g-Butyrolactone is an intermediate in the synthesis of polymers used as film formers in hair sprays, blood plasma extenders, and clarifying agents in beer and wine. Toxicology and carcinogenesis studies were conducted by administering g-butyrolactone (greater than 97% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex, 5 days per week for 16 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Drosophila melanogaster, and Chinese hamster ovary cells.
Groups of five rats of each sex received doses of 0, 75, 150, 300, 600, or 1,200 mg of g-butyrolactone per kg of body weight and groups of five mice of each sex received doses of 0, 87, 175, 350, 700, or 1,400 mg/kg. All male and female rats given 1,200 mg/kg and one male rat given 600 mg/kg died within 3 days. The mean body weight gain of female rats given 600 mg/kg was significantly lower than that of the controls. Mean body weight gains of the other female dose groups and all male dose groups were similar to those of the controls. All of the male and four female mice receiving 1,400 mg/kg died during the studies. Mean body weight gains of dosed mice were generally similar to those of the controls. Rats receiving 600 or 1,200 mg/kg and mice receiving 350 mg/kg or more became inactive or recumbent with irregular respiration following dosing.
Groups of 10 rats of each sex received doses of 0, 56, 112, 225, 450, or 900 mg of g-butyrolactone per kg of body weight and groups of 10 mice of each sex received doses of 0, 65, 131, 262, 525, or 1,050 mg/kg. One female and all male rats given 900 mg/kg died during the studies. The final mean body weight and mean body weight gain of male rats receiving 450 mg/kg were significantly lower than those of the controls; final mean body weights and body weight gains of all female rat dose groups were similar to those of the controls. There was an increased incidence of focal inflammation of the nasal mucosa in rats administered g-butyrolactone. Three male mice and one female receiving 1,050 mg/kg died from g-butyrolactone toxicity during the studies. The mean body weight gain and final mean body weight of high-dose male mice were lower than those of the controls; the mean body weight gains and final mean body weights of dosed female mice were similar to those of the controls. No lesions related to the administration of g-butyrolactone occurred in mice of either sex.
The doses administered to groups of 50 animals per sex were 0, 112, and 225 mg ofg-butyrolactone per kg of body weight for male rats; 0, 225, and 450 mg/kg for female rats; and 0, 262, and 525 mg/kg for male and female mice.
Body weight and survival in the two-year studies
The mean body weights of male rats administered g-butyrolactone were similar to those of the controls throughout the study. The mean body weight of high-dose females was lower than that of the controls after week 5 and was 10% to 20% lower than that of the controls throughout the second year. The survival of high-dose male rats was slightly higher than that of the controls (control, 24/50; low-dose, 27/50, high-dose, 32/50) due primarily to a lower incidence of mononuclear cell leukemia in the high-dose group (16/50, 15/50, 9/50). The survival of dosed females was similar to that of the controls (28/50, 27/50, 28/50).
The mean body weights of dosed male mice were lower than those of the controls throughout the study, but the differences in mean body weights decreased when male mice were housed individually at week 67. The final mean body weights of dosed male mice were 6% lower than that of the controls. Mean body weights of dosed female mice were also lower than those of the controls throughout the study, and the final mean body weights were from 14% to 17% lower than that of the controls. The survival in high-dose male mice was significantly lower than that of the controls (35/50, 30/50, 12/50) due to bite wounds and fighting in high-dose males recovering from the sedative effects of g-butyrolactone. The survival of female dosed mice was similar to that of the controls (38/50, 34/50, 38/50).
Neoplasms and nonneoplastic lesions in the two-year studies
No increased incidences of neoplasms or nonneoplastic lesions in male rats were related to the administration of g-butyrolactone for 2 years. In female rats, negative trends were observed in the incidences of cysts (42/50, 35/50, 23/50) and fibroadenomas of the mammary gland (22/50, 14/50, 6/50) and in cysts of the pituitary pars distalis (25/49, 13/37, 11/48). These decreases were considered to be related to g-butyrolactone administration.
Increased incidences of proliferative lesions, primarily hyperplasia, of the adrenal medulla in low-dose male mice were associated with g-butyrolactone administration (pheochromocytoma, benign or malignant: 2/48, 6/50, 1/50; hyperplasia: 2/48, 9/50, 4/50). The incidence of hepatocellular neoplasms in both dose groups of male mice was lower than the incidence in the controls (hepatocellular adenoma or carcinoma: 24/50, 8/50, 9/50).
g-Butyrolactone was not mutagenic, with or without exogenous metabolic activation (S9), in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537, nor did it induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster when administered in feed or by injection. Positive results were obtained, however, in cytogenetic tests with Chinese hamster ovary cells; g-butyrolactone induced sister chromatid exchanges and chromosomal aberrations in trials conducted in the presence of S9 activation.
Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of g-butyrolactone in male F344/N rats given 112 or 225 mg/kg or in female F344/N rats given 225 or 450 mg/kg in corn oil. There was equivocal evidence of carcinogenic activity of g-butyrolactone in male B6C3F1 mice based on marginally increased incidences of adrenal medulla pheochromocytomas and hyperplasia in the low-dose group. The sensitivity of the study in male mice to detect a carcinogenic effect was reduced by the low survival of the high-dose group associated with fighting. There was no evidence of carcinogenic activity of g-butyrolactone in female B6C3F1 mice given 262 or 525 mg/kg in corn oil.
A decreased incidence of hepatocellular neoplasms in dosed male mice and decreased incidences of mammary gland fibroadenomas and cysts and pituitary cysts in female rats were associated with the administration of g-butyrolactone.