The Outermost Stratum Corneum Layer is an Effective Barrier Against Dermal Uptake of Topically Applied Micronized...

In order to help clarify the controversially discussed dermal uptake properties of micronized titanium dioxide (TiO _ 2), we conducted extensive in vitro dermal absorption studies with 'Franz-type' diffusion cells on excised porcine skin. After biopsies and chemical fixation, the overall localization of TiO _ 2 in the skin was analyzed by means of transmission electron microscopy (TEM). The lateral and vertical distribution of TiO _ 2 within the stratum corneum (SC) was investigated by tape stripping and subsequent scanning electron microscopy (SEM) in combination with energy dispersive X-ray analysis (EDXA). TiO _ 2 was found exclusively on the outermost SC layer. The surface deposit, as displayed by TEM, featured clearly distinguishable agglomerates as well as single particles with a characteristic cubic shape and a primary particle size of about 20-50 nm. Concurrently, SEM/EDXA micrographs first showed an even distribution of TiO _ 2 on the skin surface. After 10-fold stripping, however, TiO _ 2 was found to be localized only in the furrows and not on the partially removed ridges of the skin surface. SEM/EDXA micrographs of the adhesive tape strips revealed a characteristic pattern of stripped material and free regions. This pattern was an imprint of the skin's topography. Hence, tape stripping initially removed TiO _ 2 and SC layers only from the ridges and not from the deeper furrows. Continued stripping increasingly yielded material from the deeper contours of the SC surface. TiO _ 2 was found only in traces in the upper part of the follicle without any evidence of uptake into the follicular epithelium. This indicates that there is not any relevant penetration via the follicular route. We conclude that due to the microtopography of the skin, the strip number normally does not reflect the SC layer number. Accordingly, tape stripping results should always be interpreted with care, especially in the case of topically applied particles, as even higher numbers of subsequent strips may still sample material from the outermost SC layer of the deeper furrows, which could be interpreted falsely as penetrated material. Our results clearly demonstrate that TiO _ 2 homogeneously and completely covers the outermost SC layer. It is neither delivered to the SC nor to the underlying skin layers when applied topically to porcine skin in vitro in the cosmetic vehicle used here. These findings underscore the safety of this micronized inorganic UV filter.