Commission Implementing Decision of 25 November 2013 on Guidelines on Annex I to Regulation (EC) No 1223/2009 of the European Parliament and of the Council on cosmetic products (Text with EEA relevance) (2013/674/EU)

Physical/chemical characteristics of substances or mixtures

This description is to include the most relevant physico-chemical properties of each substance and mixture contained in the product, for example: chemical identification, physical form, molecular weight, solubility, partition coefficient, substance purity, other parameters relevant for the characterisation of specific substances and mixtures, and, for polymers, the average molecular weight and range.

Where relevant, the particle-size distribution curve of substances should be included in the physico-chemical characteristics, especially for nanomaterials.

Cosmetics manufacturers should ensure that the specifications of raw materials are properly documented by their suppliers. Specifications should be available for each raw material actually used in the product. Based on function, additional specifications may be needed. For UV absorbers, for instance, the absorption spectra should be provided.

For each description of physico-chemical properties and specifications (for each substance and mixture contained in the product), the reference methods should be stated in the safety report.

Physical/chemical characteristics of the finished cosmetic product

This description is to contain the specifications of the finished product. Each specification should be given with relevant limits, e.g. pH between 5.5 and 6.5.

For each description of physico-chemical properties and specifications of the finished product, the reference methods should be stated in the cosmetic product safety report.

Stability of the cosmetic product

As the requirement is to assess the stability of the cosmetic product under reasonably foreseeable storage conditions, if stability is dependent on storage conditions, information about these conditions should be passed on throughout the supply chain, and, if relevant for the end user, it should be indicated on the labelling of the product.

The methodology used to determine the product’s minimum durability should be described. Any specific preservation precautions should be mentioned.

All available data used to justify the indicated minimum durability should be listed in the safety report. In order to determine the coherence of the stability study conducted, and to check the relevance of the date of minimum durability chosen for the product, the description of the tests specific to the stability study and the results of those tests should be included in the cosmetic product safety report. In addition, the following should also be provided:

1. evidence that the composition of the product used for stability testing corresponds to the product actually placed on the market;

2. the results of the preservative efficacy study, e.g. challenge test, if applicable⁽⁷⁾;

3. when applicable, the period-after-opening (PAO)⁽⁸⁾ and its justification.

The SCCS has recommended that ‘relevant stability tests, adapted to the type of cosmetic product and its intended use, should be carried out. To make sure that no stability problems are induced by the type of container and packaging used, physical stability tests are currently carried out with inert containers and those intended to be used on the market.’⁽⁹⁾

Microbiological quality of substances and mixtures

The main parameters for microbiological quality are the original level of contamination and the possibility of microbial growth. Particular attention should be paid to the raw materials (substances and mixtures) most susceptible to microbial growth (e.g. water-based mixtures, protein-rich materials, plant or animal raw materials). On the other hand, there are raw materials which do not support microbial growth, e.g. organic solvents.

Microbiological quality of the finished cosmetic product

Concerning microbiological susceptibility, there is a difference between three product categories:

1. low microbiological risk products (e.g. products with an alcohol content > 20 %, products based on organic solvents, high/low-pH products), for which neither a preservation challenge test nor microbiological quality tests on the finished product are necessary. A scientific justification is to be provided, however;

2. single-use products, and products which cannot be opened (e.g. for which the packaging allows dosing the product without it coming in contact with the air), for which only microbiological quality tests on the finished product are necessary. A scientific justification is to be provided, however;

3. all other products, for which both a preservation challenge test and microbiological quality tests on the finished product are necessary.

Specific ‘Guidelines on Microbiological Quality of the Finished Product’ are provided in the SCCS Notes of Guidance⁽¹¹⁾.

Purity of substances and mixtures

The presence of unintended substances, such as impurities and traces, can have an impact on the safety of the finished product. The cosmetic product safety report is to include data on the purity of raw materials (substances and mixtures) and the identification of the toxicologically relevant unintended substances. These substances should be taken into account in the safety assessment of the product.

Impurities are unintended substances in raw materials.

A trace is a small quantity of an unintended substance in the finished product.

The presence of traces in the finished product can be evaluated in two ways:

1. through the specifications/technical data for each raw material, based on knowledge of the process for manufacturing the raw material (origin of substance, production process, synthesis route, extraction process, solvent used, etc.);

2. through a physico-chemical analysis of possible impurities in raw materials and, if necessary, in the final product (e.g. nitrosamines which are potentially generated during or after the manufacturing process).

Traces of prohibited substances are dealt with in paragraph 3.4.2 of these Guidelines.

Some traces have regulatory concentration limits. For the presence of traces of substances that are not prohibited, and for which there are no regulatory concentration limits, but which could be expected to impact consumer safety, the safety assessment needs to be carried out by the safety assessor.

Evidence of the technical unavoidability of traces of prohibited substances

While the procedure outlined in paragraph 3.4.1 should be followed for all known impurities and traces to evaluate their toxicological impact, further investigation is required for prohibited substances present as traces in the finished product⁽¹²⁾.

When such presence is technically unavoidable, the cosmetics manufacturers are required to provide evidence of the technical unavoidability. That means they have to justify the presence of those traces by all necessary means. The presence of traces of prohibited substances should be kept as low as is reasonably achievable under good manufacturing practices. In addition, the safety assessor has to decide whether their levels are toxicologically acceptable and whether the product is still safe.

Especially in the case of non-threshold genotoxic and carcinogenic substances⁽¹³⁾, the cosmetic industry should keep improving its best practices in order to eliminate these substances (ALARA principle⁽¹⁴⁾) in the finished cosmetic product. The main concern is to ensure the protection of human health, as required by Article 3 of Regulation (EC) No 1223/2009.

Traces generated by the degradation of substances within the final product (stability issues), by preservation or transport problems, or by the interaction of raw materials should be avoided through good manufacturing practices, or possibly through re-formulation of the product.

The relevant characteristics of packaging material

Packaging material means the container (or primary packaging) that is in direct contact with the formulation. The relevant characteristics of packaging materials in direct contact with the final product are important for the safety of the cosmetic product. Reference to Regulation (EC) No 1935/2004 of the European Parliament and of the Council⁽¹⁵⁾ could be useful.

Experience with similar formulation/packaging combinations already on the market provides useful indications. Materials that have been developed for food packaging have often already been tested, so relevant information on stability and migration may be available. Additional testing may not be required. However, more evaluation may be needed for new or novel packaging.

The combination of packaging material, formulation of the cosmetic product and contact with the external environment may have an impact on the safety of the finished product, due to the following factors:

1. interaction between the product and the packaging material;

2. barrier properties of the packaging material;

3. substance migration from/to the packaging material.

The information on relevant characteristics of the packaging materials in direct contact with the product should allow an estimation of potential risks. Relevant characteristics could include, for example, the following:

1. composition of the packaging material, including technical substances such as additives;

2. technically unavoidable impurities;

3. possible migration from the packaging.

This information only indicates the hazard. It is up to the safety assessor to evaluate the risk⁽¹⁶⁾.

Studies on interactions/suitability between formulation and packaging allow testing of the potential migration of small amounts of substances from the primary packaging material to the product. These tests are performed under specific and relevant test conditions. There are, however, no standard procedures for cosmetic products. An appropriate assessment may be made based on knowledge of the formulation and primary packaging materials and experienced expert judgment.

If migration is dependent on storage conditions, the correct conditions should be indicated on the product labelling. If the formulation is sensitive to light or air, and would degrade in a way that impacts product safety or product efficacy, appropriate packaging should be used.

General considerations concerning the toxicological profile as part of the safety assessment

The relevant elements of the toxicological profile of each substance or mixture should be described in detail in the cosmetic product safety information (Part A) and assessed in the safety assessment (Part B), bearing in mind the exposure situation, the intrinsic toxicity (or hazard) of each substance, and the specific conditions of use of the product.

Human experiences, animal studies or alternative methods to animal testing are helpful in understanding the health risk for humans exposed to dangerous substances. For the toxicological profiles, toxicological studies are used to identify the hazards which could be associated with a risk to humans. It is essential to consider the quality and limitations of the studies that have been performed. The validity of a study should be taken into consideration in determining whether there is a need for new information to understand the risk to human health⁽²⁰⁾. Studies conducted in accordance with international guidelines are the most useful, but unfortunately not all studies meet these standards. Thus, the limitations of such studies should be considered in assessing the toxicological profile for each substance.

The safety assessor should ensure that the experimental data comply with the requirements of Article 18 of Regulation (EC) No 1223/2009 concerning animal testing. The 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 outlines the Commission’s interpretation of those requirements⁽²¹⁾.

Toxicological profile of substances for all the relevant toxicological endpoints

The toxicological profile for each substance is determined by the hazard identification and the dose-response characterisation.

The first essential step in developing the toxicological profile is to gather all the relevant information about the intrinsic properties of the substance. Such information should include the following:

1. as the most valuable toxicity information, actual test data from in vivo or in vitro studies obtained in accordance with Commission Regulation (EC) No 440/2008 of 30 May 2008 laying down test methods pursuant to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH)⁽²²⁾, recognised international guidelines, or standards (e.g. OECD Test Guidelines), and performed in accordance with good laboratory practice principles;

2. existing test data that have not been obtained in accordance with the latest adopted/accepted version of a test guideline or with good laboratory practice standards, but which are considered valid;

3. in vitro data or alternative data from valid test systems, to be used as a screening study to predict toxicity;

4. human data and/or experience. It is in general not acceptable to perform human toxicology studies for hazard identification, but, if data or experience exist, they should be included in the final assessment;

5. human (clinical) data, including data from clinical trials and applications in other industries such as food and medicinal products;

6. data gathered from post-marketing surveillance;

7. human volunteer compatibility studies, which should only be used to confirm safe levels of use for a relevant target population⁽²³⁾;

8. read-across⁽²⁴⁾ approaches, based on the chemical structure and properties of related substances in order to predict the toxicity of the ingredient, grouping of substances, and non-testing data from QSAR model outputs.

Based on data obtained from all available sources, and taking into account the quality of the data, the safety assessor can evaluate the likelihood of adverse effects in humans through the ‘weight of evidence’ approach⁽²⁵⁾.

A prerequisite for a proper risk assessment is the availability of adequate data. For additional support on this matter, one may consult the guidance for the preparation of safety dossiers for submission to the Scientific Committee for Consumers Safety (SCCS), set out by the Committee itself in its Notes of Guidance. Though these Notes of Guidance are provided for substances where an authorisation is needed, i.e. for colorants, preservatives and UV filters, or which otherwise raise concern, the requirements they set out may be helpful for the safety assessment of all substances used in cosmetic products. In addition, a section of the most recent Notes of Guidance focuses on the safety assessment of finished cosmetic products⁽²⁶⁾.

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, the physico-chemical characteristics of the substances, experience with the substances, etc.⁽²⁷⁾. Attention should also be paid to local effects (e.g. irritation and photo-toxicity), when relevant. Where a certain endpoint is considered to be not relevant, this should be justified.

Endpoints that may be relevant for the toxicological profile are:

1. acute toxicity via relevant routes of exposure;

2. irritation and corrosivity;

3. skin irritation and skin corrosivity;

4. mucous membrane irritation (eye irritation);

5. skin sensitisation;

6. dermal/percutaneous absorption;

7. repeated dose toxicity (normally 28- or 90-day studies)⁽²⁸⁾;

8. mutagenicity/genotoxicity;

9. carcinogenicity;

10. reproduction toxicity;

11. toxicokinetics (ADME studies);

12. photo-induced toxicity;

For the appropriate endpoints, the most relevant concentrations or No Observed Adverse Effect Levels (NOAEL) or Lowest Observed Adverse Effect Levels (LOAEL) should be identified for further use in the risk characterisation process.

Additional information regarding endpoint specific data and their interpretation can be found in the endpoint specific guidance⁽²⁹⁾ prepared by the European Chemical Agency (ECHA) for the implementation of Regulation (EC) No 1907/2006 of the European Parliament and of the Council⁽³⁰⁾ on Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH).

For some cosmetic ingredients e.g. of mineral, animal, botanical and biotechnological origin (see also Substances of Unknown or Variable composition, Complex reaction products or Biological materials or ‘UVCB substances’ under REACH)⁽³¹⁾, their identification should carefully address source, process, organisms involved, etc., in order to evaluate their toxicological profile.

If certain hazards cannot be sufficiently addressed, or if doubts remain regarding the robustness of the data, additional uncertainty factors may be introduced or additional data may need to be generated.

Consideration of all the significant routes of absorption

Dermal, oral and inhalation routes of exposure are potentially relevant for human exposure to cosmetic products. It is essential to calculate the systemic exposure in order to compare it with the relevant NOAEL. The ratio between these two is defined as the margin of safety, which is an indicator of whether the product can be considered safe or not (see also section 3.8.4 and following).

Absorption is linked to the bioavailability of a substance, and is essential for calculating the margin of safety. Systemic exposure can be calculated as:

Absorption can occur through several external routes: dermal, oral and inhalation.

If the intended exposure for the cosmetic product is not in line with the route of exposure in the safety data, route-to-route extrapolation should be considered.

In addition, there may also be a possibility of secondary inhalation exposure where cosmetic products contain volatile substances which can be inhaled unintentionally in the case of direct use, e.g. toluene in nail polish, various substances contained in nail modelling gels, etc.

Consideration of systemic effects and calculation of the margin of safety

The safety assessment of a product for systemic toxicity is highly dependent on data on each substance, since there will be no data on systemic toxicity for the finished cosmetic product.

Risk characterisation usually involves an expert evaluation of the potential non-quantifiable adverse effects, followed by calculation of an uncertainty factor or margin of safety⁽³⁵⁾. This calculation depends on the systemic exposure to the substance and its toxicological parameters.

In accordance with Point 8 part A of Annex I to Regulation (EC) No 1223/2009, systemic effects and margin of safety are to be considered in Part A of the safety report. As they are mandatory, the omission of these steps is to be duly justified. An example where this could apply would be the presence of a substance in the cosmetic product at a low level, with the expected (worst case) exposure levels being below the appropriate threshold of toxicological concern (TTC) values⁽³⁶⁾. Another example could be the inclusion of food materials for which a much higher innocuous ingestion level is known.

When the requirement to calculate the margin of safety cannot be met, a different way of expressing the safe dose for each substance may be appropriate, where justified. When a NOAEL is not available, other reference toxicology values such as No Observed Effect Level (NOEL), LOAEL, Lowest Observed Effect Level (LOEL), can be used to calculate the margin of safety; Benchmark Dose (BMD) or Virtually Safe Dose (VSD), used to qualify and quantify a risk in other fields, may be used in the context of cosmetic products safety assessment, provided a relationship with exposure is established, by comparing the exposure from cosmetics and these reference doses.

Otherwise, the safety of a particular substance in a particular product cannot be demonstrated.

According to the procedures described in the SCCS Notes of Guidance⁽³⁷⁾, the margin of safety (MoS) for a specific route of exposure can be calculated using the following formula:

where the Systemic Exposure Dose (SED) is obtained by combining the external exposure (mg/kg bw/day) with the absorption rate (typically expressed in % or μg/cm²), frequency and retention factors.

It is generally accepted that the margin of safety should be at least 100 to declare a substance safe for use in a finished product.

In the case of route-to-route extrapolation, the respective bioavailability via each route should ideally be taken into consideration. The assumption of 100 % oral bioavailability might overestimate the systemic exposure in a toxicity study via the oral route. Therefore, in the absence of data, it should be assumed that not more than 50 % of an orally administered dose is systemically available. If there is evidence to suggest poor oral bioavailability, for example if the substance is a poorly soluble particulate, it may be more appropriate to assume that only 10 % of the administered dose is systemically available⁽³⁸⁾. Whenever oral absorption data are available, these should be included in the calculations.

The NOAEL chosen for calculating the margin of safety is taken from long-term repeated dose toxicity studies (sub-acute, sub-chronic, and/or chronic toxicity tests, carcinogenesis tests, teratogenesis tests, reproduction toxicity, etc.).

The value used will be the lowest NOAEL obtained by the most pertinent study with respect to the conditions of use of the substance, to species sensitivity, etc.

From the complete toxicological profile, a NOAEL should be determined for the systemic effects. In general, the lowest relevant NOAEL of the most relevant endpoint is selected for calculating the margin of safety.

The calculation of the margin of safety based only on Median Lethal Dose (LD50) data derived from single dose tests (instead of a NOAEL from at least sub-acute tests) cannot be used to justify safe use.

When the absence of bioavailability can be clearly demonstrated, the calculation of the margin of safety is not necessary. In these cases the possible local effects on skin or mucous membranes should still be considered.

Impact on the toxicological profile of certain characteristics of the substances or the product

Use of read-across should be substantiated and justified

Several approaches exist for the read-across technique. The use of this technique should be substantiated and justified.

Identification of the sources of information

The determination of the toxicological profile requires a minimum of information on the substance to be evaluated.

This information can be collected from toxicological studies. If data from human experience exist, they should be taken into account.

Other tools such as quantitative structure-activity relationship (QSAR) or bridging approaches are only estimations of toxicity, and the weight of evidence should be substantiated and justified.

The following sources of data should be taken into consideration:

1. Safety and quality data which may be on file with the respective suppliers of the raw materials in the formulation, and which the supplier should share with the manufacturer of the cosmetic product. This is an important element in considering the availability of relevant data to demonstrate the safety of each cosmetic ingredient in the final product formulation;

2. If an opinion of the SCCS exists, the NOAEL used in the opinion should be used. The safety assessor should take into account the most up-to-date scientific opinion;

3. If an opinion of another authoritative scientific committee exists, the NOAEL used in the opinion could be used, provided that the conclusions and limitations are applicable to the expected use (the use taken into account for calculating the margin of safety can be different). The safety assessor should take into account the most up-to-date scientific opinion;

4. If no scientific opinion exists, it will be necessary to provide information to characterise the toxicological profile of each substance. The data can be obtained from several databases or literature (see the Appendix)⁽⁴¹⁾;

5. Classification under Regulation (EC) No 1272/2008 of the European Parliament and of the Council⁽⁴²⁾;

6. Studies performed or obtained by the manufacturer of the product;

7. In silico prediction (QSAR);

8. Bridging approach;

9. Assessments of non-cosmetic uses of the substance (foodstuffs, food additive, food contact materials, biocides, Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH)…) may also be used in order to complete information on the toxicological profile of the substance.

10. When available, the CSR (Chemical Safety Report) or the robust study summaries submitted pursuant to Regulation (EC) No 1907/2006 (REACH).

A number of substances and/or mixtures have not been studied sufficiently to determine all the pertinent toxicological parameters. For these missing parameters, or where the risk characterisation is based on an approach using toxicological data acquired for other substances (for example similar structures) or for uses other than cosmetics (food, biocides, pharmaceutical products, etc.), justifications should be included in the report.

Safety Evaluation of Substances and/or Mixtures

The safety evaluation of substances and/or mixtures consists of three main steps:

1. hazard characterisation of substances and mixtures;

2. assessment of the local and systemic exposure (considering absorption data);

3. risk assessment of systemic effects (calculation of margin of safety) and risk assessment of local effects (such as skin allergy, skin irritation).

For fragrance and flavour compounds, where information on their composition is confidential, a safety assessment may be provided to the responsible person for the finished cosmetic product by the manufacturer of that mixture. Taking into account the concentration in the final cosmetic product and its exposure pattern, the safety assessment of the fragrance and flavour compound should be prepared following the principles described in Annex I to Regulation (EC) No 1223/2009 and these guidelines. An appropriate document demonstrating the safety of the fragrance or flavour compound should be provided by the supplier to the responsible person for the finished cosmetic product.

Safety Evaluation of the Cosmetic Product

The safety evaluation of the cosmetic product covers three main aspects:

1. summary of the risk assessment based on the local and systemic effects of all individual substances/mixtures⁽⁵¹⁾;

2. additional assessment of the safety of the formulated product, which cannot be assessed by assessing the substances/mixtures separately. This could for instance be the formulation’s skin compatibility, assessment of possible combination effects, such as one ingredient that can increase the absorption rate of another ingredient, possible effects that could arise from interaction with packaging material, or possible effects due to chemical reactions between the individual substances/mixtures in the formulated product⁽⁵²⁾;

3. other factors that influence the safety assessment, such as stability, microbiological quality, packaging, and labelling, including use instructions and precautions for use.

The specific assessment for cosmetic products intended for use on children under the age of three which is required in accordance with Regulation (EC) No 1223/2009 should take into account the specific recommendations in the SCCS Notes of Guidance⁽⁵³⁾.

In the specific assessment required in accordance with Regulation (EC) No 1223/2009 for cosmetic products intended exclusively for use in external intimate hygiene, the particular characteristics of the application site also are to be taken into account.

The safety assessor may accept, reject, or accept under specific conditions the formulation under consideration. A product that does not comply with Regulation (EC) No 1223/2009 is to be rejected and is not be marketed. Recommendations by the safety assessor regarding the safe use of the product should be followed.

In order to ensure that the cosmetic product safety report is kept up to date as required by Article 10(1)(c) of Regulation (EC) No 1223/2009, the safety of the finished product should be reassessed regularly.

When changes in the legal requirements occur (e.g. restrictions of one of the substances included in the formulation), it should be checked, amongst others (e.g. labelling), whether the formulation still complies with the law, and the safety assessment should be reviewed and, if necessary, updated.

The safety assessment should also be reviewed and, if necessary, updated, where one or more of the following circumstances apply:

1. new scientific findings and toxicological data on the substances are available which could modify the result of the existing safety assessment;

2. changes occurring in the formulation or specifications of raw materials;

3. changes occurring in the conditions of use;

4. a rising trend in terms of the nature, severity and frequency of undesirable effects, both under reasonably foreseeable conditions of use and in the case of misuse⁽⁵⁴⁾.

Structures and processes should be established to ensure that the information relevant for the update of the cosmetic product safety report is efficiently exchanged between the responsible person and the safety assessor, and that the safety assessor is in a position to intervene where an update is necessary.