (1977) dosed rats with 0, 10, 30, or 90 mg 1,2-dichloroethane/kg/day by gavage, 5 days/week for 90 days, and found an increase in relative liver weight in males and females treated with 90 mg/kg/day. Females in this dose group also exhibited an increase in relative liver and brain weight. No other toxic effects were reported.

Munson et al. (1982) reported that male CD-1 mice exposed to 1,2-dichloroethane in their drinking water for 90 days at concentrations equivalent to dose levels of 3, 24, and 189 mg/kg/day exhibited no adverse changes in immune function and no adverse effects on organ weights or hematological parameters; however, reduced water consumption was seen in animals receiving 24 and 189 mg/kg/day, and reduced growth occurred in the high-dose group.

In a study conducted by Alumot et al. (1976), mild liver changes (15% increase in fat accumulation and increases in liver triglycerides) occurred in rats receiving 1,2-dichloroethane in their feed for 5-7 weeks at a dietary concentration equivalent to 80 mg/kg/day.

3.1.3 Chronic Toxicity

3.1.3.1 Human

Information on the chronic oral toxicity of 1,2-dichloroethane to humans by the oral route was not found in the available literature.

3.1.3.2 Animal

In cancer bioassays conducted by NCI (1978), Osborne-Mendel rats were treated with 95 mg 1,2-dichloroethane/kg/day (time-weighted average) by gavage (in corn oil), 5 days/week for 78 weeks. Effects on survival were seen by week 2 and only 50% were still alive by 55-57 weeks. Mortality was due to toxic effects and bronchopneumonia rather than cancer. Clinical signs of toxicity were also apparent in rats dosed with 47 mg/kg/day. In similar tests on B6C3F1 mice, significantly increased mortality occurred in females dosed with 299 mg/kg/day but not in females receiving 149 mg/kg/day or in males receiving 97 or 195 mg/kg/day.

In a 2-year feeding study conducted by Alumot et al. (1976), dietary concentrations of 250 or 500 ppm resulted in no adverse effects in male and female rats. The 500 ppm level was reported to be equivalent to 25 mg/kg/day.

3.1.4 Developmental and Reproductive Toxicity

3.1.4.1 Human

Information on the reproductive and developmental toxicity of 1,2-dichloroethane to humans was not found in the available literature.

3.1.4.2 Animal

Fertility, gestation, or viability were not adversely affected in male and female mice receiving 1,2--dichloroethane in their drinking water for 25 weeks at concentrations resulting in daily doses of 0, 5, 15, or 50 mg/kg (Lane et al. 1982). This treatment also failed to produce significant dominant lethal mutations, teratogenic effects, or adverse effects on survival, growth rates, and fluid intake in the Fo and F1B generations. No significant changes in fertility, litter size, fetal weight or offspring survival were observed in studies in which male and female rats were fed 1,2-dichloroethane in their diet (250 or 500 ppm) for two years (Alumot et al. 1976). The 500 ppm concentration was estimated to be equivalent to 25 mg/kg/day. No developmental effects were seen in mice treated with 510 mg/kg/day in drinking water during gestational days 7-14 (Kavlock et al. 1979).

3.1.5 Reference Dose

EPA (1993) has not adopted a subchronic or chronic oral reference dose for 1,2-dichloroethane. However, a provisional chronic RfD has been calculated by the Superfund Health Risk Technical Support Center (EPA 1994). Use of this value in risk assessment reports for specific sites must be approved by the Support Center.

3.1.5.1 Subchronic

No data for subchronic effects of 1,2-dichloroethane are available.

3.1.5.2 Chronic

  • ORAL RfD (provisional): 0.03 mg/kg/day (EPA 1994)
  • UNCERTAINTY FACTOR: 1000
  • MODIFYING FACTOR: 1
  • NOAEL: 26 mg/kg/day (gavage, female F344/N rats)
  • PRINCIPAL STUDY: (NTP 1991)
  • COMMENT: Confidence in the RfD is judged to be low because it is based on a subchronic study, and the subchronic NOAEL of 37 mg/kg/day (26 mg/kg/day, time-weighted average) is close to the Frank Effect Level (FEL) of 47 mg/kg/day. Although relative liver weight was increased at 37 mg/kg/day, no treatment-related organ lesions were observed. A suitable NOAEL could not be derived from the available chronic studies.

3.2 INHALATION EXPOSURES

3.2.1 Acute Toxicity

3.2.1.1 Human

Short-term exposures to high vapor concentrations of 1,2-dichloroethane produce irritation of the eyes, nose, and throat. Inhalation of the compound can cause dizziness, nausea, vomiting, increasing stupor, cyanosis, rapid pulse, delirium, anesthesia, partial paralysis, loss of tactile sense, abnormal EEG, and loss of consciousness (CEC 1986, ATSDR 1992). The data suggest a LOAEL of 10-37 ppm (EPA 1994). Fatalities have resulted from occupational exposures. Autopsies have revealed evidence of liver and kidney damage as well as pulmonary edema and hemorrhages throughout the body (NIOSH 1976). Congestion of the lungs, degenerative changes in the myocardium, liver necrosis (accompanied by elevated SGOT and SGPT), renal tubular necrosis, and shrunken brain cells occurred in an individual who died from cardiac arrhythmia 4 days after being exposed for only 30 minutes (concentration not reported) (Nouchi et al. 1984).

3.2.1.2 Animal

An LC50 value of 3000 ppm (7-hour exposure) has been reported for monkeys (U.S. Air Force 1989), and a LC50 of about 1000 ppm (7-hour exposure) has been reported for rats (Spencer et al. 1951). A concentration of 400 ppm (7 hour/day, 5 days/week) for less than or equal to 14 days was lethal to rats and guinea pigs, and 1500 ppm was lethal to mice, rabbits, and dogs (Heppel et al. 1946, Spencer et al. 1951). Acute toxic effects included liver and kidney damage, pulmonary edema, and fatty infiltration and degeneration of the myocardium. Monkeys exposed intermittently (7 hours/day, 5 days/week) to 400 ppm for 8-12 days developed increased clotting time, fatty degeneration of the liver, and degeneration of the renal tubular epithelium; no adverse effects were seen at 100 ppm (Spencer et al. 1951). Hepatic damage has been reported in male B6C3F1 mice exposed to greater than 500 ppm for 4 hours (Storer et al. 1984). Chronic splenitis was observed in rats exposed intermittently to 1000 ppm for 14 days, and congestion of the adrenal cortex occurred in male guinea pigs exposed intermittently to 1500 ppm for 4 days (Heppel et al. 1946).

Sherwood et al. (1987) reported on the effects of 1,2-dichloroethane on the pulmonary defenses of female CD-1 mice and male Sprague-Dawley rats. Female mice exposed to 5 or 10 ppm for 3 hours exhibited increased susceptibility to Streptococcus zooepidemicus (increased mortality following infection). A concentration of 2.5 ppm (a single 3-hour exposure or repeated daily exposures for 5 days) did not have an adverse effect on pulmonary defenses. A 3-hour exposure to 10 ppm significantly decreased bactericidal activity towards inhaled Klebsiella pneumonia; lower concentrations were without effect. In rats, single 5-hour exposures to 200 ppm or daily 5-hour exposures to 100 ppm for 12 days did not result in immunological deficiencies.

3.2.2 Subchronic Toxicity

3.2.2.1 Human

In a study of Russian aircraft industry workers exposed to 1,2-dichloroethane, Kozik (1957) found that the incidences of morbidity due to acute gastrointestinal disorders, neuritis, and radiculitis and other diseases were higher in exposed workers than in non-exposed workers (statistical analysis of the data was not presented). NIOSH (1976) estimated that the TWA concentration in the breathing zone of the exposed workers was 10-15 ppm. No information was given on the duration of employment or the length of exposure for the workers; consequently, EPA (1994) conservatively treated these data as evidence of subchronic toxicity and used this study to derive a provisional inhalation RfC (see Subsect. 3.2.5).

In a group of factory workers exposed to 1,2-dichloroethane concentrations of less than or equal to 25 ppm for 6 months to 5 years, Rosenbaum (1947) found heightened lability of the autonomic nervous system, muscular torus, bradycardia, increased sweating, and increased frequency of fatigue, irritability, and sleeplessness.

3.2.2.2 Animal

Animal data indicate that the dose-response curve for 1,2-dichloroethane is very steep such that subchronic exposures to greater than 150 ppm are lethal to several species while exposures to 100 ppm may not result in any histopathological signs of toxicity (EPA 1994). However, prolonged exposure to 50 ppm or more may be toxic to the liver or kidneys as evidenced by changes in clinical chemistry parameters.

In studies conducted by Heppel et al. (1946), rats, rabbits, guinea pigs, dogs, cats, and monkeys were exposed to 1000, 400, 200, or 100 ppm 1,2-dichloroethane, 7 hours/day, 5 days/week for varying time periods. A concentration of 1000 ppm was lethal to 20/26 rats, 5/6 rabbits, 36/42 guinea pigs, 2/6 dogs 2/6 cats, and 2/2 monkeys. Pathological examination revealed occasional pulmonary congestion, renal tubular degeneration, and fatty degeneration of the liver. Similar lesions were seen in guinea pigs, rats, and rabbits exposed to 400 ppm, some of whom died during the exposures. Dogs survived this concentration for 8 months without adverse effects except for slight fatty changes in the liver. At 200 ppm, 5 rabbits survived 125 exposures without adverse effects. Two monkeys exposed to 200 ppm survived 125 exposures; however, one showed focal calcification of the adrenal medulla and both showed fine fat droplets in the liver and myocardium. Five/14 guinea pigs, 15/24 rats, and 18/20 mice died when exposed to 200 ppm; however, these species survived 100 ppm for 4 months with no demonstrable lesions.

In studies conducted by Spencer et al. (1951), rats, rabbits, guinea pigs, and monkeys were exposed to 400 or 100 ppm 1,2-dichloroethane, 7 hours/day, 5 days/week for various time periods. In addition, rats and guinea pigs were exposed to 200 ppm. A concentration of 400 ppm was lethal to all tested rats and guinea pigs after 10-40 exposures. Three rabbits exposed to the same concentration for 232 days exhibited no adverse effects. Two monkeys killed after 8 and 12 exposures, respectively, showed varying degrees of liver damage. At 200 ppm, rats tolerated 151 exposures in 212 days without evidence of adverse effects; guinea pigs tolerated 180 exposures in 246 days with half the test animals exhibiting slight parenchymatous degeneration of the liver. All four species survived exposures to 100 ppm (198-211 days for rats; 170-226 days in guinea pigs; 248 days in rabbits; and 212 days in monkeys) without adverse effects.

Hofmann et al. (1971) reported that a 1,2-dichlorethane concentration of 500 ppm (6 hours/day, 5 days/week, for 6 weeks) was lethal to rabbits, guinea pigs, and rats. Toxic effects seen in rats and guinea pigs included hyperemia with some edema of the lungs, fatty degeneration and necrosis of the myocardium and liver, and disgorgement of the adrenals. Cats exposed to 500 ppm exhibited increased serum urea and dilation of the heart. No toxic effects or histopathology was seen in animals exposed to 100 ppm for 17 weeks.

3.2.3 Chronic Toxicity

3.2.3.1 Human

Chronic exposures to 1,2-dichloroethane in an occupational environment have been associated with loss of appetite, nausea, vomiting, epigastric pain, irritation of the mucous membranes, neurologic changes, and liver and kidney impairment (NIOSH 1976). Although fatal cases have been reported less frequently with chronic exposure than with acute exposure, chronic effects can progress unless the exposures are adequately reduced. In a study of agricultural workers who handled 1,2-dichloroethane as a fumigant, the most common symptoms of exposure were weakness, headache, conjunctival congestion and irritation, nausea, cough, liver pain, and increased heart rate. Exposure levels averaged 15 ppm. Since the workers' skin came into contact with the 1,2-dichloroethane, absorption by this route may have been significant (NIOSH 1976).

Workers exposed to 1,2-dichloroethane concentrations of 60-200 ppm reported eye irritation and lacrimation; dryness of the mouth; gastrointestinal disturbances (nausea, vomiting, and loss of appetite); dizziness; and fatigue (Cetnarowicz 1959). An increased incidence of liver effects (enlargement, epigastric pain and altered liver function tests) and gastrointestinal effects (gastritis and pyloric spasma) were also reported in workers exposed to 10-200 ppm. In general, symptoms or toxic effects were not reported in workers exposed to 10-37 ppm.

3.2.3.2 Animal

In a study conducted by Cheever et al. (1990), male and female Sprague-Dawley rats were exposed to 50 ppm 1,2-dichloroethane, 7 hours/day, 5 days/week for 2 years. Body weights and survival rates of the test animals were not significantly different from control values. The only reported histopathological finding was an increased incidence of testicular lesions in the males (24% vs. 10% in the controls).

Maltoni et al. (1980) exposed young male and female Sprague-Dawley rats and Swiss mice (age 11-12 weeks) to 0, 5, 10, 50, or 150-250 ppm 1,2-dichloroethane, 7 hours/day, 5 days/week, for 78 weeks. Increased mortality was seen in rats exposed to 250 ppm. No concentration-related changes were seen in blood chemistry parameters (non-carcinogenic histopathological evaluations were not reported). In a related study using the same experimental protocol, but lasting only 12 months and using rats 14 months of age, Spreafico et al. (1980) found significant changes in blood chemistry parameters suggestive of liver and possibly kidney toxicity.

3.2.4 Developmental and Reproductive Toxicity

3.2.4.1 Human

A number of Soviet studies have reported reproductive effects in humans following inhalation exposure to 1,2-dichloroethane; however, EPA (1985a) considered these studies to be lacking in sufficient detail to provide useful information.

3.2.4.2 Animal

In tests in which pregnant Sprague-Dawley rats or New Zealand rabbits were exposed to 0, 100, or 300 ppm 1,2-dichloroethane for 7 hours daily on days 6-15 and 6-18 of gestation, respectively, increased maternal mortality was seen in both species at both concentrations (Schlachter et al. 1979). Maternal toxicity was associated with resorptions and/or early delivery; however, no malformations or other signs of toxicity were observed in the offspring of the survivors. In a one-generation study conducted on Sprague-Dawley rats, exposure to 25, 75, or 150 ppm (5 hours/day, 5 days/week for 12 weeks) did not affect reproductive capacity, development, growth, or survival of the offspring (Rao et al. 1980). Vozovaya (1974) reported that female rats exposed to 14 ppm, 4 hours/day for 6 months, including gestation, exhibited a lengthening of the estrous cycle and a decrease in fertility. Litter size, birth weight, and peri- and postnatal survival were significantly reduced. Exposure of female rats to 4.7 ppm for 4 months and then throughout pregnancy resulted in a statistically significant increase in embryo mortality (Vozovaya 1977).

3.2.5 Reference Dose/Concentration

EPA (1993) has not adopted a subchronic or chronic inhalation reference concentration for 1,2-dichloroethane. However, the EPA Superfund Health Risk Technical Support Center has calculated a provisional RfC (EPA 1994). Use of this value in risk assessment reports for specific sites must be approved by the Support Center.

3.2.5.1 Subchronic

No subchronic data are available.

3.2.5.2 Chronic

  • INHALATION RfC (provisional): 0.005 mg/m3 (EPA 1994)
  • UNCERTAINTY FACTOR: 3000
  • MODIFYING FACTOR: None reported
  • LOAEL: 10 ppm (40 mg/m3)
  • PRINCIPAL STUDIES: Kozik 1957
  • COMMENT: Based on an increased incidence of gastrointestinal disturbances and liver and gall bladder disease in workers occupationally exposed to 10-15 ppm. Note: the LOAEL was adjusted for a continuous exposure to non-workers by assuming an inhalation rate of 10 m3/8 hour for workers and 20 m3/24 hour for non-workers. Uncertainty factors included 10 for use of a LOAEL, 10 for less than a chronic study, 10 to protect sensitive individuals, and 3 for deficiencies in the data base. Because of deficiencies in the principal study and in the data base, low confidence is placed in the provisional RfC.

3.3 OTHER ROUTES OF EXPOSURE

3.3.1 Acute Toxicity

3.3.1.1 Human

Contact of liquid 1,2-dichloroethane with the skin can result in severe irritation, moderate edema, and necrosis (Proctor 1978). Pain, irritation, lacrimation, and corneal burns can result from contact of the liquid with the eyes (Grant 1974). Eye irritation, as well as clouding of the cornea, have been reported in individuals exposed to high vapor concentrations of 1,2-dichloroethane (Garrison and Leadingham 1954).

3.3.1.2 Animal

An intraperitoneal dose of 150 mg 1,2-dichloroethane/kg resulted in hepatic DNA damage in male B6C3F1 mice (Storer et al. 1984). The dermal LD50 in rabbits was calculated to be 2.8 g/kg body weight (Clayton and Clayton 1981). Corneal opacity has been observed in dogs exposed intermittently to 1500 ppm 1,2-dichloroethane for 6 days (Heppel et al. 1945).

3.3.4 Developmental and Reproductive Toxicity

Information on the reproductive and developmental toxicity of 1,2-dichloroethane to humans or animals by exposure routes other than oral or inhalation was not found in the available literature.

3.4 TARGET ORGANS/CRITICAL EFFECTS

3.4.1 Oral Exposures

3.4.1.1 Primary target organs

  1. Nervous System: central nervous system effects in animals following subchronic exposures. Central nervous system depression and histopathological changes in the brain have been reported in cases of acute poisoning of humans.
  2. Liver: Increased weight and mild fatty changes in animals following subchronic exposures. Hepatocellular damage has been reported in cases of acute poisoning of humans.
  3. Kidney: Increased weight and severe renal effects in animals following subchronic exposures. Renal tubular necrosis has been reported in cases of acute poisoning of humans.

3.4.1.2 Other target organs

Damage to the lung (bronchitis) and gastrointestinal system (hemorrhagic gastritis and colitis) have been reported in cases of acute human poisoning. Deficiencies in the immune system have been reported in animals following short-term exposures.

3.4.2 Inhalation Exposures

3.4.2.1 Primary target organs

  1. Nervous System: central nervous system effects in humans occupationally exposed. Dizziness, nausea, vomiting, increasing stupor, cyanosis, rapid pulse, delirium, anesthesia, partial paralysis, loss of tactile sense, abnormal EEG, and loss of consciousness following acute exposures.
  2. Liver: Fatty degeneration in animals following subchronic exposures. Liver damage in humans following acute exposures.
  3. Kidney: Fatty degeneration in animals following subchronic exposures. Kidney damage and renal tubular necrosis in humans following acute exposures.
  4. Heart: Fatty degeneration in animals following subchronic exposures. Degenerative changes in the myocardium in humans following acute exposures.
  5. Reproductive System: Testicular lesions in animals following chronic exposures.

3.4.2.2 Other target organs

Irritation of the eyes, nose and throat, pulmonary edema, and hemorrhages throughout the body in humans exposed to acutely toxic concentrations. Deficiencies in the immune system have been observed in animals following short-term exposures.

4. CARCINOGENICITY

4.1 ORAL EXPOSURES

4.1.1 Human

Little direct information is available on the oral carcinogenicity of 1,2-dichloroethane in humans. An epidemiological study conducted by Isacson et al. (1985) with data from the Iowa Cancer Registry evaluated the relationship between concentrations of volatile organic compounds in drinking water with age-adjusted, sex-specific cancer rates. An association was seen between 1,2-dichloroethane and cancers of the colon and rectum in men; however, the investigators noted that the results were not indicative of a causal relationship to 1,2-dichloroethane but rather were indicative of the overall contamination of the drinking water.

4.1.2 Animal

In a long-term bioassay in which 1,2-dichloroethane was administered by gavage to rodents statistically significant increases were observed in several types of tumors (NCI 1978). Male and female Osborne-Mendel rats and B6C3F1 mice were administered technical-grade 1,2-dichloroethane in corn oil by gavage 5 days/week for 78 weeks. The daily doses were 47 and 95 mg/kg (male and female rats), 97 and 195 mg/kg (male mice), and 149 and 299 mg/kg (female mice). An increased incidence of fibromas of the subcutaneous tissue and hemangiosarcomas of the spleen, liver, pancreas, adrenal gland, and other organs occurred in male rats at both dose levels; an increased incidence of squamous-cell carcinomas of the forestomach occurred in male rats at the high dose; and an increased incidence of mammary adenocarcinomas occurred in female rats at the high dose. In the treated mice, an increased incidence of hepatocellular carcinomas and pulmonary adenomas was seen in males receiving the high dose, and an increased incidence of mammary adenocarcinomas, pulmonary adenocarcinomas, and endometrial polyps and sarcomas occurred in females at both dose levels.

The oral carcinogenicity of 1,2-dichloroethane has also been evaluated in a short-term initiation/promotion assay. Story et al. (1986) tested the compound in the rat liver foci assay. Negative results were obtained in initiation tests in which phenobarbital was used as the promoting agent, but positive results were seen in the promotion tests in which diethylnitrosamine (DENA) was used as the initiating agent. In a longer-term study, Klaunig et al. (1986) administered 1,2-dichloroethane in drinking water to B6C3F1 mice for 52 weeks (dose levels 158 or 475 mg/kg/day) following a 4-week treatment with the tumor initiator DENA. No increase in liver or lung tumors was seen in mice treated with DENA and 1,2-dichloroethane, or in those treated with 1,2-dichloroethane alone.

4.2 INHALATION EXPOSURES

4.2.1 Human

Austin and Schnatter (3043) conducted a case-control study of brain tumors in petrochemical workers but found no evidence of an association between exposure to 1,2-dichloroethane and cancer. Hogstedt et al. (1979) studied the incidence of stomach tumors and leukemia in a plant that used 1,2-dichloroethane in the production of ethylene oxide but did not find an association with exposure to 1,2-dichloroethane.

4.2.2 Animal

In a study conducted by Maltoni et al. (1980), Swiss mice and Sprague-Dawley rats of both sexes were exposed to 5, 10, 50, or 250 ppm 1,2-dichloroethane (99.8% pure), 7 hours/day, 5 days/week for 78 weeks. The 250 ppm dose was dropped to 150 ppm after a few weeks because of severe toxic effects. No treatment-related increased incidence of tumors was seen in either mice or rats. ATSDR (1992) notes that the low survival rates of the test animals, the intermittent exposure duration, and the less than a lifetime total exposure period, limit the conclusions that can be drawn from this study. In a study conducted by Cheever et al. (1990), no carcinogenic effects were seen in male and female Sprague-Dawley rats exposed to 50 ppm 1,2-dichloroethane, 7 hours/day, 5 days/week for 2 years.

4.3 OTHER ROUTES OF EXPOSURE

Positive tumorigenicity of 1,2-dichloroethane following repeated skin applications was reported by Van Duuren et al. (1979). Application of 125 mg of 1,2-dichloroethane in acetone to the dorsal skin of Swiss mice 3 times weekly for a lifetime resulted in the induction of benign lung tumors as well as a papilloma and two squamous-cell carcinomas of the forestomach.

In an in vitro cell transformation assay using BALB/c-3T3 mouse cells (without an exogenous metabolic activation system), 1,2-dichlorethane gave negative results (Tu et al. 1985).

4.4 EPA WEIGHT OF EVIDENCE

4.4.1 Oral

Classification--B2; probable human carcinogen (EPA 1993a)

Basis--Induction of several tumor types in rats and mice treated by gavage and lung papillomas in mice after topical application.

Comment--Based on the available data, IARC (1979) has listed 1,2-dichloroethane in Category 2B (sufficient evidence of animal carcinogenicity and inadequate evidence of carcinogenicity in humans) in its weight-of-evidence ranking for potential carcinogens.

4.4.2 Inhalation

Classification--B2; probable human carcinogen (EPA 1993a)

Basis--Induction of several tumor types in rats and mice treated by gavage and lung papillomas in mice after topical application.

4.5 SLOPE FACTORS

4.4.1 Oral

  • SLOPE FACTOR: 9.1E-2 (ug/kg/day)-1 (EPA 1993a).
  • DRINKING WATER UNIT RISK: 2.6E-6 (ug/L)-1 (EPA 1993a)
  • PRINCIPAL STUDIES: NCI 1978
  • VERIFICATION DATE: 12/04/86

4.4.2 Inhalation

  • SLOPE FACTOR: 9.1E-2 (ug/kg/day)-1 (EPA 1993b)
  • INHALATION UNIT RISK: 2.6E-5 (ug/m3)-1 (EPA 1993)
  • PRINCIPAL STUDIES: NCI 1978
  • VERIFICATION DATE: 12/04/86
  • COMMENT: The inhalation unit risk was calculated from the data for the oral slope factor, assuming 100% absorption and metabolism at low dose (EPA 1993a). In discussing the confidence level for the inhalation unit risk, EPA (1993a) notes that "based on the negative inhalation study of Maltoni et al. (1980), a 95% upper bound risk was inferred to be 1.0E-6 per (ug/cu.m) approximately 26 times smaller than the unit risk calculated from the rat gavage data."

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