Polysorbate 80 is a nonionic surfactant used widely as an additive in foods, pharmaceutical preparations, and cosmetics as an emulsifier, dispersant, or stabilizer. Toxicity and carcinogenicity studies were conducted by administering polysorbate 80 (which met all compendial specifications) in feed to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium.
Groups of five rats and five mice of each sex received diets containing 0, 3,000, 6,000, 12,500, 25,000, or 50,000 ppm polysorbate 80. All animals survived to the end of the studies. The mean body weight change of male rats that received 50,000 ppm was significantly lower than that of the controls. The mean body weight changes in all other groups of dosed rats and in all groups of dosed mice were similar to those of the respective controls. No clinical findings or changes in absolute or relative organ weights in rats or mice were related to polysorbate 80 administration.
Groups of 10 rats and 10 mice of each sex received diets containing 0, 3,100, 6,200, 12,500, 25,000, or 50,000 ppm polysorbate 80. All animals survived to the end of the studies. The final mean body weights of dosed rats and mice were similar to those of the controls. No clinical findings, changes in absolute or relative organ weights, or gross or microscopic lesions in rats or mice were related to polysorbate 80 administration.
Doses for the 2-year studies were selected based on the lack of observed compound-related effects at the dose levels used in the 13-week studies. Groups of 60 rats and 60 mice of each sex received diets containing 0, 25,000, or 50,000 ppm polysorbate 80 for up to 103 weeks.
15-Month Interim Evaluations
Interim evaluations were performed on 7 to 10 rats and mice from each dose group at 15 months. There were no significant changes in absolute or relative organ weights. Incidences of hyperplasia and inflammation of the forestomach were increased in female mice that received 50,000 ppm. No other chemical-related lesions occurred in rats or male mice evaluated at 15 months.
Body Weights, Clinical Findings, and Survival in the 2-Year Studies
The mean body weights in male and female rats and male mice administered polysorbate 80 were similar to those of the controls throughout the studies. The final mean body weight of female mice receiving 50,000 ppm was 11%lower than that of the controls. No clinical findings were associated with administration of polysorbate 80. The survival of dosed male rats was lower than that of the controls (0 ppm, 29/50; 25,000 ppm, 18/50; 50,000 ppm, 18/50); the survival of dosed female rats and male and female mice was similar to that of the respective controls (female rats: 23/50, 25/50, 25/50; male mice: 33/49, 34/50, 32/50; female mice: 30/50, 28/50, 26/50).
Neoplasms and Nonneoplastic Lesions in the 2-Year Studies
The incidence of adrenal medulla pheochromocytoma was marginally increased in high-dose male rats (21/50, 19/50, 29/50). The incidence of hyperplasia of the adrenal medulla was increased in low-dose male rats but not in high-dose male rats (11/50, 22/50, 12/50).
No chemical-related increases in the incidences of neoplasms occurred in male or female mice. The incidences of squamous hyperplasia and inflammation of the forestomach were significantly increased in high-dose male and female mice; forestomach ulcers were significantly increased in high-dose females.
Polysorbate 80 was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, and TA98 with or without exogenous metabolic activation (S9).
Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity for polysorbate 80 in male F344/N rats based on an increased incidence of pheochromocytomas of the adrenal medulla. There was no evidence of carcinogenic activity for polysorbate 80 in female F344/N rats or in male or female B6C3F1 mice given 25,000 or 50,000 ppm.
Administration of polysorbate 80 was associated with inflammation and squamous hyperplasia of the forestomach in male and female mice, and with ulcers of the forestomach in female mice.