[Toxicity study of cefmatilen hydrochloride hydrate (S-1090) (4)--One- and three-month repeated oral dose toxicity...

One- or three-month repeated oral dose toxicity studies of Cefmatilen hydrochloride hydrate (S-1090) were conducted in beagle dogs. Doses were set at 25, 100 and 400 mg potency/kg/day in both studies. In both studies, no deaths occurred, and reddish-brown feces (due to chelated products of S-1090 and its decomposition products with Fe3+ in the diet) were observed in all treated groups. A transient excretion of reddish urine was observed in the 400 mg potency/kg group and a slight increase in plasma irons was also observed in the 100 and 400 mg potency/kg groups of both studies. However, as no changes suggesting anemia or hepatic injury were noted in these groups, the change of plasma irons was considered to have no toxicological significance. Plasma S-1090 concentrations increased in a manner less than dose-proportional in both studies. In the one-month toxicity study, no toxicologically significant changes, including the above findings, were noted, so the NOAEL was assessed to be 400 mg potency/kg/day. In the three-month toxicity study, urinalysis in the 400 mg potency/kg group revealed a positive reaction to occult blood and erythrocytes in sediments. In the pathological examinations, submucosal edema, hemorrhage, inflammatory cell infiltration and occasionally focal mucosal thickening were observed in the urinary bladder of the 400 mg potency/kg group. The cystisis was considered to result from chronic stimulation with the metabolite(s) of S-1090 in urine, and the reversibility was demonstrable upon one-month drug withdrawal. From these results, the NOAEL of S-1090 in the three-month toxicity study was assessed to be 100 mg potency/kg/day.