Ethical considerations with respect to human testing of cosmetic products have to include the problem of the first topical contact of a human volunteer with the product to be tested. Guidelines have therefore to be based on the principle that no fortuitous e.g. badly defined contact can be allowed. Strict rules have to be defined.

The following guidelines take into consideration the ethical and practical aspects when human volunteers are involved in studies organised to assess skin and mucous membrane compatibility of cosmetic finished products.


1. Background

1.1. Legal requirements for consumer safety

According to the Council Directive (76/768/EEC), "a cosmetic product put on the market within the Community must not cause damage to human health when applied under normal or reasonably foreseeable conditions of use". According to the 6th Amendment of the Cosmetics Directive (93/35/EEC), a European dossier must be kept readily accessible for inspection by the competent authorities, containing a toxicological file based on safety assessment of the ingredients and the finished products. However, there is no legal requirement that finished products have to be tested on animals nor on human beings before marketing.

1.2. Side effects caused by cosmetic products

Cosmetic products are developed to be applied to the skin and external mucosa and to be used by the normal population. It must, however, be considered that people suffering from skin disorders or sensitive skin also use cosmetics. Occasionally undesirable side effects, both local and systemic, may occur. Local reactions may be, among others, irritation, contact allergy, allergic contact dermatitis, contact urticaria and sunlight, especially UV light, induced reactions. Skin and mucous membrane irritation are the most frequently observed reactions.

1.3. Description of terms

For the purpose of the document, the following terms are described as indicated:

- Compatibility test: corresponds to a test intended to confirm that there are no harmful effects when applying a cosmetic product for the first time to the human skin or mucous membrane.

- Acceptability test: corresponds to a test intended to confirm the fulfilment of the expectations for a cosmetic product in-use.

1.4. General statement

Since tests in animals and alternative methods are of predictive limited value with respect to human exposure, confirmatory compatibility tests of cosmetic finished products in humans may be needed scientifically and ethically, provided that the toxicological profile of their ingredients, based on animal testing and/or the use of alternative methods, is available. A high degree of safety has to be expected. Finished cosmetic products are usually tested in small populations

- to confirm the skin and mucous membrane compatibility of the finished products;

- to assess their cosmetic acceptability.

2. Ethical considerations

2.1. Basic Principles

The basic principles for testing in humans are provided by the following documents :

* World Medical Association Declaration of Helsinki in its current revisions (1964-1975-1983-1989-1996)

* Recommendation N° R(90)3, of the Committee of Ministeries/Council of Europe adopted on 4^th February 1990

* Draft Directive on Good Clinical Practice for Trials on Medicinal Products in the European Community

* National Regulations regarding human studies.

2.2. SCCNFP recommendations

According to these basic principles, the SCCNFP recommends the following ones which apply directly to the compatibility testing of cosmetic products:

• Cosmetic compatibility tests on human volunteers cannot be considered as a replacement for animal testing.
• Cosmetic compatibility tests on human volunteers can only be performed to confirm, in a limited number of subjects, that products do not damage skin and mucous membrane, as already expected from other sources.
• The study supervisor must have at his disposal, prior starting any test, the full quantitative formula of the product to be tested, its preclinical safety assessment, its conditions of use and possible warnings.
• Studies should conform to generally accepted scientific principles. They should be based on an adequate knowledge of the potential risks incurred, resulting from laboratory experimentation and/or appropriate knowledge of the scientific literature.
• Research involving human volunteers should not be carried out unless the importance of the objective is in proportion to the inherent risk for the subject.
• Tests involving human volunteers which do not conform to scientific criteria and which are unable to provide exploitable results, are unacceptable even if they do not present any risk for the consenting subjects.
• The interest of the human subject should always prevail over the interest of science and society. Therefore the Investigator should cease as soon as risk is found to outweigh the potential benefit of the study.
• Skin compatibility testing involving human volunteers should be conducted only by technically qualified persons and under the supervision of a clinically competent medical doctor/physician.
• Acceptability tests in consumers do not require review by an ethical committee.
• Compatibility test protocols of cosmetic products possibly posing a risk to volunteers ought to be submitted for consideration and comments to an ethical committee provided that this committee conforms with the laws and regulations of the country in which the study is performed.
• Human volunteers should be adequately informed of the aims, methods used and potential risks of the study and the discomfort they may entail. Free informed written consent is mandatory prior to entering the study.
• Volunteers with any current dermatitis or known past allergic contact dermatitis related to the ingredients of the cosmetic product concerned should be excluded from the panel participating in safety tests.
• Except for specific cosmetic products, especially intended to be used by pregnant women and whose safety has been specially assessed for such employment, pregnant or lactating females should never be included in safety confirmatory tests.
• Children should not be involved with the testing of the compatibility of cosmetic products.
• In selected cases when the inclusion of adolescents (10-16 years) is warranted, they should be fully informed of the aims, methods used and potential risks of the study in order to obtain their free personal co-operation. They should personally give a free informed consent in written form. Parents or guardians should also give their consent.
• Study reports have to provide all experimental information in order to allow to understand the rationale of the study and to preserve the accuracy of the results.

3. Test methods in human volunteers for the skin compatibility assessment of finished cosmetic products

• Possible adverse reactions include skin irritation, contact allergy, photomediated reactions, acne, contact urticaria, pigment changes, hair and nail changes, subjective symptoms and various end-points measured by non-invasive techniques (elasticity, skin thickness, wrinkling, roughness etc.). Therefore it is not possible to make a complete list of current testing methods. The design of the test protocol depends on the specific question asked. In each case the reasoning and the scientific background of the test should be given.
• Among the most frequently used tests for finished cosmetic products are skin irritation tests as human repeated insult patch tests, chamber scarification tests, repeated open application tests, and soap chamber tests for detergents, and various other occlusive or open test methods developed to stimulate intended use situations. Irritancy reaction in humans is not an absolute measure and should be related to appropriate controls defining the range of response.
• In some test methods the skin of the volunteers may be preconditioned by various physical and chemical factors before exposure to the cosmetic product occurs. The design of tests may vary considerably with respect to the selection of volunteers, exposure time, patch test technique and reading.
• Often visual assessment is applied. Although this type of assessment is subjective, good results can be obtained with trained experimenters.
• Non-invasive bioengineering techniques can be applied in safety assessment to quantify and objectivate the results, to measure even sub-clinical symptoms and, generally speaking, to obtain additional information ; this has not been a common practice so far and further validation of these methods is encouraged by the SCCNFP.
• An important aspect in all human testing with finished cosmetic products is that the result obtained should be regarded as relative to the result of control substances, giving the range of reactivity within the test group. At the basis lays the considerable inter-individual variation between skin responses from different volunteers.
• For specific products, confirmatory safety tests may be performed in the surrounding area of the eye. In such a case, extreme attention should be given with respect to possible local irritations. Such tests should be stopped as soon as a significant adverse effect is observed in anyone of the subjects involved in the study. In such tests only one eye should be investigated per volunteers. The study can only be carried out under the strict supervision of an ophthalmologist.