CAS Electrophile (El) Nucleophile (Nu) Parameter Unit Value Error log(Val) 818-61-1 2-Hydroxyethyl acrylate 4-Nitrobenzenethiol t1/2(NBT) min 2.45E-01 144-48-9 2-Iodoacetamide 4-Nitrobenzenethiol t1/2(NBT) min 1.83E-03 2682-20-4 2-Methyl-2H-isothiazolin-3-one 4-Nitrobenzenethiol t1/2(NBT) min 1.60E-03 25567-67-3 3-Chloro-1.2-dinitrobenzene 4-Nitrobenzenethiol t1/2(NBT) min 1.25E-02 2497-21-4 4-Hexen-3-one 4-Nitrobenzenethiol t1/2(NBT) min 2.77E-02 26172-55-4 5-Chloro-2-methyl-4-isothiazolin-3-one 4-Nitrobenzenethiol t1/2(NBT) min 5.83E-05 108-24-7 Acetic anhydride 4-Nitrobenzenethiol t1/2(NBT) min 9.83E-04 107-02-8 Acrolein 4-Nitrobenzenethiol t1/2(NBT) min 8.25E-02 100-39-0 Benzyl bromide 4-Nitrobenzenethiol t1/2(NBT) min 4.67E-05 57-57-8 beta-Propiolactone 4-Nitrobenzenethiol t1/2(NBT) min 1.62E-04 88-11-9 Diethylthiocarbamoyl chloride 4-Nitrobenzenethiol t1/2(NBT) min 1.52E-03 886-38-4 Diphenylcyclopropenone 4-Nitrobenzenethiol t1/2(NBT) min 1.05E-05 140-88-5 Ethyl acrylate 4-Nitrobenzenethiol t1/2(NBT) min 7.70E-01 50-00-0 Formaldehyde 4-Nitrobenzenethiol t1/2(NBT) min 1.25E-03 55965-84-9 Kathon CG 4-Nitrobenzenethiol t1/2(NBT) min 2.17E-04 124-63-0 Methyl sulfonyl chloride 4-Nitrobenzenethiol t1/2(NBT) min 7.67E-04 128-53-0 N-Ethylmaleimide 4-Nitrobenzenethiol t1/2(NBT) min 3.33E-04 Nitrobenzyl bromide 4-Nitrobenzenethiol t1/2(NBT) min 9.83E-06 15646-46-5 Oxazolone 4-Nitrobenzenethiol t1/2(NBT) min 9.00E-06 106-51-4 p-Benzoquinone 4-Nitrobenzenethiol t1/2(NBT) min 7.33E-06 1939-99-7 Phenylmethanesulfonyl chloride 4-Nitrobenzenethiol t1/2(NBT) min 6.00E-03 2892-51-5 Squaric acid 4-Nitrobenzenethiol t1/2(NBT) min 6.12E-02 584-84-9 Toluene 2.4-diisocyanate 4-Nitrobenzenethiol t1/2(NBT) min 4.50E-04 23726-91-2S2 Schwöbel et al.

A model has been developed to predict the kinetic rate constants (k(GSH)) of α,β-unsaturated Michael acceptor compounds for their reaction with glutathione (GSH). The model uses the local charge-limited electrophilicity index ω(q) [Wondrousch, D., et al. (2010) J. Phys. Chem. Lett. 1, 1605-1610] at the β-carbon atom as a descriptor of reactivity, a descriptor for resonance stabilization of the transition state, and one for steric hindrance at the reaction sites involved. Overall, the Michael addition model performs well (r² = 0.91; rms = 0.34). It includes various classes of compounds with double and triple bonds, linear and cyclic systems, and compounds with and without substituents in the α-position. Comparison of experimental and predicted rate constants demonstrates even better performance of the model for individual classes of compounds (e.g., for aldehydes, r² = 0.97 and rms = 0.15; for ketones, r² = 0.95 and rms = 0.35). The model also allows for the prediction of the RC₅₀ values from the Schultz chemoassay, the accuracy being close to the interlaboratory experimental error. Furthermore, k(GSH) and associated RC₅₀ values can be predicted in cases where experimental measurements are not possible or restricted, for example, because of low solubility or high volatility. The model has the potential to provide information to assist in the assessment and categorization of toxicants and in the application of integrated testing strategies.

alpha,beta-Unsaturated carbonyl compounds are common environmental pollutants that are able to interact with proteins, enzymes, and DNA through various mechanisms. As such, they are able to stimulate a range of environmental toxicities and adverse health effects. In this study, a "category" of alpha,beta-unsaturated carbonyl compounds (aldehydes and ketones), assumed to act by a common mechanism of action (Michael type addition), was formed. This toxicologically and mechanistically important category was formed on the premise of structure-activity relationships. The acute aquatic toxicities to Tetrahymena pyriformis of compounds within the category were obtained in an effort to develop approaches for (qualitative) read-across. In addition, Salmonella typhimurium (strain TA100) mutagenicity data were analyzed to establish the structural differences between mutagenic and nonmutagenic compounds. These structural differences were compared with the structural characteristics of molecules associated with acute aquatic toxicity in excess of narcosis as well as other end points, for example, skin sensitization. The results indicate that a category can be formed that allows structural information and boundaries to be elucidated. This knowledge will guide future toxicity prediction within this category and assist in the development of category formation.

The present study proposes a generic interspecies quantitative structure-activity relationship (QSAR) model that can be used to predict the acute toxicity of aldehydes to most species of aquatic organisms. The model is based on the flow-through fathead minnow (Pimephales promelas) 50% lethal concentration (LC50) data combined with other selected fish acute toxicity data and on the static ciliate (Tetrahymena pyriformis) 50% inhibitory growth concentration (IGC50) data. The toxicity of Schiff-base acting aldehydes was defined using hydrophobicity, as the calculated log 1-octanol/water partition coefficient (log Kow), and reactivity, as the donor delocalizability for the aldehyde O-site (D(O-atom)). The fish model [log 1/LC50 = -2.503(+/-1.950) + 0.480(+/-0.052) log Kow + 18.983(+/-6.573) D(O-atom), n = 62, r2 = 0.619, s2 = 0.241, F = 48.0, Q2 = 0.587] compares favorably with the ciliate model [log 1/IGC50 = -0.985(+/-1.309) + 0.530(+/-0.044) log Kow + 11.369(+/-4.350) D(O-atom), n = 81, r2 = 0.651, s2 = 0.147, F = 72.9, Q2 = 0.626]. The fish and ciliate surfaces appear to be parallel, because they deviate significantly only by their intercepts. These observations lead to the development of a global QSAR for aldehyde aquatic toxicity [log E(-1) = bE(Organism) + 0.505(+/-0.033) log Kow + 14.315(+/-3.731) D(O-atom), n = 143, r2 = 0.698, s2 = 0.187, S2(Fish) = 0.244, S2(Ciliate) = 0.149, F = 98, Q2 = 0.681]. The general character of the model was validated using acute toxicity data for other aquatic species. The aldehydes global interspecies QSAR model could be used to predict the acute aquatic toxicity of untested aldehydes and to extrapolate the toxicity of aldehydes to other aquatic species.