ECJ upholds overturning of titanium dioxide’s classification as “probably carcinogenic when inhaled”

Titanium dioxide (TiO₂short fortitanium dioxide) is produced worldwide in millions of tonnes. Most of the TiO₂short fortitanium dioxide produced is used in technical applications such as for the manufacture of paints, coatings, paper, and plastics. Under the name CI 77891, the substance is used as a white pigment in cosmetic products such as toothpaste. TiO₂short fortitanium dioxide is also used as a filter in sunscreens to protect against ultraviolet radiation. Until 2022, TiO₂short fortitanium dioxide was also approved as food additive E 171.

The current state of research on TiO₂short fortitanium dioxide with regard to genotoxicity (damage to genetic material) and carcinogenicity (cancer-causing potential) is complex and inconclusive.

In its 2021 risk assessment, the European Food Safety Authority (EFSAshort forEuropean Food Safety Authority) concluded that genotoxic potential of TiO₂short fortitanium dioxide cannot be ruled out. The remaining uncertainty led to TiO₂short fortitanium dioxide being withdrawn as food additive E 171 throughout the EU. Since 8 August 2022, foods containing E 171 may no longer be placed on the market.

In 2006, the International Agency for Research on Cancer (IARC) classified TiO₂short fortitanium dioxide as “possibly carcinogenic to humans” (Category 2B). This classification is based on animal studies in which lung cancer was detected after inhalation of high doses of respirable TiO₂short fortitanium dioxide particles (< 10 μm).

Under the CLP Regulation (EC) No. 1271/2008, which regulates the classification, labelling, and packaging of chemicals throughout the EU, the EU Commission harmonised the classification of TiO₂short fortitanium dioxide in powder form in 2020 as “probably carcinogenic when inhaled” (Category 2, H351i). A harmonised classification is a legally binding classification of a substance, which is then included in Annex VI of the CLP Regulation. However, the harmonised classification for carcinogenic effects referred exclusively to the inhalation of respirable particles. 

This decision was overturned by the Court of Justice of the European Union (CJEU) in 2022 as the underlying scientific studies had methodological weaknesses (e.g. insufficient consideration of lung overload and particle properties). An appeal was then filed against this ruling.

In this context, it is important to distinguish between risk assessment and an assessment of hazard potential. A risk assessment always considers harmful effects on human health (potential hazards) along with an exposureClose dialogexposureExposureTo glossary assessment (including investigation of exposure routes, amounts, duration, etc.). For classification in accordance with the CLP Regulation, only the hazard potential is considered. Classification is based on hazard classes (i.e. what harmful effects are possible) and hazard categories (severity of the possible damage). Assessments according to the CLP Regulation are not risk assessments and do not allow any general conclusions to be drawn regarding an actual health risk.

The study situation for TiO₂short fortitanium dioxide is unclear and ambiguous for several reasons. Existing studies differ in methodology. Some studies are based on research carried out through animal testing (in vivo), while others describe examinations of cells cultivated in the laboratory (in vitro). The TiO₂short fortitanium dioxide particles examined also differ in various particle properties, such as particle size, crystal structure, and/or surface coating. Furthermore, there are differences in the studies with regard to the exposure routes considered (oral, dermal, inhalation), the specific doses administered, and the form of administration.

Particle-specific characteristics must not only be taken into account in the subsequent evaluation of the studies, but should already be considered in the study design and implementation. This is not always done to a sufficient extent. The evaluation of studies involving particles is therefore always more time-consuming and complicated/complex than comparable studies involving soluble substances.

In 2022, the CJEU criticised methodological uncertainties in the studies that served as the basis for the European Commission's legal classification. For example, the ruling objected to the notion that TiO₂short fortitanium dioxide has the intrinsic property of causing cancer. TiO₂short fortitanium dioxide only has carcinogenic potential under very specific conditions (e.g. the presence of respirable particles in large quantities combined with simultaneous overload of the lung's clearance mechanism). The court emphasises the need to clearly distinguish between mechanisms of action in humans and context-dependent effects (e.g. particle toxicity),.

The German Federal Institute for Risk Assessment (BfRshort forGerman Federal Institute for Risk Assessment) has already compiled information on the study situation in its questions and answers on titanium dioxide.

The size of TiO₂short fortitanium dioxide particles is a decisive factor. In the context of the harmonised classification according to the CLP Regulation, the size of the particles determines whether they are inhalable and, if so, how deep the particles can penetrate into the lungs. The aerodynamic diameter is relevant in this context. A distinction is made between:

a) Larger particles (> 10 μm):

Particles of this size are not respirable and are considered less problematic as they are retained in the upper respiratory tract and subsequently coughed up.

b) Respirable particles (≤ 10 µmshort formicrometre):

Particles with an aerodynamic diameter of ≤ 10 µmshort formicrometre can be inhaled and cause inflammation or fibrosis in the lungs.

c) Particles smaller than 100 nmshort fornanometre (nanoparticles):

These particles can penetrate even deeper into the lungs (into the alveolar region) where they can cause inflammation or mechanical damage.

The harmonised classification of TiO2 targeted particle sizes that are respirable and have been shown to cause lung cancer in animal studies.

The potential risks of TiO₂short fortitanium dioxide vary greatly depending on the route of exposure. This information has already been compiled in the External Link:BfR’s FAQ on titanium dioxide.

The highest risk of potential intake is through inhalation. This applies to respirable particles (≤ 10 µmshort formicrometre) and nanoparticles. Animal studies have shown pneumonia, fibrosis and, when very high doses were administered over a long period of time, lung cancer. The postulated mechanism of action involves overloading the lungs with too many particles and overwhelming the associated lung’s clearance mechanisms. See also the External Link:Guidelines for the Application of the Harmonised Titanium Dioxide Classification (in German) by the German Federal Institute for Occupational Safety and Health (BAuA).

In its 2021 assessment, EFSAshort forEuropean Food Safety Authority stated that smaller particles in particular can be absorbed through the gastrointestinal tract and thereby become systemically available. These particles do not dissolve, meaning they are biopersistent. Furthermore, a genotoxic effect could not be ruled out.

TiO₂short fortitanium dioxide is not absorbed through intact skin, neither in micro nor in nano form. Studies show no systemic effects with dermal application (e.g. in sunscreens). There is therefore no health risk.

Based on the available evidence, nano-TiO₂short fortitanium dioxide used as a UV filter in concentrations of up to 25 percent in sunscreens is not expected to cause any adverse health effects. Studies show that nano-TiO₂short fortitanium dioxide in the forms used in cosmetic products cannot enter the human bloodstream.

The use of TiO₂short fortitanium dioxide in sunscreens has been evaluated by the Scientific Committee on Consumer Safety (SCCS) of the European Commission and is regulated in the EU Cosmetics Regulation EC (No.) 1223/2009 (Annex VI, reference numbers 27 and 27a). According to this, TiO₂short fortitanium dioxide is not generally prohibited in sprays, but only in those that, due to the (small) particle size, can lead to exposure of the user's lungs through inhalation. There are also sprays (e.g. pump sprays) in which the particles are so large that they do not reach the deeper lungs and therefore no inhalation exposure occurs.

The use of TiO₂short fortitanium dioxide in toothpastes is currently being reassessed by the SCCS. This current assessment has not yet been completed. The German Federal Institute for Risk Assessment (BfRshort forGerman Federal Institute for Risk Assessment) will refrain from commenting on ongoing SCCS assessments. However, a statement by the SCCS published in 2024 indicates that the TiO₂short fortitanium dioxide variants intended for use in cosmetic products differ from E 171, the material considered in the EFSAshort forEuropean Food Safety Authority opinion.

TiO2 (E 171) is added to medical drugs as a colourant. This use is still permitted in the EU in accordance with Directive 2009/35/EC on substances that may be added to medical drugs for colouring purposes. Through a footnote, a corresponding cross-reference has been added to the entry for TiO2 (E 171) in Regulation (EC) No. 1333/2008 on food additives in Annex B, Part 2 (contains a list of all additives).

For further questions regarding medical drugs, please refer to the German Federal Institute for Drugs and Medical Devices (BfArM).

The German Federal Institute for Risk Assessment (BfRshort forGerman Federal Institute for Risk Assessment) is a scientifically independent public health institute within the portfolio of the German Federal Ministry of Agriculture, Food and Regional Identity (BMLEH). The BfRshort forGerman Federal Institute for Risk Assessment advises the Federal Government and the States (‘Laender’) on questions related to food, feed, chemical and product safety. The BfRshort forGerman Federal Institute for Risk Assessment conducts independent research on topics that are closely linked to its assessment tasks.