1996 Volume 21 Issue SupplementIII Pages 561-588
52-week oral repeated-dose S-1 toxicity studies were conducted. Male and female dogs were orally treated with 0, 0.1, 0.5 or 2.5 mg/kg/day for 52 weeks and permitted to recover for 13 weeks. Furthermore, to estimate the no-toxic dose, male and female dogs were given S-1 orally for 52 weeks at doses of 0, 0.004 and 0.02 mg/kg/day. The 2.5 mg/kg/day regimen produced one dead or moribund dog of each sex; black-brown patch (melanin deposition) and inflammatory changes in the eyes and skin; decreased in body weight gains; increases in MCV, MCH, monocyte ratio, and serum protein and uric acid; decreases in lymphocyte ratio and erythrocyte count, hematocrit, hemoglobin, albumin, A/G ratio, cholesterol (esterified, total and free), phospholipids, triglycerides, cholinesterase activity and creatinine; increases in relative liver and adrenal weights. Histopathological examinations revealed melanin deposits in superficial lymph nodes, increases in macrophage and plasma cell accumulation, and corneal atrophy accompanied by melanin deposits and capillary proliferation. A slight black-brown patch (melanin deposition) in the conjunctiva and skin was observed in the 0.1 and 0.5 mg/kg/day groups. No drug-related changes were observed in groups that received 0.02 and 0.004 mg/kg/day. All changes observed during the treatment period disappeared during recovery except for melanin deposits in the conjunctiva dnd superficial lymph nodes, corneal opacity, and a few hematological and blood chemistry parameters. In conclusion, the no-toxic dose in these 52-week studies was estimated to be 0.02 mg/kg/day.
