The Risk Assessment Information System

Toxicity Profiles

Formal Toxicity Summary for 1,1,2,2-TETRACHLORETHANE

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

Prepared by J.C. Norris, Ph.D., Chemical Hazard Evaluation Group in the Biomedical and Environmental Information Analysis Section, Health Sciences Research Division, Oak Ridge National Laboratory*.

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

1,1,2,2-Tetrachloroethane (CAS No. 79-34-5) is a two-carbon chain molecule with two chlorine atoms on each carbon atom. Uses of 1,1,2,2-tetrachloroethane have been as a chemical intermediate, industrial solvent, and extractant. 1,1,2,2-Tetrachloroethane was found on at least 278 of the hazardous waste sites on the United States Environmental Protection Agency's National Priorities List. Chemical degradation occurs by the loss of chlorine atoms, and the half-life of 1,1,2,2-tetrachloroethane in air is about 2 months and in groundwater 1 to 3 months. Bioaccumulation of 1,1,2,2-tetrachloroethane in fish and other aquatic organisms is not expected to be significant (ATSDR 1994).

Two human studies suggested that between 50 and 97% of inspired 1,1,2,2-tetrachloroethane was retained (Lehman and Schmidt-Kehl 1936, Morgan et al. 1970). Mouse and rat gavage studies indicated that 100% of 1,1,2,2-tetrachloroethane was absorbed (Dow Chemical Company 1988). Animal metabolites were trichloroethane, trichloroacetic acid, dichloroacetic acid, glyoxylic acid, and oxalic acid (Ikeda and Ohtsuji 1972, Mitoma et al. 1985, Yllner 1971). Vinyl chloride is another possible metabolite (Hallen et al. 1986). Human and animal studies indicate that the majority of 1,1,2,2-tetrachloroethane is metabolized (ATSDR 1994). Ten percent or less of the parent compound is exhaled in humans and animals.

Humans acutely exposed by the oral route had clinical signs inclusive of pulmonary congestion and edema (Hepple 1927, Mant 1953), lung collapse (Mant 1953) shallow breathing during unconsciousness, low blood pressure, a faint pulse (Sherman 1953, Ward 1955), and epicardial and endocardial anoxic hemorrhage (Mant 1953). Acute inhalation exposure studies of humans to concentrations ranging from 116 to 262 ppm for 10 to 30 minutes resulted in mucosal irritation, nausea and vomiting, eye mucosal irritation, and dizziness (Lehman and Schmidt-Kehl 1936).

A man died after cleaning a spill of 1,1,2,2-tetrachloroethane with his bare hands. His spleen was found to be enlarged with nodular areas on the surface (Coyer 1944). Chronic exposures in humans have resulted in reports of headache, tremors, dizziness, numbness, drowsiness, gastrointestinal distress, liver destruction, fatty degeneration in the liver (Hamilton 1917, Koelsch 1915, Lobo-Mendonca 1963, Minot and Smith 1921, Willcox et al. 1915). Jaundice and enlarged livers have also been reported in exposed workers (Coyer 1944, Horiguchi et al. 1964, Jeney et al. 1957, Koelsch 1915).

Acute oral lethal concentrations in rats range from 200 to 330 mg/kg (ATSDR 1994). Centrilobular swelling was observed in mice after an oral dose of 75 mg/kg/day given for 4 days (Dow Chemical Company 1988). Body weight loss and central nervous system depression and debilitation occurred in 16% of the rats receiving 300 mg/kg/day for 3 to 4 days (Dow Chemical Company 1988). Rats orally administered a single dose of 100 mg/kg displayed necrosis and fatty degeneration of the liver, increased serum leucine aminopeptidase, increased liver ascorbic acid, and increased liver triglyceride levels (Schmidt et al. 1980a). Rats orally treated for 17 weeks with a dose of 3.2 mg/kg/day exhibited chronic inflammation of the kidney (Gohlke et al. 1977). Rats had a body weight loss of 38% for the males and 24% for the females after 6 weeks of 178 mg/kg/day but apparently recovered by the end of the 78-week treatment regiment (NCI 1978). At the 280 mg/kg/day dosage, rats died after 70 weeks. At the end of the 78 weeks of 284 mg/kg/day, male mice died of tubular nephrosis and female mice demonstrated hydronephrosis (NCI 1978). [These NCI (1978)dosages were time-weighted averages of the different doses given.] An oral reference dose (RfD) is under review by the United States Environmental Protection Agency (EPA 1995a).

Lethal exposure concentrations and exposure times for rats were approximately 1000 ppm after 4 to 6 hours (Carpenter et al. 1949, Deguchi 1972, Schmidt et al. 1980b, Smyth et al. 1969) and 5100 ppm after 30 minutes (Price et al. 1978). One of 10 rats exposed to 6300 ppm for 30 minutes exhibited myocardial damage (Price et al. 1978). Mice exposed to 600 ppm for 3 hours developed fatty changes in the liver (Tomokuni 1969, 1970; Hayrack et al. 1962). Exposure of rats to 130 ppm for 15 weeks resulted in increased liver weights, granulation and vacuolization of the liver, and liver hyperplasia (Truffert et al. 1977). Rabbits exposed to 15 ppm for 7 to 11 months exhibited signs of liver degeneration (Navrotskiy et al. 1971). One monkey exposed to a time-weighted average of 1974 ppm for 2 hours/day, 6 days/week for 9 months (no control) had transient diarrhea, anorexia, centrilobular vacuolization, and fatty degeneration of the liver (Hayrack et al. 1962). An inhalation reference concentration (RfC) has not been derived.

The dermal LD₅₀ value in rabbits was determined to be 6.36 g/kg (Smyth et al. 1969). Thickening of the cellular nucleus and pseudoeosinophilic infiltration was observed after dermal application of 514 mg/cm² for 16 hours on guinea pigs (Kronevi et al. 1981).

Army workers exposed to 1,1,2,2-tetrachloroethane vapor in a clothing processing plant had a very slight increase in death due to genital cancers, leukemia, or other lymphomas than workers not employed in a clothing plant (Norman et al. 1981). Male and female mice orally administered 142 and 284 mg/kg/day for 78 weeks had an increase in hepatocellular carcinomas (NCI 1978). Based on these results, 1,1,2,2-tetrachloroethane has been classified as Group C, possible human carcinogen (EPA 1995b). For oral exposures, the slope factor is 0.2 (mg/kg/day)^-1, and the unit risk is 5.8E-06 (g/L)^-1 (EPA 1995a). For inhalation exposures, the slope factor is 0.2 (mg/kg/day)^-1 (EPA 1995b), and the unit risk is 5.8E-05 (g/m³)^-1 (EPA 1995a).

1. INTRODUCTION

1,1,2,2-Tetrachloroethane (CAS No. 79-34-5) is a two-carbon chain molecule with two chlorine atoms on each carbon atom. It is a colorless liquid with a sweet odor similar to chloroform and has low flammability. It is a manufactured chemical and does not occur naturally. Further, 1,1,2,2-tetrachloroethane has a chemical formula of C₂H₂Cl₄, a molecular weight of 167.85, a melting point of -43.8C, a boiling point of 145.1C, and a vapor pressure of 5.95 torr at 25C (ATSDR 1994). The odor threshold has been reported as 1.5 ppm (Amoore and Hautala 1983).

Uses of 1,1,2,2-tetrachloroethane have been as a chemical intermediate, industrial solvent, and extractant. It was used to synthesize trichloroethene, tetrachloroethene, and 1,2-dichloroethene (Archer 1979). As a solvent, it was used for cleaning and degreasing metals and in paint removers, varnishes, and lacquers. Extraction of oils and fats was another use (Hawley 1981). Its production is now limited because of the availability of less toxic chemicals and new processes for manufacturing chlorinated ethylenes (HSDB 1994).

1,1,2,2-Tetrachloroethane has been detected on at least 278 of the hazardous waste sites on the United States Environmental Protection Agency's (EPA's) National Priorities List. Chemical degradation occurs by the loss of the chlorine atoms. Its half-life in air is about 2 months and in groundwater 1 to 3 months. Vinyl chloride is one decomposition product found in landfills and ground water. Bioaccumulation of 1,1,2,2-tetrachloroethane in fish and other aquatic organisms is not expected to be significant (ATSDR 1994).

2. METABOLISM AND DISPOSITION

2.1. ABSORPTION

Two reports of human inhalation exposure were found. One study suggested that 97% of 1,1,2,2-tetrachloroethane in a single breath was absorbed (Morgan et al. 1970). Another study of two humans revealed that approximately 50% of inspired 1,1,2,2-tetrachloroethane was retained (Lehman and Schmidt-Kehl 1936).

Rats and mice were exposed via inhalation to 10 ppm of 1,1,2,2-tetrachloroethane for 6 hours resulting in the absorption of 36 mole per kg in rats and 128 mole per kg in mice (Dow Chemical Company 1988). A rabbit exposed to an unknown concentration of 1,1,2,2-tetrachloroethane for 3 hours absorbed approximately 30% (Lehman and Hasagawa 1910). Orally, rats and mice absorbed approximately 100% of 150 mg/kg of 1,1,2,2-tetrachloroethane administered by gavage in corn oil (Dow Chemical Company 1988). Two other oral studies using mice and rats also suggested that the majority of the administered 1,1,2,2-tetrachloroethane was absorbed (Milman et al. 1984, Mitoma et al. 1985). 1,1,2,2-Tetrachloroethane applied to the skin (occluded site) of mice and guinea pigs was absorbed in volumes of up to 1 ml (Jakobson et al. 1982, Tsuruta 1975).

2.2. DISTRIBUTION

Higher levels (approximately 2 times) of hepatic protein binding were observed in mice than in rats after an oral dose of 1,1,2,2-tetrachloroethane was administered (Mitoma et al. 1985). No other distribution data were available.

2.3. METABOLISM

No human metabolism data for 1,1,2,2-tetrachloroethane were identified. Rats and mice exposed to 10 ppm for 6 hours and monitored for 72 hours after exposure metabolized greater than 90% of the 1,1,2,2-tetrachloroethane (Dow Chemical Company 1988). This same result was found in mice and rats orally administered 150 mg/kg (Dow Chemical Company 1988). Trichloroethane, trichloroacetic acid, and dichloroacetic acid were identified as metabolites in rodents; further metabolism produced glyoxylic acid and oxalic acid (Ikeda and Ohtsuji 1972, Mitoma et al. 1985, Yllner 1971). Vinyl chloride was another possible metabolite (Hallen et al. 1986). These analyses were apparently obtained by colorimetric techniques. Gas chromatography and mass spectrometry analyses of an in vitro mixture of hepatic microsomal cytochrome P-450 and 1,1,2,2-tetrachloroethane suggested that dichloroacetic acid and 1,1-dichloroacetyl chloride were metabolites (Casciola and Ivanetich 1984, Halpert and Neal 1981, Halpert 1982, Ivanetich and Van Den Honert 1981, Van Dyke and Wineman 1971). A reductive dechlorination pathway for 1,1,2,2-tetrachloroethane to form a carbon centered radical was proposed by Paolini et al. (1992).

2.4. EXCRETION

No excretion data for humans after oral and dermal exposure were found. Humans exposed via inhalation to 1,1,2,2-tetrachloroethane exhaled 3% of the inhaled amount in the breath, and the urinary excretion rate was 0.015% of the absorbed dose/min (Morgan et al. 1970).

A study with mice and rats (Mitoma et al. 1985) demonstrated that approximately 10% of the dose was exhaled unchanged. The remainder was metabolized by excretion in the breath (10% as CO₂) and in the urine and feces (30% combined) or retained in the carcass (27%) after 48 hours. Intraperitoneal injection of ¹⁴C-1,1,2,2-tetrachloroethane in mice showed that 4% of the parent compound was exhaled, 47% of the radioactivity was exhaled as CO₂, 28% of the radioactivity was excreted in the urine, 1% of the radioactivity was found in the feces, and 16% of the radioactivity was in the carcass (Yllner 1971). The half-life of 1,1,2,2-tetrachloroethane in blood was 2 hours in guinea pigs after a dermal exposure (Jakobson et al. 1982).

3. NONCARCINOGENIC HEALTH EFFECTS

3.1. ORAL EXPOSURES

3.1.1. Acute Toxicity

3.1.1.1. Human

The exact lethal dose of 1,1,2,2-tetrachloroethane is not known although several suicides have occurred by drinking 1,1,2,2-tetrachloroethane. Minimal lethal concentrations estimated from stomach contents ranged from 357 to 9600 mg/kg (ATSDR 1994). Clinical signs included pulmonary congestion and edema and/or lung collapse (Hepple 1927, Mant 1953). African men and women who have accidentally ingested approximately 100 mg/kg exhibited shallow breathing during unconsciousness, low blood pressure, and a faint pulse (Sherman 1953, Ward 1955). Epicardial and endocardial anoxic hemorrhage were present in a suicide victim (Mant 1953).

3.1.1.2. Animal

Lethal concentrations in rats ranged from 250 to 330 mg/kg (ATSDR 1994). Necrosis and fatty degeneration of the liver, increased serum leucine aminopeptidase, increased liver ascorbic acid, and increased liver triglyceride levels were present in rats administered an oral dose of 100 mg/kg (Schmidt et al. 1980a). Mice given 75 mg/kg/day for 4 days developed centrilobular swelling, and a dose of 25 mg/kg/day for 4 days resulted in no effect (Dow Chemical Company 1988). Body weights were decreased by 16% in rats administered 300 mg/kg/day for 3 to 4 days with no change at 150 m/kg/day (Dow Chemical Company 1988). Central nervous system depression and debilitation occurred in the rats receiving 300 mg/kg/day for 3 to 4 days. A single dose of 50 mg/kg in rats resulted in decreased avoidance learning (Wolff 1978).

3.1.2. Subchronic Toxicity

3.1.2.1. Human

Information on the subchronic toxicity of 1,1,2,2-tetrachloroethane in humans following oral exposure was not available.

3.1.2.2. Animal

Rats receiving a dose of 8 mg/kg/day for 17 weeks showed no effects on the lungs, heart, stomach, colon, pancreas, and bile ducts (Gohlke et al. 1977). Chronic inflammation of the kidney was seen in rats treated with 3.2 mg/kg/day for up to 17 weeks. (This dose was a calculated value derived from intermittent exposure of 82 out of 120 days to equal 2.2 mg/kg/day.) Thyroid cell sizes were changed (direction not specified), thyroid follicular desquamation was found, and adrenal lipoid content was changed (direction not specified). In a 6-week range finding gavage study, 178 mg/kg/day given to male rats resulted in a 38% reduction in body weight. Female rats given 100 mg/kg/day had a 24% reduction in body weight (NCI 1978). However, mice administered 316 mg/kg/day had no change in body weight. The same findings were observed for male and female rats gavaged with 108 and 76 mg/kg/day [time weighted doses], respectively, for 78 weeks (NCI 1978).

3.1.3. Chronic Toxicity

3.1.3.1. Human

Hepatotoxicity has been reported in humans (ACGIH 1991).

3.1.3.2. Animal

The NCI (1978) study involved 78 weeks of 1,1,2,2-tetrachloroethane administration to Osborne-Mendel male rats receiving 62 or 108 mg/kg/day, Osborne-Mendel female rats receiving 43 or 76 mg/kg/day, and B6C3F1 male or female mice receiving 142 and 284 mg/kg/day. (The dosages were time-weighted averages of the different doses given.) Rats receiving 108 mg/kg/day and mice receiving 284 mg/kg/day showed no effects on the lungs, heart, stomach, colon, pancreas, and bile ducts. Male mice died of tubular nephrosis, and female mice demonstrated hydronephrosis in the 284 mg/kg/day group, while no renal effect was observed in mice treated with 142 mg/kg/day or in rats treated with 108 mg/kg/day.

3.1.4. Developmental and Reproductive Toxicity

3.1.4.1. Human

Information on the developmental and reproductive toxicity of 1,1,2,2-tetrachloroethane in humans following oral exposure was not available.

3.1.4.2. Animal

Interstitial edema in the testes, clumped sperm, epithelial cells in the tubular lumen, partial necrosis and totally atrophied tubules, giant cells, and two-row germinal epithelial cells with disturbed spermatogenesis were present in rats dosed with 3.2 mg/kg/day for 120 days (82 times) (Gohlke et al. 1977). No reproductive effects were seen in rats dosed at 108 mg/kg/day and mice dosed at 284 mg/kg/day for 78 weeks (NCI 1978).

3.1.5. Reference Dose

An oral reference dose (RfD) for 1,1,2,2-tetrachloroethane is under review by the EPA (EPA 1995a).

3.2. INHALATION EXPOSURES

3.2.1. Acute Toxicity

3.2.1.1. Human

Two humans exposed to 1,1,2,2-tetrachloroethane reported mucosal irritation (116 ppm for 10 to 20 minutes), nausea and vomiting ( 116 ppm for 10 to 30 minutes), eye mucosal irritation (262 ppm for 10 minutes), and dizziness ( 116 ppm for 10 to 30 minutes) (Lehman and Schmidt-Kehl 1936).

3.2.1.2. Animal

The lethal concentration for rats was approximately 1000 ppm after 4 to 6 hours of exposure (Carpenter et al. 1949, Deguchi 1972, Schmidt et al. 1980b, Smyth et al. 1969). A 30-minute exposure to 5100 ppm induced death in rats, with labored respiration occurring during exposure (Price et al. 1978). No effects were observed at 580 ppm. Myocardial damage was not found in rats after 6 hours of exposure to 100 ppm (Deguchi 1972), but 1 of 10 rats exposed to 6300 ppm for 30 minutes had myocardial damage (Price et al. 1978). However, guinea pigs exposed to 6300 ppm for 30 minutes exhibited no myocardial and liver damage (Price et al. 1978). At 580 ppm for 5 minutes, the guinea pigs squinted and closed their eyes, and after 15 minutes lacrimation was present. Mice exposed to 600 to 800 ppm for 3 hours had fatty changes in the liver similar to the effects induced by carbon tetrachloride (Tomokuni 1969, 1970). Another study revealed fine-droplet fatty degeneration and inflammatory changes in the liver and necrotic foci but no body weight loss after acute-to-intermediate exposure times in rats with exposure concentrations ranging from 2 to 29,000 ppm (Gohlke and Schmidt 1972; Schmidt et al. 1972, 1975, 1980b). Confounding problems, such as elevated room temperatures, lack of a defined dose-response, or duration-response relationship and inconsistencies in the reported results, exist within these studies and complicate the interpretation of the data. Mice that survived for a few days after being exposed to up to 6600 ppm for 3 hours had fatty degeneration of the liver, whereas mice that died within 18 hours did not have any liver degeneration (Hayrack et al. 1962).

3.2.2. Subchronic Toxicity

3.2.2.1. Human

U.S. Army workers involved in a clothing impregnation process (Norman et al. 1981) and workers in a chemical plant (Gobbato and Bobbio 1968) have not reported any cardiovascular effects. Cirrhosis was not reported to have increased among these U.S. Army workers exposed from 5 months to 1 year. One female who died after exposure to 1,1,2,2-tetrachloroethane for 5 months (exposure concentrations were unknown) had fatty degeneration and congestion of the kidney (Willcox et al. 1915).

3.2.2.2. Animal

Fatty livers were noted in rats exposed to 9000 ppm of 1,1,2,2-tetrachloroethane for 2 hours/day, 2 days/week for 4 weeks (Hayrack et al. 1962). After 15 weeks of exposure to 130 ppm, no treatment-related lesions were found in the lungs of female rats (Truffert et al. 1977). These animals had increased liver weights, granulation and vacuolization of the liver, signs of liver hyperplasia (increased numbers of binuclear cell and the appearance of mitoses), and slightly decreased hematocrit concentrations, but no effect on the renal and endocrine systems was noted. One monkey exposed to an average of 1974 ppm (ranging from 1 to 4000 ppm), 2 hours/day, 6 days/week for 9 months (no control monkey was used) revealed no lesions in the lungs and heart and no body weight loss but exhibited transient diarrhea, anorexia, centrilobular vacuolization, and fatty degeneration of the liver (Hayrack et al. 1962).

3.2.3. Chronic Toxicity

3.2.3.1. Human

Definitive information on the chronic toxicity of 1,1,2,2-tetrachloroethane in humans via inhalation was not available. Workers in the fabric airplane wing industry (Coyer 1944, Willcox et al. 1915), a penicillin factory in Czechoslovakia (Jeney et al. 1957), and a jewelry factory in India (Lobo-Mendonca 1963) have reported pain, nausea, vomiting, loss of appetite, and/or loss of body weight. Exposure concentrations were reported to range from 1 to 248 ppm. No association was made between effects and exposure concentrations. In addition, headache, tremors, dizziness, numbness, and drowsiness have been reported following occupational exposures of 1 year (Hamilton 1917, Koelsch 1915, Minot and Smith 1921). These same effects were reported in the Lobo-Mendonca study (1963) at exposure concentrations from 9 to 98 ppm. Once individuals left employment, the effects ceased.

Workers applying a varnish containing 1,1,2,2-tetrachloroethane to fabric over airplane wings reported gastrointestinal and neurological distress (Willcox et al. 1915). Approximately 4 of the 14 workers died after being confused, delirious, and comatose. Liver destruction and fatty degeneration of the liver were found during the autopsy. In an artificial silk factory, workers exposed to unknown 1,1,2,2-tetrachloroethane concentrations had an increased number of white blood cells (Minot and Smith 1921). Jaundice and enlarged livers have been found in workers exposed to unknown concentrations of 1,1,2,2-tetrachloroethane (Coyer 1944, Horiguchi et al. 1964, Jeney et al. 1957, Koelsch 1915).

3.2.3.2. Animal

Rabbits exposed to 15 ppm for 7 to 11 months demonstrated early signs of liver degeneration (Navrotskiy et al. 1971).

3.2.4. Developmental and Reproductive Toxicity

3.2.4.1. Human

Information on the developmental and reproductive toxicity of 1,1,2,2-tetrachloroethane in humans following inhalation exposure was not available.

3.2.4.2. Animal

Male rats were exposed to 2 ppm of 1,1,2,2-tetrachloroethane for 4 hours/day for an unknown number of days for 9 months. One week before the end of the exposure period, the males were mated with unexposed females. After 12 weeks, no effects on the number of offspring/litter, neonatal body weight, viability of the offspring, sex ratios, body weight on day 84, or malformations of the offspring were seen in the F₁ generation (Schmidt et al. 1972).

3.2.5. Reference Concentration

An inhalation reference concentration (RfC) for 1,1,2,2-tetrachloroethane has not been derived.

3.3. OTHER ROUTES OF EXPOSURE

3.3.1. Acute Toxicity

3.3.1.1. Human

A man died after cleaning a 1,1,2,2-tetrachloroethane spill with his bare hands. He was found to have an enlarged spleen with nodular areas on the surface. Both dermal and inhalation exposures occurred in this situation (Coyer 1944).

3.3.1.2. Animal

In rabbits, the dermal LD₅₀ value was 6.36 g/kg (Smyth et al. 1969). Dermal application of 514 mg/cm² for 16 hours to guinea pigs caused karyopyknosis and pseudoeosinophilic infiltration (Kronevi et al. 1981).

3.3.2. Subchronic Toxicity

Information on the subchronic toxicity of 1,1,2,2-tetrachloroethane in humans or animals by other routes of exposure was not available.

3.3.3. Chronic Toxicity

Information on the chronic toxicity of 1,1,2,2-tetrachloroethane in humans or animals by other routes of exposure was not available.

3.3.4. Developmental and Reproductive Toxicity

Information on the development and reproductive toxicity of 1,1,2,2-tetrachloroethane in humans or animals by other routes of exposure was not available.

3.4. TARGET ORGANS/CRITICAL EFFECTS

3.4.1. Oral Exposures

3.4.1.1. Primary Target Organ(s)

1. Kidney: Subchronic and chronic studies revealed inflammation of the kidney in rats, tubular nephrosis in male mice, and hydronephrosis in female mice.

2. Liver: Hepatotoxicity has been reported in humans. An acute oral study using rats resulted in necrosis and fatty degeneration of the liver, increased serum leucine aminopeptidase, increased liver ascorbic acid, and increased liver triglyceride levels. Centrilobular swelling was also observed in mice acutely treated with 1,1,2,2-tetrachloroethane by oral administration.

3.4.1.2. Other Target Organ(s)

Central Nervous System: Depression, debilitation, and decreased avoidance learning were observed in rats acutely treated with 1,1,2,2-tetrachloroethane.

3.4.2. Inhalation Exposures

3.4.2.1. Primary Target Organ(s)

1. Liver: Industrial workers were found to have liver destruction and fatty degeneration of the liver. Workers exposed to 1,1,2,2-tetrachloroethane have had jaundice and enlarged livers. Acute, subchronic, and chronic studies revealed fatty changes in the livers of mice, fatty degeneration and inflammatory changes in the livers of rats, increased liver weights in rats, and granulation, vacuolization, and hyperplasia of the rat liver.

2. Central Nervous System: Neurological distress, dizziness, headaches, tremors, numbness, and drowsiness have been reported by humans chronically exposed to 1,1,2,2-tetrachloroethane.

3.4.2.2. Other Target Organ(s)

Other target organs following inhalation exposure were not identified.

3.4.3 Other Routes of Exposure

Dermal: After an acute dermal/inhalation exposure, a human was found to have an enlarged spleen with nodular areas on the surface. Guinea pigs treated dermally developed in karyopyknosis (condensed nucleus) and pseudoesoinophilic infiltration.

4. CARCINOGENICITY

4.1. ORAL EXPOSURES

4.1.1. Human

Information on the carcinogenicity of 1,1,2,2-tetrachloroethane in humans following oral exposure was not available.

4.1.2. Animal

Male and female mice orally administered 142 and 284 mg/kg/day of 1,1,2,2-tetrachloroethane for 78 weeks had a statistically significant increase in hepatocellular carcinomas (NCI 1978). [These NCI (1978) dosages were time-weighted averages of the different doses given.] Rats given 62 or 108 mg/kg/day in this study (strain: Osborne-Mendel) did not demonstrate any significant increase in tumors, but the strain of rats had a low incidence of tumors after being treated with carbon tetrachloride when used as a positive control (NCI 1976). The conclusion was that there was no evidence of a carcinogenic response in this strain of rats.

4.2. INHALATION EXPOSURES

4.2.1. Human

A very slight increase in the incidence of deaths due to genital cancers, leukemia, or other lymphomas was observed among 1099 Army workers exposed to 1,1,2,2-tetrachloroethane vapor in a clothing processing plant as compared to workers not employed in a clothing plant (Norman et al. 1981). However, because the increased incidences were small and because of confounding factors, such as exposure to other chemicals and unknown occupational histories, the authors could not conclusively attribute the increased cancer incidences to 1,1,2,2-tetrachloroethane exposure.

4.2.2. Animal

Information on the carcinogenicity of 1,1,2,2-tetrachloroethane in animals following inhalation exposure was not available.

4.3. OTHER ROUTES OF EXPOSURE

Information on the carcinogenicity of 1,1,2,2-tetrachloroethane in humans and animals by other routes of exposure was not available.

4.4. EPA WEIGHT-OF-EVIDENCE

Classification: Group C, possible human carcinogen (EPA 1995a)

Basis: Based on an increased incidence of hepatocellular carcinomas in mice (NCI 1978).

4.5. CARCINOGENICITY SLOPE FACTORS

4.5.1. Oral

Slope Factor: 0.2 (mg/kg/day)^-1 (EPA 1995a)

Unit Risk: 5.8E-06 (g/L)^-1 (EPA 1995a)

Principal Study: NCI 1978

Comment: None

4.5.2. Inhalation

Slope Factor: 0.2 (mg/kg/day)^-1 (EPA 1995b)

Unit Risk: 5.8E-05 (g/m³)^-1 (EPA 1995a)

Principal Study: NCI 1978

Comment: Based on route-to-route extrapolation.

5. REFERENCES

ACGIH (American Conference of Governmental Industrial Hygienists). 1991. Documentation of the Threshold Limit Values and Biological Exposure Indices. Sixth Edition. Cincinnati, Ohio. pp. 1506-1509.

Amoore, J. E., and E. Hautala. 1983. Odor as an Aid to Chemical Safety: Odor Thresholds Compared with Threshold Limit Values and Volatilities for 214 Industrial Chemicals in Air and Water Dilution. J. Appl. Toxicol. 3(6):272-290 (cited in ATSDR 1994).

Archer, W. L. 1979. Kirk-Othmer encyclopedia of chemical technology. 3rd ed., Vol. 5. Grayson H, Eckroth, E. eds., 722-742 (cited in ATSDR 1994).

ATSDR (Agency for Toxic Substances and Disease Registry). 1994. Toxicological Profile for 1,1,2,2-tetrachloroethane. Draft for Public Comment. Update. Prepared by Research Triangle Institute under Contract No. 205-93-0606. U.S. Department of Health and Human Services, Public Health Service.

Carpenter, C. P., Smyth, H. F., and Pozzani, U. C. 1949. The assay of acute vapor toxicity and the grading in 6 from the results on 96 chemical compounds. J. Ind. Hyg. Tox. 31:343-346 (cited in ATSDR 1994).

Casciola, L. A. F., and Ivanetich, K. M. 1984. Metabolism of chloroethanes by rat liver nuclear cytochrome p-450. Carcinogenesis 5:543-548 (cited in ATSDR 1994).

Coyer, H. A. 1944.Tetrachloroethane poisoning. Ind. Med.13:230-233 (cited in ATSDR 1994).

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