structure-toxicity relationship (QSTR) studies have proved to be a valuable approach in research on the toxicity of organic chemicals for ranking chemical substances with respect to their potential hazardous effects on living systems. With this background, we have modeled here the acute lethal toxicity of 51 benzene derivatives with recently introduced extended topochemical atom (ETA) indices [Roy and Ghosh, Internet Electron J Mol Des 2:599-620 (2003)]. We also compared the ETA relations with non-ETA models derived from different topological indices (Wiener W, Balaban J, flexibility index, Hosoya Z, Zagreb, molecular connectivity indices, E-state indices and kappa shape indices) and physicochemical parameters (AlogP98, MolRef,H_bond_donor and H_bond_acceptor). Genetic function approximation (GFA) and factor analysis (FA) were used as the data-preprocessing steps for the development of final multiple linear regression (MLR) equations. Principal-component regression analysis (PCRA) was also used to extract the total information from the ETA/non-ETA/combined matrices. All the models developed were cross-validated using leave-one-out (LOO) and leave-many-out techniques. The summary of the statistics of the best models is as follows: (1) FA-MLR: ETA model- Q 2 (LOO)=0.852, R 2=0.894; non-ETA model- Q 2=0.782, R 2=0.835; ETA + non-ETA model-Q 2 =0.815, R 2=0.859. (2) GFA-MLR: ETA model-Q 2 =0.847, R 2=0.915; non-ETA model-Q 2 =0.863, R 2=0.898; ETA + non-ETA model-Q 2 =0.859, R 2=0.893. 3. PCRA: ETA model-Q 2 =0.864, R 2=0.901; non-ETA model- Q 2=0.866, R 2=0.922; ETA + non-ETA model-Q 2=0.846, R 2=0.890. The statistical quality of the ETA models is comparable to that of non-ETA models. Again, use of non-ETA descriptors in addition to ETA descriptors does not increase the statistical acceptance of the relations significantly. The predictive potential of these models was better than that of the previously reported models using physicochemical parameters [Huang et al., Chemosphere 53:963-970 (2003)]. The relations from ETA descriptors suggest a parabolic dependence of the toxicity on molecular size. Furthermore, the toxicity increases with functionality contribution of chloro substituent and decreases with those of methoxy, hydroxy, carboxy and amino groups. This study suggests that ETA parameters are sufficiently rich in chemical information to encode the structural features that contribute significantly to the acute toxicity of benzene derivatives to Rana japonica.