02629nas a2200289   4500000000100000000000100001008004100002260000900043653002200052653001300074653000900087653001900096653003800115653001500153100001800168700002600186700002000212700002900232700001700261700002200278245010200300856006200402300001200464490000700476520184200483022001402325       2022                            d  c202210achemical analysis10ain vitro10aSkin10askin-on-a-chip10athree-dimensional skin cell model10aToxicology1 aEdith Filaire1 aRachida Nachat-Kappes1 aCamille Laporte1 aMarie-Françoise Harmand1 aMarina Simon1 aChristian Poinsot00aAlternative in vitro models used in the main safety tests of cosmetic products and new challenges  uhttps://onlinelibrary.wiley.com/doi/abs/10.1111/ics.12803  a604-6130 v443 aBackground Guided by ethical considerations and regulatory requirements such as the 7th Amendment to the European Cosmetics Directive N° 1223/2009, the cosmetic industry has developed and evaluated alternative test strategies such as in vitro assays, in silico approaches for toxicological endpoints and efficacy of cosmetic products and cosmetics ingredients. In consequence, the European Centre for the Validation of Alternative Methods (ECVAM) has proposed a list of validated cell-based in vitro models for predicting the safety and toxicity of cosmetic ingredients. These models have been demonstrated as valuable and effective tools to overcome the limitations of animal in vivo studies. For example, 3D human skin equivalent models are used to evaluate skin irritation potential; and excised human skin is used as the gold standard for the evaluation of dermal absorption. Objective This review presents, in relation to the regulatory requirements, the main alternative in vitro models used in the safety tests of cosmetic products, focusing on skin sensitization, skin corrosion, skin irritation and skin absorption, with advantages and limitations of each model. Recent innovative 3D cell technologies such as Organ-on-a-Chip (OoC) models that can bring significant improvements for toxicology and efficacy testing are also presented. Conclusion The development of OoC technology is promising for assessing the toxicity of substances contained in cosmetics, particularly for repeated dose toxicity, for which no alternative in vitro methods are currently available. Nevertheless, aside from the challenges, the technology needs to be validated and accepted by regulatory organizations as an effective method. Collaboration between researchers, regulatory organizations and industry would be required to achieve this validation.  a1468-2494