Allergic contact dermatitis in children ‐‐ strategies of prevention and risk management

ARTICLE

Auteur(s) : Birgitta KÜTTING*⁺, Randolf BREHLER*, Heiko TRAUPE*

* Department of Dermatology and Venerology University of Mnster, Von-Esmarchstr. 58, 48149 Mnster, Germany 
⁺ Institute and outpatient clinic for occupational, social and environmental medicine, 
University of Erlangen- Nrnberg, Schillerstr. 25 + 29, D- 91054 Erlangen, Germany

Article accepted on 12/01/2004

Until recently, allergic contact dermatitis was considered uncommon in children. This opinion was based on beliefs rather than on facts. It was suggested that children are less exposed to contact allergens or that the immune system in children may be less susceptible to contact allergens [1]. However, during the last 10-20 years, several reports have shown that allergic contact dermatitis is a significant clinical problem in childhood. Published series have reported positive patch test results varying from 14.5% to 70%, clinically relevant results in 20% to 92% of cases [2]. Different studies have found various percentages of reactivity in children depending on selection criteria such as age limits, sex, and type of population tested (normal children, children with a history of contact allergy or atopic children) [3]. Most studies consider only the prevalence of positive patch test reactions without evaluating the clinical relevance, e.g. the prevalence of allergic contact dermatitis [1]. Therefore, the exact incidence and prevalence of allergic contact dermatitis in children is still largely unknown. Hitherto, the general impression is that allergic contact dermatitis is rare in young children compared to older children, and that allergic contact dermatitis becomes more frequent with increasing age, especially after the 1^st decade, as exposure to environmental allergens increases.

Distribution of eczematous lesions as a diagnostic clue

Diagnosis is based upon the distribution of eczematous lesions rather than the appearance of individual lesions. Any dermatitis with an unusual shape, such as linear, or that is localized to a skin area, such as the face or the dorsum of the feet, should alert the physician to the possibility of allergic contact dermatitis.
The distribution of the reaction may also provide clues to the source or identity of the allergen.
Classic examples include involvement of the earlobes, neck, or subumbilical skin with nickel allergy (ear rings, jewellery, metal snaps on pants) [4] and in cases of foot eruption shoe dermatitis must be considered [5, 6]. The most common allergens responsible for footwear dermatitis are rubber chemicals, adhesives and leather constituents. However, rashes affecting the weight bearing area of the soles, which one might expect to indicate allergic contact dermatitis to shoe insoles, shoe linings or glues (due to rubber chemicals), occurred in contact allergy to medicaments, too. Dorsal foot dermatitis is suggestive of contact allergy to potassium dichromate, but only one out of 8 children reacted to this allergen [5].
Recently, a particular type of diaper dermatitis due to rubber chemicals [7] (mercaptobenzothiazole) or glues (p-tertiarybutylphenol-formaldehyde resin) [8] was reported. Distribution of eczema, predominantly located on the outer buttocks and hips in toddlers, is quite characteristic of this particular type of diaper dermatitis. Skin lesions recalling a cowboy’s gunbelt holster led to the term “Lucky Luke” contact dermatitis, used in the literature. This dermatitis is caused by the use of diapers with a new anti-leaking system. This system maintains elastic bands tight on the thighs. Recently, the same clinical pattern was related to a third allergen, namely cyclohexyl thiophathalimide, used as a vulcanization retarder in rubber [9].
Another diagnosis at first glance, is the so-called baboon-syndrome [10]. Here, an acute light-red symmetrical eruption involving the major flexural areas of the extremities, the buttocks and the anogenital region develops within hours or days after systemic exposure to an allergen. Andersen et al. [11] introduced the term “baboon syndrome” (the term “baboon” refers to the red gluteal region of the baboon) to illustrate the characteristic distribution of this particular type of systemic contact dermatitis. Even though the baboon syndrome is supposed to be uncommon among children, nevertheless, it has been observed in children, mainly after exposure to mercury. Goosens et al. [12] reported a typical pattern of baboon-syndrome in an 18-month-old child after oral treatment with erythromycin syrup for a sore throat, Audicana et al. [13] observed the same clinical pattern in a five-year-old girl 24 h after ingestion of a homeopathic tablet containing mercury. Alegre [14] published the case of a seven-year-old boy suffering from baboon syndrome after exposure to mercury, Bartolome [15] a similar case in a 15-year-old boy. Mercury, ampicillin, amoxycillin, nickel, erythromycin, heparin and food additives are the most frequently incriminated allergens [10-12, 16].
Recently Sharma et al. [17] reported a case series of 38 children with suspected allergic contact dermatitis to nickel who presented with prominent subumbilical and periumbilical papules and a generalized, lichenoid papular dermatitis resembling an id reaction. Patch tests were performed in 9 patients and all 9 patients had positive patch test results for nickel.
An important aspect not to be overlooked is that general worsening of atopic dermatitis while treating the skin with ointments might be caused by sensitization to ingredients of the products used as well (as described in case 3).

Risk factors and hidden risk factors

Jewellery

Body piercing, and particularly ear piercing is becoming increasingly common in young children. The potential for serious infection such as Hepatitis B, C and HIV or the risk of inducing nickel allergy is not appreciated by the parents of these children [18]. Jewellery, especially ear-piercing is known to be the most important predisposing factor for nickel allergy. The prevalence of nickel allergy among those children with pierced ears was 13% compared to 1% among those without pierced ears [19]. The risk of incurring nickel allergy is higher when earlobes are pierced before the age of 20 (p < 0.05) [20] and is increased with the number of piercings [21].

Temporary tattoos

Recently, a worldwide vogue of decorative skin painting started. Transient artists have begun to use black henna mixtures, containing indigo, henna and chemical colouring agents such as p-phenylendiamine (PPD) and/or diaminotoluens to temporarily paint the skin. Henna normally gives a temporary auburn to red colour; addition of p-phenylendiamine gives henna a darker shade of a brown to black colour. Lesions confined strictly to the painted area indicate the presence of a skin sensitizer in such preparations. Patch testing revealed severe hypersensitivity to PPD [22-26]. The use of p-phenylendiamine and other diaminobenzenes is only allowed for hair dyes in the European Union, the same directive forbids the use of p-phenylendiamine and its derivatives for dying lashes, eyebrows or skin [27]. However, these regulations are often not followed by studios or transient artists performing tattoos.

Natural remedies

The use of herbal preparations is increasing dramatically. Many of these herbal therapies have been used for centuries and show good anecdotal results, whereas randomized trials are mostly missing [28]. In response to this strong demand for natural remedies and aromatic substances the commercial production of tea tree oil, extracted from Melaleuca alternifolia Cheel, has considerably increased over the past 15 years. The number of case reports that describe allergic contact dermatitis to this essential oil is also on the rise [29-34]. Even cases of erythema multiforme-like reactions secondary to allergic contact dermatitis from tea tree oil have been reported [35, 36]. Tea tree oil is currently enjoying popularity as a “cure-all” for a variety of skin conditions, from infections (viral, bacterial and fungal) to dermatological disorders such as acne and psoriasis [28, 37-41]. Tea tree oil has about 100 components, predominating are monoterpene as terpinen-4-ol (28-58%), α- and γ-terpinene (5-28%), 1,8-Cineol (= Eukalyptol, 11-18%), terpinolen (2-6%), p-Cymene (0.5-13%) and d-Limonene (0.5-3%) (28). The allergic potential of low concentrations of tea tree oil is presumed to be low on healthy skin. But photoaged tea tree oil must be considered to be a strong sensitizer [29]. The degradation products of monoterpenes in the tea tree oil actually appear to be the sensitizing agents [42]. Children and their parents are usually not aware that tea tree oil has to be kept in the dark and that “older“ tea tree oil becomes a strong sensitizer due to oxidation.
Calendula officionalis, more commonly known as marigold, has been used topically since ancient times and is currently approved by the German Commission E as an antiseptic and to heal wounds [43]. It is widely accepted as a topical treatment for diaper dermatitis [44], but in spite of widespread use only limited data are available on its allergenic potential. In Austria 443 consecutive patients were tested with compositae mix, sesquiterpene lactone mix, arnica, marigold and propolis. 9 patients (approximately 2.03%) reacted to marigold. The Compositae mix was positive in 18 cases. Among them there were 4 out of 9 who reacted to marigold. Therefore, sensitization to marigold cannot be assessed by testing with the compositae or sesquiterpene mix alone [45]. Apart from specific hypersensitivity, Marigold belonging to the compositae family, is also known to cause irritant as well as phototoxic reactions [46].
With the growing interest in alternative and complementary therapies, practitioners need more information on phytotherapeutics. Because patients or their parents often neglect to mention that they have used natural remedies, it is important that physicians are aware of the potential adverse effects of these products.

Vaccination

Recently the mercury-based vaccine preservative thiomersal has come under scrutiny because of its presence in certain vaccines that provide the foundation of childhood immunisation schedules. The potential toxicity in children seems to be of much more concern than the hidden sensitizing properties. Therefore, as a precautionary measure efforts are under way to remove and replace thiomersal from vaccines. Over the past decade new vaccines have been added to the recommended childhood schedule, and the relation of bodyweight and surface of infants had led to concern that the cumulative exposure of mercury from infant vaccines may exceed certain guidelines for the human consumption of mercury [47].
The renewed attention to a reduction of children’s exposure to mercury from all sources will decrease the clinical relevance of hypersensitivity to thiomersal. In the near future hypertensitivity to thiomersal will hopefully be a problem of the past. At present all relevant vaccines are already available without thiomersal. Based on the potential toxicity of thiomersal, in The Netherlands, unlike many other countries, the pharmaceutical exposure to thiomersal has already been reduced. In the USA and other European countries replacement of thiomersal is still being debated [48, 49].
Data available on the overall frequency of sensitization to thiomersal in children vary; differences depend on the population selected and considerably diverging exposures between countries. In some countries (e.g. Portugal, Spain, Japan) thiomersal is also used in higher concentrations as a topical antiseptic [48, 50, 51].
Bruckner et al. [52] recruited 95 asymptomatic children between the age of six months and 5 years for patch testing. In their study population, thiomersal was the second most prevalent allergen, and 9.5% of their subjects were sensitized. Others reported a frequency varying from 2-4% of positive skin test reactions to thiomersal without related symptoms of the skin or mucous membranes in children [53-55]. Investigation of age and sex distribution of positive patch test results in 234 children with suspected contact dermatitis identified thiomersal as the most frequent contact allergen in girls from 0-7 years (37.5%), whereas in boys at the same age thiomersal was only the second most prevalent allergen (25%) [56]. Despite the high percentage of thiomersal positive patch test reactions, only a few of these were found to be clinically relevant [57, 58]. However, in children with atopic dermatitis exacerbation of skin lesions was reported 2-10 days after mandatory vaccinations with vaccines containing thiomersal. Patrizi [59] observed cutaneous lesions of nummular eczema on the trunk, limbs and face in five children, aged 7 to 28 months. A positive patch test reaction to thiomersal 0.1% pet. was observed in all five children.
These diverging data indicate that the prevalence and incidence of thiomersal hypersensitivity largely depend on selection criteria for the study population. Precautionary measurements such as replacement or reduction of thiomersal in medical and non-medical applications will decrease the clinical relevance of contact allergy to thiomersal.
In summary, hypersensitivity reactions to vaccines fall into six categories, depending on the causative agent: reactions due to some component of the infectious agent or one of its products, reactions due to adjuvants (e.g. aluminium hydroxide), reactions due to stabilizers (e.g. gelatin), reactions due to preservatives, reactions due to antibiotics (e. g. neomycin) and finally reactions due to the biological culture medium. The different causes can be detected by patch testing.

Children’s cosmetics

Fragrances are one of the major causes of allergic contact dermatitis from the use of cosmetics. In a previous study, a vapo-spray for babies was found to contain 14 of 21 selected fragrance substances. Among these, 4 were contact allergens present in fragrance mix: geraniol, hydroxycitronella, cinamic alcohol and α-amyl cinnamic aldehyde [60]. Recently, a series of 25 cosmetic products specially marketed for infants and young children was analysed to evaluate the exposure of this group to fragrance allergens. It was found that the allergens of the fragrance mix were either not used or they were present fairly low concentrations in shampoo/shower gels and creams/lotions. Hydroalcoholic products (eau de toilette and perfume) and a roll on, however were found to contain the ingredients of the fragrance mix more frequently [61]. In the study, one cosmetic toy perfume was found to contain 3.68% of cinnamic alcohol, while the IFRA guidline states that a maximum of 0.8% is allowed (International Fragrance Association, [62]).

Characteristic clinical examples of allergic contact dermatitis in children

Case 1

A nine-year-old girl presented with a 6-year history of recurrent eczema. Skin lesions usually occurred one day after wearing a bathing suit and were strictly symmetrical. Wetness and transpiration turned out to be factors of aggravation. The lesions persisted at least for one week up to several weeks. Her mother had observed itching and reddening of the skin with the use of several diapers, when she was a toddler. By the age of three, she was playing with gloves in her father’s dental office; thereafter she suffered from skin lesions on the back of her hands for several weeks. Balloons could be blown up without problems (no angioedema). She denied any history of asthma, allergic rhinitis or atopic eczema. Clinical examination revealed slight linear eczematous lesions on the buttocks in symmetric order. The extension of eczema was strictly limited to the area where rubber bands of the swimming suit had direct contact with the skin. Patch testing revealed a specific hypersensitivity to Tetramethyl-thiurammonosulfid and Benzothiazoles after 48, 72 and 96 h. Skin prick tests with standard allergens (latex, house dust mite and seasonal allergens) were negative.
Here, we recommended contacting producers of swimming suits to find a suitable material (free of thiuram mix and benzothiazoles). According to the patient’s history sensitization had already been acquired in early childhood by use of diapers.

Case 2

A 12-year-old boy applied tea tree oil on his face to treat a minimal skin affection. Four days later his face was extremely reddened and swollen, but he continued to use the tea tree oil for another three days before consulting our department. Previous use of tea tree oil was negative. He presented with massive facial oedema, erythema, vesiculation and yellow crusts. We recommended stopping the use of tea tree oil and prescribed a steroid lotion for three days. A new appointment was fixed and the patient was instructed to bring the bottle of tea tree oil along. Skin lesions cleared up within 2 weeks. Patch testing was performed when skin lesions had completely resolved. The patient reacted to diluted tea tree oil (2.5%), formaldehyde, turpentine and quaternium.

The allergic potential of fresh tea tree oil is presumed to be low in comparison to oxidized tea tree oil. Heat, light and oxygen enhance the risk of skin sensitization to this product. Therefore, photoaged tea tree oil must be considered to be a strong sensitizer [63, 64].

Case 3

The 6-year-old girl recurrently used bufexamac-containing ointments and creams for the treatment of atopic eczema since babyhood. Due to the exacerbation of atopic dermatitis bufexamac-containing ointments were applied, but this time instead of resolving, eczema worsened on day six. The girl and her mother presented in our clinic on day 14. Clinical investigation showed extreme scaling and mild erythema on the face, chest and throat. We recommended stopping treatment with bufexamac and the skin lesions resolved within 2 weeks. Patch testing to prove the suspected contact allergy to bufexamac was refused by the mother. The clinical course and clinical picture were consistent with that of allergic contact dermatitis. Almost 30 years ago the arylacanoic acid derivative bufexamac was introduced to dermatological therapy. Bufexamac – containing preparations are widely used in the treatment of atopic or other eczematous skin disorders as an alternative to topical corticosteroids. First cases of contact allergy to a 5% bufexamac cream had been reported as early as 1973, almost 20 years later a 2^nd type of adverse reaction after topical application of bufexamac was observed, an erythema multiforme-like eruption [65]. Contact allergy induced by bufexamac, which belongs to the group of nonsteroidal anti-inflammatory drugs, is still rare but increasing [65-67]. Kränke et al. [65] reported clinically relevant patch test reactions to bufexamac in 20 out of 35 patients having applied (n = 30) or having probably applied (n = 5) bufexamac ointment (57%), whereas, in their unselected test population of 500 routinely patch tested patients, the overall frequency was 4%.
In all forms of eczematous skin disorders, especially in patients suffering from chronic eczema or in patients with exacerbation of long-standing eczemas, contact allergy to bufexamac should be considered, even if bufexamac preparations were used for only a short time [68]. The appropriate test concentration is 5%.

Further comments

As outlined in the introduction, allergic contact dermatitis is, indeed, a significant clinical problem in childhood. We include in our review examples of all other cases of allergic contact dermatitis in childhood, three of our own cases to illustrate the clinical characteristics. Pediatric dermatologists, in particular, should be aware of this previously underestimated diagnosis in childhood.
Taking the patient’s history, specific questions concerning fashion trends and lifestyle such as piercing, decorative skin paintings, the hype of natural remedies and cosmetics (e.g. tea tree oil) or the use of cosmetical products with fragrances or herbal ingredients should be asked.
Leisure activities should also be a point of interest. Recently a cellist’s finger dermatitis due to PPD was reported in an 11 year-old schoolgirl. Bow hair is frequently dyed or impregnated and this may lead to allergic contact dermatitis [69]. Azurdia and King [70] observed a 12-year-old girl with a 12-month history of an itchy, red periorbital rash associated with the wearing of her swimming goggles, which improved by their avoidance for a 2-week period. Patch testing revealed positive reactions to phenol-formaldehyde resin and benzol peroxide.
The diagnosis of allergic contact dermatitis is a 2-step process: i) the establishing of delayed-type hypersensitivity and ii) the subsequent demonstration that the patient is exposed to the sensitizer and that the hypersensitivity and exposure explain the dermatitis under investigation.
Although it is more than 100 years since Jadassohn introduced the technique of epicutaneous testing, patch testing is still the method of choice to establish the diagnosis of contact allergy. A perfect patch test should give neither false-positive nor false-negative reactions [71]. The history and examination of a child with suspected allergic contact dermatitis will usually give clues to possible sensitizers. Unfortunately, it is not sufficient to patch test only with initially suspected sensitizers, unsuspected sensitizers frequently turn out to be the real cause of the dermatitis [72]. Rashes affecting the weight bearing area of the soles, which one might expect to indicate allergic contact dermatitis to shoe insoles, shoe linings or glues (due to rubber chemicals), occurred in contact allergy to medicaments, too [5].
Recommendations for patch testing in children has been controversial. Previously, several authors have suggested that children should be tested with lower concentrations of allergens than adults due to the risk of irritant reactions leading to false-positive test results. Fisher [73] proposes test concentrations of half strength for nickel, rubber chemicals and formaldehyde solution, Hjorth [74] suggested that patch test concentrations should be adjusted according to the age of patients, and that all positive patch test reactions should be repeated using the half strength concentration. However, the general opinion today is that children can be tested with the same concentration as adults [1, 2, 55, 75-78].
The major problem of patch testing in children remains the lack of space on small children’s backs, but with a reduced series of allergens, this can be easily resolved.
Due to the lack of specific therapy, allergen avoidance is the mainstay of prevention.
Legislation can be a useful tool in the prevention of contact dermatitis. The Cosmetics Directive 76/768/EEC [79] and its amendments aim to guarantee the safety of cosmetic products for human use. Parts of the Directive focus on the prevention of contact dermatitis. Annex VI gives a list of preservatives, which cosmetic products may contain. This list provides data on authorized maximum concentrations for each preservative, but limitations and requirements for children are made only according to toxicological side effects, and not in consideration of the potential risk of sensitization. Annex III lists substances which are restricted. A well-known example of a restriction due to the risk of sensitization is methylchlorisothiazolone/methylisothiazolone, which is not allowed above 15 ppm [80].
Another effective tool for primary and secondary prevention of nickel allergy is the EU Nickel Directive limiting the nickel content in some types of product [81].
In 1992 the Danish Ministry of the Environment implemented a regulation to reduce the skin nickel exposure of the population. Recently Jensen et al. [82] found an effect of ear piercing, before but not after 1992, in a study population of schoolgirls in Denmark. This study strongly suggests that implementation of the nickel-exposure regulation in 1992 in Denmark has had the intended effect of protecting the female population from becoming allergic to nickel.
Silverberg et al. [83] even suggest that the presence of a positive family history may be a positive predictor of nickel allergic contact dermatitis, requiring nickel avoidance, especially in atopic children. Knowledge of reactivity to nickel in the family would then allow parents and patients to initiate nickel avoidance earlier in life.
Nowadays, we have to be aware that children are already exposed at an early age to well-known allergens. Only precise knowledge of the allergens responsible allows us to practice successful prevention of allergic contact dermatitis in children from an early age onward.
Consequently the risk of developing allergic contact dermatitis can only be reduced by following several strategies of avoiding possible risk factors as follows:
1. The ideal paediatric detergent should be very mild to avoid irritant dermatitis, and very simple to avoid allergic dermatitis [84].
2. Topically applied products for children should generally be free of fragrances and preservatives.
3. The use of topical antibiotics in childhood should be restricted for at least two reasons: i) the high potential of sensitization of some antibiotics and ii) the development of resistance.
4. Ear piercing cannot be recommended for children under the age of ten years.
5. Parents should routinely be informed on the aspects of ideal skin care in childhood. They have to be made aware of the misconception that, because herbal supplements are “natural”, there are no adverse effects.
Prevention of allergic contact dermatitis in children is a problem of interdisciplinary concern not only for dermatologists and paediatricians, but also for midwives. Frequently, children are already exposed at an early age to well-known allergens, and therefore, strategies of avoidance must gain or regain importance and should start as early as possible. n

References

1. Mortz CG, Andersen KE. Allergic contact dermatitis in children and adolescents. Contact Dermatitis 1999; 41: 121-30.

2. Roul S, Ducomb G, Taieb A. Usefulness of the European standard series for patch testing in children. A 3-year single-center study of 337 patients. Contact Dermatitis 1999; 40: 232-5.

3. Gonçalo S, Gonçalo M, Azenha A, Barros MA, Sousa Bastos A, Brandão FM, Faria A, Marques MSJ, Pegegueiro M, Rodrigues E, Salguieiro E, Torres V. Allergic contact dermatitis in children. A mulicenter study of the Portugese Contact Dermatitis Group. Contact Dermatitis 1992; 26: 112-5.

4. Weston WL, Bruckner A. Allergic Contact Dermatitis. Pediatric Dermatology 2000; 47: 897-907.

5. Freeman S. Shoe dermatitis. Contact Dermatitis 1997; 36: 247-51.

6. Cockayne SE, Shah M, Messenger AG, Gawkroder DJ. Foot dermatitis in children: causative allergens and follow-up. Contact Dermatitis 1998; 38: 203-206.

7. Roul S, Ducoms G, Leaute-Labreze C, Taieb A. “Lucky Luke” contact dermatitis due to rubber components of diapers. Contact Dermatitis 1998; 38: 363-4.

8. Roul S, Leaute-Labreze C, Ducombs G, Taieb A. Eczema de contact aux changes complets type “lucky Luke”: un marqueur de dermatite atopique. Ann Dermatol Vénéreol 1998; 125 (suppl. 3): 3S74.

9. Belhadjali H, Giordano-Labadie F, Rance F, Bazex J. “Lucky Luke” contact dermatitis from diapers: A new allergen? Contact Dermatitis 2001; 44: 248.

10. Köler LD, Schönlein K, Kautzky F, Vogt HJ. Diagnosis at first glance: the baboon syndrome. Int J Dermatol 1996; 35: 502-503.

11. Andersen KE, Hjorth N, Menné T. The baboon syndrome: systemically induced allergic contact dermatititis. Contact dermatitis 1984; 10: 97-100.

12. Goossens C, Sass U, Song M. Baboon syndrome. Dermatology 1997; 194: 421-22.

13. Audicana M, Bernedo N, Gonzalez I, Munoz D, Fernández E, Gastaminza G: An unusual case of baboon syndrome due to mercury present in a homeopathic medicine. Contact Dermatitis 2001; 45: 185.

14. Alegre M, Pujol RM, Alomar A. A generalized itchy flexural eruption in a 7-year-old boy. Arch Dermatol 2000; 136: 1055-1060.

15. Bartolome B, Cordoba S, Sanchez-Perez J, Fernandez-Herrera JF, Garcia-Diez A. Baboon syndrome of unusal origin. Contact Dermatitis 2000; 43: 113.

16. Duve S, Worret W, Hofmann H. The baboon syndrome: a manifestation of hematogenous contact-type dermatitis. Acta Dermatol Venereol 1994; 74: 480-81.

17. Sharma V, Beyer DJ, Paruthi S, Nopper AJ. Prominent pruritic periumbilical papules: allergic contact dermatitis to nickel. Pediatr Dermatol 2002; 19: 106-9.

18. Macgregor DM. The risk of ear piercing in children. Scott Med J 2001; 46: 9-10.

19. Larsson-Stymne B, Widstrom L. Ear piercing - a cause of nickel allergy in schoolgirls. Contact Dermatitis 1985; 13: 289-93.

20. Rystedt I, Fischer T. Relationship between nickel and cobalt senzitization in hard metal workers. Contact Dermatitis 1983; 9: 195-200.

21. Dotterud LK, Falk ES. Metal allergy in north Norwegian schoolchildren and its relationship with ear piercing and atopy. Contact Dermatitis 1994; 31: 308-13.

22. Nixon R, Orchard D. Positive para-phenylene diamine (PPD) reactions following paint-on tattoos. Australas J Dermatol 1999; 40(2): 120.

23. Nikkels AF, Henry F, Pierard GE. Allergic reactions to decorative skin paintings. J Eur Acad Dermatol Venerol 2000; 15 (29): 140-142.

24. Le Coz CJ, Lefebvre C, Keller F, Grosshans E. Allergic contact dermatitis caused by skin painting (pseudotatooing) with black henna, a mixture of henna and p-phenylendiamine and its derivatives. Arch Dermatol 2000; 136 (12): 1515-7.

25. Jappe U, Hausen BM, Petzhold D. Erythema – multiforme like eruption and depigmentation following allergic contact dermatitis from a paint-on henna tattoo, due to para-phenylendiamine contact hypersensitivity. Contact Dermatitis 2001; 45: 249-50.

26. Onder M, Atahan CA CA, Oztas P, Oztas MO. Temporary henna tattoo reactions in children. Int J Dermatol 2001; 40 (9): 577-79.

27. Commission of the European Communities. Third directive of the Commission. OFF J Eur Communities, June 29, 1983: 0015. Series L 188/15. CEE publication 341).

28. Bedi MK, Shenefelt PD. Herbal Therapy in Dermatolgy. Arch Dermatol 2002; 138: 232-42.

29. Fritz TM, Burg G, Krasovec M. Allergic contact dermatitis to cosmetics containing Melaleuca alternifolia (tea tree oil). Ann Dermatol Venereol 2001; 128: 123-6.

30. Varma S, Blackford S, Statham BN, Blackwell A. Combined contact allergy to tea tree oil and lavender oil complicating chronic vulvovaginitis. Contact Dermatitis 2000; 42 (5): 309-10.

31. Bhushan M, Beck ML. Allergic contact dermatitis from tea tree oil in wart paint. Contact Dermatitis 1997; 36 (2): 117-8.

32. Knight TE, Hausen BM. Melaleuca oil (tea tree oil) dermatitis. J Am Acad Dermatol 1994; 30 (3): 423-427.

33. Selvaag E, Eriksen B, Thune P. Contact allergy due to tea tree oil and cross-sensitization to colophony. Contact Dermatitis 1994; 36 (6): 305.

34. Bruynzeel DP. Contact dermatitis due to tea tree oil. Trop Med Int Health 1999; 4 (9): 630.

35. Apted JH. Contact dermatitis associated with the use of tea-tree-oil. Australas J Dermatol 1991; 32(3): 177.

36. Khanna M, Qasem K, Sasseville D. Allergic contact dermatitis to tea tree oil with erythema multiforme-like id reaction. Am J Contact Dermat 2000; 11 (4): 234-42.

37. Veien NK, Hausen BM. Contact dermatitis associated with an erythema multiforme-like eruption. Am J Contact Dermat 2000; 11(4): 235-7.

38. Sherry E, Boeck H, Warnke PH. Percutaneous treatment of chronic MRSA osteomyelitis with a novel plant derived antiseptic. BMC Surg 2001; 1: 1-4.

39. Schnitzler P, Schon K, Reichling J. Antiviral activity of australian tea tree oil and eucalyptusoil against herpes simplex virus in cell culture. Pharmazie 2001; 56 (4): 343-7.

40. D’Auria FD, Laino L, Strippoli V, Tecca M, Salvatore G, Battinelli L, Mazzanti G. In vitro activity of tea tree oil against Candida albicans mycelia conversion and other pathogenic fungi. J Chemother 2001; 13 (4): 377-83.

41. Allen P. Tea tree oil: the science behind the antimicrobial hype. Lancet 2001; 358 (13): 1245.

42. Hausen BM, Reichling J, Harkenthal M. Degradation products of monoterpenes are sensitizing agents in tea tree oil. Am J Contact Dermatitis 1999; 10 (2): 68-77.

43. Bisset NG, Wichtl M, eds. Herbal drugs and Phytopharmaceuticals. 2^nd edition. Boca Raton, Fla:CRC Press; 2001: 119.

44. Brown DJ, Dattner AM. Phytotherapeutic approaches to common dermatologic conditions. Arch Dermatol 1998; 134: 1401-04.

45. Reider N, Komericki P, Hausen BM, Fritsch P, Aberer W. The seamy side of natural medicines: contact sensitization to arnica (Arnica montana L.) and marigold (Calendula officinalis L.) Contact Dermatitis 2001; 45: 269-72.

46. Hausen BM, Helmke H. Butenylbithiophene, a -terthienyl and hydroxytremetone as contact allergens in cultivars of marigold (Tagetes sp.). Contact Dermatitis 1995; 33: 33-37.

47. Clements CJ, Ball LK, Ball R, Pratt RD. Thiomersal in vaccines: is removal warranted? Drug Saf 2001; 24 (8): 567-74.

48. Van’t Veen AJ. Vaccines without thiomersal: why so necessary, why so long coming? Drugs 2001; 61 (5): 565-72.

49. Zimmermann RK. The 2002 recommended childhood immunization schedule and progress toward elimination of thiomersal. Am Fam Physician 2002; 65 (1): 127-8.

50. Gon Valo M, Figueiredo A, Gon Valo S. Hypertensitivity to thiomersal: the sensitizing moiety. Contact Dermatitis 1996; 34: 201-03.

51. Osawa J, Kitamura K, Ikezewabz, Nakajima H. A probable role for vaccines containing thiomersal in thiomersal hypersensitivity. Contact Dermatitis 1991; 24: 178-82.

52. Bruckner AL, Weston WL, Morelli JG. Does sensitization to contact allergens begin in infancy? Pediatrics 2000; 105 (1): 3-9.

53. Weston WL, Weston JA, Kinoshita J, et al. Prevalence of positive epicutaneous tests among infants, children and adolescents. Pediatrics 1986; 78: 1070-74.

54. Storrs FJ, Rosenthal LE, Adams RM, et al. Prevalence and relevance of allergic reactions in patients patch tested in North America 1984-85. J Am Acad Dermatol 1989; 20: 1038-40.

55. Barros MA, Bastia A, Correia TM, et al. Patch testing in children: a study of 562 schoolchildren. Contact Dermatitis 1991; 25: 156-9.

56. Wantke F, Hemmer W, Jarisch R, Gotz M. Patch test reactions in children, adults and the elderly. A comparative study in patients with suspected allergic contact dermatitis. Contact Dermatitis 1996; 34 (5): 316-319.

57. Suneja T, Belsito D. Thiomersal in the detection of clinically relevant allergic contact reactions. J Am Acad Dermatol 2001; 45: 23-27.

58. Handley J, Todd D, Burrows D. Mercury allergy in a contact dermatitis clinic in Northern Ireland. Contact Dermatitis 1993; 29: 258-61.

59. Patrizi A, Rizzoli L, Vincenzi C, Trevisi P, Tosti A. Sensitization to thiomersal in atopic children. Contact Dermatitis 1999; 40 (2): 94-7.

60. Rastogi SC, Johansen JD, Frosch P, Menné T, Bruze M, Lepoittevin JP, Drier B, Andersen KE, White I. Deodorants on the European market: quantitative chemical analysis of 21 fragrances. Contact Dermatitis 1998; 38: 29-35.

61. Rastogi SC, Johansen JD, Menné T, Frosch P, Bruze M, Andersen KE, Lepoittevin JP, Wakelin S, White IR. Contents of fragrance allergens in children’s cosmetics and cosmetic-toys. Contact Dermatitis 1999; 41: 84-88.

62. International Fragrance Association. Code of practice. Guidlines on: Cinnamic alcohol Oct 1978, last amendment June 1992.

63. Rubel DM, Freeman S, Southwell IA. Tea tree oil allergy: what is the offending agent? Report of three cases of tea tree oil allergy and review of the literature. Australas J Dermatol 1998; 39 (4): 244-7.

64. Altmann PM. Australian tea tree oil. Aust J Pharm 1988; 69: 276-8.

65. Kranke B, Szolar-Platzer C, Komericki P, Derhasching J, Aberer W. Epidemiological significance of bufexamac as a frequent and relevant contact sensitizer. Contact Dermatitis 1997; 36 (4): 212-5.

66. Gebhardt M, Wollina U. Cutaneous side-effects of nonsteroidal anti-inflammatory drugs (NSAID). Z Rheumatol 1995; 54 (6): 405-12.

67. Gniazdowska B, Rueff F, Przybilla B. Delayed contact hypersensitivity to non-steroidal anti-inflammatory drugs. Contact Dermatitis 1999; 40 (2): 63-65.

68. Perret C, Happle R. Contact allergy to bufexamac. Contact Dermatitis 1989; 20: 307-308.

69. O’Hagan AH, Bingham EA. Cellist’s finger dermatitis. Contact Dermatitis 2001; 45: 319.

70. Azurdia RM, King CM. Allergic contact dermatitis due to phenol-formaldehyde resin and benzol peroxide in swimming googles. Contact Dermatitis 1998; 38: 234.

71. Bruze M, Condé-Salazar L, Goosensens A, Kanerva L, White IR. Thoughts on sensitizers in a standard patch test series. Contact Dermatitis 1999; 41: 241-50.

72. Adams RM. Patch testing: A recapitulation. J Am Acad Dermatol 1981; 5: 629-43.

73. Fisher AA. Patch testing in children including early infancy. Cutis 1994; 54: 387-8.

74. Hjorth N. Contact Dermatitis in children. Acta Dermatovenereolica 1981; 95 (suppl): 36-39.

75. Stables GI, Forsyth A, Lever RS. Patch testing in children. Contact Dermatitis 1996; 34: 341-4.

76. Katsarou A, Koufou V, Armenaka M, Kalogeromitros D, Papanayotou G, Vareltzidis A. Patch tests in children: a review of 14 years experience. Contact Dermatitis 1996; 34: 70.

77. Romaguera C, Vilaplana J. Contact dermatitis in children: 6 years experience (1992-1997). Contact Dermatitis 1998; 39: 277-80.

78. Shah M, Lewis FM, Gawkrodger DJ. Patch testing in children and adolescents: Five years’experience and follow-up. J Am Acad Dermatol 1997; 37: 964-8.

79. Directive 76/768/EEC in CosmetLex, Volume 1 Cosmetics legislation: 55-62.

80. Lidén C: Legislative and preventive measures related to contact dermatitis. Contact Dermatitis 2001; 44: 65-69.

81. European parliament and Council Directive 94/27/EEC.

82. Jensen CS, Lisby S, Baadsgaard O, Volund A, Menne T. Decrease in nickel sensitisation in a Danish schoolgirl population with ears pierced after implementation of the nickel-exposure regulation. Br J Dermatol 2002; 146 (4): 636-42.

83. Silverberg NB, Licht J, Friedler S, Sethi S, Laude TA. Nickel contact hypersensitivity in children. Pediatr Dermatol 2002; 19: 110-3.

84. Gelmetti C. Skin cleansing in children. JEADV 2001, 15 Suppl. 1: 12-15.