REPRODUCTIVE AND DEVELOPMENTAL TOXICITY STUDY OF SODIUM N-[2-[4-(2, 2-DIMETHYLPROPIONYLOXY)PHENYLSULFONYLAMINO]BENZOYL]AMINOACETATE TETRAHYDRATE(ONO-5046·Na)(3)TERATOGENICITY STUDY IN RABBITS

Abstract

Teratogenicity of sodium N-[2-[4-(2, 2-dimethylpropionyloxy)phenylsulfonylamino]benzoyl]aminoacetate tetrahydrate(ONO-5046·Na), a novel inhibitor of human neutrophil elastase, was studied. ONO-5046·Na was injected intravenously at doses of 0, 7.5, 15 and 30 mg/kg/day to pregnant Kbl:NZW rabbits from day 6 to day 18 of pregnancy. All female rabbits were sacrificed on day 29 of pregnancy and their fetuses were examined. There were no clinical signs or death attributable to ONO-5046·Na. One dam in the control group and 3 dams in the 30 mg/kg/day group aborted. Body weight gain in the 15 and 30 mg/kg/day groups and food intake in the 30 mg/kg/day group were decreased during the administration period. These changes had recovered by the end of the study. Kidney weight was increased in the 30 mg/kg/day group. There were no effects of ONO-5046·Na in necropsy findings at cesarean section in dams at any dose levels. Developmental toxicity of ONO-5046·Na was not found at any dose levels. From these results, it is considered that the NOAEL of ONO-5046·Na is 7.5 mg/kg/day for pregnant animals and 30 mg/kg/day for fetuses.