Activation of non‐sensitizing or low‐sensitizing fragrance substances into potent sensitizers – prehaptens and prohaptens

Abstract

SummaryExperimental and clinical studies have shown that fragrance substances can act as prehaptens or prohaptens. They form allergens that are more potent than the parent substance by activation outside or in the skin via abiotic (chemical and physical factors) and/or biotic activation, thus, increasing the risk of sensitization. In the present review a series of fragrance substances with well documented abiotic and/or biotic activation are given as indicative and illustrative examples of the general problem. Commonly used fragrance substances, also found in essential oils, autoxidize on contact with air, forming potent sensitizers that can be an important source for contact allergy to fragrances and fragranced products. Some of them can act as prohaptens and be activated in the skin as well. The experimental findings are confirmed in large clinical studies. When substances with structural alerts for acting as prohaptens and/or prehaptens are identified, the possibility of generating new potent allergens should be considered. Predictive testing should include activation steps. Further experimental and clinical research regarding activation of fragrance substances is needed to increase consumer safety.Key words: abiotic and biotic activation; autoxidation; directive 76/768/ECC; fragrance allergens; prehaptens; prohaptens; SCCS; scientific opinion.Many fragrance substances act as haptens, that is, low molecular weight chemicals that are immunogenic when attached to a carrier protein in the skin. This means that the substances can directly react with skin proteins, owing to inherent chemical properties. Experimental and clinical studies have shown that there are also fragrance substances that act as prehaptens or prohaptens, forming Accepted for publication 29 June 2013 allergens that are more potent than the parent substance by activation outside or in the skin via abiotic (chemical and physical factors) and/or biotic activation, and thus increasing the risk of sensitization.A prehapten is a chemical that is itself non-sensitizing or low-sensitizing, but that is transformed into a hapten outside the skin by chemical transformation (air

Assessment of Pre- and Pro-haptens Using Nonanimal Test Methods for Skin Sensitization

“…For instance, isoeugenol (4) and eugenol (9) are described to require biotic instead of abiotic activation. 21,34 In the underlying study, adducts were found and characterized for both chemicals in the DPRA, indicating both chemicals to be also susceptible to an abiotic activation.…”

Assessing skin sensitization hazard in mice and men using non-animal test methods

“…The probable protein-binding mechanisms were assigned by the OECD QSAR Toolbox v3.2. Protein-binding mechanisms described in the scientific literature were added to build a mechanistic chemistry framework for the 213 substances (Roberts and Aptula, 2014;Karlberg et al, 2013;Aptula et al, 2009Aptula et al, , 2007Aptula et al, , 2005Patlewicz et al, 2008;Roberts et al, 2007a) (Supplementary Table). For 11 substances, two possible protein-binding mechanisms were proposed to be probable.…”

“…MAs contain a,b-unsaturated ester, ketone or aldehyde functions. a,b-unsaturated alcohols can also react as MAs after the alcohol group is oxidized to an aldehyde (Karlberg et al, 2013). Due to their high probability to react as MAs, quinone precursors could also be placed into this domain (Aptula et al, 2009), but are handled as a separate substance domain on account of their specific structural characteristics.…”

“…Opposite to pro-haptens, the activation of pre-haptens could be prevented by precautionary measures in the handling and storage of the substances (Gerberick et al, 2008). Nevertheless, pre-and pro-haptens are not always distinct since autoxidation and metabolic oxidation can result in the same product, although the underlying mechanisms may differ (Karlberg et al, 2013). Since pre-haptens may also be pro-haptens and vice versa no distinction between substances requiring biotic and abiotic activation was made.…”

Mechanistic Understanding of Contact Allergy

“…Therefore, they are also called haptens (half-antigens) and are obligatory reactive (electrophilic or complex-forming). Some chemicals must be oxidized (pre-haptens) or metabolically converted (pro-haptens) to acquire chemical reactivity [1]. Chemical reactivity is the main feature that differentiates contact allergens from irritants.…”