Zgryźliwość kojarzy mi się z radością, która źle skończyła.
Clinics in Dermatology (2011)
, 311
–
315
29
New and emerging cosmetic allergens
Rosie F. Davies, MB, Graham A. Johnston, MBChB, FRCP
*
Department of Dermatology, Leicester Royal Infirmary, Infirmary Square, Leicester, LE1 5WW, UK
Abstract Human skin is exposed to a large variety of cosmetic allergens. Most allergic contact
dermatitis occurs after exposure to fragrance, preservatives, and hair dyes. Such reactions can often be
occult. As a result, a high index of suspicion is needed in assessing the patient with facial or cosmetic
dermatitis. This contribution looks at why such a large number of chemicals are in everyday usage, at
how dermatologists monitor trends in allergy to cosmetics, and at a number of new and emerging
allergens to consider in the assessment of suspected cosmetic allergy.
© 2011 Elsevier Inc. All rights reserved.
Introduction
vesiculation can be present, with only the distribution giving
a clue to an allergic etiology. Some allergens regularly
produce clinically atypical reactions: acute facial swelling
due to type IV hypersensitivity to the black hair dye
paraphenylenediamine (PPD) is one of the most dramatic
illustrations of how facial swelling may not always be a type
I reaction.
4
Human skin is exposed to a large variety of cosmetic
allergens. Most ACD reactions occur after exposure to
fragrance, preservatives, and hair dyes. Such reactions can
often be occult. As a result, a high index of suspicion is
needed in assessing the patient with facial or cosmetic
dermatitis.
5
A review of patients patch tested in the US
reported that of women with a positive patch test reaction,
24% were due to a documented cosmetic source.
6
mediated
delayed-type hypersensitivity reaction that occurs upon a
specific hapten challenge in previously sensitized indivi-
duals. The inflammatory response in classical ACD requires
an initial sensitization phase as a result of hapten
penetration of the epidermal skin barrier. This is followed
by an elicitation phase that is responsible for the recruitment
and activation of specific T cells at the site of the hapten
skin challenge.
1
The importance of the stratum corneum barrier function,
as well as the signalling pathways that allow keratinocyte
proliferation and generation of proinflammatory factors, is
increasingly recognized.
2
The association between filaggrin
null mutations in ichthyosis vulgaris and atopic dermatitis,
3
together with protease and lipid defects, highlights the
primary role of barrier disruption in allowing increased
access of environmental toxins, microbes, and allergens.
The clinical appearance of ACD can be very similar if not
identical to other types of dermatitis. Redness, scaling, and
Allergic contact dermatitis (ACD) is a T-cell
–
So why is such a wide range of these
potentially allergenic compounds necessary?
To improve usability for the consumer, cosmetics often
have high water content. This leaves the preparation at a risk
of being contaminated by pathogenic microorganisms such
as Staphylococcus aureus and Pseudomonas aeruginosa.
Bacterial contamination can alter the composition of the
* Corresponding author. Tel.: +44 116 258 7562; fax: +44 116 258 6792.
E-mail address:
(G.A. Johnston).
0738-081X/$
–
see front matter © 2011 Elsevier Inc. All rights reserved.
doi:
312
R.F. Davies, G.A. Johnston
product or pose a health risk to the consumer. To prevent
this, preservatives, including biocides, are added to cosmetic
products. Varying concentrations of the same preservative
are found in related products, posing the question of whether
some of these preparations are over-preserved. Because the
development and elicitation of ACD is dose-dependent,
7
over-preservation of cosmetics potentially leads to an
increased incidence of contact allergy.
8
By collating patch test databases, dermatologists can track
changes in the incidence of ACD to specific cosmetic
allergens. Legislation in Europe or the US restricting or
outlawing the use of specific allergens occurs as a
consequence of this data; however, it takes some time for
these allergies to clinically manifest, so there is a lag period
after the introduction of a new preservative and the clinical
assessment of the resultant ACD.
As the use of a new agent increases, subsequent reports of
allergy increase, legislation again decreases its use, and
allergy decreases. This process is then repeated all over again
for the replacement allergenic cosmetic chemical, a phe-
nomenon known as the Dillarstone effect.
9
Dermatologists respond to this dynamic situation by the
addition of emerging contact allergens to standardized patch
testing series. In the UK, allergens with an incidence of
positive reactions greater than 1% are added to the British
Contact Dermatitis Society (BCDS) standard series, to which
nearly all patients are tested. Allergens with a lower
prevalence of positive reactions (less than 1%) are included
in additional specialized and specific series. This contribution
reviews important new cosmetic allergens identified in the
last few years and also those allergens that have reemerged
due to their introduction into modern cosmetic products.
We searched Medline from February 1995 to February
2009 using the terms allergic contact dermatitis, propolis,
sodium metabisulfite, dicaprylyl maleate, benzophenone 4,
Lyral, limonene, and iodopropynyl butylcarbamate.
positive result and therefore did not recommend continued
testing.
12
Expanding on this work in 1994, an Italian group
patch tested 2894 patients to potassium metabisulfite,
sodium metabisulfite, and sodium sulfite. They found 50
patients (1.7%) were positive to both potassium metabisulfite
and sodium metabisulfite, whereas only 2 patients were
positive to sodium sulfite. Seven of the 50 who were positive
to sodium metabisulfite were identified as having an
occupational exposure, but again, only 5 of the remaining
43 positive results were thought to be clinically relevant.
13
More recently, it has been noted that sodium metabisulfite
is present in some ketoconazole-containing products, as well
as in Trimovate® and Timodine® creams,
14
and accounts for
relevant positive results when ACD develops in patients
while using these products.
15
Sodium metabisulfite has now
been identified as a component of cosmetic creams,
14
hair
colors, and bleaching agents, and in false tanning products.
10
In 2007, a 6.8% patch test positivity to sodium metabisulfite
was described in a consecutive series of 117 patients in
Ireland.
14
As a consequence of these high rates of allergy,
sodium metabisulfite was incorporated into the BCDS
standard series of allergens in 2007.
Propolis
Propolis is a resinous substance collected from poplars
and processed by honeybees to use as a sealant to maintain
the structure of the hive. It is a well-recognized cause of
occupational contact dermatitis in apiarists.
16
Propolis has a
variable chemical composition and is regarded as a potent
skin sensitiser.
17
Cases of ACD to propolis began to emerge
in the 1970s; indeed, Petersen predicted that cases of ACD to
propolis would increase with the increasing use of propolis in
self-medicating patients.
18
Owing to its purported antibac-
terial and antiinflammatory properties, propolis is now
contained in a number of
“
”
over-the-counter products
such as cough syrups, lozenges, shampoo, conditioner,
lipsticks, lip balms, lotions, toothpastes, and cosmetics.
19
The predicted increase in ACD appears to have occurred.
Between 1997 and 2002, a Finish center observed an
increase in positive patch test reactions to propolis from
0.5% to 1.4%.
20
Propolis became part of the standard battery
in Germany and Austria in 2004, and an average of 3.5%
positive reactions were observed.
21
Propolis was therefore
also included in the BCDS standard series in 2007.
natural
Sodium metabisulfite
The sulfites are a ubiquitous group of chemicals. Sodium
metabisulfite is present in food and drink as a preservative
and antioxidant, where it is labelled as E223.
10
In addition, it
is found as a component of photographic chemicals, is used
in rubber manufacture, in leather tanning, in mineral
extraction, and as a bleaching agent in fabric treatments.
10
Sodium metabisulfite is present in certain local anaesthetic
preparations to prevent oxidation of adrenaline and has been
described as causing local anesthetic reactions.
11
Initial investigations of the ability of sulfites to cause skin
sensitization were inconclusive. A Danish study in 1992
described 1762 consecutive patients patch tested with
sodium sulfite in addition to the standard battery. Although
25 (1.4%) were positive, the authors were frequently unable
to elicit a history indicating the clinical relevance of the
Dicaprylyl maleate
Dicaprylyl maleate (DCM), also known as dioctyl
maleate, is a good example of an emollient and solvent in
which original chemical testing indicated that the compound
did not cause ACD.
22
Ten years after it was introduced into
New and emerging cosmetic allergens
313
cosmetic products, it has been found to cause ACD in
selected patients. DCM has been used as an ingredient in
fake tanning lotions, moisturizers, foundations, and sunsc-
reens.
23
Recently, a series of 22 patients who were suspected
of having DCM contact allergy were tested to both freshly
manufactured DCM and deliberately aged DCM. Only eight
patients did not have a positive DCM patch test, and of these
eight, a positive reaction to the aged DCM developed in
six.
22
This phenomenon occurs with other contact allergens
(see Limonene section) and is thought to occur due to
chemical degradation (autoxidation) producing allergenic
by-products.
24
Ironically this may be seen to support the
cosmetic industry's argument for the increased use of further
newer preservatives in cosmetic products. As a result of this
study, Boots, a major UK cosmetic manufacturer, withdrew
DCM from its product lines (personal communication from S
Kirk, March 2009); however, we continue to see patients
with ACD in our practice who are using DCM-containing
products and developing ACD.
however, fragrance allergy is common,
28
and the prevalence
of ACD due to fragrance in the general population has
been estimated as 1.8% to 4.2%.
29
Fragrance is the second
most common cause of ACD after nickel.
30
The distribu-
tion is classically axillae, facial (including the eyelids) and
neck, although well-circumscribed patches in areas of
“
perfumes (wrists, behind the ears) and
aggravation of hand eczema is also described. The degree
of sensitivity and therefore severity of dermatitis varies
considerably. In the worst cases, ACD to fragrance can
cause disseminated dermatitis beyond the site of applica-
tion and erythroderma. In addition, patients with profound
sensitivity are affectedbya rborneor
dabbing-on
”
“
connubial
”
fragrance usage.
28
The BCDS standard series of allergens contains an
original mix of fragrance allergens (Fragrance Mix I) that
was introduced in 1977. By the mid-1990s, it became
apparent that this mix missed an estimated 15% of fragrance
allergies.
31
Between 2002 and 2003 a Fragrance Mix II was
trialled.
32
This mix consisted of Lyral, citral, farnesol,
citronellol,
-hexyl-cinnamic aldehyde, and coumarin. Six
centers tested 1701 patients, and 7 patients with a strong
history of fragrance allergy were identified with Fragrance
Mix II and not Fragrance Mix I. The number of false-
positive results was also lower with Fragrance Mix II. As a
result, Fragrance Mix II entered the BCDS British Standard
series in 2007.
Lyral (hydroxyisohexyl 3-cyclohexene carboxaldehyde)
bears a lilylike odor and is commonly used in deodorant,
shampoo, soap, and fine fragrance.
33
European contact
allergy rates to Lyral vary between 1.5% and 3%.
34,35
This
rate is much higher than the US rate of 0.4%,
36
possibly due
to higher concentrations of Lyral in European deodorants.
34
As a result of its high rate of contact sensitization, Lyral has
been included in the BCDS standard series both on its own,
dissolved in 1% petrolatum, and as part of the new Fragrance
Mix II.
34
Limonene is widely used as a fragrance in cosmetics. It is
present as a component of certain essential oils (rosemary,
peppermint, lemongrass, lavender, eucalyptus, and caraway)
and in tea tree oil.
30
Owing to its solvent capacity, it is used in
domestic cleaning products and also in industry as a metal
degreaser, where it can occur in concentrations up to 95%.
37
Limonene first appeared for industrial use in the late 1980s
and became widely used because it was regarded as more
environmentally friendly than its organic solvent equivalents;
however, on exposure to air it easily oxidizes to products with
considerable sensitizing capacity, such as limonene oxide,
l-carvone, and the limonene hydroperoxides.
38
A Swedish
group patch tested 2800 patients to varying concentrations of
fresh and aged d-limonene. The highest rate of contact
allergy (5.1% of patients) was found when 5% d-limonene
was exposed to air for 10 weeks.
38
More recently, a
multicenter study patch tested consecutive patients with
dermatitis to both R-limonene and S-limonene and found
that 2.6% of patients reacted to one or both preparations.
30
α
Benzophenone 4
Many facial moisturizers, make-up, and hair care
products
25
now incorporate ultraviolet light (UV) filters to
protect the skin against photoaging and also to protect the
product itself from UV degradation to prolong shelf life.
Historically, benzophenone 3 was widely used in sunscreen
for its UVA filter properties. In a retrospective series of 2715
patients undergoing photopatch testing between 1983 and
1998, benzophenone 3 was the most common UV filter
photoallergen.
26
Benzophenone 4 (2-hydroxy-4-methoxy-
benzophenone-5-sulphonic acid: sulisobenzone) is a chem-
ical UVA filter whose spectrum of action extends into the
UVB range.
27
For this reason, benzophenone 4 is increas-
ingly being used in cosmetics. Benzophenone 3 and 4 do not
appear to cross-react.
25
A 2005 UK multicenter group photo-
patch tested 1155 patients with a history of a photoderma-
tosis or a history consistent with a sunscreen allergy.
Benzophenone 3 and 4 were each responsible for 9% of
contact allergic reactions.
Between 2003 and 2005, 553 patients with a history of
facial dermatitis or a possible cosmetic contact allergy were
tested to an extended facial/cosmetics series. Benzophenone
4 was one of the allergens, and 2.3% of patients had a
relevant positive patch test to benzophenone 4. This
prompted the authors to call for inclusion of benzophenone
4 in the facial/cosmetics series of patch test allergens.
27
Artificial fragrances
Considering the ubiquitous occurrence of fragrance
materials, the risk of allergy is small. In absolute numbers,
314
R.F. Davies, G.A. Johnston
Iodopropynyl butylcarbamate
5. Mortz CG, Andersen KE. New aspects in allergic contact dermatitis.
Curr Opin Allergy Clin Immunol 2008;8:428-32.
6. Warshaw EM, Buchholz HJ, Belsito DV, et al. Allergic patch test
reactions associated with cosmetics: Retrospective analysis of cross-
sectional data from the North American Contact Dermatitis Group,
2001-2004. J Am Acad Dermatol 2009;60:23-38.
7. Kammeyer A, Bos JD, Teunissen MB. Postelicitation model of allergic
contact dermatitis for predicting the efficacy of topical drugs. Exp
Dermatol 2009;18:44-9.
8. Lundov MD, Moesby L, Zachariae C, Johansen JD. Contamination
versus preservation of cosmetics: a review on legislation, usage,
infections, and contact allergy. Contact Dermatitis 2009;60:70-8.
9. Dillarstone A. Cosmetic preservatives. Contact Dermatitis 1997;
37:190.
10. Madan V, Walker SL, Beck MH. Sodium metabisulfite allergy is
common but is it relevant? Contact Dermatitis 2007;57:173-6.
11. Riemersma WA, Schuttelaar MLA, Coenraads PJ. Type IV hypersen-
sitivity to sodium metabisulfite in local anaesthetic. Contact Dermatitis
2004;51:148.
12. Petersen CS, Menne T. Consecutive patch testing with sodium sulfite in
eczema patients. Contact Dermatitis 1992;27:344.
13. Vena GA, Foti C, Angelini G. Sulfite contact allergy. Contact
Dermatitis 1994;31:172-5.
14. Malik MM, Hegarty MA, Bourke JF. Sodium metabisulfite
—
a marker
for cosmetic allergy? Contact Dermatitis 2007;56:241-2.
15. Tucker SC, Yell JA, Beck MH. Allergic contact dermatitis from sodium
metabisulfite in Trimovate® cream. Contact Dermatitis 1999;40:164.
16. Gulbahar O, Ozturk G, Erdem N, et al. Psoriasiform contact dermatitis
to propolis in a beekeeper. Ann Allergy Asthma Immunol 2005;94:
509-11.
17. Menniti-Ippolito F, Mazzanti G, Vitalone A, et al. Surveillance of
suspected adverse reactions to natural health products
—
the case of
propolis. Drug Safety 2008;31:419-25.
18. Petersen HO. Allergy to Propolis (bee glue. in patients with eczema.
Ugeskr Laeger 1977;139:2331.
19. Walgrave SE, Warshaw EM, Glesne LA. Allergic dermatitis from
propolis. Dermatitis 2005;16:209-15.
20. Hasan T, Rantanen T, Alanko K, et al. Patch test reactions to cosmetic
allergens in 1995-1997 and 2000-2002 in Finland
—
a multicentre study.
Contact Dermatitis 2005;53:40-5.
21. Hegewald J, Uter W, Aberer W, et al. The European Surveillance
System of Contact Allergies (ESSCA): results of patch testing the
standard series, 2004. J Eur Acad Dermatol Venereol 2008;22:174-81.
22. Lotery H, Kirk S, Beck M, et al. Dicaprylyl maleate
Iodopropynyl butylcarbamate (IPBC) is a biocide origi-
nally developed for use in an industrial context, initially in
metalworking and subsequently as a wood preservative,
where concentrations of up to 4% are permitted.
39
ACD to
IPBC in these industrial settings is well described.
40
In a
series of 251 German metalworkers with suspected ACD,
0.5% had a positive reaction to IPBC.
41
Because of its
usefulness as a biocide, IPBC has more recently been
incorporated into cosmetic products and cleansing wipes,
42
where the maximum permitted concentration is 0.1%.
Reports of ACD appeared only a few years after it was
introduced as a cosmetic ingredient.
43
Although IPBC is only thought to be weakly allergenic, it
is a small lipophilic molecule that may readily penetrate the
skin,
44
and as reports of ACD from IPBC exposure in
cosmetics have increased, it is now incorporated into the
Cosmetic Series of patch test allergens.
Conclusions
Contact allergy is an ever-changing area of dermatology
due to the evolving nature of the chemical, and more
specifically, cosmetics industry. Links between dermatology
and industry have become increasingly important to allow
early identification of allergenic compounds and to enable
patch testing of chemicals not yet commercially available.
Links between dermatologists and legislators have strength-
ened significantly,
8
especially in the European Community.
This has led to the publication of the European Community
Cosmetics Directive.
45
In 2004, this dynamic legislation
mandated the publication of ingredients on all cosmetics
products. This has made it significantly easier for consumers
and their physicians to identify and avoid the ever-increasing
numbers of allergenic chemicals added to cosmetics and
applied to the skin. ACD due to cosmetics can be occult and
has a variable and sometimes dramatic clinical presentation,
including acute facial swelling. Owing to improved product
labelling, it should now be possible for patients to avoid the
causative allergens identified on patch testing.
—
an emerging
cosmetic allergen. Contact Dermatitis 2007;57:167-72.
23. Chan I, Wakelin SH. Allergic contact dermatitis for dioctyl maleate in a
moisturizer. Contact Dermatitis 2006;55:250.
24. Nilsson J, Carlberg J, Abrahamsson P, et al. Evaluation of ionization
techniques for mass spectrometric detection of contact allergenic
hydroperoxides formed by autoxidation of fragrance terpenes. Rapid
Commun Mass Spectrom 2008;22:3593-8.
25. Alanko K, Jolanki R, Estlander T, Kanerva L. Occupational allergic
contact dermatitis from benzophenone-4 in hair-care products. Contact
Dermatitis 2001;44:188.
26. Darvay A, White IR, Rycroft RJG, et al. Photoallergic contact
dermatitis is uncommon. Br J Dermatol 2001;145:597-601.
27. Hughes TM, Stone NM. Benzophenone 4: an emerging allergen in
cosmetics and toiletries? Contact Dermatitis 2007;56:153-6.
28. de Groot AC, Frosch PJ. Adverse reactions to fragrances. A clinical
review. Contact Dermatitis 1997;36:57-86.
29. Schnuch A, Uter W, Geier J, Gefeller O. Epidemiology of contact
allergy: an estimation of morbidity employing the clinical epidemiology
and drug-utilization research (CE-DUR) approach. Contact Dermatitis
2002;47:32-9.
30. Matura M, Sköld M, Börje A, et al. Not only oxidized R-(+)- but also S-
(-)- limonene is a common cause of contact allergy on dermatitis
patients in Europe. Contact Dermatitis 2006;55:274-9.
References
1. Saint-Mezard P, Krasteva M, Chavagnac C, et al. Afferent and efferent
phases of allergic contact dermatitis (ACD) can be induced after a single
skin contact with haptens: evidence using a mouse model of primary
ACD. J Invest Dermatol 2003;120:641-7.
2. Hanifin JM. Evolving concepts of pathogenesis in atopic dermatitis and
other eczemas. J Invest Dermatol 2009;129:320-2.
3. O'Regan GM, Sandilands A, McLean WHI, Irvine A. Filaggrin in
atopic dermatitis. J Allergy Clin Immunol 2008;122:689-93.
4. Shavit I, Hoffmann Y, Shachor-Meyouhas Y, Knaani-Levinz H.
Delayed hypersensitivity reaction from black henna tattoo manifesting
as severe facial swelling. Am J Emerg Med 2008;26:515.
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31. de Groot AC, van der Kley AMJ, Bruynzeel DP, et al. Frequency of
false-negative reactions to the fragrance mix. Contact Dermatitis 1993;
28:139-40.
32. Frosch PJ, Pirker C, Rastogi SC, et al. Patch testing with a new fragrance
mix detects additional patients sensitive to perfumes and missed by the
current fragrance mix. Contact Dermatitis 2005;52:207-15.
33. Militello G, James W. Lyral: a fragrance allergen. Dermatitis 2005;16:
41-4.
34. Bruze M, Anderson KE, Goossens A. Recommendation to include
fragrance mix 2 and hydroxyisohexyl 3-cyclohexene carboxaldehyde
(Lyral®) in the European baseline patch test series. Contact Dermatitis
2008;58:129-33.
35. Baxter KF, Wilkinson SM, Kirk SJ. Hydroxymethyl pentylcyclohex-
ene-carboxaldehyde (Lyral®) as a fragrance allergen in the UK. Contact
Dermatitis 2003;48:117.
36. Belsito DV, Fowler JF, Sasseville D, et al. Delayed-type hypersensi-
tivity to fragrance materials in a selected north American population.
Dermatitis 2006;17:23-8.
37. Karlberg AT, Magnusson K, Nilsson U. Air oxidation of d-limonene
(the citrus solvent) creates potent allergens. Contact Dermatitis 1992;
26:332-40.
38. Karlberg AT, Dooms-Goossens A. Contact allergy to oxidized d-
limonene among dermatitis patients. Contact Dermatitis 1997;36:201-6.
39. Schnuch A, Geier J, Brasch J, Uter W. The preservative iodopropynyl
butylcarbamate: frequency of allergic reactions and diagnostic
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40. Davis RF, Johnston GA. Iodopropynyl butylcarbamate contact allergy
from wood preservative. Contact Dermatitis 2007;56:112.
41. Geier J, Lessmann H, Dickel H, et al. Patch test results with the
metalworking fluid series of the German Contact Dermatitis Research
Group (DKG). Contact Dermatitis 2004;51:118-30.
42. Natkunarajah J, Osborne V, Holden C. Allergic contact dermatitis to
iodopropynyl butylcarbamate found in a cosmetic cleansing wipe.
Contact Dermatitis 2008;58:316-7.
43. Bryld LE, Agner T, Rastogi SC, Menné T. Iodopropynyl butylcarba-
mate: a new contact allergen. Contact Dermatitis 1997;36:156-8.
44. Brasch J, Schnuch, Geier, J, et al. . Iodopropynylbutyl carbamate 0.2%
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45. Council of European Communities. Council directive, 27 July 1976.
Available at:
zanotowane.pl doc.pisz.pl pdf.pisz.pl hannaeva.xlx.pl
, 311
–
315
29
New and emerging cosmetic allergens
Rosie F. Davies, MB, Graham A. Johnston, MBChB, FRCP
*
Department of Dermatology, Leicester Royal Infirmary, Infirmary Square, Leicester, LE1 5WW, UK
Abstract Human skin is exposed to a large variety of cosmetic allergens. Most allergic contact
dermatitis occurs after exposure to fragrance, preservatives, and hair dyes. Such reactions can often be
occult. As a result, a high index of suspicion is needed in assessing the patient with facial or cosmetic
dermatitis. This contribution looks at why such a large number of chemicals are in everyday usage, at
how dermatologists monitor trends in allergy to cosmetics, and at a number of new and emerging
allergens to consider in the assessment of suspected cosmetic allergy.
© 2011 Elsevier Inc. All rights reserved.
Introduction
vesiculation can be present, with only the distribution giving
a clue to an allergic etiology. Some allergens regularly
produce clinically atypical reactions: acute facial swelling
due to type IV hypersensitivity to the black hair dye
paraphenylenediamine (PPD) is one of the most dramatic
illustrations of how facial swelling may not always be a type
I reaction.
4
Human skin is exposed to a large variety of cosmetic
allergens. Most ACD reactions occur after exposure to
fragrance, preservatives, and hair dyes. Such reactions can
often be occult. As a result, a high index of suspicion is
needed in assessing the patient with facial or cosmetic
dermatitis.
5
A review of patients patch tested in the US
reported that of women with a positive patch test reaction,
24% were due to a documented cosmetic source.
6
mediated
delayed-type hypersensitivity reaction that occurs upon a
specific hapten challenge in previously sensitized indivi-
duals. The inflammatory response in classical ACD requires
an initial sensitization phase as a result of hapten
penetration of the epidermal skin barrier. This is followed
by an elicitation phase that is responsible for the recruitment
and activation of specific T cells at the site of the hapten
skin challenge.
1
The importance of the stratum corneum barrier function,
as well as the signalling pathways that allow keratinocyte
proliferation and generation of proinflammatory factors, is
increasingly recognized.
2
The association between filaggrin
null mutations in ichthyosis vulgaris and atopic dermatitis,
3
together with protease and lipid defects, highlights the
primary role of barrier disruption in allowing increased
access of environmental toxins, microbes, and allergens.
The clinical appearance of ACD can be very similar if not
identical to other types of dermatitis. Redness, scaling, and
Allergic contact dermatitis (ACD) is a T-cell
–
So why is such a wide range of these
potentially allergenic compounds necessary?
To improve usability for the consumer, cosmetics often
have high water content. This leaves the preparation at a risk
of being contaminated by pathogenic microorganisms such
as Staphylococcus aureus and Pseudomonas aeruginosa.
Bacterial contamination can alter the composition of the
* Corresponding author. Tel.: +44 116 258 7562; fax: +44 116 258 6792.
E-mail address:
(G.A. Johnston).
0738-081X/$
–
see front matter © 2011 Elsevier Inc. All rights reserved.
doi:
312
R.F. Davies, G.A. Johnston
product or pose a health risk to the consumer. To prevent
this, preservatives, including biocides, are added to cosmetic
products. Varying concentrations of the same preservative
are found in related products, posing the question of whether
some of these preparations are over-preserved. Because the
development and elicitation of ACD is dose-dependent,
7
over-preservation of cosmetics potentially leads to an
increased incidence of contact allergy.
8
By collating patch test databases, dermatologists can track
changes in the incidence of ACD to specific cosmetic
allergens. Legislation in Europe or the US restricting or
outlawing the use of specific allergens occurs as a
consequence of this data; however, it takes some time for
these allergies to clinically manifest, so there is a lag period
after the introduction of a new preservative and the clinical
assessment of the resultant ACD.
As the use of a new agent increases, subsequent reports of
allergy increase, legislation again decreases its use, and
allergy decreases. This process is then repeated all over again
for the replacement allergenic cosmetic chemical, a phe-
nomenon known as the Dillarstone effect.
9
Dermatologists respond to this dynamic situation by the
addition of emerging contact allergens to standardized patch
testing series. In the UK, allergens with an incidence of
positive reactions greater than 1% are added to the British
Contact Dermatitis Society (BCDS) standard series, to which
nearly all patients are tested. Allergens with a lower
prevalence of positive reactions (less than 1%) are included
in additional specialized and specific series. This contribution
reviews important new cosmetic allergens identified in the
last few years and also those allergens that have reemerged
due to their introduction into modern cosmetic products.
We searched Medline from February 1995 to February
2009 using the terms allergic contact dermatitis, propolis,
sodium metabisulfite, dicaprylyl maleate, benzophenone 4,
Lyral, limonene, and iodopropynyl butylcarbamate.
positive result and therefore did not recommend continued
testing.
12
Expanding on this work in 1994, an Italian group
patch tested 2894 patients to potassium metabisulfite,
sodium metabisulfite, and sodium sulfite. They found 50
patients (1.7%) were positive to both potassium metabisulfite
and sodium metabisulfite, whereas only 2 patients were
positive to sodium sulfite. Seven of the 50 who were positive
to sodium metabisulfite were identified as having an
occupational exposure, but again, only 5 of the remaining
43 positive results were thought to be clinically relevant.
13
More recently, it has been noted that sodium metabisulfite
is present in some ketoconazole-containing products, as well
as in Trimovate® and Timodine® creams,
14
and accounts for
relevant positive results when ACD develops in patients
while using these products.
15
Sodium metabisulfite has now
been identified as a component of cosmetic creams,
14
hair
colors, and bleaching agents, and in false tanning products.
10
In 2007, a 6.8% patch test positivity to sodium metabisulfite
was described in a consecutive series of 117 patients in
Ireland.
14
As a consequence of these high rates of allergy,
sodium metabisulfite was incorporated into the BCDS
standard series of allergens in 2007.
Propolis
Propolis is a resinous substance collected from poplars
and processed by honeybees to use as a sealant to maintain
the structure of the hive. It is a well-recognized cause of
occupational contact dermatitis in apiarists.
16
Propolis has a
variable chemical composition and is regarded as a potent
skin sensitiser.
17
Cases of ACD to propolis began to emerge
in the 1970s; indeed, Petersen predicted that cases of ACD to
propolis would increase with the increasing use of propolis in
self-medicating patients.
18
Owing to its purported antibac-
terial and antiinflammatory properties, propolis is now
contained in a number of
“
”
over-the-counter products
such as cough syrups, lozenges, shampoo, conditioner,
lipsticks, lip balms, lotions, toothpastes, and cosmetics.
19
The predicted increase in ACD appears to have occurred.
Between 1997 and 2002, a Finish center observed an
increase in positive patch test reactions to propolis from
0.5% to 1.4%.
20
Propolis became part of the standard battery
in Germany and Austria in 2004, and an average of 3.5%
positive reactions were observed.
21
Propolis was therefore
also included in the BCDS standard series in 2007.
natural
Sodium metabisulfite
The sulfites are a ubiquitous group of chemicals. Sodium
metabisulfite is present in food and drink as a preservative
and antioxidant, where it is labelled as E223.
10
In addition, it
is found as a component of photographic chemicals, is used
in rubber manufacture, in leather tanning, in mineral
extraction, and as a bleaching agent in fabric treatments.
10
Sodium metabisulfite is present in certain local anaesthetic
preparations to prevent oxidation of adrenaline and has been
described as causing local anesthetic reactions.
11
Initial investigations of the ability of sulfites to cause skin
sensitization were inconclusive. A Danish study in 1992
described 1762 consecutive patients patch tested with
sodium sulfite in addition to the standard battery. Although
25 (1.4%) were positive, the authors were frequently unable
to elicit a history indicating the clinical relevance of the
Dicaprylyl maleate
Dicaprylyl maleate (DCM), also known as dioctyl
maleate, is a good example of an emollient and solvent in
which original chemical testing indicated that the compound
did not cause ACD.
22
Ten years after it was introduced into
New and emerging cosmetic allergens
313
cosmetic products, it has been found to cause ACD in
selected patients. DCM has been used as an ingredient in
fake tanning lotions, moisturizers, foundations, and sunsc-
reens.
23
Recently, a series of 22 patients who were suspected
of having DCM contact allergy were tested to both freshly
manufactured DCM and deliberately aged DCM. Only eight
patients did not have a positive DCM patch test, and of these
eight, a positive reaction to the aged DCM developed in
six.
22
This phenomenon occurs with other contact allergens
(see Limonene section) and is thought to occur due to
chemical degradation (autoxidation) producing allergenic
by-products.
24
Ironically this may be seen to support the
cosmetic industry's argument for the increased use of further
newer preservatives in cosmetic products. As a result of this
study, Boots, a major UK cosmetic manufacturer, withdrew
DCM from its product lines (personal communication from S
Kirk, March 2009); however, we continue to see patients
with ACD in our practice who are using DCM-containing
products and developing ACD.
however, fragrance allergy is common,
28
and the prevalence
of ACD due to fragrance in the general population has
been estimated as 1.8% to 4.2%.
29
Fragrance is the second
most common cause of ACD after nickel.
30
The distribu-
tion is classically axillae, facial (including the eyelids) and
neck, although well-circumscribed patches in areas of
“
perfumes (wrists, behind the ears) and
aggravation of hand eczema is also described. The degree
of sensitivity and therefore severity of dermatitis varies
considerably. In the worst cases, ACD to fragrance can
cause disseminated dermatitis beyond the site of applica-
tion and erythroderma. In addition, patients with profound
sensitivity are affectedbya rborneor
dabbing-on
”
“
connubial
”
fragrance usage.
28
The BCDS standard series of allergens contains an
original mix of fragrance allergens (Fragrance Mix I) that
was introduced in 1977. By the mid-1990s, it became
apparent that this mix missed an estimated 15% of fragrance
allergies.
31
Between 2002 and 2003 a Fragrance Mix II was
trialled.
32
This mix consisted of Lyral, citral, farnesol,
citronellol,
-hexyl-cinnamic aldehyde, and coumarin. Six
centers tested 1701 patients, and 7 patients with a strong
history of fragrance allergy were identified with Fragrance
Mix II and not Fragrance Mix I. The number of false-
positive results was also lower with Fragrance Mix II. As a
result, Fragrance Mix II entered the BCDS British Standard
series in 2007.
Lyral (hydroxyisohexyl 3-cyclohexene carboxaldehyde)
bears a lilylike odor and is commonly used in deodorant,
shampoo, soap, and fine fragrance.
33
European contact
allergy rates to Lyral vary between 1.5% and 3%.
34,35
This
rate is much higher than the US rate of 0.4%,
36
possibly due
to higher concentrations of Lyral in European deodorants.
34
As a result of its high rate of contact sensitization, Lyral has
been included in the BCDS standard series both on its own,
dissolved in 1% petrolatum, and as part of the new Fragrance
Mix II.
34
Limonene is widely used as a fragrance in cosmetics. It is
present as a component of certain essential oils (rosemary,
peppermint, lemongrass, lavender, eucalyptus, and caraway)
and in tea tree oil.
30
Owing to its solvent capacity, it is used in
domestic cleaning products and also in industry as a metal
degreaser, where it can occur in concentrations up to 95%.
37
Limonene first appeared for industrial use in the late 1980s
and became widely used because it was regarded as more
environmentally friendly than its organic solvent equivalents;
however, on exposure to air it easily oxidizes to products with
considerable sensitizing capacity, such as limonene oxide,
l-carvone, and the limonene hydroperoxides.
38
A Swedish
group patch tested 2800 patients to varying concentrations of
fresh and aged d-limonene. The highest rate of contact
allergy (5.1% of patients) was found when 5% d-limonene
was exposed to air for 10 weeks.
38
More recently, a
multicenter study patch tested consecutive patients with
dermatitis to both R-limonene and S-limonene and found
that 2.6% of patients reacted to one or both preparations.
30
α
Benzophenone 4
Many facial moisturizers, make-up, and hair care
products
25
now incorporate ultraviolet light (UV) filters to
protect the skin against photoaging and also to protect the
product itself from UV degradation to prolong shelf life.
Historically, benzophenone 3 was widely used in sunscreen
for its UVA filter properties. In a retrospective series of 2715
patients undergoing photopatch testing between 1983 and
1998, benzophenone 3 was the most common UV filter
photoallergen.
26
Benzophenone 4 (2-hydroxy-4-methoxy-
benzophenone-5-sulphonic acid: sulisobenzone) is a chem-
ical UVA filter whose spectrum of action extends into the
UVB range.
27
For this reason, benzophenone 4 is increas-
ingly being used in cosmetics. Benzophenone 3 and 4 do not
appear to cross-react.
25
A 2005 UK multicenter group photo-
patch tested 1155 patients with a history of a photoderma-
tosis or a history consistent with a sunscreen allergy.
Benzophenone 3 and 4 were each responsible for 9% of
contact allergic reactions.
Between 2003 and 2005, 553 patients with a history of
facial dermatitis or a possible cosmetic contact allergy were
tested to an extended facial/cosmetics series. Benzophenone
4 was one of the allergens, and 2.3% of patients had a
relevant positive patch test to benzophenone 4. This
prompted the authors to call for inclusion of benzophenone
4 in the facial/cosmetics series of patch test allergens.
27
Artificial fragrances
Considering the ubiquitous occurrence of fragrance
materials, the risk of allergy is small. In absolute numbers,
314
R.F. Davies, G.A. Johnston
Iodopropynyl butylcarbamate
5. Mortz CG, Andersen KE. New aspects in allergic contact dermatitis.
Curr Opin Allergy Clin Immunol 2008;8:428-32.
6. Warshaw EM, Buchholz HJ, Belsito DV, et al. Allergic patch test
reactions associated with cosmetics: Retrospective analysis of cross-
sectional data from the North American Contact Dermatitis Group,
2001-2004. J Am Acad Dermatol 2009;60:23-38.
7. Kammeyer A, Bos JD, Teunissen MB. Postelicitation model of allergic
contact dermatitis for predicting the efficacy of topical drugs. Exp
Dermatol 2009;18:44-9.
8. Lundov MD, Moesby L, Zachariae C, Johansen JD. Contamination
versus preservation of cosmetics: a review on legislation, usage,
infections, and contact allergy. Contact Dermatitis 2009;60:70-8.
9. Dillarstone A. Cosmetic preservatives. Contact Dermatitis 1997;
37:190.
10. Madan V, Walker SL, Beck MH. Sodium metabisulfite allergy is
common but is it relevant? Contact Dermatitis 2007;57:173-6.
11. Riemersma WA, Schuttelaar MLA, Coenraads PJ. Type IV hypersen-
sitivity to sodium metabisulfite in local anaesthetic. Contact Dermatitis
2004;51:148.
12. Petersen CS, Menne T. Consecutive patch testing with sodium sulfite in
eczema patients. Contact Dermatitis 1992;27:344.
13. Vena GA, Foti C, Angelini G. Sulfite contact allergy. Contact
Dermatitis 1994;31:172-5.
14. Malik MM, Hegarty MA, Bourke JF. Sodium metabisulfite
—
a marker
for cosmetic allergy? Contact Dermatitis 2007;56:241-2.
15. Tucker SC, Yell JA, Beck MH. Allergic contact dermatitis from sodium
metabisulfite in Trimovate® cream. Contact Dermatitis 1999;40:164.
16. Gulbahar O, Ozturk G, Erdem N, et al. Psoriasiform contact dermatitis
to propolis in a beekeeper. Ann Allergy Asthma Immunol 2005;94:
509-11.
17. Menniti-Ippolito F, Mazzanti G, Vitalone A, et al. Surveillance of
suspected adverse reactions to natural health products
—
the case of
propolis. Drug Safety 2008;31:419-25.
18. Petersen HO. Allergy to Propolis (bee glue. in patients with eczema.
Ugeskr Laeger 1977;139:2331.
19. Walgrave SE, Warshaw EM, Glesne LA. Allergic dermatitis from
propolis. Dermatitis 2005;16:209-15.
20. Hasan T, Rantanen T, Alanko K, et al. Patch test reactions to cosmetic
allergens in 1995-1997 and 2000-2002 in Finland
—
a multicentre study.
Contact Dermatitis 2005;53:40-5.
21. Hegewald J, Uter W, Aberer W, et al. The European Surveillance
System of Contact Allergies (ESSCA): results of patch testing the
standard series, 2004. J Eur Acad Dermatol Venereol 2008;22:174-81.
22. Lotery H, Kirk S, Beck M, et al. Dicaprylyl maleate
Iodopropynyl butylcarbamate (IPBC) is a biocide origi-
nally developed for use in an industrial context, initially in
metalworking and subsequently as a wood preservative,
where concentrations of up to 4% are permitted.
39
ACD to
IPBC in these industrial settings is well described.
40
In a
series of 251 German metalworkers with suspected ACD,
0.5% had a positive reaction to IPBC.
41
Because of its
usefulness as a biocide, IPBC has more recently been
incorporated into cosmetic products and cleansing wipes,
42
where the maximum permitted concentration is 0.1%.
Reports of ACD appeared only a few years after it was
introduced as a cosmetic ingredient.
43
Although IPBC is only thought to be weakly allergenic, it
is a small lipophilic molecule that may readily penetrate the
skin,
44
and as reports of ACD from IPBC exposure in
cosmetics have increased, it is now incorporated into the
Cosmetic Series of patch test allergens.
Conclusions
Contact allergy is an ever-changing area of dermatology
due to the evolving nature of the chemical, and more
specifically, cosmetics industry. Links between dermatology
and industry have become increasingly important to allow
early identification of allergenic compounds and to enable
patch testing of chemicals not yet commercially available.
Links between dermatologists and legislators have strength-
ened significantly,
8
especially in the European Community.
This has led to the publication of the European Community
Cosmetics Directive.
45
In 2004, this dynamic legislation
mandated the publication of ingredients on all cosmetics
products. This has made it significantly easier for consumers
and their physicians to identify and avoid the ever-increasing
numbers of allergenic chemicals added to cosmetics and
applied to the skin. ACD due to cosmetics can be occult and
has a variable and sometimes dramatic clinical presentation,
including acute facial swelling. Owing to improved product
labelling, it should now be possible for patients to avoid the
causative allergens identified on patch testing.
—
an emerging
cosmetic allergen. Contact Dermatitis 2007;57:167-72.
23. Chan I, Wakelin SH. Allergic contact dermatitis for dioctyl maleate in a
moisturizer. Contact Dermatitis 2006;55:250.
24. Nilsson J, Carlberg J, Abrahamsson P, et al. Evaluation of ionization
techniques for mass spectrometric detection of contact allergenic
hydroperoxides formed by autoxidation of fragrance terpenes. Rapid
Commun Mass Spectrom 2008;22:3593-8.
25. Alanko K, Jolanki R, Estlander T, Kanerva L. Occupational allergic
contact dermatitis from benzophenone-4 in hair-care products. Contact
Dermatitis 2001;44:188.
26. Darvay A, White IR, Rycroft RJG, et al. Photoallergic contact
dermatitis is uncommon. Br J Dermatol 2001;145:597-601.
27. Hughes TM, Stone NM. Benzophenone 4: an emerging allergen in
cosmetics and toiletries? Contact Dermatitis 2007;56:153-6.
28. de Groot AC, Frosch PJ. Adverse reactions to fragrances. A clinical
review. Contact Dermatitis 1997;36:57-86.
29. Schnuch A, Uter W, Geier J, Gefeller O. Epidemiology of contact
allergy: an estimation of morbidity employing the clinical epidemiology
and drug-utilization research (CE-DUR) approach. Contact Dermatitis
2002;47:32-9.
30. Matura M, Sköld M, Börje A, et al. Not only oxidized R-(+)- but also S-
(-)- limonene is a common cause of contact allergy on dermatitis
patients in Europe. Contact Dermatitis 2006;55:274-9.
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Available at: