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607J.D. Johansen et al. (eds.), Contact Dermatitis ,DOI: 10.1007/978-3-642-03827-3_33, Springer-Verlag Berlin Heidelberg 2011

33.1 Introduction

The applications o ragrances are numerous and con-tact may be di cult to avoid, even i one wishes.

Fragrances are used in all kinds o cosmetics and toi-letries, in cleansing agents, air resheners, over-the-counter topical pharmaceutical products, toys andtextiles, and in industrial settings. Many ragranceingredients are also used as favors in ood and someare naturally occurring in spices. Fragrance productsare used in aromatherapy, may be contained in herbalremedies, and in some regions, natural ragrance prod-ucts are used as topical medicaments or their antisep-tic properties. Fragrances are capable o neutralizingunpleasant odors. They are added to products to pro-

duce a pleasant scent, add special character to theproduct, or as unctional ingredients, e.g., providingantibacterial e ects.

33.2 Fragrance Ingredients

The International Fragrance Association (IFRA)de nes ragrance ingredients as any basic ingredient

used in the manu acture o ragrance materials or itsodorous, odor enhancing, or blending properties ( www.i raorg.org). A ragrance ingredient may be a chemi-cally de ned substance or a natural product.

Natural ragrance products are obtained by process-ing material rom ragrance-producing plants. The ra-grance can be present in almost any part o the plantand is obtained by pressing or steam distillation to giveessential oils or by organic solvent extraction to giveconcretes and absolutes [ 1]. The content and consis-tency o the naturals depend on climatic and soil

Fragrances

Jeanne Duus Johansen and Jean-Pierre Lepoittevin

J.D. Johansen ( )Copenhagen University Hospital Gento te, National AllergyResearch Centre, Department o Dermato-allergology,Niels Andersens Vej 65, 2900 Hellerup, Denmark e-mail: [email protected]

J.-P. LepoittevinInstitut le Bel, Labo. Dermatochimie,4, rue Blaise Pascal, 67070 Strasbourg Cedex, Francee-mail: jplepoit@unistra. r

33

Contents

33.1 Introduction .......................................................... 607

33.2 Fragrance Ingredients ......................................... 607

33.3 The Fragrance Formula ...................................... 608

33.4 Chemistry ............................................................. 608

33.5 Fragrance Contact Allergens .............................. 60833.5.1 Fragrance Chemicals .............................................. 60933.5.2 Oxidation Products ............ ............ ........... ............ . 61033.5.3 Fragrance Naturals ........... ............ ........... ............ ... 611

33.6 Epidemiology of Fragrance Contact Allergy ..... 612

33.7 Clinical Aspects .................................................... 613

33.8 Exposure to Fragrance Allergens ....................... 61433.8.1 Consumer Products ........... ........... ............ ............ .. 614

33.8.2 Occupational Exposure ........... ........... ............ ........ 61633.9 Diagnosis of Fragrance Contact Allergy ............ 617

33.10 Clinical Relevance and Patient Advice .............. 620

33.11 Other Skin Effects ................................................ 62133.11.1 Immediate Reactions...... ........... ............ ........... ...... 62133.11.2 Photoallergy/Phototoxic Reactions ........... ........... .. 62233.11.3 Irritant Contact Dermatitis .......... ............ ............ ... 622

33.12 Case Reports ......................................................... 622

References ........................................................................... 622
http://www.ifraorg.org/http://www.ifraorg.org/http://www.ifraorg.org/http://www.ifraorg.org/


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608 J.D. Johansen and J.-P. Lepoittevin

conditions or the plant, as well as many other actors,which make it very di cult, i not impossible, to ullystandardize the contents and quality o the endproduct.

The volatile ragrance product obtained rom plantsusually contains numerous ingredients. The character-istic odor o the ragrance product may be due either toa particular ingredient, or in the case o a complexcomposition, the blending o a number o ingredients[2]. Oak moss absolute contains at least 250 ingredi-ents and has several odor-determining agents [ 3], whileclove oil contains up to 80% eugenol, which is thedetermining odor agent [ 4].

Previously, also animal secretions, such as musk rom deer and ambergris rom the sperm whale, were

used as the basis or the production o natural ragranceingredients. These are now replaced by blends o ra-grance chemicals.

Originally, all per umes were composed o naturalproducts, but with the scienti c and technical develop-ments in the rst hal o the nineteenth century, chem-ists were able to identi y the odor-determining majoringredients o natural ragrance materials. Followingthis development, industrial production o synthetic

ragrance materials began. The synthesized ingredientsare o ten nature-identical chemicals, that is, imitationso naturally occurring substances; however, also, theproduction o entirely new chemicals takes place.

Based on in ormation rom industry, it is estimated thatabout 2,500 di erent ragrance ingredients are in use.

33.3 The Fragrance Formula

A ragrance ormula consists o a mixture o 10300 ormore di erent ragrance ingredients, naturals, and/orchemicals. The ragrance ormula is incorporated intothe end product, e.g., a cosmetic. Some cosmetic prod-ucts are used primarily or their scent, such as per-

umes, eau de cologne, and a tershaves. These products

consist mainly o ragrance ingredients diluted withalcohol/water. A per ume usually contain 1530% ra-grance ingredients, a cologne about 35%, a deodorant1%, a cream 0.4%, and undiluted soaps 0.52% [ 5].

The creation o a per ume, the ragrance ormula, isregarded as an art. In designing a per ume, components

rom di erent odor amilies and o di erent volatili-ties are combined to orm an esthetic whole. The mostvolatile ingredients are called top notes, usually ruityand spicy, which is ollowed by the heart note, built upby foral accords, orming the most essential part o theper ume; the long-lasting materials are known as thebottom notes. These include woody, moss-like, andsweet vanilla-like ingredients [ 6]. The basic patternand principal structure o per umes have not changeddramatically throughout the history o per umery. Thedi erence lies in the quality and availability o the rawmaterials and a di erent way o compounding [ 7].

33.4 Chemistry

Fragrance ingredients are organic compounds andmust be volatile to be perceived. There ore, in additionto the nature o the unctional groups and the molecu-lar structure o a substance, the molecular mass is animportant actor. Molecular masses o about 200 occurrelatively requently [ 4]; urther, many o the ragranceingredients are lipophilic in nature and, thus, havegood penetration abilities, even o intact skin [ 8].

A ragrance ormula is a mixture o molecules withvery di erent physico-chemical properties; allergensmay be ormed in the mixture, e.g., by oxidation [ 7, 9, 10] or in the skin by metabolism [ 11]. The mixture o molecules may result in interactions during skin pen-etration, skin metabolism, and epitope ormation [ 8].These interactions may lead to a change in sensitiza-tion and elicitation potential [ 1214 ], e ects, which,as yet, have only been seldom investigated.

33.5 Fragrance Contact Allergens

Allergenic ragrance ingredients have been identi edby predictive assays in humans [ 15] and animals [ 16].Due to the high number o ragrance ingredients inuse, structure activity relationship (SAR) analysis has

Core Message

Two thousand ve hundred (2,500) ragranceingredients are in current use or compoundingper umes. The ingredients are natural extractso plant products, nature-identical, or entirelysynthetic chemicals.


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60933 Fragrances

been employed to identi y potential allergens, e.g., indeodorants [ 17]. Testing a series o individual alde-hydes in the animal assay, local lymph node assay(LLNA), and combining these results with reactivityand lipophilicity parameters has developed urtherquantitative SARs (QSARs). Equations derived romthese QSARs allow improvement o the predictionsmade based on chemical structure alone o new alde-hydes [ 16, 18 ]. However, most clinically relevantknowledge comes rom patch testing eczema patientswith ragrance ingredients suspected o causing aller-gic reactions. In this way, the rst screening test or

ragrance contact allergy was designed [ 19], anapproach ollowed by others [ 2030 ]. This rst truescreening test or ragrance allergy, called the ra-grance mix (FM I), was composed in the late 1970s byLarsen [ 19]. It consists o a mixture o eight ingredi-ents: seven chemicals and a natural extract with theaddition o an emulsi er (Table 33.1 ). Among theingredients o FM I, the natural oak moss absolute(INCI: evernia prunastri) has, or some years, been thetop ranked, usually ollowed by isoeugenol, cinnamal,and/or hydroxycitronellal. In recent multinationalstudies, additional important allergens have been iden-ti ed [ 2327 ]. Among these are both chemicals, suchas hydroxyisohexyl 3-cyclohexene carboxaldehyde(HICC) [ 31], arnesol, citral, a -hexylcinnamic alde-hyde [ 23], as well as natural extracts, such as ylangylang oil, lemongrass oil, narcissus absolute, sandal-wood oil, and jasmine absolute [ 24]. The ollowingsections are comments on selected ragrance chemi-cals and naturals o special interest.

33.5.1 Fragrance Chemicals

Cinnamal (chemical name cinnamic aldehyde) is astrong allergen [ 15] and has, or many years, been atop-ranking ragrance allergen [ 32, 33 ], though recentlya decline in reactions has been seen [ 34]. Cinnamal isthe main component o cinnamon oil. It is also used asa favoring and is described as an occupational allergenin bakers on a case basis [ 35, 36 ]. Cinnamal was oundlabeled in 7% o 243 cosmetic products in an investi-gation in UK, most o ten in womens per umes [ 37].The chemically related substance, cinnamyl alcohol,seems to be converted in the skin to cinnamal [ 11, 38]and exposure may be o relevance in those allergic to

cinnamal. Isoeugenol is a strong allergen [ 15]. Itcaused contact allergy in 1.7% o 2,261 consecutivelytested eczema patients in a European multicenter study[39]. It is ound in many cosmetic products and may bepresent in relatively high concentrations, especially incolognes and similar products [ 40]. There seems to beno relation between the metabolism o eugenol, whichis also a constituent o ragrance mix, and isoeugenol[41, 42 ]. Isoeugenol is restricted to 0.02% in cosmeticproducts in the Cosmetic Directive (ec.europa.eu/ enterprise/cosmetics/cosing) Despite this, an increas-ing trend has been ound in isoeugenol allergy rom2001 to 2005 [ 40]. Patients with isoeugenol contactallergy may react to esters o isoeugenol [ 43], which is

Fragrance ingredients, INCI name(chemical name)

Concentration% in mixture

FM I a -Amyl cinnamal(a -amylcinnamicaldehyde)

1

Cinnamal (cinnamic aldehyde) 1

Cinnamyl alcohol (cinnamic alcohol) 1

Eugenol (eugenol) 1

Geraniol (geraniol) 1

Hydroxycitronellal(hydroxycitronellal)

1

Isoeugenol (isoeugenol) 1

Evernia prunastri (oak moss absolute) 1

Emulsi erSorbitan sesquioleate 5

FM II

Hydroxyisohexyl 3-cyclohexenecarboxaldehyde

2.5

Citral 1.0

Farnesol 2.5

Citronellol 0.5

a -Hexyl cinnamal 5.0

Coumarin 2.5

Table 33.1 Ingredients o ragrance mix I (FM I) and ragrancemix II (FM II)

For FM I, each ingredient is tested at the same concentration inFM I as individually, except sorbitan sesquioleate, which is indi-vidually tested at 20% in petrolatum, while the individual test con-centration or FM II is the double as in the mix see Table 33.5


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commonly used in cosmetics [ 44]. Hydroxycitronellalis classi ed as a relatively weak allergen based on itsinherent properties; [ 45] even so, it is one o the topranking causes o ragrance contact allergy. It is widelyused in cosmetic products, both per umes and deodor-ants, and o ten in relatively high concentrations. It isrestricted to 1% in cosmetic products according to theCosmetic Directive.

Hydroxyisohexyl 3-cyclohexene carboxaldehyde(Lyral ) has been used or many years without restric-tions. It is related to hydroxycitronellal and has prob-ably been used as a substitute in many cases ashydroxycitronellal was restricted [ 46]. The use con-centrations have generally been very high; more than3.0% in per umes have been reported [ 46]. A series o systematic investigations have shown that hydroxyiso-hexyl 3-cyclohexene carboxaldehyde is one o themost requent allergens, giving positive reactions in12.7% o consecutively patch-tested patients inEurope [ 22, 23, 26, 31, 33 ].

It seems that allergy to hydroxyisohexyl 3-cyclo-hexene carboxaldehyde is especially related to expo-sures rom deodorants [ 4749 ]. A voluntary restictiono 1.5% hydroxyisohexyl 3-cyclohexene carboxalde-hyde in cosmetics was made in 2003 by IFRA, and in2007 this was changed to various concentrations rom0.11 to 1.5% depending on the product type. The inci-dence o contact allergy to hydroxyisohexyl 3-cyclo-hexene carboxaldehyde has remained una ected [ 50].

Farnesol is both used as a ragrance ingredient andas a biocide, e.g., in deodorants [ 51]. It has been shownto cause allergy in 0.91.1% o patients consecutivelypatch tested by the German In ormation Network o Departments o Dermatology (IVDK) [ 33, 52]. Thosepositive to arnesol were characterized by being young

emales and having hands and ace more o ten a ectedthan patients negative to arnesol [ 52]. Probably, manycases o deodorant contact allergy due to arnesol havebeen missed in the past, as most o the patients reactingto arnesol are negative to the ragrance mix [ 36, 52 ].

Citral is a relatively weak allergen, which also hasirritant properties. It has a steep dose-response curve[53] and has been shown to be o possible signi cance inpatients with long-term chronic hand eczema, whichmay be due to its combined allergenic and irritant e ects[53, 54 ]. The irritant properties o citral have been shownto be temperature dependent [ 55]. In European multi-center studies, 0.71.1% o consecutively tested eczemapatients gave a positive reaction to citral 2% [ 23, 26 ].

Coumarin is the subject o several studies and caseinvestigations [ 23, 56]. It has been reported to causereactions in 0.4% o consecutively tested patients [ 57]and also gave rise to positive reactions in 0.3% o patients in a European multicenter study [ 23]. Impuritieshave been blamed or the sensitizing e ect [ 58, 59 ].

33.5.2 Oxidation Products

d-Limonene is obtained as a byproduct rom the citrus juice industry. Peal oil rom the skins o citrus ruitscontains normally more than 95% d-limonene. It isused as a ragrance ingredient, but also has many otherapplications. In itsel , it is not a sensitizer or a veryweak one, but rapidly oxidizes when in contact withair [ 7]. Antioxidants such as butylated hydroxytoluene(BHT) are, there ore, o ten added to commercial prod-ucts. However, once the antioxidant is consumed, theoxidation starts immediately. The allergens ormed aremainly hydroperoxides [ 60], with strong sensitizingpotential [ 7]. Testing consecutive patients in di erentclinics with oxidized d-limonene gave positive resultsin 0.36.5% o cases [ 61]. A patch test concentrationo 6% in pet. o oxidized linalool has been suggestedas optimal [ 9].

Similar ndings have been obtained or linalool,another terpene [ 62, 63 ]. This emphasizes the need ortesting with the chemicals that are in the products andnot just what was originally added. Patch test materialo the oxidized orms o linalool and limonene are cur-rently being developed . In terms o prevention, expirydates taking autooxidation into consideration will helpsolve the problem.

Geraniol, an ingredient o FM I, is also a terpene.The oxidation process ollows two paths in whichhydroperoxide, as or other terpenes, is ormed, and inaddition, the aldehydes geranial and neral [ 10].Autooxidation greatly infuences the sensitizing e ecto geraniol, which becomes a potent allergen [ 10].

Core Message

Hydroxyisohexyl 3-cyclohexene carboxalde-hyde (Lyral ) has, or a number o years, beenone o the most requent causes o contactallergy to ragrance ingredients


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33.5.3 Fragrance Naturals

Oak moss absolute is derived rom the lichen Evernia prunastri . It has been used as a basic ingredient and a

xative in many per umes. It is a constituent o the ra-grance mix and is a top-ranking allergen when the sin-gle ingredients are tested [ 34, 64 ]. A systematic searcho the allergens in the extract has been per ormed. Abio-guided ractionation procedure was used based onthe testing o patients sensitized to oak moss absolutewith ractions o the natural in question. This was com-bined with chemical analysis and SAR analysis to ulti-mately identi y the allergens in oak moss absolute [ 3].Several allergens were identi ed, and among these,chloroatranol, atranol, and methyl- b-orcinol carboxy-late gave the most reactions. These allergens are ormedduring the processing o the lichen ( or details, pleasesee Chap. 5). Chloroatranol and atranol have been ur-ther studied and are shown to be strong allergens andpotent elicitors, giving reactions at extremely low levels[58]. An explanation o the high rates o sensitization tooak moss absolute was ound by assessing exposure.Chloroatranol and/or atranol were ound in 87% o 31investigated products, mostly per umes [ 65].

Based on these investigations, the Scienti cCommittee on Consumer Products (SCCP) advisory tothe EU Commission has published an opinion that nei-ther chloroatranol nor atranol should be present in con-sumer products. Attempts have been made to removechloroatranol and atranol down to a level o 100 ppmo each in the concentrate. IFRA recommended that amaximum o 0.1% oak moss absolute is used in a

nished product, which will give a maximum level o 0.1 ppm o these allergens in the product. Patch testingo the chemically modi ed oak moss absolute with alow level o chloroatranol and atranol still gave posi-tive patch test reactions in 8 out o 14 patients with aknown allergy to oak moss absolute [ 66]. The SCCPhas recommended a urther assessment o the sa ety.

Ylang ylang oil is produced by steam distillation o the fowers o Cananga odorata . Four grades are pro-duced, which di er in odor, price, and composition.Ylang ylang oil is a major cause o allergic contactdermatitis in Asian countries, where it is requently

ollowed by hyperpigmentation [ 67]. In a Europeanmulticenter study including 1,606 patients, ylang ylangoils o grades I and II were tested and gave a positivepatch test reaction in 2.6 and 2.5% o patients, respec-tively, with the highest requency in London, possiblydue to the citys large Asian population; detailed in or-mation can be ound in a paper by Frosch et al. [ 24].

Lemongrass oil, narcissus absolute, jasmine abso-lute, geranium oil bourbon, spearmint oil, sandalwoodoil, lavender oil, and others have also been reported as

requent sensitizers [ 24, 2729, 67] (Table 33.2 ).It was recently shown that natural lavendel oil o ers

no protection against autooxidation and is as allergenicas a synthetic lavender scent composed o the threemain terpenes present in lavendel oil [ 68].

Core Message

Strong allergens are ormed by autooxidationo d-limonene, linalool, and geraniol. This canprobably be extended to other terpenes. I patch testing is done with nonoxidized material,

alse-negative results may be expected.

Ingredient n = 1,606[24]a (%)

n = 218[27]b (%)

n = 178[28]c (%)

Ylang ylang oil I 2.6

Ylang ylang oil II 2.5

Lemongrass oil 1.6

Narcissus abs. 1.3

Jasmine abs. 1.2 16.9

Sandalwood oil 0.9

Patchouli oil 0.8

Spearmint oil 0.8 5.0

Dwar pine needleoil

0.7

Cedarwood oil 0.6

Peppermint oil 0.6

Clove bud oil 19.3

Lavender oil 2.8

Eucalyptus oil 1.8

Geranium oilbourbon

8.4

Table 33.2 Patch test reactions to selected natural ingredients[24, 2730 ]

a Consecutively tested patientsb, c Selected patients with ragrance sensitivity


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Myroxylon pereirae (MP) (balsam o Peru) is derivedrom the sap o a tree, MP, and is composed o 250 con-

stituents, o which 189 are known structurally [ 69]. MPhas been used in topical medicaments, such as woundtreatment, or its antibacterial properties [ 70], but alsoas a favor and per ume ingredient. In many countries,the use o MP in topical medicaments has been discon-tinued due to its sensitizing properties; however, it maystill occur in herbal and natural products [ 71]. The crude

orm o MP has been banned rom use in per umes byIFRA since 1982; however, extracts and destillates o MP are still used in per umes [ 72]. It is likely that thesecan cause allergic reactions in MP sensitized individu-als. MP has been in the standard series since its rstedition and is still causing many reactions [ 64], eventhough a decline has been seen in some countries [ 73].

Colophony (rosin) is a resin obtained rom di erentspecies o coni erous trees. It is a complex mixture o resin acids and natural substances. Its composition var-ies with the species rom which it is obtained and alsodepends on the recovery processes and storage condi-tions [ 74]. Unmodi ed colophony is known to causecontact allergy. The main allergenic components areoxidized resin acids ormed on exposure to air. Theallergenicity can be changed by chemical modi ca-tion, e.g., it can be decreased by hydrogenation, whileother kinds o modi cations may enhance the allerge-nicity [ 74]. Colophony has many applications and hasalso been used as a ragrance ingredient. The use o unmodi ed colophony in per umes was banned in1992 by IFRA; however, it is unknown i modi ed

orms o colophony are used in per umes.An extensive review has been published listing ra-

grance ingredients, chemicals, and natural productsidenti ed in the available literature as allergens in clin-ical studies o groups o patients or single cases; [ 75]about 100 chemicals and a similar number o naturalproducts are in these lists.

33.6 Epidemiology of FragranceContact Allergy

Frequencies o sensitization to per ume ingredientswere previously di cult to estimate due to the lack o a reliable test substance to screen or this allergy, but itwas regarded as a common condition [ 76]. MP wasshown by Hjorth to be a marker o contact allergy to

ragrances in the 1960s [ 70], and later the FM I wasdeveloped, which enabled assessment o the problem[19]. A second ragrance mix was o caly included inthe baseline serie in 2008 [ 77].

Contact allergy to ragrance ingredients as identi-ed with FM I is seen in all geographical regions o the

industrialized world [ 25, 7880 ]. Studies o the gen-eral population show that about 2% o adolescents and14% o adults have contact allergy to FM I [ 73, 8184], depending on the age group o investigation.One-third o 12- to 16-year-old children had, at the time o diagnosis, symptoms o their allergy, as did hal o theadult population [ 81, 82 ]. In a recent study rom Poland7.3% o 7-year-old children were patch test positive toFM I and none among a sample o 16-year-olds [ 156].

An estimation based on the sales o patch test materi-als in Germany and patient data showed that 1.84.2% o the German population is sensitized to FM I amountingto 1.43.4 million people in the German population o 82 million inhabitants [ 85]. A decreasing trend in FM Iallergy has been seen in eczema patients since 1998 [ 48, 64, 86] and has now been con rmed among youngerwomen o the general population [ 73]. Comparing theresults rom three cross-sectional studies done in a sam-ple o the general population in 1990, 1998, and 2006, itwas shown that the prevalence o FM I and MP contactallergy ollowed an inverse V-pattern among womenaged 1841 years, increasing rom 1990 to 1998 andthen decreasing to a level o 2.3 % with a postive reactionto FM I in 2006 [ 73]. This was ollowed by a decreasingtrend in MP allergy. No signi cant changes were seen inmen or in other age groups [ 73]. In 2006, FM I allergywas still signi cantly associated with reporting cosmeticdermatitis and use o health care [ 73]. No data rom test-ing FM II in the general population exist, yet.

In adults with contact eczema undergoing patchtesting, FM I and FM II are some o the the most re-quent causes o contact allergy. In multicenter investi-gations in Europe covering the period o 19962000,9.7% o adult eczema patients reacted to the FM I, and

Core Message

The main allergens in the natural extract oak moss absolute (INCI: evernia prunastri ) havebeen identi ed as chloroatranol and atranol,which elicit contact allergy at very low levels.A ban on those ingredients in cosmetics hasbeen proposed.


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61333 Fragrances

in a di erent investigation rom 2002 to 2003 6.7%reacted to FM I [ 87, 88 ]; the data rom the NorthAmerican Contact Dermatitis Group rom 2005 to 2006showed that 11.5% o consecutive patients tested gavea positive reaction to FM I [ 89]. Among Thai eczemapatients, the requency o positive reaction to FM I was20.7% [ 90]. The FM II gives positive reactions in 2.94.6% o consecutively tested eczema patients [ 25, 91].

The requency o ragrance allergy in patch-testedpatients increases with age; [ 92, 93 ] nevertheless, FM Iis also among the top ranking allergens in children witheczema [ 94, 95 ], and cases down to 2 years o age havebeen reported, even though it is rare [ 92]. In eczemapatients, the emale: male ratio o FM I allergy is usu-ally 2:1 [ 34, 64, 96], while in the general population,especially in the younger years, a more equal sex dis-tribution is seen [ 81]. It has been suggested that patientswith current or past atopic dermatitis has reduced rateso contact allergy to ragrance allergens with dietaryexposures such as cinnamic compounds, as a sign o oral tolerance, compared to those with cutanous expo-sure only such as evernia prunastri [ 97].

In accordance with the decrease in FM I, a chemicalanalysis o ten prestige per umes showed that ewer FMallergens were present in newly launched per umes incomparison with per umes manu actured more than10 years ago [ 98]. MP has shown a similar downwardtrend in some countries [ 73]. However, in Germany MPsurpassed the FM I in requency in 2002 [ 64]. This maybe a reminder that the use o other allergenic ragrancecompounds, structurally similar to ingredients in MP,may have increased [ 64]. Certainly, high requencies o contact allergy to natural extracts such as ylang ylang oiland jasmine absolute have been demonstrated [ 24, 27, 28] and, in addition, a number o chemicals not includedin FM I and II may be o importance [ 23, 2729, 99].Thus, the epidemiology o ragrance contact allergy isonly partly displayed by the results rom testing withFM I and II, which should be borne in mind both inassessing the size o the problem on a community leveland in the diagnostic workup o the individual patient.

33.7 Clinical Aspects

Allergic contact dermatitis may develop as itchyeczematous patches where per ume has been applied,usually behind the ears, on the neck, the upper chest,

and sometimes the elbow fexures and wrists [ 76].Another typically presenting eature is a bilateral axil-lary dermatitis caused by per ume in deodorants; i thereaction is severe, it may spread to other areas o thebody [ 76] (Fig. 33.1 ). It is not always that such patientswill consult a dermatologist, but a history o such rst-time symptoms have been shown to be statistically sig-ni cantly related to the diagnosis o per ume allergyby FM I in eczema patients [ 100].

Facial eczema is a classical mani estation o ra-grance allergy rom the use o di erent ragrancedcosmetic products [ 30, 48, 101, 102 ]. In men, a ter-shave lotion may cause a eczematous eruption o thebeard area and adjacent part o the neck [ 76] (Fig. 33.2 )and men using wet shaving opposed to dry have beenshown to have an increased risk o being ragrance-allergic [ 103].

Data rom St Johns in London in 1980s showed thatper umes and deodorants were the most requentsources o sensitization in women, and a tershavelotions and deodorants were usually the most respon-sible in men [ 76]. More recent investigations have con-

rmed that this is still the case [ 40, 47, 104108 ].

Fig. 33.1 Allergic contact dermatitis rom per ume in deodor-ant (courtesy o N. Veien)


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Primary hand eczema or aggravation o handeczema can be caused by contact to ragranced prod-ucts, as seen in occupational settings [ 109]. Also, asigni cant relationship between hand eczema and ra-grance contact allergy has been ound in some studiesbased on patients investigated or contact allergy [ 110112 ]. However, hand eczema is a multi actorial diseaseand the clinical signi cance o ragrance contactallergy in chronic hand eczema is controversial. Areview on the subject has been published by Heydornet al. [ 109].

Pigmented contact dermatitis has been described inJapan as a mani estation o contact allergic reaction toa range o contact allergens, e.g., ylang ylang oil and

jasmine absolute [ 67]. The pigmentation disappears orimproves upon avoidance.

Systemic contact dermatitis may occur in selectedcases. The phenomenon that patients, sensitized byskin contact, react with a rash to oral intake o favored

ood has especially been described in conjunction withMP sensitivity [ 71, 113115 ]. In general, the problemis to quanti y exposure and determine the relevance tochronic eczema. Systemic contact dermatitis is thesubject o a separate chapter in this book.

33.8 Exposure to Fragrance Allergens

33.8.1 Consumer Products

Exposure may be by direct skin contact, and the lon-ger the time o contact, the higher the risk o sensiti-zation and elicitation, even though the requency o applications also plays a role. The most signi cantnonoccupational exposure is rom cosmetics prod-ucts. Chemical analysis o more than 150 di erentcosmetic products has shown that the ragrance mixingredients occur widely and, in some products, inhigh concentrations (Table 33.3). Isoeugenol was

ound in 24% o products in a concentration o between


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61533 Fragrances

N D n o

t d o n e ;

N Q n o

t q u a n

t i f e d ;

N G

n o t g i v e n ;

P P M m g / m

L ( 1 0 , 0 0 0 p p m

= 1 % )

a C o n s e c u

t i v e

l y t e s t e d p a

t i e n

t s

b , c

S e l e c

t e d p a

t i e n

t s w

i t h r a g r a n c e s e n s i

t i v i

t y

d A

l l e r g e n s

i n o a

k m o s s a b s o

l u t e

I n g r e d

i e n t

P r e s t

i g e p e r u m e s , n

= 1 0 a ; n =

N G b ;

n =

3 1 c ; [ 4 0 ] a

, [ 4 6 ] b

, [ 5 8 ] c

N a t u r a l - i n g r e

d i e n

t - b a s e d

p e r u m e s n =

2 2 [ 1 1 7 ]

D e o

d o r a n t s n =

7 3 [ 1 5 5 ]

H o u s e

h o l d p r o d u c

t s n =

5 9 [ 1 1 9 ]

I n %

o a n a l y z e d

p r o d u c

t s

C o n c e n t r a

t i o n

r a n g e

( p p m

)

I n %

o

a n a l y z e d

p r o d u c

t s

C o n c e n t r a

t i o n

r a n g e

( p p m

)

I n %

o a n a l y z e

d

p r o d u c

t s

C o n c e n t r a

t i o n

r a n g e

( p p m

)

I n %

o

a n a l y z e d

p r o d u c

t s

C o n c e n t r a

t i o n

r a n g e

( p p m

)

a - A m y l c i n n a m a l

3 0 a

3 0 0 6 , 9 0 0

3 6

1 , 9 4 0 3 0

, 3 9 0

3 1

1 6 1 7

8

N Q

C i n n a m a l

0 a

0

1 7

1 4 2 4

3

N Q

C i n n a m y l a l c o

h o l

6 0 a

3 0 0 7 , 9 0 0

1 4

8 9 0 2 1

, 0 1 0

3 9

6 1 , 1 6 9

2

N Q

E u g e n o l

9 0 a

4 0 0 8 , 9 0 0

3 6

3 5 0 2 2

, 8 9 0

5 7

1 2 , 3 5 5

2 7

3 2 3

4 9

G e r a n

i o l

9 0 a

8 0 0 4 , 8 0 0

6 3

N Q

7 6

1 1 , 1 7 8

4 1

5 3 1 , 7

5 8

H y d r o x y c i

t r o n e l

l a l

9 0 a

2 , 5 0 0 1 1

, 9 0 0

2 3

1 , 3 5 0 6 0

, 4 4 0

5 0

1 1 , 0 2 3

1 2

1 5 1

4 0

I s o e u g e n o

l

7 0 a

5 0 0 3 , 4 0 0

9

2 7 0 1 , 3 9 0

2 9

1 4 5 8

5

N Q

L y r a l

4 6 b

3 2 , 0

0 0 ( m e a n )

N D

5 3

1 1 , 8 7 4

1 0

3 6 1

0 3

F a r n e s o

l

N D

N D

N D

N D

C i t r a

l

N D

N D

N D

2 5

4 8 1 , 0

8 8

L i m o n e n e

N D

N D

N D

7 8

6 9 , 4 4 3

L i n a l o o

l

9 0 b

4 7 , 0

0 0 ( m e a n )

N D

9 7

9 1 , 9 2 7

6 1

3 4 3 9

C h l o r o a t r a n o

l d

8 7 c

0 . 0 0 4 5 3

N D

N D

N D

A t r a n o l

d

7 7 c

0 . 0 1 2 1 9 0

N D

N D

N D

T a

b l e 3 3

. 3

E x p o s u r e a s s e s s m e n

t o r a g r a n c e a l

l e r g e n s

i n c o s m e t

i c s a n

d h o u s e h o l

d p r o d u c

t s b y c h e m

i c a l a n a l y s

i s a n

d i n o r m a t

i o n

r o m

t h e i n d u s t r y


10/21


11/21

61733 Fragrances

same association was ound among male eczemapatients undergoing patch testing, possibly due to con-commitant sensitization. Cross-reactivity has beensuggested but never proven [ 125].

33.9 Diagnosis of FragranceContact Allergy

The basic investigation o suspected ragrance contactallergy is made by patch testing with the standard patchtest series, which currently entail our potential indicatorso ragrance contact allergy: FM I, FM II, MP, hydroxy-isohexyl 3-cyclohexene carboxaldehyde. Further, a posi-tive reaction to colophony may in some cases indicate

ragrance allergy. FM I has been used as an indicator o ragrance contact allergy since the late 1970s. The ingre-

dients o the mix have remained unchanged since, whilethe test concentration o the mix was lowered rom 16%originally to 8% in 1984, as data suggested that thehigher concentration gave irritant reactions [ 126]. Thus,the individual ingredients were lowered rom 2 to 1%,which may give rise to alse-negative results when test-ing the ingredients separately [ 127]. The emulsi er sor-bitan sesquioleate was later added to the individualingredients, as it was shown to improve the positive rate[128]. FM I is a heterogeneous mix, which means that itcontains molecules that di er widely in size and reactiv-ity [8]. In this way, it is a realistic imitation o per umes.Further, its composition has been shown to be a relevantrefection o exposure [ 129]. It has been assessed thatFM I detects 5080% o eczema patients with reactionsto per umes in cosmetics [ 40, 130, 131 ]. The sameapplies i individual ragrance allergens are tested [ 21, 23, 24, 2729 ]. However, the developments in the ra-grance industry, changing ashion, and regulatory inter-ventions mean that the exposure pattern is constantlychanging and ragrance ingredients other than FM I arerelevant to test [ 20, 2224, 2729, 112, 130, 132 ].

An EU- unded research program was aimed at design-ing an additional screening test or ragrance allergy, ra-grance mix II (FM II) [ 25, 26 ]. Based on previousinvestigations [ 2022, 2729, 46], published in ormationin general, and the IFRA guidelines, a selection o candi-dates or testing was made, chemicals [ 23] and naturals[24]. Fourteen chemical were tested in 1,855 patients; thesix chemicals with the highest reactivity ollowing FM Iwere hydroxyisohexyl 3-cyclohexene carboxaldehyde

(2.7%), citral (1.1%), arnesol (0.5%), citronellol (0.4%),a -hexylcinnamal (0.3%), and coumarin (0.3%) [ 23].These six chemicals were urther tested as a mixture inthree di erent concentrations, and with the correspond-ing individual ingredients in 1,701 consecutive patients[25]. Positive reactions to the FM II were dose-dependentand 2.9% reacted to the FM II in a test concentration o 14%, which was recommended as an additional diagnos-tic screening tool [ 25]. About one-third o those reactingto FM II, 14% were negative at testing with FM I. Inbreakdown testing o the single ingredients, 74% gave aresponse, i doubt ul reactions were included [ 26], andthe rank order o the ingredients was as in the rst study[23], except that no unequivocal positive reaction to cou-marin was observed. Hydroxyisohexyl 3-cyclohexenecarboxaldehyde was the dominant single constituent,with positive reactions in 36% o patients reacting to 14%FM II and was recommended or inclusion in the base-line series in Germany [ 133]. Assessments made o clini-cal relevance by di erent methods showed that FM IIdetects additional relevant cases o contact allergy to ra-grances [ 25, 26 ] (Fig. 33.3 ).

Both the FM II 14% pet. and hydroxyisohexyl3-cyclohexene carboxaldehyde 5% pet., as a ragranceingredient o special importance, are in the most recentedition o the European baseline series [ 77]. The aller-gens present in FM I and II also cover the most re-quent ragrance allergens detected in patients withhand eczema: citral, hydroxycitronellal, hydroxyiso-hexyl 3-cyclohexene, and eugenol [ 54], though oxi-dized limonene, which gave positive patch tests in0.9% o chronic hand eczema patients [ 54], is not com-mercially available.

The unction o MP as an indicator o ragrance con-tact allergy is more complex and heterogeneous than FMand may vary in di erent parts o the world due to localhabits. MP contains ingredients also present in FM I,such as cinnamates, which comprise more than 35% o the MP constituents and isoeugenol/eugenol [ 71].Hausen has hypothesized that the pattern o reactionsmay indicate sources o exposure, so that contact allergyto MP and isoeugenol/eugenol can be traced back to ra-grances, especially i the reaction to FM I is moderate orstrong, while reactions to cinnamal/cinnamates can betraced to essential oils and possible sunscreens [ 71].

A statistically signi cant relationship betweenreactions to FM I and MP was seen in a study cover-ing several countries [ 26]. This may be explained bythe contents o mutual allergens, while only a weak


12/21


association was seen with FM II, the ingredients o which are not in MP, except or arnesol in traceamounts [ 71]. MP unctions as an indicator o ra-grance allergy, but has not in its crude orm been usedin per umery since 1982 [ 72]. Only extracts, PeruBalsam oil and Peru Balsam absolute, are used. Theirmain ingredient is benzyl benzoate, which accounts

or at least hal o the composition, in addition a num-ber o cinnamate-derivatives are present, but not cin-namal itsel , neither any other ingredient o the FM I,according to ragrance industry [ 72]. Still, a majorityo patients with MP contact allergy react to theMP-derivatives at patch testing (personel communi-cation M Bruze) and may, thus, have a relevant ra-grance allergy.

In 2005 an ingredient labeling o 26 ragranceingredients identi ed as allergens in the consumercame into orce, and concerns cosmetic products as

well as detergents. The selection was done in 1998 andbased on the comprehensive work o de Groot andFrosch [ 75]. The list entails the eight ingredients o theFM I and the six o the FM II and additional 12 sub-stances (Table 33.5 ). These extra 12 substances arecommercially available or patch testing in cases sus-pected o ragrance allergy. A screen with the 26 sub-stances done in Germany showed that some o thesubstances seldom gave reactions, while others were

requent causes o positve patch test reactions [ 33]. Arevision o the list is ongoing. Recently, the optimalpatch test concentrations or the 12 ingredients not parto the FM I or FM II have been identi ed [ 134]. Therecommended patch test concentration or 10 o the 12ingredients are higher than those being used currently,identical or evernia ur urcea (1%), and lower or onesubstance, methyl 2-octynate (chemical name: methylheptine carbonate). Methyl 2-octynate has caused

a b

Fig. 33.3 Patch test reaction to the new ragrance mix (FM II)in dose-dependent intensity (day 3) ( a ). Breakdown testing

revealed high sensitivity to HICC (Lyral). The repeated open

application test (ROAT) with HICC (Lyral) was strongly posi-tive already on day 4 ( b ) (courtesy o P.J. Frosch)


13/21

61933 Fragrances

INCI name CAS no. concentration Recommended test o individual ingredientsin w/w % [ 77, 134]

Ingredients of FM I a

Amyl cinnamal 122407 1

Cinnamal 104552 1

Cinnamyl alcohol 104541 1

Eugenol 97530 1

Evernia prunastri (oak moss) extract 90028685 1

Geraniol 106241 1

Hydroxycitronellal 107755 1

Isoeugenol 97541 1

Ingredients of FM II b

Citral 5392405 2Citronellol 106229 1

Coumarin 91645 5

Farnesol 4602840 5

Hexyl cinnamal 101860 10

Hydroxyisohexyl 3-cyclohexene carboxaldehyde 31906044 5

Additional substances

Alpha-Isomethyl ionone 127515 10

Amylcinnamyl alcohol 101859 5

Anisyl alcohol 105135 10

Benzyl alcohol 100516 10

Benzyl benzoate 120514 10

Benzyl cinnamate 103413 10

Benzyl salicylate 118581 10

Butylphenyl methylpropional (Lillial) 80546 10

Evernia furfuracea (tree moss) extract 90028674 1

d-Limonene 5889275 10 c

Linalool 78706 10c

Methyl 2-octynoate 111126 0.2 d

Table 33.5 Fragrance ingredients to be labeled as ingredients i present in cosmetics or detergents

The presence o the substance must be indicated in the list o ingredients when its concentration exceeds 0.001% in leave-on prod-ucts and 0.01% in rinse-o products ( http://ec.europa.eu/enterprise/cosmetics/cosing )aFM I: ragrance mix I 8% in pet; bFM II: ragrance mix II 14% in pet; cTest concentration or unoxidised d-limonene, linalool;dMethyl 2-octynate have caused active sensitization when tested in 1% in pet and 2% in pet.; 0.2% has been tested without anyproblems was noted [ 134]
http://ec.europa.eu/enterprise/cosmetics/cosinghttp://ec.europa.eu/enterprise/cosmetics/cosing


14/21


active sensitization when tested at 1 and 2% in pet., theconcentration recommended or uture testing is 0.2%in pet [ 134, 135 ].

In addition, benzenpropanol (Majantol ) 5% hasrecently been recommended or screening o ragrance-allergic individuals and is commercially available [ 99].

Some advances in the diagnostics o contact allergyto natural ragrance ingredients have also been attempted[24, 2729 ]. Larsen tested a natural mix consisting o

jasmine absolute, ylang ylang oil, narcissus absolute,sandalwood oil, and spearmint oil, and ound that itidenti ed 84% o per ume-allergic patients [ 30]. Naturalextracts, such as ylang ylang oil, narcissus oil, sandal-wood oil, and jasmine absolute, were identi ed as re-quent sensitizers by Frosch [ 24], and relevant cases aremissed by only testing with FM I. Still, a screeningseries o naturals awaits development and it is notknown to which extent MP and oil o turpentine aregood indicators o ragrance allergy to natural extractsin general, as has been suggested previously [ 64].

The role o colophony in detecting ragrance con-tact allergy is minor compared to MP, FM I, and FM II.Colophony has many di erent applications and it isuncertain i it is used in ragrances; however, ingredi-ents o colophony may be present in ragrances orcross-reactivity may occur. No relationship betweenreactions to FM I or FM II and colophony was ound inconsecutive eczema patients tested in a European mul-ticenter study [ 26]. While a signi cant relationshipbetween colophony and FM I, as well as colophonyand MP, was ound in 747 patients suspected o ra-grance contact allergy [ 102], it was also shown that theprobability o a reaction to an extended ragrancesseries increased with the number o positive reactionsto the ragrance indicators o the standard series [ 102].In a recent investigation entailing a datamaterial o 10,128 patients, signi cant realtionships were oundbetween FM I and colophony, FM I and MP, FM I andhydroxyisohexyl 3-cyclohexene carboxaldehyde, andbetween colophony and MP, all associations with anodds ratio over 5 [ 48].

As none o the current diagnostic tools is per ect, itis important to test with the cosmetic products, ne

ragrances, essential oils, etc. used by the patient. Itshould generally be con ned to stay-on products, aswash-o products, due to their irritant nature, makethe interpretation o patch test reactions di cult.Further investigations o reactions to commercial prod-ucts can be made based on the ingredient labeling o

sensitizing ragrance substances introduced or cos-metics and detergents in the EU region in 2005(Table 33.5 ), by obtaining in ormation/ingredients

rom the manu acturer [ 136] or by chemical raction-ation in special cases [ 49] see Chap. 5.

33.10 Clinical Relevanceand Patient Advice

Clinical relevance can be assessed based on the patientshistory o rashes to per umes/per umes products. Asigni cant relationship between such a history and pos-itive patch test to FM I has been shown previously [ 100, 128]. Currently, a higher proportion o patients giving apositive history is ound among those reacting to thenewly developed FM II than those reacting to FM I[25]. Assessment o exposure is an important compo-nent o clinical relevance. In a case study, all patientswith a positive patch test to FM I ingredients wereshown to be exposed to these allergens in cosmeticproducts causing eczema [ 129]. Similar ndings exist

or hydroxyisohexyl 3-cyclohexene carboxaldehyde[31, 129] and other FM II ingredients [ 29]. Simulationso exposure by repeated open application tests (ROAT)with commercial products containing FM I allergenshave been shown to cause eczema in 60% o exposedpatients who patch tested positive to FM I [ 40, 105].Dummy products spiked with a single ragrance aller-gen in realistic concentrations have also been tested. Ina series o deodorant exposure studies with cinnamaland hydroxycitronellal, 94100% o eczema patientssensitized to the ingredient in question reacted, whileall controls were negative [ 106, 107 ]. ROAT with real-istic concentrations o hydroxyisohexyl 3-cyclohexenecarboxaldehyde applied in ethanol caused reactions in16 o 18 (89%) sensitized patients [ 116 ] and in 14/14(100%) using a deodorant spiked with hydroxyisohexyl3-cyclohexene carboxaldehyde [ 49].

Core Message

A new ragrance mixture called FM II has beendeveloped, which detects additional relevantcases o ragrance contact allergy. A validatedscreening agent or screening series or contactallergy to natural ragrance extracts is needed.


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62133 Fragrances

Another indicator o clinical relevance is thestrength o the patch reaction. Patients with strongreactions to the standard patch test FM I are morelikely to react to the individual ingredients o the mix,to a low level o allergen [ 137], and to give a positiveROAT with the allergen in question [ 138]. Further,they are more likely to have a positive history o adverse reactions to ragranced products [ 128].

Thus, the advice given to the patient depends on theclinical presentation and the degree o allergy. Somepatients have a weak degree o allergy and no chronicor recurrent eczema problem; they can usually tolerate(some) scented products on the skin. Others are moresensitive and have to abstain rom stay-on products,while some cannot use any scented products at all,including wash-o products, such as shampoos.Patients with a chronic or relapsing eczema diseaseshould be advised to use unscented emollients, regard-less o whether they are allergic to ragrances or not,due to the risk o becoming sensitized and aggravationo their disease. In this context, it is important or thepatient to know that the labeling ragrance- ree maybe misleading [ 139, 140 ]. Such products may contain

ragrance ingredients, which are o ten various foweror plant extracts or chemicals acting as preservatives,e.g., geraniol and arnesol.

The mandatory labeling o 26 ragrance ingredientswill enable the ragrance-allergic patient, who maywish to use ragranced cosmetics, to make a preselec-tion o products based on the ingredient in ormation.Further, it will provide the dermatologists with a tool

or improving diagnostics and assessing clinical rele-vance. In a recent investigation o 147 ragrance-aller-gic patients, 45.3 % had ound some kind o scentedproduct they could tolerate, 31.6 % had not tried to ndany scented products and 22 % had tried, but could not

nd any .The methods most o ten used were trying di -erent products and reading the ingredient label [ 141].

The limits or labeling o the individual 26 ingredi-ents are 10 ppm in stay-on products and 100 ppm inwash-o products. These limits are administrative anddecided, as, otherwise, a labeling o all per umed cos-metics was expected due to the presence o chemicalallergens in trace amounts in essential oils. In ormationabout presence o other ragrance ingredients in cos-metics can be obtained on a case basis by contact to the

ragrance industry [ 136]. Clinical relevance is not astatic phenomenon, especially not in the area o ra-grance allergy. It is a question o interaction between

individual predisposition/susceptibility and environ-mental exposures. Changes in general exposure to theallergens by interventions, e.g., legislation or justchanges o ashion, will a ect the clinical conse-quences o being contact allergic, de ned by a positivepatch test. These dynamics mean that assessment o the value o a diagnostic test such as FM I or FM II ata given time is only a snapshot. The ocus, which hasbeen on the ingredients o FM I and FM II by researchprograms on an EU-commission-level and by con-sumer organizations, means that exposure maydecrease [ 98], as actually intended by these initiatives.The consequence is that ewer individuals will becomesensitized to the allergens in question, as already indi-cated or FM I [ 73], and that ewer o those alreadysensitized will have clinical problems.

This should not lead to the con usion that the lack o clinical relevance is a sign o alse-positive patchtests. It is a consequence o changing exposures andmay be di erent in other geographical regions or maychange again with time and exposure.

33.11 Other Skin Effects

33.11.1 Immediate Reactions

Fragrances have been reported to cause contact urti-caria o the nonimmunological type. This is a high-dose e ect, and cinnamal, cinnamic alcohol, and MPare known causes o contact urticaria, but others havebeen reported also [ 142144 ]. The reactions to MPmay be due to its containing cinnamates [ 71]. A rela-tionship to delayed contact hypersensitivity has beensuggested [ 145], but in a recent study no signi cantdi erence was ound between a ragrance-allergic

Core Message

Twenty six ragrance ingredients with a sensiti-zation potential has been mandated on the labelo cosmetics and detergents rom 2005 as in or-

mation to the consumer. An administrativelimit or the labeling has been set to 10 ppm.

or stay-on products and 100 ppm. or wash-o products.


16/21


group and a control group in the requency o immedi-ate reactions to ragrance ingredients [ 144]. This is inkeeping with a nonimmunological basis or the reac-tions seen [ 144]. A case o contact uricaria leading toanaphylaxis ollowing an open patch test with cinna-mal has been reported [ 146].

33.11.2 Photoallergy/Phototoxic Reactions

Musk ambrette produced a considerable number o photocontact allergic reactions in the 1970s [ 147, 148 ]and was later banned. Today, photoallergic contact der-matitis is uncommon [ 149]. Psoralens in naturallyoccurring ragrance ingredients were previously thecause o phototoxic reactions, giving rise to erythema,

ollowed by hyperpigmentation in its characteristicorm, called Berloque dermatitis [ 150]. There are now

limits o the amount o psoralens in ragrance products.Phototoxic reactions still occur, but are rare [ 151].

33.11.3 Irritant Contact Dermatitis

Irritant e ects o single ragrance ingredients are wellknown, e.g., citral [ 53, 55 ]. Autooxidation o ragranceterpenes not only increase the allergenicity, but alsothe irritant potential [ 152]. Probably, irritant contactdermatitis is requent; however, no investigations existsubstantiating this [ 75]. Many more people complainabout rashes to per umes/per umed products than areproven allergic by testing [ 100]. This may be due toirritant e ects or insu cient diagnostic apparatus.

33.12 Case Reports

A 23-year-old-woman presented with a long history o axillary dermatitis. Symptoms improved on changingto a di erent deodorant spray and worsened again withreuse o the ormer deodorant. Patch testing with thedeodorant as is showed a ++ reaction, no reactionwas seen to FM I 8% or colophony, while a ?+ wasseen to MP. The per ume o the deodorant was testedin the same concentration as in the product and showed

a + reaction. Farnesol was present in the deodorant andgave ++ reaction upon testing at 1% in pet. [ 153].

Comment : Many cases o per ume allergy due to arne-sol in deodorants have probably been overlooked inthe past. It is important to test with the relevant prod-

ucts used by the patient and to use this test as guidanceor urther investigation. Farnesol is a constituent o the new diagnostic test FM II and is entailed by theingredient labeling o selected ragrance allergens.

A 50-year-old-woman presented with an erythematouseruption, characterized by papules, vesicles, and crustingover the neck and chest. At patch testing, initially, theonly positive reaction observed was with her own eau detoilette, named Women. FM I was negative. Chemical

ractionation o the Womens per ume concentrate wascombined with a sequenced patch testing procedure andwith SAR studies. Ingredients supplied by the manu ac-turer were also included in the study. Benzophenone-2,Lyral , a -hexyl cinnamic aldehyde, and alpha-damasconewere ound to be responsible or the patients contactallergy to the eau de toilette, Women [ 154].

Comment : It is important to test with relevant productsused by the patient. Light absorbers, such as benzo-phenone-2, are used in per umes to protect againstdegradation. These may also be the cause o contactallergy. Some patients are allergic to several ragrance

ingredients. In ormation about the contents o ra-grance ingredients can be obtained rom the ragrancemanu acturer [ 136] and or selected ragrance aller-gens rom the label o the product.

References

1. Mller J (1992) The H&R book o per ume. Understandingragrance. Origin, history, development. Guide to ragrance

ingredients. Glss, Hamburg2. Poucher WA (1993) Pouchers per umes, cosmetics and

soaps. The production, manu acture and application o per-umes, vol 2, 9th edn. Chapman and Hall, London3. Bernard G, Gimnez-Arnau E, Rastogi SC, Heydorn S,

Johansen JD, Menn T, Goossens A, Andersen K, LepoittevinJP (2003) Contact allergy to oak moss: search or sensitizingmolecules using combined bioassay-guided chemical rac-tionation, GC-MS, and structure-activity relationship analy-sis. Arch Dermatol Res 295:229235

4. Bauer K, Garbe D, Surburg H (1990) Common ragrance andfavor materials, 2nd edn. VCH Verlagsgesellscha t, Weinheim

5. Johansen JD (2002) Contact allergy to ragrances: clinicaland experimental investigations o the ragrance mix and itsingredients. Contact Dermat 46(Suppl 3):431


17/21

62333 Fragrances

6. Harder U (1998) The art o creating a per ume. In: Frosch PJ,Johansen JD, White IR (eds) Fragrances bene cial andadverse e ects. Springer, Berlin, Heidelberg, New York,pp 35

7. Christensson JB, Johansson S, Hagvall L, Jonsson C,Brje A, Karlberg AT (2008) Limonene hydroperoxideanalogues di er in allergenic activity. Contact Dermat

59(6):3443528. Lepoittevin JP, Mutterer V (1998) Molecular aspects o ra-grance sensitisation. In: Frosch PJ, Johansen JD, White IR(eds) Fragrances bene cial and adverse e ects. Springer,Berlin, Heidelberg, New York, pp 4956

9. Christensson JB, Matura M, Gruvberger B, Bruze M,Karlberg AT (2010) Linaloola signi cant contact sensitizera ter air exposure. Contact Dermat 62(1):3241

10. Hagvall L, Bcktorp C, Svensson S, Nyman G, Brje A,Karlberg AT (2007) Fragrance compound geraniol ormscontact allergens on air exposure. identi cation and quanti -cation o oxidation products and e ect on skin sensitization.Chem Res Toxicol 20:807814

11. Basketter DA (1992) Skin sensitization to cinnamic alcohol:

the role o skin metabolism. Acta Derm Venereol (Stockh)72:264265

12. Nilsson AM, Jonsson C, Luthman K, Nilsson JL, KarlbergAT (2004) Inhibition o the sensitizing e ect o carvone bythe addition o non-allergenic compounds. Acta DermVenereol (Stockh) 84:99105

13. Karlberg AT, Nilsson AM, Luthman K, Nilsson JL (2001)Structural analogues inhibit the sensitizing capacity o car-vone. Acta Derm Venereol (Stockh) 81:398402

14. Johansen JD, Skov L, Volund A, Andersen K, Menn T(1998) Allergens in combination have a synergistic e ect onthe elicitation response: a study o ragrance-sensitized indi-viduals. Br J Dermatol 139:264270

15. Marzulli FN, Maibach HI (1980) Contact allergy: predictivetesting o ragrance ingredients in humans by Draize andmaximization methods. J Environ Pathol Toxicol 3:235245

16. Patlewicz GY, Wright ZM, Basketter DA, Pease CK,Lepoittevin JP, Arnau EG (2002) Structure-activity relation-ships or selected ragrance allergens. Contact Dermat47:219226

17. Rastogi SC, Lepoittevin JP, Johansen JD, Frosch P, Menn T,Bruze M, Dreier B, Andersen KE, White I (1998) Fragrancesand other materials in deodorants search or potentiallysensitizing molecules using combined GCMS and structureactivity relationship (SAR) analysis. Contact Dermat39:293303

18. Patlewicz GY, Basketter DA, Pease CK, Wilson K,Roberts DW, Bernard G, Arnau EG, Lepoittevin JP (2004)Further evaluation o quantitative structure activity relation-ship models or the prediction o the skin sensitization potencyo selected ragrance allergens. Contact Dermat 50:9197

19. Larsen WG (1977) Per ume dermatitis. A study o 20patients. Arch Dermatol 113:623626

20. Malten KE, van Ketel WG, Nater JP, Liem DH (1984)Reactions in selected patients to 22 ragrance materials.Contact Dermat 11:110

21. de Groot AC, Liem DH, Nater JP, van Ketel WG (1985)Patch tests with ragrance materials and preservatives.Contact Dermat 12:8792

22. Frosch PJ, Pilz B, Andersen KE, Burrows D, Camasara JG,Dooms-Goossens A, Ducombs G, Fuchs T, Hannuksela M,Lachapelle JM, Lahti A, Maibach HI, Menne T, Rycro tRJG, Shaw S, Wahlberg JE, White IR, Wilkinson JD (1995)Patch testing with ragrances: results o a multicenter studyo the European Environmental and Contact DermatitisResearch Group with 48 requently used constituents o per-

umes. Contact Dermat 33:33334223. Frosch PJ, Johansen JD, Menn T, Pirker C, Rastogi SC,Andersen KE, Bruze M, Goossens A, Lepoittevin JP, WhiteIR (2000) Further important sensitizers in patients sensitiveto ragrances. I. Reactivity to 14 requently used chemicals.Contact Dermat 47:7885

24. Frosch PJ, Johansen JD, Menn T, Pirker C, Rastogi SC,Andersen KE, Bruze M, Goossens A, Lepoittevin JP, WhiteIR (2002) Further important sensitizers in patients sensitiveto ragrances. II. Reactivity to essential oils. Contact Dermat47:279287

25. Frosch PJ, Pirker C, Rastogi SC, Andersen KE, Bruze M,Svedman C, Goossens A, White IR, Uter W, Arnau EG,Lepoittevin JP, Menn T, Johansen JD (2005) Patch testing

with a new ragrance mix detects additional patients sensi-tive to per umes and missed by the current ragrance mix.Contact Dermat 52:207215

26. Frosch PJ, Rastogi SC, Pirker C, Brinkmeier T, Andersen KE,Bruze M, Svedman C, Goossens A, White IR, Uter W, ArnauEG, Lepoittevin JP, Johansen JD, Menn T (2005) Patchtesting with a new ragrance mix reactivity to the singleconstituents and chemical detection in relevant cosmeticproducts. Contact Dermat 52:216225

27. Larsen W, Nakayama H, Lindberg M, Fischer T, Elsner P,Burrows D, Jordan W, Shaw S, Wilkinson J, Marks J Jr,Sugawara M, Nethercott J (1996) Fragrance contact derma-titis: a worldwide multicenter investigation, part I. Am JContact Dermat 7:7783

28. Larsen W, Nakayama H, Fischer T, Elsner P, Frosch P,Burrows D, Jordan W, Shaw S, Wilkinson J, Marks J Jr,Sugawara M, Nethercott M, Nethercott J (2001) Fragrancecontact dermatitis: a worldwide multicenter investigation,part II. Contact Dermat 44:344346

29. Larsen W, Nakayama H, Fischer T, Elsner P, Frosch P,Burrows D, Jordan W, Shaw S, Wilkinson J, Marks J Jr,Sugawara M, Nethercott M, Nethercott J (2002) Fragrancecontact dermatitis: a worldwide multicenter investigation,part III. Contact Dermat 46:141144

30. Larsen W, Nakayama H, Fischer T, Elsner P, Frosch P,Burrows D, Jordan W, Shaw S, Wilkinson J, Marks J Jr,Sugawara M, Nethercott M, Nethercott J (1998) A study o

new ragrance mixtures. Am J Contact Dermat 9:20220631. Frosch PJ, Johansen JD, Menn T, Rastogi SC, Bruze M,Andersen KE, Lepoittevin JP, Arnau EG, Pirker C,Goossens A, White IR (1999) Lyral is an important sensi-tizer in patients sensitive to ragrances. Br J Dermatol141:10761083

32. Enders F, Przybilla B, Ring J (1989) Patch testing with ra-grance mix 16% and 8%, and its individual constituents.Contact Dermat 20:237238

33. Schnuch A, Uter W, Geier J, Lessmann H, Frosch PJ (2007)Sensitization to 26 ragrances to be labelled according tocurrent European regulation. Results o the IVDK andreview o the literature. Contact Dermat 57(1):110


18/21


34. Buckley DA, Wakelin SH, Holloway D, Rycro t RJG, WhiteIR, McFadden JP (2000) The requency o ragrance allergyin a patch test population over a 17-year period. Br JDermatol 142:279283

35. Meding B, Wrangsjo K, Brisman J, Jarvholm B (2003) Handeczema in 45 bakers a clinical study. Contact Dermat48:711

36. Bauer A, Geier J, Elsner P (2002) Type IV allergy in theood processing industry: sensitization pro les in bakers,cooks and butchers. Contact Dermat 46:228235

37. Buckley DA (2007) Fragrance ingredient labelling in prod-ucts on sale in the UK. Br J Dermatol 157(2):295300

38. Elahi EN, Wright Z, Hinselwood D, Hotchkiss SA, BasketterDA, Pease CK (2004) Protein binding and metabolism infu-ence the relative skin sensitization potential o cinnamiccompounds. Chem Res Toxicol 17:301310

39. Tananka S, Royds C, Buckley D, Basketter DA, Goossens A,Bruze M, Svedman C, Menn T, Johansen JD, White IR,McFadden JP (2004) Contact allergy to isoeugenol and itsderivatives: problems with allergen substitution. ContactDermat 51:288291

40. Johansen JD, Rastogi SC, Menn T (1996) Contact allergyto popular per umes; assessed by patch test, use test andchemical analysis. Br J Dermatol 135:419422

41. Barratt MD, Basketter DA (1992) Possible origin o the skinsensitization potential o isoeugenol and related compounds,(I). Preliminary studies o potential reactions mechanisms.Contact Dermat 27:98104

42. Bertrand F, Basketter DA, Roberts DW, Lepoittevin JP (1997)Skin sensitization to eugenol and isoeugenol in mice: possi-ble metabolic pathways involving ortho-quinone and quinonemethide intermediates. Chem Res Toxicol 10:335343

43. White JM, White IR, Glendinning A, Fleming J, Je eries D,Basketter DA, McFadden JP, Buckley DA (2007) Frequencyo allergic contact dermatitis to isoeugenol is increasing: areview o 3636 patients tested rom 2001 to 2005. Br JDermatol 157(3):580582

44. Rastogi SC, Johansen JD (2008) Signi cant exposures toisoeugenol derivatives in per umes. Contact Dermat58(5):278281

45. Basketter DA, Wright ZM, Warbrick EV, Dearman RJ,Kimber I, Ryan CA, Gerberick GF, White IR (2001) Humanpotency predictions or aldehydes using the local lymphnode assay. Contact Dermat 45:8994

46. Fenn RS (1989) Aroma chemical usage trends in modernper umery. Per umer Flavorist 14:110

47. Uter W, Geier J, Schnuch A, Frosch PJ (2007) Patch testresults with patients own per umes, deodorants and shaving

lotions: results o the IVDK 1998-2002. J Eur Acad DermatolVenereol 21(3):37437948. Nardelli A, Carbonez A, Ottoy W, Drieghe J, Goossens A

(2008) Frequency o and trends in ragrance allergy over a15-year period. Contact Dermat 58(3):134141

49. Jrgensen PH, Jensen CD, Rastogi S, Andersen KE,Johansen JD (2007) Experimental elicitation with hydroxy-isohexyl-3-cyclohexene carboxaldehyde-containing deodor-ants. Contact Dermat 56(3):146150

50. Braendstrup P, Johansen JD, Danish Contact DermatitisGroup (2008) Hydroxyisohexyl 3-cyclohexene carboxalde-hyde (Lyral) is still a requent allergen. Contact Dermat59(3):187188

51. Goossens A, Merckx L (1997) Allergic contact dermatitisrom arnesol in a deodorant. Contact Dermat 37:179180

52. Schnuch A, Uter W, Geier J, Lessmann H, Frosch PJ (2004)Contact allergy to arnesol in 2021 c onsecutively patchtested patients. Results o the IVDK. Contact Dermat50:117121

53. Heydorn S, Menn T, Andersen KE, Bruze M, Svedman C,

White IR, Basketter DA (2003) Citral a ragrance allergenand irritant. Contact Dermat 49:323654. Heydorn S, Johansen JD, Andersen KE, Bruze M, Svedman

C, White IR, Basketter DA, Menn T (2003) Fragranceallergy in patients with hand eczema clinical study. ContactDermat 48:317323

55. Rothenborg HW, Menn T, Sjolin KE (1977) Temperaturedependent primary irritant dermatitis rom lemon per ume.Contact Dermat 3:3748

56. Mutterer V, Gimenez Arnau E, Lepoittevin JP, Johansen JD,Frosch PJ, Menn T, Andersen KE, Bruze M, Rastogi SC,White IR (1999) Identi cation o coumarin as the sensitizerin a patient sensitive to her own per ume but negative to the

ragrance mix. Contact Dermat 40:196199

57. Kunkeler AC, Weijland JW, Bruynzeel DP (1998) The roleo coumarin in patch testing. Contact Dermat 39:327328

58. Johansen JD, Andersen KE, Svedman C, Bruze M, BernardG, Gimenez-Arnau E, Rastogi SC, Lepoittevin JP, Menn T(2003) Chloroatranol, an extremely potent allergen hiddenin per umes: a dose-response elicitation study. ContactDermat 49:180184

59. Vocanson M, Valeyrie M, Rozires A, Hennino A, Floch F,Gard A, Nicolas JF (2007) Lack o evidence or allergenicproperties o coumarin in a ragrance allergy mouse model.Contact Dermat 57(6):361364

60. Matura M, Goossens A, Bordalo O, Garcia-Bravo B,Magnusson K, Wrangsjo K, Karlberg AT (2003) Patch test-ing with oxidized R-(+)-limonene and its hydroperoxide

raction. Contact Dermat 49:152161. Matura M, Goossens A, Bordalo O, Garcia-Bravo B,

Magnusson K, Wrangsjo K, Karlberg AT (2002) Oxidizedcitrus oil (R-limonene): a requent skin sensitizer in Europe.J Am Acad Dermatol 47:709714

62. Skold M, Borje A, Matura M, Karlberg AT (2002) Studieson the autoxidation and sensitizing capacity o the ragrancechemical linalool, identi ying a linalool hydroperoxide.Contact Dermat 46:267272

63. Skold M, Borje A, Harambasic E, Karlberg AT (2004)Contact allergens ormed on air exposure o linalool.Identi cation and quanti cation o primary and secondaryoxidization products and e ects on skin sensitization. Chem

Res Toxicol 17:1697170564. Schnuch A, Lessmann H, Geier J, Frosch PJ, Uter W, IDVK(2004) Contact allergy to ragrances: requencies o sensiti-zation rom 1996 to 2002. Results o the IVDK. ContactDermat 50:6576

65. Rastogi SC, Bossi R, Johansen JD, Menn T, Bernard G,Gimnez-Arnau E, Lepoittevin JP (2004) Content o oak moss allergens atranol and chloroatranol in per umes andsimilar products. Contact Dermat 50:367370

66. Nardelli A, Gimnez-Arnau E, Bernard G, Lepoittevin JP,Goossens A (2009) Is a low content in atranol/chloroatranolsa e in oak moss-sensitized individuals? Contact Dermat60(2):9195


19/21

62533 Fragrances

67. Nakayama H (1998) Fragrance hypersensitivity and its con-trol. In: Frosch PJ, Johansen JD, White IR (eds) Fragrances bene cial and adverse e ects. Springer, Berlin, Heidelberg,New York, pp 8391

68. Hagvall L, Skld M, Brred-Christensson J, Brje A,Karlberg AT (2008) Lavender oil lacks natural protectionagainst autoxidation, orming strong contact allergens on air

exposure. Contact Dermat 59(3):14315069. Hausen BM, Simatupang T, Bruhn G, Evers P, Koenig WA(1995) Identi cation o new allergens constituents and proo o evidence or coni eryl benzoate in balsam o Peru. Am JContact Dermat 6:199208

70. Hjorth N (1961) Eczematous allergy to balsams. Allied per-umes and favoring agents with special re erence to bal-

sam o Peru. Thesis, University o Copenhagen, Denmark 71. Hausen BM (2001) Contact allergy to balsam o Peru. II.

Patch test results in 102 patients with selected balsam o Peru constituents. Am J Contact Dermat 12:93102

72. Api AM (2006) Only Peru Balsam extracts or distillates areused in per umery. Contact Dermat 54(3):179

73. Thyssen JP, Linneberg A, Menn T, Nielsen NH, Johansen

JD (2009) The prevalence and morbidity o sensitization toragrance mix I in the general population. Br J Dermatol

161:9510174. Karlberg AT (2000) Colophony. In: Kanerva L, Elsner P,

Wahlberg J, Maibach H (eds) Handbook o occupationaldermatology, vol 64. Springer, Berlin, Heidelberg, NewYork, pp 509516

75. de Groot AC, Frosch PJ (1997) Adverse reactions to ra-grances. A clinical review. Contact Dermat 36:5787

76. Cronin E (1980) Per umes: contact dermatitis. ChurchillLivingstone, Edinburgh, pp 158170

77. Bruze M, Andersen KE, Goossens A (2008) Recommendationto include ragrance mix 2 and hydroxyisohexyl 3-cyclohex-ene carboxaldehyde (Lyral ) in the European Baseline patchtest series. Contact Dermat 58:129133

78. Maouad M, Fleischer AB, Sherertz EF, Feldman SR (1999)Signi cance-prevalence index number: a reinterpretationand enhancement o data rom the North American ContactDermatitis group. J Am Acad Dermatol 41:573576

79. Li LF, Guo J, Wang J (2004) Environmental contact actorsin eczema and the results o patch testing Chinese patientswith a modi ed European standard series o allergens.Contact Dermat 51:2225

80. Greig JE, Carson CF, Stuckey MS, Riley TV (2000)Prevalence o delayed hypersensitivity to the European stan-dard series in a sel -selected population. Australas J Dermatol41:8689

81. Mortz CG, Lauritsen JM, Bindslev-Jensen C, Andersen KE(2002) Contact allergy and allergic contact dermatitis in ado-lescents: prevalence measures and associations. The OdenseAdolescence Cohort Study on Atopic Diseases and Dermatitis(TOACS). Acta Derm Venereol (Stockh) 82:352358

82. Nielsen NH, Menn T (1992) Allergic contact sensitizationin an unselected Danish population. The Glostrup AllergyStudy. Acta Derm Venereol (Stockh) 72:456460

83. Nielsen NH, Linneberg A, Menn T, Madsen F, Frolund L,Dirksen A, Jorgensen T (2001) Allergic contact sensitizationin an adult Danish population: two cross-sectional surveyseight years apart (the Copenhagen Allergy Study). ActaDerm Venereol (Stockh) 81:3134

84. Dotterud LK (2007) The prevalence o allergic contact sen-sitization in a general population in Troms, Norway. Int JCircumpolar Health 66(4):328334

85. Schnuch A, Uter W, Geier J, Ge eller O, IDVK study group(2002) Epidemiology o contact allergy: an estimation o morbidity employing the clinical epidemiology and drug-utilization research (CE-DUR) approach. Contact Dermat

47:323986. Thyssen JP, Carlsen BC, Menn T, Johansen JD (2008)Trends o contact allergy to ragrance mix I and Myroxylonpereirae among Danish eczema patients tested between 1985and 2007. Contact Dermat 59(4):238244

87. Bruynzeel DP, Diepgen TL, Andersen KE, Brando FM,Bruze M, Frosch PJ, Goossens A, Lahti A, Mahler V,Maibach HI, Menn T, Wilkinson JD, EuropeanEnvironmental and Contact Dermatitis Research Group(2005) Monitoring the European standard series in 10 cen-tres 1996-2000. Contact Dermat 53(3):146149

88. Uter W, Hegewald J, Aberer W, Ayala F, Bircher AJ, BraschJ, Coenraads PJ, Schuttelaar ML, Elsner P, Fartasch M,Mahler V, Belloni Fortina A, Frosch PJ, Fuchs T, Johansen

JD, Menn T, Jolanki R, Krcisz B, Kiec-Swierczynska M,Larese F, Orton D, Peserico A, Rantanen T, Schnuch A (2005)The European standard series in 9 European countries,2002/2003 rst results o the European Surveillance Systemon Contact Allergies. Contact Dermat 53(3):136145

89. Zug KA, Warshaw EM, Fowler JF Jr, Maibach HI, BelsitoDL, Pratt MD, Sasseville D, Storrs FJ, Taylor JS, MathiasCG, Deleo VA, Rietschel RL (2009) Patch-test results o theNorth American Contact Dermatitis Group 2005-2006.Dermatitis 20:149160

90. Boonchai W, Lamtharachai P, Sunthonpalin P (2008)Prevalence o allergic contact dermatitis in Thailand.Dermatitis 19:142145

91. Geier J, Lessmann H, Uter W, Schnuch A (2006) experi-ences with ragrance mix II the German perspective.Contact Dermat 55:12

92. Buckley DA, Rycro t RJG, White IR, McFadden JP (2003)The requency o ragrance allergy in patch-tested patientsincreases with their age. Br J Dermatol 149:986989

93. Uter W, Schnuch A (2004) Fragrance allergy increases withage. Br J Dermatol 150:12121234

94. Mortz C, Andersen KE (1999) Allergic contact dermatitis inchildren and adolescents. Contact Dermat 41:121130

95. Heine G, Schnuch A, Uter W, Worm M (2004) Frequency o contact allergy in German children and adolescents patchtested between 1995 and 2002: results rom the In ormationNetwork o Departments o Dermatology and the German

Contact Dermatitis Group. Contact Dermat 51:11111796. Johansen JD, Menn T, Christophersen J, Kaaber K, Veien N(2000) Changes in the sensitization pattern to common aller-gens in Denmark between 19851986 and 19971998, witha special view to the e ect o preventive strategies. Br JDermatol 142:490495

97. White JML, White IR, Kimber I, Basketter DA, BuckleyDA, McFadden JP (2009) Atopic dermatitis and allergicreactions to individual ragrance chemicals. Allergy64:312316

98. Rastogi SC, Menn T, Johansen JD (2003) The composi-tion o ne ragrances is changing. Contact Dermat 48:130132


20/21


99. Schnuch A, Geier J, Uter W, Frosch PJ (2007) Majantol anew inportant ragrance allergen. Contact Dermat 57:4850

100. Johansen JD, Andersen TF, Veien N, Avnstorp C, AndersenKE, Menn T (1997) Patch testing with markers o ra-grance contact allergy. Do clinical tests correspond topatients sel -reported problems? Acta Derm Venereol(Stockh) 77:149153

101. Katz AS, Sheretz F (1999) Facial dermatitis: patch test resultsand nal diagnosis. Am J Contact Dermat 10:153156102. Whrl S, Hemmer W, Focke M, Grtz M, Jarisch R (2001)

The signi cance o ragrance mix, balsam o Peru, colo-phony and propolis as screening tools in the detection o

ragrance allergy. Br J Dermatol 145:268273103. Edman B (1994) The infuence o shaving method on per-

ume allergy. Contact Dermat 31:291292104. Johansen JD, Andersen TF, Kjller M, Veien N, Avnstorp C,

Andersen KE, Menn T (1998) Identi cation o risk prod-ucts or ragrance contact allergy: a case-re erent studybased on patients histories. Am J Contact Dermat 2:8087

105. Johansen JD, Rastogi SC, Bruze M, Andersen KE, FroschPJ, Dreier B, Lepoittevin JP, White IR, Menn T (1998)

Deodorants: a clinical provocation study in ragrance-sen-sitive individuals. Contact Dermat 39:161165

106. Svedman C, Bruze M, Johansen JD, Andersen KE, GoossensA, Frosch PJ, Lepoittevin JP, Rastogi S, White IR, Menne T(2003) Deodorants: an experimental provocation study withhydroxycitronellal. Contact Dermat 48:217223

107. Bruze M, Johansen JD, Andersen KE, Frosch P, LepoittevinJP, Rastogi S, Wakelin S, White I, Menne T (2003)Deodorants: an experimental provocation study with cin-namic aldehyde. J Am Acad Dermatol 48:194200

108. von Peter C, Hoting E (1993) Anwendungstest mit par mi-erten Kosmetika bei Patienten mit positivem Epikutantestau Du tssto -Mischung. Dermatosen 41:237241

109. Heydorn S, Menn T, Johansen JD (2003) Fragrance allergyand hand eczema a review. Contact Dermat 48:5966

110. Buckley DA, Rycro t RJG, White IR, McFadden JP (2000)Contact allergy to individual ragrance mix constituents inrelation to primary site o dermatitis. Contact Dermat43:304305

111. Christophersen J, Menne T, Tanghoj P, Andersen KE,Brandrup F, Kaaber K, Osmundsen PE, Thestrup-PedersenK, Veien NK (1989) Clinical patch test data evaluated bymultivariate analysis. Danish Contact Dermatitis Group.Contact Dermat 21:291299

112. Katsarma G, Gawkrodger DJ (1999) Suspected ragrancecontact allergy requires extended patch testing to individual

ragrance allergens. Contact Dermat 41:193197

113. Veien NK (1989) Systemically induced eczema in adults.Acta Derm Venereol Suppl (Stockh) 147:158114. Niinimaki A (1995) Double-blind placebo-controlled pero-

ral challenges in patients with delayed-type allergy to bal-sam o Peru. Contact Dermat 33:7883

115. Veien NK, Hattel T, Laurberg G (1996) Can oral challengewith balsam o Peru predict possible bene t rom a low-balsam diet? Am J Contact Dermat 7:8487

116. Johansen JD, Frosch PJ, Svedman C, Andersen KE, BruzeM, Pirker C, Menn T (2003) Hydroxyisohexyl 3-cyclo-hexene carboxaldehyde known as Lyral: quantitativeaspects and risk assessment o an important ragrance aller-gen. Contact Dermat 48:310316

117. Rastogi SC, Johansen JD, Menn T (1996) Natural ingredi-ent based cosmetics. Content o selected ragrance sensitiz-ers. Contact Dermat 34:423426

118. Rastogi SC, Johansen JD, Menn T, Frosch PJ, Bruze M,Andersen KE, Lepoittevin JP, Wakelin S, White IR (1999)Contents o ragrance allergens in childrens cosmetics andcosmetic-toys. Contact Dermat 41:8488

119. Rastogi SC, Heydorn S, Johansen JD, Basketter D (2001)Fragrance chemicals in domestic and occupational prod-ucts. Contact Dermat 45:221225

120. Nardelli A, DHooghe E, Drieghe J, Dooms M, GoossensA (2009) Allergic contact dermatitis rom ragrance com-ponents in speci c topical pharmaceutical products inBelgium. Contact Dermat 60(6):303313

121. Wallenhammar LM, Ortengren U, Andreasson H, BarregardL, Bjorkner B, Karlsson S, Wrangsjo K, Meding B (2000)Contact allergy and hand eczema in Swedish dentists.Contact Dermat 43:192199

122. Uter W, Schnuch A, Geier J, P ahlberg A, Ge eller O, IVDKstudy group. In ormation Network o Departments o Dermatology (2001) Association between occupation and con-

tact allergy to the ragrance mix: a multi actorial analysis o national surveillance data. Occup Environ Med 58:392398

123. Geier J, Lessmann SA, Uter W (2004) Contact sensitizationin metalworkers with occupational dermatitis exposed towater-based metalworking fuids: results o the researchproject FaSt. Int Arch Occup Environ Health 77:543551

124. Owen CM, August PJ, Beck MH (2000) Contact allergy tooak moss resin in a soluble oil. Contact Dermat 43:112

125. Pontn A, Bjrk J, Carstensen O, Gruvberger B, IsakssonM, Rasmussen K, Bruze M (2004) Associations betweencontact allergy to epoxy resin and ragrance mix. ActaDerm Venereol (Stockh) 84:151175

126. Larsen WG (1987) Detection o allergic dermatitis to ra-grances. Acta Derm Venereol (Stockh) 134:8386

127. de Groot AC, van der Kley AM, Bruynzeel DP, MeinardiMM, Smeenk G, van Joost T, Pavel S (1993) Frequency o

alse-negative reactions to the ragrance mix. ContactDermat 28:139140

128. Frosch PJ, Pilz B, Burrows D, Camarasa JG, LachapelleJ-M, Lahti A, Menn T, Wilkinson JD (1995) Testing with

ragrance mix. Is the addition o sorbitan sesquioleate tothe constituents use ul? Contact Dermat 32:266272

129. Johansen JD, Rastogi SC, Menn T (1996) Exposure toselected ragrance materials. A case study o ragrance-mix-positive eczema patients. Contact Dermat 34:106110

130. Trattner A, David M (2003) Patch testing with ne ra-grances: comparison with ragrance mix, balsam o Peru

and a ragrance series. Contact Dermat 49:287289131. Johansen JD, Rastogi SC, Andersen KE, Menn T (1997)Content and reactivity to product per umes in ragrancemix positive and negative eczema patients. A study o per-

umes used in toiletries and skin-care products. ContactDermat 36:291296

132. de Groot AC, Coenraads PJ, Bruynzeel DP, Jagtman BA,van Ginkel CJ, Noz K, van der Valk PG, Pavel S, Vink J,Weyland JW (2000) Routine patch testing with ragrancechemicals in the Netherlands. Contact Dermat 42:184185

133. Geier J, Brasch J, Schnuch A, Lessmann H, Pirker C,Frosch PJ, For the In ormation Network o Departments o Dermatology (IVDK) and the German Contact Dermatitis


21/21

62733 Fragrances

Research Group (DKG) (2002) Lyral has been included inthe patch test standard series in Germany. Contact Dermat46:295297

134. Bruze M, Svedman C, Andersen KE, Bruynzeel D,Goossens A, Duus Johansen J, Matura M, Orton D, ViganM, On Behal O The ESCD (2009) Patch test concentra-tions or the 12 non-mix ragrance substances regulated by

European legislation. Contact Dermatitis under submission135. Heisterberg MV, Vigan M, Johansen JD (2010) Active sen-sitization and allergic contact dermatitis caused by methylheptine carbonate. Contact Dermat 62(2):97101

136. Roberts G (2002) Procedures or supplying ragrance in or-mation to dermatologists. Letter to the editor. Am J ContactDermat 13:206207

137. Johansen JD, Andersen KE, Rastogi SC, Menn T (1996)Threshold responses in cinnamic-aldehyde-sensitive sub-

jects: results and methodological aspects. Contact Dermat34:165171

138. Johansen JD, Andersen KE, Menn T (1996) Quantitativeaspects o isoeugenol contact allergy assessed by use andpatch tests. Contact Dermat 34:414418

139. Scheinman PL (2001) Exposing covert ragrance chemi-cals. Am J Contact Dermat 12:225228

140. Scheinman PL (1999) The oul side o ragrance- ree prod-ucts: what every clinician should know about managingpatients with ragrance allergy. J Am Acad Dermatol41:10201024

141. Lysdal SH, Johansen JD (2009) Fragrance allergicpatients-strategies or use o cosmetic products and per-ceived impact on li e situation. Contact Dermat 61(6):320324

142. Sa ord RJ, Basketter DA, Allenby CF, Goodwin BF (1990)Immediate contact reactions to chemicals in the ragrancemix and a study o the quenching action o eugenol. Br JDermatol 123:595606

143. Temesvari E, Nemeth I, Balo-Banga MJ, Husz S, KohankaV, Somos Z, Judak R, Remenyik EVA, Szegedi A,Neben hrer L, Meszaros C, Horvath A (2002) Multicentrestudy o ragrance allergy in Hungary. Immediate and latetype reactions. Contact Dermat 46:325330

144. Tanaka S, Matsumoto Y, Dlova N, Ostlere LS, GoldsmithPC, Rycro t RJG, Basketter DA, White IR, Banerjee P,McFadden JP (2004) Immediate contact reactions to ra-grance mix constituents and Myroxylon pereirae resin.Contact Dermat 51:2021

145. Katsarou A, Armenaka M, Ale I, Kou ou V, KalogeromitrosD (1999) Frequency o immediate reactions to the European

standard series. Contact Dermat 41:276279146. Diba VC, Statham BN (2003) Contact urticaria rom cin-namal leading to ana ylaxis. Contact Dermat 48:119

147. Kroon S (1979) Musk Ambrette, a new cosmetic sensitizerand photo sensitizer. Contact Dermat 5:337338

148. Cronin E (1984) Photosensitivity to musk ambrette. ContactDermat 11:8892

149. Darvay A, White IR, Rycro t RJ, Jones AB, Hawk JL,McFadden JP (2001) Photoallergic contact dermatitis isuncommon. Br J Dermatol 145:597601

150. Cronin E (1980) Phototoxic reactions. Contact dermatitis.Churchill Livingstone, Edinburgh, pp 417432

151. Wang L, Sterling B, Don P (2002) Berloque dermatitisinduced by Florida water. Cutis 70:2930

152. Brred Christensson J, Forsstrm P, Wennberg AM, KarlbergAT, Matura M (2009) Air oxidation increases skin irritation

rom ragrance terpenes. Contact Dermat 60:3240153. Hemmer W, Focke M, Leitner B, Grtz M, Jarisch R (2000)

Axillary dermatitis rom arnesol in a deodorant. ContactDermat 42:168

154. Gimenez-Arnau A, Giminez-Arnau E, Serra-Bladrich E,Lepoittevin JP, Camarasa JG (2002) Principels and meth-odology or identi cation o ragrance allergens in con-sumer products. Contact Dermat 47:345352

155. Rastogi SC, Johansen JD, Frosch PJ, Menn T, Bruz

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