Extended Fragrance Ingredients Surveillance Study (EFISS) - Surveillance Study to Monitor the Frequency of Contact Allergy to a Defined Group of Fragrance Ingredients with a View to Providing Reliable Information onTrends

Background of the study:
Fragrance contact allergy (CA) is frequently associated with allergic contact
dermatitis, which is a well-known health problem. For
example, it has been estimated that 1-4% of Danish adults drawn from the
general population may have CA to fragrance
substances, while the frequency of CA among European and American dermatitis
patients has been shown to be between about
6.5% and 10.4%. In general, CA or dermal sensitization to a given substance
will not be observed until an individual has been
exposed to a concentration of a given substance that exceeds the induction
threshold, thus sensitizing the individual.
The prevention of contact allergy and subsequent potential allergic contact
dermatitis has been recognized to be critical to industry
governance by The International Fragrance Association (IFRA) and the Research
Institute for Fragrance Materials, Inc. (RIFM).
These groups have worked together to develop a quantitative risk assessment
(QRA) and later refined via the QRA 1 (2008) into
QRA2 (2017). The key steps of the QRA comprise: 1) determination of the *no
expected sensitization induction lever (NESIL); 2)
application of sensitization assessment factors (SAF); and 3) consumer exposure
level (CEL) calculated from product use data. This
process allows one to set an acceptable exposure level (AEL), a level at which
sensitization is not likely to take place, which can
then be compared to the CEL. Provided that the AEL is less than the CEL,
allergic sensitization leading to subsequent CA should not
occur for the vast majority of the population.
The QRA is achieving recognition and credibility among regulators and critical
stakeholders, for example the SCCS (Scientific
Committee for Consumer Safety) and is well regarded by the Joint Research
Centre (JRC). However, it has been criticised by some
as not yet demonstrating reduced incidence of skin CA in populations, i.e., no
demonstration in real people. Similarly, the credibility
of the QRA relative to regulators and regulatory scientists requires that
industry commit to efforts to demonstrate its effectiveness
over time.
As part of the overall effort to address CA issue, the IDEA project
(International Dialogue for the Evaluation of Allergens,
www.ideaproject.info ) was set up. It is designed to provide a broadly agreed
and transparent framework for assessing fragrance
sensitizers globally. It presents an opportunity to build partnerships between
the international fragrance industry and its stakeholders
in order to improve the risk assessment of those fragrance ingredients,
identified as relevant skin allergens with a view to achieving
better consumer protection. As part of this stakeholder partnership initiative,
there is a need to make the post-market monitoring
more relevant and up-to-date, to provide greater insights into potential trends
in skin contact allergy, which specifically addresses
induction of dermal sensitization. In order to address these questions, a
number of potential options for studies were developed and
discussed extensively in a series of workshops (April 6, 2016, February 15,
2017 and December 7, 2017) with representatives of
industry, IFRA and RIFM plus dermatologists, epidemiologists, biostatisticians
from academia and observers from the SCCS.
The following three major possibilities for a study, as summarised below, were
identified and examined at length in these workshops.
The first option was an intervention study using a fragrance ingredient that is
a known dermal sensitizer that has never been
marketed and where there are no intentions of marketing the material. The study
would involve calculating the NESIL, using QRA 2
and testing it via participant exposure to selected products containing the
target material, at the calculated levels, over a period of 6
months. This would be followed by a patch test. A control group using the same
products without the target material would also be
run and similarly tested at the end of the 6-month period. This proposal was
considered and rejected on ethical grounds. Also, it only
served to demonstrate the QRA 2 in the context of a single material.
The second option was a study In which a naïve cohort was followed versus a
baseline over a period of at least 10 years, with
testing every 3 years, supported by a well-designed questionnaire, e.g., LEHC
(Life Events History Calendar), to determine
exposure. This study presented problems in identifying a genuinely naïve
population and how the baseline would be established. A
further problem was the cohort size. With up to 30% loss to follow-up predicted
due to the length between each round of testing, a
starting cohort of in excess of 12,000 subjects was estimated to be necessary.
Finally, it was concluded that despite the study
population size and substantial costs, there was little certainty that the
study would return meaningful results as to the effectiveness
or not of the QRA.
Finally, in conjunction with the various stakeholders and experts, it was
decided that a surveillance study, testing for additional
fragrance materials in addition to the existing Standard sets and individual
substances, run over an extended period, provided the
best and most workable approach. The limitations of such a study in terms of
producing a definite conclusion on QRA effectiveness,
in the short or even medium term, were recognized and discussed at length.
A key issue for successful monitoring in trends has been that testing has
relied on a set of patch test substances, i.e., the screening
Fragrance Mix 1 and Fragrance Mix 2 (FM 1 and FM 2), their component materials
and the so-called non-fragrance mix materials.
FM 1 and FM 2 that have remained unchanged for over 35 and 15 years
respectively. with no additional materials being added to
these or the other materials in this "Standard set*.
More recently, there have been a number of developments including the evolution
of the QRA as described above, two relevant
(2012 & 2017) opinions of the SCCS (Scientific Committee on Consumer Safety)
and the Regulation (2023/1545) on labelling of
allergens. Further, there is an ongoing process of updating of IFRA Standards
with regard to QRA2.
In addition, there has been the ongoing challenge of intra- and inter-clinic
variations in patch test results (See Annex I for a review of
the literature in relation to this issue). Additionally, there are number of
materials of varying potency, which hitherto have not been
tested on a systematic basis and which are in use in product types with high
consumer exposure.
Consequently, it is opportune to design an industry-sponsored surveillance
study incorporating both additional and Standard
materials that has the possibility of identifying trends in the incidence of
skin contact allergy. It is also the case that, as a first step, by
adding seven (7) selected additional materials to the existing Standard series
mixes and individual materials (Annex II), which will be
provided for free to the participating clinics (Annex lil), new insights may be
gained and the likelihood of identifying trends increased.
It should be noted that these materials are all currently in use with moderate
to high levels of use (approximately 8,000-280,000
kg/year based on 2015 data - See Annex II) in personal care products but not
currently tested in a systematic manner. A further
refinement is that by conducting such a study with a comprehensive protocol and
quality coordination, there is potential to reduce
intra- and inter-clinic variations. Hence important and relevant Information on
trends in patch test reactions to fragrance ingredients
and markers can be obtained.
In preparation for this main EFISS study, a pilot was conducted in 2022 with
the following objectives:
• Carry out range-finding and determination of patch testing concentrations for
use in the main EFISS study;
• Gain familiarisation with the ad

Primary Objective:
Identify trends in the incidence of skin contact allergy with particular
reference to fragrance materials that have not hitherto been
tested on a systematic basis.
Secondary Objective(s):
A subsidiary objective is to gather data on intra- and inter-clinic variations
with a view reducing these.

Observational, non-invasive study with the application of additional
epicutaneous patch test series on the back. Without the use of
medicinal product, non-blinded and non- randomized.
Duration:
The duration for an individual participant is one week during which there will
be three visits of variable time durations.
Visit 1, day 0:
A short interview will be held to reconfirm basic Information about the subject
and to check the inclusion and exclusion criteria.
Informed consent will be signed. This visit also includes the preparation of
material, the application of the patch test on the back.
This visit will take about 15 minutes. The actual patch test needs to be in
situ for 48 hours.
Visit 2, day 3, 72 hours after application:
The visit will take about 10 minutes and includes reading and photographing of
the (possible) skin reactions at the sites of
application.
Visit 3, day 7,168 hours after application:
Subjects might benefit directly from participation in this study. If a positive
reaction to one of the seven additional tested substances is observed, subject
will know he/she is allergic to this allergen which is included in cosmetic
products in daily life
This visit includes the final reading and photographing of the (possible) skin
reaction at the sites of applications and will take about
15 minutes. It may be longer if the treating physician sees a positive result
to any of the materials (Standard and test materials) and this precipitates a
discussion with the patient on the meaning of the results..

It is important to note that included subjects are already scheduled for
routine diagnostic patch test investigation because of
dermatitis. Therefore, subjects do not have to Schedule additional visits for
study participation. For the routine diagnostic patch test
investigation three visits will be planned. At During the first visit, after
inclusion, subjects will be asked to answer questions
concerning medical history and concomitant medication.
Subjects are at risk for developing an allergic skin reaction on the test
sites. This skin reaction is self-limiting in nature, but can be
treated with a local corticosteroid cream if the reaction is inconvenient.
Subjects might benefit directly from participation in this study. If a positive
reaction to one of the seven additional tested substances is observed, subject
will know he/she is allergic to this allergen which is included in cosmetic
products in daily life