title: Structure-Potency Relationships for Epoxides in Allergic Contact Dermatitis.
abstract: Epoxides are known or proposed to be involved in skin sensitization in various ways. Some are encountered directly, and others have been shown to be formed abiotically and metabolically from various unsaturated chemicals. They can react as SN2 electrophiles. To date no quantitative mechanistic models (QMMs) are known for skin sensitization potency of this subcategory of SN2 electrophiles. Here we have considered the reaction mechanistic chemistry of epoxides and combined published experimental kinetic data (rate constants k for reaction with a cysteine-based peptide) together with calculated hydrophobicity data (logP) to derive a QMM correlating potency in the local lymph node assay (LLNA), expressed as EC3, with a relative alkylation index (RAI, calculated as logk + 0.4 logP). The QMM equation, pEC3 = 2.42(±0.26) RAI + 4.04 (±0.25), n = 9, R2= 0.928, R2(adj) = 0.917, F = 90, s = 0.18, fits the data well, with one positive outlier. The outlier can be rationalized by its exhibiting an alert for oxidation of an amine moiety to give, in this case, the highly reactive glycidaldehyde. The epoxide QMM predicts the potency of a nonepoxide SN2 electrophile (predicted EC3, 0.48%; observed EC3, 0.5%), which suggests that it could form the basis for a more general H-polar SN2 QMM that could be a valuable tool in skin sensitization risk assessment for this quite extensive and structurally diverse reaction mechanistic domain.
authors.affiliation: School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University , Liverpool L3 3AF, United Kingdom.
authors.forename: David W
authors.initials: DW
authors.lastname: Roberts
authors.affiliation: Unilever Safety and Environmental Assurance Centre, Colworth Science Park, Sharnbrook, Bedford MK44 1LQ, United Kingdom.
authors.forename: Aynur
authors.initials: A
authors.lastname: Aptula
authors.affiliation: Research Institute for Fragrance Materials, Inc. , 50 Tice Boulevard, Woodcliff Lake, New Jersey 07677, United States.
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Api
mesh_terms: D000818:Animals; D017449:Dermatitis, Allergic Contact / Q000209:etiology*; D004852:Epoxy Compounds / Q000737:chemistry* / Q000633:toxicity*; D006801:Humans; D008962:Models, Theoretical; D013329:Structure-Activity Relationship
chemical_list: D004852:Epoxy Compounds