Efforts to fully replace the OECD TG 404, were reinforced with the seventh Amendment of the Cosmetic Directive and the REAChregulation. In 2007, the EpiSkinalone method to discriminate skin irritants (R38) from non-irritants (no label) according to the definitionof the EU risk phrases. An ECVAM performance standards (PS) document was defined to evaluate theaccuracy and reliability of other analogous test methods (ECVAM SIVS, May 2007). The present testwas designed to determine the reliability and relevance of the Reconstructed Human Epidermis (RHE)model commercialized by SkinEthictopically the test substances for 42 min followed by a 42 h post-incubation. The main selected endpointwas the cell viability (MTT reduction), with a threshold of 50% viability. The RHE test method showed agood intra and inter-laboratory reproducibilities in a multicentric study involving three independent laboratories.The SkinEthicand a specificity of 80% (MTT only) and was not improved by integrating another endpoint such as IL-1the ECVAM Scientific Advisory Committee in November 2008, as a stand alone replacement test methodfor the Draize rabbit approach, for classifying non-irritant and irritant test substances, depending on countryrequirements.in vivo Draize skin irritation test, according to the Directive 67/548/ECC orTM test method was scientifically validated and recognized as the standTM. The RHE skin irritation test method consisted to topically applyTM RHE test method showed to be relevant and reliable with a sensitivity of 90%a. The overall accuracy was 85% resulting in the recognition of the SkinEthicTM RHE test method, byin vivo test, as a screen, or as part of a sequential testing strategy in a weight of evidence