Amino Reactivity of Glutardialdehyde andMonoaldehydes─Chemoassay Profile vs Skin Sensitization Potency.

Abstract

Chemoassay profiling of organic electrophiles through the direct peptide reactivity assay has become an OECD-accepted nonanimal component in the REACH evaluation of potential skin sensitizers. For aldehydes forming imines (Schiff bases), however, existing chemoassays yielded inconclusive results, indicating issues with their NH2 sensitivity and the reversibility of the reaction. In the present study, a new kinetic chemoassay employing the N terminus of glycine-para-nitroanilide, Gly-pNA, as a model nucleophile for protein NH2 groups is introduced and applied to nine aliphatic monoaldehydes and glutardialdehyde (1,5-pentanedial) that have log Kow (octanol/water partition coefficient) values from 0.63 to 3.99. The Gly-pNA second-order rate constants k1 range from 8.56 to 150 L·mol-1·min-1 for the monoaldehydes. Interestingly, glutardialdehyde with a k1 of 17 731 L·mol-1·min-1 is 170-fold more reactive than its monoaldehyde counterpart pentanal. This can be rationalized by hydration or tautomerization of the dialdehyde to monoaldehydic forms, now facilitating Schiff base formation through an intramolecular H bond. Comparison with murine local lymph node assay data from the literature reveals that adduct stability in terms of reaction thermodynamics (K = k1/k-1pseudo) rather than formation kinetics (k1) governs the skin sensitization potency of Schiff-base-forming aldehydes. The discussion includes analytically determined adduct patterns, and the impact of α- and β-carbon substitution as well as hydrophobicity on aldehyde reactivity.