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Fifty-six adult beagle dogs (28 male, 28 female) were orally administered thalidomide at 43, 200, or 1000 mg/kg/day for 53 weeks. Sixteen (2/sex/dose group) and 32 (4/sex/dose group) dogs were euthanized and necropsied after 26 and 53 weeks of dosing, respectively. The remaining 8 animals (2/sex/group; high-dose and control groups) were dosed for 53 weeks, euthanized, and necropsied at 58 weeks after a 5-week recovery period. There were no deaths during the study. The only observed clinical signs attributable to thalidomide administration were green-colored urine, white-colored fecal residue presumed to be unchanged thalidomide, enlarged and/or blue coloration of female mammary tissue, and prolonged estrus. There were no thalidomide-related changes in body weights, food consumption, electrocardiography, ophthalmoscopy, neurological function, and endocrine function. The mostly slight and/or transient variations observed in some hematology and blood chemistry values of dosed dogs were considered to be toxicologically insignificant and were supported by the lack of histopathologic correlates. The only gross finding attributable to thalidomide was a yellow-green discoloration of the femur, rib, and/or calvarium that was observed at each euthanization interval including recovery. There was no microscopic correlate for this finding. No thalidomide-related microscopic changes were seen in any of the organs and tissues at 26 weeks. Mammary duct dilatation and/or glandular hyperplasia observed in females at 53 and 58 weeks and hepatic bile pigment exhibited by high-dose males at 53 weeks were microscopic changes considered to be thalidomide-related. There was no gross and histopathologic evidence of any tumors. In summary, thalidomide at up to 1000 mg/kg/day for 53 weeks did not induce any major systemic toxicity or tumors in dogs. The NOAEL was 200 mg/kg/day. [ABSTRACT FROM PUBLISHER]

The subchronic toxicology of thalidomide was determined in CD-1 mice and F344 rats. Animals (10/sex/dose) were orally dosed at 30, 300, and 3000 mg/kg/day over 13 weeks. Control animals were given 1% carboxymethylcellulose. No thalidomide-related mortality occurred throughout the study. Some species and sex differences were seen. In mice, thalidomide had no effect on body weight, food consumption, ophthalmic function or clinical chemistry/hematology, but a dose-dependent orange-pink urine was observed in both sexes. The discoloration was probably due to chromogenic breakdown products of thalidomide. The only significant finding in the mouse study was dose-related hepatic centrilobular hypertrophy in the males. This appeared only at the highest dose in the females. The hypertrophy was correlated with increased liver weight for the high dose of both sexes suggesting enzyme induction. In rats, thalidomide produced lower body weights in both sexes compared to control with a dose-response more evident in males. Male rats dosed at 30, 300, and 3000 mg/kg had body weights that were 8, 11, and 19% below control weight just before necropsy. Corresponding female rats were only 6 - 7% below control weights at all dose levels. Lower food consumption was observed in male rats and varied between 6 - 13% below control with no dose-response. Decreased forelimb strength was noted in males and could be due to the lower body weights. Functional observational battery tests and histopathology of the sural nerve and lumbar spinal cord sections suggested that the rat did not develop thalidomide-induced peripheral neuropathy. Mild anemia and leukopenia were seen only in some treated males. A decrease in total and free T4 was more consistent in females. Both sexes had lower thymus weights with no histological correlate compared to control. The no-observed-adverse-effect level for mice and female rats were 3000 mg/kg and 30 mg/kg for male rats. [ABSTRACT FROM AUTHOR]