Model Suite for Predicting the Aquatic Toxicity of α,β‐Unsaturated Esters Triggered by Their Chemoavailability

For a Michael‐acceptor set of 45 α,β‐unsaturated esters, the 2 nd ‐order rate constant of reaction with glutathione, log  k GSH , was modeled through the quantum chemical reaction barrier (Δ E ≠ ) employing methane thiol as model nucleophile. Regression of their 48‐h toxicity toward the ciliates Tetrahymena pyriformis (log EC 50 , 50 % growth inhibition) on log  K ow (octanol/water partition coefficient) and log  k GSH revealed a variation in the relative weights of hydrophobicity and electrophilic reactivity as determinants of the aquatic toxicity. The difference D Kk =log  K ow −log  k GSH turned out as a suitable means for predictively discriminating between narcosis‐level ( D Kk >3.0) and excess‐toxic ( D Kk <2.0) compounds. In the intermediate D Kk range (2.0≤ D Kk ≤3.0), both narcosis‐level and reactive‐toxicity models are applicable for predicting aquatic toxicity. As such, D Kk represents the chemoavailability of Michael‐acceptor esters, characterizing their likelihood for undertaking covalent reactions with thiol sites of endogenous peptides and proteins. At the same time, D Kk introduces a straightforward way for characterizing the applicability domain of QSAR (quantitative structure‐activity relationship) models for predicting the toxicity of Michael‐acceptor esters. The resultant model suite comprising QSARs for reactive toxicity and baseline narcosis is triggered by the compounds’ chemoavailability, and yields predictions superior to existing approaches.