Amino Chemoassay Profiling of Aromatic Aldehydes–Unraveling Drivers of Their Skin Sensitization Potency

Abstract

Aromatic aldehydes are ubiquitous in humans’ everyday life. As aldehydes, they can form imines (Schiff bases) with amino groups of skin proteins, leading to immune response-triggered allergic contact dermatitis. Many known aromatic aldehydes are considered as weak or nonsensitizers, but others like atranol and chloratranol, two components of the fragrance oak moss absolute, show strong sensitization potency. This large discrepancy in potency and, in particular, the underlying reaction mechanisms are only little understood so far. To reduce this knowledge gap, our chemoassay employing glycine-para-nitroanilide (Gly-pNA) as an amino model nucleophile was applied to 23 aromatic aldehydes. The determined Gly-pNA second-order rate constants for imine formation (k 1 ≤ 2.85 L·mol–1·min–1) and the imine stability constant (K ≤ 333 L·mol–1) are on the lower end of the known amino reactivity scale for aldehydes, confirming many aromatic aldehydes as less potent sensitizers in line with animal and human data. The substantially higher sensitization potency of atranol and chloratranol, in turn, is reflected by their unique reaction chemistry profiles, inter alia, identifying them as cross-linkers able to form thermodynamically more stable epitopes with skin proteins (despite low formation kinetics, k 1). The discussion further includes a comparison of experimentally determined k 1 values with computed reactivity data (Taft σ*), the impact of the substitution pattern of the aryl ring on the reactivity with Gly-pNA, and analytically determined adduct patterns. Overall, this work provides new insights into the reaction of aromatic aldehydes with amino groups under aqueous conditions and fosters a better understanding of the chemistry underlying skin sensitization.