FS04.3Hair dyes, prediction of sensitization potential with QSAR

Objectives:  To identify substances and tonnage data for use for hair dyes registered in Europe. To predict the sensitization potential of each substance and to rank the substances due to their sensitization potential. Further to group the substances in clusters based on their physical chemical properties with a cluster analysis.
Methods:  The Inventory list of Cosmetics Ingredients (INCI), new regulation on cosmetics, tonnage data for use and Toxnet were used to identify and quantify the hair dyes. Salts were disregarded. A QSAR (Qualitative structure‐activity relationship) model called TOPS‐MODE, based on local lymph node assay (LLNA) data and physical chemical properties were used to predict the sensitization potential and make a cluster analysis.
Results:  Out of 315 hair dye substances 229 meet the inclusion criteria. Most of the hair dye substances 75% were predicted to be strong to moderate sensitizers. Less were predicted to be weak 22% and only a small part 3% were predicted to be extremely weak or non sensitizing. The 8 most used hair dye substances were predicted to be strong to moderate sensitizers. Ppd is the most used hair dye allergy marker but some azodyes were predicted to be more potent than para‐phenylenediamine (ppd).
Conclusions:  Most hair dye substances are predicted to be strong to moderate sensitizers, which explain why some people gets hair dye dermatitis. A patch test series with potent, much used azodyes, might prove useful in diagnosing ppd‐negative patients, with hair dye allergy. The cluster analysis grouped the substances which can be helpful choosing substances for clinical patch test.     

Clinical and experimental aspects of allergic contact dermatitis to para-phenylenediamine

The allergenicity of para-phenylenediamine (PPD) is related to oxidative processes on and in the skin. Patients with stronger reactions to PPD are significantly more likely to have a clear history of reacting to normal consumer hair dye. Those with stronger reactions are much less likely to be still dyeing their hair. Individuals allergic to PPD have a significant frequency of simultaneous sensitivity to chemically related clothing dyes. A 24-hour test application of hair dye, which has been proposed as a self-screen, does not reliably predict all individuals allergic to PPD. Duration studies have proven that exposures of 5 to 30 minutes, the period used for hair dyeing, are sufficient to elicit reactions. A significant rise in the frequency of PPD allergy was observed over 7 years among our patch test population. Active sensitization from standard PPD patch testing is not common. Immunologic findings relating to PPD can correctly predict that if hair dyes are commonly used there will be a significant prevalence of allergy to PPD among the normal adult population and that some clinical reactions will be severe. To protect the public from allergy to chemicals in consumer products, immunologic and epidemiologic data should both be used by regulatory authorities.     

Analysis of the Results from the Patch Test to Para-Phenylenediamine in the TRUE Test in Patients with a Hair Dye Contact Allergy

BackgroundPara-phenylenediamine (PPD) is the primary patch test screening agent for hair dye contact allergy (HDCA). However, no recent studies have been published that describe the results of reactions to patch tests using PPD and hair dyes in Korea.ObjectiveTo analyze the results of the patch tests to PPD using the thin-layer rapid use epicutaneous (TRUE) Test system in patients with HDCA and to investigate patients'' awareness that hair dyes contains allergens, which cause the development of HDCA.MethodsEighty-four patients with suspected HDCA (32 men and 52 women) underwent patch testing using the TRUE Test system and their own hair dyes. The patients'' demographic data, behavior associated with hair dyeing, and clinical manifestations of HDCA were examined retrospectively.ResultsPositive patch-test reactions to hair dyes occurred in 53.6% of patients who used hair dyes, and they were diagnosed with HDCA. Although there was a significant correlation between HDCA and PPD sensitization (p=0.001), only 40% of the patients with HDCA showed positive reactions to PPD. Of the 45 patients diagnosed with HDCA, only 7 (15.6%) were aware that their hair dyes contained allergens that caused HDCA.ConclusionThis study''s findings show that PPD is an effective HDCA marker. However, we propose that investigations on hair dye components other than PPD should be conducted to develop and validate additional predictive HDCA markers.     

Potent skin sensitizers in oxidative hair dye products on the Swedish market

Background: In recent years, the alarming increase in contact allergy to hair dyes has drawn much attention. It has been shown that many of the currently allowed hair dye substances are potent skin sensitizers.
Objectives: To study the prevalence of hair dye substances, categorized as potent skin sensitizer, in oxidative hair dye products on the Swedish market.
Materials and Methods: Ingredient labels of 122 oxidative hair dye products from 20 brands were examined. All ingredients were recorded, and the prevalence of hair dye substances categorized as potent skin sensitizers was assessed.
Results: According to ingredient labelling, 120 out of 122 examined oxidative hair dye products contained hair dye substances categorized as potent skin sensitizers. More than 80% of the products contained at least four such substances; 37 hair dye substances categorized as potent skin sensitizers were identified, and 10 of these were more prevalent than p-phenylenediamine.
Conclusions: Hair dye substances categorized as potent skin sensitizers are very common in oxidative hair dye products. A substantial number of potent skin sensitizers are more frequently used than p-phenylenediamine, while only a few are commercially available as patch test substances.     

Allergic contact dermatitis to para‐phenylenediamine

Exposure to hair dye is the most frequent route of sensitisation to para‐phenylenediamine (PPD), a common contact allergen. International studies have examined the profile of PPD, but Australian‐sourced information is lacking. Patients are often dissatisfied with advice to stop dyeing their hair. This study examines patients' characteristics, patch test results and outcomes of PPD allergy from a single Australian centre, through a retrospective analysis of patch test data from 2006 to 2013 at the Liverpool Hospital Dermatology Department. It reviews the science of hair dye allergy, examines alternative hair dyes and investigates strategies for hair dyeing. Of 584 patients, 11 were allergic to PPD. Our PPD allergy prevalence rate of 2% is at the lower end of international reported rates. About half these patients also react to para‐toluenediamine (PTD). Affected patients experience a significant lifestyle disturbance. In all, 78% tried alternative hair dyes after the patch test diagnosis and more than half continued to dye their hair. Alternative non‐PPD hair dyes are available but the marketplace can be confusing. Although some patients are able to tolerate alternative hair dyes, caution is needed as the risk of developing an allergy to other hair dye ingredients, especially PTD, is high.     

p-Phenylenediamine and other hair dye sensitizers in Spain

Background. Oxidative hair dyes are important skin sensitizers, causing contact allergy and dermatitis in hairdressers and consumers. Objectives. To study the prevalence of hair dye substances, categorized as potent skin sensitizers, in consumer‐available oxidative hair dye products on the market of a southern European country and to compare it with that in Sweden. Methods. Ingredient labels of 105 oxidative hair dye products from 19 brands were studied, and the prevalence and use pattern of hair dye substances, categorized as potent skin sensitizers, was assessed. Network diagrams were used to display results. Results. According to the labelling, all 105 products contained hair dye substances categorized as potent skin sensitizers. A total of 25 different hair dye substances categorized as potent skin sensitizers were identified. Eighty‐seven per cent of the products contained at least four such substances. Either p‐phenylenediamine, toluene‐2,5‐diamine or toluene‐2,5‐diamine sulfate was present in 103 products. Conclusions. Hair dye substances categorized as potent skin sensitizers were used in all studied hair dye products on the Spanish market. The prevalence of p‐phenylenediamine was higher in the present study than in a similar study in Sweden. More than 20 potent sensitizers were identified in each country. Not only p‐phenylenediamine should be used to diagnose allergy to hair dyes.     

Is there a risk of active sensitization to PPD by patch testing the general population?

Para-phenylenediamine (PPD), a constituent of permanent hair dyes, may cause contact allergy in exposed individuals. It has previously been questioned whether a patch testing with PPD in population-based epidemiological studies is entirely safe. The Glostrup allergy studies patch tested the same cohort twice. In 1990, 567 persons were patch-tested and only one person had a (+) positive reaction to PPD. In 1998, 540 persons were re-invited to a new patch test and 365 (participation rate 68%) were re-tested. There were no positive reactions to PPD. These studies indicate that patch testing with PPD in individuals with no previous positive reactions to PPD or with only one previous positive reaction does not cause active sensitization and can be performed with minimal risk.     

Severe allergic hair dye reactions in 8 children

Serious adverse skin reactions to permanent hair dyes and temporary black tattoos have been reported. As temporary tattoos have become fashionable among adolescents, the risk profile for p-phenylenediamine (PPD) sensitization of the population has changed simultaneously with an increasing use of hair dyes in this age group. This investigation reports PPD sensitization in children with regard to cause of sensitization, clinical presentation and consequences. Clinical history and patch test results for consecutive children below 16 years of age with suspected hair dye allergic reactions and positive patch tests to PPD were collected over 2 years in 2 Danish dermatology clinics. 8 children aged 12-15 years were collected, and they all reacted to several hair dye ingredients. 5 of the patients were hospitalized, 1 in the intensive care unit. 6 of the patients gave a history of prior reaction to temporary black tattoos. These children showed simultaneous positive patch reactions to N-isopropyl-N-phenyl-p-phenylenediamine and local anaesthetics, while such reaction patterns were not seen in children with hair dye reactions only. The clinical consequences of these reactions are unknown. A re-evaluation of the risk assessment/risk management for hair dyes is required.     

Addressing the conundrums of p‐phenylenediamine hair dye allergy by applying Friedmann's principles of contact sensitization

In the first conundrum, permanent hair dyeing involves the use of aromatic amines such as p‐phenylenediamine (PPD), whose oxidation is pivotal to the dyeing process, but also generates potent allergens. Despite prolonged efforts by industry to search for safer alternatives, hair dyeing is still reliant on this type of aromatic amine. In the second conundrum, patch testing with 1% PPD remains the most useful screen for hair dye contact allergy. However, there is a very small but real risk of actively sensitizing the patient. Lowering the PPD concentration below 1% significantly reduces test sensitivity and diagnostic utility. Here, we argue that by applying Friedmann's principles of contact sensitization each conundrum can be addressed from a new perspective. These principles indicate that, when the exposed area of skin is small (<1 cm²), induction of contact allergy is sharply reduced, whereas elicitation of allergy is unaffected. Careful reflection on this principle suggests that we can predict where hair dye sensitization is most likely to occur, indicates a strategy to reduce the chance of contact sensitization occurring in consumers as a result of hair dyeing, and how we might mitigate the risk of active sensitization resulting from diagnostic patch testing.     

p-Phenylenediamine sensitization is more prevalent in central and southern European patch test centres than in Scandinavian: results from a multicentre study

Background:  Positive patch test reactions to p -phenylenediamine (PPD) are common. PPD is used in oxidative hair dyes and is also present in dark henna temporary 'tattoos'. Cross-sensitization to other contact allergens may occur. Because subjects sensitized to PPD are at risk of clinically severe reactions upon hair dyeing, there is a need for 'current' prevalence data on PPD sensitization.
Objectives:  To compare PPD patch test results from dermatitis patients tested between 2003 and 2007 in 10 European patch test centres and to analyse the causes and determine relevance of positive PPD patch test reactions.
Materials:  Patch testing was performed using PPD (1% free base in petrolatum from Trolab (Almirall Hermal GmbH, Reinbeck, Germany) or Chemotechnique (Malmö, Sweden), equivalent to 0.090 mg/cm² in the TRUE^® test from MEKOS Laboratories AS). Statistical analysis was performed using the chi-squared test.
Results:  The weighted average prevalence was 4.6% among 21 515 patients. PPD sensitization occurred more often in centres located in Central and Southern Europe than in Scandinavian centres (odds ratio = 2.40; 95% confidence interval = 2.07–2.78). The overall proportion of positive patch test reactions to PPD that were registered as being of either current or 'past' relevance was high (weighted average 53.6% and 20.3%, respectively). Consumer hair dyeing was the most prominent cause of PPD sensitization (weighted average 41.8%). Furthermore, occupational hair dye exposure (10.6%) and cross-sensitization to textile dyes (12.6%) were frequently reported.
Conclusions:  PPD sensitization caused by exposure to hair dyes is frequent and remains a present problem for patients visiting contact dermatitis clinics, especially in patch test centres located in Central and Southern Europe.     

Allergy to 3-nitro-p-hydroxyethylaminophenol and 4-amino-3-nitrophenol in a hair dye

Contact allergy to 3‐nitro‐p‐hydroxyethylaminophenol in a hair dye is described for the first time. p‐Phenylenediamine is the most common screening allergen when allergic contact dermatitis is suspected, but sometimes the allergen is not sufficient for diagnosing allergic contact dermatitis to hair dyes. A 50‐year‐old woman developed a severe scalp dermatitis and developed vesicular hand eczema for the first time in her life. Patch testing was performed with the European Standard Series. The patch testing was supplemented with a local series of cosmetic allergens and the hairdresser's series. At the initial patch testing, there was a + reaction to nickel and a +? to PPD at days 3 and 7. Further, she reacted with a +? to her own hair collected at day 3 after the hair dying which elicited the dermatitis reaction. Open exposure to the product, which had initiated the dermatitis, was negative both before and after the allergic reaction to the product. None of the screening chemicals in the hairdresser's series gave a definite positive reaction. Only by patch testing with the individual hair dye product ingredients, the patient's reactions were explained. The patient gave a positive patch test to 4‐amino‐3‐nitrophenol and 3‐nitro‐p‐hydroxyethylaminophenol at days 3–4 reading.     

Is contact allergy to disperse dyes and related substances associated with textile dermatitis?

Background  Disperse dyes (DDs) are the most common sensitizers among textile dyes, but there is little knowledge of the clinical relevance of positive patch test reactions.
Objective  To investigate if patient-reported textile-related skin problems can be explained by contact allergy to eight different DDs and/or to chemically related substances, by occupation or by atopic constitution, and if the skin problems are influenced by age or sex.
Methods  A questionnaire on textile-related skin problems was answered by 858 of 982 consecutively patch tested patients in Malmö, Sweden and in Leuven, Belgium. The baseline series used for patch testing was supplemented with a textile dye mix (TDM) consisting of the eight DDs and with the separate dyes. The association between textile-related skin problems and contact allergy to the DDs and other risk factors was investigated using multiple logistic regression analysis.
Results  Eighteen per cent of the patients suspected textiles as a cause of their skin problems. Atopic constitution and female sex were risk factors for skin reactions. Synthetic materials were the most common textiles to give skin problems. A significant association was found between self-reported textile-related skin problems and contact allergy to para -phenylenediamine (PPD) [adjusted odds ratio (OR) 2·1; 95% confidence interval (CI) 1·0–4·3]. A similar, but more imprecise, adjusted OR was found for TDM (OR 1·9; 95% CI 0·57–5·6). Contact allergy to black rubber mix was too rare to be evaluated.
Conclusions  Contact allergy to PPD was a more prevalent indicator for skin reactions to textiles than the TDM used in this study.     

Elicitation response characteristics to permanent hair dye in paraphenylenediamine-allergic volunteers

BACKGROUND: Elicitation response characteristics to complete permanent hair dye products in paraphenylenediamine (PPD)-allergic volunteers have not previously been explored in detail. OBJECTIVES: To assess the elicitation response characteristics observed in PPD-allergic volunteers upon patch testing with complete hair dyes. METHODS: PPD-allergic volunteers were assigned to 1 of 3 groups depending upon whether they elicited + (group 1), ++ (group 2) or +++ (group 3) reactions following the standard diagnostic procedure. Each group was subsequently patch tested with 2 complete hair dyes (A and B) for 30 min, 1 hr and 24 hr. Patch sites were examined 1 day, 2 days and 3 days after patch removal. RESULTS: Exposure to either hair dye for 30 min or 1 hr was insufficient to yield positive patch test reactions in all of the PPD-allergic patients in groups 1 or 2. Application of either hair dye for 24 hr was sufficient to yield positive reactions in all of the individuals within groups 2 and 3. CONCLUSIONS: The frequency of positive patch test reactions observed following 24-hr exposure to complete permanent hair dyes is comparable to that observed following 48-hr exposure to 1% PPD/petrolatum in those individuals whose degree of sensitization is such that they typically present ++ or +++ reactions diagnostically.     

Contact sensitivity to hair dyes can be detected by the consumer open test

To avoid allergic reactions to hair dyes, an open test ("skin sensitivity test" or "dab test") is recommended 48 hours before the hair colouring procedure. We have investigated in a multicenter study, under standardized conditions and medical supervision, the validity of this test as a practical method to detect allergy to paraphenylenediamine (PPD)-containing hair dyes in 30 PPD patch test-positive and 30 PPD patch test-negative subjects. A defined volume of a marketed hair colouring product containing 1.8% PPD was applied in an open patch test to the retroauricular area. The grading method comprised the dermatologist's clinical evaluation and objective numerical scores. Allergic reactions were elicited in all PPD-positive subjects with a maximal intensity on Day 2; no allergic reactions were elicited in PPD-negative subjects. Increased severity of reactions by the dermatologist's clinical evaluation was correlated strongly with increasing numerical scores. The "skin sensitivity test" can be considered as an effective method to detect type IV hair dye allergy and as such, as an important factor in its secondary prevention.     

Is PPD a useful screening agent?

In this study, the usefulness was assessed of para-phenylenediamine (PPD) base as a marker for contact allergy to para-compounds and disperse dyes. 59 patients with a positive reaction to PPD were patch tested with a series of para compounds and disperse dyes. This dyes series was also tested in patients with a suspect medical history of contact allergy to hair, fabric or leather dyes. In total 610 patients were tested. As 24 patients became positive over the weekend, late readings, day 6 or 7, are important. These reactions were most probably relevant in 17/24 patients. Positive reactions to PPD correlated well with reactions to para compounds like p-aminoazobenzene and p-toluenediamine sulphate but not with disperse dyes. Reactions to Disperse Blue (106, 124) and Orange (1 and 3) were seen most frequently. PPD is a good screening agent for hair dye, but not for disperse dye, sensitivity.     

Hair dye-sensitized hairdressers: the cross-reaction pattern with new generation hair dyes

Hair dye allergies are a frequent cause of occupational skin disease among hairdressers. Conventional hair dyes contain 4-phenylenediamine (PPD), 2, 5-diaminotoluene sulfate (DTS) and 2-nitro-4-phenylenediamine (ONPPD) as allergens. In new generation hair dyes, FD & C and D & C dyes are used in the hair dye formulations. This study investigated the cross-reaction pattern of new generation hair dyes among hairdressers (n = 40) with a known allergy to PPD and/or DTS and/or ONPPD. In the 40 hairdressers no positive reactions were observed to the single FD & C and D & C dyes. In two hairdressers, doubtful reactions were observed to one or more of the hair dye formulations. The data from this study suggest that for hairdressers sensitized to PPD and/or DTS and/or ONPPD this new generation of hair dyes is a safe alternative for use in their salons.     

Comparative sensitizing potencies of fragrances,preservatives, and hair dyes

The local lymph node assay (LLNA) is used for assessing sensitizing potential in hazard identification and risk assessment for regulatory purposes. Sensitizing potency on the basis of the LLNA is categorized into extreme (EC3 value of ≤0.2%), strong (>0.2% to ≤2%), and moderate (>2%). To compare the sensitizing potencies of fragrance substances, preservatives, and hair dye substances, which are skin sensitizers that frequently come into contact with the skin of consumers and workers, LLNA results and EC3 values for 72 fragrance substances, 25 preservatives and 107 hair dye substances were obtained from two published compilations of LLNA data and opinions by the Scientific Committee on Consumer Safety and its predecessors. The median EC3 values of fragrances (n = 61), preservatives (n = 19) and hair dyes (n = 59) were 5.9%, 0.9%, and 1.3%, respectively. The majority of sensitizing preservatives and hair dyes are thus strong or extreme sensitizers (EC3 value of ≤2%), and fragrances are mostly moderate sensitizers. Although fragrances are typically moderate sensitizers, they are among the most frequent causes of contact allergy. This indicates that factors other than potency need to be addressed more rigorously in risk assessment and risk management.     

PCS.07Establishment of safe exposure limits for the elicitation of allergy – hair dyes

It is well known that a subtle balance exists between consumer desire to use hair dyes of various kinds and the sensitizing effects of particular dye ingredients. Of these, p‐phenylenediamine (PPD) is the mostly commonly reported contact allergen and which serves as a general model for hair dye allergy. PPD is reported as a strong sensitizer in all predictive tests; it is fairly commonly identified as a contact allergen in diagnostic patch testing, with relevance to hair dye ACD being about 50%. Whilst it may not be possible always to eliminate, or even greatly reduce, the extent to which sensitisation is induced, a final opportunity for limiting the degree of ACD occurs at the elicitation phase. Here, ensuring the extent of skin exposure is below the level at which all except the most strongly sensitized will react can provide clear consumer benefits. To achieve this aim, it is necessary to ensure a full appreciation of the variables impacting the elicitation of ACD exist. To this end, series of investigations of the elicitation of p‐phenylenediamine (PPD) sensitization has been conducted. In particular, the impact of duration and frequency of exposure on elicitation has been studied. Using groups of PPD sensitized volunteers, in patch tests and repeated open application tests, we have shown that exposures of only a few minutes are often without consequence in such individuals, except where the exposure is often repeated and/or the individual is highly allergic. With volunteers who were 1+ or 2+ positive to the diagnostic patch test, and where exposure to PPD was at 0.5%–1.0% in a short contact rinse‐off hair colouring product, no scalp reactions were experienced. It is our view that the establishment of safe exposure limits to contact allergens should be based wherever possible on a detailed assessment of the risk to sensitized humans.     

Patch testing with hydroxyethyl-p-phenylenediamine sulfate - cross-reactivity with p-phenylenediamine

Background. Adverse reactions to permanent hair dyes are frequent, and primarily result from sensitization to p‐phenylenediamine (PPD). Objectives. To investigate the degree of cross‐reactivity to a chemically similar dye, hydroxyethyl‐p‐phenylenediamine sulfate (HPPS), and whether this might be a dyeing alternative for patients who are sensitive to PPD. Method. HPPS was patch tested in two concentrations in a total of 216 patients suspected of having contact dermatitis caused by hair dyes and/or hair cosmetics. A regular use test with a hair dye containing HPPS was suggested to every patient who had had an adverse reaction to a PPD hair dye in the past. Results. Forty of 216 (19.9%) patients reacted to 1% PPD, whereas only 2/216 (0.9%) showed a positive reaction to 1% HPPS. Reactivity to 2% HPPS was only slightly higher (5/216, 2.3%). On the basis of the 43 PPD‐positive patients, the reactivity to 2% HPPS amounted to 12%; the corresponding figure for toluene‐2,5‐diamine was 15% (5/33). In a use test on two PPD‐positive patients with a hair dye containing HPPS, no adverse reaction was seen, even after several years of regular dyeing. Conclusions. HPPS may be an alternative hair dye for individuals not tolerating PPD‐containing dyes. However, cross‐reactivity with PPD and other aromatic amines may occur. HPPS is also a known sensitizer, and the risk of de novo sensitization can only be assessed by a controlled study on a large panel and under regular use conditions.     

Para‐phenylenediamine‐specific lymphocyte activation test: a sensitive in vitro assay to detect para‐phenylenediamine sensitization in patients with severe allergic reactions

Please cite this paper as: Para‐phenylenediamine‐specific lymphocyte activation test: a sensitive in vitro assay to detect para‐phenylenediamine sensitization in patients with severe allergic reactions. Experimental Dermatology 2010; 19: 435–441. Abstract: Patients sensitized to para‐phenylenediamine (PPD) by semi‐permanent tattoos increasingly develop threatening allergic reactions in response to black hair dye. The gold standard to diagnose allergic contact dermatitis is to perform epicutaneous patch tests, however, iatrogenic sensitizations and severe patch test reactions to PPD have been described, the latter especially in patients with severe allergic reactions. We examined nine patients with severe allergic reactions in response to permanent hair dyes. Patch tests using the standard concentration of 1% or 0.5% PPD resulted in severe and sometimes even bullous reactions in all patients responsive to PPD. Titration revealed that at 1% of the standard concentration (0.01% PPD), patch test sensitivity decreased and only 50% of patients responded. Consequently, we established an in vitro assay to diagnose PPD allergy. Freshly isolated peripheral blood mononuclear cells (PBMC) were cultured with titrated concentrations of PPD with or without IL‐2 supplementation, and cell proliferation was determined by [3H]‐thymidine incorporation. Lymphocyte activation test (LAT ) detected PBMC cell proliferation specific to PPD, with at least 3.5‐fold increase in [3H]‐thymidine uptake in all PPD allergic patients. Most importantly, PPD – LAT without IL‐2 supplementation remained negative in three out of eight PPD allergic patients. Thus, PPD‐LAT with IL‐2 supplementation demonstrated a sensitivity of 100%, remained unresponsive in controls not sensitized to PPD, and in one patient sensitive to other p‐amino compounds. These data demonstrate that LAT with PPD can be used to detect PPD sensitization as a possible alternative to patch testing at least in patients with severe allergic reactions to PPD.