Toxicology and carcinogenesis studies were conducted on oxytetracycline hydrochloride (greater than 98.8% pure), a broad-spectrum antibiotic. Groups of F344/N rats and B6C3F1 mice were fed diets containing oxytetracycline hydrochloride for a series of 14-day, 13-week, and 2-year studies. In the 14-day studies, no compound-related gross pathologic effects were seen in rats or mice (groups of five animals per sex per species) given up to 100,000 ppm in their feed. The final mean body weight of male rats receiving in feed was 27% lower than that of the controls. Final mean body weights of mice that received 25,000, 50,000, or 100,000 ppm were lower (male: 11%; 16%; 17%; female: 6%; 5%; 17%) than those of the controls. In the 13-week studies, groups of 10 male and 10 female rats and mice were fed diets containing up to 50,000 ppm in feed, and no chemically related gross or histopathologic effects were observed in mice of either sex or in female rats. In male rats, fatty metamorphosis of minimal severity was diagnosed in the liver of 5/10 animals at 6,300, 12,500, and 50,000 ppm and in 2/10 animals at 3,100 and 25,000 ppm. None was seen in the controls. Oxytetracycline levels in bones of rats and mice (as determined fluorometrically) at the end of the 13-week studies increased with dose, the highest levels (3-10 times background levels) being observed at 50,000 ppm.
The 2-year toxicology and carcinogenesis studies were conducted by administering diets containing 0, 25,000, or 50,000 ppm oxytetracycline hydrochloride to groups of 50 male and 50 female rats and diets containing 0, 6,300, or 12,500 ppm oxytetracycline hydrochloride to groups of 50 male and 50 female mice for 103 weeks. The highest dose selected for rats was considered to be the maximum level that would not affect the nutritional value of dosed feed. The dietary concentrations correspond to the following approximate doses: rats-- 0, 1,000, or 2,000 mg/kg body weight per day; mice-- 0, 650, or 1,400 mg/kg per day.
Mean body weights were approximately 5%-8% lower than those of controls in high dose male rats during weeks 4-47, in high dose male mice after week 31, and in high dose female mice after week 26. The mean body weights of dosed female rats and low dose male and female mice were comparable to those of controls. The survival of control male rats was lower than that of the high dose group (22/50 vs 38/50). No significant differences in survival were observed between the remaining groups of rats or between any groups of mice.
Pheochromocytomas of the adrenal gland occurred with positive trends in male rats (control, 10/50; low dose, 18/50; high dose, 24/50), and the incidence in the high dose group was greater than that in the controls. Two additional control males and one additional low dose male had malignant pheochromocytomas. The incidence of adrenalgland medullary hyperplasia was elevated slightly but not significantly in dosed male rats (7/50; 14/50; 9/50).
Adenomas and adenomas and adenocarcinomas (combined) of the pituitary gland in female rats occurred with positive trends, and the incidences in the high dose group were greater than that in the controls (adenomas: 19/50; 17/50; 30/50; adenomas or adenocarcinomas [combined]: 20/50; 24/50; 32/50). The incidence of pituitary gland hyperplasia was slightly decreased in dosed female rats (16/50; 10/50; 11/50).
No compound-related increases in nonneoplastic or neoplastic lesions were observed in male or female mice.
Oxytetracycline hydrochloride was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98 in the presence or absence of Aroclor 1254-induced male Sprague-Dawley rat or male Syrian hamster liver S9 when assayed according to the preincubational protocol. Oxytetracycline hydrochloride was mutagenic in L5178Y/TK+/- mouse lymphoma cells in the presence but not in the absence of Aroclor 1254-induced male rat liver S9. In cultured Chinese hamster ovary cells, oxytetracycline was weakly positive in inducing sister-chromatid exchanges both with and without Aroclor 1254-induced male Sprague-Dawley rat liver S9 but did not induce chromosomal aberrations.
An audit of the experimental data was conducted for these 2-year carcinogenesis studies of oxytetracycline hydrochloride. No data discrepancies were found that influenced the final interpretations.
Under the conditions of these 2-year feed studies of oxytetracycline hydrochloride, there was equivocal evidence of carcinogenicity for male F344/N rats, as indicated by increased incidences of pheochromocytomas of the adrenal gland. There was equivocal evidence of carcinogenicity for female F344/N rats fed diets containing oxytetracycline hydrochloride, as indicated by increased incidences of adenomas of the pituitary gland. There was no evidence of carcinogenicity for male or female B6C3F1 mice fed diets containing 6,300 or 12,500 ppm oxytetracycline hydrochloride for 2 years.