A comparative study of skin irritation caused by novel bis-quaternary ammonium compounds and commonly used antiseptics by using cell culture methods

New bis-quaternary ammonium compounds (bis-QACs) 3-(3-hydroxy-2-(hydroxymethyl)-2-{[(1-dodecylpyridinium-3-yl)oxy]methyl}propoxy)-1-dodecylpyridinium dibromide (3HHDMP-12) and 3,3'-[1,4-phenylenebis(oxy)]bis(1-dodecylpyridinium) dibromide (3PHBO-12) were compared with commonly-used antiseptics such as benzalkonium chloride (BAC), octenidine dihydrochloride (OCT), chlorhexidine digluconate (CHG) and polyhexamethylene biguanide (PHMB), to evaluate their potential to cause skin irritation. The cytotoxicity of these compounds in various cultured cells, as well as their effect on the expression of inflammatory cytokine genes such as IL-1α were evaluated. The cytotoxic effect of these bis-QACs on several types of human-derived cells was lower than that of common quaternary ammonium compounds (BAC and OCT), although the bis-QACs showed higher cytotoxicity than the biguanide-based compounds (CHG and PHMB). In addition, IL-1α mRNA expression was more strongly induced by BAC and OCT than by the new bis-QACs, at concentrations below the IC₅₀ obtained in normal human epidermal keratinocytes. Furthermore, even at the actual therapeutic concentration, the new bis-QACs did not alter inflammatory cytokine mRNA expression or IL-1α secretion as demonstrated using the reconstructed human epidermis model LabCyte EPI-MODEL. The results suggested that the potential of 3PHBO-12 and 3HHDMP-12 to induce skin irritation is comparable to or less than that of existing antiseptics, and these bis-QACs may be useful antiseptics with few side effects.