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.

The evidence also suggests that the toxicity of TiO₂ particles may be reduced when eaten as part of the diet. This is because proteins and other molecules in a person's diet can bind to the TiO₂ particles. This binding alters the physical and chemical properties of the particles, which influences how they interact with cells, tissues and organs.

Lithopone was developed in the 1870s as a substitute for lead carbonate (lead white), to overcome its drawbacks of toxicity and poor weathering resistance. Within a few years, titanium dioxide displaced lithopone to become the white pigment (PW6) par excellence in the industry and the world’s best-selling inorganic pigment. However, titanium is a product whose price is subject to large price variations due to product availability. These price increases affect the competitiveness of finished products, and so the search for an alternative to titanium dioxide has generated a variety of possibilities to optimise its use.