Kazumasa Yamashita

ACUTE TOXICITY STUDY OF 6-AMIDINO-2-NAPHTHYL 4-[(4, 5-DIHYDRO-1H-IMIDAZOL-2-YL) AMINO] BENZOATE DIMETHANESULFONATE (FUT-187) IN MICE, RATS AND DOGS

Single oral, subcutaneous or intravenous administration to mice and rats and oral administration to dogs were performed to investigate the acute toxicity of FUT-187. 1) LD50 values in mice were 4,395 mg/kg for males and 3,626 mg/kg for females orally, 6,284 mg/kg for males and 5,492 mg/kg for females subcutaneously, and 39.4 mg/kg for males and 41.4 mg/kg for females intravenously. In rats, these values were 4,653 mg/kg for males and 3,761 mg/kg for females orally, 6,799 mg/kg for males and 3,343 mg/kg for the females subcutaneously and 21.8 mg/kg for males and 15.8 mg/kg for females intravenously. 2) Death occurred 2 hours after administration in a male dog of the 3,000 mg/kg group just after convulsion and nasal discharge were observed. 3) General symptoms in mice and rats included a creeping gait, convulsion, singultus, cyanosis, decreased locomotor activity, piloerection and salivation which were commonly observed by all routes. All dogs showed vomiting and decreased locomotor activity; the prone or lateral position, crouching, ataxic gait and salivation were also observed in many cases. 4) On autopsy, changes attributable to local irritation by FUT-187 were seen in all species except mice and rats dosed intravenously. For the gastro intestinal-tract (GIT), inflammation of the stomach, adhesions between the stomach and the liver and sclerosis, petechiae or ulcer were observed in mice and rats dosed orally. In the subcutaneous route, retention of the test compound and necrosis at the injection site were observed. Reddening and loss of mucosal smoothness were observed in the GIT of a dog which died; desquamation, congestion, hemorrhage and retention of tested compound in the digestive mucosa were observed on histopathology.