Toxicity Risk Assessment of Clethodim Enantiomers in Rats and Mice: Insights from Stereoselective Effects

Clethodim is a chiral herbicide with two enantiomers. The herbicidal activity of (-)-clethodim is 1.3-2.0-fold that of (+)-clethodim, but the absolute configurations of (-)-clethodim have not been clarified. In this study, enantiomers 1 and 2 resolved from a racemate by preparative HPLC equipped with a Chiralpak IA column were confirmed as R-(-)-clethodim and S-(+)-clethodim, respectively. Both enantiomers showed significant stereoselectivity in vivo. The AUC_0-72h of R-(-)-clethodim was 4.50 and 4.90 times that of S-(+)-clethodim in plasma after intragastric and intravenous administration, respectively. However, the bioavailability of R-(-)-clethodim (12.96%) was lower than that of S-(+)-clethodim (14.14%). S-(+)-clethodim was found in a relatively high abundance in most tissues. No mutual transformation between the two enantiomers was observed in vivo, indicating that configuration conversion did not contribute to the differences in the content of the enantiomers in the plasma and tissues. This may be due to the binding of clethodim enantiomers to serum albumin and acetyl-CoA carboxylase, which was verified by the molecular docking experiment. In summary, the findings from this study provided novel insights into the stereoselective risk assessment of the chiral clethodim and valuable evidence for toxicity risk assessments.