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The mode of toxic action (MOA) is recognized as a key determinant of chemical toxicity and as an alternative to chemical class-based predictive toxicity modeling. However, MOA classification has never been standardized in ecotoxicology, and a comprehensive comparison of classification tools and approaches has never been reported. Here we critically evaluate three MOA classification methodologies using an aquatic toxicity data set of 3448 chemicals, compare the approaches, and assess utility and limitations in screening and early tier assessments. The comparisons focused on three commonly used tools: Verhaar prediction of toxicity MOA, the U.S. Environmental Protection Agency (EPA) ASsessment Tool for Evaluating Risk (ASTER) QSAR (quantitative structure activity relationship) application, and the EPA Mode of Action and Toxicity (MOAtox) database. Of the 3448 MOAs predicted using the Verhaar scheme, 1165 were classified by ASTER, and 802 were available in MOAtox. Of the subset of 432 chemicals with MOA assignments for each of the three schemes, 42% had complete concordance in MOA classification, and there was no agreement for 7% of the chemicals. The research shows the potential for large differences in MOA classification between the five broad groups of the Verhaar scheme and the more mechanism-based assignments of ASTER and MOAtox. Harmonization of classification schemes is needed to use MOA classification in chemical hazard and risk assessment more broadly.