The most significant uncertainty identified by the EU experts was the concern that TiO₂ particles may have genotoxic effects. Genotoxicity refers to the ability of a chemical to directly damage genetic material within a cell (DNA), which may lead to cancer in certain situations. Although the experts did not conclude that TiO₂ particles in E171 are genotoxic, they could not rule out the concern that they might be.

In vitro, in the hemocytes of the marine mussel Mytilus hemocytes, suspension of TiO₂ NPs (Degussa P25, 10 μg/ml) stimulated immune and inflammatory responses, such as lysozyme release, oxidative burst and nitric oxide production. Vevers and Jha demonstrated the intrinsic genotoxic and cytotoxic potential of TiO₂ NPs on a fish-cell line derived from rainbow-trout gonadal tissue (RTG-2 cells) after 24 h of exposure to 50 μg/ml. Reeves et al. demonstrated a significant increase in the level of oxidative DNA damage in goldfish cells, and suggested that damage could not repaired by DNA repair mechanisms. Another suggestion from the mentioned study was that hydroxyl radicals are generated also in the absence of UV light. It has been shown that fish cells are generally more susceptible to toxic/oxidative injury than mammalian cells.