Titanium dioxide (TiO₂), previously banned as a food additive (E 171) in 2022 due to safety concerns, is used in medicines as an excipient. French scientists have estimated the intake of TiO₂ from oral medications, finding that 54% contained TiO₂, with an average daily intake of 1.71 mg. This is lower compared to the exposure from food when E 171 was still allowed. The European Medicines Agency (EMA) warns that an immediate ban on TiO2 in medicine could lead to shortages. The European Commission is expected to give more clarity on the use of TiO₂ as excipient in medicines by 2025.

The use of E 171 in food and medicines

The food additive E 171, which contains poorly soluble TiO₂ nanoparticles, has been banned in food products within the EU European Union (European Union ) since 2022. The European Food Safety Authority (EFSA) concluded that it cannot guarantee the safety of this substance, as the potential for genotoxicity cannot be ruled out. Because TiO₂ is used as an excipient in medicines, people in the EU are still orally exposed to it through this source.

Estimated daily intake of TiO₂ through medicines in France

French scientists estimated the intake of TiO₂ from oral medications available in the French market between 2012 and 2020. They calculated the intake based on reported or estimated concentrations of TiO₂ in medicines, and information about their use from health insurance reimbursements. The study found that 54% of these oral medications contained TiO₂, particularly in capsules (95%) and film-coated tablets (92%). They calculated the average daily intake of TiO₂ to be 1.71 mg, with variations by gender and age – 1.81 mg/day for women, 1.54 mg/day for men, 0.21 mg/day for individuals under 20, and 4.00 mg/day for adults over 59. It is important to note that the estimated intake may underestimate the actual exposure by about 30%, according to the authors, as not all medicines are claimed for reimbursement. On the other hand, some reimbursed medications may not actually be used.

Alternatives for TiO₂ in medicine: balancing quality and safety

The use of food additives as excipients in medicines is currently coupled with their admission to be used as food additives. Although the food additive E 171 was banned in 2022, an exemption was made for its use in medicines(). This exemption must be reevaluated after three years. At present, there are no suitable alternatives that offer the same unique combination of properties as TiO₂. For example, while providing a white colour to medicinal products, TiO2 also protects against UV light and improves opacity. Compared to other excipients, TiO₂ also allows for a thinner, less fragile outer layer of a tablet. Thus, according to the European Medicines Agency (EMA)(PDF), TiO₂ is important for maintaining the quality of medicinal products.

Possible consequences of banning TiO₂ from medicines

According to the EMA, an immediate ban on the use of TiO₂ in medication could lead to shortages or even removal of certain medicines from the market, which could have significant consequences for patients. Possible alternatives for TiO₂, such as calcium carbonate, talc and starch would have to be investigated. The influence of such a change on the quality, safety and efficacy of these formulations requires reassessment by regulatory authorities. This process might affect a large number of medicines and could take a long time. In 2025, the European Commission is expected to present new information on the use of TiO₂ in medicines.

Reflections by RIVM

The level of exposure to TiO₂ from medicines has not been estimated before. The French study provides the first estimate of this exposure, reporting an average intake. However, individual intake can vary significantly depending on medication use, the study’s data do not allow for this distinction.

The average daily intake through medicines is roughly 0.02 mg TiO₂ per kilogram of body weight. When E 171 was still permitted in food, RIVM, in collaboration with RIKILT, estimated the realistic intake of E 171 from food (and food supplements). From those sources, the median intake was 0.25 mg/kg for children aged 2-6 years, 0.08 mg/kg for individuals aged 7-69 years, and 0.03 mg/kg for the elderly (over 69 years). This suggests that exposure to TiO₂ through food was higher than the current exposure levels through medicine, and decreased with age rather than increased.

For food additives, uncertainty about a possible risk can lead to banning their use. In contrast, for medicines, a benefit-risk evaluation must be performed, which means that certain risks may be considered acceptable. The replacement of TiO₂ as an excipient in medicine would have severe implications for the availability of medicines. For the time being, the EMA is reminding applicants to do everything possible to expedite the research and development of alternatives to TiO₂.

Read the Dutch summary: Geschatte inname van titaniumdioxide via medicijnen