Background: p‐Phenylenediamine (PPD) is the primary patch test screening agent for hair dye contact allergy, and approximately 100 different hair dye chemicals are allowed. Objectives: To examine whether PPD is an optimal screening agent for diagnosing hair dye allergy or whether other clinically important sensitizers exist. Methods: Two thousand nine hundred and thirty‐nine consecutive patients in 12 dermatology clinics were patch tested with five hair dyes available from patch test suppliers. Furthermore, 22 frequently used hair dye ingredients not available from patch test suppliers were tested in subgroups of ∼ 500 patients each. Results: A positive reaction to PPD was found in 4.5% of patients, and 2.8% reacted to toluene‐2,5‐diamine (PTD), 1.8% to p‐aminophenol, 1% to m‐aminophenol, and 0.1% to resorcinol; all together, 5.3% (n = 156). Dying hair was the most frequently reported cause of the allergy (55.4%); so‐called ‘temporary henna’ tattoos were the cause in 8.5% of the cases. p‐Methylaminophenol gave a reaction in 20 patients (2.2%), 3 of them with clinical relevance, and no co‐reaction with the above five well‐known hair dyes. Conclusions: Hair dyes are the prime cause of PPD allergy. PPD identifies the majority of positive reactions to PTD, p‐aminophenol and m‐aminophenol, but not all, which justifies additional testing with hair dye ingredients from the used product.
2‐amino‐3‐hydroxypyridine; 3‐nitro‐p‐hydroxyethylaminophenol; hair dye allergy; m‐aminophenol; p‐aminophenol; p‐methylaminophenol; PPD; p‐phenylenediamine; p‐toluenediamine; toluene‐2; 5‐diamine
Hair dyes may cause allergic reactions [
A combination of local lymph node assay (LLNA) data and physical/chemical properties have previously been used in a quantitative structure–activity relationship (QSAR) analysis to predict sensitization potential for > 200 hair dye chemicals. The details of the analysis were described by Søsted et al. in 2004 [
The aim of this multicentre evaluation was to identify substances suitable for inclusion in an extended patch test series for contact allergy to hair dye ingredients. The first aim was to study the frequency of allergic reactions to 22 not previously tested potential allergenic hair dye ingredients in eczema populations. The second aim was to study the relationship between reactions to one or more of the hair dye ingredients and a history of hair dye dermatitis. The third aim was to study the relationship between reactions to one or more of 22 rarely tested hair dye substances and a series of five well‐known hair dye screening agents.
Two thousand nine hundred and thirty‐nine consecutive eczema patients attending 12 dermatology clinics during a 6‐month period (in 2007/2008) were patch tested with an extended series of hair dye ingredients, consisting of five basic hair dye ingredients from the European baseline and hairdressers series: PPD, PTD, resorcinol, m‐aminophenol, and p‐aminophenol. Moreover, 22 hair dye substances identified as potential contact allergens on the basis of their chemical structure and the volume of use in Europe [
Baseline characteristics of the cohort of eczema patients
Centre Number tested Males, no. (%) Occupational, no. (%) AD, no. (%) Hand, no. (%) Leg Face, no. (%) Age > 40 years, no. (%) London 183 30 (16) 3 (2) 49 (27) 69 (38) 5 (3) 47 (26) 80 (44) SF 75 NG NG NG NG NG NG NG Strasbourg 184 48 (26) 49 (27) 52 (28) 68 (37) 14 (8) 80 (43) 92 (50) Total 442 — — — — — — — Gentofte 455 152 (3) 131 (29) 100 (22) 214 (47) 13 (3) 105 (23) 294 (65) Leuven 233 68 (29) 17 (7) 61 (26) 83 (36) 10 (4) 92 (39) 141 (61) Heidelberg 159 75 (47) 128 (81) 35 (22) 125 (79) 0 2 (1) 62 (39) Total 847 295 (35) 276 (33) 196 (23) 422 (50) 23 (3) 199 (23) 497 (59) Malmö 282 105 (37) 164 (58) 73 (26) 90 (32) 32 (11) 47 (17) 151 (54) Odense 148 54 (36) 6 (4) 36 (24) 56 (38) 10 (7) 33 (22) 99 (67) Coimbra 306 80 (26) 73 (24) 71 (23) 122 (40) 24 (8) 65 (21) 171 (56) Total 736 239 (32) 243 (33) 180 (24) 268 (36) 66 (9) 145 (20) 421 (57) Amsterdam 610 194 (32) 3 (0.5) NG 149 (24) 62 (10) 101 (17) 234 (38) Barcelona 202 50 (25) 5 (2) 37 (18) 33 (16) 19 (9) 14 (7) 132 (65) Roskilde 102 43 (42) 10 (10) 5 (5) 30 (29) 3 (3) 4 (4) 13 (13) Total 914 287 (31) 18 (2) — 212 (23) 84 (9) 119 (13) 379 (41) Sum 2939 899 (31.4) 589 (20.6) 477 (24.5) 1039 (36.3) 192 (6.7) 590 (20.1) 1469 (51.3)
1 AD, atopic dermatitis; Face, face eczema; Hand, hand eczema; Leg, leg eczema; NG, not given; SF, San Francisco.
- 2 Of 2864 patients.
- 3 Of 1950 patients.
Results from patch testing of 27 hair dye ingredients in 2939 consecutive patients
All centres Substances Chemical cluster (A) No. tested No. positive No. doubtful (%) No. irritant (%) + ++ +++ Total (%) m‐Aminophenol 5 2939 12 13 4 29 (1) 13 (0.4) 1 (0.03) p‐Aminophenol 5 2939 17 23 13 53 (1.8) 121 (4.1) 3 (0.1) Resorcinol 6 2939 0 2 1 3 (0.1) 16 (0.5) 0 PTD 8 2939 25 33 25 83 (2.8) 103 (3.5) 11 (0.4) PPD 8 2939 47 49 37 133 (4.5) 119 (4.0) 0 London, San Francisco, Strasbourg 4‐Amino‐2‐hydroxytoluene 5 442 3 2 1 6 (1.4) 1 (0.2) 0 1‐Hydroxyethyl‐4,5‐diaminopyrazole sulfate 8 442 1 0 0 1 (0.2) 0 0 HC Blue 2 2 442 0 0 0 0 2 (0.4) 0 2‐Methyl‐5‐hydroxyethylaminophenol 6 442 0 0 0 0 0 0 2‐Methylresorcinol 6 442 1 0 0 1 (0.2) 0 0 Heidelberg, Gentofte, Leuven 2,4‐Diaminophenoxyethanol‐HCl 8 847 3 1 0 4 (0.5) 2 (0.2) 0 4‐Chlororesorcinol 5 847 1 0 0 1 (0.1) 0 0 4‐Amino‐m‐cresol 5 847 2 2 0 4 (0.5) 2 (0.2) 1 (0.1) N,N′‐Bis(2‐hydroxyethyl)‐p‐phenylenediamine 5 847 2 0 0 2 (0.2) 2 (0.2) 0 2‐Amino‐6‐chloro‐4‐nitrophenol 2 847 0 0 0 0 2 (0.2) 3 (0.3) Coimbra, Malmø, Odense 2,4,5,6‐Tetraaminopyrinidine 8 736 0 0 0 0 7 (6) (1.0%) 0 1‐Naphthol 6 736 0 0 0 0 15 (15) (2.0) 0 4‐Hydroxypropylamino‐3‐nitrophenol 5 736 0 0 0 0 141(133)(19) 0 HC Red 3 2 736 0 0 0 0 132 (127) (17) 0 Acid Violet 43 1 736 0 0 0 0 70 (70) (9.5) 0 2,7‐Naphthalenediol 6 736 0 0 0 0 1 (1) (0.1) 0 Amsterdam, Barcelona, Roskilde 4‐Amino‐3‐nitrophenol 2 914 0 1 0 1 (0.1) 0 0 Disperse Violet 1 2 914 0 0 0 0 1 (0.1) 1 (0.1) 2‐Amino‐3‐hydroxypyridine 5 914 1 0 1 2 (0.2) 1 (0.1) 0 3‐Nitro‐p‐hydroxyethylaminophenol 5 914 2 0 0 2 (0.2) 7 (0.8) 1 (0.1) p‐Methylaminophenol 6 914 17 2 1 20 (2.2) 5 (0.5) 1 (0.1) Picramic acid 2 914 0 0 0 0 3 (0.3) 1 (0.1)
- 4 PPD, p‐phenylenediamine; PTD, toluene‐2,5‐diamine. A: chemical cluster is an arbitrary number that refers to physical/chemical properties. Chemicals with the same cluster number are closely related concerning their physical/chemical properties. It is expected that substances from the same clusters will give patch test cross‐reactions in patients.
- 5 Odense numbers: 352 of 366 (96.2%) of the doubtful reactions were registered at one clinic, where discoloration of the skin was taken as doubtful.
- 6 Six of these 20 patients were also positive for PTD, and 5 of these 20 patients were also positive for PPD; see Table .
The patch test materials were prepared by the pharmacy of the Capital Region of Copenhagen, Denmark.
The test concentrations were 1% in petrolatum for all of the 22 substances, based on knowledge of use concentrations from the producers and experience of testing in one centre, which had patch tested individual hair dye cases with ingredients in patients using hair dye products. The characteristics of the participants in this study are shown in Table [NaN] , and Table [NaN] shows where each substance was patch tested.
The extended series were applied on the upper back of the patients with 8‐mm Finn Chambers
If a patient had had a doubtful or positive patch test reaction to any of the hair dye substances, they were asked if they had ever had symptoms from hair dyes and the nature of the symptoms. It was possible to choose: itch only, facial/scalp rash, spreading rash, facial oedema, and/or hand eczema. It was not specified whether the symptoms were immediate or delayed.
In 4.5% of patients a positive reaction to PPD was found, in 2.8% a positive reaction to PTD, in 1.8% a positive reaction to p‐aminophenol, in 1% a positive reaction to m‐aminophenol, and in 0.1% a positive reaction to resorcinol (Table [NaN] ). In total, 5.3% (156/2939) reacted positively to one or more of the five basic substances (Table [NaN] ).
Concomitant patch test reactions among five basic hair dye ingredients in 156 patients
Hair dye substance (cluster no.) m‐Aminophenol (5), n = 29, no. (%) p‐Aminophenol (5), n = 53, no. (%) Resorcinol (6), n = 3, no. (%) PTD (8), n = 83, no. (%) PPD (8), n = 133, no. (%) m‐Aminophenol (5) — 22 (41.5) 1 (33.3) 22 (26.5) 24 (18.0) p‐Aminophenol (5) 22 (75.8) — 2 (66.6) 46 (55.4) 46 (34.5) Resorcinol (6) 1 (3.4) 2 (3.7) — 1 (1.2) 2 (1.5) PTD (8) 22 (75.8) 46 (86.8) 1 (33.3) — 67 (50.3) PPD (8) 24 (82.7) 46 (86.8) 2 (66.6) 67 (80.7) — Isolated positive 2 (6.9) 3 (5.6) 1 (33.3) 13 (15.6) 60 (45.1)
- 7 PPD, p‐phenylenediamine; PTD, toluene‐2,5‐diamine.
- 8 The five basic hair dye ingredients were: PPD; PTD; m‐aminophenol; p‐aminophenol; and resorcinol.
- 9 One or more positive patch test reactions in 156 patients. N = 2939.
PPD was the substance with most single positive reactions [60/133 (45.1%)], and identified 80.7–86.8% of the positive reactions to PTD, m‐aminophenol, or p‐aminophenol. Concerning resorcinol, 3 positive reactions were seen, in 2 of 3 cases with a concomitant positive reaction to PPD.
In 55.4% of the cases positive for one or more of the five substances, there was a history of rash caused by hair dyes, eyebrow dye, or semi‐permanent tattoo, more often in women (59.8%) than in men (36.4%) (Table [NaN] ).
Characteristics of 155 patients with a positive patch test reaction to one or more of the five basic hair dye substances
Women, n = 122, no. (%) Men, n = 33, no. (%) Total, n = 155, no. (%) Dyed hair, ever 101 (82.8) 11 (33.3) 112 (72.3) Within last year 66 (54.1) 5 (15.2) 71 (45.8) Previously 35 (28.7) 6 (18.2) 41 (26.5) Worked as hairdresser 22 (18.0) 0 22 (14.2) Within last year 16 (13.1) 0 16 (10.3) Previously 6 (4.1) 0 6 (3.9) Ever symptoms from hair dyes among those who had dyed their hair 69 (56.6) 11 (33.3) 80 (51.6) Nature of symptoms among those with symptoms Itch only 19 (15.6) 2 (6.1) 21 (13.5) Facial/scalp rash 47 (38.5) 9 (27.3) 56 (36.1) Spreading rash 14 (11.5) 2 (6.1) 16 (10.3) Facial oedema 20 (16.4) 2 (6.1) 22 (14.2) Hand eczema 13 (10.7) 3 (9.1) 16 (10.3) Semi‐permanent tattoo 21 (17.2) 2 (6.1) 23 (14.8) Within last year 5 (4.1) 0 5 (3.2) Previously 16 (13.1) 2 (6.1) 18 (11.6) Rash from semi‐permanent tattoo 11 (9.0) 2 (6.1) 13 (8.4) Within last year 3 (2.5) 0 3 (1.9) Previously 8 (6.6) 2 (6.1) 10 (6.5) Dyed brows/lashes 19 (15.6) 0 19 (12.3) Within last year 11 (9.0) 0 11 (7.1) Previously 8 (6.6) 0 8 (5.2) Rash caused by brow/lash dye 4 (3.3) NR 4 (2.6) Within last year 2 (1.6) NR 2 (1.3) Previously 2 (1.6) NR 2 (1.3) Ever rash from hair dyes, semi‐permanent tattoo, or brow/lash dye 73 (59.8) 12 (36.4) 85 (54.8) Current relevance assessed by doctor Explains current dermatitis 45 (36.9) 11 (33.3) 56 (36.1) Contributes to current dermatitis 29 (23.8) 9 (27.3) 38 (24.5) Current relevance (total) 74 (60.7) 20 (60.6) 94 (60.6)
10 Five basic hair dye substances: p‐Phenylenediamine; toluene‐2,5‐diamine; resorcinol; m‐aminophenol and p‐aminophenol.
Facial rash or scalp rash caused by hair dyes constituted by far the largest group of adverse reactions (Table [NaN] ). Facial/scalp rash and facial oedema were the most prominent symptoms among those having experienced adverse reactions to hair dyes.
In total, 22 women and no men had worked as hairdressers, and 19 of these had current hand eczema. In 2 hairdressers, facial or scalp eczema was seen, and in 1 case there was no current dermatitis.
Among the additional substances that were tested in subgroups of patients, seven gave reactions in more than 1 patient (Tables [NaN] and [NaN] ). p‐Methylaminophenol gave a positive reaction in 20 patients (2.2%), and 4‐amino‐2‐hydroxytoluene gave a positive reaction in 6 patients (1.8%).
Concomitant positive reactions to one or more of the five basic hair dye allergens and each of the seven additional hair dye substances causing more than isolated positive patch test reactions
Substances Number positive Concomitant positive reactions to: One or more of the five, no. (%) m‐Aminophenol, no. (%) p‐Aminophenol, no. (%) Resorcinol, no. (%) PTD, no. (%) PPD, no. (%) 4‐Amino‐2‐hydroxytoluene 6 5/6 (83) 5/6 (83) 5/6 (83) 0/6 5/6 (83) 5/6 (83) 2,4‐Diaminophenoxyethanol‐HCl 4 4/4 (100) 3/4 (75) 2/4 (50) 0/4 3/4 (75) 4/4 (100) 4‐Amino‐m‐cresol 4 4/4 (100) 2/4 (50) 3/4 (75) 0/4 4/4 (100) 4/4 (100) N,N′‐Bis(2‐hydroxyethyl)‐p‐phenylenediamine 2 2/2 (100) 2/2 (100) 2/2 (100) 0/2 2/2 (100) 2/2 (100) 2‐Amino‐3‐hydroxypyridine 2 1/2 (50) 0/2 0/2 1/2 (50) 0/2 0/2 3‐Nitro‐p‐hydroxyethylaminophenol 2 0 0/2 0/2 0/2 0/2 0/2 p‐Methylaminophenol 20 8/20 (40) 3/20 (30) 6/20 (30) 2/20 (10) 6/20 (30) 5/20 (25)
- 11 PPD, p‐phenylenediamine; PTD, toluene‐2,5‐diamine.
- 12 The five allergens are: PPD; PTD; m‐aminophenol; p‐aminophenol; and resorcinol.
- 13 Not all reactions to 4‐amino‐2‐hydroxytoluene, 2‐amino‐3‐hydroxypyridine, 3‐nitro‐p‐hydroxyamoniphenol and p‐methylaminophenol were identified by the five traditional commercially available hair dye patch test allergens.
In the case of 4‐amino‐2‐hydroxytoluene, 5 of the 6 positive patients had concomitant positive reactions to PPD, PTD, m‐aminophenol, and p‐aminophenol. In patients reacting positively to p‐methylaminophenol, 8 of 20 (40%) had concomitant positive reactions to one or more of the five basic substances, and among the 12 other patients negative for the five basic substances, 3 had presented a rash caused by a hair dye only, and not one caused by any other consumer product (25%). No brand names were given. In 2 of these cases, the physician had considered that the reaction to p‐methylaminophenol explained the current dermatitis.
3‐Nitro‐p‐hydroxyethylaminophenol was positive in 2 patients who gave negative reactions to all of the five basic substances. None of these gave a history of rash caused by hair dye, semi‐permanent tattoo, or eyebrow colour.
The patients with positive reactions to 2,4‐diaminophenoxyethanol‐HCl, 4‐amino‐m‐cresol or N,N′‐bis(2‐hydroxyethyl)‐p‐phenylenediamine were also positive for PPD in all cases.
None of the hairdressers showed positive reactions to any of the additional substances.
In 43 patients, a particular product with a brand name or producer was mentioned as the cause of the allergic reaction. In 2 cases, these were black henna/Turkish henna; the remainder were hair dyes most often produced by l'Oreal (12 cases), Wella (5 cases), Schwarzkopf (3 cases), and Clairol (4 cases). In all cases, the reactions concerned PPD, PTD, resorcinol, or the aminophenols, and these chemicals were labelled on the product.
Eleven of the 27 tested hair dye substances gave no positive patch test reactions in the patients (Table [NaN] ).
Contact allergy to PPD was a very frequent cause of contact allergy in European eczema patients in the present study, which is in line with previous experience over a century [
In the current study, 4.5% of a cohort of almost 3000 consecutive eczema patients from different countries in Europe gave a positive patch test reaction to PPD 1% pet. The frequency of PPD allergy is compatible with previous retrospective studies in 21 515 patients tested between 2003 and 2007 in 10 European centres (4.6% reacted to PPD) [
Other hair dye ingredients, such as PTD, p‐aminophenol, m‐aminophenol, and resorcinol, are also well‐known hair dye allergens [
In our study, PTD came second after PPD with 2.8%, followed by p‐aminophenol, m‐aminophenol, and resorcinol (Table [NaN] ). PTD is found more often than PPD in permanent hair dyes in Sweden [
In total, 72% of 155 patients reacting to one or more of the five basic hair dye ingredients from the hairdressing patch test series had ever dyed their hair; this applied to more women (82.8%) than men (33.3%) (Table [NaN] ). Among those who had ever dyed their hair, 71.4% had experienced symptoms related to hair dyeing, most frequently facial/scalp rash. In total, 27.5% had experienced more severe reactions in the form of facial swelling, and 20% had had a more generalized rash. Clinical manifestations in PPD patch test‐positive subjects who reacted to hair dyes have been described previously; 97% reported eczema of the scalp or neighbouring skin, 29% oedema of the eyelids, forehead, or neck, and 12% whole facial oedema [
As shown in Table 4, a total of 14.8% had received a semi‐permanent tattoo, and 56% (13/23) of these had experienced a rash in the tattoo, suggesting the tattoo as the cause of contact allergy: this was equal to 8.3% (13/155) of those sensitized to one or more of the five basic hair dye patch test allergens. This is in line with the retrospective study of PPD allergy in Europe [
Hairdressers constituted 14% (22/156) of those with contact allergy to one or more of the five basic hair dye ingredients, and the majority had hand eczema of a probable occupational origin. No current or previous hairdressers reacted to any of the additional substances, which may indicate that the exposure to PPD is of sufficient magnitude to make it a prime cause of allergy in hairdressers [
The selection of 22 other hair dye ingredients with different chemical composition (clusters) [
For three substances – 2‐amino‐3‐hydroxypyridine (n = 2), 3‐nitro‐p‐hydroxyethylaminophenol (n = 2), and p‐methylaminophenol (n = 20) – no or very little overlap with PPD was seen. This is what we expected, owing to their different cluster numbers (Table [NaN] ). PPD is a cluster 8 substance, whereas 2‐amino‐3‐hydroxypyridine and 3‐nitro‐p‐hydroxyethylaminophenol are cluster 5 substances. We would have expected a cross‐reaction with m‐aminophenol or p‐aminophenol, which are also in cluster 5. A different cluster number is a sign of different physical/chemical properties, and less cross‐reactivity was therefore expected [
The clinical relevance of the positive reactions among those not reacting to one or more of the five basic hair dye ingredients was 25% (3/12), and was thus less than for PPD. These results show that it is important to test patients with suspected allergy to hair dye with the ingredients in the products, to detect patients not allergic to PPD and to correctly inform patients about possible future problems and avoidance. In this study, none of the patients who only had reactions to 3‐nitro‐p‐hydroxyethylaminophenol gave a history of rash caused by hair dye, semi‐permanent tattoo, or eyebrow colour.
p‐Methylaminophenol was a frequent cause of reactions; based on experience from routine testing in one centre with 1% in pet., it was not expected to be irritant, and only a few irritant reactions were scored in this study, but further assessment of the optimal patch test concentration may be necessary.
The clinical data presented in this study show that we still have much to learn about cross‐reactions between the hair dye substances. The cross‐reaction hypothesis that chemicals with similar physical/chemical properties give cross‐reactions in humans [
A final patch test series for hair dyes cannot be based on the data from this investigation. A study is needed in which the hair dye substances are patch tested in different concentrations. Zero reactions of some substances might be false‐negative results, because of concentrations that are too low. Furthermore, the study is relatively small, as the 22 additional hair dye ingredients were only tested in three different centres. Therefore, on the basis of the current results, it is still recommended to test with those substances that, in this study, showed zero reactions.
In conclusion, PPD allergy is common among European eczema patients, and both the current and previous studies have shown that hair dyes constitute the prime cause of PPD allergy. PPD identified the majority of positive reactions to PTD, p‐aminophenol, and m‐aminophenol, but not all, which justifies continued screening with these basic ingredients of hair dyes. The testing with additional hair dye ingredients shows that it is important to test with the ingredients of the particular hair dye in question, to diagnose hair dye allergy and to correctly inform patients about possible future problems and avoidance.
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By Heidi Søsted; Thomas Rustemeyer; Margarida Gonçalo; Magnus Bruze; An Goossens; Ana M. Giménez‐Arnau; Christophe J. Le Coz; Ian R. White; Thomas L. Diepgen; Klaus E. Andersen; Tove Agner; Howard Maibach; Torkil Menné and Jeanne D. Johansen