Acetaminophen is a widely consumed analgesic found in several nonprescription pharmaceuticals. Toxicology and carcinogenesis studies were conducted by administering acetaminophen (purity >99%) 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 and Chinese hamster ovary cells.
Fourteen-day studies
Rats were fed diets containing 0, 800, 1,600, 3,100, 6,200, or 12,500 ppm acetaminophen, and mice were fed diets containing 0, 250, 500, 1,000, 2,000, or 4,000 ppm acetaminophen. There were no deaths among any groups during the study; the final mean body weight of male rats that received 12,500 ppm was significantly lower than that of the controls. Final mean body weights of male and female mice and female rats that received acetaminophen were similar to those of the controls. Feed consumption by male and female rats that received 12,500 ppm acetaminophen was lower than that of the controls; feed consumption by all other exposed groups was higher than that of the controls.
Thirteen-week studies
Rats and mice were fed diets containing 0, 800, 1,600, 3,200, 6,200, 12,500, or 25,000 ppm acetaminophen. Two male and two female rats, and one male and one female mouse that received 25,000 ppm, and two male mice that received 12,500 ppm died from acetaminophen-related toxicity before the end of the studies. Final mean body weights of male and female rats and mice that received 12,500 or 25,000 ppm were lower than those of the controls. The patterns of feed consumption and reduced body weights that occurred among rats and mice that received diets containing 12,500 or 25,000 ppm were indicative of poor feed palatability.
Acetaminophen-related lesions were observed in the liver (necrosis, chronic active inflammation, hepatocytomegaly), kidney (tubule cast, tubule necrosis, tubule regeneration), reproductive organs (atrophy of testis, ovary, and uterus), thymus and lymph nodes (lymphoid depletion) of rats that received 25,000 ppm, and of the live (chronic active inflammation, hepatocytomegaly) and testis (atrophy) of male rats receiving 12,500 ppm. Compound-related lesions in mice were found in the liver (hepatocytomegaly, focal calcification, pigmentation, necrosis) of males that received 6,200, 12,500, or 25,000 ppm and females that received 12,000 or 25,000 ppm.
Dose selection for the 2-year studies was based on reduced body weights and the liver lesions observed in rats and mice at 12,500 and 25,000 ppm.
Two-year studies
Diets containing 0, 600, 3,000, or 6,000 ppm acetaminophen were given continuously to groups of 60 rats and mice of each sex for up to 104 weeks. After 65 weeks of exposure, 10 animals from each group were evaluated for histopathology and for hematology, urinalysis, and clinical chemistry parameters.
Survival and mean body weights of rats that received acetaminophen were similar to those of the controls throughout the study. The average severity of nephropathy was increased in exposed male and female rats. In males this was associated with an increased incidence of parathyroid hyperplasia (renal hyperparathyroidism). The incidence of focal renal tubule hyperplasia was also increased in exposed male rats. The incidence of mononuclear cell leukemia was increased in exposed female rats and was significantly increased in the 6,000 ppm group (9/50; 17/50; 15/50; 24/50).
Survival of exposed and control mice was similar throughout the study. Mean body weights of mice that received acetaminophen were generally lower than those of the controls throughout the study. Although the incidence of thyroid follicular cell hyperplasia increased with dose among groups of exposed male and female mice, there was no increase in the incidence of follicular cell neoplasms. Renal tubule hyperplasia occurred in one low-dose and two high-dose males and a renal tubule adenoma was present in one low-dose and one high-dose male.
Genetic toxicology
Acetaminophen was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98 with or without S9. In cytogenetic tests with Chinese hamster ovary cells, acetaminophen induced sister chromatid exchanges and chromosomal aberrations in both the presence and absence of S9.
Conclusions
Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of acetaminophen in male F344/N rats that received 600, 3,000, or 6,000 ppm. There was equivocal evidence of carcinogenic activity of acetaminophen in female F344/N rats based on increased incidences of mononuclear cell leukemia. There was no evidence of carcinogenic activity of acetaminophen in male and female B6C3F1 mice that received 600, 3,000, or 6,000 ppm.
Nonneoplastic lesions associated with exposure to acetaminophen included increased severity of nephropathy and increased incidences of renal tubule hyperplasia and parathyroid hyperplasia in male rats, increased severity of nephropathy in female rats, and increased incidences of thyroid follicular cell hyperplasia in male and female mice.