Re: A Slippery Slope: Is Benzyl Alcohol a Contact Allergen?

In an Editorial [1], Aerts et al. (2025) point out that ‘new approach methodologies’ (NAMs) used to determine sensitisation potential, which I suppose encompass ‘non-animal technologies’ (NATs), fail to detect a known (although ‘weak’) contact allergen like benzyl alcohol, adding that this might signal a systemic flaw in methodology. First, do we know that it is benzyl alcohol that is the (weak) allergen? Or could it be a hitherto unsuspected impurity in the benzyl alcohol? Benzyl alcohol slowly oxidises to benzaldehyde and then to benzoic acid. And the benzaldehyde can react with benzyl alcohol to produce benzaldehyde dibenzyl acetal (BDBA) [2]. Benzaldehyde is at best only a weak sensitizer [3] notwithstanding its aldehydic ‘structural alert’ [4]. A patient [5] described by Mitchell and Beck (1988), who had evidently become sensitised to benzyl alcohol through occupational exposure, and who was found to react (2+) to benzyl alcohol (1% pet) on patch testing, produced a weaker reaction (+) to benzaldehyde (5% pet). So, metabolic conversion of benzyl alcohol to benzaldehyde in the skin would seem not to explain the contact sensitising/eliciting activity of benzyl alcohol. But we have here (and in many other reports) evidence that it is benzyl alcohol rather than any benzaldehyde that may be present as an impurity that is the contact sensitiser. BDBA has seemingly never been investigated as a possible contact allergen. Second, benzyl alcohol does display a ‘structural alert’ for contact allergenic potential, a structural alert that evidently has been overlooked or ignored by existing NAMs and NATs. That structural alert is the benzylic methylene group. BDBA also carries this structural alert. The benzylic methylene C–H bond dissociation energy (BDE) in benzyl alcohol is ~79 kcal/mol [6]. The low BDE makes the hydrogen atom relatively easy to remove homolytically. In other words, benzyl alcohol can act as an antioxidant, competing for this role in the skin with ascorbic acid (vitamin C; BDE 73–78 kcal/mol) [7] and with α-tocopherol (vitamin E; BDE 78 kcal/mol) [8], the principal aqueous phase and lipid phase endogenous chain-breaking antioxidants in our redoxome [9, 10]. This means that benzyl alcohol, on entering the skin, will compete with these endogenous antioxidants for a role as an antioxidant, especially in those patients whose diets are deficient in either or both of these two vitamins and/or who have developed a chronic systemic low-grade inflammatory (oxidative stress-related) condition with reduced availability of ‘reducing equivalents’ [11, 12]. α-Tocopheroxyl, the free radical species that is produced when vitamin E acts as an antioxidant is ‘repaired’ by vitamin C [10, 13]. The ascorbate radical produced from vitamin C is essentially unreactive when compared with other free radicals under physiological conditions, and it too is soon enzymically ‘repaired’ [10, 13]. But the radical species produced when benzyl alcohol gives up a hydrogen atom can then [presumably; this has never been formally investigated] alkylate proteins and thereby generate ‘foreign protein’ if not first quenched by one of the principal endogenous antioxidants vitamin C, vitamin E, or glutathione. This is the antioxidant hypothesis of prohapten activation as proposed by Schmidt in 2007 [14], and elaborated upon in 2022 [15], but already being contemplated in 1996/1997 [16, 17]. The field of oxidative stress biochemistry has more recently been conceptualised as the redoxome: ‘the network of redox reactions and redox active species (ReAS), involving carbohydrates, lipids, nucleic acids, proteins and other molecules and macromolecules that determine the redox environment of cells and tissues’ [18]. So, is the systemic flaw in methodology of NAMs/NATs to which Aerts et al. (2025) allude no more than a failure to take into account the capacity of penetrating xenobiotics to perturb the redoxome/redox homeostasis in the skin and a failure to take into account the physiological circumstances that might adversely predispose an individual to such perturbation/disruption of redox homeostasis? Richard J. Schmidt: conceptualization, writing – review and editing, writing – original draft. The author declares no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.