Toxicity of a hypoglycemic agent, 2-p-methoxybenzenesulfonamido-5-isobutyl-1,3,4-thiadiazole

Abstract Hypoglycemic, acute, and chronic toxicity studies were carried out in animals with 2- p -methoxybenzenesulfonamido-5-isobutyl-1,3,4-thiadiazole. Oral administration of the drug reduced blood sugar in normal rats at 30 mg/kg, in dogs at 25 mg/kg, and in rabbits at 765 mg/kg. The single oral dose LD 50 's of the drug in mice and rats were 468 (416–527) mg/kg and 534 (464–615) mg/kg, respectively. Emesis at high doses prevented determination of the LD 50 in dogs. Feeding of the drug to rats at concentrations of 0.4, 0.6, and 0.8% in the diet retarded growth of females but not of the males during 52 weeks. Food consumption over the same period of time, was unaffected in male rats but declined slightly in the females at 0.6 and 0.8%. Dogs tolerated 200 mg/kg, 5 days a week, for 3 years with no effects on feeding habits or weight. No changes in hematology were found in rats at levels of the drug up to 0.4% in the diet over 52 weeks of feeding. Dogs at dosages of 50 mg/kg and above, for 56 weeks, showed a moderate to marked decrease in total circulating leukocytes and granulocytes. Organ weights of the rats after 52 weeks of feeding of the drug were comparable in all groups with two exceptions. The lungs of the female rats at 0.6 and 0.8% were heavier than those of the control animals, and pancreases in both sexes were lighter at high drug concentrations. The bone marrow of dogs given 50, 100, or 200 mg/kg of the drug for 56 weeks showed less cellularity and had lower myeloid and erythroid ratios than the marrow of control dogs. Urotheliomas of the bladder were found in rats fed 0.6 and 0.8% dietary concentrations of the drug for 12–18 months. None was seen at lower concentrations or in control rats. No uretheliomas were found in dogs given the drug for a period of 3 years.