Red tattoo allergies after REACH regulation: a continuing problem.

Treatment of a refractory allergic reaction to a red tattoo on the lips with methotrexate and Q-switched Nd-Yag laser

As tattooing practices increase, delayed-type inflammatory reactions represent an uncommon adverse event to tattoo pigments. Different reaction patterns, such as eczematous, lichenoid, granulomatous and pseudolymphomatous reactions, have been previously reported, especially in association with metals contained in red tattoo pigments. We report a lichenoid papular reaction to an organic red tattoo ink, characterized by an intense mononuclear infiltrate dominated by CD8(+) T cells and CD56(+) lymphocytes and distributed in the superficial dermis around the red pigment and in the epidermis. Cytofluorimetric analysis of the lesional skin infiltrate confirmed the high frequency of cytotoxic CD8(+ )T cells and CD56(+)CD16(-) lymphocytes, most of which release type 1 cytokines. Chemical analysis of the red tattoo pigment confirmed its organic nature and the presence of intermediate reactive compounds. The lichenoid tissue reaction to red organic tattoo pigment showed the prototypical features of a cytotoxic inflammatory response to foreign substances (xenobiotics). The chemically unstable and reactive nature of modern tattoo pigments has to be taken into account by the clinician as well by the tattoo recipients.

EC Regulation 1907/2006 Concerning the Regulation, Evaluation, and Authorisation of Chemicals (REACH Regulation) (OJ 2006 L 396/1) is a work in progress, being under review and subject to further amendment every year. These amendments are presented below. EU Regulation 2017/227 amends Annex XVII of REACH (OJ 2017 L 35/6), introducing restrictions on the manufacture, placing on the market, and use of certain dangerous substances, preparations, and articles regarding bis(pentabromophenyl)ether (decaBDE). However, EU Regulation 2017/227 incorporates exceptions on these stipulations, allowing the use of decaBDE for the production of an aircraft (civil, military) before 2 March 2027 and for motor vehicles before 2 March 2019. EU Commission Regulation 2017/735 amends the Annex to EC Regulation 440/2008 laying down test methods pursuant to EC Regulation no. 1907/2006 (OJ 2017 L 112/1). EU Regulation 2017/735 introduces new and updated test methods for the determination of a physicochemical property, for the assessment of ecotoxicity, to assess the environmental fate and behaviour for the determination of effects on human health. It also deletes six test methods for which the corresponding Organisation for Economic Co-operation and Development test guidelines have been cancelled.

This year, some of the annexes to EC Regulation 1907/2006 Concerning the Regulation, Evaluation, and Authorization of Chemicals (REACH Regulation) were amended, and case law emerged. Outside of the REACH Regulation, a certain substance was approved as an active substance for use in biocidal products, and the commission decided on its position to be taken in negotiations about the Stockholm Convention on Persistent Organic Pollutants (Stockholm Convention). EU Regulation 2015/282 amends Annexes VIII, IX and X to the Reach Regulation, specifying the scope of a new modular test method called the extended one-generation reproductive toxicity study (EOGRTS), which was adopted by the Organisation for Economic Co-operation and Development in 2011. According to the current amendment, a two-generation reproductive toxicity study is regularly required to fulfil the standard information requirements in point 8.7.3 of Annexes IX and X. However, under EOGRTS, breeding and assessment of a second filial generation and testing for developmental neurotoxicity and developmental immunotoxicity constitute distinct and independent modules (Commission Regulation (EU) 2015/282, preamble, para. 3). EOGRTS focuses on the analysis of the first filial generation and addresses additional parameters in the hope of improvements in sensitivity and the level of information that can be gained from the tests.

Systemic contact dermatitis to a surgical implant presenting as red decorative tattoo reaction

The introduction of pigments or dyes during tattooing may trigger various histological types of hypersensitivity reaction, mainly lichenoid, granulomatous, sarcoidosis-like, pseudolymphomatous and eczematous (1). The time of appearance of these reactions is highly variable, from immediately after tattooing to 45 years later (2). We report here an unusual case of dermal sclerosis restricted to the red part of tattoos. Such “scleroderma-like” reactions have been reported on very few occasions (3, 4). CASE REPORTAn otherwise healthy 47-year-old woman presented for an inflammatory infiltration of an ankle tattoo, which had become symptomatic almost immediately after tattooing. Eighteen months earlier, a yellow, orange, red, white and black “sacred heart” had been tattooed on her ankle in a professional tattoo parlour (Fig. 1A). Within the first week, she noticed unusual swelling and delayed healing. Pruritus had been intense, with a severe impact on daily living and sleep for the past 18 months. This episode was the first she had reported after tattooing, as she had been tattooed three times pre-viously without complication. However, a concomitant itchy reaction had also developed at this time on the red part of another tattoo located in the lumbar area, which had been drawn by the same artist with the same red ink 6 months before the “sacred heart”. Both reactions had remained stable without improvement. She refused to apply any corticosteroid ointment during this time. Examination of the 18-month-old tattoo showed an inflamed, squamous and indurated infiltration confined to the red parts. Several exulcerations were noted over the red area (Fig. 1B). Physical examination was other-wise normal, with no sign of systemic scleroderma. The clinical features were suggestive of a red tattoo pigment hypersensitivity reaction. Histological examination of a 4-mm punch biopsy of the red tattoo revealed a lichenified epidermis with com-pact hyperkeratosis, hypergranulosis and acanthosis. An inflammatory sclerosis was located in the superficial and mid-dermis with thickened and homogenized collagen bundles, lymphocytes and macrophages. Exogenous red tattoo pigments were localized around mid-dermal vessels free in the dermis or in macrophages. Focal lichenoid reaction was observed (Fig. 2). The features were not indicative of localized scleroderma. A diagno-sis of dermal sclerosis related to a chronic inflammatory reaction to the red pigment was suspected. No test could be performed on the culprit red ink as the manufacturer did not reply to our request for a sample or information on its composition. Betamethasone dipropionate 0.05% ointment was applied daily for a month and then tapered slowly over 3 months. Pruritus resolved within a week and lesions improved within the first 2 months. After 3 months, no inflammation was noted. We suggested that the patient avoid further tattooing with any type of red ink in the absence of identified components. She had two new tattoos done with various colours (yellow, green, blue, orange, pink, violet, brown and black) without complication. However, one of them was a pink cat with red ink from a different manufacturer applied for the nose. Pruritus occurred on that very location after tattooing, but no recall reaction occurred elsewhere. She and her tattooist have decided to stop using red ink.DISCUSSIONWe report here an unusual and severe “scleroderma-like” reaction after tattooing, which was restricted to the red parts of a tattoo. Symptoms of hypersensitivity reaction to tattoo pigments are often non-specific, including discomfort, swelling, papules or nodules and pruritus (5). Clinical induration is not an uncom-mon manifestation of tattoo reactions (5), but the

Ultraviolet radiation (UVR) induces skin cancer. The combination of UVR and red tattoos may be associated with increased risk of skin cancer due to potential carcinogens in tattoo inks. This combination has not been studied previously. Immunocompetent C3.Cg/TifBomTac hairless mice (n=99) were tattooed on their back with a popular red tattoo ink. This often used ink is banned for use on humans because of high content of the potential carcinogen 2-anisidine. Half of the mice were irradiated with three standard erythema doses UVR thrice weekly. Time to induction of first, second and third squamous cell carcinoma (SCC) was measured. All UV-irradiated mice developed SCCs. The time to the onset of the first and second tumor was identical in the red-tattooed group compared with the control group (182 vs 186days and 196 vs 203days, P=ns). Statistically, the third tumor appeared slightly faster in the red-tattooed group than in the controls (214 vs 224days, P=.043). For the second and third tumor, the growth rate was faster in the red-tattooed group compared with the control (31 vs 49days, P=.009 and 30 vs 38days, P=.036). In conclusion, no spontaneous cancers were observed in skin tattooed with a red ink containing 2-anisidine. However, red tattoos exposed to UVR showed faster tumor onset regarding the third tumor, and faster growth rate of the second and third tumor indicating red ink acts as a cocarcinogen with UVR. The cocarcinogenic effect was weak and may not be clinically relevant.

To the Editor: INTRODUCTION Tattoo has numerous potential medical complications well described in the literature. Among these complications, sensitivity reactions to tattoo ink have higher frequency. Clinically, these reactions can present with pruritus, focal edema, papules, nodules, plaques. Usually these lesions confined to the site of causative tattoo pigment. Less commonly generalized reactions have also been reported.1,2 Furthermore anaphylactic reaction has been described in association with colored tattoo pigments.3 Histologically these hypersensitivity conditions could present with allergic, foreign body sarcoidal granulomatous reactions. Particularly mercuric sulfide (cinnabar) containing red tattoos are the most common causes of these delayed allergic reactions.1,4 In addition, cadmium has been reported responsible for photosensitivity reactions in red tattoos.5 CASE REPORT A 41-year-old man presented to our outpatient clinics with papular and nodular overgrowth arising within his tattoo performed 1 month ago situated over his right biceps and on right forearm. As shown in Figures 1–3, on examination there was dome-shaped red papules and nodules with variety of size in the shape of red figures; other colors were unaffected. There was no history of contact allergy and atopic diathesis. Lesions were not photosensitive. Routine blood tests, urinalysis, antinuclear antibodies, inflammatory markers, complements were in reference range. There was no evidence of peripheral lymphadenopathy. Chest x-ray was normal. Biopsy was taken for histopathology from one of the nodules. Histopathological examination showed heavy dermal inflammation with numerous pigment containing histiocytic macrophages and exogenous red pigment deposition in intercellular area, foreign body granulomas containing foreign body giant cells and few mononuclear cells as it is seen in Figure 4. An infectious etiology was not identified. We were unable to identify the trade name of the red pigment used. Patient did not accept any surgical therapies and he has still been on follow-up with topical steroid therapy.FIGURE 1.: Indurated red nodules confined to red portion of the tattoo.FIGURE 2.: Closer view of red nodules.FIGURE 3.: Multiple red papules with diameter of several millimeters.FIGURE 4.: Infiltraton of pigment containing inflammatory cells and deposition of exogenous pigment. (H&E, original magnification, X100).CONCLUSION Tattoo-associated infectious, allergic, and/or granulomatous complications were seen with ratio of 2.1%.1 Nodular, lichenoid,6 pseudolymphomatous,7 granulomatous.8,9 Histological tattoo reaction patterns were well recognized in red tattoos. Granulomatous reactions could occur, either as a foreign body–type reaction to pigment with numerous pigment containing giant cells or as a hypersensitivity reaction with few giant cells. Sarcoidal reactions within a tattoo with systemic disease or without were less common.10 They might present as the first sign of systemic disease11; however, the patient presented did not show any findings of systemic sarcoidosis. Organic pigments containing red tattoo reactions were also strongly associated with UV exposure.12 Our patient's reaction was not photoaggravated. In summary, our report aimed to emphasize tattoo-associated granulomatous tissue reactions. Careful clinicopathologic evaluation is advised to avoid misdiagnosis of systemic sarcoidosis or any other systemic granulomatous diseases.

The aim of this study was to assess the feasibility of Raman spectroscopy as a screening technique for chemical characterisation of tattoo pigments in pathologic reacting tattoos and tattoo ink stock products to depict unsafe pigments and metabolites of pigments. Twelve dermatome shave biopsies from allergic reactions in red tattoos were analysed with Raman spectroscopy (A 785-nm 300 mW diode laser). These were referenced to samples of 10 different standard tattoo ink stock products, three of these identified as the culprit inks used by the tattooist and thus by history the source of the allergy. Three primary aromatic amine (PAA) laboratory standards (aniline, o-anisidine and 3,3'-dichlorobenzidine) were also studied. Application of Raman spectroscopy to the shave biopsies was technically feasible. In addition, all ten inks and the three PAA standards could be discriminated. 10/12 shave biopsies provided clear fingerprint Raman signals which differed significantly from background skin, and Raman spectra from 8/12 biopsies perfectly matched spectra from the three culprit ink products. The spectrum of one red ink (a low cost product named 'Tattoo', claimed to originate from Taiwan, no other info on label) was identified in 5/12 biopsies. Strong indications of the inks 'Bright Red' and 'Crimson Red' were seen in three biopsies. The three PAA's could not be unambiguously identified. This study, although on a small-scale, demonstrated Raman spectroscopy to be feasible for chemical analysis of red pigments in allergic reactions. Raman spectroscopy has a major potential for fingerprint screening of problematic tattoo pigments in situ in skin, ex vivo in skin biopsies and in tattoo ink stock products, thus, to eliminate unsafe ink products from markets.

Kératoacanthomes sur tatouages récents : deux cas

Induction of delayed hypersensitivity reactions by red tattoos has been occasionally reported. Little is known about the inks used. Azo pigments have been implicated in some instances, but there is only one reported case involving quinacridones. To describe the clinical and pathological features and outcome of skin reactions induced by red tattoo pigments. Six patients with a cutaneous reaction induced by a red tattoo pigment underwent biopsy and prick and patch testing with the inks supplied. We observed seven reactions in the 6 patients. Histology showed various patterns: three lichenoid, two eczematous, and two pseudolymphomatous. Five reactions occurred with azo pigments, and two with quinacridones, in both cases with Violet 19 and Red 122. Four inks were tested. Only one patch test gave a positive result at a late reading (day 7). Prick tests gave negative results. The reactions required various treatments, including laser treatment for 2 patients. Activation of the reaction in 1 case was transient. Azo pigments and quinacridones both triggered reactions with similar clinical aspects but with varying histological findings. Patch and prick test results were disappointing with both. Reactions occurred following laser use in 1 case.

Delayed reactions caused by red tattoo pigments are often difficult to treat. We report a 31-year-old female patient with a lichenoid reaction to a red tattoo on the right ankle who was successfully treated with five sessions of a surgical Erbium:Yag laser, using several passes in each session. Our work leads us to consider that Er:Yag laser therapy may be an effective and safe treatment for these therapeutically challenging reactions.

Despite popularity of tattoos, complications may occur. In particular, red tattoo reactions due to allergic reactions are the most frequent chronic tattoo reactions. However, little is known about its histopathology and underlying pathomechanisms. The aim of this article is to analyze the histopathology of red tattoo reactions for diagnostic purposes and to acquire more insight into pathogenesis. A retrospective cross-sectional study was conducted by reviewing the histopathology of 74 skin biopsies of patients with allergic red tattoo reactions. Histopathological findings, such as inflammation patterns, inflammatory cells and pigment depth and color, were semi-quantified with an in-house validated scoring system by 2 independent senior investigators. Histiocytes and lymphocytes were both present in >93%. Histiocytes were the predominant inflammatory cells in 74.3%, but well-defined granulomas were mostly absent (78.0%). Eosinophils were uncommon (8.1%) The predominantly histiocytic reaction combined with interface dermatitis was the main inflammation pattern (37.9%). Most biopsies showed more than one reaction pattern. Interface involvement was observed in 64.8%, despite the intended depth of standard tattoo procedures, in which pigment is placed deeper, in the upper- and mid-dermis. Statistical analyses showed a significant association between inflammation severity and pigment depth (P = 0.024). In 6 cases (8.1%) pigments could not be retrieved histologically. In this cohort we demonstrated that cutaneous reactions to red tattoo ink are frequently characterized by the combination of dermal predominantly histiocytic infiltrates and epidermal interface dermatitis. Allergic reactions to red tattoo pigments probably represent a combination of a subtype IVa and IVc allergic reaction. Clinicians should be aware of the specific histopathology of these reactions and therefore the importance of taking a diagnostic skin biopsy.

Considering the ever increasing popularity of tattoos, significant reactions remain unusual. Red pigments are the commonest cause of delayed tattoo reactions. Histology typically shows extensive lichenoid basal damage, well away from the dermal pigment. We report two cases of lichenoid reactions to red tattoo pigment and review the literature on the subject.

Complications of cosmetic decorative tattoos were uncommon some decades ago. The practice is increasing and more cases are being reported. Red pigments are by far the commonest cause in tattoo reactions. We report two cases of lichenoid reactions limited to red tattoo pigment and review the literature on the subject.