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

Our novel para-phenylenediamine (PPD)analogues, with enhancedoxidation potential, represent safer alternatives as permanent hairdyes. Besides working even in the absence of strong oxidizers andbeing nontoxic and nonallergenic, they are also expected to be nonhazardousto the environment when disposed, as they do not undergo uncontrolledpolymerizations (as in the case of conventional PPD activated withstrong oxidizers and couplers). Mostpermanent hair dyes include the hair color precursorpara-phenylenediamine(PPD). It is also, regrettably, a well-recognized powerful contactallergen that, when exposed to the skin, may cause severe allergiccontact 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 inPPD-sensitive people, making them less-than-ideal dyes. Due to thehigh risk of severe allergy with PPD and the effect in the environmentdue to the uncontrolled polymerizations associated with the dyeingprocess, its use in cosmetic products has been criticized, clearlyhighlighting the dire need for suitable nontoxic alternatives to PPD.In this study, through the structural modification of PPD, we designedhair dye precursors that were both nontoxic and preserved good dyeingproperties while minimizing eventual toxicity to people and the environment.The modifications were based on (a) the addition of electron-donating-O-R & PRIME; chains with polar functional groups at the ortho position that decrease binding affinity to nucleophilicskin proteins and (b) inclusion of hydrophilic functional groups inPPD to improve solubility. The in vitro experimentssuch as the MTT assay, direct peptide reactivity assay (DPRA), humancell line activation test, vertical Franz diffusion cell, and hairnuance tests were performed on six novel aromatic amine compounds( G1 -G6) to investigatetheir 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 & mu;M, DPRA values between19.5 & PLUSMN; 3.6% and 22.5 & PLUSMN; 3.8%, without inducing IL-8 expression)and could dye hair dark even without an oxidizer (& UDelta;E values within 2.43-5.73). All compounds were roughly 3 ordersof magnitude less permeable to the skin than PPD, indicating limitedaccumulation at the epidermis and consequently avoidance of immunecell activation. Taken together, these novel PPD derivatives representpromising permanent hair dyes as safer and sustainable alternativesto PPD.