Effect of succinimide ring modification on N-(3,5-dichlorophenyl)succinimide-induced nephrotoxicity in Sprague-Dawley and Fischer 344 rats.

N-(3,5-Dichlorophenyl)succinimide (NDPS) has proven to be an effective experimental agricultural fungicide. However, NDPS produces marked nephrotoxicity in Sprague-Dawley and Fischer 344 rats. The purpose of this study was to determine the importance of an intact, unsubstituted succinimide ring for acute NDPS-induced nephrotoxicity. Structural modifications included ring opening, reduction of one or both carbonyl groups, breaking the ethylene carbon-carbon bond and mono- or dialkyl substitution on the succinimide ring. Sprague-Dawley or Fischer 344 rats were administered NDPS or an NDPS analog (0.1, 0.2, 0.4, 0.8 or 1.0 mmol/kg) or sesame oil (2.5 ml/kg, i.p.) and renal function was monitored at 24 h and 48 h. All structural modifications produced compounds with markedly reduced nephrotoxic potential in both Sprague-Dawley and Fischer 344 rats when compared to NDPS. However, N,N-diacetyl-3,5-dichloroaniline and N-(3,5-dichlorophenyl)pyrrolidine-2-one were more lethal than NDPS. The reduced renal effects of the NDPS analogs did not correlate with lipophilic character. These results indicate that an intact, unsubstituted succinimide ring is optimal for acute NDPS-induced nephrotoxicity.