Autoxidized citronellol: Free radicals as potential sparkles to ignite the fragrance induced skin sensitizing pathway

Citronellol, one of the most used fragrance compounds worldwide, is one ingredient of Fragrance Mix II used to assess skin allergy to fragrances in dermatitis patients. Pure citronellol is non-allergenic. Main issue is it autoxidizes when exposed to air becoming then allergenic. The increased skin sensitizing potency of air-exposed citronellol has been attributed to the hydroperoxides detected at high concentrations in the oxidation mixtures. It has been postulated that such hydroperoxides can give rise to specific antigens, although chemical mechanisms involved and the pathogenesis are far from being unraveled. Hydroperoxides are believed to react with skin proteins through mechanisms involving radical intermediates. Here, insights on the potential radicals involved in skin sensitization to citronellol hydroperoxides are given. The employed tool is a multispectroscopic approach based on (i) electron paramagnetic resonance and spin trapping, that confirmed the formation of oxygen- and carbon-radicals when exposing reconstructed human epidermis to concentrations of hydroperoxides close to those used for patch testing patients with air-oxidized citronellol; (ii) liquid chromatography-mass spectrometry, that proved the reaction with amino acids such as cysteine and histidine, known to be involved in radical processes and (iii) density functional theory calculations, that gave an overview on the preferential paths for radical degradation.