The Risk Assessment Information System

Toxicity Summary for TETRACHLOROETHYLENE

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.

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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

MARCH 1993

Prepared by: Mary Lou Daugherty, M.S., Chemical Hazard Evaluation Group, Biomedical Environmental Information Analysis Section, Health and Safety Research Division, Oak Ridge National Laboratory*, 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

Tetrachloroethylene (CAS No. 127-18-4) is a halogenated aliphatic hydrocarbon with a vapor pressure of 17.8 mm Hg at 25C (U.S. EPA, 1982). The chemical is used primarily as a solvent in industry and, less frequently, in commercial dry-cleaning operations (ATSDR, 1990). Occupational exposure to tetrachloroethylene occurs via inhalation, resulting in systemic effects, and via dermal contact, resulting in local effects. Exposure to the general population can occur through contaminated air, food and water (ATSDR, 1990).

The respiratory tract is the primary route of entry for tetrachloroethylene (NTP, 1986; U.S. EPA, 1988). The chemical is rapidly absorbed by this route and reaches an equilibrium in the blood within 3 hours after the initiation of exposure (Hake and Stewart, 1977). Tetrachloroethylene is also significantly absorbed by the gastrointestinal (g.i.) tract, but not through the skin (Koppel et al., 1985; ATSDR, 1990). The chemical accumulates in tissues with high lipid content, where the half-life is estimated to be 55 hours (Stewart, 1969; ATSDR, 1990), and has been identified in perirenal fat, brain, liver, placentofetal tissue, and amniotic fluid (Savolainen et al., 1977). The proposed first step for the biotransformation of tetrachloroethylene is the formation of an epoxide thought to be responsible for the carcinogenic potential of the chemical (Henschler and Hoos, 1982; Calabrese and Kenyon, 1991). Tetrachloroethylene is excreted mainly unchanged through the lungs, regardless of route of administration (NTP, 1986). The urine and feces comprise secondary routes of excretion (Monster et al., 1979; Ohtsuki et al., 1983). The major urinary metabolite of tetrachloroethylene, trichloroacetic acid, is formed via the cytochrome P-450 system (ATSDR, 1990).

The main targets of tetrachloroethylene toxicity are the liver and kidney by both oral and inhalation exposure, and the central nervous system by inhalation exposure. Acute exposure to high concentrations of the chemical (estimated to be greater than 1500 ppm for a 30-minute exposure) may be fatal to humans (Torkelson and Rowe, 1981). Chronic exposure causes respiratory tract irritation, headache, nausea, sleeplessness, abdominal pains, constipation, cirrhosis of the liver, hepatitis, and nephritis in humans; and microscopic changes in renal tubular cells, squamous metaplasia of the nasal epithelium, necrosis of the liver, and congestion of the lungs in animals (Chmielewski et al., 1976; Coler and Rossmiller, 1953; Stewart et al., 1970; von Ottingen, 1964; Stewart, 1969; NTP, 1986).

Some epidemiology studies have found an association between inhalation exposure to tetrachloroethylene and an increased risk for spontaneous abortion, idiopathic infertility, and sperm abnormalities among dry-cleaning workers, but others have not found similar effects (Kyyronen et al, 1989; van der Gulden and Zielhuis, 1989). The adverse effects in humans are supported in part by the results of animal studies in which tetrachloroethylene induced fetotoxicity (but did not cause malformations) in the offspring of treated dams (Schwetz et al., 1975; Beliles et al., 1980; Nelson et al., 1980).

Reference doses (RfDs) for subchronic and chronic oral exposure to tetrachloroethylene are 1E-1 mg/kg/day and 1E-2 mg/kg/day, respectively (Buben and Flaherty, 1985; U.S. EPA, 1990; 1992a). These values are based on hepatotoxicity observed in mice given 100 mg tetrachloroethylene/kg body weight for 6 weeks and a no-observed-adverse effect level (NOAEL) of 20 mg/kg.

Epidemiology studies of dry cleaning and laundry workers have demonstrated excesses in mortality due to various types of cancer, including liver cancer, but the data are regarded as inconclusive because of various confounding factors (Lynge and Thygesen, 1990; U.S. EPA, 1988). The tenuous finding of an excess of liver tumors in humans is strengthened by the results of carcinogenicity bioassays in which tetrachloroethylene, administered either orally or by inhalation, induced hepatocellular tumors in mice (NCI, 1977; NTP, 1986). The chemical also induced mononuclear cell leukemia and renal tubular cell tumors in rats. Tetrachloroethylene was negative for tumor initiation in a dermal study and for tumor induction in a pulmonary tumor assay (Van Duuren et al., 1979; Theiss et al., 1977).

Although U.S. EPA's Science Advisory Board recommended a weight-of-evidence classification of C-B2 continuum (C = possible human carcinogen; B2 = probable human carcinogen), the agency has not adopted a current position on the weight-of-evidence classification (U.S. EPA, 1992b). In an earlier evaluation, tetrachloroethylene was assigned to weight-of-evidence Group B2, probable human carcinogen, based on sufficient evidence from oral and inhalation studies for carcinogenicity in animals and no or inadequate evidence for carcinogenicity to humans (NCI, 1977; NTP, 1986; U.S. EPA, 1987). The unit risk and slope factor values for tetrachloroethylene have been withdrawn from IRIS and HEAST. The upper bound risk estimates from the 1985 Health Assessment Document (U.S. EPA, 1985) as amended by inhalation values from the 1987 addendum (U.S. EPA, 1987) have not yet been verified by the IRIS-CRAVE Workgroup. For oral exposure, the slope factor is 5.2E-2 (mg/kg/day)^-1; the unit risk is 1.5E-6 (µg/L)^-1. For inhalation exposure, the slope factor is 2.0E-3 (mg/kg/day)^-1; the unit risk ranges from 2.9E-7 to 9.5E-7 (µg/m³)^-1 with a geometric mean of 5.8E-7 (µg/m³)^-1 (U.S. EPA, 1987). When the Agency makes a decision about weight-of-evidence, the CRAVE-IRIS verification will be completed and the information put on IRIS (U.S. EPA, 1992b).

1. INTRODUCTION

Tetrachloroethylene (perchloroethylene, CAS No. 127-18-4), a halogenated aliphatic hydrocarbon, is a colorless liquid with a molecular weight of 165.85, and a vapor pressure of 17.8 mm Hg at 25C (U.S. EPA, 1988). Tetrachloroethylene has half-lives of 47 days in the atmosphere and 30 to 300 days in surface water and groundwater (U.S. EPA, 1988). Tetrachloroethylene is used primarily as an industrial solvent for a number of applications, and is routinely used in laundry and dry-cleaning operations. Inhalation exposure is the primary concern for workers. The general public can also be exposed to tetrachloroethylene by inhalation, mainly in areas of concentrated industry and population (ATSDR, 1990). Some of the highest outdoor air levels (up to 58,000 ppt) have been associated with waste disposal sites (ATSDR, 1990). Exposure can also occur through contact with contaminated food and water supplies. An estimated 7 to 25% of the water supply sources in the United States may be contaminated with tetrachloroethylene (ATSDR, 1990).

Although the general toxicity of tetrachloroethylene is low, chronic exposure to the chemical has been associated with the induction of cancer in animals (IARC, 1979; NTP, 1986). Tetrachloroethylene has produced either weakly positive or negative responses in genotoxicity assays; however, its metabolic epoxide is mutagenic in bacteria and may contribute to the carcinogenicity (Calabrese and Kenyon, 1991).

2. METABOLISM AND DISPOSITION

2.1. ABSORPTION

The respiratory tract is the primary route of human exposure to tetrachloroethylene; the gastrointestinal (g.i.) tract is another, but less common, route of entry for the chemical (NTP, 1986; U.S. EPA, 1988). The absorption of tetrachloroethylene via inhalation is rapid and blood levels reach an equilibrium within 3 hours after the initiation of exposure (Hake and Stewart, 1977). Factors that influence respiratory abso rption include exercise, lean body mass, respiratory minute volume, concentration of tetrachloroethylene in inspired air, and duration of exposure (Monster, 1979; Hake and Stewart, 1977). Tetrachloroethylene is also absorbed from the g.i. tract of humans and animals, as evidenced by the presence of the chemical in the blood of a 6-year-old boy who ingested the chemical (Koppel et al., 1985) and by the elimination of 85-98% of the oral dose in expired air by rats and mice (Daniel, 1963; Schumann et al., 1980). Dermal absorption of tetrachloroethylene is not significant for either humans or animals (ATSDR, 1990).

2.2. DISTRIBUTION

As with other lipid-soluble materials, tetrachloroethylene accumulates in tissues with high lipid content (Stewart, 1969). Examination of rats exposed to tetrachloroethylene concentrations of 200 ppm, 6 hours/day for 4 days revealed the presence of the chemical in perirenal fat, brain, and liver tissue (Savolainen et al. 1977). The levels of tetrachloroethylene in the fat were approximately 145 times greater than those in blood, whereas levels in brain and liver were approximately 5 times those in blood.

Tetrachloroethylene also crosses the placenta to the fetus and amniotic fluid (Ghantous et al., 1986). Following exposure of pregnant mice to radioactive tetrachloroethylene, unmetabolized tetrachloroethylene was detected in fetoplacental tissues and a high concentration of radioactivity was detected in maternal body fat, brain, nasal mucosa, blood, liver, kidneys, and lungs.

2.3. METABOLISM

The main site for the metabolism of tetrachloroethylene is the liver, where the chemical is transformed via the cytochrome P-450 system to trichloroacetic acid, its major urinary metabolite (ATSDR, 1990). In one study, the trichloroacetic acid content of the urine reached a plateau after repeated exposure to >50 ppm (Ikeda et al., 1972), suggesting that the metabolism of tetrachloroethylene is a saturable process (NTP, 1986). Henschler and Hoos (1982) proposed that the first step in the biotransformation of tetrachloroethylene and other haloethylenes is the formation of highly reactive epoxides (oxiranes) that can induce mutations and cancer through covalent binding to nucleic acids.

Studies in rats, mice, and hamsters identified trichloroacetic as the major urinary metabolite of tetrachloroethylene, and oxalic acid and ethylene glycol as minor metabolites (Yllner, 1961; Daniel, 1963; Ikeda and Imamura, 1973, Moslen et al., 1977). Dekant et al. (1985) detected seven metabolites of tetrachloroethylene in the urine of rats and mice given single oral doses of 800 mg/kg of the chemical. These included oxalic acid, N-oxalylaminoethanol, dichloroacetic acid, trichloroacetic acid, N-trichloracetylaminoethanol, free and conjugated trichloroethanol, and an unidentified metabolite. One other group of investigators found only oxalic acid in the urine of treated rats (Pegg et al., 1979).

2.4. EXCRETION

The primary route of excretion of the absorbed dose of tetrachloroethylene, administered either orally or by inhalation, is through the lungs (NTP, 1986). Humans excrete a small fraction of the absorbed dose of tetrachloroethylene in the urine following inhalation of the chemical (Monster et al., 1979; Ohtsuki et al., 1983). For example, Ohtsuki et al. (1983) estimated that at the end of an 8-hour shift involving exposure to 50 ppm tetrachloroethylene, 38% of the chemical absorbed through the lungs would be exhaled unchanged, and 2% of the dose would be metabolized and excreted in the urine; the remainder would be eliminated from the body later. Trichlorinated compounds, particularly trichloroacetic acid, have been identified in the urine of exposed workers (Weiss, 1969; Ikeda and Ohtsuji, 1972; Ikeda et al., 1972; Ikeda and Imamura, 1973; Münzer and Heder, 1973). Humans experimentally exposed to 70-200 ppm tetrachloroethylene for 1-8 hours excreted less than 2% of the absorbed dose as urinary trichloroacetic acid (Fernandez et al., 1976; Hake and Stewart, 1977; Monster, 1979).

For animals, the proportional excretion of tetrachloroethylene is influenced by dose, route, and species. Pegg et al. (1979) observed that male Sprague-Dawley rats exposed to ¹⁴C-tetrachloroethylene by either inhalation (10 ppm over 8 hours) or gavage (1.0 mg/kg) excreted approximately 70% of the dose unchanged in expired air. Of the remainder, approximately 3% was excreted as carbon dioxide and approximately 23% was excreted in the urine and feces as nonvolatile metabolites. Increasing the doses to 600 ppm and 500 or 1000 mg/kg increased the proportion excreted in expired air to 89% in Wistar rats (Daniel, 1963). Similarly, mice exposed for 2 hours to 200 ppm by inhalation excreted 70% in expired air, 20% in the urine, and <0.5% in the feces (Yllner, 1961); but mice exposed to 10 ppm for 6 hours excreted only 12% of the dose via the lungs (Schumann et al., 1980).

The biological half-life for tetrachloroethylene is estimated at 144 hours for occupationally exposed individuals (Ikeda and Imamura, 1973). Based on concentration-time course data for tetrachloroethylene in the exhaled air and blood, the half-lives of inhaled tetrachloroethylene in three major body compartments were calculated to be 12-16 hours for highly vascular tissue, 30-40 hours for the muscle group, and 55 hours for the adipose group (ATSDR, 1987). The longer half-life in adipose tissue was attributed to the high adipose/blood partition coefficient and the low rate of blood perfusion to adipose tissue.

3. NONCARCINOGENIC HEALTH EFFECTS

3.1. ORAL EXPOSURES

3.1.1. Acute Toxicity

3.1.1.1. Human

Single doses of tetrachloroethylene produce low to moderate toxicity. Humans have survived acute oral doses of 500 mg/kg of the chemical (Torkelson and Rowe, 1981).

3.1.1.2. Animal

Oral LD₅₀ values for tetrachloroethylene range from 2600 mg/kg for rats (Pozzani et al., 1959) to 8850 mg/kg for mice (Torkelson and Rowe, 1981). Dogs and cats survived 4000 mg/kg; rabbits survived 5000 mg/kg.

3.1.2. Subchronic Toxicity

3.1.2.1. Human

Information on the oral subchronic toxicity of tetrachloroethylene in humans was not available.

3.1.2.2. Animal

Hepatotoxicity is the most significant effect of orally administered tetrachloroethylene in animals. Two oral subchronic studies examined the potential hepatotoxicity of the chemical. In the first, Buben and O'Flaherty (1985) administered the chemical (>99% pure, in corn oil) to mice by gavage at doses of 0, 20, 100, 200, 500, 1000, 1500 or 2000 mg/kg, 5 days/week for 6 weeks. Hepatotoxicity parameters evaluated included relative liver weight, triglycerides, glucose-6-phosphatase (G6P) activity, and SGPT activity. No effects were evident at 20 mg/kg, liver weight and triglycerides were significantly increased at 100 mg/kg, and G6P was significantly decreased and SGPT activity significantly increased at 500 mg/kg. Each effect was generally dose-related. Microscopic examination of liver tissues of the 200 and 1000 mg/kg groups revealed severe degenerative changes with evidence of karyorrhexis (nuclear disintegration) and centrilobular necrosis. A comparison of hepatotoxicity parameters with total urinary metabolites revealed a linear relationship between the hepatotoxicity and the metabolism of tetrachloroethylene.

In the second study, Hayes et al. (1986) administered doses of 0, 15, 400, or 1400 mg/kg/day of tetrachloroethylene in the drinking water to groups of 20 male and 20 female Sprague-Dawley rats for 90 days. At the two highest doses, body weights were decreased and relative liver and kidney weights were increased. The only serum indicator of potential hepatic toxicity was a dose-related increase in 5-nucleotidase activity. Parameters of general toxicity, including hematology, clinical chemistry, urinalysis, and gross appearance of tissues, were unaffected by treatment.

3.1.3. Chronic Toxicity

3.1.3.1. Human

Information on the oral chronic toxicity of tetrachloroethylene in humans was not available.

3.1.3.2. Animal

A carcinogenicity bioassay in mice and rats (NCI, 1977) provided the only available chronic oral toxicity data for tetrachloroethylene. For both mice and rats, dosage adjustments were made during the study. The time-weighted average doses of the chemical, administered for 78 weeks in corn oil, were as follows: male B6C3F₁ mice, 536 or 1072 mg/kg; female mice, 386 or 772 mg/kg; Osborne-Mendel male rats, 471 or 941 mg/kg; and female rats, 474 or 949 mg/kg. Toxic nephropathy was observed at all doses in both sexes of mice and rats. The nephropathy was characterized by degenerative changes in the proximal convoluted tubule at the junction of the cortex and medulla, with fatty degeneration, cloudy swelling, and necrosis of the tubular epithelium.

3.1.4. Developmental and Reproductive Toxicity

Information on the oral developmental and reproductive toxicity of tetrachloroethylene in humans and animals was not available.

3.1.5. Reference Dose

3.1.5.1. Subchronic

ORAL RfD: 1E-1 mg/kg/day (U.S. EPA, 1992a)

UNCERTAINTY FACTOR: 100

NOAEL: 20 mg/kg/day (converted to 14 mg/kg/day)

COMMENT: The same study applies to the subchronic and chronic RfD. The study is described in Section 3.1.2.2.

3.1.5.2. Chronic

ORAL RfD: 1E-2 mg/kg/day (U.S. EPA, 1990)

UNCERTAINTY FACTOR: 1000

NOAEL: 20 mg/kg/day (converted to 14 mg/kg/day)

CONFIDENCE:

Study: Low

Database: Medium

RfD: Medium

VERIFICATION DATE: 9/17/87

PRINCIPAL STUDY: Buben and O'Flaherty (1985)

COMMENTS: The study provided a NOAEL of 20 mg/kg/day that was converted to 14 mg/kg/day to account for noncontinuous exposure (U.S. EPA, 1992a); an uncertainty factor of 1000 results from factors of 10 to account for intraspecies variability, interspecies variability and extrapolation of a subchronic effect level to its chronic equivalent. The value is verified in IRIS (U.S. EPA, 1990).

3.2. INHALATION EXPOSURES

3.2.1. Acute Toxicity

3.2.1.1. Human

The current OSHA PEL for the chemical is 25 ppm (170 mg/m³) TWA; NIOSH recommends minimizing workplace exposure levels and the numbers of workers exposed (Calabrese and Kenyon, 1991).

Many victims of overexposure to tetrachloroethylene vapors have died, usually as a result of central nervous system (CNS) depression (Torkelson and Rowe, 1981). Other victims, who may have been unconscious for hours, survived with no ill effects. Exposure levels are not available for most cases; however, autopsy on one victim (found unconscious after performing work on a plugged line in a commercial dry-cleaning shop) revealed high levels of the compound in the blood (4.4 mg/100 mL) and brain (36 mg/100 g) (Lukaszewski, 1979).

Based on human experiments and industrial experience, Dow Chemical Co. (unpublished data, cited in Torkelson and Rowe, 1981) characterized the acute toxicity of tetrachloroethylene to humans as follows: 50 and 100 ppm, no physiological effects; 200 ppm, faint to moderate eye irritation, minimal light-headedness; 400 ppm, definite eye irritation, faint nasal irritation; 400 ppm, definite eye and slight nasal irritation, definite incoordination (2 hours); 600 ppm, definite eye and nasal irritation, dizziness, loss of inhibitions (10 min); 1000 ppm, markedly irritating to eyes and respiratory tract, considerable dizziness (2 min); 1500 ppm, almost intolerable irritation to eyes and nose, complete incoordination within minutes to unconsciousness within 30 min. In these studies, odor, which was faint at 100 ppm, progressed to almost intolerable at 1500 ppm. Other symptoms of tetrachloroethylene toxicity include anesthesia, nausea, headache, and anorexia (Torkelson and Rowe, 1981).

Mild, transient liver injury is associated with acute exposures to high concentrations of tetrachloroethylene. In one study, urine urobilinogen and serum bilirubin levels were elevated 9 days after a 3 hour exposure to 275 ppm, followed by a 0.5 hour exposure to 1000 ppm of a petroleum-based solvent containing about 50% tetrachloroethylene (Stewart et al., 1961). In another study, hepatitis and elevated SGOT activity resulted from exposure to anesthetic levels of tetrachloroethylene for 30 minutes (Stewart, 1969).

3.2.1.2. Animal

High level, single exposures of tetrachloroethylene to animals produced central nervous system depression, with death occurring during or immediately after exposure (Torkelson and Rowe, 1981). Rats tolerated 2000 ppm for up to 14 hours and 3000 ppm for 4 hours without deaths; rats exposed to 6000 ppm for a few minutes and 3000 ppm for several hours became unconscious (Rowe et al., 1952). The reported 8-hour LC₅₀ for tetrachloroethylene in rats is 5040 ppm (Pozzani et al., 1959), and the 4-hour LC₅₀ for mice is 5200 ppm (Friberg et al., 1953). In a mouse study, the highest concentration that did not produce death was 2450 ppm, the lowest concentration to produce death was 3000 ppm (Friberg et al. 1953).

Various investigators have reported acute liver toxicity in animals exposed to tetrachloroethylene. For example, Kylin et al. (1963) observed dose-related fatty infiltration of the liver in rats exposed to concentrations of the chemical ranging from 200-1600 ppm for 4 hours, and Drew et al. (1978) observed dose-related increases in SGOT, SGPT, glucose-6-phosphatase, and ornithine carbamyl transferase in rats exposed to concentrations ranging from 500-2000 ppm for 4 hours. Gehring (1968) determined that, for mice exposed to tetrachloroethylene, liver toxicity was of relatively low importance compared with anesthesia. At the concentration of 3700 ppm, the anesthetic ED₅₀ occurred at about 24 minutes, whereas the SGPT ED₅₀ occurred at 470 minutes and the LT₅₀ at 730 minutes.

3.2.2. Subchronic Toxicity

3.2.2.1. Human

Some subjects exhibit liver injury following excessive subacute inhalation exposure to tetrachloroethylene (Torkelson and Rowe 1981). Hepatic effects that have been associated with high or unknown levels of tetrachloroethylene include cirrhosis, toxic hepatitis, liver cell necrosis, and enlarged liver (U.S. EPA, 1985). In one study, 16 of 25 workers, exposed to 59-442 ppm for 2 months to 27 years, had significantly elevated SGOT and SGPT activity compared with controls (Chmielewski et al., 1976).

3.2.2.2. Animal

An NTP (1986) bioassay provided subchronic toxicity data for animals exposed to tetrachloroethylene. Groups of male and female F344/N rats and B6C3F₁ mice were exposed to tetrachloroethylene concentrations of 100-1,600 ppm 6 hours/day, 5 days/week for 13 weeks. For both species, mortality was increased and body weight decreased at 1,600 ppm. In rats, pulmonary congestion was observed in 8/10 males and 7/10 females exposed to 1,600 ppm, but was not observed in animals exposed to 800 ppm. Minimum to mild, dose-related, hepatic congestion occurred in all groups. In mice, minimal to mild microscopic liver and kidney changes were observed at 200-1,600 ppm. Leukocytic infiltration, centrilobular necrosis, bile stasis, and mitotic alteration were noted in the liver; and karyomegaly of the tubular epithelial cells was observed in the kidney. The kidney changes, minimal at 200 ppm, were dose-related.

Pegg et al. (1978), in a study of the disposition of tetrachloroethylene in Sprague-Dawley rats, noted that animals exposed to 4 g/m³ (600 ppm), 6 hours/day, 5 days/week for 12 months had unspecified reversible liver damage.

Other investigators have reported LOAELs for tetrachloroethylene in rats as follows:

1. 15 ppm, 4 hours/day for 5 months (EEG changes and protoplasmal swelling of cerebral cortical cells, some vacuolated cells and signs of karyolysis) (Dmitrieva, 1966) and

2. 230 ppm, 8 hours/day, 5 days/week for 7 months (congestion of the liver and spleen, and kidney injury) (Carpenter, 1937).

LOAELs for tetrachloroethylene in mice include:

1. 9 ppm, continuously for 30 days (abnormal gross liver appearance, increased liver weight, and liver histopathology) (Kjellstrand et al., 1984);

2. 37 ppm continuously for 30 days (increased butyrylcholinesterase activity) (Kjellstrand et al., 1984); and

3. 15 ppm, 5 hours/day for 3 months (decreased electroconductance of muscle and amplitude of muscular contraction) (Dmitrieva, 1968).

A LOAEL for tetrachloroethylene in rabbits was 15 ppm, 3-4 hours/day for 7-11 months (depressed agglutinin formation, moderately increased urinary urobilinogen, pathomorphological changes in the parenchyma of liver and kidneys) (Mazza, 1972; Navrotskii et al., 1971).

Guinea pigs exposed to 100 ppm, 7 hours/day, 5 days/week for 132 or 169 exposures had increased liver weights; and guinea pigs exposed to 400 ppm had cirrhosis, increased neutral fat and esterified cholesterol and moderate central fatty degeneration (Rowe et al., 1952). Liver effects were dose-related.

3.2.3. Chronic Toxicity

3.2.3.1. Human

Human health effects resulting from chronic exposure to various concentrations of tetrachloroethylene include respiratory tract irritation, headache, nausea, sleeplessness, abdominal pains, constipation, cirrhosis of the liver, hepatitis, and nephritis (Coler and Rossmiller, 1953; Stewart et al., 1970; von Ottingen, 1964; Stewart, 1969). In one study, 16 of 25 workers, exposed to 59-442 ppm for 2 months-27 years, had significantly elevated SGOT and SGPT activity compared with controls (Chmielewski et al., 1976).

3.2.3.2. Animal

An NTP bioassay provided chronic toxicity data for animals exposed to tetrachloroethylene. Groups of 50 male and 50 female F344/N rats and B6C3F₁ mice inhaled the chemical 6 hours/day, 5 days/week for 103 weeks (NTP, 1986). The exposure concentrations consisted of 0, 200, or 400 ppm for rats and 0, 100, or 200 ppm for mice. In rats, nonneoplastic effects consisted of dose-related renal tubular cell karyomegaly (males and females) and renal tubular cell hyperplasia (males only) and dose-related increases in the incidences of nasal thromboses and squamous metaplasia (the thromboses were believed to have been secondary to tetrachloroethylene-induced leukemia). The incidence of renal tubular cell karyomegaly was higher in males than in females. In mice nonneoplastic effects consisted of dose-related hepatic degeneration, hepatic necrosis, and hepatic nuclear inclusion; dose-related renal tubular cell karyomegaly; and pulmonary congestion.

Pegg et al. (1978), reported in a fate and disposition study that rats inhaling a tetrachloroethylene concentration of 600 ppm (4 g/m³) 6 hours/day, 5 days/week for 12 months developed unspecified reversible liver damage.

3.2.4. Developmental and Reproductive Toxicity

3.2.4.1. Human

A study involving dry cleaner and laundry workers throughout Finland was conducted to determine if exposure to tetrachloroethylene during the first trimester of pregnancy had harmful effects on pregnancy outcome (Kyyronen et al., 1989). The population consisted of 5700 workers, half of whom had been pregnant during the study period (1973-1983); one pregnancy per worker was randomly selected for the study. The study population included 247 cases of spontaneous abortion and 33 cases of malformed infants, indicating a significantly high association between exposure to tetrachloroethylene and spontaneous abortion; the odds ratio was 3.6. The investigators concluded that exposure of pregnant women to tetrachloroethylene should be minimized.

van der Gulden and Zielhuis (1989) reviewed available epidemiological and animal studies to further define the reproductive effects of tetrachloroethylene. Some epidemiological studies suggested a risk of idiopathic infertility among female dry cleaning operators and an increased risk of sperm abnormalities among men working in this field, whereas other studies did not suggest an effect. The investigators concluded that, because tetrachloroethylene interacts with mechanisms (e.g. enzyme systems, genetic apparatus) capable of leading to defects in reproductive processes, one might expect the chemical to affect reproduction; however, the currently available epidemiological studies are inconclusive for reproductive effects, and prospective studies are needed.

3.2.4.2. Animal

The results of developmental toxicity studies in animals have been inconsistent. Pregnant Swiss Webster mice (17) and Sprague-Dawley rats (17) were exposed by inhalation to 300 ppm tetrachloroethylene for 7 hours/day on gestational days 6-15 (Schwetz et al., 1975). Caesarean sections were performed on day 18 for the mice and day 21 for the rats. The exposed rats exhibited a slightly increased incidence of resorptions and their pups had reduced body weights. The pups of exposed mice had reduced body weights, delayed ossification of the skull, increased subcutaneous edema, and split sternebrae. Malformations were not observed in either mice or rats. In another study, Hardin et al. (1981) exposed pregnant rats and rabbits to 500 ppm of tetrachloroethylene 6-7 hours/day on gestational days 1-19, and saw no indication of reproductive or developmental toxicity in either species.

Beliles et al. (1980) exposed Sprague-Dawley rats to 0 or 300 ppm of tetrachloroethylene 7 hours/day, presumably 5 days/week for 3 weeks before mating and on gestation days 0-18 or 6-18. Maternal toxicity and fetal skeletal ossification anomalies were observed, but other developmental effects were absent.

Behavioral effects were evaluated in the offspring of Sprague-Dawley rats exposed to 900 ppm of tetrachloroethylene on gestational days 7-13 or 14-20 (Nelson et al., 1980). Seven behavioral tests evaluated the effects of exposure at several stages during postnatal days 4-46, and neurochemical analyses were conducted on brain tissue of pups 0 or 21 days old. Exposure of the dams to 900 ppm on days 7-13 produced maternal toxicity and decreased the performance of the pups on the ascent and rotorod tests of neuromuscular ability. Twenty-one day old offspring had decreased brain levels of dopamine (exposed on days 14-20) and acetylcholine (exposed on days 14-20 or 7-13). Similar exposures did not produce external or skeletal malformations in the fetuses. The offspring of a group of dams treated with 100 ppm on days 14-20 of gestation did not show any adverse effects in comparison to controls.

The reproductive performance of Sprague-Dawley rats was not affected by exposure to 70, 230, or 470 ppm tetrachloroethylene, 8 hours/day, 5 days/week for 28 weeks (Carpenter, 1937). Long-Evans rats were exposed to 1000 ppm of tetrachloroethylene 6 hours/day, 5 days/week for 2 weeks pre-mating through day 20 of gestation or for days 0-20 of gestation (Tepe et al., 1982; Manson et al., 1982). Treatment-related effects included the following: increased maternal liver weight, reduced fetal body weight, increased skeletal and soft-tissue anomalies indicative of embryotoxicity. Postnatal parameters, monitored for 18 months and consisting of body weight, neurobehavioral activity, and gross lesions at autopsy, were not adversely affected.

3.2.5. Reference Concentration

Subchronic and chronic reference concentrations for tetrachloroethylene, administered by inhalation, were not available.

3.3. OTHER ROUTES OF EXPOSURE

3.3.1. Acute Toxicity

3.3.1.1. Human

Liquid tetrachloroethylene can cause pain, lacrimation and burning of the eyes; high concentrations of the vapors may also cause eye discomfort (Torkelson and Rowe, 1981). Tetrachloroethylene on the skin has no significant effect if allowed to evaporate, but can cause dermatitis, if confined on the skin or if exposures are prolonged and frequent (Torkelson and Rowe 1981). Although some absorption of liquid tetrachloroethylene through the skin occurs, this is not a likely route of toxic exposure to the chemical (Stewart and Dodd, 1964). Vapor concentrations of 600 ppm were not absorbed through the skin of human subjects (Riihimaki and Pfaffli, 1978).

3.3.1.2. Animal

The LD₅₀ for tetrachloroethylene administered by subcutaneous injection is 390 mg/kg (Plaa et al., 1958). The hepatotoxicity and renal toxicity of tetrachloroethylene were mild following i.p injection (dose not given) (Plaa et al., 1958; Plaa and Larson, 1965).

3.3.2. Subchronic Toxicity

Information on the subchronic toxicity of tetrachloroethylene by other routes of exposure in humans or animals was not available.

3.3.3. Chronic Toxicity

Information on the chronic toxicity of tetrachloroethylene by other routes of exposure in humans or animals was not available.

3.3.4. Developmental and Reproductive Toxicity

Information on the developmental and reproductive toxicity of tetrachloroethylene by other routes of exposure in humans and animals was not available.

3.4. TARGET ORGANS/CRITICAL EFFECTS

3.4.1. Oral Exposures

3.4.1.1. Primary Target Organ(s)

1. Liver: Hepatotoxicity was observed in subchronic animal studies.

2. Kidney: Toxic nephropathy was observed in a chronic animal study.

3.4.1.2. Other Target Organ(s)

Other target organs for the oral toxicity of tetrachloroethylene were not identified.

3.4.2. Inhalation Exposures

3.4.2.1. Primary Target Organ(s)

1. Central nervous system (CNS): Death from acute occupational exposure to tetrachloroethylene has been attributed to CNS depression. High levels of the chemical were found in the brain of one victim of overexposure.

2. Liver: Hepatotoxicity has been associated with exposure to tetrachloroethylene vapor in human case studies and in acute, subchronic, and chronic studies in animals.

3. Kidney: Renal effects were observed in humans and animals exposed chronically to the chemical.

3.4.2.2. Other Target Organ(s)

Reproductive system: Spontaneous abortion in humans and fetal toxicity in animals have been related to exposure to tetrachloroethylene.

4. CARCINOGENICITY

4.1. ORAL EXPOSURES

4.1.1. Human

Information on the oral carcinogenicity of tetrachloroethylene in humans was not available.

4.1.2. Animal

In an NCI carcinogenicity bioassay, B6C3F₁ male mice were given tetrachloroethylene in corn oil by gavage. Dosage adjustments were made during the study and the time-weighted average doses of the chemical, administered for 78 weeks, were 536 or 1072 mg/kg for 50 males/group and 386 or 772 mg/kg for 50 females/group (NCI, 1977). Untreated and vehicle-treated animals served as controls. The treated mice had statistically significant, but not clearly dose-related, increases in hepatocellular carcinomas (for males and females combined: 4/37 in untreated controls, 2/40 vehicle controls, 51/97 low-dose, 46/96 high-dose). Osborne-Mendel male rats given time-weighted-average doses of 471 or 941 mg/kg and female rats, given 474 or 949 mg/kg for 78 weeks did not develop tumors (NCI, 1977). Fifty animals per group started on treatment; however, NCI (1977) noted that increased mortality in the rats precluded the proper assessment of carcinogenic potential.

4.2. INHALATION EXPOSURES

4.2.1. Human

In a Danish study, a cohort of laundry and dry-cleaning workers was studied for cancer incidence among persons exposed to tetrachloroethylene (the most commonly used solvent in Danish dry-cleaning shops) (Lynge and Thygesen, 1990). The 10-year follow-up study evaluated 8567 women and 2033 men employed in laundry and dry-cleaning in 1970. The study revealed a significant excess risk for primary liver cancer among the women (7 observed, 2.1 expected); but not one case of primary liver cancer was found among the men, for whom the expected value was 1.1. Although the majority of primary liver cancer cases in Denmark have been associated with excess alcohol consumption, the investigators did not believe this to be the exclusive explanation for the excess tumors among the dry-cleaning workers.

A retrospective mortality epidemiologic study of dry cleaning workers with exposure to tetrachloroethylene reported an excess of mortality from kidney and bladder cancer (8 cases vs. 2.7 expected; SMR=296) and cancer of the cervix (10 observed vs. 5.1 expected; SMR=296) (Brown and Kaplan, 1985). The cohort consisted of 1690 workers with 23 years of employment. The results of this study were inconclusive because the workers had potential occupational exposure to petroleum solvents, in addition to tetrachloroethylene. However, a subcohort of the study, consisting of 615 workers with no known exposure to petroleum solvents, demonstrated no excess risk for cancer at any site (Brown and Kaplan, 1985). Other studies of dry cleaning and laundry workers have demonstrated excesses in mortality due to various types of cancer (lung, cervix, kidney, skin and/or colon), but the data are also regarded as inconclusive because of various confounding factors (U.S. EPA, 1988).

4.2.2. Animal

In a carcinogenicity bioassay, groups of 50 male and 50 female F344/N rats and B6C3F₁ mice inhaled tetrachloroethylene 6 hours/day, 5 days/week for 103 weeks (NTP, 1986). The exposure concentrations were 0, 200, or 400 ppm for rats and 0, 100, or 200 ppm for mice. Exposure to tetrachloroethylene under the conditions of the study resulted in: (a) clear evidence of carcinogenicity for male F344/N rats as shown by an increased incidence of mononuclear cell leukemia (controls, 28/50; low dose, 37/50; high dose, 37/50) and renal tubular cell adenomas or carcinomas combined (1/49, 3/49, 4/50) (the incidence of the renal tumors was not statistically significant, but these uncommon tumors had been found consistently at low incidences in male rats in other studies of chlorinated ethanes and ethylenes); (b) some evidence of carcinogenicity for female rats as shown by increased incidences of mononuclear cell leukemia (18/50, 30/50, 29/50); and (c) clear evidence of carcinogenicity for mice as shown by increased incidences of hepatocellular adenomas (11/49, 8/49, 18/50) and carcinomas (7/49, 25/49, 26/50) in males and of hepatocellular carcinomas (1/48, 13/50, 36/50) in females. There were no neoplastic changes in the respiratory tract of either species, but there was an increased incidence (non-dose-related) of squamous metaplasia in the nasal cavities of treated male rats.

Tumors were not observed in groups of 96 male and 96 female Sprague-Dawley rats exposed to tetrachloroethylene concentrations of 300 or 600 ppm, 6 hours/day, 5 days per week for 52 weeks and observed for the rest of their lives (Rampy et al., 1978).

4.3. OTHER ROUTES OF EXPOSURE

In an initiation-promotion study, female ICR/Ha Swiss mice did not develop tumors when given a single application of 163 mg of tetrachloroethylene (maximum tolerated dose) followed by topical applications of phorbol myristate acetate three times/week for 428-576 days (Van Duuren et al, 1979). In the same study, other groups of mice given three weekly applications of 18 or 54 mg of tetrachloroethylene in acetone for 440-594 days, also did not develop tumors.

In a pulmonary tumor bioassay, strain A/St mice injected intraperitoneally with tetrachloroethylene (80 mg/kg x 14, 200 mg/kg x 24, 400 mg/kg x 48) had no increase in the incidence of pulmonary tumors (Theiss et al., 1977). U.S. EPA (1985) analyzed this study and determined that a negative result is not considered conclusive because (1) several chemicals known to be carcinogenic in chronic rodent bioassays were not carcinogenic in the pulmonary tumor assay, and (2) the strain A mouse pulmonary tumor assay is relatively insensitive to mouse carcinogens that mainly affect the liver.

4.4. EPA WEIGHT-OF-EVIDENCE

Classification: C-B2 continuum (C = possible human caarcinogen; B2 = probable human carcinogen (U.S. EPA, 1992b).

Comment: This classification is a recent recommendation by EPA's Science Advisory Board. However, EPA has not adopted a current position on the weight-of-evidence classification (U.S. EPA, 1992b). An earlier evaluation (U.S. EPA, 1987) classified tetrachloroethylene as a weight-of-evidence B2 chemical, based on sufficient evidence in animals (the induction of liver tumors in the mouse and leukemia in the rat and inadequate carcinogenicity data for humans.

4.5. CARCINOGENICITY SLOPE FACTORS

4.5.1. Oral

SLOPE FACTOR: 5.2E-2 (mg/kg/day)^-1 (U.S. EPA, 1985)

UNIT RISK: 1.5E-6 (µg/L)^-1 (U.S. EPA, 1985)

PRINCIPAL STUDIES: NCI (1977)

COMMENT: The unit risk and slope factor values for tetrachloroethylene have been withdrawn from IRIS and HEAST. The upper bound risk estimates from the 1985 Health Assessment Document (U.S. EPA, 1985) as amended by inhalation values from the 1987 addendum (U.S. EPA, 1987) have not been verified by the IRIS-CRAVE Workgroup. When the Agency makes a decision about weight-of-evidence, the CRAVE-IRIS verification will be completed and the information put on IRIS (U.S. EPA, 1992b).

4.5.2. Inhalation

SLOPE FACTOR: 2.0E-3 (mg/kg/day)^-1 (U.S. EPA, 1987)

UNIT RISK: 2.9E-7 to 9.5E-7 (µg/m³)^-1 (U.S. EPA, 1987)

PRINCIPAL STUDIES: NTP (1986)

COMMENT: The unit risk and slope factor values for tetrachloroethylene have been withdrawn from IRIS and HEAST. The upper bound risk estimates from the 1985 Health Assessment Document (U.S. EPA, 1985) as amended by inhalation values from the 1987 addendum (U.S. EPA, 1987) have not been verified by the IRIS-CRAVE Workgroup. When the Agency makes a decision about weight-of-evidence, the CRAVE-IRIS verification will be completed and the information put on IRIS (U.S. EPA, 1992b).

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