A recent study conducted by the Japanese National Institute of Health Sciences (NIHS) has provided new support for the safety of titanium dioxide as a food additive, finding no toxic effects associated with oral consumption.

Titanium dioxide has been a contentious topic among the food industry in recent years. In 2019, in response to a French proposal to reevaluate the substance, the European Commission reclassified titanium dioxide as a as a category 2 carcinogen, especially when exposed to the substance by inhalation in powder form containing 1 percent or more of particles of a diameter equal to or below 10 micrometers (μm). The European Food Safety Authority (EFSA) subsequently banned its use in foods as of summer 2022. However, in November 2022, the Court of Justice of the EU ruled to annul the Commission’s classification of titanium dioxide as a carcinogen, calling into question the reliability and acceptability of the study on which the decision was based.

Additionally, although other national food regulatory bodies—such as Health Canada, Food Standards Australia New Zealand (FSANZ), the U.S. Food and Drug Administration (FDA), and the UK Food Standards Agency (FSA)—have maintained the position that titanium dioxide is safe, the chemical was targeted by a 2023 California Assembly bill aiming to ban toxic chemicals from foods sold in the state. However, titanium dioxide was dropped from the bill’s list of targeted substances before passing the Senate, based on FDA’s opinion that it is safe as a regulated color additive in foods.

The Joint FAO/WHO Expert Committee on Food Additives (JECFA) also previously evaluated the safety of titanium dioxide and decided not to establish a limit for oral intake.

The present NIHS study was conducted to add to the body of knowledge about the food safety of titanium dioxide. Specifically, the study addresses a concern raised by EFSA about an existing data gap for nanoparticles of titanium dioxide, leaving room for the possibility that the chemical is genotoxic. In a 2022 opinion, the French Agency for Food, Environmental and Occupational Health and Safety (ANSES) also called attention to the lack of data on titanium dioxide’s safety for particles smaller than 10 nanometers (nm).

For the study, NIHS researchers evaluated a sensitive key marker for DNA strand breaks and a conventional genotoxicity endpoint (micronuclei). The toxicological effects of the smallest available titanium dioxide nanoparticles with a crystallite size of 6 nm were examined in male and female rats by repeated oral administration of 10, 100, and 1000 miligrams per kilogram of bodweight per day (mg/kg bw/day) for 28 days, and of 100, 300, and 1000 mg/kg bw/day for 90 days.

Independent measurements showed that the particle size used in the study—6 nm—is 16 times smaller than the average particle diameter of titanium dioxide used as a food additive. A dispersant was used in the preparation of the mice feed to prevent particle agglomeration and to maximize exposure to the particles. The study was carried out according to Organization for Economic Cooperation and Development (OECD) standards.

Overall, in both 28- and 90-day studies, no mortality or adverse effects were observed after repeated oral administration of titanium dioxide with a crystallite size of 6 nm at up to 1000 mg/kg bw/day regarding general toxicity; accumulation of titanium in the liver, kidneys, and spleen; abnormality of colonic crypts; and induction of DNA strand breaks and chromosomal aberrations.