Measurement and Estimation of Electrophilic Reactivity for Predictive Toxicology

Abstract

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.

Mutagenic and carcinogenic structural alerts and their mechanisms of action

“…In the first stage, the leaving group is branched off, and in the second stage, the resulting carbenium ion reacts with a nucleophile. S N 2 is a second-order nucleophilic substitution where the leaving group disconnects and attacks a nucleophile in a single step (31). Acylation is a reaction where reactive tetrahedral intermediate is formed with a nucleophile, and the leaving group is released.…”

Integrating non-animal test information into an adaptive testing strategy – skin sensitization proof of concept case

“…BN to build upon results from this proof-of-concept work, a follow up BN ItS will need to be constructed with a comprehensive data set to establish more certain relationships among individual inputs and between inputs and target information. As the amount of data on originally used tests grows, other alternative tests and data relevant to skin sensitization assessment are becoming available (e.g., additional in chemico reactivity data as reviewed in Schwoebel et al (2011) and HClAt dendritic cell activation assays (Nukada et al, 2010)) which could be used in an ItS. As the consequence of adding new tests, the follow up BN ItS may result in a revised structure.…”

Investigation on modes of toxic action to rats based on aliphatic and aromatic compounds and comparison with fish toxicity based on exposure routes

“…If we use log TR = 0.5 as a threshold of reactive compounds for rat toxicity, chemicals, such as nitrophenols, phenyl hydrazones and phenyl hydrazides, exhibit excess toxicity and can be predicted as reactive compounds. Most of these compounds have been identified as reactive compounds in fish toxicity (Russom et al, 1997;Enoch et al, 2011;Schwöbel et al, 2011). They can undergo covalent binding to nucleophilic sites on one or more biological macromolecules, thus acting as electrophilic toxicants Schwöbel et al, 2011).…”

“…The interaction of polar compounds with biological macromolecules may be through physical interaction rather than chemical reaction. It is well-known that the reactive mechanism includes the formation of covalent bonds between electron-poor (electrophilic) substrate and a biological electron-rich (nucleophilic) target molecule, especially biological macromolecules such as nucleic acids and proteins (Lipnick, 1999;Schwöbel et al, 2011). Such as Schiff base formation, bi-molecular nucleophilic substitution (S N 2), acylation and aromatic nucleophilic substitution (S N Ar), these are the most important direct acting covalent binding mechanisms Schultz et al, 2006;Roberts et al, 2007).…”