14-Day Toxicity Study of 1-Methylethyl 2-Chloro-5-(((1-Methylethoxy)Thiomethyl)Amino)Benzoate (NSC-D629243) in Hamsters. Volume 1.

摘要

Mortality attributed to the test drug occurred in 4/26 males and 4/26 females administered 500 mg/kg/dose NSC-D629243 and in 10/26 animals/sex administered the 700 mg/kg/dose level. Relative to the vehicle control group (VCTL), dose-dependent reductions in group mean body weights occurred in all drug-treatment groups during the 14-day treatment period. Drug-treated hamsters had increased leukocyte values and reduced numbers of reticulocytes, principally at the 700 mg/kg/dose level. Serum chemistry effects observed during the dosing period were increased group mean cholesterol, triglycerides, AST, ALT, ALP, BUN/creatinine values and alterations of serum K and Cl primarily at the 500 and 700 mg/kg/dose levels. Those changes were transient and were not evident in animals during the post-treatment period. Histopathological alterations seen in animals necropsied on Study Day 15 included lymphoid depletion of the thymus, spleen, and mesenteric lymph nodes and centrilobular hepatocyte hypertrophy in both sexes from the 500 and 700 mg/kg/dose groups (with centrolobular hepatocyte hypertrophy occurring in one male in the 350 mg/kg/dose group). Renal tubule dilation and/or necrosis occurred in females from the 350 mg/kg/dose level and in both sexes from the 500 and 700 mg/kg/dose levels. Bone marrow depletion, degeneration of the testicular germinal epithelium and degeneration of ovarian follicles occurred in the 500 and 700 mg/kg/dose groups. Partial to complete resolution of all lesions occurred in animals necropsied on Study Day 30, and no other microscopic lesions were detected in other tissues examined. Bone marrow, ovaries, lymphoid tissues, kidney, testes and liver were identified as target tissues, due to the combination of drug-treatment and stress-related effects. The no-effect-level for the study was considered to be 175 mg/kg/dose for both sexes (although only a single male in the 350 mg/kg/dose group had a drug-related lesion - hepatocyte hypertrophy.