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Background: In Sweden, cobalt chloride 0.5% has been included in the baseline series since the mid-1980s. A recent study from Stockholm showed that cobalt chloride 1% petrolatum (pet.) was more suitable than 0.5%. Cobalt chloride at 1.0% has been patch tested for decades in many European countries and around the world., Objectives: To study the suitability of patch testing to cobalt 1.0% vs 0.5% and to analyze the co-occurrence of allergy to cobalt, chromium, and nickel., Results: Contact allergy to cobalt was shown in 90 patients (6.6%). Eighty (5.9%) patients tested positive to cobalt 1.0%. Thirty-seven of the 90 patients (41.1%) with cobalt allergy were missed by cobalt 0.5% and 10 (0.7%) were missed by cobalt 1.0% (P < .001). No case of patch test sensitization was reported. Allergy to chromium was seen in 2.6% and allergy to nickel in 13.3%. Solitary allergy to cobalt without nickel allergy was shown in 61.1% of cobalt-positive individuals. Female patients had larger proportions of positive reactions to cobalt (P = .036) and nickel (P < .001) than males., Conclusion: The results speak in favor of replacing cobalt chloride 0.5% with cobalt chloride 1.0% pet. in the Swedish baseline series, which will be done 2021., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Knowledge about the required duration of exposure for elicitation of allergic nickel dermatitis in nickel-allergic individuals is limited. However, it often has been proposed that short skin contact is safe., Objectives: To examine whether repeated skin contact with nickel over short time periods (3 × 10 min) can elicit allergic nickel dermatitis., Methods: Sixteen nickel-allergic adults and 10 controls were exposed to, respectively, nickel- and aluminium-containing discs on each volar forearm and on each earlobe for 3 × 10 min. One arm was pretreated for 24 h with sodium lauryl sulfate (SLS) 0·5% under occlusion before exposure. One aluminium and one nickel exposure site were clinically evaluated, and blood flow was measured with laser Doppler flowmetry at day 2 and day 4., Results: Ten of 16 (63%) nickel-allergic participants developed allergic nickel dermatitis on SLS-pretreated arm skin and three of 16 (19%) developed it on normal skin on the earlobe. On the SLS-pretreated arms of nickel-allergic participants, blood flow increased significantly more on the nickel-exposed skin than on the aluminium-exposed skin on days 2 and 4. No change in clinical reactivity or blood flow was found on normal forearm skin in nickel-allergic participants or on any skin in controls., Conclusions: This experimental study showed that relatively short repeated skin contact (3 × 10 min) with metallic nickel elicits allergic nickel dermatitis in irritated skin and at sites with previous dermatitis. The results support the restrictions in current nickel regulation., (© 2018 British Association of Dermatologists.)

Background: Chromium (Cr) is a common skin sensitizer. The use of Cr(VI) in leather is restricted in the EU, but that of Cr(III) is not., Objectives: To assess whether prolonged exposure to Cr-tanned leather with mainly Cr(III) release may elicit allergic contact dermatitis in Cr-allergic individuals., Method: Ten Cr-allergic subjects and 22 controls were patch tested with serial dilutions of Cr(III) and Cr(VI), and with leather samples. They then conducted a use test with a Cr-tanned and a Cr-free leather bracelet over a period of 3 weeks, for 12 h per day. Cr deposited on the skin from the bracelets was measured in the controls, and the diphenylcarbazide test for Cr(VI) and extraction tests for Cr(III) and Cr(VI) were conducted for the different leathers., Results: Four of 10 Cr-allergic subjects developed positive reactions to the Cr-tanned bracelet within 7-21 days, whereas only 1 of 10 had a positive patch test reaction to this leather. Cr released from the Cr-tanned leather was most probably entirely Cr(III), with a quantifiable amount being deposited on the skin., Conclusions: This study strongly suggests that prolonged and repeated exposure to Cr-tanned leather with mainly Cr(III) release is capable of eliciting allergic contact dermatitis in Cr-allergic individuals., (© 2018 The Authors. Contact Dermatitis published by John Wiley & Sons Ltd.)

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., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Contact allergy prevalence rates change over time as a result of variations in allergen exposure. Data from patch test clinics are often used as markers for allergy trends., Objectives: The aim of the present retrospective study was to describe trends in rates of sensitization to allergens in the Swedish baseline series., Patients/materials/methods: Prevalence rates are described by comparing consecutive patch test data from 1992, 2000 and 2009 in Swedish patch test clinics. In total, 3680 patients were included in 1992, 3825 in 2000, and 3112 in 2009., Results: Among test substances with a sensitization rate above 2% in 2009, significant decreases were noted for nickel sulfate, cobalt chloride, colophonium, and methylchloroisothiazolinone (MCI)/methylisothiazolinone (MI), and a significant increase for p-phenylenediamine, as compared with 1992. Potassium dichromate reactions had increased among younger women, whereas reactions to nickel and cobalt had decreased in this group. Sensitization to chromium, cobalt and fragrance mix I had decreased among older men, and sensitization to nickel had decreased among younger men., Conclusions: It is probable that these changes in 1992-2009 reflect both changes in regulations for nickel, lower levels of chromium in cement and of MCI/MI in cosmetics, and increasing use of hair dyes., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The use of cosmetics exposes consumers to mixtures of ingredients, many of which are potential allergens. Ultraviolet (UV) filters are used not just in sunscreens, but also in other products. Many UV filters are known contact allergens and photoallergens., Objective: To examine the pattern of co-exposure to UV filters in cosmetics., Methods: A survey of products marketed in Germany, conducted in 2006-2009 by the Chemical and Veterinary Investigation Office in Karlsruhe, identified 4447 products (of all 5667 cosmetic products examined) (i) that were categorizable according to Annex I to the Cosmetics Directive, and (ii) with information on the presence of UV filters or zinc oxide. The occurrence and co-occurrence of UV filters were analysed and presented in tabular and graphical format., Results: UV filters or zinc oxide were present in 22.5% of all 4447 products, ranging from almost 100% in sunscreens to a few per cent in, for example, some hair products; they were absent in two product categories. Frequently, several different UV filters were included in one product, for example in sunscreens (median 4) and in perfumes (median 3). The overall most frequent UV filters were butyl methoxydibenzoylmethane and titanium dioxide, combined mostly with octocrylene in sunscreens and with ethylhexyl methoxycinnamate in creams., Conclusions: The frequent co-occurrence of UV filters in cosmetic products possibly facilitates sensitization, and may explain why patients often react to chemically unrelated UV filters., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Hair dye products constitute an important source of allergen exposure, and contribute importantly to allergic contact dermatitis in consumers and hairdressers., Objectives: To evaluate the presence of potent contact sensitizers in oxidative hair dye products intended for home use on the US market., Methods: Ingredient labels of 107 hair dyes from 10 major brands were examined and used to assess the prevalence of hair dye substances known to be potent contact sensitizers., Results: One hundred and six of 107 (99%) products contained at least one potent sensitizer, and the average product contained six (range 0-11). p-Phenylenediamine (PPD) was found in 83 products (78%), but resorcinol (89%), m-aminophenol (75%), p-aminophenol (60%) and toluene-2,5-diamine (21%) were also frequently identified., Conclusions: Potent contact sensitizers were almost universally included in the hair dyes investigated in the United States. Although PPD is a common allergen, resorcinol and m-aminophenol were found more frequently. In total, 30 potent sensitizers were found. Clinicians should consider other allergens in addition to PPD when evaluating patients with suspected hair dye allergy., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The use of cosmetics exposes consumers to mixtures of ingredients, many of which are potential allergens. Many cosmetics contain one or several preservatives, some being important contact allergens., Objective: To examine the pattern of co-exposure to preservatives in different categories of cosmetics., Methods: A survey of products marketed in Germany, conducted in 2006-2009 by the Chemical and Veterinary Investigation Office in Karlsruhe, identified 4680 products categorizable according to Annex I to the Cosmetics Directive with information on the presence of preservatives. The occurrence and co-occurrence of preservatives were analysed and presented in tabular and graphical format., Results: Thirty per cent of all products were not declared to contain any preservatives; for 8%, no INCI labelling was present. For the remainder, the number of preservatives used tended to be higher in leave-on than in rinse-off products. Most often, combinations of (up to all five) parabens were used (39% of all products). Combinations with phenoxyethanol were also frequent. Formaldehyde releasers were found in 8% of products overall., Conclusions: The pattern of co-exposure to preservatives in important categories of cosmetic products illustrates the 'cocktail' of allergens that may facilitate sensitization, although, conversely, the combination of preservatives allows individual use levels to be kept lower, thereby possibly reducing sensitization risk., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Experimental and clinical studies have shown that fragrance substances can act as prehaptens or prohaptens. They form allergens that are more potent than the parent substance by activation outside or in the skin via abiotic (chemical and physical factors) and/or biotic activation, thus, increasing the risk of sensitization. In the present review a series of fragrance substances with well documented abiotic and/or biotic activation are given as indicative and illustrative examples of the general problem. Commonly used fragrance substances, also found in essential oils, autoxidize on contact with air, forming potent sensitizers that can be an important source for contact allergy to fragrances and fragranced products. Some of them can act as prohaptens and be activated in the skin as well. The experimental findings are confirmed in large clinical studies. When substances with structural alerts for acting as prohaptens and/or prehaptens are identified, the possibility of generating new potent allergens should be considered. Predictive testing should include activation steps. Further experimental and clinical research regarding activation of fragrance substances is needed to increase consumer safety., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The use of cosmetics exposes consumers to mixtures of ingredients, many of which are contact allergens. Fragrances in particular are mostly used in combination; combinations of fragrances have been shown to enhance sensitization and elicitation., Objective: To examine the pattern of co-exposure to fragrances in different categories of cosmetics, addressing the 26 fragrances that need to be identified on the label according to the Cosmetics Directive 76/768/EEC amended by 2003/15/EC., Methods: A survey of products marketed in Germany, conducted in 2006-2009 by the Chemical and Veterinary Investigation Office in Karlsruhe, identified 4991 products with information on the presence of fragrances. The products were categorized according to Annex I to the Cosmetics Directive. The occurrence and co-occurrence of fragrances were analysed in tabular form and as social network diagrams., Results: The median number of fragrances in products varied greatly between categories, ranging up to nine in perfumes. Limonene and linalool were the most commonly identified fragrances, often used together, but also with other fragrances. Thirty per cent of all products were not declared to contain any fragrances., Conclusions: For the first time, the pattern of co-exposure to fragrance ingredients in important categories of cosmetic products has been described. The observations illustrate and quantify the 'cocktail' of fragrance allergens that may facilitate sensitization., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: A spot test was recently developed for easy and rapid testing to detect whether cobalt is available on surfaces in contact with skin., Objectives: To explore the potential use of the cobalt spot test as a tool for skin dose assessment, and to verify the sensitivity under laboratory conditions., Methods: A cobalt dilution series (cobalt standards mixed with cobalt spot test reagent solution) was prepared to determine the threshold for colour change. Defined doses of cobalt were applied to the fingers of 5 volunteers. Acid wipe sampling was used to measure the recovery of applied cobalt skin doses on one hand, and cobalt-exposed areas on the other hand were spot tested., Results: A weak colour gradient was visible from approximately 1 to 1.5 µg cobalt/ml in the dilution series. For a skin dose of 0.125 µg cobalt/cm(2) , 80% of the cobalt dose was collected by acid wipe sampling. Spot tests gave positive results in all cases (n = 5)., Conclusions: The cobalt spot test can be used to show cobalt on the skin. More experience is needed to understand and describe the most suitable test conditions., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Contact allergy to fragrances is still relatively common, affecting ∼ 16% of patients patch tested for suspected allergic contact dermatitis, considering all current screening allergens. The objective of the review is to systematically retrieve, evaluate and classify evidence on contact allergy to fragrances, in order to arrive at recommendations for targeting of primary and secondary prevention. Besides published evidence on contact allergy in humans, animal data (local lymph node assay), annual use volumes and structure-activity relationships (SARs) were considered for an algorithmic categorization of substances as contact allergens. A total of 54 individual chemicals and 28 natural extracts (essential oils) can be categorized as established contact allergens in humans, including all 26 substances previously identified as contact allergens (SCCNFP/0017/98). Twelve of the 54 individual chemicals are considered to be of special concern, owing to the high absolute number of reported cases of contact allergy (>100). Additionally, 18 single substances and one natural mixture are categorized as established contact allergens in animals. SARs, combined with limited human evidence, contributed to the categorization of a further 26 substances as likely contact allergens. In conclusion, the presence of 127 single fragrance substances and natural mixtures should, owing to their skin sensitizing properties, be disclosed, for example on the label. As an additional preventive measure, the maximum use concentration of 11 substances of special concern should be limited to 100 ppm. The substance hydroxyisohexyl 3-cyclohexene carboxaldehyde and the two ingredients chloroatranol and atranol in the natural extracts Evernia prunastri and Evernia furfuracea should not be present in cosmetic products., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Sesquiterpene lactone mix detects contact allergy to these compounds present in the plant family Asteraceae. This marker is present in many baseline series. An additional marker is Compositae mix, which is not present in many baseline series. To investigate whether this allergen should be inserted into the Swedish baseline series, six dermatology centres representing the Swedish Contact Dermatitis Research Group included Compositae mix into their baseline series for 1.5 years. Of 2818 patients tested, 31 (1.1%) reacted to Compositae mix and 26 (0.9%) to Sesquiterpene lactone mix. Active sensitization to Compositae mix was noted in two cases. Only 0.4% of Asteraceae contact allergy cases would have been missed if Compositae mix had not been tested, a frequency too low to merit its inclusion in the baseline series. Due to obvious geographical differences in frequency in frequency of simultaneous allergic reactions to Compositae mix and Sesquiterpene lactone mix, the question as to whether specific baseline series (including Compositae mix or not as a "tail" substance) should be used in the different centres must be addressed. Another option could be to remove Sesquiterpene lactone mix from the baseline series and substitute it with Compositae mix.

In July 2001, the EU Nickel Directive came into full force to protect European citizens against nickel allergy and dermatitis. Prior to this intervention, Northern European governments had already begun to regulate consumer nickel exposure. According to part 2 of the EU Nickel Directive and the Danish nickel regulation, consumer items intended to be in direct and prolonged contact with the skin were not allowed to release more than 0.5 µg nickel/cm2/week. It was considered unlikely that nickel allergy would disappear altogether as a proportion of individuals reacted below the level defined by the EU Nickel Directive. Despite this, the EU Nickel Directive part 2 was expected to work as an operational limit that would sufficiently protect European consumers against nickel allergy and dermatitis. This review presents the accumulation of epidemiological studies that evaluated the possible effect of this major public health intervention. Also, it evaluates recent exposure assessment studies that have been performed using the dimethyl glyoxime test. It is concluded that the EU Nickel Directive has started to change the epidemiology of nickel allergy in Europe but it should be revisited to better protect consumers and workers since nickel allergy and dermatitis remain very frequent., (© 2011 John Wiley & Sons A/S.)

Background: Cobalt, nickel, and chromium are important skin sensitizers. However, knowledge about cobalt exposure and causes of cobalt sensitization is limited., Objectives: To study release of cobalt, nickel, and chromium from some cobalt-containing hard metal alloys and to test reactivity to the materials in cobalt-sensitized patients., Methods: Discs suitable for patch testing were made of some hard metal alloys. Cobalt, nickel, and chromium release from the materials was determined by immersion in artificial sweat (2 min, 1 hr, 1 day, and 1 week). Patch test reactivity to the discs and to serial dilutions of cobalt and nickel was assessed in previously patch-tested dermatitis patients (19 cobalt positive and 18 cobalt-negative controls)., Results: All discs released cobalt, nickel, and chromium. Some discs released large amounts of cobalt (highest concentration: 290 microg/cm(2)/week). Seven discs elicited three or more positive test reactions., Conclusions: The concentration of released cobalt was high enough to elicit allergic contact dermatitis in cobalt-sensitized patients. As the materials in the discs are used in wear parts of hard metal tools, individuals with contact allergy to cobalt may develop hand eczema when handling such materials.

There is a great need to accurately assess skin exposure to contact allergens. We have developed a technique for assessment of skin exposure to nickel, chromium and cobalt using acid wipe sampling by cellulose wipes with 1% nitric acid. Chemical analysis was performed by inductively coupled plasma mass spectrometry (ICP-MS). The recovery of nickel, chromium and cobalt from arms and palms was 93%. The analytical result is expressed in terms of mass per unit area (microg/cm(2)). The developed acid wipe sampling technique is suitable for determination of nickel, chromium and cobalt deposited on the skin. The technique may be used in workplace studies, in studies of individuals in the general population, in dermatitis patients, in identification of risk groups, as well as in developing preventive strategies and in follow-up after intervention.

The Nickel Directive aims at the prevention of sensitization and elicitation of nickel dermatitis. It limits nickel release from, and nickel content in, certain items. The Directive came into full force by July 2001. The aim of this study was to investigate the frequency on the market of items that release nickel and of nickel content in piercing posts, 2 years after coming into force of the Directive. Of special interest was to study changes compared to the situation in 1999, when a baseline study had been carried out. Nickel release from 786 items covered by the Nickel Directive was tested with the dimethylglyoxime (DMG) test, and nickel content in 18 piercing posts was analysed. Nickel release was shown from 8% of items intended for direct and prolonged contact with the skin, and 17% of the piercing posts contained too much nickel, a decrease compared to 1999. There has been significant adaptation to the requirements of the Nickel Directive. The DMG test is useful for screening for nickel release and for monitoring the market. Provided there is further adaptation to the requirements, the risk of sensitization and elicitation of nickel dermatitis will be significantly reduced.

Nickel allergy is the most frequent contact allergy and is also one of the major background factors for hand eczema. The clinical significance of nickel release from coins was discussed when the composition of euro coins was decided. Current European coinage is dominated by cupro-nickel coins (Cu 75; Ni 25); other nickel-containing and non-nickel alloys are also used. Nickel release from used coinage from the UK, Sweden and France was determined. It was shown that nickel ions are readily available on the surface of used coins. After 2 min in artificial sweat, approximately 2 microg of nickel per coin was extracted from cupro-nickel coins. Less nickel was extracted from non-nickel coins. Nickel on the surface was mainly present as chloride. After 1 week in artificial sweat approximately 30 microg/cm2 was released from cupro-nickel coins: less nickel was released from coins made of other nickel alloys. Theoretically, several microg of nickel salts may be transferred daily onto hands by intense handling of high-nickel-releasing coins.

A multi-dose-response induction protocol for the guinea pig maximization test (GPMT), including a statistical computer program, has earlier been developed to improve the power of predictive tests for identification of contact allergens. This dose-response protocol, with 2 modifications (i.e., increased number of animals in each group and increased number of challenge concentrations) was evaluated in the GPMT, the cumulative contact enhancement test (CCET) and the Freund's complete adjuvant test (FCAT), using potassium dichromate and hydroxycitronellal as model contact allergens. Application of the dose-response protocol on the CCET and the FCAT resulted in either monotone or non-monotone curves with significant dose-response. However, application of the dose-response protocol on the GPMT gave curves with no significant dose-response. The protocol makes it possible to obtain an EC50 value, thus improving the possibility of ranking contact allergens, which is of substantial use for risk assessments. The dose-response protocol could benefit from a few adjustments: a wider span in the induction doses; change to simultaneous increase in intradermal and topical induction doses to obtain a proper dose-response for the GPMT; the addition of further challenge concentrations. In addition the computer program should allow calculation of threshold concentration for sensitization and EC50 value for a non-monotone curve.

Cross-reactivity is usually studied with patch test techniques, but the relevance of a single 1-2 day exposure under occlusion can be questioned. To study relevance, animals were induced with PdCl2 or NiSO4 according to the guinea pig maximization test method and then treated for 10 days according to the repeated open application test (ROAT) method. Animals induced with PdCl2 reacted in the ROATs to PdCl2 (100%) but rarely to NiSO4. Animals induced with NiSO4 reacted in ROATs to the same degree with NiSO4 and PdCl2 (23-30%). The concordance between pre-ROAT patch test results and ROAT outcome was high for PdCl2 (100%) and low (10-40%) for NiSO4. Patch testing seems to overestimate the risk of skin reactions when guinea pigs sensitive to PdCl2 are treated topically with NiSO4. The finding from patch test studies that animals induced with NiSO4 react only to NiSO4 but not to PdCl2 was not confirmed. Repeated open applications more adequately mimic exposure conditions than does patch testing.

The aim was to mimic the repeated open application test (ROAT) procedure, well established in humans, in an animal model. Guinea pigs were induced with cobalt chloride (CoCl2). They were then challenged by repeated open application (4 sites/animal) of various concentrations of the allergen in 10% DMSO 1 x a day for 7 days, to study dose dependency, morphology of test reactions and time course. The reactivity at the test sites to repeated open application was dose- and time-dependent. There was good agreement between the results of the treatments with CoCl2 and the post-treatment patch test results. Among 26 of the 29 animals, such agreement was found when 10% DMSO was used as vehicle. However, some reactivity was also observed in pretests at sites exposed to petrolatum. We suspect that this may be due to contamination and/or irritancy of the vehicle.

In order to investigate whether abietic acid itself is the allergenic component of colophony, 2 commercial samples were extensively purified and tested in guinea pigs and in colophony-sensitive patients. In the modified FCAT method, sensitization was obtained with Portuguese colophony and when challenged with purified abietic acid, the animals showed no reaction. In the GMPT method, the animals were exposed to purified abietic acid. Challenging with 2 different samples of it gave no significant reaction. When patch tested, patients sensitive to colophony showed no reactions to abietic acid which had been purified immediately before the test. It is concluded that abietic acid itself is not a contact allergen.