Specifications of raw materials

If the raw material is described in a pharmacopoeia, the monograph from this can be used. The Danish Agency of Environmental Protection considers the European, the British, the French, the Japanese, and the American pharmacopoeia suitable in this connection.

Raw materials of botanical and animal origin

In case of raw materials extracted from plants or raw materials, which are part of plants, the following should be stated for further identification:

1. Botanical name and family.
2. Which part of the plant is used.
3. From where does the plant descend geographically.
4. When was the plant reaped and which stage of growth had the plant reached.
5. Treatment with pesticides during growth.
6. Production process, including extraction, distillation or cleaning out.
7. Commercial form: A powder or a solution, and solvent, if any.
8. Characteristic ingredients, e.g. active ingredients (in %), microbiological quality as well as impurities.

Generally, material from plants and parts of plants should be examined for pesticide residues etc., radioactivity, toxic metals, possibly contaminated substances and falsifications. If the raw material contains active ingredients described in a pharmacopoeia the analytical methods stated in the pharmacopoeia should be followed.

Corresponding requirements for identification may be relevant for raw materials extracted from animals. As an example can be mentioned tissue from cattle, sheep and goats where certain forms of tissue are not allowed in cosmetic products due to transmittable mad-cow-decease (TSE), cf. Annex 2 to the Order of Cosmetics.

2.2.3 Criteria for physico-chemical purity of raw materials

Physico-chemical purity of the raw materials

Any known impurity, which might have a toxicological effect, must be stated by name and level of content. It could be content of solvent residues, e.g. benzene in Vaseline, monomer residues in polymer compositions, e.g. acryl amide, nitro amines in alkanolamides, heavy metals, pesticide residues etc.

All impurities arising from the production process of the raw materials, or the breakdown products produced during the stability test must be identified. The identification can be made by means of HPLC, GC, AAS or IR.

2.2.4 Physico-chemical specifications of the finished product

Specifications of the finished product

Relevant specifications of the finished product should be stated including physico-chemical specifications as mentioned under raw materials in order that the ordinary quality of the product can be guaranteed by means of these specifications.

2.2.5 Physico-chemical purity of the finished product

Physico-chemical purity of the finished product

It is the responsibility of the manufacturer that the finished product does not contain other impurities or substantial amounts of the impurities than mentioned in the product specifications, e.g. nitro amines, and that these impurities do not influence the safety of the cosmetic product.

2.2.6 Microbiological control of the raw materials and the finished cosmetic product

Microbiological control of the raw materials

It is important to limit the existence of microorganisms in cosmetic products not only to protect the user from harmful effects but also to secure that the product will keep fresh and will not degrade quickly and be spoiled. Aqueous products, for instance, will often have limited keeping qualities as they are especially sensitive to microbial growth.

Raw materials may contribute considerably to microbial pollution of the product, all dependant on their nature and origin, and the demands on microbial purity must be described in the specifications of the raw materials. Especially water must be tested frequently for growth. As a rule, water, which is not sterilised, should not be stored. It might turn out to be necessary to sterilise the water after a demineralisation in order to obtain a sufficiently pure quality of the water, as microorganisms may often pollute ion exchanger columns.

When setting up criteria for microbial pollution there is a differentiation between the following product categories:

1. Products for children under 3 years, skin products and products intended for eye surroundings and mucous membranes.
2. Other products, e.g. rinse off products.

Acceptable levels

The Danish Agency of Environmental Protection considers the following levels to be acceptable in respect of microbial pollution:

Re 1.)

- less than 10² aerobe bacteria and fungi per gram or per millilitre of the raw material or the finished product.

Re 2.)

- less than 10³ aerobe bacteria and 10² fungi per gram or per millilitre of the raw material or the finished product.

Further, the following microorganisms must not be found in cosmetic products:

The probability of finding the micro-organisms mentioned is, however, extremely limited under the clean manufacturing conditions which are necessary to observe the requirements of no more than 10² bacteria and fungi. Consequently, a test for these may, in general, be omitted, when the above-mentioned requirements have been satisfied.

An appropriate number of samples of at least 1-10 g or 1- 10 ml must be taken for control. The amount of samples and the frequency of the control very much depend on the composition and type of product. The control may also depend on how often the product is manufactured. A guideline for the determination of sampling can be to test the first 3 batches in order to get an impression of normal manufacturing conditions. Based on the experience of these tests, compared with the experience from challenge experiments (cf. below) it is determined whether it is necessary to test all batches, or if test of e.g. every 3, every 5, or every 10 etc. will be a sufficient control.

Procedure for microbiological control

A suitable procedure for microbiological control of finished cosmetic products can be found in the European pharmacopoeia, "Total viable aerobic count", (Ph.Eur. 2.6.12) and "Test for specified micro-organisms" (Ph.Eur. 2.6.13.), (4).

The individual manufacturer can perform the microbiological control of the cosmetic products himself. To perform the control correctly it will among other things require controlled, clean premises, microbiological know-how and equipment. The test for specific bacteria and fungi is more demanding to perform.

Efficacy test of the anti-microbial properties

When developing a new cosmetic product, or when changing existing products it is important to secure that the product has anti-microbial properties in order that the content of bacteria and fungi will not cause damage to the product or the user. This can be done either through the anti-microbial properties of the ingredients or by adding suitable preservatives.

The efficacy of the anti-microbial properties of the cosmetic products is tested in a challenge test. In this test the product is exposed to a definite amount of micro organisms (10⁵-10⁶ germ/ml). When, at normal use, the user runs the risk of being infected, or there is a risk of deterioration of the product, this test must be performed.

Challenge test

The challenge test is described more closely in "Efficacy of anti-microbial preservation" (Ph.Eur. 5.1.3) (4). This describes which micro organisms should be used in the test as well as the entire procedure for adding micro organisms, sampling and count of micro organisms, which survive within the indicated period. The Technical Guidance Notes from SCCNFP (3) state that the micro organisms to be used in the test must be Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans; however, tests with other micro organisms may in certain instances be necessary.

Acceptance criteria

For cosmetic products it is recommended to follow the acceptance criteria described in U.S.P. (Anti-microbial Preservation - Effectiveness) (5). This implies that the bacteria must be reduced to 0,1% of the initial concentration after 14 days, and that the concentration of bacteria after further 14 days is not increased. As to fungi the concentration after 14 days must not exceed the initial concentration, and must stay on the same level after further 14 days.

The anti-microbial properties for the product are sufficient if a significant decrease or no increase in the number of micro organisms can be observed when the product is tested for the intended storage and use. In this connection it is important also to examine whether the packing of the product protects the contents sufficiently. Further addition of preservatives is not desirable, and addition of a higher dose of preservative must in no way replace the demands for good manufacturing practices.

The challenge test should be repeated if it is doubtful whether the product is sufficiently preserved. It must be emphasised that challenge tests do not replace routinely control.

2.3 Method of manufacture

2.3.1 In general

Method of manufacture

According the Order of Cosmetics the following outlines have been laid down for the actual manufacture of cosmetic products:

It is recommended to follow the Guideline for Good Manufacturing Practices of Cosmetic Products (GMPC) from the Council of Europe (6). It should be emphasised that in order to be able to meet the rest of the requirements of the dossier it is important to ensure full traceability in the manufacturing process.

The manufacturing method must be described by all relevant stages of the process. A documentation system for all stages in the manufacturing process must be set up with reference to the journal for the production series (batch journal), for the finished product and the batch journals for the raw materials. The description of the manufacturing method must, among other things, comprise:

1. A well-defined manufacturing procedure covering all stages of the production, determined by directions for composition, directions for manufacturing and directions for packaging including the choice of suitable packaging to keep the quality of the product. Any deviation from the directions must be reported.
2. Suitable manufacturing facilities, including the staff and training of the staff; apparatus and manufacturing equipment including cleaning requirements as well as raw materials of good quality.
3. Quality control by means of suitable, well-defined and updated test methods.
4. An effective manufacturing journal which as a minimum must contain the following data for each product:

- Trade name, internal code number etc.
- Batch number and date.
- Reference to specifications and methods of control.
- The result of control test of the product as well as the initials of the person who carried out the tests.

2.3.2 Sub-contractor manufacture

Sub-contractor manufacture and manufacturing method

In case of sub-contractor manufacture it is important that the specifications of the products are clear and unambiguous, and that the person responsible for marketing ensures that the sub-contractor is living up to the above-mentioned requirements (Chapter 2.3.1) and has the necessary manufacturing facilities, equipment, staff etc. at his disposal. Furthermore, directions, specifications etc. must be available in a language, which can be understood in the country from which the product is placed on the market.

There ought to be a written agreement covering the entire manufacturing process, and the person responsible for the marketing should frequently control whether the wage producer is living up to the defined specifications.

2.4 Safety assessment of the finished product

2.4.1 In general

According to the Order the following assessment regarding hazardous properties of the cosmetic products, if any, applies:

Procurement of information

Sufficient information to assess the safety of the finished cosmetic product must be procured. The hazardous effects of the individual substances must be assessed based on the criteria of the harmfulness of the substances specified in the Order of Classification (7). It is the intention that the retrieval in the traditional toxicological literature regarding the ingredients should form sufficient basis of the assessment of the finished product without having to test the finished product on animals or human beings. However, as described below, further tests may in certain cases be necessary.

Detailed guidelines for use have already been laid down for several ingredients in cosmetic products in of Annex 3 to 6 in the Order of Cosmetics. Corresponding annexe can be found the Directive on Cosmetics. The determination of the restrictions for use in the annexe mentioned has been made by the Commission based on assessments of the safe use of the substances in cosmetic products in one of the specified ways. If the ingredients are used in the way specified, the safety assessment of the substance in question can as a rule be made with reference to the fact that the substance has been approved for the purpose in question. If the substance, however, is used for other purposes than those laid down in the Order of Cosmetics, or in other concentrations (which for instance is allowed for certain preservatives), an independent assessment is still necessary.

It should, however, be emphasised that it is always the company which places a cosmetic product on the market which is responsible for the safety of the product, cf. §9 of the Order of Cosmetics. Therefore, when assessing the safety of any new, commonly known information on the properties of a substance should be taken into account, if such information is considered to be of importance to the safety of the product.

A bibliography of works of reference suitable for the preparation of the general toxicological profiles for raw materials can be found in Annex 2.

It is important that the toxicological profiles for the substances are adapted to the technical progress in this field.

2.4.2 The general toxicological profile

The general toxicological profile

The assessment of the toxicological effects of the substances is the first step in the safety assessment. The safety assessment must be based on data on the substances and the test results regarding the properties mentioned below.

There may be instances when it does not appear to be necessary or to be technically possible to provide the information: In such cases scientific justification needs to be given.

1. Acute toxicity.
2. Skin absorption.
3. Skin irritation.
4. Mucous membrane irritation.
5. Skin sensitisation
6. Sub-chronic toxicity.
7. Mutagenicity.
8. Phototoxicity and photomutagenicity (only in case of UV-light absorbing substances).
9. Human data (if available).
10. Toxicokinetics.
11. Teratogenicity, reproduction toxicity, carcinogenicity, and additional genotoxicity.

Tests ought to be conducted by using a substance with the same chemical and physical characteristics as can be found in the finished product. When using a known raw material in a new connection the published data of the raw material must be assessed carefully, as it might have been tested as an ingredient in the type of product of which it usually forms part.

Supplementary information

The safety assessment of the final cosmetic products can generally be made based on the knowledge of the toxicity of the individual ingredients. In special cases supplementary information might, however, be necessary:

If skin penetration or the irritating effects of the substance are increased because of the fact that the ingredients in the cosmetic product in question have another influence on the substance than the solution used in the previous tests of the substance.

If a new dangerous substance may develop when mixing the individual ingredients and can be proved in the final cosmetic product.

Test procedures

The information can be obtained from data retrieved by means of internationally recognised test procedures. Data can also be obtained from recognised validated alternative test procedures in vitro (in e.g. tissue or cells from living organisms), or, when alternative procedures are not recognised or exist, from in vivo tests (in living animals).

It is recommended to use the test procedures stated by the Commission in Council Directive 67/548/EEC incorporating amendments (8), (9), or as described in OECD guidelines (10).

If human clinical observations exist, these should also be assessed. Human data can be retrieved from:

- specific toxicological studies or from studies performed for other regulatory purposes, e.g. for working environment purposes;

- the supplier of the raw materials supplemented by data retrieved from databases or published literature.

Also data from previous consumer surveys may be of value in this connection, just as experience and reports regarding undesirable effects of the product (see Chapter 2.7) must be considered carefully.

2.4.3 The chemical structure of the substance

Chemical structure of the substance

The chemical structure, the properties and structural formula of the substance have been described previously in Chapter 2.1 and 2.2. Further, the degree of purity has been determined. For all relevant impurities the allowed maximum concentration of the impurities should be defined based on toxicological data.

It is the responsibility of the manufacturer that there are no other impurities or major amounts of impurities than those, which are chemically defined or technologically unavoidable, which may influence the safety of the finished product.

2.4.4 Safety assessment

Safety assessment

The safety assessment of a cosmetic product to a considerable extent depends on its route of application. The route of application of the product has an influence on how much of the product - and in this connection - how much of each ingredient can be ingested, inhaled or absorbed through skin and mucous membranes. Further, the amount of each ingredient in the individual product has an influence on the safety assessment.

Risk assessment

Before a safety assessment and a risk assessment of a cosmetic product can be initiated, the degree and route of application must be described thoroughly. This cannot be done generally, but must be done case-by-case, all dependent on the unique composition and use of the individual product. An evaluation of whether the application of a cosmetic product can be considered safe for especially vulnerable groups such as children, must as a principal rule form part of the risk assessment. At least, the following factors in the risk assessment must be considered before weighting the individual ingredients:

	Type of cosmetic product, such as shampoo, sunscreens, toothpaste.
	Method of application, e.g. rub-in, rinse-off or non-rinse-off, spray, brush
	The concentration of each ingredient in the product.
	The amount of the product applied at normal use.
	The frequency of the applications, short-term-/long-term use.
	The total skin area of the body to which the product is applied.
	The type of application area, e.g. mucous membranes, eyelashes, sunburned skin, lips.
	The duration of contact, e.g. in connection with rinse-off products.
	Foreseeable misuse which may increase the exposure.
	Type of consumer, e.g. children, old people, people with sensitive skin.
	Amount, which may enter the body and be absorbed.

Which exposure is relevant in connection with the safety evaluation of each product/substance depends on the toxic effect examined. As to toxic effects such as skin irritation or photo toxicity it will be important to know the exposure of the substances per unit of the skin area, whereas for a systemic toxic effect the exposure per unit of the body weight will be relevant.

The way or ways of exposure (e.g. skin, skin exposed to sunlight, mucous membranes, eyelashes, ingestion or inhalation) must be considered at every risk assessment of the products, or when setting up a test program. Other possible ways of exposure than those for which the product is intended must be considered when assessing the safety of the product, e.g. inhalation of hair spray, ingestion of lipsticks etc. Other possible exposure to problematic substances from other sources than those from the cosmetic product should also form part of the risk assessment.

Further, the use of cosmetic products is dependent on many factors, such as season, fashion, age, habits, income, and novelty value. As many of these factors will change in time it will not be possible to stick to a specific level of exposure for each type of cosmetic product. The safety evaluation should therefore be made individually for the products in question.

Examples of typical amounts of ordinary cosmetic products, which follow the normal degree and route of application, are entered in a technical guideline document from the Commission. The data are from 1981 and 1993 (11).

2.5 Educational requirements of the safety assessor(s)

Educational requirements

According to the Order there are the following educational requirements of the person(s) performing the safety assessment of cosmetic products, cf. Chapter 2.4:

The directive mentioned refers to the introduction of a general agreement on mutual recognition in the EU of diplomas in qualifying higher educations.

It is recommended to enclose an complete curriculum vitae for the person stating education, experience etc.

2.6 Undesirable effects on human health

2.6.1 In general

Undesirable effects

According to the Order, the following data on undesirable effects must be submitted:

2.6.2 Registration

Registration of undesirable effects

Each product must be described by trade name and composition stating the complaints of undesirable effects. The information regarding undesirable effects must include the name and address of the complainant as well as the date of the complaint; the name and address do not have to be submitted to the authorities, but are to be used for the follow-up on the complaint. A description of the undesirable effect must include information about which part of the body was affected, how long after the application of the cosmetic product the undesirable effect arose, and whether the product had been used earlier with or without a similar reaction.

In order to increase the value of the information the age, sex , and, if possible, the state of health of the user should be included. The information about undesirable effects should not be limited only to the information reported by a doctor. Careful report data can be valuable for both the safety assessment of the product and for further development or reformulation of the product.

Further, the manufacturer’s reaction and handling of the complaint should be stated. Correcting as well as preventive measures must be described.

Data ought to be kept at least as long as the product is on the market.

2.7 Proof of claimed effects

2.7.1 In general

According to the Order the following data must be accessible:

Proof of the claimed effects

It is of special importance to be able to document effects, which may have influence on the health of the consumer of the product. As an example of this can be mentioned the sun protection factor in sunscreens for which it must be documented that the sun protection factor provides the claimed safety. Further, a number of other effects may be of significance to health.

If a cosmetic product is claimed to have a specific effect, which makes the consumer expect quite special results, this must also be documented, even if the effect is of no importance in relation to health.

The claimed effect of a cosmetic product must be proved on the basis of scientifically correct testing. In the following a number of principles for correct testing will be described. Annex 3 to this guideline represents the technical background and gives an analysis of methods and principles of efficacy testing.

The principles used for the evaluation and documentation of the effects and adverse effects of medical and non-medicinal treatment are immediately applicable for cosmetic products.

2.7.2 Principles of retrieval of data

The Danish Environmental Protection Agency expects that documentation of the claimed effect of a cosmetic product is based on scientifically correct testing, and that the measurements made are relevant to the claimed effect.

Further, the claimed effect must be tested on the finished products, identical to the products marketed.

Data retrieved from laboratory tests or from literature, including articles from scientific magazines, on the ingredients, which are expected to have the claimed effect, cannot replace documentation in the form of a correctly performed testing of the effects of the finished product. These data are, however, valuable as background documentation when determining a relevant test and evaluating the test results.

Retrieval and presentation of data

Documentation of the effect of a substance must not be made capital of a claimed effect of the cosmetic product. Neither must such results be modified in the form of e.g. praises, in a way, which gives another impression of the product than that documented/found at the testing of the cosmetic product.

Documentation of the claimed effect must be obtained from the testing of the product on humans. It is important that the claimed effect of the product is not tested until it is secured that the product cannot cause health hazards.

When testing on humans ethical as well as practical principles must be considered, among other things the Helsinki Declaration on protection of human test persons, provisions of the Data Surveillance Authority and guidelines for good clinical practice (GCP). Observance of full GCP is not likely to be obtained when testing cosmetic products; however, it is expected that the principles of GCP be used. Further, the Scientific Committee on Cosmetic Products and Non-Food Products Intended for Consumers (SCCNFP) has described several fundamental principles and recommendations regarding the use of test persons for the examination of cosmetic products in annex 12 of a technical guidance document for testing of cosmetic products (3).

Today there are several non-invasive instrumental methods, which make it possible to test the effects of products on the skin objectively and without surgical intervention. It is important that the measurements are relevant to the claimed effects of the product. Consumer investigations, and examination of relevant effects performed by skilled personnel may also be applicable methods for testing the effect of the product on humans.

Today a number of in vitro test methods can also be used; however, these will only give a rough impression of the effect of the product on humans.

The test report must as a minimum contain a description of:

	Raw materials tested.
	Name, title, qualifications and possibly curriculum vitae of the scientist in charge of the tests.
	Method used for the retrieval of information.
	Criteria for the assessment
	Other conditions for the implementation of the test, e.g. frequency and duration of application, -area, -amount etc.

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