Updated assessment of the genotoxic potential of titanium dioxide based on reviews of in vitro comet, mode of action and cellular uptake studies, and recent publications

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In 2021 the European Food Safety Authority (EFSA) concluded that “ A concern for genotoxicity of TiO2 particles that may be present in E 171 could therefore not be ruled out. ”. A detailed review of the genotoxicity of titanium dioxide (TiO 2 ) was subsequently published by Kirkland et al. (2022) using a comprehensive weight of evidence (WoE) approach in which test systems and endpoints were allocated different levels of relevance. At that time only 34 publications met the reliability and quality criteria for being most relevant in the evaluation of genotoxicity, and based on these it was concluded that the existing evidence did not support a direct DNA damaging mechanism for TiO 2 . Recently a number of regulatory opinions have been published, in which papers were cited that described in vitro DNA damage (mainly comet), mode of action, and cellular uptake studies that were not discussed in Kirkland et al. (2022) . Furthermore, a number of additional papers have been published recently or have been identified from the regulatory opinions as a result of using extended search criteria. A total of 70 publications not previously reviewed in Kirkland et al. (2022) have been reviewed here, and again show that the published data on the genotoxicity of TiO 2 are inconsistent, often of poor quality, and in some cases difficult to interpret. The cellular uptake studies show some evidence of cytoplasmic uptake, particularly in cells treated in vitro , but there is no convincing evidence of nuclear uptake. In terms of genotoxicity, the conclusions of Kirkland et al. (2022) that existing evidence does not support a direct DNA damaging mechanism for titanium dioxide (including nano forms), and that the main mechanism leading to TiO 2 genotoxicity is most likely indirect damage to DNA through generation of reactive oxygen species (ROS), are still valid. • EFSA have banned titanium dioxide in foods due to concerns over genotoxicity • An additional weight of evidence analysis was performed on genotoxicity data for TiO 2 , updating with new studies since the 2022 review as well as including in vitro comet, mechanistic data and exposure studies, 70 additional publications were assessed. • Published data on the genotoxicity of TiO 2 are inconsistent, often of poor quality, and in some cases difficult to interpret. • Cellular uptake studies show some evidence of cytoplasmic uptake, particularly in cells treated in vitro , but there is no convincing evidence of nuclear uptake. • Review of an additional 70 publications does not change the 2022 conclusion that existing evidence does not support a direct DNA damaging mechanism for titanium dioxide (including nano forms), and that the main mechanism leading to TiO 2 genotoxicity is most likely indirect damage to DNA through generation of reactive oxygen species (ROS).