ARTICLE
Auteur(s) : Maya
Krasteva1, Brigitte Bons1, Sarah
Tozer2, Kim Rich2, Edo Hoting3,
Detlef Hollenberg3, Anne Fuchs4, Rolf
Fautz4
1L’Oréal Research and Development,
25-29 quai Aulagnier, 92600 Asnières, France
2P&G Technical Centres, Rusham Park, Whitehall Lane,
Egham, Surrey, TW20 9NW, UK
3Henkel AG & Co. KGaA, Henkelstr. 67, 40589
Düsseldorf, Germany
4KPSS – Kao Professional Salon Services GmbH,
Pfungstaedter Strasse 92 – 100, 64297 Darmstadt, Germany
accepté le 17 Août 2009
Oxidative hair dyes have repeatedly come to the attention of the
dermatological community due to concerns of contact sensitivity
(type IV allergic reactions). It has recently been stated that
contact allergy to p-phenylenediamine (PPD) has increased
significantly in the general population in the recent decades [1,
2]. Two exhaustive reviews of epidemiological data on consumer
allergy to PPD, however, showed no clear increase of positive patch
tests to PPD in eczema patients and in the general population in
Europe over the last 40 years [3, 4]. All the parameters through
which the frequency of hair dye dermatitis was evaluated have been
stable in Europe with a few exceptions [4].
This paper analyses post-marketing undesirable events (UEvs) to
hair colouring products notified to the cosmetovigilance
departments of four major companies in the European Union in a
4-year period. These companies are referred to as Company 1, 2, 3
and 4. To date, no paper has been published on post-marketing
surveillance data of hair colouring products.
The objective of the analysis was to determine whether there was
any:
- – time effect (trend to increase or decrease of notified
undesirable events and effects);
- – country effect (significant difference between the
countries included in the analysis);
- – product type effect (direct or oxidation);
as well as to identify risk factors.
Material and methods
Spontaneous reporting and post-marketing surveillance
procedures
Cosmetovigilance is a post-marketing surveillance method, mainly
based on the analysis of spontaneous reports. It is effected via an
integrated stepwise process requiring collection, monitoring and
evaluation of undesirable events.
A spontaneous report is an unsolicited communication by a
consumer, a healthcare professional, a regulatory authority or
another organisation that describes an undesirable reaction in a
consumer who used a cosmetic product.
Monitoring of spontaneous reporting is an efficient method for
capturing changes in market place acceptance or tolerance of
products and can provide important information on “at-risk groups”,
risk factors, and clinical features of known serious undesirable
reactions. Caution should be exercised in evaluating spontaneous
reports, especially when comparison is made between different
countries or between companies where cosmetovigilance systems are
implemented differently. The rate at which cases are reported is
dependent on many factors, including the time since product launch,
cultural consumer habits, media attention or environmental/public
health concern and current national regulatory requirements on
cosmetovigilance.
In countries or in companies where cosmetovigilance has been
implemented for several years, spontaneous reporting gives a
meaningful indication on reporting rate. The reporting rate is
based on the number of spontaneously reported undesirable events
(the numerator) and the population exposure (the denominator).
Reporting rates are not incidence rates; they are, however, a
useful indicator to identify and describe a signal.
Cosmetic companies conduct post-marketing surveillance by
collecting undesirable events that have occurred during or after
use of their products. In 2005, Colipa issued “Guidelines on the
Management of Undesirable Events, Final version adopted by Board of
Directors, August 23, 2005” which describes the consistent
processes to be implemented by the cosmetic industry [5]. These
guidelines provide methodology on receiving, centralizing,
recording and analyzing genuine undesirable event reports, allowing
the consistent generation of high quality and reliable data, using
a common method of causality assessment.
The processes in place for collecting undesirable events are
similar between the cosmetic companies concerned. Complaints
related to intolerance are reported to persons responsible locally
in the different countries. All available medical information on an
initial complaint is collected, including the results of
complementary investigations if performed (such as patch tests in
case of suspected allergic reactions). It is important to underline
that cosmetovigilance is mainly based on consumer self-reporting
and as such not all the medical information required for reliable
assessment is available in all cases.
Causality assessment
All cases of alleged undesirable events (UEvs) are entered into a
centralized database. Thereafter causality assessment is performed
on a case-by-case basis, where feasible. The objective of the
causality assessment is to determine the probability that a product
used by a consumer is responsible for an undesirable event. The
causal relationship between the use of a cosmetic product and the
event can be qualified as: very likely, likely, questionable,
unlikely or excluded, according to the following criteria
(algorithm shown in figure 1): i) the type of
clinical reaction which may be more or less evocative of a skin
disorder related to the use of the suspected cosmetic product; ii)
the time sequence (chronology) of events which may be compatible
with the appearance of clinical manifestations characteristic of a
particular skin disorder elicited by the product and iii) the
results or the absence of specific medical investigations, or the
result of re-exposure to the suspected product. If another cause is
identified, the relationship between the reaction and the product
is excluded.
Undesirable events (UEvs) given a causality assessment of
“likely” or “very likely” are classified as undesirable effects
(UEfs), which are reasonably attributable to product use (figure 2).
An event is qualified as a serious or non-serious undesirable
event/effect depending on the objective symptoms, the outcome or
the necessity of specific treatment (WHO and ICH guidelines).
Serious events are those that are i) fatal; ii) life-threatening;
iii) permanently/significantly disabling; iv) require or prolong
hospitalization; v) cause congenital anomaly or vi) require
intervention to prevent permanent impairment or damage.
Products
Included in the analysis are the following types of hair colouring
products:
- – Oxidation (permanent, demi-permanent/tone on tone)
hair dyes (approximately 80 to 90% market share);
- – Direct (semi-permanent and temporary) hair dyes
(approximately 10% to 20% of market share).
Different brands of both types are marketed for home use and for
professional use. Some of the hair dye manufacturers market only
professional use products.
Company 1 presents data on both professional and home use
products; Companies 2 and 3 present data only on home use products,
due to missing reporting from professionals in the past and, in
some instances, to lack of sales figures, and Company 4 presents
data only on professional products.
Data collection and reporting rates
Each Companies has collected the alleged undesirable events (UEvs)
reported for their hair colouring products in the key European
markets during a 4 year period, from 2003 to 2006. The rates are
reported company by company. The reporting rates for products for a
particular country are calculated as the number of UEvs and UEfs
collected with the products per million units sold for the period
considered (1 year or 4 year period). The European
reporting rate for products for a particular year is calculated as
the sum of all the countries’ UEvs and UEfs collected during that
year, per million units of product sold for the same year. Where a
4 year rate (2003 to 2006) is given, it is calculated as the total
number of UEvs or total number of UEfs reported with hair colouring
products sold during the 4 years, per million units sold.
From these data, three main series of reporting rates are
provided:
European reporting rates for all types and levels of causality
assessment of alleged UEvs
For the calculation of these rates, data are based on 11 countries
for Company 1, 10 countries for Company 2, 23 countries for Company
3 and 1 country for Company 4. These countries are selected by each
company as key European markets.
Yearly and country rates of UEvs were calculated for all hair
colouring products and, separately, for oxidation and for direct
hair colouring products.
European reporting rates for UEfs (causality assessment
likely and very likely) with manifestations compatible
with allergic contact dermatitis
The method of calculation is the same as above and the data are
issued from the same countries as above. These rates are provided
by each company for the 4 year period and are given for oxidation
hair colouring products and direct colouring products separately.
Specific analysis of UEvs and UEfs (causality
assessment likely and very likely) related
to the use of oxidation hair colouring products
in selected countries
A detailed analysis was performed in order to investigate for an
increase in the rates of allergy to permanent (oxidation) hair
colouring products across the EU Member States. The countries
selected by each company fulfil the following criteria:
- – Each Company has a large and/or stable sales
market;
- – The cosmetovigilance processes have been efficient for
a significant period;
- – Northern and Southern European regions are
covered.
For this specific analysis, data are issued from:
- – 3 countries for Company 1 (UK, France, Germany);
- – 4 countries for Company 2 (UK, Sweden, Spain and
Greece);
- – 7 countries for Company 3 (UK, Germany, Scandinavian
countries (4 countries), France);
- – 1 country for Company 4 (Germany).
The following (I to VI) reporting rates were calculated for each
year from 2003 to 2006, for each selected country and when
feasible, for each product distribution network (home use or
salon): I) All types of undesirable effects to oxidation hair
colouring products; II) A breakdown of undesirable effects
into allergic contact dermatitis and scalp and skin irritation [6,
7]; III) Oedematous-type contact allergic dermatitis cases. Oedema
is taken as an indication that the reaction is severe; IV) Serious
cases of allergic contact dermatitis; V) Allergic contact
dermatitis following the use of black henna tattoos. The reporting
rates concerning black henna tattoos will be given separately for
serious and non serious cases of allergic contact dermatitis; VI)
The age distribution for serious and non serious undesirable
effects compatible with allergic contact dermatitis.
All data are normalised against the units of product sold
(number/million units sold).
Statistical methods
Time effect was analyzed using a regression analysis. When p <
5%, it was considered that there was a statistically significant
decrease or increase of reporting rates. When p > 5% it was
considered that there was no statistical time effect during the
period, but it could be considered that a trend exists when p is
between 5 and 10%.
Reporting rates in different countries for the same company and
reporting rates to different types of products (direct vs oxidation
hair colour) or distribution networks (professional vs home use)
were compared and analysed using a Chi-square test. When p < 5%,
it was considered that there was a statistically significant
difference between 2 countries, types of products or distribution
networks. When p > 5% it was considered that there was no
statistical difference between 2 countries, types of products or
the 2 distribution networks. But it could be considered that a
trend exists if p is between 5 and 10%.
The influence of having a henna tattoo on the reaction type
(serious reaction or non serious reaction), was analyzed by
comparing with a Chi-square test the rate of having a serious
reaction among people who had an undesirable event, according to
whether they have had a henna tattoo or not. When p < 5%, it was
considered that there was a statistically significant difference in
the incidence of serious UEfs in the group of consumers with past
history of black henna tattoos and the incidence of severe UEfs in
the group of consumers with negative or unknown history of black
henna tattoo applications. When p > 5% it was considered that
there was no statistically significant difference in the incidence
of severe UEfs in the two groups.
It was not possible to do a statistical analysis on the age
distribution of serious UEfs as the actual number of units sold to
each age group is unknown.
Results
European reporting rates on all types of alleged UEvs
(all type of events, all levels of causality
assessment)
These results concern medical complaints notified to the companies
before any causality assessment is performed to determine which of
them are reasonably attributable to product use. After causality
assessment is performed, these rates will correspond to all five
levels of causality assessment.
Country yearly rates were calculated for all kinds of hair
colouring products together, and then for oxidation and direct hair
colour separately. The yearly European rates for the four companies
are shown in table 1. There is no time
effect for the European area as a whole for any of the companies,
for all hair colouring products and for the two product types
analysed separately. The UEvs rates to direct hair colour were
significantly lower than to oxidation hair colour for 3 of the 4
companies; there was no statistically significant difference
between product types for Company 2.
Table 1 European reporting rates of undesirable events
(UEvs, all levels of causality assessment) for all hair colouring
products and separately, for oxidation and direct hair colouring
products. Rates are calculated as the number of UEvs per million of
units sold
|
Year
|
4-year rate 2003 to 2006
|
|
2003
|
2004
|
2005
|
2006
|
|
Company 1 (11 countries)
|
All products
|
5.4
|
3.6
|
4.3
|
4.0
|
4.3
|
|
Oxidation hair colour
|
6.4
|
4.1
|
4.9
|
4.9
|
5.1
|
|
Direct hair colour
|
0.8
|
1.2
|
0.9
|
0.7
|
0.9
|
|
Company 2 (10 countries)
|
All products
|
34.9
|
45.3
|
38.2
|
24.9
|
37.8
|
|
Oxidation hair colour
|
37.7
|
49.9
|
37.2
|
25
|
47.6
|
|
Direct hair colour
|
19.4
|
14.9
|
51.1
|
23.7
|
26.1
|
|
Company 3 (23 countries)
|
All products
|
3.4
|
3.9
|
4.2
|
4.0
|
3.9
|
|
Oxidation hair colour
|
3.5
|
4.1
|
4.3
|
3.7
|
3.9
|
|
Direct hair colour
|
1.3
|
0.8
|
2.3
|
3.5
|
2.0
|
|
Company 4 (1 country)
|
All products
|
0.6
|
0.5
|
0.4
|
0.6
|
0.5
|
|
Oxidation hair colour
|
0.6
|
0.5
|
0.4
|
0.6
|
0.5
|
|
Direct hair colour
|
0.0
|
0.0
|
0.0
|
0.0
|
0.0
|
European reporting rates for UEfs with manifestations
compatible with allergic contact dermatitis (causality
assessment likely and very likely)
These results concern notifications which, after causality
assessment, are considered reasonably attributable to product use
(UEfs) and which, furthermore, have medical manifestations,
chronology characteristics and eventually medical investigations
which are compatible with allergic contact dermatitis to hair
colouring products. European reporting rates (per million units
sold) are shown in table 2.
The analysis of these rates for time effect shows that there is
no significant increase or decrease with time for any company
reporting in the European area as a whole, neither for allergic
contact dermatitis related to oxidation hair colouring products nor
for allergic contact dermatitis related to direct hair colouring
products.
These data show that the reporting rates of UEfs compatible with
allergic contact dermatitis to direct hair colouring products are
significantly lower than the reporting rates to oxidation hair
colouring products for each company.
European reporting rates on the 4-year period for each of the
companies are presented in table 3.
These include alleged UEvs prior to medical assessment and
reporting rates for UEfs compatible with allergic contact
dermatitis. These rates have been calculated for the two types of
hair colouring products together and then separately.
Table 3 shows that the incidence of
allergic contact dermatitis related to hair colouring products is
significantly less than the incidence of all alleged UEvs. This is
true both for oxidative and direct dyes. The incidence of allergic
contact dermatitis related to direct hair colouring products is
lower than the incidence for oxidative hair colouring products.
Table 2 European reporting rates of undesirable effects
(UEfs) with manifestations compatible with allergic contact
dermatitis (causality assessment likely and very likely) for
oxidation and direct hair colouring products. Rates are calculated
as the number of UEfs per million of units sold
|
Year
|
|
2003
|
2004
|
2005
|
2006
|
|
Company 1 (11 countries)
|
Oxidation hair colour
|
1.4
|
0.9
|
1.3
|
1.3
|
|
Direct hair colour
|
0.1
|
0.3
|
0.1
|
0.1
|
|
Company 2 (4 countries)
|
Oxidation hair colour
|
3.4
|
4.8
|
4.6
|
4.2
|
|
Direct hair colour
|
0.4
|
0.28
|
0.89
|
0.0
|
|
Company 3 (23 countries)
|
Oxidation hair colour (very likely)
|
0.2
|
0.5
|
0.8
|
0.3
|
|
Oxidation hair colour (very likely + likely)
|
0.2
|
0.5
|
1.2*
|
1.0*
|
|
Direct hair colour (very likely)
|
0.0
|
0.3
|
0.5
|
0.2
|
|
Direct hair colour (very likely + likely)
|
0.0
|
0.3
|
0.7*
|
0.4*
|
|
Company 4 (1 country)
|
Oxidation hair colour
|
0.3
|
0.2
|
0.3
|
0.2
|
|
Direct hair colour
|
0.0
|
0.0
|
0.0
|
0.0
|
Table 3 European 4-year reporting rates of alleged UEvs
(prior to medical evaluation, all levels of causality assessment)
and UEfs with manifestations compatible with allergic contact
dermatitis (causality assessment likely and very likely) for
oxidation and direct hair colouring products. Rates are calculated
as the number of events per million of units sold
|
Company 1
|
Company 2
|
Company 3
|
Company 4
|
|
11 countries
|
4 countries
|
23 countries
|
1 country
|
|
Alleged undesirable events (unselected consumer reports, all levels
of causality assessment)
|
To all hair colouring products
|
4.3
|
43.8
|
3.9
|
0.5
|
|
To oxidation hair colouring products
|
5.1
|
47.6
|
3.9
|
0.5
|
|
To direct hair colouring products
|
0.9
|
26.1
|
2
|
0
|
|
Undesirable effects with manifestations compatible with allergic
contact dermatitis (causality assessment likely and very
likely)
|
To oxidation hair colouring products
|
1.2*
|
4.5*
|
0.8*
|
0.28*
|
|
To direct hair colouring products
|
0.2*#
|
0.4*#
|
0.3*#
|
0*#
|
Specific analysis on oxidation hair colouring products
in selected countries
Time and Country effect on UEvs and UEfs
reported with oxidation hair colouring products
The yearly reporting rates (per million units sold) of alleged UEvs
(all levels of causality assessment) and UEfs (causality assessment
likely and very likely) reported with oxidation hair colouring
products for each company in selected countries are shown in table 4.
Table 4 Time and country effects on rates of alleged
UEvs and UEfs reported with oxidation hair colouring products.
Rates are calculated as the number of events per million of units
sold
|
Alleged UEvs/million units sold
|
Likely and very likely UEfs/million units sold
|
|
2003
|
2004
|
2005
|
2006
|
4-year rate 2003 to 2006
|
2003
|
2004
|
2005
|
2006
|
4-year rate 2003 to 2006
|
|
Company 1
|
UK
|
11.1
|
5.5
|
10
|
13.5
|
10.1
|
6
|
3.1
|
5.5
|
6.9
|
5.2
|
|
France
|
6.2
|
4.5
|
4.4
|
4.8
|
5.0
|
2
|
1.4
|
1.5
|
1.4
|
1.4
|
|
Germany
|
9.8
|
7.5
|
8.2
|
3.7
|
7.3
|
3.1
|
2.3
|
2.9
|
0.9
|
2.0
|
|
Company 2
|
UK
|
38.8
|
67.9
|
72.1
|
42.5
|
55.1
|
3.8
|
5.9
|
5.5
|
4.7
|
5.0
|
|
Sweden
|
5.8
|
19.6
|
13.1
|
20.2
|
16.7
|
5.8
|
8.4
|
8.3
|
9.0
|
7.9
|
|
Spain
|
nm
|
5.6
|
9.9
|
4.9
|
7.1
|
nm
|
3.8
|
8.4
|
4.2
|
5.4
|
|
Greece
|
0.0
|
1.0
|
11.5
|
8.2
|
7.8
|
0.0
|
0.0
|
1.6
|
5.6
|
1.8
|
|
Company 3
|
UK
|
6.2
|
6.3
|
10.5
|
8
|
7.7
|
0
|
0.2
|
1.0*
|
0.3*
|
0.5
|
|
Germany
|
5.6
|
7.6
|
7.8
|
5.1
|
6.6
|
0.3
|
0.9
|
2.6*
|
2.0*
|
1.8
|
|
Scandinavian countries
|
1.4
|
1.6
|
4
|
7
|
3.3
|
0.2
|
0.6
|
1.3*
|
1.1*
|
1.0
|
|
France
|
1.6
|
1.4
|
1.4
|
4.1
|
2.2
|
0.2
|
0
|
0.4*
|
1.3*
|
0.6
|
|
Company 4
|
Germany
|
0.58
|
0.5
|
0.42
|
0.58
|
0.52
|
0.33
|
0.25
|
0.25
|
0.33
|
0.29
|
Time effect
Analysis of these rates over time shows that there are no
statistically significant differences in the yearly reporting rates
for Company 1 and 4 during the period of analysis in any of the
countries. For Company 2, a trend to increase was observed in
Greece for UEfs, although the level of complaints was very low: 0
complaints for 2003 and 2004, 3 complaints in 2005 and 11
complaints in 2006, corresponding to 0, 1.6 and 5.6 events per
million of units sold (table 4). The
numbers of complaints are too low to produce a meaningful analysis.
For the other countries there are no statistically significant
differences. For Company 3, a trend to increase of alleged UEvs was
noted in the Scandinavian countries (Sweden, Denmark, Norway and
Finland) (p = 0.059), which the company explains with improved data
collection due to restructuring of data collection and
cosmetovigilance processes.
Country effect
For Company 1, the reporting rates (UEvs and UEfs) are higher in
the UK than in France and in Germany (statistically significant
difference by Chi-square test, which compares the 4 year period
reporting rate of each country). For Company 2, the reported UEvs
are higher in the UK than in Sweden, Spain and Greece, but there is
no difference in the notification rates of UEfs confirmed as
causally linked to the product (likely and very likely) in the UK,
Sweden, Spain and Greece. For Company 3, there is no statistically
significant difference between countries (UK, Germany, Scandinavian
countries and France), both for UEvs and UEfs.
Effect of Home use versus Salon use on rates
of alleged UEvs and UEfs due to oxidation hair
colouring products
This analysis is provided only for Company 1 and the breakdown of
UEvs and UEfs accordingly to the distribution network (home use or
professional) for each country is shown in table
5, for each year from 2003 to 2006 and for the whole 4 year
period. The comparison between rates for home use products and
rates for professional products, year per year and for the 4 year
period, shows that the reporting rates to home use products are
altogether higher than the reporting rates for professional
products in all three countries included in the analysis, both for
UEvs and for UEfs. The reporting rates of UEvs and UEfs do not show
any increase within each distribution network, neither for home use
nor for professional products.
Table 5 Reporting rates of UEvs and UEfs to oxidation
hair colouring products depending on the distribution network
(professional vs home use)
|
Alleged UEvs/million units sold
|
UEfs/million units sold (causality assessment likely and very
likely
|
|
2003
|
2004
|
2005
|
2006
|
4-year rate 2003 to 2006
|
2003
|
2004
|
2005
|
2006
|
4-year rate 2003 to 2006
|
|
professional
|
home-use
|
professional
|
home-use
|
professional
|
home-use
|
professional
|
home-use
|
professional
|
home-use
|
professional
|
home-use
|
professional
|
home-use
|
professional
|
home-use
|
professional
|
home-use
|
professional
|
home-use
|
|
UK
|
10.1
|
11.5
|
4.2
|
6.3
|
6.2
|
12.7
|
11.0
|
14.8
|
7.7
|
11.5
|
6.4
|
5.8
|
2.5
|
3.4
|
4.0
|
6.6
|
6.0
|
7.3
|
4.7
|
5.8
|
|
France
|
1.2
|
11.5
|
0.8
|
8.6
|
0.7
|
8.6
|
0.7
|
9.1
|
0.9
|
9.5
|
0.5
|
3.6
|
0.3
|
2.5
|
0.3
|
2.9
|
0.4
|
2.5
|
0.4
|
2.9
|
|
Germany
|
0.7
|
12.6
|
1.4
|
9.6
|
2.1
|
10.5
|
2.5
|
4.1
|
1.7
|
9.2
|
0.3
|
3.9
|
0.0
|
3.0
|
0.6
|
3.8
|
1.3
|
0.8
|
0.6
|
2.9
|
Type of manifestations and henna tattoo effect
on the severity of the reaction
UEfs (causality assessment likely and very likely) were analysed
further according to the type of manifestations (chiefly scalp and
skin irritation or allergic contact dermatitis) and to the severity
of the allergic contact dermatitis reactions. This breakdown is
shown in table 6 (last 2 columns: 2006
data only).
Oedema was used as a criterion of greater severity throughout
the period, the definition of a serious undesirable event becoming
available only in 2005 (Colipa Guideline on the management of
undesirable event reports) [5]. Serious UEvs were less than 5% of
all UEvs notified to companies.
As shown in table 6, there was a
known history of black henna tattoo application in a significant
number of serious undesirable events: 50% for Company 1 (2006). For
other companies who started more recently to collect data on henna
tattoos, an indication of association is also observed. However, in
a great number of cases, exposure to black henna tattoos cannot be
characterised: it is difficult to obtain an answer from the
consumers due to different reasons inherent to spontaneous
reporting methods (in many cases people cannot be contacted
directly by company for a more detailed questionnaire).
To better characterise the importance of black henna tattoos in
the elicitation of serious UEfs to hair colouring products, the
incidence of serious undesirable effects in consumers with known
black henna tattoo applications has been compared to the incidence
of serious undesirable effects in consumers with unknown or absent
black henna tattoo application, for each Company. The incidence of
serious undesirable effects was calculated as follows:
- – for consumers with known black henna tattoo
applications, the percentage of people who had a serious reaction
among all the people who had a reaction (serious or not serious)
and who declared that they had a black henna tattoo
application;
- – for consumers with unknown or absent black henna
tattoo applications, the percentage of people who had a serious
reaction among all the people who had a reaction (serious or not
serious) and who declared that they had no black henna tattoo
application.
The comparison between the incidence of serious UEfs in
consumers with known black henna tattoo applications to the
incidence of serious UEfs in consumers with unknown or absent black
henna tattoo applications (table 7)
shows that there is a statistically significant difference for
Company 1 and for the three companies together (p < 0.001,
Chi-square test). Black henna tattoo application increases by more
than four times the reporting of occurrence of a serious reaction
to hair colouring products.
Table 6 Type of manifestations to oxidation hair
colouring products and effect of black henna tattoos on the
seriousness of the reaction. Rates are calculated as the number of
UEfs per million of units sold
|
All UEfs (causality assessment likely and very likely)
|
Scalp and skin irritation
|
Allergic contact dermatitis
|
Oedematous allergic contact dermatitis
|
Serious Events*
|
Serious UEfs with past history of black henna tattoo
application
|
|
Company 1
|
UK
|
5.21
|
1.40
|
3.81
|
2.55
|
1.00
|
0.48
|
|
France
|
1.42
|
0.36
|
1.07
|
0.50
|
0.08
|
0.06
|
|
Germany
|
2.01
|
1.24
|
0.77
|
0.32
|
0.12
|
0.04
|
|
Total
|
2.87
|
0.95
|
1.92
|
1.15
|
0.41
|
0.20
|
|
Company 2
|
UK
|
4.97
|
0.48
|
4.48
|
2.56
|
0.5
|
0.14
|
|
Sweden
|
7.91
|
1.35
|
6.56
|
2.26
|
0.00
|
0.00
|
|
Spain
|
5.45
|
2.85
|
2.60
|
0.49
|
0.00
|
0.00
|
|
Greece
|
1.82
|
1.05
|
0.77
|
0.00
|
0.00
|
0.00
|
|
Total
|
5.09
|
0.76
|
4.33
|
2.31
|
0.5
|
0.14
|
|
Company 3
|
Germany
|
1.8
|
0.05
|
1.8
|
0.4
|
0.4
|
0.06
|
|
France
|
0.6
|
0.06
|
0.5
|
0.12
|
0.3
|
0
|
|
UK
|
0.5
|
0.0
|
0.5
|
0.1
|
0.06
|
0
|
|
Scandinavia
|
1.0
|
0.15
|
0.8
|
0.2
|
0.2
|
0
|
|
Total
|
0.9
|
0.05
|
0.8
|
0.2
|
0.2
|
0.02
|
|
Company 4
|
Germany
|
0.29
|
0
|
0.29
|
0.0
|
0.0
|
0
|
Table 7 Serious UEfs in oxidation hair dyes consumers
depending on previous use of black henna tattoos
|
Company 1
|
Company 2
|
Company 3
|
Total three companies
|
|
Black henna tattoo
|
Incidence (%)
|
Relative risk
|
Incidence (%)
|
Relative risk
|
Incidence (%)
|
Relative risk
|
Incidence (%)
|
Relative risk
|
|
Serious UEfs in consumers with known black henna tattoo
application
|
52.7
|
52.7: 11.2 = 4.7
|
50*
|
50: 7.1 = 7.0
|
100
|
100: 20 = 5
|
54.8
|
58.8: 12.8 = 4.3
|
|
Serious UE in consumers with no black henna tattoo and in consumers
who have not answered the question
|
11.2
|
7.1
|
20
|
12.8
|
Age effect on serious and non-serious UEfs
with manifestations compatible with allergic contact
dermatitis
The age distribution of serious and non-serious undesirable effects
compatible with manifestations of contact dermatitis (causality
assessment likely and very likely) for Companies 1 and 2 is shown
in figure 3.
It should be taken into consideration that the serious
undesirable events with known exact age are over-represented on the
graph compared to the non-serious events with known age because age
is known in almost all cases of serious adverse events. Although it
was not possible to get the actual number of units sold for each
age to allow for statistical analysis, it can be visually observed
that serious undesirable events apparently occur at a higher
frequency in the younger age groups in the UK (Company 1).
Discussion
Review of reporting rates
The review of post-marketing undesirable events data for hair
colouring products reported from the four major companies across
Europe for the period 2003-2006 contributes to the evaluation of
the incidence of allergy in hair dye users and identification of
possible risk factors.
Level of incidence
Spontaneous notifications: alleged UEvs
The reporting rates are linked to the cosmetovigilance system. As
expected, the reporting rates of alleged cases are somewhat
different from one company to the other, from one European country
to the other within the same company, and different for the type of
hair dye products (for instance, reporting rates to direct hair
colouring products are significantly lower than reporting rates to
oxidation hair colouring products). Nevertheless, when the
cosmetovigilance systems are stable over time for a company in an
area, these reporting rates of alleged UEvs, all levels of
causality assessment included, are important to follow for possible
signal detection.
Incidence of contact allergy related to hair
colouring products
The reporting of UEvs associated with cosmetic products, which
often relies on self diagnosis and self medication, is largely
underestimated as most reactions are not severe and consequently
are not always declared by consumers. As is the case with
post-marketing surveillance (PMS) on drugs, spontaneous reporting
is mainly used for identifying signals and validating the cause of
well identified serious cases. A medical evaluation of the
reactions initially attributed to cosmetics by consumers is
necessary for establishing the cause-of-effect to allow appropriate
individual follow-up measures [8-10]. Indeed, after a case-by-case
examination by dermatologists, only 31% of people notifying adverse
events to a cosmetic company were found to have manifestations
causally related to normal use of the respective product [8]. In
another study, 151 subjects related UEvs to 533 products: after
causality assessment by dermatologists, 25 products were found to
be certainly related and 50 products were found to be
probably/likely related to notified manifestations [9]. Thus,
causality assessment of each case is a key factor for the
validation of signals in PMS.
Historically, consumers in the UK have always had a higher rate
of reporting of undesirable events for all types of cosmetic
products. The data presented here for the hair colour category
reflects the same trend. However, there is no specific concern with
these incidence rates.
The incidence of adverse skin reactions to hair colouring
products in Europe is comparable to other types of cosmetic
products as reported in consecutive eczema patients [9, 10],
cosmetovigilance studies (notifications by health professionals)
[11] and in consumer complaint-based studies [12, 13].
Analysis of cases of allergic contact dermatitis to oxidation
hair dyes in our study showed some unusual clinical features
(pronounced facial oedema) in a small subset of consumers; the
outcome of these cases is the same as the one described in
classical contact dermatitis. The percentage of serious cases
notified to companies (< 5%) appears to be lower than that
which is found by regulatory authorities (15-27%) [14, 15]. As we
believe that there is less under-reporting for serious UEvs than
for non-serious UEvs and that almost all serious UEvs are finally
notified to companies, one possible explanation could be the
different source of notifications. The public cosmetovigilance
systems are notified chiefly by dermatologists and dermatologists
see more severe cases; as consumers are the main actors in private
cosmetovigilance systems, this allows the companies to have a more
exhaustive view on all the diverse manifestations with varying
levels of severity.
Analysis of main parameters examined across companies
A review of several possible contributing factors on reporting
rates such as time, country and type of products has led to the
following conclusions:
Time effect (for the whole European area)
The European reporting rates for alleged UEvs to all hair colouring
products (unselected consumer reports, all kinds of causality
assessment) are stable through the years. This is also verified for
each country reporting rate and for each company. For countries
with no market and for those with zero events in 2003 the increase
is due to progressive penetration of the products on the market at
the beginning of the analysed period, as well as to improvement of
the structure of consumer call centres, post-marketing surveillance
process and resulting improved data collection (see country
effect). The European reporting rates for alleged UEvs to each
oxidation and direct hair colouring products are also stable across
the years. In the same way, the European reporting rates of UEfs
with manifestations compatible with allergic contact dermatitis
(causality assessment likely and very likely) to each oxidation and
direct hair colouring are also stable across the years.
Country effect
Yearly country reporting rates (alleged UEvs, medically validated
UEfs, allergic contact dermatitis to oxidation and direct hair
colouring products) are stable in all countries with a few
exceptions:
- – A trend for an increase in alleged UEvs to all hair
colouring products (oxidation and direct) in Austria (new market)
and Finland (very low level of complaints, not allowing a
meaningful analysis) (Company 2).
- – A trend for an increase in alleged UEvs to oxidation
hair colouring products in Scandinavian countries due to
restructuring and improved data collection (Company 3).
- – A trend for an increase in UEfs to oxidation hair
colour was seen in Greece (very low level of complaints, not
allowing a meaningful analysis) (Company 2).
Four-year reporting rates for medically confirmed UEfs to
oxidation hair colouring products are similar in all countries
within the same company with a few exceptions:
- – UK, with significantly greater rates for medically
confirmed UEfs, allergic contact dermatitis, oedematous allergic
contact dermatitis and serious undesirable events (Company 1).
- – UK and in Sweden with higher rates of oedematous
contact dermatitis compared to Spain and Greece (Company 2).
Product type effects
Generally rates (UEvs and UEfs) with direct hair colouring products
are significantly lower than the rates with oxidation hair
colouring products, with the exception of alleged UEvs for Company
2. The significance of these differences should be taken with
caution as the market share for direct hair dyes is considerably
smaller than the market share for oxidative hair dyes.
Additionally, the population, age and mode of use of this category
of products are not the same and this may have an impact on the way
of reporting.
The same caution should be taken when assessing differences
between rates to Home use products versus Professional products; an
under-reporting of UEs from the distribution circuit of
Professional products compared to Home use products contributes to
these differences.
Risk factors
The complete analysis of the serious reactions reported with
oxidation hair colouring products shows that there is a
statistically significant association with a previous exposure to
black henna tattoos. This relative risk is more than 4-fold. This
is because black henna tattoos can contain high concentrations
(> 15%) of PPD [16]. A consumer, pre-sensitised by a
black henna tattoo, will be at a higher risk of elicitation of a
serious reaction when using a hair colouring product containing PPD
[17-20] and potentially cross-reacting colourants. There are more
than 100 reports in the literature on sensitization to PPD by black
henna tattoos. Severe oedematous reactions to hair colouring
products leading to hospitalisation or visits to emergency
departments of adolescents sensitized by black henna tattoos have
been described [21-26].
The impact of black henna tattoos has been acknowledged by some
health authorities in the last few years. In France, since 2006,
Afssaps has conducted a consumer awareness campaign on the risks
associated with this practice [15, 27]. In 2008, the European
Commission launched a campaign in all member states to provide
information to the public that black henna tattoos can cause
serious health injuries [28].
Conclusion
An analysis of undesirable events reported following the use of
hair colouring products in Europe 2003-2006, shows that the
reporting rates of undesirable events, including contact
allergy-type events, are stable. This is true for both oxidative
and direct hair colouring products. The few exceptions of trends to
increase are related to biasing factors such as low number of sales
in the beginning of the period (i.e. new launches), changes to
cosmetovigilance processes, and most importantly to extremely low
numbers of undesirable events, which do not allow a meaningful
statistical analysis.
The incidence of adverse skin reactions following the use of
hair colouring products is comparable with other cosmetic product
types, although some reactions can be more serious. Some severe
allergic contact dermatitis to oxidative hair colouring products
has been observed in a subset of consumers. The analysis of these
cases shows that a key contributory risk factor identified for
these events is previous application of black henna tattoos.
In recognizing some of the safety concerns, the industry has
gradually increased the safety labeling of hair colouring products
through the years. Product labels now include, besides the
ingredient listing, warning statements alerting users, (i) that
hair colourants may cause reactions which may be severe, (ii) not
to apply products in people who have already experienced some
reactions, and (iii) increased allergy risk as a result of previous
exposure to black henna tattoos. In addition, there is a
recommendation to conduct a skin alert/compatibility test before
proceeding to colour the hair [29, 30].
In conclusion, hair colouring products may be used by consumers
with the same level of confidence as other cosmetic products,
provided that use instructions are followed carefully. In some
cases where follow-up was more thorough or more information was
available, it is clear that some consumers did not follow the use
and safety instructions recommended. Prospective studies are needed
to understand risk and risk factors in the younger age groups
(< 16 years).
Acknowledgements
Financial support: none. Conflict of interest: none.
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