NTP Toxicology and Carcinogenesis Studies of Glycidol (CAS No. 556-52-5) In F344/N Rats and B6C3F1 Mice (Gavage Studies).
Glycidol is a viscous liquid that is used as a stabilizer in the manufacture of vinyl polymers, as an additive for oil and synthetic hydraulic fluids, and as a diluent in some epoxy resins. NTP Toxicology and Carcinogenesis studies were conducted by administering glycidol (94% pure, containing 1.2% 3-methoxy-1,2-propanediol, 0.4% 3-chloro-1,2-propanediol, 2.8% diglycidyl ether, and 1.1% 2,6-dimethanol-1,4-dioxane) in water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary (CHO) cells, Drosophila melanogaster, and the bone marrow of male B6C3F1 mice. Sixteen-Day Studies: Glycidol doses for groups of five rats or five mice of each sex ranged from 37.5 to 600 mg/kg; vehicle controls received distilled water. All rats that received 600 mg/kg died between days 3 and 13. Edema and degeneration of the epididymal stroma, atrophy of the testis, and granulomatous inflammation of the epididymis occurred in males that received 300 mg/kg. All mice that received 600 mg/kg and two males and two females that received 300 mg/kg died by day 4 of the studies. Focal demyelination in the medulla and thalamus of the brain occurred in all female mice that received 300 mg/kg. Thirteen-Week Studies: Doses for groups of 10 rats ranged from 25 to 400 mg/kg, and doses for groups of 10 mice ranged from 19 to 300 mg/kg; vehicle controls received distilled water. All rats that received 400 mg/kg died by week 2; three males and one female that received 200 mg/kg died during weeks 11-12. Final mean body weights of male rats that received 50, 100, or 200 mg/kg were 96%-85% that of vehicle controls; final mean body weights of female rats receiving the same doses were 95%-89% that of vehicle controls. Sperm count and sperm motility were reduced in male rats that received 100 or 200 mg/kg. Necrosis of the cerebellum, demyelineation in the medulla of the brain, tubular degeneration and/or necrosis of the kidney, lymphoid necrosis of the thymus, and testicular atrophy and/or degeneration occurred in rats that received 400 mg/kg. All mice that received 300 mg/kg died by week 2; deaths of mice that received 150 mg/kg occurred during weeks 4-8 for males and weeks 1-5 for females. Mean body weights of chemically exposed mice surviving to the end of the studies were generally 90%-94% those of vehicle controls. Sperm count and sperm motility were reduced in dosed male mice. Compound-related histopathologic lesions included demyelination of the brain in males and females that received 150 or 300 mg/kg, testicular atrophy in males at all doses, and renal tubular cell degeneration in male mice that received 300 mg/kg. Based on reduced survival, reduced weight gain, and histopathologic lesions in the brain and kidney in rats that received 200 or 400 mg/kg and on reduced survival and histopathologic lesions of the brain in mice that received 150 or 300 mg/kg, doses selected for the 2-year studies of glycidol were 37.5 and 75 mg/kg for rats and 25 and 50 mg/kg for mice. Body Weights and Survival in the Two-Year Studies: Mean body weights of chemically exposed male rats generally ranged from 80% to 94% of those of vehicle controls, and mean body weights of chemically exposed female rats were from 90% to 97% those of vehicle controls. Mean body weights of chemically exposed male mice were similar to those of vehicle controls; mean body weights of chemically exposed female mice were 79%-95% of those of vehicle controls. Virtually all male and female rats that received glycidol died or were killed in a moribund condition as a result of the early induction of neoplastic disease (final survival--male: vehicle control, 16/50; low dose, 0/50; high dose, 0/50; female: 28/50; 4/50; 0/50). Survival of vehicle control male rats was lower than that usually observed; however, specific causes of deaths could not be determined. The survival of male mice and low dose female mice was similar to that of vehicle controls; survival of female mice that resurvival of male mice and low dose female mice was similar to that of vehicle controls; survival of female mice that received 50 mg/kg was lower than that of vehicle controls after week 101 (final survival--male: 33/50; 25/50; 27/50; female: 29/50; 27/50; 17/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Chemical-related nonneoplastic lesions in both rats and mice included hyperkeratosis and epithelial dysplasia of the forestomach. Fibrosis of the spleen was also present in rats of each sex, and cysts of the preputial gland and kidney were present in male mice. Exposure to glycidol induced dose-related increases in the incidences of neoplasms in numerous tissues in both rats and mice (see summary table on page 5 of the Technical Report). In male rats, mesotheliomas arising in the tunica vaginalis and frequently metastasizing to the peritoneum were considered the major cause of early death. Early deaths in female rats were associated with the presence of mammary gland neoplasms. Genetic Toxicology: Glycidol was mutagenic in a variety of in vitro and in vivo short-term tests. Mutagenic activity was observed in S. typhimurium strains TA97, TA98, TA100, TA1535, and TA1537 exposed to glycidol with and without exogenous metabolic activation. Glycidol was positive in the absence of exogenous metabolic activation in the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y/TK cells; it was not tested with activation. In cytogenetic tests with CHO cells, glycidol induced both sister chromatid exchanges and chromosomal aberrations in the presence and absence of exogenous metabolic activation. Glycidol induced sex-linked recessive lethal mutations and reciprocal translocations in the germ cells of male D. melanogaster exposed by feeding. The incidence of micronucleated polychromatic erythrocytes was increased in the bone marrow of male B6C3F1 mice administered glycidol by intraperitoneal injection. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of glycidol for male F344/N rats, based on increased incidences of mesotheliomas of the tunica vaginalis; fibroadenomas of the mammary gland; gliomas of the brain; and neoplasms of the forestomach, intestine, skin, Zymbal gland, and thyroid gland. There was clear evidence of carcinogenic activity for female F344/N rats, based on increased incidences of fibroadenomas and adenocarcinomas of the mammary gland; gliomas of the brain; neoplasms of the oral mucosa, forestomach, clitoral gland, and thyroid gland; and leukemia. There was clear evidence of carcinogenic activity for male B6C3F1 mice based on increased incidences of neoplasms of the harderian gland, forestomach, skin, liver, and lung. There was clear evidence of carcinogenic activity for female B6C3F1 mice, based on increased incidences of neoplasms of the harderian gland, mammary gland, uterus, subcutaneous tissue, and skin. Other neoplasms that may have been related to the administration of glycidol were fibrosarcomas of the glandular stomach in female rats and carcinomas of the urinary bladder and sarcomas of the epididymis in male mice. Synonym: 2,3-epoxy-1-propanol