Outcome of the International Workshop on Regulatory Issues regarding the Use of Nanotechnologies in Cosmetics, July 2009

European Commission, Joint Research Centre
Institute for Health and Consumer Protection
Ispra (Italy), 8-9 July 2009

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The initiative to hold this Workshop was taken at the second meeting of the International Cooperation on Cosmetics Regulation (ICCR) held in summer 2008 in Rockville, Maryland. The Workshop was organized by the European Commission’s Joint Research Centre in collaboration with the Directorate-General for Enterprise and Industry (DG ENTR) to include representatives from the four ICCR jurisdictions (Canada, EU, Japan and the USA). Regulatory bodies, industry associations, and scientific committees/academia were invited (see participants list in ANNEX 1).

AIMS OF THE WORKSHOP

The workshop opened with a review of the aims of the workshop. Specific and scientific objectives included:

• understanding the market for cosmetics containing nanotechnology 
• setting priorities for consumer safety related research activities 
• providing feedback for integrated concepts concerning test method development and strategies for generation of data 
• improving regulatory clarity with respect to safety assessment 
• stimulating international convergence on science and regulatory policies for safety

The first day addressed, through presentations, the ICCR activities of the relative to nanotechnology since the launch of ICCR in the Fall of 2007, followed by positions of regulatory bodies and industry associations and included the recent findings of the EU Scientific Committee on Scientific Consumer Safety (SCCS). The principal issues related to 'Definition – Substance Identification, Detection and Characterization' and 'Regulatory Safety Testing' were discussed in detail in two breakout groups during the second day.

SUMMARY OF THE DISCUSSIONS AND ISSUES ADDRESSED

The group of participants fully supported using ICCR as the conduit to discuss nanomaterials in cosmetics and expressed their commitment to be transparent. It was agreed to report the outcome of the meeting to ICCR-3 to be held in Tokyo on September 9-11, 2009. In general, the group recognized the importance of the role of science for regulation and emphasised the necessity of discussing and understanding not just the risks, but also the benefits for consumers from using nanotechnology in cosmetic products.

Each of the four jurisdictions presented their regulatory approaches to nanomaterials in cosmetics. The key points are summarized as follows:

• Until now the EU’s position was that existing regulation is sufficient to cover cosmetics containing nanomaterials. However, at the request of the European Parliament, the upcoming Cosmetics Regulation foresees a flexible and sector-specific definition, the labeling of nano-ingredients and pre-market notification for cosmetics containing nanomaterials; 
• The US believes that, for the time being, existing FDA regulation adequately covers nano forms of substances. In addition, at this stage a definition may be too restrictive. More information is needed on methods for detection of nanomaterials in cosmetic products and for monitoring the safety; 
• Canada is currently using existing chemical/product legislations to assess nanomaterials and has no legal definition of nanomaterials for the purpose of regulation and data collection. The main challenges they are facing are the lack of international nomenclature to identify nano versus bulk materials and establishing appropriate risk assessment methods. However, Health Canada announced that they are working on a ‘working definition’ as an interim measure in the absence of finalized internationally accepted definitions. The definition is to be used to support the legislative and regulatory frameworks under the authority of Health Canada and to help further the development of policy, guidance and programs applicable to nanomaterials. 
• Japan also believes it is appropriate to deal with nanomaterials under current regulations for the time being, because there is no scientific evidence for introducing nano-specific regulations. There was a general agreement, that the current regulatory risk assessment paradigms were applicable for safety assessment of nanomaterials in cosmetic products. The request of the European Parliament for labelling nanomaterials as ingredients in cosmetic products emphasized the importance of a harmonised and appropriate definition of nanomaterials used in cosmetics. Characterisation of nanomaterials was recognised as one of the central issues in addition to the need for developing, adapting and harmonising testing methods for safety assessment.

RESULTS OF BREAKOUT-GROUP 1: DEFINITION- SUBSTANCE IDENTIFICATION, DETECTION AND CHARACTERIZATION

This breakout-group focused on the urgent need for a harmonized definition that could be used in all four jurisdictions. This had to be reconciled with the FDA’s approach which does not consider a rigid definition of nanomaterials as necessary at this stage, given that the regulatory approach and risk assessments are for products and not technologies. A list of criteria was considered as the preferred option to reconcile the different approaches, allowing for the case-by-case approaches recommended by expert committees in most jurisdictions, and allowing more flexibility for future consideration of the rapid advancement of scientific knowledge in the area of nanomaterials risk assessment.

The Breakout-group raised several issues to be addressed:

• Review of existing definitions – how useful are they for regulatory and risk assessment purposes? It was agreed that criteria used for regulatory purposes is expected to be far simpler than a full characterization needed for scientific purposes. 
• Is it only size that matters? The answer from a scientific standpoint is clearly no. Which properties need to be taken into account when defining nanomaterials? 
• From theory to practice – Even size, while simple sounding, would need further clarification to be useful in a regulatory setting (i.e. does it or doesn’t require special labelling.) 
  • what does "size" of a nanomaterials in a non-homogenous preparation mean?
  • how is "size" influenced by coatings (engineered or acquired from environment)? 
  • how to account for aggregation/agglomeration? 
  • What are the quantitative measures of qualitative terms like stable and insoluble? 
• Whatever we choose to measure, do we have the appropriate methods for determination of size and other physico-chemical properties under relevant conditions? 

Identification and Characterisation of nanomaterials: 

• Properties that need to be determined for a potential nanomaterial when used in cosmetics 
• Properties that need to be taken into account to identify a nanomaterial 
• Practical aspects and issues when characterising nanomaterials in cosmetics

Results of the discussions:

1. Regulatory authorities in the four jurisdictions have different positions regarding the need for a definition of the “nano form” for regulatory purposes. For example, FDA concluded it was unnecessary, while the EU needs a legal definition to implement nano-specific elements of the cosmetics recast. 
2. Regulatory authorities in the four jurisdictions have different positions regarding safety assessments of cosmetics. For example, FDA looks at the safety of final products, while in the EU, safety assessment is mainly ingredient-based. 
3. From a regulatory perspective, ideally a nanomaterial in cosmetics should be characterized as it appears in the final formulation used by the consumer. Recognizing the limitations of existing methodologies to achieve this, the group proposed, as the next best possibility, to characterize the ingredient itself and to take into account worst case considerations about the possible behaviour of the material in formulation for the safety assessment. 
4. The ISO Technical Specification (ISO/TS 27687), which was also adopted by OECD as a ‘Working Specification’ (at an early (unfinished) stage of the ISO Technical Specification), should also be taken into account. 
5. The list of criteria discussed at ICCR2 was mentioned. These included the following properties: chemically stable and insoluble, intentionally manufactured (excludes natural substances and by-products), physical-chemical properties include size and shape distribution, uniformity of particles, aggregated materials (surface criterion). 
6. Industry felt that whatever criteria are ultimately agreed on, further definition would be required to enable them to determine if the regulatory obligation was triggered. For example, even size, while simple sounding, would need further clarification to be useful in a regulatory setting (i.e. does it or doesn’t require special labelling.) 
7. A range of methods is usually used to gather information on the physico-chemical characteristics of a material. These methods measure, depending on their technique, different characteristics, and the combination of the different techniques is needed to get a thorough understanding of the properties of a material. The characterisation strategy needs adaptation to the material to be analysed, therefore a standardised test battery seems not feasible. 
8. The break out session discussed in detail variation in results achieved by different measurement techniques. It is critical for industry to be able to characterise particles by meaningful techniques. It has been shown by previous presentations that characterization of particles by XRD, LASER SCATTERING, X-RAY DISC CENTRIFUGATION etc can provide very different particle size results, without any of those results being better or “more correct” than others.

Overall the group agreed that a complete characterization, as would be needed for the scientific characterization of nano-materials within a hazard identification and risk assessment framework, was far more detailed than that needed within a regulatory framework. It was agreed that for regulatory purposes simpler criteria, like those advanced within the ICCR framework would be sufficient. Even so additional work would be needed to fully clarify terminology like stable, insoluble, or size (1 to 100 nanometers?).

 

 

RESULTS OF BREAKOUT-GROUP 2: REGULATORY SAFETY TESTING 

It was agreed that the table below was useful to initiate the discussion on regulatory safety testing, as it addressed the specific endpoints.

Nanomaterials in the Body
Nanomaterial	Powder Embedded in matrix or on surfaces
Dispersion	Deposition in the lung Alveolar, intestinal, dermal penetration
Uptake in the body	Deposition in the lung, Alveolar, intestinal, dermal penetration
Modification in the body	Surface coating changes Agglomeration, desagglomeration
Primary effect	Inflammation Catalysing formation of reactive compounds Direct interaction with cellular structures
Toxic effect	Organ toxicity Genotoxicity

Table 1: Nanomaterials in the body: Scheme on mechanistics leading to potential adverse effects

The group considered the following items:

• What information is required to address safety of nanomaterials in cosmetics following endpoints and/or mechanistic analysis as presented in Table 1? 
• Which requirements may deviate from those concerning "normal" bulk chemicals? 
• Which tests are currently used and what is their validity? 
• What is the current state of play of alternative test methods? 
• Which regulatory needs exist to appropriately test nanomaterials and to compare results from different studies?

Opinions expressed during the discussions:

1. Looking at regulatory endpoints, the group considered only those related to human health as being relevant for cosmetics. Environmental endpoints are addressed in REACH. Nevertheless, the availability of information for the respective substances needs to be ensured. It was said that nanomaterials are considered not to cross intact epidermis. Nevertheless, a number of studies currently being performed address e.g. sun-burnt skin and a review of the subject may be needed taking specific exposure conditions and scenarios into account. Current in vitro and in vivo tests only address intact skin or models thereof (though models addressing damaged skin exist). In general, it was pointed out that the ongoing OECD WPMN programme is currently reviewing the test guidelines established and accepted for macroscale chemical substances with regard to their applicability and appropriateness for nanomaterials' testing. Although part of the analysis has been done, further development is expected and adaptations or even new or revised protocols are to be expected. 
2. The endpoints were considered as relevant in general. Only few very specific aspects may require specific nano-related attention including ROS production, possible direct effects at the bio-nano interface, deviations concerning AD(M)E. Testing ADME, distribution, barrier functions and retention times were regarded as being of importance to provide a sound basis for structured testing approaches. They have been recognized as being needed before performing target studies including in vivo experiments. Metrics is an issue for nanomaterials that impacts on dose and dose descriptors. 
3. Test methods used at present are test guideline methods as used for bulk chemical substances. It was stated that it was well known that some of the assays do not perform well even for non-nanoscale materials. This is seen to be a known issue of traditional methods and should not be dealt with under the flag of nanomaterials, but needs to be addressed separately. For experiments, a point of reference is missing concerning both appropriate test methods and representative nanomaterials for testing. These would be required to harmonise approaches and achieve comparability of results. 
4. A number of alternative test methods is used and regarded as being useful. This comprises skin irritation and corrosion, eye irritation, phototoxicity, skin penetration, skin sensitization (screening), genotoxicity tests. Genotoxicity assays were described as being over-predictive and application of the three recommended assays identifies about 95 % positives for this endpoint. Skin irritation, corrosion and phototoxicity were regarded as very useful and the outcome is routinely used for safety assessment. The increased need for dermal absorption studies was also mentioned. 
5. The material preparation for testing was discussed. The importance was seen to test the material or preparation as close as possible mimicking the real exposure situation. It was acknowledged that the conditions may be very different for nanomaterials in a matrix and that a raw material is not necessarily the best model. The requirements need to be addressed as described in GLP and following the logics of exposure scenarios.

GENERAL DISCUSSION POINTS

• Industry representatives stressed the importance of global harmonisation. 
• Information from the Woodrow Wilson Center indicates that about 800 consumer products claim to include nanomaterials. 60% are used in cosmetic and personal care products. Source: www.nanotechproject.org/inventories/consumer/). 
• Industry representatives reported that the use of nanomaterials in cosmetic products has a long history, e.g. inorganic nanomaterials in sun screens about 30 years. The most used substances are titanium dioxide, zinc oxide and silica. To their knowledge fullerenes, gold or platinum nanomaterials are not used in cosmetic products in any significant volume. 
• The definition "nanotoxicology" was briefly discussed. Test methods to investigate the toxicity of nanomaterials need to be adapted on a case by case basis to ensure that the test substances reach the target organ. 
• One discussion point concerned the absorption, distribution and biokinetics of nanomaterials used in cosmetic products. Industry stated that the most relevant exposure for cosmetic products is via the skin, and that so far no skin penetration of nanomaterials used in cosmetic products had been detected. However, some participants expressed the need to look also to exposure via inhalation and ingestion. There was agreement that further information on exposure is needed. 
• The use (and validation) of in-vitro methods / alternative endpoints was addressed. There is currently no guidance on how to use the results of these methods in a safety assessment, but it was acknowledged that this is not a nano specific issue.

CONCLUSIONS

• The representatives of the regulatory authorities as well as the cosmetics industry representatives expressed their confidence in the ICCR process as an open and transparent forum for discussion on nanomaterials; 
• Existing scientific and legal paradigms seem to be sufficient to cover nanomaterials, however, challenges remain as they might need to be adapted to the specific characteristics of such materials; 
• A list of common criteria specific to the context of cosmetics to determine if a particle should be considered as a nanomaterial seems to be a more realistic objective for ICCR. Need expert involvement to define realistic tests; 
• As far as regulatory safety testing of cosmetic ingredients is concerned, no new endpoints specific to nanomaterials were identified at this time. However, the characterization and tox-test preparation and read-out methods used on nanomaterials pose challenges as they might generate differentiated test results and interpretations.

NEXT STEPS

Taking into consideration the outcomes of the Workshop, ICCR-3 will decide the next steps. Agreement was reached that another “Nanotechnology in Cosmetics Workshop” could meet in the future, according to the needs identified by ICCR. This will be discussed at ICCR-3.

 

 

ANNEX 1

Participants’ list

The meeting was attended by representatives of :

• U.S. Food and Drug Administration (FDA) 
• Japan, Ministry of Health, Labour and Welfare (MLHW) 
• Health Canada Federal Department (HC) 
• European Commission, Joint Research Center, Institute for Health and Consumer Protection (JRC, IHCP) 
• European Commission, Directorate-General for Enterprise and Industry 
• European Commission, Directorate-General for Health and Consumer Protection 
• Industry and Industrial Associations:
• Personal Care Council 
• Shiseido 
• Kanebo Cosmetics 
• Croda 
• Colipa (The European Cosmetics Association) 
• L'Oréal 
• Nanotechia (Nanotechnology Industries Association)
• European Commission, Joint Research Center, Laboratory team

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