Experimental and Theoretical Investigations of the Autoxidation of Geranial: A Dioxolane Hydroperoxide Identified as a Skin Sensitizer

Abstract

The autoxidation of geranial with O(2) was studied both experimentally and using density functional theory. Computational results were used to interpret experimentally observed product ratios. Geranial was found to autoxidize, forming 6,7-epoxygeranial as the main oxidation product. Hydroperoxides corresponding to those identified as important skin sensitizers in previous studies of fragrance terpenes could not be detected. Instead, a dioxolan derivative and its corresponding hydroperoxide were identified and detected in high concentrations. The distribution of products in autoxidation generally depends on the stabilities of the intermediate peroxyl radicals. In this study, the formation of a peracyl radical was found to be highly favored. This radical forms peracid which epoxidizes geranial. The epoxide thus produced can react with acyl radical to yield the dioxolan hydroperoxide. The dioxolan derivative is believed to form in an acid catalyzed closed shell reaction between 6,7-epoxygeranial and geranial. The dioxolan hydroperoxide and 6,7-epoxygeranial are strong sensitizers and are considered to be the compounds mainly responsible for the skin sensitization potency of air-exposed geranial.

Can the epoxides of cinnamyl alcohol and cinnamal show new cases of contact allergy?

“…Activation of fragrance compounds to sensitizing epoxides has previously been seen for geranial, for which a highly sensitizing geranial epoxide is detected as the main product of both autoxidation and cutaneous metabolism of geranial . However, as the geranial epoxide has never been used in patch testing, the clinical importance of these findings has not been investigated.…”

“…5,6 Activation of fragrance compounds to sensitizing epoxides has previously been seen for geranial, for which a highly sensitizing geranial epoxide is detected as the main product of both autoxidation and cutaneous metabolism of geranial. 20,24 However, as the geranial epoxide has never been used in patch testing, the clinical importance of these findings has not been investigated. As the epoxides of cinnamyl alcohol and cinnamal studied here did not give many positive patch test reactions in patients with contact allergy to cinnamyl alcohol and cinnamal, it may be that these epoxides are not important metabolites of cinnamyl alcohol and cinnamal.…”

“…The epoxides identified in activation studies of cinnamyl alcohol have not been investigated clinically. Moreover, an increased sensitizing potency of cinnamal resulting from the formation of epoxycinnamal on air exposure, analogous to the formation of sensitizing epoxides seen for geranial, could also be expected …”

“…Moreover, an increased sensitizing potency of cinnamal resulting from the formation of epoxycinnamal on air exposure, analogous to the formation of sensitizing epoxides seen for geranial, could also be expected. 20 The aim of the present study was to investigate the clinical importance of epoxycinnamyl alcohol and epoxycinnamal in comparison with contact allergy to cinnamyl alcohol and cinnamal. Could the epoxides be important haptens in contact allergy to flavours and fragrances?…”

Evaluation of Different Electrochemical Transducers Based on Polystyrene Sulfonate – Carbon Composites with Nickel Catalyst for Rapid Detection of Fragrance Allergens

“…These substances have also bioactive properties [2]. Moreover, the allergic reactions can be enhanced as a consequence of the formation of highly allergenic oxidation products when these compounds are air-exposed [6]. Despite these excellent properties, some of them are potent allergens and can cause adverse reactions in humans by contact or inhalation [5].…”