<p>A review of <i>in vitro</i> genotoxicity studies on titanium dioxide nanoparticles (TiO<sub>2</sub>-NPs) published between 2010 and 2016 was performed by France in the framework of the CLP Regulation 1272/2008/EC. Neither the few <i>in vivo</i> studies of low quality nor the larger number of acceptable <i>in vitro</i> studies available for genotoxicity allowed France to conclude on the genotoxicity of TiO<sub>2</sub>-NPs. Based on this work, it was decided to compare the acceptable <i>in vitro</i> studies to understand the reasons for the diverging results observed, such as the materials tested or of the protocols used and their inherent interferences. The systematic review performed on <i>in vitro</i> genotoxicity data for TiO<sub>2</sub>-NPs was then restricted to studies with the highest level of confidence among studies following OECD guidelines and the largely applied comet assay. Indeed, the aim of this article is to understand why, even if judged of good quality, the 36 publications selected and analyzed did not lead to a clear picture. Some recommendations to be taken into account before performing new <i>in vitro</i> genotoxicity assays for insoluble particles such as TiO<sub>2</sub>-NPs are proposed. Although secondary genotoxic effects consequent to oxidative stress seem to be the major mechanism responsible for the genotoxicity of TiO<sub>2</sub>-NPs reported in some studies, primary genotoxic effects cannot be excluded. Further studies are needed to clarify the exact mode of action of TiO<sub>2</sub>-NPs and to highlight which physicochemical properties lead to their genotoxicity <i>in vitro</i> to ultimately identify a specific combination of parameters that could represent a risk <i>in vivo.</i></p
