Classification of toxicity of phenols to Tetrahymena pyriformis and subsequent derivation of QSARs from hydrophobic, ionization and electronic parameters

Phenolic compounds were classified into different groups based on the structure and functional groups of the phenol. Quantitative structure–activity relationship (QSAR) analysis was performed between the toxicity and octanol/water partition coefficient (log P) for these groups. The results showed that the toxicity of non-ionisable phenols is dependent on their hydrophobicity. Poor relationships were found between the toxicity and log P for ionisable compounds, and the use of methods based on log P to predict the toxicity of ionisable compounds can result in considerable errors. Ionized and unionized forms have different contributions to toxicity; the unionized form plays a more important role than the ionized form because the toxicity of organic acids and phenols decreases as the pH increases. In order to investigate the effect of ionization, the fraction of ionized and unionized forms of phenols at different pH values were calculated from the pKa values, and a corrected distribution partition coefficient (DT) was derived from QSAR analysis for ionisable compounds. The prediction of toxicity of non-reactive ionisable compounds was improved remarkably by using the DT parameter. Ionization not only affects the bio-uptake of ionisable compounds, but interaction with the receptor micromolecule can also depend on the electronic situation, which is also related to the ionization. Stepwise regression showed that the reactivity of ionisable phenols was strongly correlated with the fraction of negatively charged form (F–). Interpretable QSAR equations with good statistical fits were developed from hydrophobic, ionization and electronic parameters for 207 phenols.