Toxicology and carcinogenesis studies of chloroethane (99.5% pure), an alkylating agent and chemical intermediate, as well as a topical and inhalation anesthetic, were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex to chloroethane by whole-body inhalation once for 4 hours or for 6 hours per day, 5 days per week for 14 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium.
Single-exposure, fourteen-day, and thirteen-week studies
In the single-exposure and 14-day inhalation studies, all rats and mice exposed to 19,000 ppm chloroethane survived. The animals were not exposed at lower concentrations. No clinical signs of toxicity were seen. In the 14-day studies, final mean body weights of exposed male rats and exposed mice were higher than those of controls. Mean body weights of exposed and control female rats were similar.
In the 13-week studies, rats and mice were exposed to 0, 2,500, 5,000, 10,000, or 19,000 ppm chloroethane. No compound-related deaths occurred in rats or mice. The final mean body weight of rats exposed to 19,000 ppm was 8% lower than that of controls for males and 4% lower for females. Final mean body weights of exposed mice were generally higher than those of controls. No compound-related clinical signs or gross or microscopic pathologic effects were seen in rats or mice. The liver weight to body weight ratios for male rats and female mice exposed to 19,000 ppm were greater than those for controls. Although no chemically related toxic effects were observed in the short-term studies, concerns about potential flammability and explosion led to the selection of 0 and 15,000 ppm as the exposure concentrations for rats and mice for the 2-year studies.
Body weight and survival
Mean body weights of exposed male rats were 4%-8% lower than those of controls after week 33. Mean body weights of exposed female rats were generally 5%-13% lower than those of controls throughout the study. Although survival of male rats and exposed female rats was low at the end of the studies (male: control, 16/50; exposed, 8/50; female: 31/50; 22/50), no statistically significant differences in survival were observed between exposed and control groups of either sex. Survival at week 90 for male rats was 37/50 (control) and 31/50 (exposed) and for females, 43/50 (control) and 33/50 (exposed). The high incidence of mononuclear cell leukemia may have contributed to the high mortality.
Mean body weights of exposed male mice were up to 13% higher than those of controls throughout the study. Mean body weights of exposed and control female mice were generally similar throughout the study. The survival of the exposed groups of both male (after day 330) and female (after day 574) mice was significantly lower than that of controls (final survival-- male: 28/50; 11/50; female: 32/50; 2/50). The majority of exposed female mice died as a result of uterine carcinomas. Male mice, and particularly exposed mice, died early as a result of an ascending urinary tract infection.
Nonneoplastic and neoplastic effects
Malignant astrocytomas of the brain were seen in three exposed female rats, and gliosis was observed in a fourth. The historical incidence of glial cell neoplasms in untreated control female F344/N rats is 23/1,969. The highest incidence observed in an untreated control group is 3/50.
Trichoepitheliomas (1/50), sebaceous gland adenomas (1/50), basal cell carcinomas (3/50), and squamous cell carcinomas (2/50) of the skin were observed only in exposed male rats. Keratoacanthomas occurred in four control and two exposed male rats.
Exposure of female mice to chloroethane caused a high incidence of uterine carcinomas of endometrial origin (control, 0/49; exposed, 43/50). One control female did have a uterine carcinoma, although it was not of endometrial origin. The tumors observed in 34 exposed females were highly malignant, invading the uterine myometrium and metastasizing to a wide variety of organs, primarily lung (23), ovary (22), lymph nodes (18), kidney (8), adrenal gland (8), pancreas (7), mesentery (7), urinary bladder (7), spleen (5), and heart (4), and to a lesser extent, colon, stomach, gallbladder, small intestine, ureter, and liver.
Two marginally increased incidences of other neoplasms were observed in exposed male and female mice. The incidence of hepatocellular carcinomas in exposed female mice was greater than that in controls (3/49; 7/48). One other exposed female had a hepatocellular adenoma. The incidence of alveolar/bronchiolar neoplasms of the lung in exposed male mice was greater than that in controls (adenomas or carcinomas, combined: 5/50; 10/48).
Chloroethane, tested within the closed environment of a desiccator, was mutagenic with and without exogenous metabolic activation in S. typhimurium strain TA1535; in strain TA100, a positive response was observed only with activation. No mutagenic activity was observed in S. typhimurium strain TA98 with or without metabolic activation.
Under the conditions of these 2--year inhalation studies, there was equivocal evidence of carcinogenic activity of chloroethane for male F344/N rats, as indicated by benign and malignant epithelial neoplasms of the skin. For female F344/N rats, there was equivocal evidence of carcinogenic activity, as indicated by three uncommon malignant astrocytomas of the brain in the exposed group. The study of male B6C3F1 mice was considered to be an inadequate study of carcinogenicity because of reduced survival in the exposed group. However, there was an increased incidence of alveolar/bronchiolar neoplasms of the lung. There was clear evidence of carcinogenic activity for female B6C3F1 mice, as indicated by carcinomas of the uterus. A marginally increased incidence of hepatocellular neoplasms was observed in the exposed group.