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Issue
44 — Januar 2009 |
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The discussions held at the Karlsruher Kosmetiktag, a meeting of cosmetics experts
which took place in Karlsruhe, Germany, March 2008, focused on requirements associated
with the safety assessment of cosmetic products mady by industry, authorities
and committees.
The talks were associated with a new European Cosmetics Directive issued by the
European Commission (Simplification Cosmetics Directive 76/768/EEC), which in
future wants to give its current draft of the safety assessment of cosmetic products
a higher priority.
More than 100 experts participated in the meeting and elucidated the topic with
the primary aim of establishing practice-oriented criteria for the safety assessment
of cosmetic agents.
In this report, a few selected presentations have been summarized in the following:
The TTC Concept: Evaluating the systemic toxicity without
further data
Dr. Marcus Kleber, Cognis GmbH
In the risk assessment of substances, the concentration which is usually taken
up by human beings (exposure) is compared to the ADI, the dose which is safe for
human health (ADI = acceptable daily intake). An intake which is regarded to be
safe for humans, results from animal tests where animals are fed with various
concentrations over a long period of time, thus leading to "systemic toxicity".
When safety factors are included, the ADI is obtained.
The TTC Concept (Threshold of toxicological concern) which is introduced in this
presentation provides a human exposure threshold value for chemicals below which
there is no appreciable risk for indiviudal chemicals to human health, without
testing the substance in long-term animal tests. The concept is based on investigations
by Munro (1990) FDA (1995) and JECFA (1998) who introduced a general threshold
as "Threshold of Toxicological Concern (TTC)" or indirect food additives
and flavoring substances. They defined that no risk hazard is given at a concentration
of a substance < 1,5 µg/person/day.
The findings are based on an analysis of the Carcinogenic Potency Database and
a politically accepted lifetime cancer risk of 1:1 million. This concept was further
elaborated and the current status of science was summarized in the works of Kroes
et al. (2004+2006). Substance classes (Cramer Classes 1-3) were integrated into
the concept according to their chemical structure and additional endpoints were
defined. The threshold values are also based on toxicological long-term data,
especially nongenotoxic and non-mutagenic substances.
In conclusion, the following TTC values were established:
A particularly low TTC of 0.15 µg/day/person is attributed to highly potent
mutagenic/cancerogenic substances. The general TTC for substances which do not
belong to the first category is 1.5 µg/day/person. In dependence on structure
classes (Cramer Classes), further values were established. With a decreasing reactivity,
these are 90 µg/day/person (Cramer Class 3), 540 µg/day/person (Cramer
Class 2), 1800 µg/day/person (Cramer Class 1). If these exposures fall below
the established values, no risks are expected, independent of the actual active
profile.
Special substance groups are currently not included in the evulations (metals,
metalcontaining compounds, polyhalogenized dibenzodioxines, dibenzofuranes, biphenyls,
proteins), because the current database does not hold sufficient data.
Enlarged version
Comparison of the DGK's concept on the safety assessment
of cosmetic products and minimum standards of the official surveillance
Dr. Gerd Mildau (Chemical and Veterinary Research Office, CVUA Karlsruhe);
Dr. Uwe Rossow (Dalli-Werke Stollberg)
In 2005, the DGK (Deutsche Gesellschaft für Kosmetik, German Society for
Scientific and Applied Cosmetics) first published the basic elements which should
be contained in a safety assessment of cosmetic products in order to recommend
a minimum standard for such evaluations. In 2007, this was succeeded by a publication
of minimum standards for a safety assessment made by official cosmetic experts.
In both publications, the stated requirements for a safety assessment were relatively
similar. The major contents are outlined in the following in more detail.
1. Product identity and conclusion
It is of major importance that a safety assessment can be clearly assigned to
the product which is under evaluation. Only thus it can be ensured that product
information and samples can be assigned to a specific safety assessment if authorities
or court start a verification. A clear product identification should include the
following details:
o Product name
o Product type
o Formulation number
o Manufacturer of cosmetic product
A safety assessment must clearly indicate that the product is harmless for the
intended use as well as for the reasonably forseeable use. It is essential that
safety is guaranteed in the sense of the current legal requirements (Cosmetics
Directive 76/768/EC) and its respective national versions (German Kosmetik-VO,
KVO). This must be clearly stated in the text.
2. Product description: Formulation and packagings
It is not legally required to give a description of a product within the safety
assessment procedure. In practice it has shown, however, that testers, experts
and non-experts, e.g. judges get a first impression from the description of an
evaluated product. Furthermore, it is not legally required to describe packagings,
but it is a major clue for the evaluation of compatibility tests of packagings
and microbiological stability tests.
3. Product description: Quantitative formulation
A major element of a safety assessment procedure is to describe how a product
is composed. According to §5b KVO, the safety assessor has to consider the
toxicological profiles of the components, their chemical structure and their degree
of exposure in his evaluation.
4. Specification of components
The specification of components is a major prerequisite for proving the suitability
of a raw material for the use in cosmetic products. Primarily, a sufficient purity
of the raw material has to be verified.
5. Product description: Quantitative INCI declaration
The listing of a quantitative INCI declaration and the formulation used by the
manufacturer are also essential parts of a safety assessment. The toxicological
evaluation of a finished product is made almost exclusively by means of the INCI
components and not by means of the raw materials used by the manufacturer. For
the toxicological evaluation of a cosmetic product, the actual concentrations
of the individual INCI components have also to be considered for all calculations.
Many INCI components are incorporated in formulations as single components on
the one hand, or as components of raw materials made up by various ingredients
on the other.
6. Specifications of finished product: Physicochemical and microbiological stability
The physicochemical or microbiological stability of a cosmetic product are basic
requirements for product safety. For any evaluation, only validated test methods
should be applied. When testing the stability of a product, its minimum storage
time should be considered. Products with a storage time of 30 months or longer
can be physicochemically and microbiologically stable within this period of time
(unopened). "Old" product samples (e.g. three months of simulated aging
at 40 °C) should be tested for their physicochemical stability. Such storage
test samples should also undergo microbiological stability testing.
7. Conditions of use
The intended purpose of a cosmetic product is the decisive factor for determining
the application of a product under normal conditions and plays a role in the examination
of its exposure. If the intended purpose of a product may not be recognized by
consumer by reading the packaging, labelling or description of the product, wrong
applications are not avoidable. Reasonably forseeable conditions of use may lead
to wrong applications even if the intended purpose of a product has been clearly
stated. As cosmetic products must not present a health risk for all intended and
reasonably foreseeable purposes, a safety assessment of cosmetic products must
include a description of wrong applications and should be an indispensable part
of the safety assessment.
8. Information on application, safety, and warnings
In Annexes 2, 3, 6 and 7 KVO, the legislator has provided use instructions on
the application and safety of specific cosmetic raw materials and may also issue
warnings if required. Use instructions which have to made according to §
4 paragraph 2, No. 3, KVO are of a more complex nature. Here, it lies within the
scope of direction of the safety assessor to decide about the use instructions
for preventing the consumer from health risks. Thus, a safety assessment must
include respective directions.
9. Exposure assessment of finished product
An exposure assessment of a finished product is a prerequisite for the toxicological
evaluation of the raw materials used and/or the INCI components of the formulation
assessed. The exposure assessment should be made following the Notes of Guidance
for the testing of cosmetic ingredients and their safety evaluation of the
SCCP (Scientific Committee on Consumer Products). These guidelines are monitored
on a regular basis and, updated if required and represent state-of-the-art with
regard to the exposure assessment of cosmetic raw materials and finished products.
10. Exposure assessment of individual components
An exposure assessment of the single components is another central element of
a safety assessment. It allows an evaluation of the safety of many raw materials
because the systemic availability and effects may only be determined by the exposed
amount of a substance combined with its percutaneous intake (e.g. oral absorption
in the case of specific applications such as lip care and oral care products).
As is the case in the exposure assessment of finished products, the Notes of
Guidance for the testing of cosmetic ingredients and their safety evaluation
of the SCCP is to be regarded as state-of-the-art.
11. Efficacy studies
Only in exceptional cases, efficacy studies must be considered in safety evaluations.
If the efficacy of a product has a decisive influence on the health of the person
who applies it, it is however required to include efficacy studies in product
evaluations. Examples of this are sun care products and tooth care products which
claim a caries prophylaxis.
12. Statistics of complaints
Well-founded complaints include undesirable effects which have been confirmed
by dermatological tests. While safety assessments are mainly based on theoretical
calculations and considerations, a statistics of complaints provides facts on
the actual compatibility of a product under market conditions.
13. Validity, date, signature
Each safety assessment should contain the date of creation and the signature of
the safety assessor. It is recommended that the evaluation states that it is solely
valid for the formulation and that changes made at a later point of time lead
to the safety assessment's invalidity. Furthermore, it should be stated that the
evaluation was made on the basis of valid legislation and state-of-the-art applicable
at the time of the signature.
14. Short toxicological profile of individual components
According to §5b paragraph 2, KVO, a safety assessment of the finished product
is based on the toxicological profile of the individual components. The quality
and usability of the data presented are of major importance. In addition to the
mere toxicological data, further parameters such as the chemical purity of a component,
production-dependent impurities (e.g. rest monomers, solvents, etc.), origin (BSE!)
or use restrictions according to Annexes 2, 3, 6 and 7 KVO are relevant for an
evaluation of raw materials.
Percutaneous absorption: Proof of evidence and models
Dr. Wolfgang Pittermann
In cosmetics, the penetration depth of active ingredients applied on the skin
is a largely discussed topic. It is assumed by scientists that the penetration
depth of active ingredients is dependent on the formulation and on the method
of detection used and that it is not fully known what really penetrates through
the uppermost skin layer after repeated application.
The penetration of cosmetic or dermatological formulations through the natural
barrier of the horny layer is dependent on a combination of physiological and
physical effects. Such results cannot be obtained by applying physical methods
alone.
The skin as a living, dynamic, growing biomembrane, is closely associated with
psychic factors. The most important factors influencing the permeability of active
ingredients are the barrier and reservoir functions of the horny layer. The barrier
and reservoir functions are characterized in a special way: With growing depth,
the barrier function increases whereas its function to form a reservoir for topically
applied substances decreases. Under natural conditions, this mainly concerns the
blood vessel systems and, to a minor degree, the lymph vessels. The subpapillary
capillar network also shows particular organ-specific properties, namely partly
fenestrated vessel walls. They display a higher "leakage" for the absorption
of foreign substances than the remaining organism.
A transportation of active ingredients is possible via the appendages of the skin,
or through the epidermis. Under the aspect of providing an up-to-date proof of
efficiency, both the penetration into sebaceous glands and hair follicles (root
of hair) and the transepidermal route leading to the connective tissue of the
dermis are of interest.The illustration shows various routes which a substance
may take to penetrate the skin's barrier.
For penetration studies, various methods and models are available, such as microdialysis,
the perfused bovine udder skin model (BUS) or the Franz Diffusion Chamber, also
see Figures 1 and 2. There, the barrier and receptor arrangements differ largely,
and therefore the models are applicable in various ways. Formulation concepts
which have been developed in the past few years and which are based on microemulsions
or nanodispersing vehicle systems, set new and higher demands on model situations.
An improvement of the physical penetration of substances is made possible by iontophoresis,
for example.
Figure 1 shows a schematic diagram of the skin including sebaceous glands and
hair follicle. For the analytical work, strips (stratum corneum) of the treated
skin surface were taken as well as dermatome sections which reach up to the depths
of the hair follicle including the regions of the sebaceous glands. Histoshaver
samples (Figure 2) were excised of stripped and unstripped skin in order to estimate
the reservoir capacity of the stratum corneum at each exposure period.
| Figure 1:
Schematic diagram of the skin including sebaceous glands and hair follicle |
|
Enlarged
version
|
Figure 2 demonstrates a Histoshaver sample of unstripped skin. The depth of the
skin biopsy lies between 80 and 200 µm, well above the region of the sebaceous
glands (~ 600 µm depth).
Note:
The German version of the articles contributed by Dr. Gerd Mildau and Dr. Marcus
Kleber were originally published in: Sicherheitsbewertung kosmetischer Mittel
- Fazit des Karlsruher Kosmetiktages, Teil 1, SOWF-Journal 134, 11-2008, 48-56;
Teil 2, SOWF-Journal, 12-2008, 58-63.
For the original version of the article authored by Dr. Wolfgang Pittermann, please
also see Skin Care Forum 43.
