The EU Cosmetics Regulation Restrictions for Certain Substances and Special Provisions Dr. Qasim Chaudhry The Food and Environment Research Agency Sand Hutton, York, United Kingdom Member European Commission’s Scientific Committee on Consumer Safety Member Scientific Committee of the European Food Safety Authority

The Cosmetics Regulation: Limitation of Certain Substances CMR substances Traces of prohibited substances Regulatory arrangements for nanomaterials Safety assessment for nanomaterials

The Cosmetics Regulation: Limitation of certain substances Annex II - list of 1328 prohibited substances Annex III – list of 256 restricted substances Also prohibited are: certain colorants (other than those in Annex IV), preservatives (other than those in Annex V) and UV-filters (other than those in Annex VI); substances recognised as Carcinogenic, Mutagenic or toxic for Reproduction (CMR), apart from exceptional cases; nanomaterials – subject to a high level of protection of human health.

The Cosmetics Regulation: CMR classification [Regulation N° 1272/2008] Carcinogenic Cat. 1A: Known to have carcinogenic potential for humans Cat. 1B: Presumed to have carcinogenic potential for humans Cat. 2: Suspected human carcinogen Mutagenic Cat. 1A: Substance known to induce heritable mutations in the germ cells of humans Cat. 1B: Substance to be regarded as if it induces heritable mutations in the germ cells of humans Cat. 2: Substance which causes concern for humans owing to the possibility that it may induce heritable mutations in the germ cells of humans Reproductive toxicants Cat. 1A: Known human reproductive toxicant Cat. 1B: Presumed human reproductive toxicant Cat. 2: Suspected human reproductive toxicant

The Cosmetics Regulation: Derogation to the Ban on CMR Substances CMR2 substances Possibility to allow where, in view of exposure and concentration, they have been found safe for use in cosmetic products by the SCCS, and are regulated by the EC in the Annexes to the Regulation. CMR 1A or 1B substances Possibility, in the exceptional case that these substances comply with food safety requirements, inter alia as a result of their naturally occurring in food, and that no suitable alternative substances exist, to use such substances in cosmetic products on the condition that such use has been found safe by the SCCS.

The Cosmetics Regulation: Trace impurities/ contaminants Presence of small quantities of a non-intended prohibited substance, that is technically unavoidable in good manufacturing practice, is allowed, provided that it does not cause harm to human health during the product use. Annex I requires the following information concerning the impurities and traces in the cosmetic product safety report: The purity of the substance and mixtures. In the case of traces of prohibited substances, evidence for their technical unavoidability. The relevant characteristics of packaging material, in particular purity and stability. There are currently not regulatory limits for most non-intended traces Safety is the responsibility of the manufacturer or the person under whose responsibility the product is placed on the market. e.g. impurities of natural or synthetic ingredients, manufacturing process, storage, migration from packaging

The Cosmetics Regulation: Nanomaterials In Europe nano cosmetic ingredients will be regulated under the Cosmetics Regulation (EC) No 1223/2009. The Regulation provides the first regulatory definition of a nanomaterial* Requires: cosmetic products containing nanomaterials to be notified to the Commission 6 months prior to being placed on the market; nanoscale ingredients to be labelled (name of the ingredient, followed by ‘nano’ in brackets); if there are concerns over safety of a nanomaterial, the EC will refer it to the Scientific Committee on Consumer Safety (SCCS) for opinion. T *“nanomaterial" means an insoluble or biopersistant and intentionally manufactured material with one or more external dimensions, or an internal structure, on the scale from 1 to 100 nm.”

New applications in consumer products Nanomaterials New applications in consumer products Increased surface area Greater functionality per equivalent mass Better control of material properties Potential new properties Improved dispersions Stable formulations Less use of chemical substances Enhanced uptake of nutrients & supplements Effective UV protection

Nano-sized Cosmetic Ingredients Colorants, antioxidants, antimicrobials, UV filters, supplements (vitamins, minerals); Materials include: inorganic, organic uncoated, coated, doped manufactured particles, micelles, liposomes R&D on functional nanomaterials Used for better dispersibility, antimicrobial or antioxidant properties, effective UV protection, visual clarity of sunscreen formulations, etc; A growing range of products worldwide. Only a few products currently in Europe – mainly sunscreens containing nano UV filters.

Other cells and tissues Nanomaterials Safety Concerns N a n o p a r t i c l e s Skin Gut Lung Inhalation Skin application Ingestion Other cells and tissues ? Scientific evidence indicates that: Nanoparticles may cross membrane barriers, and reach new targets in the body; Nanoparticles may interact with biological entities close to the molecular level; Exposure to insoluble/ biopersistent nanoparticles may cause concerns over adverse health effects. 10

Nanomaterial Safety Hazard identification (acute, chronic) Local/ systemic effects Dose response characterisation Exposure assessment Routes of exposure Likelihood & extent of exposure Exposure Hazard Risk Uncertainty factors Margins of safety

Nano-related Considerations Solubility/dispersion In an assay system, nanoparticles will be present as insoluble particulates in a dispersion/suspension (not in solution); Nanoparticles tend to agglomerate/aggregate due to high surface energy. They may also stick to containers, or sediment out. Maintaining a uniform concentration during the assay may be problematic. Surface adsorption/ binding Nanoparticles may bind/adsorb various substances and moieties on the surface – and potentially carry them into cells/tissues Nanomaterials may bind with components of the test media and interfere with the assay. Formulation effects Nanomaterials may bind with components of a formulation and this may affect their physicochemical properties.

Nano-related Considerations Metrics for toxicological measurements The use of mass alone in dosimetry is not appropriate for nanomaterials. It is recommended that other parameters, such as particle number, surface area, should also be used. Bioavailibility – toxicokinetics Nanoparticles may have a different bioavailability and biokinetic behaviour in the body; Surface characteristics, surface modification, coatings are likely to play a major role. Some nanoparticles may cross biological membranes and reach unintended target in the body. Surface reactions Potential interaction of nanomaterials with biological entities and processes close to the molecular level; Potential surface catalysed reactions.

SCCS Guidance (2012) on safety assessment of nanomaterials in cosmetics

Physicochemical Characterisation Detailed characterisation should include: pristine nanoparticles as produced, as added to the cosmetic product, as present during toxicological investigations; Physicochemical parameters to be measured should include: chemical identity, chemical composition, concentration, particle size distribution, morphology and surface characteristics, solubility and dissolution constant, surface area, catalytic activity, dustiness, density and pour density, redox potential, pH, viscosity, stability in formulation and biological media Measurements should be carried out using mainstream methods - preferably more than one method – with due consideration of the nano-aspects.

Source: skindiagram.jpg (healthy-skin-guide.com) Exposure Assessment Exposure assessment should consider possible translocation of nanoparticles via all possible routes – skin, lung, or gastrointestinal tract - mimicking anticipated use scenarios. Data on dermal penetration is an important element of safety assessment; A large body of scientific evidence indicates that healthy human skin is a good barrier to particle materials, including nanomaterials; A few studies have reported translocation of certain nanomaterials through skin (e.g. QDs, surface modified fullerenes, ZnO), but questions remain; Other routes of exposure (especially lung) are not likely to be as good a barrier to nanoparticles as skin. Source: skindiagram.jpg (healthy-skin-guide.com)

Hazard Identification/ Characterisation All toxicological endpoints needed for safety evaluation of a (non-nano) cosmetic ingredient should be addressed: Dermal/ percutaneous absorption; Toxicokinetics; Acute toxicity; Irritation and corrosivity; Skin sensitisation; Mutagenicity/genotoxicity; Repeated dose toxicity; Where appropriate, further studies on Carcinogenicity; Reproductive toxicity; Photo-induced toxicity; Additional human data (where available) . In vivo and in vitro methods may be used for toxicological evaluation. However, none of the in vitro methods has so far been validated against nanomaterials. Only a few elementary in silico models are currently available.

Safety Assessment Any route-to-route extrapolation should be performed on a case-by-case, based on expert judgment of the available scientific information; Where data from valid/validated tests are available and uncertainties are not large, there may not be a reason for applying higher margins of safety than those used for a conventional substance; Where data are either insufficient or from inadequate tests, a Risk Assessor may consider applying additional uncertainty factors for a nanomaterial; Potential persistence and accumulation of nanoparticles should also be considered.

Nanomaterials Current Challenges Lack of validated methods for detection/ characterisation of nanomaterials – especially in cosmetic products and in biological tissues; Uncertainties and knowledge gaps in relation to properties, behaviour and toxicological effects of nanomaterials; Lack of validated methods for assessment of exposure via dermal, inhalation, ingestion routes; Imminent ban on animal testing of cosmetic ingredients in Europe, and the lack of validated alternative testing methods for nanomaterials; Difficulties in the use of a category approach to safety assessment of nanomaterials;

Nanomaterials Guidance on Risk Assessment/ Scientific Opinions SCCS Guidance (2012): http://ec.europa.eu/health/scientific_committees/consumer_safety/docs/ sccs_s_005.pdf. SCCS Opinion on the use of nano-ETH50 (1,3,5-Triazine, 2,4,6-tris[1,1’- biphenyl]-4-yl-) as a UV filter in cosmetic products: http://ec.europa.eu/health/scientific_committees/consumer_safety/docs/ sccs_o_070.pdf SCCS Opinion on the use of nano-zinc oxide as a UV filter in cosmetic products: http://ec.europa.eu/health/scientific_committees/consumer_safety/docs/ sccs_o_103.pdf

Summary The use of CMR substances in cosmetics is prohibited – subject to certain derogations; Presence of non-intended trace impurities/ contaminants is only allowed subject to certain provisions; The use of nanomaterials will require a thorough assessment of safety, with consideration of nano- aspects. Guidance on safety assessment is available. First scientific opinions on nano cosmetic ingredients are available. Ban on animal testing will pose a major challenge to safety evaluation of new cosmetic ingredients - especially nanomaterials.