Patch-test cross-reactivity to a novel, probably non allergenic hair-dye precursor (PPD-derivative F000175918)

INTRODUCTION AND RATIONALE

Para-phenylenediamine (PPD) is an organic molecule which is used in e.g. dark
hair dyes, manufactory dyes, dyed leather and rubber.[1] It is categorized in
the so-called para-group of aromatic amines. PPD is mainly known because of its
use in permanent oxidative hair dyes. These contain colorless
low-molecular-weight precursors (e.g. PPD or para-toluenediamine (PTD)) and
couplers (e.g. m-aminophenol and resorcinol). Prior to application, the hair
dye needs to be mixed with hydrogen peroxide in order to activate the dyeing
process.

It is estimated that globally around 70% of the oxidative hair dyes contain
PPD.[2] Important properties that make PPD suitable for use in oxidative hair
dyes are: a low molecular weight, its penetration ability of the hair shaft and
follicle, a high protein binding capacity and its ability to rapidly polymerize
in the presence of a coupler and an oxidator.[3]

However PPD is notorious for these features as well; it is a very potent
allergen and the global cause of 4-7% of all cases of allergic contact
dermatitis.[2] This is one reason why it is included in several standard series
for epicutaneous patch-testing.

The clinical relevance of allergic contact dermatitis to PPD is most apparent
in individuals exposed to oxidative hair dye, namely consumers and
hairdressers. Once sensitization has occurred, re-exposure to a PPD containing
compound leads to a dermatitis which, depending on the strength of the T-cell
mediated immune response (type IV), varies in severity. Symptoms may include
redness, swelling, itching, blistering and/or scaling of the scalp, neck, ears,
face and (in hairdressers) hands.[4]

Despite this, the use of oxidative hair dyes, and thus the prevalence of PPD
sensitization, is growing worldwide. In the past hair dyeing was mainly a
proceeding to camouflage grey hair, today it's a certain part of fashion and
commerce. Nowadays 60% of Dutch women dye their hair. In men over 40 years of
age this is 10%. Also consumers are starting at a younger age with dyeing their
hair, and they continue this for a longer period. The most commonly used hair
care products in the Netherlands are the permanent oxidative hair dyes, with a
market share of 65%.[5]

Sensitization and type IV reactions to PPD and other molecules from the
para-group can also be caused by a cross-reaction between these molecules.[6,7]
For example, a previously PPD-sensitized individual can develop an allergic
contact dermatitis to PTD without ever been in contact with that molecule.

The immunological causes for cross-reactivity are not fully explained yet. One
possible theory is that contact allergens consist of so called pro-haptenes,
which are metabolized in the skin to common metabolites, namely haptenes. Bound
to a protein these then function as allergenes and may stimulate the
proliferation of T-cells.[8] Why in case of exposure to PPD some people will
develop sensitization, whereas others not, is still subject of research. One
possibility is that differences in enzymatic breakdown of PPD (by
N-acetyltransferase 1 in keratinocytes) exist due to interindividual genetic
variation and/or environmetal factors.[9] At present the problem of
cross-reactivity is, in assessing the toxicological profile of newly developed
molecules, no routine yet.

In our study a newly developed molecule, which is planned to substitute for
PPD, will be examined for possible cross-reactivity in PPD-sensitized
individuals. PPD-derivative F000175918 has been subjected to extensive
pre-clinical studies of acute and repeated dose toxicity, genotoxicity,
reproductive toxicity, irritation, sensitization and skin penetration.[10] The
safety evaluation for PPD-derivative F000175918 was conducted in accordance
with the "Notes of Guidance for Testing of Cosmetic Ingredients and Their
Safety Evaluation by the SCCP", released by the European Commission in 2006.

Summary of this safety evaluation:


•The maximum on-skin concentration of PPD-derivative F000175918 is 3%.

•The use of PPD-derivative F000175918 in the salon testing phase with more than
100 volunteers has been successfully completed (data not published).

•At the maximum on-skin concentration of 3%, PPD-derivative F000175918 is not
considered to cause eye irritation, skin irritation or skin corrosion.

•From a local lymph node assay (LLNA) PPD-derivative F000175918 is categorized
as a moderate skin sensitizer, with an EC3 value of 7.11%. As a comparison, PPD
is a strong sensitizer with an EC3 value of 0.1%. Thus PPD-derivative
F000175918 is very unlikely to give sensitization and it also seems to have
very low potency to induce cross-reactivity.

•PPD-derivative F000175918 did not show teratogenic potential up to the highest
dose.

•PPD-derivative F000175918 has no genotoxic potential under in vivo conditions.
Therefore, PPD-derivative F000175918 is considered not to give any risk to
humans with regard to mutagenicity.


A previously performed study of PPD-derivative F000175918, with patch-testing
16 PPD-sensitized subjects for 48 hours with 1% of the substance in petrolatum,
gave 1 positive (+++) reaction. (Toxicology Department, University of Trier,
Germany, data not published)

In conclusion, with the increasing use of oxidative hair dyes worldwide and the
concomitant increase in PPD-allergy, the development and industrial
introduction of a moderately allergenic substitute for the strongly allergenic
PPD is very desirable.

Objective:

Determination of cross-reactivity to a newly developed PPD-derivative
(F000175918) in previously PPD-sensitized patients.

Hypothesis:

Since PPD-derivative F000175918 is categorized as a moderate sensitizer, based
on pre-clinical toxicological studies and given the result of the pilot study
with regular patch-testing, our hypothesis is that no subjects, yet at the most
one subject, will react positive at patch-testing in our study design.

Observational study with the use of epicutaneous patch-testing and without the
use of a medicinal product or other invasive measurements.

Epicutaneous patch-testing with PPD-derivative F000175918 in a basic compound
and with the basic compound alone (control testing).

No serious side effects can be expected during and after patch-testing. A
possible cross-reaction to the PPD-derivative or an irritant reaction to the
test-chambers are issues that have been discussed in this form and in the
research protocol.

The time burden on subjects is minimal and also discussed before.

Subjects do not directly benefit from this study.