[Toxicological studies on a new cephamycin, MT-141. VI. Its chronic toxicity in beagle dogs].
MT-141 was dosed to male and female Beagle dogs through intravenous (i.v.) route at 100, 200, 400 and 800 mg/kg/day for 182 days. The toxic effects of MT-141 were as follows. The male and female Beagle dogs exhibited no particular behavior and symptom except vomiting and soft stool after treatments with 800 mg/kg/day i.v. of MT-141. MT-141 even at the high doses of 400 to 800 mg/kg/day i.v. did not significantly change toxicological parameters such as consumption of food and water, volume of excreted urine, electrocardiogram, eyeground and analysis of blood, serum and urine. Only one of 4 male Beagle dogs died of severe intestinal invagination, which is not related to the drug effect, at 120th day after the start of treatments with the highest dose of 800 mg/kg/day i.v. of MT-141. The fatality of Beagle dogs for 800 mg/kg/day of MT-141 was 25% (1/4) in males and 0% (0/4) in females. MT-141 caused the hemorrhage accompanied with fibrosis and round cells at the site of injections but the change induced by MT-141 was not so much different from that by saline. MT-141 at the highest dose induced histopathological changes in only 2 females, such as atrophy and degeneration of cardiac muscle, necrosis and fibrosis of hepatic cells and hyperplasia of spleen and bone marrow cells. Electron-microscopic examinations revealed no ultrastructural change related to the toxicity of MT-141 in the livers and kidneys. It is considered from the above-mentioned results that the maximal "no effective" dose is 400 mg/kg/day i.v. in male and female Beagle dogs.