Task I: Characterization of fragrance allergens
1. Why do we need to characterize fragrance allergens?
Some fragrance ingredients have the potential to cause dermal sensitization. However, such fragrance allergens may be described in various ways, so there is a need to define them via a collaborative approach between stakeholders to ensure that effective consumer safety can be delivered.
A clear understanding of what is a skin sensitizer and what are the tools to identify it remains a prerequisite to define a fragrance allergen. Allergy includes two phases:
Skin sensitization is not an ‘all or none’ phenomenon: there is a sequence of immunobiological events that need to be activated to produce first an induction of sensitization and secondly to elicit a clinical reaction. In consequence, induction and elicitation of contact allergy are threshold phenomena and allergic contact dermatitis therefore is to a considerable extent a preventable disease.
2. What are the different options?
The simplest level of definition is by hazard classification. There exists already a formal definition of substances, including fragrances, which present an allergenic hazard, under the UN GHS and EU CLP regulations. This definition is primarily developed to protect workers handling raw materials. This may result in the classification of a substance used in fragrances as a skin sensitizer, which is important to ensure correct classification & labeling and subsequent handling during manufacturing. This approach also has implications for the labeling of some consumer products, for example detergents in the EU.
The UN GHS criteria are certainly a useful element to take into consideration but insufficient for addressing the full scope of the topic as it is only a hazard assessment tool.
Several in vivo test methods have been used to identify skin sensitizers. Traditional guinea pig methods identify allergenic hazard based on the % of animals exhibiting a response after repeated applications of the substance at a fixed concentration. However, guinea pig tests are not designed for the determination of potency, although in the recent ATP to the CLP Regulation a scheme is proposed to distinguish between two potency categories based on guinea pig data. In contrast, the murine LLNA is more widely used not only to determine the potential of a material to induce contact sensitization, but also for the measurement of the relative potency. Much work has been done to correlate the dose-response data obtained in the mouse LLNA with what is known about potency in humans.
Of great relevance in the near future is the development and validation of in vitro methods, since this area is progressing rapidly, being one of the most important research topics nowadays linked to skin sensitization. How these methods will deliver potency as well as hazard information is a key question of relevance to risk assessment.
Another important element in understanding skin allergies is clinical (patch test) data. As recently pointed out by Basketter and White in the Editorial to Contact Dermatitis (2012, Contact Dermatitis, 67, 1-2), for the dermatologist facing a patient with a suspected allergic contact dermatitis, the application of a baseline patch test series, often supplemented by additional selected substances based on the patient’s history, represents a key component of their diagnostic ‘toolbox’.
Initial patch test data provide the information that these materials are contact allergens. A comprehensive risk assessment system therefore has to include them as an important alert instrument since diagnostic patch test data offer:
The recently published SCCS Opinion contains a classification of (fragrance) allergens using the number of positive patch test results from clinics as the qualifying element.
Research has been initiated to further refine the patch testing protocol (execution, standardization of patch test material, verification of reactions as allergic rather than irritating). This is important work that will help provide additional value to this important instrument.
It is well recognized that positive patch tests identify whether a patient has contact allergy to a substance, (with the exclusion of false positive patch tests are correctly identified), but do not directly determine whether it has relevance for the eczema that led to the consultation. It does not identify what exposures caused the induction of contact allergy (e.g. natural versus consumer product exposure, or which product type) nor does it give any dose-response information or inform on what types of exposure may be tolerated This must be derived from the clinical history (anamnesis), evidence of relevant exposure, the experience of the dermatologist and more importantly through use tests such as (repeated) open application tests.
A comprehensive risk assessment approach should therefore also include the thorough consideration of the aspect of clinical relevance.
Finally, other information, not adequately incorporated so far, and that could be of relevance, e.g. cosmetovigilance data from consumer product companies and/or poison centers, are also important when identifying the existence or emergence of allergy in consumers.
3. Recommended actions
Industry, the dermatological community, and regulators need to work together to find a common ground and understanding of how to best integrate clinical (and cosmetovigilance) data into the risk assessment process.
The industry is proposing a new approach to bring the stakeholder input together in a collaborative program, with a structured framework that will enable more effective dialogue but also clearer approaches to defining allergens as well as processes to assess their risk. It is envisaged that this would be managed with a combination of industry/non-industry toxicologists, clinical and experimental dermatologists as well as risk assessors, to enable a comprehensive, robust and pragmatic weight of evidence based approach to address the risks deriving from fragrance allergens.
An IDEA workshop was held on August 27-29, 2013 to start addressing this task. All documents produced at this workshop are publicly available