Schäfer-Korting1, M., Bock2, U., Diembeck3, W., Düsing3, H-J., Gamer4, A., Haltner-Ukomadu2, E., Hoffmann5, C., Kaca2, M., Kamp4, H., Kersen6, S., Kietzmann7, M., Korting8, H.C., Krächter9, H-U., Lehr10, C-M., Liebsch11, M., Mehling9, A., Müller-Goymann5, C., Netzlaff10, F., Niedorf7, F., Rübbelke8, M.K., Schäfer10, U., Schmidt11, E., Schreiber1, S., Spielmann11, H., Vuia1, A., and Weimer6, M. 1Freie Universität Berlin, Institut für Pharmazie, Berlin, Germany; 2Across Barriers GmbH, Saarbrücken, Germany; 3Beiersdorf AG, Hamburg, Germany; 4BASF Aktiengesellschaft, Experimental Toxicology & Ecology, Ludwigshafen, Germany; 5Technische Universität Carolo-Wilhelmina zu Braunschweig, Institut für Pharmazeutische Technologie, Braunschweig, Germany; 6Fraunhofer Institut für Grenzflächen- & Bioverfahrenstechnik, Stuttgart, Germany; 7Stiftung Tierärztliche Hochschule Hannover, Institut für Pharmakologie, Toxikologie & Pharmazie, Hannover, Germany; 8Ludwig-Maximilians-Universität München, Klinik & Poliklinik für Dermatologie & Allergologie, Munich, Germany; 9Cognis Deutschland GmbH & Co. KG, Düsseldorf, Germany; 10Universität des Saarlandes, Biopharmazie & Pharmazeutische Technologie, Saarbrücken, Germany; 11Zentralstelle zur Erfassung & Bewertung von Ersatz- & Ergänzungsmethoden zum Tierversuch (ZEBET) am Bundesinstitut für Risikobewertung, Berlin, Germany.

This formal validation study by scientists at the Freie Universität Berlin, Across Barriers GmbH, Beiersdorf AG, BASF Aktiengesellschaft, Technische Universität Carolo-Wilhelmina zu Braunschweig, Stiftung Tierärztliche Hochschule Hannover, Ludwig-Maximilians-Universität München, Cognis Deutschland GmbH & Co. KG, Universität des Saarlandes and ZEBET demonstrated that MatTek’s EpiDerm in vitro human skin tissue equivalent is an appropriate alternative to human and pig skin for the in vitro assessment of the permeation and penetration of substances when applied as aqueous solutions. A formal validation study was performed in order to investigate whether the commercially available reconstructed human epidermis (RHE) models EPISKIN®, EpiDerm™ and SkinEthic® are suitable for in vitro skin absorption testing. The skin types currently recommended in the OECD Test Guideline 428, namely, ex vivo human epidermis and pig skin, were used as references. Based on the promising outcome of the pre-validation study, the panel of test substances was enlarged to nine substances, covering a wider spectrum of physicochemical properties. The substances were tested under both infinite-dose and finite dose conditions in ten laboratories under strictly controlled conditions. The data were subjected to independent statistical analyses. Intra-laboratory and inter-laboratory variability contributed almost equally to the total variability which was in the same range as that in preceding studies. In general, permeation of the RHE models exceeded that of human epidermis and pig skin (the SkinEthic RHE was found to be the most permeable), yet the ranking of substance permeation through the three tested RHE models and the pig skin reflected the permeation through human epidermis. In addition, both infinite-dose and finite-dose experiments are feasible with RHE models. The RHE models did not show the expected significantly better reproducibility as compared to excised skin despite a tendency toward lower variability of the data. Importantly, however, the permeation data showed a sufficient correlation between all the preparations examined. Thus, the RHE models, EPISKIN, EpiDerm and SkinEthic are appropriate alternatives to human and pig skin for the in vitro assessment of the permeation and penetration of substances when applied as aqueous solutions.


Benzoic acid, Caffeine, Clotrimazole, Digoxin, EPI-606-X, EpiDerm, EpiSkin®, Flufenamic acid, Human skin, Ivermectin B1a, Lag-time, Mannitol, Nicotine, OECD Test guidline 428, Octanol-water partition coefficient, Permeation, Permeation coefficient (Papp), Pig skin, Skin absorption, SkinEthic®, Testosterone

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