Utilizing metabolism-based structure-activity relationships and biokinetic modeling for toxicological evaluation: A case study on L-menthyl D-Lactate

Abstract

Structure activity relationship (SAR) based read across uses existing toxicity data from an analog to predict the toxicity of a target chemical. An analog can be classified as suitable, suitable with interpretation, suitable with precondition or not suitable. Few have evaluated the scenario of “suitable with precondition”; thus, we present a case study where the systemic safety of L-menthyl D-lactate is established via suitable with precondition analogs, DL-menthol and D-lactic acid, which are predicted ester hydrolysis metabolites of the target chemical. In vitro metabolism assays demonstrated the ester hydrolysis pathway for L-menthyl D-lactate, indicating that the ester hydrolysis metabolites could be used as analogs. The rate and extent of L-menthyl D-lactate metabolism by human skin and liver S9 and plasma were determined and inputted into a human physiologically based pharmacokinetic (PBPK) model to estimate internal exposure to L-menthyl D-lactate following different exposure scenarios. Margins of internal and external exposure were determined by comparing scenario specific exposures to an internal threshold of toxicological concern or toxicity data from the metabolites. Additional analysis conducted with a rat PBPK model to prospectively estimate internal exposure to L-menthyl D-lactate that would occur from an oral toxicity study demonstrated that it would be metabolized rapidly and extensively by rats and the predominate (99.8 %) systemic exposure would be to the ester hydrolysis metabolites with only a minor, transient exposure occurring to L-menthyl D-lactate. Reapplication of the current approach for human safety assessments holds promise for ensuring human health by using robust approaches for read across.