Approaches to assess the role of absorption, metabolism and excretion of cosmetic ingredients that are based on
the integration of different in vitro data are important for their safety assessment, specifically as it offers an
opportunity to refine that safety assessment. In order to estimate systemic exposure (AUC) to aromatic amine
hair dyes following typical product application conditions, skin penetration and epidermal and systemic metabolic
conversion of the parent compound was assessed in human skin explants and human keratinocyte
(HaCaT) and hepatocyte cultures. To estimate the amount of the aromatic amine that can reach the general
circulation unchanged after passage through the skin the following toxicokinetically relevant parameters were
applied: a) Michaelis–Menten kinetics to quantify the epidermal metabolism; b) the estimated keratinocyte
cell abundance in the viable epidermis; c) the skin penetration rate; d) the calculated Mean Residence Time in
the viable epidermis; e) the viable epidermis thickness and f) the skin permeability coefficient. In a next step,
in vitro hepatocyte Km and Vmax values and whole liver mass and cell abundance were used to calculate the scaled
intrinsic clearance, which was combined with liver blood flow and fraction of compound unbound in the blood to
give hepatic clearance. The systemic exposure in the general circulation (AUC) was extrapolated using internal
dose and hepatic clearance, and Cmax was extrapolated (conservative overestimation) using internal dose and
volume of distribution, indicating that appropriate toxicokinetic information can be generated based solely on
in vitro data. For the hair dye, p-phenylenediamine, these data were found to be in the same order of magnitude
as those published for human volunteers