Citral a fragrance allergen and irritant

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1 Contact Dermatitis 2003: 49: Copyright # Blackwell Munksgaard 2003 Printed in Denmark. All rights reserved CONTACT DERMATITIS ISSN Citral a fragrance allergen and irritant S. HEYDORN 1,T.MENNE 1,K.E.ANDERSEN 2,M.BRUZE 3,C.SVEDMAN 3,I.R.WHITE 4 AND D. A. BASKETTER 5 1 Department of Dermatology, Gentofte Hospital, University of Copenhagen, 2 Department of Dermatology, Odense University Hospital, University of Southern Denmark, Denmark, 3 Department of Occupational and Environmental Dermatology, Malmo University Hospital, Lunds University, Malmo, Sweden, 4 St John s Institute of Dermatology, St Thomas Hospital, London, and 5 SEAC Toxicology, Unilever Research, Sharnbrook, UK Citral is a well known contact allergen and a contact irritant. Routine patch testing in the past may have been restricted because of possible irritant (IR) patch test responses. 586 consecutive patients, with hand eczema, were patch tested with a selection of fragrances including citral 2% petrolatum and the European standard series. 28 of the patients showed a positive patch test reaction (þ to þþþ) to citral and 82 at least 1 IR patch test reaction and no positive patch test reaction to citral. A statistically significant association between a positive patch test reaction to citral and positive patch test reactions to other fragrances compared with IR reactions (n ¼ 82) was established. The difference regarding fragrance history found between those with IR and positive reactions to citral was not significant. Citral could be an allergen and/or irritant, worthy of further more extensive studies. Key words: citral; contact allergen; contact irritant; fragrance; patch testing. # Blackwell Munksgaard, Accepted 14 July 2003 Citral (3,7-dimethyl-(2,6)-octadienal) constitutes 75 85% of oil of lemon grass and, to a minor extent, is also present in oils of verbena, lemon and orange (1). Citral from natural sources is a mixture of the 2 geometric isomers geranial and neral. It is a widely used fragrance and flavour material with a strong lemon-like odour and a characteristic bittersweet taste (2) and may be an efficient preservative in the presence of non-ionic surfactants such as polysorbate 20, 40 or 80 (Tween 1 20, 40, 80) (3). Methods for identification of potential skin sensitizers such as the local lymph node assay, the guinea pig maximization test and the human maximization test have all found citral to be a skin sensitizer (4, 5). Several human patch test studies have described citral as an allergen (6 8), but citral has also been described as an irritant (9, 10). Patients with hand eczema are exposed to citral from various products (11). The aim was to study the outcome of patch testing, with citral 2% petrolatum (pet.), in consecutive patients with hand eczema and compare the data with other simultaneous fragrance patch test data and the patients history of fragrance allergy. Materials and Methods The materials and methods for this study have been described in a previous publication (12). The present part concentrates on the citral patch testrelated problems. In this study, we included 586 patients with hand eczema. Standard patch testing was supplemented with a selection of fragrances in 3 clinics. In the period March 2001 September 2002, Malmo contributed 137 patients with hand eczema, Odense 229 and Gentofte 220. The selected fragrances consisted of 14 fragrances chosen according to their sensitizing abilities, and their presence in products intended for hand contact. Those selected included the following fragrances: citral 2% pet. ( ), hydroxycitronellal 5% pet. ( ), Lyral 1 5% pet. ( ), eugenol 5% pet. ( ), oxidized L-limonene 3% pet. ( ), oxidized D-limonene 3% pet. ( ), lilial 10% pet. ( ), coumarin 5% pet. ( ), a-hexylcinnamic aldehyde 10% pet. ( ), benzyl salicylate 5% pet. ( ), galaxolide 10% pet. ( ), isopropylmyristate 10% pet., citronellol 5% pet. ( ) and benzyl benzoate 5% pet. ( ). IPM: isopropylmyristate was tested

2 CITRAL A FRAGRANCE ALLERGEN AND IRRITANT 33 at 10% pet.lilial 1 : 2-methyl-3-(4-tert-butyl-phenyl) proanal. Lyral 1 : 4-(4-hydroxy-4-methylpenthyl)- 3-cyclohexene carbaldehyde. INCI: hydroxyisohexyl 3-cyclohexene carboxaldehyde. Galaxolide 1 : 4,6,6,7,8,8-hexamethyl-1,3,4,6,7,8-hexahydrocyclopental[g]benzopyran. INCI: 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylindeno[5,6-c]pyran. Questionnaire On the first day of patch testing, all participants were given a short questionnaire. It included: * Sex * Age * Did you have eczema in the elbow/knee folds (child eczema) as a child? * Did you have asthma or hay fever as a child? 4 different questions concerning exposure-defined relevance, which were combined into 1 variable called fragrance history. This was positive, if at least 1 positive reply were given to 1 of the 4 questions: * Have you ever had eczema after use of perfumed household and/or cleaning products? * Have you ever had eczema after use of perfumed cosmetics or skin care products? (examples given) * Have you had eczema after use of perfumed products in the last 12 months? * Do you think that use of perfumed products worsens your eczema? The questionnaire also included several other questions; details were published elsewhere (12). Patch test material Details are given in a previous publication (12). A positive patch test reaction was defined as homogeneous erythema and infiltration, whereas erythema alone was not. Statistical methods A positive patch test for citral meant at least a þ reaction at any reading. An irritative patch test reaction meant an IR reaction according to the ICDRG guidelines (13), at any reading. 2 patients gave a þþ reaction to citral and were noted as positive to citral, despite also showing an IR reaction at a previous or later reading. The variable other fragrances was the patch test results from testing with the standard series and selected fragrances. Balsam of Peru was not counted as a fragrance ingredient. We used chi-square test, Fisher s exact test and two-sample test for proportions in the SAS 1 system for Windows 1 release 8.02 TS level 02MO copyright (c) by SAS Institute Inc., Cary, NC, USA. Results Amongst the total of 586 hand eczema patients, we found 28 patients with at least 1 positive patch test reaction to citral at any reading and 82 patients with at least 1 IR patch test reaction to citral and no positive patch test reactions to citral 2% pet. at any reading. 46 hand eczema patients showed IR patch test readings alone or in combination with a negative patch test reading, whereas the remaining 36 of the 82 patients also included?þ and follicular reactions. The 82 patients with an IR patch test reaction consisted of 33 (144%) from Odense, 41 (186%) from Gentofte and 8 (58%) from Malmo. The 28 patients with a positive patch test reaction consisted of 15 (66%) from Odense, 6 (27%) from Gentofte and 7 (51%) from Malmo. Finally, the calculations from this study have been repeated in patch test data deriving only from Gentofte in order to minimize any potential difference in patch test reading (Fig. 1). Basic characteristics of the patients with hand eczema and positive and IR patch test reactions, respectively, to citral are summarized in Table 1. In both cases, it seemed to be mostly women in the working age group and often with a time of onset, of eczema, more than 1 year ago. Mean age seemed to be slightly higher in those positive to citral, but the very low numbers and small difference have to be taken into account. There were a higher number of positive patch tests to fragrances other than citral in those with a % % % % % % % 0. 00% IR Positive fragrance history Positive other fragrances positive Fig. 1. The variables positive fragrance history and positive other fragrances in those participants labelled positive and IR to citral 2% petrolatum in Gentofte.

3 34 HEYDORN ET AL. Table 1. Characteristics of 110 patients with hand eczema Positive patch test reaction to citral (n ¼ 28) IR patch test reaction to citral (n ¼ 82) Non-responders (n ¼ 82)/(n ¼ 28)* Age [mean SD (range)] 4925 years 1644 (25 79) 4018 years 1299 (19 72) 0/0 Sex 8 males (2857%), 20 females (7143%) 36 males (4390%), 46 females (5610%) 0/0 Eczema in the knee/elbow folds as child 5 (1786%) 24 (2963%) 1/0 Hay fever/asthma as child 1 (357%) 10 (122%) 0/0 0 3 months ¼ 1(122%) 3 12 months ¼ 6(732%) 13 months 5 years ¼ 30 (3659%) 5 years ¼ 45 (5488%) 0 3 months ¼ 2(714%) 3 12 months ¼ 5 (1786%) 13 months 5 years ¼ 8 (2857%) 5 years ¼ 13 (4643%) Time since onset of first eczema (months) Facial/neck eczema 11 (4074%) 28 (3500%) 2/1 Axillary eczema 2 (741%) 18 (2308%) 4/1 IR, irritant. *Non-responders mean participants in the 2 groups that did not complete that part of the questionnaire. positive patch test reaction to citral than in those with an IR reaction (Table 2). Altogether, a positive patch test to fragrances other than citral was found in 16 (571%) of those positive to citral, compared with 11 (1341%) of those with an IR patch test to citral (Table 2). This was significantly different using a chi square test (P-value <00001). 20 (714%) versus 45 (549%) had a positive fragrance history in those with a positive patch test reaction to citral and an IR reaction, respectively. The difference was not statistically significant (Table 3). Discussion We have previously found that 43% of 658 consecutively tested hand eczema patients showed a positive patch test to citral 2% pet. (12). Frosch et al. (6) found citral 2% pet. to be positive in 11% of consecutively patch-tested patients. As hand eczema patients usually make up 1/4 1/3 of consecutively patch-tested patients in a referral clinic, these figures are in close accordance. The higher frequency in hand eczema patients could be explained by frequent hand exposure to citralcontaining products, and a chronic disease course may also be important. In this study, we found significantly more positive patch tests to other fragrances in those with a positive patch test to citral, compared with those with an IR patch test reaction, 57 versus 13%, respectively (Table 2). This finding could support the view that citral is a fragrance allergen. Friedmann (14) found proportionately more subjects sensitized by DNCB, if they were already sensitized to 3 or more allergens in the European standard patch test series. This experimental study is in agreement with the present data. Furthermore, Friedmann argued that there was no evidence that these individuals were able to show greater non-specific inflammatory responses, for example, to irritants. A positive fragrance history was found in 71% of those with a positive patch test to citral and in 55% of those with an IR patch test reaction (Table 3). This difference is not significant. This could be explained by citral acting both as an allergen and an irritant. As mentioned earlier, citral has been described as an irritant in previous studies (9, 10). Experience from the past has shown that citral may give rise to clinical dermatitis based on its property as a contact irritant. The possible contemporary effects of citral as an allergen and an irritant are not contradicted by the fact that patch testing the hand eczema patients with citral 1% pet. and ½% pet. gave

4 CITRAL A FRAGRANCE ALLERGEN AND IRRITANT 35 Table 2. Positive patch test to perfumes other than citral in consecutive patients with hand eczema with either irritant (IR) or positive patch test reaction to citral. n ¼ 110 Positive patch test to fragrances other than citral? Positive patch test to citral (%) IR patch test reaction to citral (%) Yes 1 16 (5714) 11 (1341) No 12 (4286) 71 (8659) Chi-square test: P < Fisher s exact test confirms the very low P value. All 110 patients were tested with the selected fragrances, but 3 (having an IR patch test reaction) were not tested with fragrance mix. 1 Excludes balsam of Peru. only 3 and 1 positive patch test reactions, no IR reactions and only 6?þ reactions. In a pilot study carried out in London (I.R.W), citral 5% pet. was found to give too many IR reactions. The present study contains certain methodological problems which are difficult to standardize in a clinical multicentre study. The thesis by Bjørnberg (15) in the 1960s showed that patients with active hand eczema may have increased reactivity to some irritants and some allergens, but as we did not intend to patch test patients with active eczema, we had no variable taking this into account and, therefore, we cannot exclude such an effect on the patch test results. The effect of active eczema on the patch test results is not agreed about by all authors. Brasch et al. (16) did not find that the existence of inflammatory dermatoses at sites other than the back had a significant influence on the relative number of discordant reactions when double-patch testing 1285 patients with 10 standard allergens. Also, we have not taken into account the idea of an increased likelihood of positive patch tests in the proximity of an existing positive patch test. Almost half a decade ago, several publications investigated this phenomenon, although without agreeing about its existence (16 18). Mirroring this, several publications has not taken either of these phenomena into account (19 21). Excluding the doubtful patch test reactions (?þ) from our comparisons was an arbitrary choice to compare allegedly more homogeneous groups. All these variables might have influenced the present data, but the large number of patients included support the conclusion. The robustness of the idea is illustrated in Fig. 1, representing data from only 1 of the participating centres. The problem that chemicals acting as haptens are also irritants is well-known; the patch test concentration of the original fragrance mix has, for example, been reduced from 16 to 8% because of too many IR reactions. These types of problems are also well known from patch testing with, for example, preservatives and chromates (22). In general clinical practice, the accurate diagnosis of allergic contact dermatitis is most complicated when the chemical under suspicion possesses substantial irritant activity but is a relatively modest allergen. There is evidence from predictive models that citral could be an allergen (5). It could be hypothesized that citral is such a common allergen in hand eczema patients due to the combined effects of allergic and irritant properties (23). Citral could be an allergen and/or irritant worthy of further more extensive studies. Acknowledgements The present study was supported by the Quality of Life and Management of Living Resources programme of the European Commission under the key action Environment and Health Contract QLK4- CT Fragrance chemical allergy: a major environmental and consumer problem in Europe. Research participants: Jean-Pierre Lepoittevin and Elena Giménez Arnau, University Louis Pasteur, Strasbourg, France; Ann-Therese Karlberg, Mihaly Matura, Maria Sko ld and Anna Bo rje, National Institute for Working Life, Stockholm, Sweden; David Basketter and Grace Patlewicz, SEAC Toxicology, Unilever Research, Bedford, UK; Torkil Menne, Jeanne Duus Johansen and Siri Heydorn, Department of Dermatology, Gentofte Hospital, University of Copenhagen, Denmark; Peter Frosch, Department of Dermatology and University of Witten/Herdecke, Dortmund, Germany; Ian White, Department of Contact Dermatitis and Occupational Dermatology, St John s Institute of Dermatology, St Thomas Table 3. Fragrance history in positive versus irritant (IR) patch test reactions to citral in 110 patients with hand eczema Positive fragrance history? Positive patch test to citral (n ¼ 28) (%) IR patch test reaction to citral (n ¼ 82) (%) Yes 1 20 (7143) 45 (5488) No 8 (2857) 37 (4512) Chi-square test: P ¼ Fisher s exact test: P ¼ At least 1 positive reply to 4 exposure-defined questions in the questionnaire.

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