Substituted phenols, anilines, pyridines and mononitrobenzenes can be classified as polar narcotics. These chemicals differ from non-polar narcotic compounds not only in their toxic potency (normalized by log Kₒw), but also in their Fish Acute Toxicity Syndrome profiles, together suggesting a different mode of action.For 97 polar narcotics, which are not ionized under physiological conditions, 11 physico-chemical and quantum-chemical descriptors were calculated. Using principal component analysis, 91 % of the total variance in this descriptor space could be explained by three principal components which were subsequently used as factors in a statistical design. Eleven compounds were selected based on a two-level full factorial design including three compounds near the center of the chemical domain (a 2³+3 design).QSARs were developed for both the design set and the whole set of 63 polar narcotics for which guppy and/or fathead minnow data were available in the literature. Both QSARs, based on partial least squares regression (3 latent variables), resulted in good models (R²=0.96 and Q²=0.82; R²=0.86 and Q²=0.83 respectively) and provided similar pseudo-regression coefficients. In addition, the model based on the design chemicals was able to predict the toxicity of the 63 compounds (R² =0.85).Models show that acute fish toxicity is determined by hydrophobicity, HOMO-LUMO energy gap and hydrogen-bond acceptor capacity.