dl-Amphetamine sulfate is used for the treatment of narcolepsy in adults and behavioral syndromes in children. Toxicology and carcinogenesis studies were conducted by administering dl-amphetamine sulfate (USP grade) in feed to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary (CHO) cells.
The chemical was administered at dietary concentrations of 0, 47, 94, 188, 375, or 750 ppm for rats and 0, 125, 250, 500, 1,000, or 2,000 ppm for mice. Decreased body weight gain was seen at the higher concentrations, but no chemical-related deaths or toxic lesions were observed.
The chemical was administered at dietary concentrations of 0, 47, 94, 188, 375, or 750 ppm for rats and 0, 125, 250, 500, 1,000, or 2,000 ppm for mice. None of the rats died, but 6/10 male mice and 7/10 female mice that received 2,000 ppm, 3/10 male mice that received 1,000 ppm, and 8/10 male mice that received 500 ppm died before the end of the studies. Decreased body weight gain and hyperactivity were seen in dosed rats and mice. Final body weights of rats receiving 188 ppm or more were 62% to 89% those of controls, and final body weights of mice receiving 250 ppm or more were 70% to 86% those of controls. There were no lesions that were considered to be a primary effect of the chemical.
Based on decreased body weight gain and hyperactivity in the 13-week studies, 2-year studies were conducted by feeding diets containing 0, 20 or 100 ppm dl-amphetamine sulfate to groups of 50 rats or 50 mice of each sex.
Body Weights and Survival in the 2-Year Studies
No significant differences in survival were observed between any groups of rats or mice (male rats: control, 30/50; low dose, 31/50; high dose, 33/50; female rats: 33/50; 42/50; 37/50; male mice: 48/50; 48/50; 49/50; female mice: 35/50; 36/50; 44/50).
Final body weights of dosed rats and mice were decreased relative to those of controls. Final body weights were 92% and 86% those of controls for low- and high-dose male rats, 89% and 70% those of controls for low- and high-dose female rats, 85% and 72% those of controls for low- and high-dose male mice, and 81% and 66% those of controls for low- and high-dose female mice. Hyperactivity was observed in all dosed groups.
Feed consumption was similar among control and exposed groups with the exception of high-dose female rats (84% of controls) and high-dose male mice, for which hyperactivity resulted in scattering of feed and overestimation of feed consumption. The average amount of dl-amphetamine sulfate consumed per day was estimated to be 1 or 5 mg/kg for low- and high-dose rats, 4 or 30 mg/kg for low- or high-dose male mice, and 3 or 19 mg/kg for low- or high-dose female mice.
Nonneoplastic and Neoplastic Effects in the 2-Year Studies
Myelofibrosis, cataracts, and retinal atrophy in female rats, and ovarian atrophy in female mice occurred in a larger proportion of high-dose animals than in controls.
Dose-related increases in neoplasms did not occur in rats or mice receiving amphetamine. The administration of dl-amphetamine sulfate was associated with decreases in the incidence of total neoplasms and in the incidences of certain site-specific neoplasms, including pheochromocytomas of the adrenal gland in male rats (23/49, 15/44, 7/50), fibroadenomas of the mammary gland in female rats (21/50, 11/50, 2/50), adenomas of the anterior pituitary gland in male and female rats and female mice (male rats: 15/49, 15/48, 9/49; female rats: 31/50, 24/48, 19/50; female mice: 12/49, 6/49, 1/46), endometrial stromal polyps of the uterus of female rats (10/50, 6/50, 3/50), adenomas or carcinomas (combined) of the liver in male and female mice (male: 14/50, 12/50, 2/50; female: 5/50, 1/50, 1/47), adenomas of the harderian gland in male and female mice (male: 4/50, 2/50, 0/50; female: 5/50, 2/50, 0/47), and adenomas or carcinomas (combined) of the lung in male and female mice (male: 8/50, 3/50, 4/50; female: 8/50, 6/50, 1/47).
dl-Amphetamine sulfate was tested for induction of gene mutations in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 with and without exogenous metabolic activation (S9); the only response observed was in strain TA98 in the presence of S9, and it was judged to be equivocal. No induction of sister chromatid exchanges or chromosomal aberrations occurred in Chinese hamster ovary cells treated with amphetamine sulfate in either the presence or the absence of S9.
Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of dl-amphetamine sulfate for male or female F344/N rats or male or female B6C3F1 mice fed 20 or 100 ppm. The administration of dl-amphetamine sulfate was associated with decreased body weight. There were decreased incidences of total neoplasms in dosed rats and mice, of adrenal pheochromocytomas in male rats, of mammary gland fibroadenomas and uterine polyps in female rats, of pituitary gland adenomas in male and female rats and female mice, and of harderian gland adenomas, liver neoplasms, and lung neoplasms in male and female mice.