The Risk Assessment Information System

Toxicity Profiles

Formal Toxicity Summary for 1,1,1-TRICHLOROETHANE

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 M. W.Daugherty, M.S., and Carol S. Forsyth, Ph.D., Chemical Hazard Evaluation Group, Biomedical and Environmental Information Analysis Section, Health Sciences Research Division, *.

Prepared for OAK RIDGE RESERVATION ENVIRONMENTAL RESTORATION PROGRAM

*Managed by Martin Marietta Energy Systems, Inc., for the U.S. Department of Energy under Contract No. DE-AC05-84OR21400.

EXECUTIVE SUMMARY

1,1,1-Trichloroethane is absorbed via the inhalation, oral, and dermal exposure routes (ATSDR 1995). After cessation of exposure, clearance of the chemical from the blood is rapid; 60 to 80% is eliminated within 2 hours, and greater than 95% is eliminated within 50 hours (Monster et al. 1979, Nolan et al. 1984). A large fraction of the absorbed dose is excreted unchanged in exhaled air, regardless of route of exposure (Torkelson 1994).

The distribution of absorbed 1,1,1-trichloroethane is similar for all routes of exposure. The chemical has been detected in the fat, liver, lung, and muscle of humans and in the fat, liver, kidney, brain, muscle, and skin of animals (Alles et al. 1988, Holmberg et al. 1977, Savolainen et al., 1977, Schumann et al. 1982, Takahara 1986). Humans and animals metabolize less than 10% of a dose of 1,1,1-trichloroethane regardless of the route of exposure; the major urinary metabolites are trichloroethanol and its glucuronide conjugate, trichloroacetic acid, and volatile carbon dioxide (ATSDR 1995, Nolan et al. 1984). These urinary metabolites are excreted slowly in comparison to the rate of expiration of 1,1,1-trichloroethane in the breath (elimination half-times, 10 to 27 and 70 to 85 hours, respectively), and may accumulate with repeated exposure, such as in the workplace (Nolan et al. 1984).

Few data were found for the oral toxicity of 1,1,1-trichloroethane. One case study reported gastrointestinal and hepatic effects in an individual who accidentally ingested approximately 600 mg/kg of the chemical (Stewart and Andrews 1966). In animals, oral LD₅₀ values range from 5660 mg/kg (rabbits) to 12,300 mg/kg (rats) (Torkelson et al. 1958). Death in most cases has been attributed to central nervous system depression resulting from anesthesia. Chronic oral doses of 1500 mg/kg reduced body weight gain and increased the effects of aging in rats and reduced body weight gain and decreased survival in mice (NCI 1977). No other effects were noted in either species.

In both humans and animals, the first and primary response to acute, high concentrations of inhaled 1,1,1-trichloroethane is central nervous system depression. The chemical also can sensitize the heart to epinephrine at high levels but has little effect on other organs. Accidental exposures to concentrations ranging from 6000 to 20,000 ppm have been fatal to humans (ATSDR 1995, Torkelson 1994).

The effects of subchronic and chronic inhalation exposure to 1,1,1-trichloroethane are generally mild, characterized by growth reduction in guinea pigs (650 ppm) (Adams et al. 1950) and minimal hepatic effects in mice (247 ppm, continuous exposure) and rats (1500 ppm, intermittent exposure) (McNutt et al. 1975, Quast et al. 1988). At 1000 ppm for 7 hours/day, 5 days/week for 6 months, female guinea pigs had fatty liver changes and increased liver weights; the no observed adverse effects level was 500 ppm (Torkelson et al. 1958). Fatty liver in humans has been associated with exposure to 1,1,1-trichloroethane (Hodgson et al. 1989).

One epidemiology study and several animal studies did not establish a relationship between exposure to 1,1,1-trichloroethane and adverse developmental or reproductive effects (Wrensch et al. 1990, Riddle et al. 1981, Verschuuren and de Rooij 1990).

The subchronic and chronic oral RfD values for 1,1,1-trichloroethane were withdrawn from the Integrated Risk Information System database on August 1, 1991 (EPA 1995a) and from Health Effects Assessment Summary Tables (EPA 1995b). A provisional chronic inhalation reference concentration value of 1 mg/m³ has been recommended (EPA 1995c) based on fatty liver changes in guinea pigs.

Regarding the carcinogenicity of 1,1,1-trichloroethane, oral bioassays were inconclusive and inhalation studies were negative (NCI 1977, Maltoni et al. 1986, Rampy et al. 1977, Quast et al. 1988). No epidemiological data for 1,1,1-trichloroethane and inadequate carcinogenicity data for animals place the chemical in the United States Environmental Protection Agency's weight-of-evidence group D, not classifiable as to human carcinogenicity (EPA 1995a).

1. INTRODUCTION

1,1,1-Trichloroethane (methyl chloroform) (CAS No. 71-55-6) has a typical sweetish odor that may be noticeable at concentrations near 100 ppm, significantly less than those that cause physiologic response. At 1000 ppm, the odor is not unpleasant enough to discourage exposure, but at 1500 and 2000 ppm has been described as strong and unpleasant (Torkelson 1994). 1,1,1-Trichloroethane has a molecular weight of 133.42, a specific gravity of 1.3249 (26/4C), and a vapor pressure of 127 torr at 25C (Torkelson 1994). It is soluble in acetone, benzene, carbon tetrachloride, methanol, and ether but is insoluble in water (Budavari et al. 1989). The 1989 use pattern for 1,1,1-trichloroethane is as follows: vapor degreasing (34%), cold cleaning (12%), aerosols (10%), adhesives (8%), intermediate (7%), coatings (5%), electronics (4%), other (5%), and exports (15%) (Chemical Marketing Reporter 1989).

Both the Occupational Safety and Health Administration (OSHA) (1993) and the American Conference of Governmental Industrial Hygienists (ACGIH) (1995-96) have established time-weighted averages of 350 ppm for 1,1,1-trichloroethane. The ACGIH short-term exposure limit is 450 ppm. In 1989, the Chemical Marketing Reporter (1989) noted that the chemical was under study by the United States Environmental Protection Agency (EPA) as a possible threat to the ozone layer.

2. METABOLISM AND DISPOSITION

2.1 ABSORPTION

1,1,1-Trichloroethane is absorbed via the inhalation, oral, and dermal exposure routes (ATSDR 1995). In humans, inhaled 1,1,1-trichloroethane is rapidly absorbed, reaching a steady state for lung retention of 25 to 30% following 4 to 6 hours of continuous exposure (Monster et al. 1979, Nolan et al. 1984). Both human and animal studies suggest that the steady state level of inhaled 1,1,1-trichloroethane in the blood can be increased by increased air concentration and increased alveolar ventilation and cardiac output (Hobara et al. 1982). The uptake of 1,1,1-trichloroethane, governed by tissue loading and metabolism, is expected to be low after steady state is reached (Dallas et al. 1989). In rats, for example, the uptake of inhaled 1,1,1-trichloroethane decreased from 80% at the beginning of a 4-hour exposure to 50% after 2 hours of exposure to 50 or 500 ppm (Dallas et al. 1989).

Based on animal experiments, 1,1,1-trichloroethane is rapidly and completely absorbed from the gastrointestinal tract (ATSDR 1995). Maximum blood levels in rats were detected approximately 5 minutes after an oral dose of 14.2 mg/kg (Reitz et al. 1988). Following administration of radiolabeled compound to mice or rats either by gavage or in drinking water, 88 to 98% of the administered dose was accounted for in expired air and urine (ATSDR 1995).

The absorption of 1,1,1-trichloroethane by the intact human skin is dependent on the duration of exposure and the area of skin exposed (Fukabori et al. 1977, Riihimaki and Pfaffli 1978, Stewart and Dodd 1964). During whole body exposure, 1,1,1-trichloroethane vapors are absorbed through the skin to some extent, but absorption through the respiratory tract is expected to prevail (ATSDR 1995). For example, one study in humans equipped with respiratory protection demonstrated that whole body dermal exposure to a 1,1,1-trichloroethane concentration of 600 ppm for more than 3.5 hours corresponded to an absorbed inhalation dose of only 0.6 ppm over the same time period (Riihimaki and Pfaffli 1978).

2.2 DISTRIBUTION

The only tissue distribution data found for humans consisted of the findings of 30 autopsies performed on individuals exposed to 1,1,1-trichloroethane by unspecified routes. Detectable levels of 1,1,1-trichloroethane were found in the subcutaneous fat, kidney fat, liver, lung, and muscle (Alles et al. 1988). In animals exposed by inhalation, the chemical was distributed primarily to fat, the liver, and to a lesser extent, the kidney and brain and was rapidly cleared from the tissues when exposure ceased (Holmberg et al. 1977, Schumann et al. 1982, Takahara 1986). Holmberg et al. (1977) observed a positive linear relationship between exposure and tissue concentrations. Furthermore, exposure to a high concentration for a short duration produced higher 1,1,1-trichloroethane concentrations in the liver, brain, and kidney than exposure to a lower level over a long time. In pregnant mice, 1,1,1-trichloroethane was distributed to the placenta and fetus but was cleared from the tissues within 24 hours of exposure (Danielsson et al. 1986).

In oral studies, the chemical was distributed primarily to the adipose tissue of rats and mice and smaller quantities of 1,1,1-trichloroethane or its metabolites were distributed to skeletal muscle, liver, and skin (RTI 1987).

No data were found regarding distribution of the chemical to organs following dermal exposure.

The pattern of distribution of 1,1,1-trichloroethane in rats and mice following intravenous exposure is similar to that after oral exposure; the highest concentration was found in adipose tissue and lesser amounts in the skeletal muscle, liver, and skin (RTI 1987).

2.3 METABOLISM

The major metabolites of 1,1,1-trichloroethane are trichloroethanol and its glucuronide conjugate, trichloroacetic acid, and volatile carbon dioxide (ATSDR 1995). However, humans and animals metabolize less than 10% of a dose of 1,1,1-trichloroethane, and a large fraction of the absorbed dose is excreted unchanged in exhaled air, regardless of route of exposure (ATSDR 1995). Metabolism is saturable in animals over the range of 150 to 1500 ppm (Schumann et al. 1982); therefore, as exposure level and absorbed dose of 1,1,1-trichloroethane increase, metabolism contributes less to the overall elimination of the chemical. Limited reductive dechlorination is mediated by cytochrome P-450 but appears to account for < 1% of the amount metabolized (Durk et al. 1992).

1,1,1-Trichloroethane administered orally and intraperitoneally to animals is metabolized similarly to 1,1,1-trichloroethane administered by inhalation (ATSDR 1995). No data were found for the metabolism of 1,1,1-trichloroethane following dermal exposure.

2.4 EXCRETION

Regardless of the route of exposure, humans excrete approximately 80 to 90% of absorbed 1,1,1-trichloroethane unchanged in expired air and much of the remainder as exhaled carbon dioxide and as the urinary metabolites trichloroethanol and trichloroacetic acid (Monster et al. 1979; Morgan et al. 1970, 1972; Nolan et al. 1984).

The kinetics of the clearance of 1,1,1-trichloroethane from blood into exhaled air are exponential, with estimated half-times of 44 minutes for the initial phase, 5.7 hours for the intermediate phase, and 53 hours for the terminal phase (Nolan et al. 1984). The major metabolites, trichloroethanol and trichloroacetic acid, are eliminated from the blood with half-times of 10 to 27 hours and 70 to 85 hours, respectively (Monster et al. 1979, Nolan et al. 1984). In a study of male printing workers, Kawai et al. (1991) demonstrated a linear relationship between the time-weighted average inhalation exposure to the chemical and excretion of the metabolites in urine at the end of a work shift. During a work week, daily occupational exposure to 1,1,1-trichloroethane results in a progressive increase in the levels of urinary metabolites, but the levels decline over the weekend (ATSDR 1995). Animals have exhibited a pattern of excretion similar to that of humans following inhaled, oral, or injected doses (ATSDR 1995).

3. NONCARCINOGENIC HEALTH EFFECTS

3.1 ORAL EXPOSURES

3.1.1 Acute Toxicity

3.1.1.1 Human

One man survived after accidentally drinking approximately 600 mg/kg of 1,1,1-trichloroethane (Stewart and Andrews 1966). The victim experienced vomiting and diarrhea beginning one hour after and continuing for 6 hours after exposure; serum bilirubin levels became slightly elevated after 48 hours, indicative of mild hepatotoxicity, but serum transaminase levels remained normal. Four hours after the incident, no abnormalities were noted in EKG, hematological parameters, BUN, or neurological parameters.

3.1.1.2 Animal

Estimated oral LD₅₀ values for various animal species are as follows: rat, 12,300 mg/kg (males) and 10,300 mg/kg (females); female mice, 11,240 mg/kg; male guinea pigs, 9470 mg/kg; and female rabbits, 5660 mg/kg (Torkelson 1994). Death was attributed primarily to central nervous system depression; surviving animals recovered rapidly and completely (Torkelson 1994). Rats given nine doses in 11 days of 0, 0.5, 5.0, or 10.0 g/kg showed hyperexcitability and protracted narcosis at the middle and high doses but little evidence of toxicity at the low dose (Torkelson 1994).

3.1.2 Subchronic Toxicity

3.1.2.1 Human

Information on the subchronic oral toxicity of 1,1,1-trichloroethane in humans was not available.

3.1.2.2 Animal

Rats given 0, 0.5, 2.5, or 5.0 g/kg/day, 5 days/week for 12 weeks had reduced body weights, central nervous system effects (hyperactivity and narcosis), and 35% mortality at the middle and high doses; serum enzyme changes occurred at the 5 g/kg/day dose (EPA 1993).

Male and female rats and mice were given 1,1,1-trichloroethane for 13 weeks at concentrations in the feed of 0, 0.5, 1, 2, 4, and 8% by weight. Body weights were significantly reduced as compared to controls for all dosed male mice (except 1.0%), high-dose female mice, and high-dose male rats. Heart weights were reduced in male mice (2%) and rats (8%); liver and kidney weights were reduced in female mice (2%); and liver weighs were reduced in male rats (8%). Male rats had a dose-related increase in the incidence of hyaline degeneration renal tubule casts and chronic inflammation (NTP 1995).

3.1.3 Chronic Toxicity

3.1.3.1 Human

Information on the chronic oral toxicity of 1,1,1-trichloroethane in humans was not available.

3.1.3.2 Animal

In an National Cancer Institute bioassay (NCI 1977), Osborne-Mendel rats were treated by gavage with 750 or 1500 mg of 1,1,1-trichloroethane/kg body weight in corn oil 5 days a week for 78 weeks. The only adverse effects observed in the rats were decreased body weights at both doses and more severe signs of aging in treated versus control animals. In the same bioassay, B6C3F₁ male and female mice given time-weighted average doses of 2500 or 4011 mg/kg/day, 5 days/week for 78 weeks exhibited a reduced body weight gain, and female mice had a dose-related decrease in survival.

3.1.4 Developmental and Reproductive Toxicity

3.1.4.1 Human

In an epidemiology study, Wrensch et al. (1990) investigated the possible relationship of miscarriages and birth defects to exposure to 1,1,1-trichloroethane in drinking water. A leak in an underground storage tank resulted in contamination of well water with 1,1,1-trichloroethane and other chemicals. 1,1,1-Trichloroethane was the predominant chemical with levels reaching 1700 ppb. An excess of miscarriages and birth defects occurred within one exposed community but not another. Levels in the community where the developmental effects occurred were lower than in communities where the incidences of effects were not increased. The study concluded that the leak was probably not the cause of an excess of adverse pregnancy outcomes in the community.

3.1.4.2 Animal

Female rats were given up to 750 mg/kg/day by gavage on gestation day 6 through lactation day 10. No treatment-related effects were observed in the offspring for body weight; physical maturation landmarks; motor activity; functional observation battery; brain measurements and neuropathology; and evaluation of learning capacity, task performance, and short-term memory.

George et al. (1989) evaluated 1,1,1-trichloroethane for pre- and postnatal developmental effects in Sprague-Dawley rats. Males and females were exposed to control solutions or 1,1,1-trichloroethane concentrations of 3, 10, or 30 ppm in the drinking water for 14 days prior to cohabitation and for up to 13 days during cohabitation. Treatment to females was continued during pregnancy and lactation to postnatal day 21. No effects were observed on parental reproductive competence or on morphological development and postnatal growth and development of the offspring.

Rats were given 8% 1,1,1-trichloroethane in the feed for 13 weeks. No significant change in the length of the estrous cycle was measured in females, but males had reduced epididymal sperm counts (NTP 1995).

Lane et al. (1982) conducted a two-generation reproductive toxicity study that included developmental toxicity and dominant lethal assays in male and female ICR Swiss mice. The animals received 1,1,1-trichloroethane at daily doses of 0, 100, 300, or 1000 mg/kg in their drinking water. The investigators did not observe dose-related effects on fertility, gestation, viability, or lactation indexes of the dams or on survival and weight gain of the pups. 1,1,1-Trichloroethane did not produce dominant lethal mutations or terata in either of the two generations tested.

In a similar multigeneration reproduction study, Riddle et al. (1981) administered 1,1,1-trichloroethane to mice in their drinking water at doses of 0, 99, 2640, or 8520 mg/kg/day. The investigators reported that there were no dose-dependent effects on fertility, gestation, viability, or lactation indexes of the dams or on survival and weight gain of the pups. Gross necropsy of male and female F₀ generation mice did not reveal compound-related effects.

3.1.5 Reference Dose

COMMENT: The subchronic and chronic oral reference dose (RfD) values for 1,1,1-trichloroethane were withdrawn from the Integrated Risk Information System (IRIS) database on August 1, 1991 (EPA 1995a) and from the Health Effects Assessment Summary Tables (HEAST) (EPA 1995b). Available data were reviewed and determined to be inadequate for the derivation of an oral RfD (EPA 1993). Subchronic studies are too limited in scope (subtle neurological parameters not monitored), and cancer bioassays do not sufficiently report noncancer endpoints (EPA 1993).

3.2 INHALATION EXPOSURES

3.2.1 Acute Toxicity

3.2.1.1 Human

Intentional and accidental inhalation of 1,1,1-trichloroethane has resulted in human fatalities as reported in several case studies (Hall and Hine 1966, MacDougall et al. 1987, Stahl et al. 1969). Estimations for fatal exposure concentrations range from 6000 to 20,000 ppm (ATSDR 1995). Death has been attributed to either depression of the central nervous system, resulting in respiratory arrest (Hall and Hine 1966, Jones and Winter 1983, Stahl et al., 1969), or sensitization of the heart to epinephrine, resulting in cardiac arrhythmia (Guberan et al. 1976, MacDougall et al. 1987, Travers 1974). A 15-year-old boy who sniffed typing eradicator containing 1,1,1-trichloroethane had complained of double vision and hallucinations before he collapsed and died (D'Costa and Gunasekera 1990). Autopsy revealed a grossly edematous brain; edema of the lungs, liver and gut; and tonsillar herniation. Levels of 1,1,1-trichloroethane in the blood were 1.7 ng/mL (1.7 ppb). Levels of 1,1,1-trichloroethane in the blood of three other victims of fatal intoxication (ingested or inhaled) were estimated at 60, 62, and 120 ppm (Stahl et al. 1969). In addition to central nervous system and cardiovascular effects, volatile substance abusers may suffer permanent damage to the kidneys, liver, and lungs (Marjot and McLeod 1989). In human fatalities, failure to prevent inhalation of high concentrations, lack of adequate ventilation of confined spaces, or deliberate sniffing have been implicated (Torkelson 1994).

Based on laboratory studies to evaluate equilibrium, coordination, alertness, and other signs of anesthetic action, no adverse effects (other than odor considerations) are evident with exposures of human subjects to 500 ppm for 78 minutes; at 900 to 1000 ppm for up to 73 minutes, minor central nervous system impairment is observed (Stewart et al. 1969). Mild eye irritation was noted by subjects exposed to concentrations above 1000 ppm. Other laboratory studies have shown that sublethal concentrations of 1,1,1-trichloroethane (350 ppm for 3 hours) caused changes in reaction time, perceptual speed, manual dexterity, and equilibrium (Gamberale and Hultengren 1973); and inhalation of 450 ppm for 8 hours caused irritation of the eye, nose, and throat and impairment of perceptive capabilities under stress conditions (Salvini et al. 1971). Twenty human subjects exposed to 500 ppm 1,1,1-trichloroethane for 7.5 hours/day, 5 days/week for 3 weeks complained of fatigue, irritation, and headache but exhibited no effects on clinical blood or urine chemistries or measurements of pulmonary function (Stewart et al. 1975).

3.2.1.2 Animal

Median lethal concentration (LC₅₀) values for 1,1,1-trichloroethane range from 3911 ppm (2 hours) in mice to 38,000 ppm (15 minutes) in rats (Horiguchi and Horiuchi 1971, Adams et al. 1950, Bonnet et al. 1980, Clark and Tinston 1982). As with humans, animal deaths following acute exposure to 1,1,1-trichloroethane have been attributed to respiratory arrest or cardiac failure (Adams et al. 1950, Clark and Tinston 1982, Krantz et al. 1959). Gehring (1968) demonstrated that liver function, as measured by SGOT, was virtually unaffected unless acute exposure concentrations approached those causing anesthetic death. Maximum time-concentrations with no detectable injury in rats are 18 minutes at 18,000 ppm and 5 hours at 8000 ppm (Adams et al. 1950). Mice exposed to 5000 ppm for 4 hours exhibited increased motor activity (Kjellstrand et al. 1990).

3.2.2 Subchronic Toxicity

3.2.2.1 Human

Information on the subchronic inhalation toxicity of 1,1,1-trichloroethane in humans was not available.

3.2.2.2 Animal

No effects were seen in Long-Evans and Sprague-Dawley rats, Hartley guinea pigs, squirrel monkeys, New Zealand rabbits, and beagle dogs exposed continuously to 1,1,1-trichloroethane concentrations of 135 or 370 ppm for 90 days (EPA 1982, Prendergast et al. 1967). In another study, the following species were exposed to 1,1,1-trichloroethane 7 hours/day, 5 days/week for approximately 1 to 3 months: guinea pigs (650, 1500, 3000, or 5000 ppm), rats (5000 or 3000 ppm); rabbits (5000 ppm); and monkeys (3000 ppm) (Adams et al. 1950). Body weights, relative organ weights, and BUN levels were measured, and histopathological examinations were performed on selected major organs. Rats were unaffected by exposure; rabbits showed slight retardation of growth at 5000 ppm; and guinea pigs had "slight" liver degeneration at 3000 ppm, "slight to moderate" degeneration at 5000 ppm, testicular degeneration at 5000 ppm, and slight, but significantly reduced growth rate, at all exposure levels. The lowest observed adverse effects level (LOAEL) for guinea pigs in this study was 650 ppm.

McNutt et al. (1975) exposed CF-1 mice, rats, dogs, and monkeys to 1,1,1-trichloroethane concentrations of 1350 mg/m³ (250 ppm) or 5400 mg/m³ (999 ppm) continuously for 14 weeks. Mice of the high-dose group had increased triglyceride accumulation in the liver that peaked at 7 weeks of exposure, then decreased during subsequent weeks, and necrosis of hepatocytes (in 40% of the animals) after 12 weeks. Electron microscopic examination revealed cytoplasmic alterations in the centrilobular hepatocytes of the high-dose group that were decreased in severity at the low dose. No exposure-related effects were observed in rats, dogs, and monkeys exposed to either concentration.

Quast et al. (1988) conducted a chronic toxicity study in B6C3F₁ mice and F344 rats that included interim sacrifices at 6 and 12 months. Both species were exposed to vapor concentrations of 0, 150, 500 or 1500 ppm 1,1,1-trichloroethane 6 hours/day, 5 days/week. Parameters measured included mortality, clinical signs, hematology, urinalysis (rats only), clinical chemistry, body and organ weights, gross pathology, and histopathology. No exposure-related effects were observed in mice at any concentration at either sacrifice. Male and female rats exposed to 1500 ppm had slight microscopic hepatic effects at 6 and 12 months. No other effects were reported.

Torkelson et al. (1958) exposed rats, rabbits, guinea pigs, and monkeys to 1,1,1-trichloroethane concentrations of 500, 1000, 2000, or 10,000 ppm 7 hours/day, 5 days/week for 6 months. Growth rate, general appearance, mortality, hematology, organ weights, and gross and microscopic pathology were evaluated. The female guinea pig was the most sensitive species. At 1000 ppm, the female guinea pigs had fatty changes in the liver and statistically significant increases in liver weights. The no observed adverse effects level (NOAEL) for the guinea pigs of this study was 500 ppm.

3.2.3 Chronic Toxicity

3.2.3.1 Human

Hodgson et al. (1989) described four cases of fatty liver disease associated with approximately 1 to 19 years of occupational exposure to 1,1,1-trichloroethane. The subjects, all males, had complained of nausea, anorexia, chills, and fatigue. Diagnosis of fatty liver disease was made by liver biopsy, which also revealed active cirrhosis in the oldest (50 years old) subject. In addition to working with 1,1,1-trichloroethane for approximately 10% of his working hours, this individual was in the vicinity while electricians sprayed 1,1,1-trichloroethane (simulations revealed levels ranging from 350 to 500 ppm). Analytical data for industrial hygiene samples taken over 11 years suggested that another of the subjects worked in an area where 1,1,1-trichloroethane levels ranged from 35 ppm to 17,718 ppm (50 times greater than the permissible exposure level.) Two of the subjects reported minimal exposures to perchloroethylene, but otherwise there were no predisposing factors for fatty liver disease. In other studies, cardiac arrhythmias persisted after exposure ceased in individuals exposed repeatedly to "high" concentrations of 1,1,1-trichloroethane, but no effects were observed on blood pressure, heart rate, electrocardiogram, or liver function in workers exposed to <250 ppm (ATSDR 1995).

Peripheral neuropathy in three female workers following "prolonged" exposure to 1,1,1-trichloroethane was described by Howse et al. (1989). The patients had frequent and prolonged contact with the solvent on the hands, as well as exposure to high ambient atmospheric concentrations. Sural nerve biopsy in two of the patients revealed evidence of chronic neuropathy with both axonopathy and myelinopathy. The symptoms of neuropathy, more prominent in the hands than the feet, improved after exposure ceased.

In an occupational exposure study, cardiovascular and hepatic functions were unaffected in employees exposed to 1,1,1-trichloroethane at an 8-hour time-weighted average of 4 to 217 ppm for approximately 6 years (Kramer et al. 1976).

3.2.3.2 Animal

Quast et al. (1988) conducted a chronic toxicity study in B6C3F₁ mice and F344 rats that included sacrifices at 18 and 24 months. Both species were exposed to vapor concentrations of 0, 150, 500, or 1500 ppm 1,1,1-trichloroethane for 6 hours/day, 5 days/week. Parameters measured included mortality, clinical signs, hematology, urinalysis (rats only), clinical chemistry, body and organ weights, gross pathology, and histopathology. No exposure-related effects were observed in mice at any concentration at either sacrifice. Male and female rats exposed to 1500 ppm had slight microscopic hepatic effects at 18 months, but these effects were not observed at 24 months because of confounding geriatric changes. The hepatic changes consisted of accentuation of the normal hepatic lobular pattern, altered cytoplasmic staining, and decreased size of cells surrounding the central vein. Female rats exposed to 1500 ppm had a significant decrease in body weights at 24 months. No other effects were reported.

3.2.4 Developmental and Reproductive Toxicity

3.2.4.1 Human

A review of case-controlled epidemiology studies on adverse pregnancy outcomes found no clear evidence for a relationship with maternal or paternal exposure to 1,1,1-trichloroethane (ATSDR 1995).

3.2.4.2 Animal

In a developmental toxicity study, groups of mice and rats were exposed to 875 ppm (4.7 g/m³) of 1,1,1-trichloroethane 7 hours/day on gestational days 6 to 15 (Schwetz et al. 1975). The average number of implantation sites/litter, litter size, incidence of fetal resorptions, fetal sex ratios or fetal body measurements and the incidence of skeletal or visceral malformations were not affected by treatment. York et al. (1981) exposed female Long-Evans rats to 2100 ppm of 1,1,1-trichloroethane from 2 weeks before breeding through day 20 of gestation and observed neither teratogenicity nor neurobehavioral effects on the offspring.

Verschuuren and de Rooij (1990) briefly summarized a study (HSIA 1987) in which exposure of rats and rabbits to 1000, 3000, and 6000 ppm 1,1,1-trichloroethane resulted in no embryotoxicity or teratogenicity (HSIA 1987). No details were given.

No evidence of toxicity was found on histological examination of the reproductive organs of mice, rats, or rabbits following acute, subchronic, or chronic inhalation exposure to 1,1,1-trichloroethane. However, testicular degeneration was observed in male guinea pigs following exposure to 5000 ppm for 45 days (ATSDR 1995).

3.2.5 Reference Concentration

3.2.5.1 Subchronic

COMMENT: The subchronic inhalation reference concentration for 1,1,1-trichloroethane has been withdrawn (EPA 1995b).

3.2.5.2 Chronic

INHALATION RfC_C: 1 mg/m³ (0.3 mg/kg/day)

UNCERTAINTY FACTOR: 1000

NOAEL: 500 ppm

PRINCIPAL STUDY: Torkelson et al. (1958)

VERIFICATION DATE: not verified

COMMENT: This is a provisional value (EPA, 1995c) based on fatty liver changes in guinea pigs. However, the NOAEL was the only dose tested, the study duration was for 6 months, and other studies suggest that neurochemical and neurobehavioral changes might be more sensitive endpoints. Inadequacies among other studies include acute exposure duration, inconsistencies between studies, and failure to investigate more than one endpoint (EPA 1995c).

3.3 OTHER ROUTES OF EXPOSURE

3.3.1 Acute Toxicity

3.3.1.1 Human

The dermal effects of 1,1,1-trichloroethane appear to be generally mild and reversible (ATSDR 1995). Humans exhibited mild erythema when exposed dermally to 30 mg/kg of 1,1,1-trichloroethane for 5 minutes (LOAEL) but were not affected when exposed to 2 mg/kg/day for 10 days (NOAEL) (Wahlberg 1984a,b). Volunteers who immersed their thumbs in containers of 1,1,1-trichloroethane for 30 minutes complained of mild burning pain after about 10 minutes of exposure; immersion of the entire hand produced similar, but more intense, burning followed by a feeling of cold (Stewart and Dodd 1964). Upon contact with 1,1,1-trichloroethane, the skin becomes red and scaly. Repeated exposure exacerbates the effect, and confinement of the test area results in considerable pain and irritation (Torkelson 1994).

3.3.1.2 Animal

1,1,1-Trichloroethane is lethal via the dermal route only when very high doses are applied (ATSDR 1995). For example, exposure to 15,800 mg/kg failed to kill half the rabbits tested, and no deaths occurred at 3900 mg/kg in 24 hours (Torkelson et al. 1958).

LOAELs for acute effects following dermal application to the guinea pig include the following: 1299 mg/kg/day, single exposure (epidermal degeneration) (Kronevi et al. 1981); 7134 mg/kg/day for 5 to 7 days (decreased body weight gain) (Wahlberg and Boman 1979); and 223 mg/kg/day for 10 days (dermal edema) (Wahlberg 1984b).

Klaassen and Plaa (1966) reported an intraperitoneal LD₅₀ for 1,1,1-trichloroethane of 3.9 g/kg in rats and an LD₅₀ of 16 g/kg in mice. The chemical produces mild or no eye irritation in rabbits (ATSDR 1995, Torkelson 1994).

3.3.2 Subchronic Toxicity

3.3.2.1 Human

Information on the subchronic toxicity of 1,1,1-trichloroethane by other routes in humans was not available.

3.3.2.2 Animal

Rats exhibited mild hepatic effects as evidenced by significantly increased serum levels of SGOT and ornithine carbamyl transferase following 16 daily dermal applications of 280 mg/kg/day of 1,1,1-trichloroethane (Viola et al. 1981). These results were supported by the histological observation of damaged hepatocytes and the presence of small focal intralobular inflammatory infiltrates. A dramatic increase in the level of -glutamyl transferase was also observed, indicative of liver toxicity. In another study, however, hepatic effects were not observed in rabbits receiving dermal applications of 500 mg/kg/day, 5 days/week for 90 days (Torkelson et al. 1958). In addition, no adverse effects were observed in the respiratory, cardiovascular, gastrointestinal, or hematopoietic systems or the kidneys.

3.3.3 Chronic Toxicity

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

3.3.4 Developmental and Reproductive Toxicity

Information on the developmental and reproductive toxicity of 1,1,1-trichloroethane by other routes in humans or animals was not available.

3.4 TARGET ORGANS/CRITICAL EFFECTS

3.4.1 Oral Exposures

3.4.1.1 Primary target organs

1.Liver: Increased bilirubin levels, observed in one individual following accidental ingestion of 1,1,1-trichloroethane, is the main available evidence for hepatotoxicity of the chemical following oral exposure.

2.Central nervous system: Anesthesia is one of the main effects of 1,1,1-trichloroethane administered orally to animals, resulting in death at high doses.

3.4.1.2 Other target organs

No other target organs were identified for orally administered 1,1,1-trichloroethane.

3.4.2 Inhalation Exposures

3.4.2.1 Primary target organs

1.Liver: Subchronic exposure to 1,1,1-trichloroethane has produced hepatic degeneration in the guinea pig, mouse, and rat.

2.Nervous system: Peripheral neuropathy has been described for female workers following prolonged exposure.

3.4.2.2 Other target organs

No other target organs were identified for inhaled 1,1,1-trichloroethane.

4. CARCINOGENICITY

4.1 ORAL EXPOSURES

4.1.1 Human

Isaacson et al. (1985) investigated the possible association between the incidence of cancer among residents of Iowa communities and the presence of organic chemicals, including 1,1,1-trichloroethane, in their drinking water. In a comparison of towns that had detectable quantities of 1,1,1-trichloroethane in the water supply with those that did not, there was no difference in the incidence of bladder, colon, lung, rectum, breast, or prostate cancer in individuals over the age of 55. Levels greater than 0.1 µg/L were detected in the study. A concentration of 1,1,1-trichloroethane of 0.1 µg/L in the drinking water would roughly produce a dose of 0.000003 mg/kg/day, assuming the average adult weighs 70 kg and drinks 2 L of water/day. The investigators indicated that their data are not sensitive enough to make inferences regarding the presence of 1,1,1-trichloroethane in the drinking water and cancer.

4.1.2 Animal

Two oral carcinogenicity assays in animals were found. The National Cancer Institute (1977) tested technical grade 1,1,1-trichloroethane in Osborne-Mendel rats. Fifty rats/sex/dose were given doses of 750 or 1500 mg/kg/day, by gavage, 5 days/week for 78 weeks. The controls were untreated. An observation period of 32 weeks followed. Treated males and females exhibited early mortality with a statistically significant dose-related trend (P<0.04). A variety of neoplasms was observed in both treated and matched control rats, but these were common to aged rats and were not dose-related. The investigators suggested that the low survival of rats of both sexes possibly precluded the detection of tumors late in life.

The National Cancer Institute (1977) also treated B6C3F₁ mice with time-weighted average doses of 2807 or 5615 mg 1,1,1-trichloroethane/kg/day, by gavage, 5 days/week for 78 weeks. An observation period of 12 weeks followed. A variety of neoplasms were observed in both treated and control groups, but only 25 to 45% of the treated animals survived until terminal sacrifice. Because of the high early mortality in both species, the investigators did not consider this study to be an adequate test of carcinogenicity.

Maltoni et al. (1986) conducted a carcinogenicity screening study in rats, using only one dose, a small sample size, and no statistical analyses. The animals received 500 mg/kg/day for 104 weeks and were examined for the induction of leukemia. An increase in the total incidence of "leukemias" (13 in treated rats and 4 in vehicle controls) was observed. The increase was attributed mainly to an increased incidence of immunoblastic lymphosarcomas (7 in treated rats, 1 in controls). The biological and statistical significance of these data were not clear. The investigators, unable to draw definite conclusions from these data because of limitations in experimental design, suggested that further carcinogenicity studies were needed.

4.2 INHALATION EXPOSURES

4.2.1 Human

Heineman et al. (1994) calculated job-exposure matrices for six chlorinated aliphatic hydrocarbons, which accounted for industrial and occupational use, job tenure, and provided estimates of probability and intensity of exposure. When the job-exposure matrix for 1,1,1-trichloroethane was applied to a case-control study of astrocytic brain cancer in white men, no correlation was found.

4.2.2 Animal

In one study, groups of 96 male and 96 female Sprague-Dawley rats, exposed to 1,1,1-trichloroethane vapors of 875 or 1750 ppm (4.7 or 9.5 g/m³) 6 hours/day, 5 days/week for 12 months and observed for up to 30 months, had no increased incidence of tumors (Rampy et al. 1977).

Quast et al. (1988) conducted a chronic toxicity/carcinogenicity study in B6C3F₁ mice and F344 rats. Both species were exposed to vapor concentrations of 0, 150, 500 or 1500 ppm 1,1,1-trichloroethane 6 hours/day, 5 days/week for 24 months. Parameters measured included mortality, clinical signs, hematology, urinalysis (rats only), clinical chemistry, body and organ weights, gross pathology, and histopathology. Female rats exposed to 1500 ppm had a significant decrease in body weights at 24 months. No indications of a carcinogenic effect were observed in either mice or rats.

4.3 OTHER ROUTES OF EXPOSURE

Information on the carcinogenicity of 1,1,1-trichloroethane in humans or animals by other routes of exposure was not available.

4.4 EPA WEIGHT-OF-EVIDENCE

Classification: Group D, not classifiable as to human carcinogenicity (EPA 1995a).

Basis: No data in humans; animal studies have not demonstrated carcinogenicity.

4.5 CARCINOGENICITY SLOPE FACTORS

No slope factors have been calculated for 1,1,1-trichloroethane.

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