Titanium Dioxide Classification - What Scientists Say

Apparently, the European Commission will no longer try to win over Member State representatives for its proposal to classify titanium dioxide as potentially carcinogenic. Instead, the Commission wants to make use of its new powers under the "delegated acts" procedure (link to article). It is expected that the Commission reveals their plan at the next CARACAL expert meeting 1/2 July. This articles looks back at the origins of the proposal and explains the critique by scientists on the weak scientific basis of the proposal.

How the proposal came about

Contrary to what one would normally expect, the reason for the proposal is not scientific but purely political - from the very start. Official Commission documents (e.g. Doc. CA/90/2017) explain en detail the background of the classification proposal: Apparently, it all started with a dispute between France and the European Chemicals Agency (ECHA), on the one hand, and the titanium dioxide producers, on the other hand, regarding the scope of information in the REACH dossier on titanium dioxide. Reviewing the registration dossier for titanium dioxide in 2014, France and ECHA demanded additional information from the manufacturers, including titanium dioxide nanomaterials. This refers back to the French anti-nano policy which has resulted inter alia in a French nano-register and the latest unilateral ban of titanium dioxide (E171) in food. Back then, the lead registrant objected to the request and the issue was handed over to ECHA´s Board of Appeal. In 2017, the Board ruled in favour of the lead registrant, concluding that ECHA´s demand for information regarding nanomaterials was not covered by the REACH regulation and was therefore unjustified (link). Earlier, however, in May 2016, on the instruction of the French Ministry of Labour, the French authority ANSES submitted a proposal for a harmonised classification of titanium dioxide as "May cause cancer” (category 1B) (link).

Therefore, politics - not science - has been the trigger for the classification process for titanium dioxide. And until today the process is marked by this "birth defect".

The Scientific Basis of the Proposal

Titanium dioxide is one of the best studied substances in the world. Since a long time it is used as a reference substance for, among other, inhalation studies. That is because the substance has no toxic effect, is not mutagenic and not genotoxic. It is (bio-) chemically inert and, due to its very low solubility in biological fluids, not bioavailable.

Provided it is present as a solid in respirable, alveolar form, titanium dioxide belongs to the group of so called “Poorly Soluble particles with Low Toxicity” (PSLTs). Chronic inhalation exposure to PSLTs can lead to inflammatory reactions in the lungs as a result of overloaded natural lung cleansing processes (so called “lung overload”). In Germany as well as in many other EU Member States, there are defined binding limits in place for the exposure of particles/dust in the workplace (occupational dust exposure limits, OEL, see here for overview).

RAC recommendation is based on a single, controversial animal study

On 8 June 2017, based on a hazard assessment, ECHA's Risk Assessment Committee (RAC) recommended that titanium dioxide should be classified as a "suspected carcinogen in humans" by inhalation (Category 2) (link).

The decision by the RAC is essentially based on a single, more than 20-year-old animal study by Prof Uwe Heinrich on rats, which - measured against today's standards - is not valid: Specifically, there are considerable methodological doubts about the usability of the research by Heinrich in 1995 for the classification proposal: For example, only female rats were tested, which are particularly vulnerable to lung tumours. Instead of the scientifically recommended 6-8 hours, the rats were exposed to titanium dioxide in powder form for 18 hours a day.

In professional circles, this study is not considered to be of current importance. For example, the well known expert Prof Harald Krug (University of Bern) criticised that the experiments "were carried out under conditions that are actually unacceptable today, for example with regard to concentrations. I find it extremely odd that we should make such a classification for titanium dioxide on the basis of questionable tests, although there are results to the contrary."(Source: ScienceMediaCenter, 14 June 2017).

Due to these methodological weaknesses, the French authority ANSES in its proposal had classified the Heinrich study as ”not reliable”. This view is confirmed by the joint statement of German authorities BfR and UBA of 2011 (No. 005/2011), which, having noted this study, stated: "... the data currently available are not sufficient to support these materials [including titanium dioxide] as "potentially carcinogenic to humans" with reasonable certainty". In addition, as is known today, due to physiological differences the results from "lung overload" studies are not transferable from rats to humans. The relevant guidelines of the ECHA, OECD and ECETOC make this clear (OECD Guidelines for the Testing of Chemicals (No 403, 433), ECETOC Technical Report No 122).

Epidemiological studies show no risk for humans

General particle effects pose a potential risk only in the workplace. For consumers titanium dioxide does not present a relevant risk. This is confirmed by a Commission statement: “The risk for consumers is negligible given the very high levels of exposure that would be required, which are unrealistic under normal and foreseeable conditions.” (Minutes of the CARACAL Sub-Group meeting on 23 April 2018, accessible via CIRCAB).

Epidemiological studies on approximately 24,000 workers in 18 titanium dioxide factories, inter alia in Germany, over several decades showed no adverse effects of titanium dioxide on health. Regarding these studies, Prof Harald Krug confirmed that "reliable studies known to me ... [have] not produced any alarming results for humans under real conditions and the epidemiology definitively says 'not carcinogenic'". Prof Ulrike Diebold (University of Vienna) confirms this view: "It seems to me that there is no reason to panic: if titanium dioxide is inhaled as fine dust, this seems to cause lung cancer in animal experiments. However, this seems to be less due to the titanium dioxide itself than to the fact that it is simply not good to inhale small particles." (Source: ScienceMediaCenter, 14 June 2017).

During the latest public consultation, among others the German Statutory Accident Insurance confirmed that there is not a single case of an occupational disease know that relates to titanium dioxide (link to the statement in German).

Unfortunately, during the entire assessment the broad epidemiological data on titanium dioxide - which showed no adverse effects – was not taken into consideration at all.

Titanium dioxide will be the first prominent issue the Commission has to deal with under the new rules of the "delegated acts" procedure. The new procedure strengthens the role of the Commission, which in future can classify substances without the approval of the Member States. However, in the Agreement between the European Parliament, the Council of the European Union and the European Commission on Better Law-Making (link) of 2016, the Commission has committed itself to carry out an impact assessment for delegated acts which have "significant" effects. Surely, the fact that 489 stakeholders participated in the latest public consultation and nearly all raised their concerns should signal that this issue is of significant importance (see here for a summary). On top, many international trading partners (e.g. the US, Canada, Mexico, Japan etc.) issued critique on the classification proposal during the WTO-notification (see link for more).

The very weak scientific basis together with the significant socio-economic impacts of a classification should give the Commission sufficient reason to take a step back in the consideration of this specific case. Titanium dioxide is not a substance that should be treated under CLP. Instead, the alternative proposal to harmonise occupational dust limit values in Europe shows the right path to increase health and safety in Europe (see link for more).