Safety assessment of titanium dioxide (E171) as a food additive

The present opinion deals with an updated safety assessment of the food additive titanium dioxide (E&nbsp;171) based on new relevant scientific evidence considered by the Panel&nbsp;to be reliable, including data obtained with TiO2&nbsp;nanoparticles (NPs) and data from an extended one-generation reproductive toxicity (EOGRT) study. Less than 50% of constituent particles by number in E&nbsp;171 have a minimum external dimension &lt; 100 nm. In addition, the Panel&nbsp;noted that constituent particles &lt; 30 nm amounted to less than 1% of particles by number. The Panel&nbsp;therefore considered that studies with TiO2&nbsp;NPs &lt; 30 nm were of limited relevance to the safety assessment of E&nbsp;171. The Panel&nbsp;concluded that although gastrointestinal absorption of TiO2&nbsp;particles is low, they may accumulate in the body. Studies on general and organ toxicity did not indicate adverse effects with either E&nbsp;171 up to a dose of 1,000 mg/kg body weight (bw) per day or with TiO2&nbsp;NPs (&gt; 30 nm) up to the highest dose tested of 100 mg/kg bw per day. No effects on reproductive and developmental toxicity were observed up to a dose of 1,000 mg E 171/kg bw per day, the highest dose tested in the EOGRT study. However, observations of potential immunotoxicity and inflammation with E&nbsp;171 and potential neurotoxicity with TiO2&nbsp;NPs, together with the potential induction of aberrant crypt foci with E&nbsp;171, may indicate adverse effects. With respect to genotoxicity, the Panel&nbsp;concluded that TiO2&nbsp;particles have the potential to induce DNA strand breaks and chromosomal damage, but not gene mutations. No clear correlation was observed between the physico-chemical properties of TiO2&nbsp;particles and the outcome of either&nbsp;in&nbsp;vitro&nbsp;or&nbsp;in&nbsp;vivo&nbsp;genotoxicity assays. A concern for genotoxicity of TiO2&nbsp;particles that may be present in E&nbsp;171 could therefore not be ruled out. Several modes of action for the genotoxicity may operate in parallel and the relative contributions of different molecular mechanisms elicited by TiO2&nbsp;particles are not known. There was uncertainty as to whether a threshold mode of action could be assumed. In addition, a cut-off value for TiO2&nbsp;particle size with respect to genotoxicity could not be identified. No appropriately designed study was available to investigate the potential carcinogenic effects of TiO2&nbsp;NPs. Based on all the evidence available, a concern for genotoxicity could not be ruled out, and given the many uncertainties, the Panel&nbsp;concluded that E&nbsp;171 can no longer be considered as safe when used as a food&nbsp;additive.</p