The Risk Assessment Information System

Toxicity Profiles

Formal Toxicity Summary for CARBON TETRACHLORIDE

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

DECEMBER 1992

Prepared by: Andrew Francis, M.S., D.A.B.T., Chemical Hazard Evaluation and Communication Group, Biomedical Environmental Information Analysis Section, Health and Safety 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

Humans are sensitive to carbon tetrachloride intoxication by oral, inhalation and dermal routes. Oral and inhalation exposure to high concentrations of carbon tetrachloride results in acute central nervous system effects including dizziness, vertigo, headache, depression, confusion, incoordination and, in severe cases, respiratory failure, coma and death. Gastrointestinal problems including nausea, abdominal pain and diarrhea, often accompany these narcotic effects. Liver and kidney damage can appear after the acute symptoms subside. All symptoms can occur following a single oral or inhalation exposure. Milder narcotic effects followed by liver and kidney damage have been reported following dermal exposure. Although an inhalation exposure of about 1000 ppm for a few minutes to hours will cause the narcotic effects in 100% of the population, large variations in sensitivity are seen. Alcohol intake greatly increases human sensitivity to carbon tetrachloride; consequently, exposure to 250 ppm for 15 minutes can be life threatening to an alcoholic.

Subchronic and chronic exposure to doses as low as 10 ppm can result in liver and kidney damage (Sax and Lewis, 1989; ATSDR, 1989). Lung damage has also been reported in animals and humans but is not route specific and is believed to be secondary to kidney damage (Sax and Lewis, 1989). Prolonged exposure has been observed to cause visual effects in both humans and animals. Changes in the visual field, reduced corneal sensitivity, subnormal dark adaption, and changes in color perception have been reported in humans exposed by inhalation to a minimum concentration of 6.4 ppm, 1 hour/day for an average of 7.7 years. Increased hepatic enzyme activities indicative of liver damage have also been observed (Smyth et al., 1936; Barnes and Jones, 1967; Moeller, 1973; ATSDR, 1989).

Maternal toxicity and fetotoxic effects have been reported in rats following oral or inhalation exposure to carbon tetrachloride during gestation (Wilson, 1954; Schwetz et al., 1974). Repeated inhalation exposure of male rats to carbon tetrachloride concentrations of 200 ppm or greater has been reported to cause degeneration of the testicular germinal epithelium as well as severe liver and kidney damage (Adams et al., 1952).

A subchronic reference dose (RfDs) of 0.007 mg/kg/day has been calculated for oral exposure from a no-observed-adverse-effect level (NOAEL) of 0.71 mg/kg/day determined in a 12-week rat study (U.S. EPA, 1992a). Significantly higher doses caused minimal liver damage (Bruckner et al., 1986). A dose of 7.1 mg/kg/day was considered a lowest-observed-adverse-effect level (LOAEL). A chronic reference dose (RfDc) of 0.0007 mg/kg/day was calculated by adding an additional uncertainty factor of 10 to account for the use of a subchronic study. Confidence in the oral RfD values is rated medium by EPA (1992b).

A chronic or subchronic reference concentration (RfC) for inhalation exposure is currently under development by the EPA.

Although data for the carcinogenicity of carbon tetrachloride in humans are inconclusive, there is ample evidence in animals that the chemical can cause liver cancer. Hepatocellular carcinomas have been induced in hamsters, rats and mice after oral carbon tetrachloride treatment for 16 to 76 weeks. Liver tumors have also been demonstrated in rats following inhalation exposure, but the doses were not quantitatively established. The EPA weight-of-evidence classification for both oral and inhalation exposure is B2, probable human carcinogen based on adequate animal evidence. Carcinogenicity slope factors of 0.13 (mg/kg/day)-1 for oral exposure and 0.053 (mg/kg/day)-1 for inhalation exposure have been calculated from the oral exposure experiments with hamsters, rats and mice (U.S. EPA, 1992a,b; Della Porta et al., 1961; Edwards et al., 1942; NCI, 1976a, 1976b; Weisburger, 1977). A drinking water unit risk of 3.7 x 10-6 (µg/L)-1 and an inhalation unit risk of 1.5 x 10-5 (µg/m3)-1 have also been calculated by U.S.EPA (1992b).

1. INTRODUCTION

Carbon tetrachloride (tetrachloromethane, CCl4, CAS registry number 56-23-5) is a clear oily liquid at room temperature with an aromatic sweet odor. It is heavier than water (density = 1.59) in which it is sparingly soluble (about 0.8 grams/L at 20o C). It is volatile with a vapor pressure of 90 mm Hg at 20o C, and a boiling point of 76.5o C (Weiss, 1980). Carbon tetrachloride is not flammable, and until the mid 1960's was used in fire extinguishers. Other uses, which have been discontinued, include a solvent for cleaning and household products, as a fumigant for insects, and as an oral treatment for certain parasitic infections. Industrial uses include the production of chlorofluorocarbons used in refrigeration, and as a degreasing solvent. These uses are expected to decline (ATSDR, 1989).

Carbon tetrachloride is relatively stable in the environment. Volatilization is the primary removal mechanism from water and soil. It eventually diffuses into the stratosphere where it undergoes photolysis by ultraviolet light (U.S. EPA, 1989).

It can form explosive, impact-sensitive mixtures with particulates of metals including aluminum, barium, beryllium, potassium, lithium, sodium and zinc. Carbon tetrachloride also forms explosive mixtures with chlorine trifluoride, calcium hypochlorite, calcium disilicide, triethyldialuminum trichloride, decaborane and dinitrogen tetraoxide. It will react violently with fluorine, boranes, allyl alcohol and other related chemicals. Phosgene and Cl- are decomposition products when carbon tetrachloride is heated (Sax and Lewis, 1989).

2 METABOLISM AND DISPOSITION

2.1. ABSORPTION

Carbon tetrachloride is absorbed by humans after both oral and inhalation exposure as demonstrated by accounts of poisoning. Quantitative oral data in humans, however, is not available. Data derived from rats indicate that between 65 and 86% of an orally administered dose of radiolabeled carbon tetrachloride can be accounted for by measuring the excretion of the compound and its metabolites in expired air over a 10 to 24 hour period (U.S. EPA, 1989; Seawright and McLean, 1967; Marchand et al., 1970). Concurrent ingestion of alcohol or fats has been shown to increase the rate and amount of carbon tetrachloride absorption by the gastrointestinal tract (Nielsen and Larsen, 1965).

The absorption following inhalation exposure of humans has been estimated to be about 60% based on the difference in carbon tetrachloride concentration in inhaled and expired air (Lehmann and Schmidt-Kehl, 1936). A similar measurement in female monkeys exposed to radiolabeled carbon tetrachloride indicated that absorption was 30.4% of the total amount inhaled. The animals were exposed for 139 to 300 minutes and the absorption rate was calculated to be 0.022 mg carbon tetrachloride/kg/minute (McCollister et al., 1951; U.S. EPA, 1989).

2.2. DISTRIBUTION

Quantitative studies on the distribution of carbon tetrachloride in humans were not available, but animal studies indicate that the compound is generally distributed as a function of blood flow and fat content of the tissues. Using an autoradiographic technique and an inhalation protocol, Bergman (1983) demonstrated a considerable higher uptake of [14C] carbon tetrachloride into the white matter of brain, spinal cord and spinal nerves of rats than in the kidney, lung, spleen, muscle and blood. A similar distribution was reported following oral exposure in rats, except a higher concentration was found in the liver than in the brain. This is due to the absorption of the material from the intestine into the portal circulation. Peak concentrations in the blood, striated muscle, brain and liver were reached within 2 hours after exposure but were not reached in the fat tissue until 5.5 hours. Maximum concentrations in the fat were 50 times the peak blood concentrations (Marchand et al., 1970; ATSDR, 1989).

2.3. METABOLISM

No information is available on the metabolism of carbon tetrachloride in humans; however, animal studies have revealed that the molecule is metabolized in the liver by cytochrome P-450 (Sipes et al., 1977). One of the resulting products of the metabolic activity is believed to be a trichloromethyl radical that leads to the formation of chloroform, hexachloroethane, carbon monoxide, trichloromethanol, phosgene and carbon dioxide (ATSDR, 1989). The radical is thought to induce lipid peroxidation resulting in membrane destruction and the loss of organelle and cell function (Rao and Recknagel, 1968). Based on a pharmacokinetic model developed by Paustenbach et al. (1988), about 4% of the carbon tetrachloride that is metabolized is converted to and excreted as carbon dioxide. The remaining metabolic products may bind to proteins, lipids and DNA. For inhalation exposure, the metabolic process is saturated when the ambient concentration is about 100 ppm. Above this concentration an increased percentage of the initial dose is excreted unchanged (ATSDR, 1989).

2.4. EXCRETION

Human studies have shown a biphasic excretion of carbon tetrachloride in expired air after oral or inhalation exposure. Quantitative excretion data are not available for humans, but the initial half-life was less than one hour, whereas the second phase half-life was about 30-40 hours following inhalation exposure. The slower second phase is likely due to the degradation of adducts of carbon tetrachloride metabolites from proteins and other cellular molecules (Stewart et al., 1965; Stewart et al., 1963).

Studies with monkeys and rats have indicated that 30-40% of an inhaled dose is excreted in expired air unchanged, 50-60% is excreted in the feces and only small amounts are found in the urine. The feces and urine contain unknown non-volatile metabolites (McCollister et al., 1951; Paustenbach et al., 1986). The relative amount of unchanged carbon tetrachloride excreted in expired air following oral exposure was found to be dose dependent. Oral doses in rats of 50 mg/kg/day or higher resulted in 70-90% recovery of unchanged carbon tetrachloride in expired air, lower doses resulted in increasing percentages recovered as carbon dioxide. The relative rate of excretion was found to decrease with increasing doses possibly due to an increased amount of binding to fat with the higher doses (Reynolds et al., 1984).

3. NONCARCINOGENIC HEALTH EFFECTS

3.1. ORAL EXPOSURES

3.1.1. Acute Toxicity

3.1.1.1. Human

Initial symptoms result from a narcotic effect similar to that of chloroform: dizziness, vertigo, headache, depression, mental confusion and incoordination. These symptoms can rapidly progress to loss of consciousness, respiratory failure and death. Gastrointestinal effects also occur and include nausea, vomiting, abdominal pain and diarrhea. An LDLo of 43 mg/kg has been reported for human oral exposure. Individuals who recover from the acute symptoms may suffer from liver and/or kidney damage. Concurrent intake of alcohol increases the probability of injury (Torkelson and Rowe, 1978; Sax and Lewis, 1989).

3.1.1.2. Animal

The narcotic symptoms described for humans (Section 3.1.1.1.) are also observed in animals orally exposed to carbon tetrachloride. Oral LD50 values of 2800 mg/kg for rats, 8263 mg/kg for mice, and 5760 mg/kg for rabbits and guinea pigs have been reported (Sax and Lewis, 1989). Animals appear to be less sensitive to the kidney effects of carbon tetrachloride than humans.

3.1.2. Subchronic Toxicity

3.1.2.1. Human

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

3.1.2.2. Animal

Different experimental animals exhibit a range of sensitivities to carbon tetrachloride under various experimental conditions. When golden hamsters were given 12.3 mg/kg/day in corn oil, 50% mortality was seen within a 30 week experiment (Della Porta et al., 1961). Bruckner et al. (1986) dosed Sprague-Dawley rats by gavage with 1, 10 or 33 mg carbon tetrachloride in corn oil/kg body weight, 5 times/week for 12 weeks. Liver cirrhosis was observed with the high dose, whereas the low dose was a NOAEL. The 10 mg/kg dose resulted in slightly increased sorbitol dehydrogenase activity and has been considered a LOAEL (U.S. EPA, 1992b). Condie et al. (1986) in a similar experiment compared the effects of corn oil versus Tween-60 used as the solvent/vehicle. Doses of 1.2, 12 or 120 mg carbon tetrachloride/kg body weight were given to CD-1 mice 5 days/week for 90 days. Corn oil used as the solvent/vehicle increased the toxicity of the carbon tetrachloride. The 1.2 mg/kg dose was the NOAEL when corn oil was used compared to the NOAEL of 12 mg/kg with Tween-60 as the vehicle. All animals exhibited signs of hepatotoxicity as measured by increased serum enzyme activities and histopathology; however the symptoms were more severe when corn oil was used as the vehicle. Hayes et al. (1986) gave CD-1 mice 12, 120, 540 or 1200 mg carbon tetrachloride in corn oil/kg/day for 90 consecutive days. Evidence of liver damage was observed with all doses and was dose related. Increased spleen weights as well as liver weights were seen with all doses.

3.1.3. Chronic Toxicity

3.1.3.1. Human

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

3.1.3.2. Animal

Alumot et al. (1976) fed rats 0, 80 or 200 ppm carbon tetrachloride for 2 years. The daily dose was estimated to be 10-18 mg/kg/day for the 200 ppm dietary concentration. This dose was established as the NOAEL because no biochemical changes attributable to carbon tetrachloride intake were seen. The experiment, however, was flawed by a high incidence of respiratory infections in the experimental animals.

3.1.4. Developmental and Reproductive Toxicity

3.1.4.1. Human

Information on developmental and reproductive toxicity of carbon tetrachloride in humans was not available.

3.1.4.2. Animal

Alumot et al. (1976) (discussed in section 3.1.3.2) found no change in the reproductive activity of male and female rats receiving 80 or 200 ppm carbon tetrachloride in the diet for 2 years. Wilson (1954) reported marked maternal toxicity and resorption of fetuses in rats given 0.6-0.9 mL carbon tetrachloride/day by gavage during gestation. No teratogenic or other adverse effects were observed among the surviving offspring.

3.1.5. Reference Dose

3.1.5.1. Subchronic

  • ORAL RfDs: 0.007 mg/kg/day (U.S. EPA, 1992a)
  • UNCERTAINTY FACTOR: 100
  • NOAEL: 0.71 mg/kg/day
  • PRINCIPAL STUDIES: The same studies and comments apply to both the subchronic and chronic RfD derivations. See section 3.1.5.2.

3.1.5.2. Chronic

  • ORAL RfDc: 0.0007 mg/kg/day (U.S. EPA, 1992b)
  • UNCERTAINTY FACTOR: 1000
  • MODIFYING FACTOR: 1
  • NOAEL: 0.71 mg/kg/day
  • CONFIDENCE: Study: High Data Base: Medium RfD: Medium
  • VERIFICATION DATE: 05/20/85
  • PRINCIPAL STUDY: Bruckner et al. (1986).
  • COMMENTS: The NOAEL was calculated from a 12 week experiment in which Sprague-Dawley rats were given 1, 10, or 33 mg carbon tetrachloride in corn oil/kg body weight by gavage 5 days/week. The NOAEL of 1 mg/kg, 5 days/week and LOAEL of 10 mg/kg, 5 days/week were converted to 0.71 and 7.l mg/kg/day, respectively, by expanding the doses to continuous exposure. Liver damage was observed at the 33 mg/kg dose. See section 3.1.2.2.

3.2. INHALATION EXPOSURES

3.2.1. Acute Toxicity

3.2.1.1. Human

Central nervous system and gastrointestinal effects have also been observed following inhalation exposure in humans (see section 3.1.1.1.). Exposure to air concentrations of 1000 to 1500 ppm for several minutes to hours will cause these effects. Repeated or prolonged exposure to such concentrations will result in liver cirrhosis and/or kidney injury. Significant kidney damage has been reported following what were believed to be single exposures to carbon tetrachloride (Torkelson and Rowe, 1978). Lung damage has also been reported several days after exposure; however, this effect is also seen with oral exposure and is thought to be secondary to kidney failure. Exposure to 250 ppm for as little as 15 minutes can be life threatening to alcoholics. Alcoholism greatly increases the sensitivity to carbon tetrachloride (Sax and Lewis, 1989; ATSDR, 1989).

3.2.1.2. Animal

Adams et al. (1952) studied the acute effects of carbon tetrachloride inhalation in rats. The maximum survival times were 15 minutes at 12,000 ppm, 1.5 hours at 7,300 ppm, and 8 hours at 3,000 ppm. No adverse effects were seen at exposures of 3,000 ppm for 6 minutes, 800 ppm for 30 minutes, or 50 ppm for 7 hours. Similar data for rabbits and guinea pigs indicate these animals may be slightly less sensitive than rats to carbon tetrachloride (Torkelson and Rowe, 1978). Inhalation LC50 values of 8,000 ppm for 4 hours for rats and 9,526 ppm for 8 hours for mice have been reported (Sax and Lewis, 1989).

3.2.2. Subchronic Toxicity

3.2.2.1. Human

Intermittent exposure to concentrations in the 10 to 200 ppm range over several months to years has resulted in restricted visual fields and in slight increases in serum enzyme activities and bilirubin levels, which indicate mild liver damage. However, quantitative subchronic data on inhalation exposure levels that cause liver injury in humans were not available (Smyth et al., 1936; Barnes and Jones, 1967; ATSDR, 1989).

3.2.2.2. Animal

Prendergast et al. (1967) exposed guinea pigs, rats, monkeys and rabbits to 1 or 10 ppm (6 or 63 mg/m3) carbon tetrachloride continuously for 90 days. Only the guinea pigs showed an increased incidence of mortality at the 10 ppm dose; however, all species exhibited decreased growth rates, liver enlargement with fatty infiltration, hepatocytic degeneration, fibroblastic proliferation, and collagen deposition at this dose. With the exception of a decreased growth rate seen in rats, no mortality or gross signs of toxicity were observed at the 1 ppm dose in these species. The same investigators reported increased mortality and severe liver damage in guinea pigs and monkeys after exposure to 80 ppm (503 mg/m3), 8 hours/day, 5 days/week for 6 weeks (U.S. EPA, 1989).

3.2.3. Chronic Toxicity

3.2.3.1. Human

In addition to the symptoms described in section 3.2.2.1., studies by Moeller (1973) indicate additional visual effects including reduced corneal sensitivity, subnormal dark adaption, restricted outer limits of white visual fields, abnormal color limits of the visual field and changes in color perception. The minimum exposure in this study was estimated to be 6.4 ppm, 1 hour/day for an average of 7.7 years (U.S.EPA, 1983).

3.2.3.2. Animal

Adams et al. (1952) exposed guinea pigs, rats, rabbits and monkeys to concentrations of carbon tetrachloride ranging from 5 ppm to 400 ppm, 8 hours/day, 5-6 days/week for up to 258 days. High incidence of mortality was seen in the guinea pigs exposed to greater than 100 ppm and in rats exposed to doses greater than 200 ppm. Guinea pigs exhibited elevated liver weights at all doses but fatty degeneration was not observed below 10 ppm. Cirrhosis and fatty degeneration of the liver was seen at 25 ppm in guinea pigs and rabbits and at 50 ppm in rats. Monkeys appeared more resistant to carbon tetrachloride and showed some indications of microscopic liver damage at a dose of 100 ppm. Because of the reversibility of the hepatomegaly seen in guinea pigs exposed to 5 ppm, this dose was considered a LOAEL (U.S.EPA, 1989).

Smyth et al. (1936) also exposed guinea pigs, rats and monkeys to carbon tetrachloride concentrations ranging from 25 to 200 ppm, 8 hours/day, 4-6 days/week for up to 321 days. Greater than 50% mortality of the guinea pigs was observed in all treated groups. Pathologic changes were observed in the livers of guinea pigs. Optic nerve degeneration and degeneration of the ocular muscles were observed in all exposed groups. These changes were also observed in rats at doses of 50 ppm or higher. In addition, kidney damage and degeneration of the myelin sheath of the sciatic nerve were observed in rats at this dose. No increase in mortality was observed. Monkeys exposed to 200 ppm for 93-231 days also showed damage to the sciatic nerve.

3.2.4. Developmental and Reproductive Toxicity

3.2.4.1. Human

Information on developmental and reproductive toxicity of carbon tetrachloride in humans was not available.

3.2.4.2. Animal

Schwetz et al. (1974) observed both maternal and fetal toxicity in Sprague-Dawley rats exposed for 7 hours/day on days 6-15 of gestation to 300 ppm carbon tetrachloride. Decreased fetal weights, crown-rump lengths and sternebrae ossification were seen but no grossly observable developmental anomalies appeared. Adams et al. (1952) reported moderate to marked degeneration of the testicular germinal epithelium in rats exposed repeatedly to 200 ppm or greater (see section 3.2.3.2.) (U.S. EPA, 1989).

3.2.5. Reference Concentration

3.2.5.1. Subchronic

The subchronic Reference Concentration is currently under development by the EPA.

3.2.5.2 Chronic

The chronic Reference Concentration is currently under development by the EPA.

3.3. OTHER ROUTES OF EXPOSURE

3.3.1. Acute Toxicity

3.3.1.1. Human

Dermal contact with carbon tetrachloride results in removal of skin oils and causes a mild burning and erythema in human subjects. Sensitive individuals can develop swelling and blistering of the skin. Although quantitative data are not available, carbon tetrachloride has been reported to be rapidly absorbed through the skin and can cause the same systemic effects seen with oral and inhalation exposure (Stewart and Dodd 1964). The application of a carbon tetrachloride-based lotion to three individuals was reported to lead to the characteristic central nervous system effects, gastrointestinal problems, acute kidney failure and elevated serum liver enzymes. The possible compounding effect from other components of the lotion was not determined nor was there any quantitative estimate of the amount of carbon tetrachloride absorbed (Perez et al., 1987; ATSDR, 1989). Other cases of serious human poisoning have been reported in which carbon tetrachloride was used as a skin cleaner or a dry shampoo, however, it was believed that inhalation was a also a major route of absorption in these cases (ATSDR, 1989).

3.3.1.2. Animal

Dermal contact with 120 mg/cm2 carbon tetrachloride has been reported to cause skin irritation in guinea pigs and rabbits within 24 hours. In guinea pigs, dermal exposure to 510 mg/cm2 for 15 minutes also resulted in degenerative changes in epidermal cells and intracellular edema. These symptoms increased in severity upon longer exposure (Roudabush et al., 1965; Kronevi et al., 1979; ATSDR, 1989). Wahlberg and Boman (1979) reported that dermal exposure of guinea pigs to 260 mg/cm2 resulted in 25% mortality within five days. Exposure to 1,000 mg/cm2 resulted in 65% mortality. Roudabush et al. (1965) estimated the dermal LD50 at greater than 15,000 mg/kg in rabbits and guinea pigs. The dermal LD50 in rats has been reported to be 5070 mg/kg (Sax and Lewis, 1989). Kronevi et al. (1979) reported that contact with 510 mg/cm2 caused hydropic changes and isolated necrotic areas in the livers of guinea pigs after exposure for 16 hours.

3.3.2. Subchronic Toxicity

3.3.2.1. Human

Information on the subchronic toxicity of carbon tetrachloride by other routes of exposure in humans or animals was unavailable.

3.3.3. Chronic Toxicity

3.3.3.1. Human

Information on the chronic toxicity of carbon tetrachloride by other routes of exposure in humans or animals was unavailable.

3.3.4. Developmental and Reproductive Toxicity

3.3.4.1. Human

Information on the developmental and reproductive toxicity of carbon tetrachloride by other routes of exposure in humans or animals was unavailable.

3.4. TARGET ORGANS/CRITICAL EFFECTS

3.4.1. Oral Exposures

3.4.1.1. Primary Target Organ(s)

  1. Liver: Symptoms of liver damage are likely to occur after subchronic or chronic exposure to lower doses that may not cause other effects, however liver damage can follow central nervous system effects a few days after an acute exposure to a single high dose. The liver damage, particularly following acute exposure, is often reversible. The clinical symptoms include jaundice, swollen and tender liver, and elevated levels of liver enzymes in the blood. Chronic exposure to small amounts can result in cirrhosis or fibrosis. Alcohol consumption increases the severity of liver damage by carbon tetrachloride.
  2. Kidney: Symptoms most often appear a few days after acute exposures to high doses and are seen clinically as oliguria or anuria. The kidney failure often leads to hypertension and pulmonary edema, but is usually reversible if the victim survives the acute phase (one to two weeks). Animal studies indicate that subchronic and chronic exposure to low doses of carbon tetrachloride can also cause kidney damage.
  3. Central nervous system: Symptoms are primarily seen after acute exposures to large doses. Effects appear rapidly after oral or inhalation exposure and usually include headache, dizziness, confusion and lethargy. These symptoms are usually accompanied by nausea, vomiting and abdominal pain. Prolonged exposure can result in respiratory depression and loss of consciousness.

3.4.1.2. Other Target Organ(s)

  1. Eyes: See section 3.4.2.2. for inhalation exposure. Symptoms seen following chronic inhalation exposure are probably not route specific, but no comparable chronic oral study is available.

3.4.2. Inhalation Exposures

3.4.2.1. Primary Target Organ(s)

  1. Liver: The symptoms are the same as those observed following oral exposure.
  2. Kidney: The symptoms are the same as those observed following oral exposure.
  3. Central nervous system: The symptoms are the same as those observed following acute oral exposure.

3.4.2.2. Other Target Organ(s)

  1. Eyes: Some minor visual disturbances have been reported following acute exposures that initiate a variety of neurological effects, however, more subtle and specific symptoms have been reported after chronic inhalation exposure. These symptoms include reduced corneal sensitivity, subnormal dark adaptation, restricted visual fields and changes in color perception.

4. CARCINOGENICITY

4.1. ORAL EXPOSURES

4.1.1. Human

Information on the oral carcinogenicity of carbon tetrachloride in humans was unavailable.

4.1.2. Animal

A number of experiments have established the hepatocarcinogenicity of carbon tetrachloride in three different species. Della Porta et al. (1961) found liver cell carcinomas in all golden hamsters treated for 30 weeks with doses of 10 to 20 mg/week and observed for up to 10 weeks following treatment. Edwards et al. (1942) reported hepatomas in strain L mice treated with 46 doses of carbon tetrachloride (0.1 mL of a 40% solution/dose) over a 4 month period. The strain L mice were chosen for their low spontaneous rate for hepatomas. The incidence seen varied from 27% in older females to 54% in older male mice; the control group incidence was 1%. In similar experiments, Edwards and Dalton (1942) also reported significant increases in hepatoma incidence following carbon tetrachloride treatment in mouse strains C3H, A, Y and C of 0.1 mL of a 40% solution 2 or 3 times/ week for 23 to 58 treatments. Significant increases in hepatomas were also seen with 0.1 mL of a 5% carbon tetrachloride solution given 3 times/week for 2 months. Weisberger (1977), in a NCI-sponsored bioassay, observed increases in the incidence of hepatocellular carcinomas in both Osborne-Mendel rats and B6C3F1 mice. The animals were given carbon tetrachloride (47 or 94 mg/kg for males, and 80 or 160 mg/kg for females) in corn oil 5 days/week by gavage for 78 weeks. A slight increase in tumor incidence was observed in the rats, whereas almost all of the mice developed tumors (96-100%) (NCI, 1976a, 1976b; U.S. EPA, 1992b).

4.2. INHALATION EXPOSURES

4.2.1. Human

Reports indicate that some individuals developed liver cancer within few years following carbon tetrachloride exposure, but a cause and effect relationship can not be developed from these data. Blair et al. (1979) studied a group of 330 dry cleaning workers and found 87 cancer deaths in the group compared to an expected 67.9 deaths in that of the U.S. population. This report was criticized for not using a more relevant control group (U.S. EPA, 1989).

4.2.2. Animal

Rats exposed to carbon tetrachloride by inhalation were shown to develop liver nodules and hepatocellular carcinomas following 7 months of treatment (Costa et al., 1963). The dose of carbon tetrachloride was not quantitatively established in this experiment.

4.3. OTHER ROUTES OF EXPOSURE

Information on the carcinogenicity of carbon tetrachloride in humans with other routes of exposure was unavailable.

4.4. EPA WEIGHT-OF-EVIDENCE

4.4.1. Oral

CLASSIFICATION: Group B2 -- Probable Human Carcinogen (U.S. EPA, 1989, 1992b).

BASIS: Based on established oral carcinogenicity in hamsters, mice and rats (Della Porta et al., 1961; Edwards et al., 1942; NCI, 1976a and b; Weisburger, 1977). Direct human evidence has been judged inadequate to confirm human carcinogenicity (U.S. EPA, 1989, 1992b).

4.4.2. Inhalation

CLASSIFICATION: Group B2 -- Probable Human Carcinogen (U.S. EPA, 1989, 1992b).

BASIS: Based on established oral carcinogenicity in hamsters, mice and rats (Della Porta et al., 1961; Edwards et al., 1942; NCI, 1976a and b; Weisburger, 1977). Direct human evidence has been judged inadequate to confirm human carcinogenicity (U.S. EPA, 1989, 1992b).

4.5. CARCINOGENICITY SLOPE FACTORS

4.5.1. Oral

  • SLOPE FACTOR: 1.3E-1 (mg/kg/day)-1 (U.S. EPA, 1989, 1992b)
  • DRINKING WATER UNIT RISK: 3.7E-6 (µg/L)-1 (U.S. EPA, 1989, 1992b)
  • VERIFICATION DATE: 12/4/86
  • PRINCIPAL STUDY: Della Porta et al. (1961); Edwards et al. (1942); NCI (1976a and b); Weisburger (1977)
  • COMMENTS: The verified slope factor is the geometric mean of values calculated from 4 data sets.

4.5.2. Inhalation

  • SLOPE FACTOR: 5.3E-2 (mg/kg/day)-1 (U.S. EPA, 1992a)
  • INHALATION UNIT RISK: 1.5E-5 (µg/m3)-1 (U.S. EPA, 1992b)
  • VERIFICATION DATE: 12/4/86
  • PRINCIPAL STUDY: Della Porta et al. (1961); Edwards et al. (1942); NCI (1976a, 1976b); Weisburger (1977)
  • COMMENTS: The unit risk is the geometric mean of values calculated from 4 oral data sets. Calculations were made assuming an air intake of 20 m3/day and 40% absorption rate by humans.

5. REFERENCES

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