6. What are the gaps in the current knowledge about perfume allergies?
The SCCS opinion states:
12. Data gaps and research needed
In the course of working on this opinion, the following points are highlighted as important data gaps, ordered by research area:
12.1. Clinical and epidemiological research
- Clinical data on more fragrance substances are needed to assess more fully the epidemiology of fragrance contact allergy and pin-point the culprit substances for induction and elicitation of contact allergy in man.
- Data from a broader range of EU countries on the clinical and epidemiological picture of fragrance contact allergy is needed, as difference in exposure and use habits are expected across Europe.
- A co-ordinated strategy for data collection should be developed.
- Very little is known about susceptible groups of the population, e.g. up 10% of the European population carry mutations, which impairs the skin barrier and which seem to increase the risk of fragrance allergy. Data are needed to qualify and quantify the increase in risk of susceptible groups in order to provide a better protection of all consumers.
- Aberrant enzyme activity in certain individuals, often related to genetic enzyme polymorphisms, may give an increased or reduced risk of sensitisation to prohaptens (that need enzymatic activation) in certain individuals or populations. More research into the role of relevant traits is needed.
- Dose-response data from clinical studies are available for only a few allergens. To establish individual safe levels such data are required for all established allergens of concern and covering an appropriate range of product types. This would also consolidate the basis of the use of a general threshold for safe use of fragrance allergens.
- Data on human exposure to fragrances from the use of different product categories is very scarce and therefore does not provide an optimal basis of risk assessment, e.g. exposure data on use for perfume/eau de cologne are lacking.
- Most experimental studies are done on individual fragrance ingredients, while exposure to allergens in cosmetic products is usually to mixtures of allergens. The risk of sensitisation and elicitation may depend on the mixture of substances, but very few studies on this exist. It is necessary to improve the knowledge base on cocktail effects on sensitisation/elicitation to improve the basis of risk assessment and management.
- Screening in dermatitis patients should be performed with air exposed samples of such fragrance substances that in experimental studies have been demonstrated to act as prehaptens, i.e. autoxidise and form oxidation mixtures containing allergenic oxidation products.
- Patch testing should if possible, be performed with the isolated true haptens formed from prehaptens and prohaptens to increase the possibility to diagnose allergy from these type of substances.
- There is a need for more experimental research to further establish the impact of the behaviour of fragrance substances when applied on the skin (including factors such as volatility, autoxidation, skin penetration, reactivity in skin and bioactivation).
12.2. Non-human studies
- Several studies in the industry submission (164) were of insufficient quality, not following the OECD guidelines.
- In some cases it was found that either very few concentrations points had been used in LLNAs, or concentrations were insufficient for achieving a 3-fold increase of the SI.
- A sufficient number of doses (concentrations) should be applied in LLNAs (at least 5) so that interpolation (for deriving an EC3 value) can rely on more than two or three actual data points to be more reliable. SCCS therefore suggests a change in the OECD guideline 429. (It is important to remember that the production of unreliable data is a waste of animals.) Moreover, the maximum concentration should be high enough to achieve a > 3-fold increase in SI, as far as this is possible with the substance/vehicle combination chosen.
- Data on experimental results are often not published, but available only on file in the companies having performed the tests. Access to such results would be important for the scientific community, e.g. in the context of REACH, or independently, either to the public domain, or to a Public Trustee.
- The OECD guideline 429 recommends several vehicles. It is well known that a difference in the EC3 value can be obtained for the same substance depending on which vehicle is used in the LLNA. Thus, as an additional control, supplementary to the guideline based LLNA control, a clinically relevant solvent or the commercial formulation in which the test substance is marketed may be used.
- As long as no validated in vitro method exists, more research is needed. Until one or more method(s) have been decided to fulfil the requirements for substituting in vivo testing, the in vivo testing for prediction of skin sensitisation has to be used.
- Applying only mechanism-based QSAR (QMM) as a tool in non-animal based risk assessment for skin sensitisation is of limited value for fragrance substances. This is due to major information gaps in the present model when addressing substances that act via abiotic or metabolic activation, and the high incidence of such substances in fragrances. Therefore, further experimental and clinical research in the area of abiotic and/or metabolic activation of fragrance substances is needed to increase the safety for the consumer, i.e. experimental studies which include air oxidation and bioactivation.
- Further experimental investigations of the sensitisation potential of fragrance substances are needed to determine the impact of the volatility of the substance as well as the effect of the vehicle on skin penetration/absorption and reactivity.
- From a clinical perspective it is important for the individual who is sensitised to one fragrance substance to know if they must also avoid other fragrance substances that can cause allergic contact dermatitis due to cross-reactivity with the original sensitiser. Prediction of risks for cross-reactivity requires sound application of theoretical principles in combination with well-designed experimental studies. This is a field that has not been studied very much so far and needs to be focused on much more in the future.
- Quantitative structure activity relationship (QSAR) models should be further developed, combining, as appropriate, information from in silico, in chemico and in vitro methods as possible. Prediction of different activation pathways should be included.
- Effect estimates such as proportions of sensitised humans or animals, or mean stimulation indices, EC3 values and other derivations should ideally be accompanied by an interval estimate (confidence interval) to address precision (297).
Source & ©: SCCS,
26-27 June 2012, 12. Data gaps and research needed. p. 103-104.