Safety profile of thalidomide after 53 weeks of oral administration in beagle dogs

Fifty-sis adult beagle dogs (28 male, 28 female) were orally administered t halidomide at 43,200, or 1000 mg/kg/day for 53 weeks. Sixteen (2/sex/dose g roup) and 32 (4/sex/dose group) dogs were euthanized and necropsied after 2 6 and 53 weeks of dosing, respectively. The remaining 8 animals (2/sex/grou p; high-dose and control groups) were dosed for 53 weeks, euthanized, and n ecropsied at 58 weeks after a 5-week recovery period. There were no deaths during the study. The only observed clinical signs attributable to thalidom ide administration were green-colored urine, white-colored fecal residue pr esumed to be unchanged thalidomide. enlarged and/or blue coloration of fema le mammary tissue, and prolonged estrus. There were no thalidomide-related changes in body weights, food consumption, electrocardiography, ophthalmosc opy, neurological function, and endocrine function. The mostly slight and/o r transient variations observed in some hematology and blood chemistry valu es of dosed dogs were considered to be toxicologically insignificant and we re supported by the lack of histopathologic correlates. The only gross find ing attributable to thalidomide was a yellow-green discoloration of the fem ur, 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 b y high-dose males at 53 weeks were microscopic changes considered to be tha lidomide-related. There was no gross and histopathologic evidence of any tu mors. In summary thalidomide at up to 1000 mg/kg/day for 53 weeks did not i nduce any major systemic toxicity or tumors in dogs. The NOAEL was 200 mg/k g/day.