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Poorly soluble, low toxicity particles facing review

In 2016, the French competent authority, Anses, submitted a harmonised classification and labelling (CLH) report, proposing that the European Commission classify the white pigment titanium dioxide (TiO2) as carcinogenic under EU CLP. Echa’s Risk Assessment Committee (Rac) subsequently reviewed the report and decided that TiO2 should be classified as a category 2 carcinogen by inhalation.

Industry has consistently and vehemently opposed both the proposal and Rac’s Opinion, giving a range of scientific, legal and socio-economic arguments. The issue is important, not least because TiO2 is a major product, in both volume and value terms: research firm MarketsandMarkets says the global market was worth $10.6bn in 2016.

Last year, the British Coatings Federation said that the requirements resulting from the classification could cause "major and unnecessary alarm to users and consumers". Certain products containing TiO2 would have to be labelled as ‘suspected of causing cancer’, even though in many cases there would be no possibility of inhalation because, for example, the particles were too large or suspended in a liquid, as in a paint.

For some downstream sectors using the substance, the classification could even affect market access, because several pieces of EU legislation incorporate regulatory measures linked directly to CLP carcinogenicity classifications. For example, Article 15 of the cosmetics Regulation prohibits the use of carcinogens in cosmetics without a specific risk assessment by the EU’s Scientific Committee on Consumer Safety (SCCS). Similarly, the toy safety Directive restricts the use of carcinogens in accessible parts of toys below a certain concentration stipulated in CLP and also in inaccessible parts if the substance can be inhaled.

While the TiO2 classification is not yet law, opportunities remain for influencing the outcome of the process. The Competent Authorities for REACH and CLP (Caracal) is likely to discuss a draft amendment to technical progress (ATP) for harmonised classification at its next meeting in March.

At some point after that, Echa’s REACH Committee will make the final decision, usually signing off harmonised classifications according to Rac Opinions with few changes. Publication of the legislative changes is expected in early 2019, followed by an 18-month transition period.

Many parties opposed to the classification are still focusing on the justifications. Damjana Drobna, professor of toxicology at the University of Ljubljana in Slovenia, is leading a task force within NanoSafetyCluster, a Commission initiative for research projects on nanomaterial safety, specifically to address the volume of toxicological data, which she says is "completely unmanageable for regulators". 

The aim is to review the data on TiO2 safety and provide "independent and transparent" advice to stakeholders. The task force, which launched in January, comprises ten scientists from EU member state authorities, consultancies and universities, and will provide a scientific opinion on the CLH proposal. Similarly, members of the Titanium Dioxide Manufacturers Association (TDMA) have embarked on a €14m science programme to answer remaining questions about all forms of TiO2, including surface-treated nanoforms.

The EU courts

Even after the classification becomes law, if indeed that happens, there would remain the possibility of legal action, for which there is some precedent. In January, the European Court of Justice (ECJ) dismissed an appeal by the European Commission, effectively ending a long-running case concerning the classification of ‘coal tar pitch high temperature’ (CTPHT).

When the Commission set the classification, several companies complained that it had not taken into account a key factor, the overall solubility of the substance. The Commission argued that it could not do so, because the CLP legal text did not refer explicitly to that. The courts disagreed and annulled the classification, saying that the Commission was obliged to identify and consider all relevant factors, not just those mentioned in the text.

Koen van Maldegem, a partner at law firm Fieldfisher and the lead legal representative for the companies involved in the case, said at the time that the case had wider implications. In particular, from then on, the Commission and Echa would have to demonstrate that they had taken into account comments and scientific data submitted by concerned companies, he said.

The relevance of this case to that of TiO2 remains to be seen, but industry might argue that the Commission has not done this in relation to TiO2. During the public consultation on the Rac Opinion of the TiO2 proposal, the Carbon Black for REACH Consortium (CB4REACH) accused Anses of ignoring the "vast literature of mortality studies" on TiO2 and carbon black production workers, as well as coal miners. The scientific issues raised in the proposal were based partly on other respirable substances, including carbon black, it added.

In its response, Anses said that it had not specifically assessed references relating to other related substances, because the proposal was based on specific data for TiO2. Data for other substances were only used to support the hypothesised carcinogenic mode of action. "Overall, references submitted during public consultation do not constitute new data and do not impact the CLH proposal," it said.

Implications

Elsewhere, the conversation seems to have moved away from the justifications and towards the implications. At the most recent Competent Authorities for REACH and CLP (Caracal)meeting, for example, the Commission asked members to come up with solutions to the labelling problem. It suggested various labelling ‘derogations’ as a possible solution for discussion.

There are also other, related substances to consider. Rac recognised that the mechanism of toxicity outlined in the report was not unique to TiO2. In fact, it is common to a broad set of substances, used as particles and characterised by very low solubilities called poorly soluble, low toxicity particles (PSLTs) or poorly soluble particles (PSPs).

The TMDA said in the documents submitted to the Caracal meeting that the classification "sets a precedent and may have regulatory consequences on other common particulate substances in the EU".

It proposed that the member states, Echa, the Commission, NGOs and industry experts establish a working group to consider "the appropriate mechanism for any regulation of PSLTs". It also asked the Commission to pause the process for the working group and additional consultation, and to focus on the ‘real world’ implications of any decision.

Meanwhile, the German Chemical Industry Association (VCI) and a group of 16 industry associations representing downstream users of TiO2 warned of a ‘domino effect’ for PSLTs in documents submitted. "If the EU continues on the path of classification of titanium dioxide, despite all arguments, all PSLTs will have to be assessed according to this Opinion," it said. "We consider this way unworkable and not as useful."

The VCI said it did not have a full list of PSLTs and would not consider one useful. "Particle-induced inflammatory processes are not substance-specific. The threshold limits for dust at the workplace in Germany and EU member states already protects from general particle-related inflammatory processes in the lungs as a result of inhalative dust exposure. These rules thereby already implement a group approach when dealing with PSLTs," the association said.

The documents submitted by the associations listed, as examples:

  • carbon black;
  • inorganic colour pigments;
  • iron oxides;
  • cerium dioxide;
  • aluminium oxide;
  • magnesium oxide;
  • plastic dusts;
  • barium sulfate; and 
  • zinc oxide.

Ecetoc, an industry centre for toxicology research, suggested a scientific definition of PSLTs in its 2013 report on the relationship between such particles and the lung overload mechanism. However, it did not attempt to list them.

A spokesperson for Cefic said that the organisation did not yet have a position on PSLTs because it was still unclear how the member states would like to proceed and there were "more question marks than answers".

The Commission has speculated about whether a CLH proposal for the whole group would be justified. At the Caracal meeting in November last year, it asked whether it was appropriate to limit harmonised classification to TiO2, or if it would be preferable to classify PSLTs, or a well-defined group of them, in the same way, using a grouping approach.

It is unlikely that the TiO2 proposal could be changed to include more substances. According to an Echa spokesperson, it is not normally possible to consider a broader Annex VI entry without a new CLH proposal and related public consultation. But in general CLH proposals for groups are valid. In such cases, the classification and labelling requirements would apply to all the substances in the group, the spokesperson said.

Evaluations

The German competent authority, Baua, is already evaluating zinc oxide under REACH and in 2019 it will evaluate cerium dioxide, while Anses is evaluating carbon black. Like TiO2, these are major products in terms of volume and value. MarketsandMarkets estimated that the global markets for carbon black and for zinc oxide were worth $11.2bn in 2015 and $3.5bn last year, respectively. 

One of the key features of the TiO2 evaluation has been the discussion about information on specific forms. Commercial TiO2 varies across a range of properties, such as crystal phase, surface treatment and particle size but the proposed classification is not limited by any of these.

Anses justified this approach with reference to the REACH registration dossier for TiO2, which covered all forms and assumed them to be equivalent in terms of toxicity. Furthermore, the authority said that the registrants had not transparently and exhaustively reported the various forms, meaning that differences between them could not be determined based on variation in their properties. It concluded, therefore, that the scope of the CLH proposal should cover all forms.

Echa had asked the registrants to provide more information about the forms in a Decision adopted in 2014. However, several of them contested the request, which was annulled by the Board of Appeal in 2017. The question arises as to whether the evaluations for zinc oxide, carbon black and cerium dioxide will proceed similarly.

In the Corap justification document for carbon black, Anses said that more substance identification information is required to link specific forms to uses and toxicological profiles. The documents for zinc oxide and cerium dioxide said that the evaluations are targeted at the nanoforms.

Three forms are identified in the zinc oxide dossiers: standard, nano and "lower grade". In addition, the dossiers include several toxicological study records for zinc oxide in nanoform. 

However, Baua says that the information provided is nonetheless ‘insufficient’, making it hard to relate important physico-chemical properties to toxicological effects. For example, particle size information is often missing in the toxicological records and no information specific to the nanoform is provided for several endpoints, including carcinogenicity.

Furthermore, the records that include the nanoform often used a specifically coated version from BASF called Z-Cote HP1, without reference to how representative this is to the nanoform referred to for classification, according to Baua. Lastly, neither the derived no-effect levels (Dnels) nor the consumer uses differentiate between the bulk and nanoforms, it adds.

The lead dossier for cerium dioxide differentiates bulk and nanoforms. However, Baua says that only two endpoints are addressed by studies specific to the nanoform. Furthermore, no such information is provided regarding inhalation repeated dose toxicity. Baua was scheduled to submit to Echa its outcome documents for the evaluation of zinc oxide by 21 March this year.

PSLTs under evaluation
Like TiO2, zinc oxide can act as a UV filter and a white pigment. It is also valued for its antibacterial properties, its ability to increase resistance to abrasion when used 
in materials and its behaviour as a semiconductor. 
 
More than half of all zinc oxide is used to make rubber. The rest is used in a wide range of products, including ceramics, medicines, paints, coatings, adhesive, sealants, concrete, foods, batteries, plastics, glass and lubricants.
 
Carbon black can act as a black pigment, but is also valued for its mechanical and thermal properties. When added to materials, it can increase their tensile strength and their resistance to wear and heat. 
 
About 70% of all carbon black produced is used in automotive tyres. The rest is used in a wide range of products, including inks, coatings, plastics, adhesives, sealants, putties, lubricants, greases, paper, cosmetics and textiles.
 
Cerium dioxide is valued for its hardness, its ability to absorb UV light, and its optical, electrical and catalytic properties. Nano-structured cerium dioxide films are used in optical and electronic devices, while the nanoform is used in such applications as:
  • a polishing material for glass surfaces and silicon wafers;
  • an anti-corrosion material in exterior architectural paint, steel and other metal plates; in solid oxide fuel cells; and
  • as a catalytic diesel fuel additive for decreasing toxic diesel emissions and increasing fuel efficiency.
BASF is conducting a long-term inhalation study of cerium oxide and barium sulfate, with EU funding. A BASF toxicologist, Lan Ma-Hock, presented preliminary findings at EuroTox in Bratislava last year but the company has since declined to comment further. 

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