Quantum‐chemical Descriptors for Estimating the Acute Toxicity of Electrophiles to the Fathed minnow (Pimephales promelas): An Analysis Based on Molecular Mechanisms

Abstract

Estimating the toxicity of reactive xenobiotics to aquatic organisms requires physicochemical descriptors of passive transport and chemical reactions with nucleophilic biological ligands. Herein, electrophiles whose toxic action is attributed to nucleophilic substitution (SN), Michael-type addition and Schiff-base formation were examined. Training sets for each molecular mechanism were generated through substructure search applied to chemicals in a fathead minnow (Pimephules promelus) database. Based on a delineation of compounds by a presumed molecular mechanism, relationships between modes of toxic action, potency (96-hour LC,, values) and mechanistically-appropriate quantum-chemica1 descriptors were explored. Monohalo-C(sp3) function which may give rise to S, reactivity was encountered in 35 compounds.The inclusion of E L , , , , a nonspecific electrophilicity descriptor, to the generic LC,, -hydrophobicity relation increased the explained variance from r' = 36% to 69%. Eighteen potential Michael-type acceptors, mainly acrylates, were identified by the presence of a localized CC double bond at an E, position to a polar group. Due to different modes of action, the toxic potency of these chemicals varies almost independently of hydrophobicity (? = 0.12). Two additional electronic descriptors that are consistent with the likely molecular mechanism provide a multivariate QSAR with ? = 0.78. Forty-five aldehydes and 3 formamides comprised the training set associated with probable Schiff-base mechanism of toxicity. The results suggest a marginal increase of toxic potency from that expected due to narcosis for more electrophilic carbonyl groups. Overall, it was concluded that regressions based on data sets that combine reactive chemicals with narcotics typically require an electronic descriptor in addition to hydrophobicity, even if the compounds all contain a common electrophilic moiety related to the putative specific reaction mechanism. However, without the generation of additional toxicity data from chemical sets that incorporate a broader range of electronic and steric character, it will likely remain extremely difficult to develop a quantitative ability to predict the potency of electrophilic compounds.

Prediction of the reduced glutathione (GSH) reactivity of dental methacrylate monomers using NMR spectra-Relationship between toxicity and GSH reactivity

“…Taking into consideration the results of the present study and those of published literature 6,23) , it could be claimed that acrylates with a high GSH reactivity showed higher toxicity than methacrylates with a low GSH reactivity.…”

“…In previous studies 6,23) , acrylates such as EAA and iBAA were reported to exhibit markedly greater toxicity than methacrylates such as MMA and iPMA in fathead minnow or mice. Taking into consideration the results of the present study and those of published literature 6,23) , it could be claimed that acrylates with a high GSH reactivity showed higher toxicity than methacrylates with a low GSH reactivity.…”

A Theoretical Approach to the Ferguson Principle and its Use with Non‐Reactive and Reactive Airborne Chemicals

“…Such an approach has also been successful to estimate toxicity in aquatic organisms (Karabunarliev et al 1996).…”

Relationships between the Reduced Glutathione (GSH) Reactivity of Dental Methacrylates, Michael-reaction Acceptors and their 13C-NMR Chemical Shift of -Carbons

“…On the comparative introduce, a causal connection between Invivo LD 50 in mice and or log k esteem for 2-hydroxyethyl acrylate (2HEA) and ethyl acrylate (EA). This was proven by looking at the individual information for 2HEA (log P=-0.21, esteem=3.214 eV, separately) to EA (log P=1.33, esteem=3.1981 eV, individually); i.e., both have for all intents and purposes comparable values, yet altogether unique response rates (log k=1.92 versus 1.43, individually) and dangerous potencies (LD 50 =5.2 m mol/kg versus 18 m mol/kg, separately) [23]. Take note of that the δ C β estimation of 2HEA is 130.4 ppm, though EA is 130.24 ppm.…”

“…Dynamic acrylates, for example, 2HEA, MA, EA and iBA were already answered to demonstrate notably more prominent poisonous quality in fathead minnow or mice than methacrylates, for example, MMA [6,17]. Acrylates with a high GSH reactivity indicate higher lethality than methacrylates with a low GSH reactivity [6,23]. Then again, in spite of the fact that allylMA indicates bring down GSH reactivity than the acrylates EA and iBA, AllyMA demonstrated more noteworthy lethality than the last [22].…”