IDEA - International Dialogue for the Evaluation of Allergens

Task IV: Validity of the QRA methodology & possibilities of further refinement

 1 Where is the Fragrance Industry with the QRA today?

The Dermal Sensitization QRA is considered by the industry as an important step forward in dermal sensitization risk assessment, and the method, first published in 2001 (Gerberick et al., Contact Dermatitis, 45:333-340) has been implemented by the fragrance industry since 2006. An update has been published in 2008 (Api et al., Regulatory Toxicology and Pharmacology, 52:3-23) and the QRA Expert Group[1] encourages further refinement to the QRA for fragrance ingredients. Some areas of improvement are considered below.   

  • Consumer Exposure:

Improved exposure data (Hall, 2011) is being incorporated into the QRA methodology. In addition, RIFM has sponsored work to investigate the effects of aggregate dermal exposure. The outcome of this work is being accounted for in the methodology and we suggest that an open discussion be held on the validity of the QRA and on this initiative in particular.

  • Safety Assessment Factor (SAF):

A paper which specifically addresses the use of uncertainty factors in QRA for skin sensitization has been published (Felter, et al., Contact Dermatitis, 2003, 47:257-266). However it is acknowledged that further dialogue on SAFs would be appropriate. This would include better clarification of what the SAFs are applied to (e.g. not to clinically diseased skin).  

  • Acceptable Exposure Levels (AEL) and Exposure Data:

A more detailed explanation of AELs and how they are applied should be provided. There also is a need for more details on the pragmatic approach and a review of aspects of having high calculated values in (mainly) rinse-off products.

  • Current boundaries of the QRA

While occupational exposures to consumer products can be an important source of exposure they are not considered in the current QRA. This mainly stems from a lack of adequate exposure data.

Furthermore the QRA methodology does not cover aromatherapy (neither workers nor customers). These currently not reflected exposures remain a potential area of research.

  • Use of Diagnostic Patch Test Data and Retrospective Analysis

Diagnostic patch test data from dermatology clinics are not used in the primary determination of safe use levels based on induction. This is because these data are a measure of elicitation of allergic contact dermatitis, not induction. Nevertheless, the diagnostic patch test data provide feedback on whether thresholds of used based on the QRA has been correctly established (see Task II.2).

A review of retrospective data for three fragrance ingredients has been published (Api et al., 2010). Retrospective review of other fragrance ingredients and other non-fragrance ingredients should also be considered.

Thus, clinical results from the dermatology community (including targeted studies) and company post-market surveillance data should be used to evaluate the effectiveness of QRA-based interventions.

 

2. Recommended action

The best way to address the validity of the QRA methodology and the possibilities of further refinement would be to organize an in-depth dialogue between experts. We recommend that a specific workshop be held on the QRA methodology.

 

3. What has been done so far?

Three IDEA workshops have been dedicated to the QRA methodology until now (March 19-20, 2013, March 11-13, 2014 and may 13-15, 2014) and resulted in many important observations, conclusions and recommendations. Based on this scientific exchange, the IDEA Management Team developed a dossier highlighting the refinements and improvements that need to be brought to the QRA model. This dossier will be submitted to the Commission (DG SANCO, B2 Unit) beginning of July 2014 for consideration. We invite you to consult the section 'events' for more details as all documents of the workshops are made publicly available. In summary, the key conclusions of the three workshops dedicated to QRA are:

3.1. Workshop 1, March 2013

QRA is seen as a promising tool to prevent induction of contact sensitization for people with normal skin. However, it requires further refinements for the general population as follows:

  • Prospective and retrospective evaluation of its effectiveness by clinical and epidemiology data using sensitization as the relevant endpoint
  • Review of underlying methodologies and assumptions:
    • SAFs (Sensitization Assessment Factors)
    • NESILs (No Expected Sensitization Induction Levels)
    • Exposure (accumulation, aggregate exposure, chemical analysis, usage, retention and professional exposure)
  • Adaptation for people with compromised skin
  • SAFs are seen as being set appropriately with current state of knowledge. Re-evaluation of the inter-individual variability factor with scientific rationale is considered essential.
  • An estimate of expected new induction when following QRA is encouraged.
  • There could be value in developing ‘QRA 2.0’, based on latest data and including aggregate / occupational exposure.

3.2. Workshop 2, March 2014

The starting point of the QRA is the NESIL which is defined as the threshold known not to induce skin sensitization, considering all available hazard data in a weight of evidence approach, under the specific exposure conditions of a standard protocol HRIPT.  The workshop participants reviewed the SAFs and supported SAFs for 1) inter-individual variability not accommodated in the NESIL is reflected by a SAF of 10., 2) impact of product use factors such as degree of occlusion, frequency / duration of product use and the product matrix itself are reflected in SAFs that range between 0.3 and 6 and 3) The role of skin condition / site is determined by a stepwise consideration of pre-existing inflammation, irritation by product, and penetration / permeation of product and is reflected in SAFs each of 1 or 3. 

3.3. Workshop 3, May 2014

During the third workshop, held on May 14-15, 2014, examples of how the SAFs were applied and how aggregate exposure were presented.  The details for these SAFs and application of the RIFM Creme aggregate exposure model are provided in this dossier.

 


[1] The QRA Expert Group is a RIFM Task Force of ten toxicologists from the fragrance and the downstream users industry. This group worked on the adaptation of the QRA methodology to the Fragrance Industry and continues to watch the outcome of the QRA implementation in view to improve the model.