NTP Toxicology and Carcinogenesis Studies of Tetrachloroethylene (Perchloroethylene) (CAS No. 127-18-4) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).
Tetrachloroethylene is used primarily as a dry cleaning agent, an industrial solvent for fats, oils, tars, rubber, and gums, and a metal degreasing agent. Tetrachloroethylene had antihelminthic uses, particularly for hookworms (1.6-8 g/60 kg), and was formerly used in combination with some grain protectants and fumigants. Toxicology and carcinogenesis studies of tetrachloroethylene (99.9% pure) were conducted by inhalation exposure of groups of 50 male and 50 female F344/N rats and B6C3F1 mice 6 hours per day, 5 days per week, for 103 weeks. The exposure concentrations used (0, 200, or 400 ppm for rats and 0, 100, or 200 ppm for mice) were selected on the basis of results from 13-week inhalation studies in which groups of 10 rats and 10 mice of each sex were exposed to tetrachloroethylene at 100-1,600 ppm for 6 hours per day, 5 days per week. During the 13-week studies, 1,600 ppm tetrachloroethylene was lethal to 20%-70% of the rats and mice and reduced the final body weights of survivors. In rats, tetrachloroethylene at 200-800 ppm caused minimal to mild hepatic congestion. In dosed male and female mice, minimal to mild hepatic leukocytic infiltration, centrilobular necrosis, bile stasis (400-1,600 ppm), and mitotic alteration (200-1,600 ppm) were produced. Tetrachloroethylene exposure also caused minimal renal tubular cell karyomegaly in mice at concentrations as low as 200 ppm. During the 2-year studies, exposure to tetrachloroethylene did not consistently affect body weight gains in either rats or mice. Exposure at 400 ppm tetrachloroethylene reduced the survival of male rats (control, 23/50; low dose, 20/50; high dose, 12/50). This reduced survival may have been related to an increased incidence of mononuclear cell leukemia. Tetrachloroethylene at both exposure concentrations reduced the survival of male mice (46/50; 25/50; 32/50), whereas exposure at 200 ppm reduced female mouse survival (36/50; 31/50; 19/50). Early deaths in mice may have been related to the development of hepatocellular carcinomas. Both concentrations of tetrachloroethylene were associated with increased incidences of mononuclear cell leukemia in male rats (28/50; 37/50; 37/50). In female rats, tetrachloroethylene increased the incidence of leukemia (18/50; 30/50; 29/50) and decreased the time to occurrence of the disease. Tetrachloroethylene produced renal tubular cell karyomegaly in male and female rats, renal tubular cell hyperplasia in male rats, and renal tubular cell adenomas or adenocarcinomas (combined) in male rats (1/49; 3/49; 4/50). The incidence of the renal tubular cell tumors was not statistically significant; these uncommon tumors have been consistently found at low incidences in male rats in other 2-year studies of chlorinated ethanes and ethylenes. One low dose male rat had a kidney lipoma, and another had a nephroblastoma. Four high dose male and two high dose female rats had gliomas of the brain, whereas one control male and one control female had this tumor. In male and female mice, tetrachloroethylene caused dose-related increases in the incidences of hepatocellular neoplasms. In males, tetrachloroethylene at 200 ppm increased the incidence of hepatocellular adenomas (11/49; 8/49; 18/50) and at both concentrations increased the incidence of hepatocellular carcinomas (7/49; 25/49; 26/50). In female mice, tetrachloroethylene at both concentrations increased the incidences of hepatocellular carcinomas (1/48; 13/50; 36/50). Tetrachloroethylene also produced renal tubular cell karyomegaly in both sexes of mice, and one low dose male mouse had a tubular cell adenocarcinoma. In these inhalation studies, there were no neoplastic changes in the respiratory tracts of either species, but there was an increase in the incidence of squamous metaplasia in the nasal cavities in dosed male rats (0/50; 5/50; 5/50). Tetrachloroethylene was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 in the presence or absence of male Syrian hamster or male Sprague-Dawley rat liver S9. Tetrachloroethylene was not mutagenic in was not mutagenic in L5178Y/TK&plusmn; mouse lymphoma cells with or without metabolic activation and did not induce sex-linked recessive lethal mutations in Drosophila melanogaster. Tetrachloroethylene did not induce sister-chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells in the presence or absence of metabolic activation. An audit of the experimental data was conducted for these 2-year studies on tetrachloroethylene. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year inhalation studies, there was clear evidence of carcinogenicity of tetrachloroethylene for male F344/N rats as shown by an increased incidence of mononuclear cell leukemia and uncommon renal tubular cell neoplasms. There was some evidence of carcinogenicity of tetrachloroethylene for female F344/N rats as shown by increased incidences of mononuclear cell leukemia. There was clear evidence of carcinogenicity for B6C3F1 mice as shown by increased incidences of both hepatocellular adenomas and carcinomas in males and of hepatocellular carcinomas in females. Synonyms: carbon bichloride; carbon dichloride; ethylene tetrachloride; per; perc; perchlor; perchlorethylene; perchloroethylene; perk; tetrachlorethylene; 1,1,2,2-tetrachloroethylene Trade names: Ankilostin; Antisal 1; Dee-Solv; Didakene; Dow-Per; ENT 1860; Fedel-Un; Nema; Perclene; Percosolv; Perklone; PerSec; Tetlen; Tetracap; Tetraleno; Tetravec; Tetroguer; Tetropil