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

Abstract

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.

In vitro Percutaneous Absorption and in vivo Stratum Corneum Distribution of an Organic and a Mineral Sunscreen

“…Many other studies, in vitro and in vivo, with lipophilic organic filters [9] , insoluble TiO 2 [3,7] and the organic pigment MBBT [16] , have confirmed this distribution in the SC with 1 90% of the dose recovered in the first 5-15 tape strippings. In contrast, with Mexoryl SX [8] only 0.008 % of the applied dose was recovered in 16 tape strippings, and 91.9% was found at the skin surface.…”

“…In our work, in order to be closer to realistic conditions, indeed in maximized conditions, after application of the 2-mg/cm 2 sunscreen formulation no washing procedure was carried out, as is the case in percutaneous studies on sunscreens [3,7,16] . In these maximized conditions, the SC profile of the 2 sunscreens decreased with each tape stripping ( fig.…”

“…The quantities of MBBT were analyzed using HPLC, after extraction from the various skin compartments. A similar analysis was made for TiO 2 , with colorimetric assay, transmission electron microscopy (TEM) [3,4] and micro-PIXE (particle-induced X-ray emission) analysis [10] . The PIXE microbeam technique has recently been used to investigate the percutaneous penetration of TiO 2 in cross sections of pig skin [11] , providing qualitative and quantitative analyses of the distribution of TiO 2 in the skin.…”

“…Similar diffusion data were found with octyl methoxycinnamate and benzophenone 4 in a study comparing human and pig skin models [2] . The evaluation of the distribution of the mineral sunscreen titanium dioxide (TiO 2 ) showed that no penetration of TiO 2 microparticles was found in the viable skin tissue [3][4][5] , and ! 1% of the total amount applied [5] was found in the follicles.…”

Rhetorical gamesmanship in the nano debates over sunscreens and nanoparticles

“…After an exhaustive review of the literature, the majority of the research indicates that titanium oxide nanopigments do not cross the skin barrier, the stratum corneum (Mavon et al 2007;Nohynek et al 2007;Bütz et al 2005: Gamer et al 2006Roberts 2006;Dussert et al 1997;Lademann et al 1999;Pflücker et al 1999) transfollicular pathways notwithstanding (Gottbrath and Müller-Goymann 2003;Lekki et al 2007). Some NANODERM research makes the same claims in the cases of both healthy and skin compromised by acne and psoriasis (Pinheiro et al 2007).…”