ANNEX 7 - GUIDELINES FOR THE SAFETY ASSESSMENT OF THE FINISHED COSMETIC PRODUCT

Introduction

o approve the cosmetic product under consideration. Therefore, the guidance hereafter should not be used as a check list but rather be considered and adapted case by case when assessing the safety of a finished cosmetic product.

1- Identity of the ingredients

Glossary of terms: a cosmetic ingredient may be

a chemically well-defined single substance with a molecular and structural formula;
a complex preparation, requiring a clear definition and often corresponding to a mixture of substances of unknown or variable composition and biological nature;
a mixture of 1. and 2., used in the composition of a finished cosmetic product.

1-1 Qualitative and quantitative formula

(Directive 93/35/EEC, Article 7a, 1(a))

Precise identification and description of all ingredients used in a given finished cosmetic product are crucial for its safety assessment.

- When chemically well-defined substances are present, their quantity and molecular and structural formula should be given together with their analytical specifications (degree of purity, identification of major impurities, criteria and tests used).

- When complex ingredients are present, their quantity together with a clear definition of the preparation and the material(s) used should be given in order to identify the ingredients with regard to their composition and effects (manufacturing and purification processes including all physical, chemical, enzymatic, biotechnological and microbiological steps); purity criteria and tests used should be provided.

- When a mixture of both is present, the specifications mentioned above also apply. Examples of complex ingredients: these could be of mineral, botanical, animal (including human) or biotechnological origin. Also commercial addition mixtures and fragrance compositions are classified under this group. The following text gives some examples as a guidance on how complex ingredients, depending on their nature and preparation, can be defined.

1-1-1 Complex ingredients of mineral origin

starting material
description of:
- the preparation process: physical processing, chemical modifications, possible purification,

- characteristic elements of the composition: characteristic components, toxic components (%).

physical and chemical specifications
microbiological quality
preservatives added.
1-1-2 complex ingredients of animal origin

species (bovine, ovine, crustacean, human,...)
organs, tissues, biological liquids (placenta, serum, cartilage,...)
country of origin
description of:
- the preparation process: conditions of extraction (solvent, pH, temperature,...);
type of hydrolysis (acidic, enzymatic,...); other chemical modifications;
possible purification;

- commercial form: powder product, solution, suspension, freeze-dried,...

- characteristic elements of the composition: characteristic amino acids,
total nitrogen, polysaccharides, molecular mass,...

- preservatives added

physico-chemical specifications
microbiological quality including relevant viral contamination
additional external contamination
preservatives added.
1-1-3 Complex ingredients of botanical origin

botanical name and family (Linneaus system)
part of the plant processed
description of:
- preparation process: extraction, distillation, destructive destillation,
possible purification;

- commercial form: powder product, solution, suspension,...;

- characteristic elements of the composition: characteristic components,
toxic components (%);

physical and chemical specifications
microbiological quality including relevant fungi
additional external contamination
preservatives added.
1-1-4 Complex ingredients derived from biotechnology

For special biotechnologically derived ingredients, where a modified micro-organism or a potential toxin has not been fully removed, specific data must be available, which can comprise:

description of organisms involved: donor organisms, recipient organisms, modified micro-organisms
host pathogenicity
toxicity, and when possible, identity of metabolites, toxins produced by the organisms
fate of viable organisms in the environment-survival-potential for transfer of characteristics to e.g. natural bacteria
physico-chemical specifications
microbiological quality
additional external contamination
preservatives added.
1-1-5 Commercial addition mixtures

All ingredients (with INCI names when available) entering the composition of commercial mixtures supplied as "raw materials" must be given in the qualitative and the quantitative formula of the finished product. These could be: main components, preservatives, antioxidants, chelators, buffering agents, solvents, other additives and additional external contamination.

1-2 Physico-chemical and microbiological specifications of ingredients

(Directive 93/35/EEC, Article 7a, 1(b))

1-2-1 Relevant physico-chemical specifications

Relevant physico-chemical specifications of all ingredients should be provided:

- physical state (solid, liquid, gas)

- organoleptic properties (colour, odour, taste if relevant)

- solubility properties in water and relevant organic solvents (at ..°C)

- partition coefficient (Log Pow, at ..°C), if applicable

- flash point

- physical properties depending on the physical state:

boiling point, density (at ..°C), pH (at ..°C), viscosity (at ..°C), vapour pressure, ... for liquids;

general appearance (crystal form, amorphous, ...), melting point, pH (..% in ..., at ..°C), ... for solids;

density (at ..°C), ignition point, ... for gases.

1-2-2 Microbiological specifications

Microbiological specifications of ingredients should be provided and in particular of ingredients of biological origin (botanical, animal, human), biotechnical or mineral sources (talc, silica,...). Of ingredients in which it is obvious that micro-organisms cannot survive, no microbiological data should be included (e.g. ethanol, sorbitol, glycerol, preservatives, etc.). The criteria and tests applied should be clearly mentioned.

2- Characterisation of the finished cosmetic product

2-1 Stability of the finished cosmetic product

2-1-1 Physical stability

The physical stability of the finished product should be established, making sure that no changes in physical state of the finished product (e.g. coalescence of emulsions, phase separation, crystallisation or precipitation of ingredients, colour changes, ...) occur during transport, storage or handling of the product. Indeed, exposure to changing temperatures, humidity, UV light, mechanical stress ... could reduce the intended quality of the product and the safety for the consumer.

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 recipient and packaging used, physical stability tests are currently carried out with inert recipients and those intended to be used on the market.

2-1-2 Microbiological stability

The microbiological stability of the finished cosmetic product, established during its development, is dealt with in Annex 8 of the Notes of Guidance. Quantitative and Qualitative limits, according to the category to which the cosmetic product belongs, and challenge testing are described there.

2-2 Physico-chemical specifications of the finished cosmetic product

Relevant physico-chemical parameters should be controlled for each batch of the finished product coming on the market.

General parameters could be:

- physical state

- type of preparation (emulsion o/w or w/o, suspension, lotion, powder, aerosol, ...)

- organoleptic properties (colour, odour, whenever relevant)

- pH (at ...°C) for aqueous preparations

- viscosity (at ...°C) for liquid forms

- other according to specific needs.

The criteria and methods used, and the results obtained per batch should be specified.

2-3 Microbiological specifications of the finished cosmetic product

Routine microbiological analysis of each batch of the finished product coming on the market should be carried out in order to ensure the quality and safety for the consumer.

The parameters examined, the criteria and methods used, and the results obtained per batch should be specified.

3- Transparency of the safety assessment of the finished cosmetic product

s, acidic components, etc.), the presence of a chemical reaction between individual ingredients rendering the formation of a new substance of toxicological significance highly probable, the presence of a special galenic form (liposomes, membrane-like fractions, etc.), when the potential toxicity of a particular ingredient is claimed to be decreased, etc.

3-1 Toxicological profile of the ingredients

(Directive 93/35/EEC, Article 7a, 1(d))

When safety assessment of a finished cosmetic product is carried out, all the toxicological data available for all the ingredients being present should be taken into consideration by the safety assessor. The data sources used should each time be clearly indicated and may consist of one or more of the following possibilities:

in vivo tests using experimental animals
in vitro tests using officially validated alternative methods (see Annex 2)
human data from clinical observations and compatibility tests in human volunteers
data from data banks, published literature, in house experience and data obtained from raw data suppliers. Often scientifically developed alternative methods are used to obtain in vitro supportive results. This is acceptable on the condition that these methods have a good history of being used in the safety assessment of a particular class of compounds and are supported by results of appropriate positive and negative controls.
All these data can be obtained either by tests on ingredients carried out with the specific purpose of the safety assessment of the finished product under consideration, or can be derived from other toxicological studies conducted for other regulatory purposes.

The list of the general toxicological requirements for cosmetic ingredients in the EU is taken up in Annex 1. Focus lays in particular on local toxicity evaluation being skin and eye irritation, skin sensitisation, and in the case of UV-absorption also on photo-irritancy and photo-sensitisation. When certain test results are not available, a scientific justification should be included. It is essential to mention here that for each ingredient the toxicological data given should be derived from tests with the same substance(s) as the one(s) included in the finished cosmetic product. Experience, however, learns that this is often not the case and that the discrepancies between skin tolerance in real life and observed under test conditions often are based on this mistake.

3-2 Assessment of the safety of the finished product

The scientific reasoning by the safety assessor must be taken up in the safety assessment report of the finished product. This means that all toxicological data available on the individual ingredients and the end product (favourable and unfavourable), all chemical and/or biological interactions and human exposure via intended and likely routes must be taken into account. Exposure routes are considered in more details under Point 6 of the index of the Notes of Guidance and safety margins for specific ingredients are being shown in Annexes 4, 5 and 6.

The conclusions made by the safety assessor must be well-argumented and the inclusion in the formulation of particular ingredients of special concern (low safety threshold) must receive special attention. The safety assessor may accept, reject, or accept under specific conditions the formulation under consideration. A rejected product cannot be marketed. Recommendations by the safety assessor, which are relevant for the safety-in-use of the product, must be followed.

3-3 Qualifications of the safety assessor

(Directive 93/35/EEC, Article 7a, 1(e))

The curriculum vitae of the safety assessor must be included in the dossier. The safety assessor may be employed by the manufacturer or may be an external consultant. No connection should exist with production or marketing. As well as having the training requested, the safety assessor must also provide evidence of having relevant experience in the field of toxicology, as well as a controlled independence in matters of product related decision.

3-4 Regular review of the safety of the finished product

The safety of the product should be reviewed on a regular basis. To that end, undesirable effects on human health during use of the product should be filed (complaints during normal and improper use, plus the follow-up done) and taken into account in the next safety assessment of the product.

4- Fragrances

The certificate of conformity attached to a fragrance compound should be systematically supplemented by:

a semi-quantitative concentration of the ingredients in the coded fragrance compound (i.e., <0.1%; 0.1 to <1%, 1% to <5%, 5% to <10%, 10% to <20%, 20% and more) using the preferred terminology as indicated in Section II of the Inventory of Cosmetic Ingredients and the INCI name if available;
for natural ingredients, there should be either
1) an analysis of the composition of the batch of the natural ingredient, or

2) an indication of the maximum levels of components which may be present in the natural ingredient, taking into account batch to batch variation;

an indication of which of the ingredients have an established potential to cause contact sensitisation, phototoxicity, systemic toxicity etc., or are subject to restriction either by industry guidelines, the Cosmetics Directive or by SCCNFP opinions. Confirmation that any such restrictions have been conformed to;
an indication of the types of cosmetic products in which the compound may be used and at what maximum concentrations.
The safety assessor of the finished cosmetic product should have available the above. In the assessment, reference should be made to the semi-quantitative formulation of the fragrance compound and consideration taken as to the toxic potential of the ingredients considered singularly or in combination and with relevance to the finished cosmetic product considered as a whole.