Preliminary evaluation of ex vivo and in vivo skin permeability of aromatic amines

A potential link has been reported between skin exposure to aromatic amines, such as ortho-toluidine (OT) and 3,3'-dichloro-4,4'-diaminodiphenylmethane (MOCA), and bladder cancer cases observed in Japanese chemical factories. To evaluate this association, we explored the permeability of OT and MOCA through pig skin and investigated the subsequent changes in plasma and urine concentrations in rats following percutaneous exposure. Employing Yucatan micropig skin, we first executed a permeability test by affixing the skin to a diffusion cell and applying 14C-labeled OT or MOCA. The receptor fluid's radioactivity was quantified at intervals of 1, 3, 6, 8, 24, and 48 h after application using a liquid scintillation counter. Next, we applied lint cloths drenched in OT and MOCA solutions to the backs of 7-week-old male F344 rats and monitored plasma and urine concentrations over time. Additionally, we investigated the pharmacokinetics of 14C-labeled OT or MOCA solutions for 8 h following percutaneous administration. Both OT and MOCA demonstrated high skin penetration; in particular, plasma concentrations significantly rose at 6 h for OT and 8 h for MOCA after exposure. However, OT was rapidly absorbed into the bloodstream and swiftly excreted into the urine, indicating quick absorbability. In contrast, MOCA penetrated the skin quickly but exhibited delayed bloodstream entry and urinary excretion, suggesting slower absorbability. Pharmacokinetic findings revealed the rapid urinary excretion of OT, whereas MOCA was excreted in the urine and potentially in the feces as well via bile. These findings indicate that implementing measures based on chemical absorbability could significantly enhance the management of industrial chemicals where percutaneous absorbability is a concern.