Evidence Supporting the Use of Optically Pure <i>S</i> ‐(+)‐Indoxacarb: Discovery and Toxicokinetic Characterization of Two New Pairs of Metabolite Enantiomers in Rats

Indoxacarb is a typical chiral pesticide composed of two enantiomers, of which only S-(+)-indoxacarb exhibits strong insecticidal activity. Growing interest in its enantioselective toxicology and metabolites has highlighted the need for more data on mammalian metabolism to assess human health risks. In this study, two new pairs of enantiomeric metabolites were identified from indoxacarb metabolism in rats: S-IN-RM493 and S-IN-RM541 derived from S-(+)-indoxacarb, and R-IN-RM493 and R-IN-RM541 derived from R-(-)-indoxacarb. To facilitate a more comprehensive risk assessment, the toxicokinetics of both metabolite pairs (IN-RM493 and IN-RM541) were evaluated in rats. The results showed that IN-RM493 was primarily formed in the stomach, which then entered the systemic circulation and was ultimately eliminated via feces. In contrast, IN-RM541 was primarily produced in the small intestine. Only a small portion of indoxacarb was converted to IN-RM541 in the small intestine, and this metabolite was poorly absorbed by the bloodstream. Consequently, IN-RM541 remained largely confined to intestinal tissues (small intestine, cecum, and large intestine) and feces. Toxicokinetic comparisons revealed that the S-enantiomeric metabolites were cleared more rapidly and accumulated less in tissues than their R-enantiomeric counterparts. This was consistent with the inherent property of S-(+)-indoxacarb, which is more easily metabolized and less prone to accumulation in vivo. Overall, S-(+)-indoxacarb demonstrates a more favorable safety profile than R-(-)-indoxacarb with respect to mammals. These findings provide valuable insights into the toxicology of indoxacarb in mammals, thereby paving the way for the informed agricultural application of its optically pure S-(+)-indoxacarb.