The market for cosmetic products is large and was estimated globally at €175 billion in 2013 (or approx. $227 billion).¹ The largest market is Europe estimated at one-third of the global cosmetics market.² With its large size, the European Union (EU) is a key component of the business strategy of most cosmetic companies, suppliers of final formulations and ingredients. To achieve their goals, companies must comply with European regulations. In today’s global world, even if the European market is not the primary target, it is nevertheless a good approach to think globally and to integrate European regulations right from the beginning of the marketing efforts. This ensures that some expenses are not repeated due to lack of compliance and that companies are ready when opportunities arise.

Regulation (EC) No. 1223/2009, published in 2009, (which replaced the Cosmetics Directive) is the primary legislation governing the area of cosmetic products in Europe and is fully applicable since July 11, 2013.³ A key objective of this European regulation for cosmetic (substances), final formulations and ingredients is the health safety to consumers. Before being placed on the market, the cosmetic product must undergo a safety assessment. The Scientific Committee on Consumer Safety (SCCS) has offered guidance on the safety evaluation of cosmetic products in December 2012.⁴ In addition, the European Commission published in November 2013 guidelines to help when assessing the safety of cosmetic products.⁵

This article focus on the safety data in relation with the regulation and provide some recommendations on what to do.

Cosmetic Products (Final Formulations)
Regulation (EC) No. 1223/2009 main objective is the safety of a cosmetic product for human health: “A cosmetic product made available on the market shall be safe for human health when used under normal or reasonably foreseeable conditions of use“ (Article 3).

The regulation describes what elements are mandatory to be able to market a cosmetic product within the EU as an in-market process. Three series of documents are critical for the safety: a Product Information File (PIF) is required to be drawn up for each product before it is placed on the market (Art. 11) and it includes 5 sections. One of these sections,  a Cosmetic Product Safety Report (CPSR) must be prepared that includes a Cosmetic Product Safety Assessment (Article 10). From a safety point of view, the CPSR is the most important element of the PIF and referred to in Article 10(1).

The Cosmetic Product Safety Report
Manufacturers need to follow specific requirements in the preparation of a product safety report prior to placing a product on the market, and particularly, a “Responsible Person” has to be designated within the Community (Article 4). As stated in Article 10, “in order to demonstrate that a cosmetic product complies with Article 3, the Responsible Person shall, prior to placing a cosmetic product on the market, ensure that the cosmetic product has undergone a safety assessment on the basis of the relevant information and that a cosmetic product safety report is set-up in accordance with Annex I.”

A CPSR must be prepared for every product placed on the EU market. The minimum content of the CPSR is listed in Annex I of the Regulation 1223/2009. It is to contain, “as a minimum,” the information required under each of the headings of Part A, Cosmetic product safety information, and Part B, Cosmetic product safety assessment. Part A aims to gather all the data necessary for the safety assessment of the product, while Part B sets out the reasoning, starting from the data, for drawing conclusions as to the safety of the product.

Part A includes 10 sections and a previous paper provided an overview of them.6 From a safety point of view, the most important element is section 8: Toxicological profile of the substances. The aim of this section is to describe the toxicological hazard of each of the substances in the finished product, determine the potential exposure, and draw up a risk characterization. The toxicological profile may address a number of different endpoints. A final decision about which endpoints are relevant is made by the safety assessor on a case-by-case basis, taking into account exposure, use of the product, physico-chemical characteristics of the substances, experience with the substances, etc. Endpoints that may be relevant for the toxicological profile include data on:

• Skin absorption,
• Chronic toxicity via relevant routes of exposure,
• Skin and eye irritation,
• Skin sensitization,
• Mutagenicity/genotoxicity and
• Photo-induced toxicity (in case of UV absorption).

Chronic toxicity is particularly important for the risk assessment of the daily exposure via the calculation of the Margin of Safety (MOS).

Safety Assessment
Part B of the CPSR is the actual assessment of the safety of the product. The cosmetic product safety assessment is an account of the scientific reasoning to support the safety of the cosmetic product and it includes four sections.  The cosmetic product safety assessment must be carried out by a suitably qualified safety assessor with the competence as required in the Regulation and being responsible for it. The Responsible Person is to ensure that the intended use of the cosmetic product and the anticipated systemic exposure to individual ingredients in a final formulation are taken into account in the safety assessment.

Each cosmetic product is considered as an individual combination of cosmetic substances. It is generally accepted that a safety evaluation can be done by ascertaining substance toxicity, provided information is available on the most relevant toxicological endpoints of its constituent substances. In some cases, however, additional information on the finished product is needed in the interest of a sound safety assessment. Examples are cosmetics for specific target consumers groups (babies, sensitive skin, etc.), the presence of certain substances that increase skin penetration and/or skin irritancy (penetration enhancers, organic solvents, acidic components, etc.), the presence of a chemical reaction between individual substances rendering the formation of a new substance of toxicological significance highly probable, the presence of a specific galenic form (liposomes and other vesicular forms, etc.), when the potential toxicity of a particular substance is claimed to be decreased, etc.

When, after an in-depth evaluation of the safety of the final product, the safety assessor does not expect it to cause any adverse effect under foreseeable conditions of use, it is recommended to undertake compatibility/tolerance testing on a number of human volunteers before the product is finally marketed; skin irritation tests on human volunteers may be necessary to confirm the safety of the product.⁴

The responsible person and the safety assessor should work closely together to ensure that the safety of the product is properly assessed and documented and that the assessment is kept up to date.

Cosmetic Ingredients
Cosmetic products/final formulations comprise a list of ingredients that must be safe for consumers. Cosmetic ingredients are mostly chemicals and often mixtures of chemicals of synthetic origin or natural extracts. The careful selection of ingredients is the key issue for ensuring the safety of the finished product. Safety of cosmetic products is in the EU principally based on the safety of the ingredients. The rationale comes from the fact that many thousand of different cosmetic products on the EU market are all derived from a limited number of substances. Hence toxicity testing has been concentrated on ingredients, and particularly on those that are intended to react with biological matrices and therefore are of most concern for human health.⁴

Animal Testing Ban
Since March 11, 2013, a complete ban (testing and marketing) on animal testing for cosmetic products has been in place in the EU.7 The ban applies to all new cosmetics and their ingredients sold in the EU, regardless of where in the world testing on animals was carried out. Since this date, no animal testing can take place in the EU and no company can carry out new animal tests for cosmetics purposes outside of the EU for products to be sold in the EU. The Cosmetic Regulation 1223/2009 contains the same provisions (Article 18).

There is a trend toward animal testing bans and many other countries have implemented such regulation (India, New Zealand) or are in the process of implementing it. Because animal testing is banned in Europe, alternative in vitro methods must be used to provide data about the toxicological profile of each ingredient. The ban applies even if alternative methods to animal testing are not available.

Alternative Test Methods
The European Center for Validation of Alternatives Methods (ECVAM) plays a key role in the development, validation and international recognition of alternative methods.8 Replacement methods have been successfully validated and adopted as OECD (Organization for Economic Cooperation and Development) test guidelines for the endpoints of skin and eye irritation and corrosion, genotoxicity, skin penetration, phototoxicity and, recently, for two skin sensitization tests.

Specific mentions must be made about the following endpoints:
Eye irritation. Several in vitro alternatives to the rabbit eye test have been validated and adopted by the OECD: the bovine corneal opacity and permeability test (BCOP), the isolated chicken eye test (ICE) and the Fluorescein Leakage Test, OECD 437, 438 and 460 respectively. These tests can be used as a screening tool for severe irritant/corrosive substances. However, they cannot reliably detect mild and moderate irritants.

Other alternatives include the hen’s egg test on the chorioallantoic membrane (HET-CAM assay), reconstructed human corneal epithelium models (EpiOcular, SkinEthic). The use of testing strategies is generally recommended, due to the fact that the range of criteria for injury and inflammation covered by the rabbit eye test is unlikely to be covered by a single in vitro test.

Skin corrosion/irritation. Several tests also exist for skin corrosion/irritation evaluation and here again an integrated testing strategy is required to properly assess this parameter. The existing validated alternative methods are the Assay on Reconstituted Epidermis OECD 431, the Transcutaneous Electrical Resistance OECD 428 and the Corrositex OECD 435 for Corrosion Evaluation and the Assay on ReconstitutedEpidermis OECD 439 for Skin Irritation.

Genotoxicity. The assessment of genotoxicity is an important component of the safety assessment of cosmetic ingredients. A number of tests can be used; they include: Ames test (bacterial reverse mutation assay), mammalian cell chromosomal aberration test, mammalian cell gene mutation test (MLA mouse lymphoma assay), and Micronucleus test. No individual test can cover all endpoints and only the use of a battery of tests would provide the adequate coverage of the endpoints. The SCCS recommends today performing a minimum package composed by the Ames and Micronucleus tests.⁹

Skin sensitization. It is one of the most important toxicological endpoint in the development and evaluation of ingredients used in fragrance, cosmetic and personal care products. Since the ban on animal testing in March 2013, EU invested significantly in the development of alternative in vitro methods. The main tests include DPRA (Direct Peptide Reactivity Assay), KeratinoSens, MUSST (Myeloid U937 Skin SensitizationTest), and h-CLAT (Human Cell Line Activation Test). Validation is completed for DPRA and KeratinoSens and OECD has just issued testing guidelines (OECD 442C and OECD 442D respectively). Validation is still ongoing for h-CLAT and its completion is expected shortly. More information about the tests can be found in a recent paper.¹⁰

The toxicological endpoints and OECD-validated alternative in vitro test methods are summarized in Table 1.

In addition, in order to ensure the traceability and quality of the data, all in vitro regulatory toxicological tests have to be performed in compliance with the Good Laboratory Practices (GLPs): Non-clinical safety studies referred to in the safety assessment according to paragraph 1 and carried out for the purpose of assessing the safety of a cosmetic product shall comply with Community legislation on the principles of good laboratory practice (Art 10.3 of the Regulation). Such principles are described in OECD documents.¹³

Testing Strategies
It is critical to develop testing strategies to address the relevant endpoints using in vitro methods whenever applicable. Only a few in vitro tests can be used stand-alone. This is the case for the phototoxicity and the skin absorption tests, respectively OECD 432 and OECD 428. Except for these two previous endpoints, replacement will not be achieved by replacing one animal test with one in vitro test. In most cases, replacement can only be achieved through integrated testing strategies (ITS), combining several in vitro, in silico ((Q) SAR) (quantitative) structure activity relationship, and read-across approaches (see comments in Table 1). Other concepts have also been developed and are more and more used in order to overcome the lack of data, such as QRA (Quantitative Risk Assessment)11 for sensitization (as none of the methods for skin sensitization will replace skin sensitization testing as a stand-alone method) and TTC (Threshold of Toxicological Concern)12 for impurities. All these elements constitute puzzle pieces used in a Weight of Evidence (WoE) approach needed for a comprehensive risk assessment.⁵

Conclusion
The global cosmetics market is vast; a specific emphasis must be put to ensure the safety of consumers. For the biggest market, the European Union, regulations require that each cosmetic product must undergo a safety assessment prior to being placed on the market and banned the use of testing on animals, hence they require the use of alternative in vitro testing methods. The safety of cosmetic products is mainly based on the safety of their ingredients. Typically, cosmetic ingredients undergo toxicological testing for eye and skin irritation, genotoxicity, skin sensitization and phototoxicity (if relevant). Depending on the product specifications; i.e. formulation and recommended/foreseeable usage, the safety assessor will select the relevant specific in vitro and/or clinical tests and integrated testing strategies to develop its analysis and opinion. Compliance to the European regulations and its safety requirements will not only address potential safety concerns but will also expand business opportunities.

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About the Author
Pascal Yvon, PharmD, MBA, has over 25 years of global experience in the life sciences industries, including the cosmetic, biotech, pharmaceutical and diagnostic sectors. He has authored a number of trade journal articles and speaks at leading industry events and conferences. Dr. Yvon holds a doctorate in pharmacy from the Pharmacy University, Paris, and an executive MBA from Rutgers University, NJ. He is a member of the Society of Cosmetic Chemists.  Contact: [email protected]

References:

1. Ernst & Young – Luxury and cosmetics factbook 2014
2. CTPA (Cosmetic, Toiletry & Parfumery Association) – Key facts about the cosmetics industry
3. Regulation (EC) No 1223/2009 of the European Parliament and of the Council of 30 November 2009 on cosmetic products (Cosmetics Regulation)
4. SCCS’s note of guidance for the testing of cosmetic substances and their safety evaluation, 8th edition, December 11, 2012 (SCCS/1501/12)
5. Commission Implementing Decision 2013/674/EU of 25 November 2013 in Guidelines on Annex I to Regulation (EC) No 1223/2009 of the European Parliament and of the Council on cosmetic products (Guidelines on the Cosmetic Products Safety Report)
6. Fioravanti C. Cosmetic Product Safety Report: your missions and those of your safety assessor in order to comply with the European regulation. Soap, Perfumery & Cosmetics (SPC) September 2013, 38-40
7. Communication from the Commission to the European Parliament and the Council on the animal testing and marketing ban and on the state of play in relation to alternative methods in the field of cosmetics. COM (2013) 135 final, March 11, 2013
8. EURL-CVAM Technical Report 2013 provides a more detailed overview of progress made in the development, validation, and regulatory acceptance of alternatives.
9. SCCS’s Notes of Guidance for the testing of Cosmetic Ingredients and their Safety Evaluation 8th revision – Addendum – April 2014
10. Nunzi F. In vitro sensitization tests: a long and winding road. Soap, Perfumery & Cosmetics (SPC) September 2014, 34-36
11. SCCP’s Opinion on Dermal Sensitisation Quantitative Risk Assessment – June 2008 (SCCP/1153/08)
12. SCCP’s Opinion on Use of the Threshold of Toxicological Concern (TTC) Approach for Human Safety Assessment of Chemical Substances with focus on Cosmetics and Consumer Products – June 2012 (SCCP/1171/08)
13. OECD series on principles of Good Laboratory Practice and compliance monitoring – N° 1 OECD Principles on Good Laboratory Practice ENV/MC/CHEM (98)17