Fourteen-Day and Thirteen-Week Studies:
The same dietary concentrations were used for the 14-day and 13-week studies (0, 3,125, 6,250, 12,500, 25,000 and 50,000 ppm tetracycline hydrochloride). In the 14-day studies, none of the rats or mice died. The final mean body weight of male rats that received 50,000 ppm was 24% lower than that of the controls. The final mean body weight of mice that received 50,000 ppm in the diet was 18% lower than that of the controls for males and 15% lower for females. No compound-related effects were observed in rats or mice at necropsy.
During the 13-week studies, none of the rats or mice died. The final mean body weight of male rats that received 50,000 ppm was 18% lower than that of the controls. Compound-related effects included cytoplasmic vacuolization in the liver of male rats at 25,000 and 50,000 ppm. Bone tetracycline concentrations in rats and mice increased with increasing dose of tetracycline hydrochloride. The final mean body weight of mice that received 50,000 ppm was 16% lower than that of the controls for males and 6% lower for females. Estimated feed consumption by dosed rat and mouse groups was similar to that of the controls. No compound-related gross or microscopic pathologic effects were observed in mice.
Based on these results, 2-year studies of tetracycline hydrochloride were conducted by feeding diets containing 0, 12,500, or 25,000 ppm tetracycline hydrochloride to groups of 50 rats and 50 mice of each sex for 103 weeks.
Body Weight, Survival, and Feed Consumption in the Two-Year Studies:
Mean body weights of dosed and control male and female rats were similar throughout most of the studies. The survival of both the low and high dose female groups was greater than that of the controls. No significant differences in survival were observed between any groups of male rats (male: control, 27/50; low dose, 24/50; high dose, 31/50; female: 27/50; 39/50; 38/50). Mean body weights of dosed mice were markedly (more than 10%) lower than those of the controls throughout most of the studies. The survival rates of the dosed groups of male mice were greater than that of the control group. No significant differences in survival were observed between any groups of female mice (male: 31/50; 43/50; 43/50; female: 37/50; 35/50; 38/50). Feed consumption was similar by dosed and control rats and mice of either sex throughout the studies.
Nonneoplastic and Neoplastic Effects in the Two-Year Studies:
Basophilic cytoplasmic change and clear cell change were positively correlated with tetracycline hydrochloride administration in male rats. Otherwise, no significant increases in neoplastic or nonneoplastic lesions in rats or mice of either sex were considered related to tetracycline hydrochloride administration.
The incidence of adenomas or carcinomas (combined) of the pancreatic islets in low dose male rats was greater than that in the controls (control, 0/49; low dose, 5/49; high dose, 0/49). This marginal effect in the low dose group was not considered to be chemically related. The historical control rate of pancreatic islet cell neoplasms from previous studies at this laboratory is 6% (9/148).
Decreased incidences and severity of chronic nephropathy in male rats were associated with tetracycline hydrochloride administration (48/50; 35/50; 36/50). Female mice administered tetracycline hydrochloride in feed did not develop hepatocellular adenomas or carcinomas (combined incidence: 10/49; 0/48; 0/50). The historical control rate for hepatocellular adenomas or carcinomas (combined) from previous studies at this laboratory is 18/149 (12%). Other decreases in tumor incidence involving several tissues were considered to be of marginal biologic significance.
Tetracycline hydrochloride was not mutagenic in four strains of Salmonella typhimurium (TA98, TA100, TA1535, or TA1537) when tested in a preincubation protocol in the presence or absence of exogenous metabolic activation. Tetracycline hydrochloride was negative in the mouse lymphoma L5178Y/TK+/- assay with or without induced rat liver S9 but gave a marginally positive response when tested in the presence of noninduced S9. In cytogenetic assays with Chinese hamster ovary (CHO) cells, treatment with tetracycline hydrochloride, both with and without S9, did not induce chromosomal aberrations or sister chromatid exchanges (SCEs). Tetracycline hydrochloride did not induce sex-linked recessive lethal mutations when administered by feeding or injection to adult male Drosophila.
Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of tetracycline hydrochloride for male or female F344/N rats and B6C3F1 mice fed diets containing 12,500 or 25,000 ppm. Tetracycline hydrochloride-dosed female rats and male mice had greater survival rates than the respective controls during these studies. Dosed mice had lower body weight than controls, and dosed female mice had no hepatocellular adenomas or carcinomas.