Small Molecule Para-Phenylenediamine Analogues with Enhanced Oxidation Potential as Viable Permanent Hair Dyes

Most permanent hair dyes include the hair color precursor para-phenylenediamine (PPD). It is also, regrettably, a well-recognized powerful contact allergen that, when exposed to the skin, may cause severe allergic contact dermatitis as well as systemic responses that might be life-threatening. Para-toluenediamine (PTD) and 2-methoxymethyl-p-phenylenediamine (ME-PPD) are less sensitizing PPD substitutes that have been put on the market, but they have also shown significant rates of cross-reactivity in PPD-sensitive people, making them less-than-ideal dyes. Due to the high risk of severe allergy with PPD and the effect in the environment due to the uncontrolled polymerizations associated with the dyeing process, its use in cosmetic products has been criticized, clearly highlighting the dire need for suitable nontoxic alternatives to PPD. In this study, through the structural modification of PPD, we designed hair dye precursors that were both nontoxic and preserved good dyeing properties while minimizing eventual toxicity to people and the environment. The modifications were based on (a) the addition of electron-donating −O-R′ chains with polar functional groups at the ortho position that decrease binding affinity to nucleophilic skin proteins and (b) inclusion of hydrophilic functional groups in PPD to improve solubility. The in vitro experiments such as the MTT assay, direct peptide reactivity assay (DPRA), human cell line activation test, vertical Franz diffusion cell, and hair nuance tests were performed on six novel aromatic amine compounds (G1–G6) to investigate their cytotoxicity profile, sensitizing potential, skin permeability, and hair dyeing efficiency. Notably, compounds G1–G3, with O-alkyl hydroxyl chains, were safer than their precursor (IC₅₀ = 218.9–282.8 μM, DPRA values between 19.5 ± 3.6% and 22.5 ± 3.8%, without inducing IL-8 expression) and could dye hair dark even without an oxidizer (ΔE values within 2.43–5.73). All compounds were roughly 3 orders of magnitude less permeable to the skin than PPD, indicating limited accumulation at the epidermis and consequently avoidance of immune cell activation. Taken together, these novel PPD derivatives represent promising permanent hair dyes as safer and sustainable alternatives to PPD.