The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) is an established nephrotoxicant in male Fischer 344 rats at i.p. doses of > or = mmol/kg. Since gender differences often exist in the susceptibility to toxicants, the nephrotoxic potential of NDPS was examined in female Fischer 344 rats. Rats (4-5/group) were administered NDPS (0.1, 0.2, 0.4, or 1.0 mmol/kg, i.p.) or vehicle (sesame oil, 2.5 ml/kg) and renal function monitored for 48 h. At a dose of 0.1 mmol/kg, NDPS had no effect on renal function. However, administration of NDPS at a dose of 0.2 or 0.4 mmol/kg resulted in marked nephrotoxicity characterized by diuresis, increased proteinuria, glucosuria, hematuria, elevated blood urea nitrogen (BUN) concentration and kidney weight, decreased organic ion accumulation and proximal tubular necrosis. NDPS treatment of 1.0 mmol/kg resulted in oliguric renal failure rather than polyuric renal failure in 3 of 4 rats. Proximal tubular damage was observed primarily in the S3 segment of the proximal tubule in NDPS-treated female rats, while in male rats the S1 and S2 segments are the initial renal targets. These results demonstrate that female Fischer 344 rats are more susceptible to NDPS nephrotoxicity than male Fischer 344 rats and that the site of the renal lesion is gender dependent.