These isothiazolinones are the active ingredients in Kathon CG (Rohm and Haas, Philadelphia, PA, USA), a cosmetic preservative on the market since the 1980s. They appear in the preservative mixture in the ratio of 3:1. MI alone has been approved as a cosmetic preservative since 2005, as it was considered less sensitising compared to the chlorinated moiety. However, it had to be used in a much higher concentration to be effective and therefore caused the current epidemic of MI allergy [6].

Other isothiazolinones such as benzisothiazolinone (BIT) and octylisothiazolinone (OIT) are used extensively as effective biocides to preserve the water content of industrial products, such as metalworking fluids and water-based paints. Isothiazolinones are marketed under many brand names, which makes it easy to overlook the presence of these chemicals in the formulations. Over the last 15 years, the incidence of MCI/MI contact allergy has remained around 2.0–2.5 % of consecutively tested eczema patients in Europe [7]. However, the introduction of MI alone has caused an epidemic of MCI/MI and MI contact allergy, raising the frequency of contact allergy to these preservatives to 5–7 % among consecutively patch-tested dermatitis patients [8]. These allergens are important for hand eczema and facial dermatitis, and it may also cause urticaria and airborne contact dermatitis in the face of sensitised individuals who stay in newly painted rooms, and the diagnosis is easily missed unless specifically considered. In cosmetic products, the permissible level of MCI/MI is 15 ppm, and it appears that this concentration in rinse-off products is rather safe, since most subjects previously sensitised to MCI/MI tolerated the use of a shampoo preserved with MCI/MI for 2 weeks [9]. In leave-on products, a maximum concentration of 7.5 ppm is recommended.

Patch test reactions to MCI/MI may show unusually sharp borders and can still be true allergic reactions. The patch test concentration was 100 ppm in aqueous solution, until recently when it was recommended to raise the test concentration to 200 ppm [6]. Due to the activity of isothiazolinones on the skin, it is imperative that exact dosing be used, when isothiazolinones are used for patch testing. In the T.R.U.E. Test, the concentration is 4 μg/cm². There may be cross-sensitisation between MCI/MI and two other isothiazolinones, benzisothiazolinone and octylisothiazolinone [10]. Patients sensitised to MI often also react to MCI while the opposite is not obligatory [11].

In the mid-1980s, the preservative methyldibromo glutaronitrile (MDBGN) was approved for the use in cosmetic products at a maximum concentration of 1000 ppm in both leave-on and rinse-off cosmetics except for sunscreen products, in which MDBGN was not allowed to exceed a concentration of 250 ppm. MDBGN was effective at low in-use concentrations, and animal tests indicated that the preservative was a weak sensitiser. These attributes were favourable, and MDBGN gradually became more widespread throughout the 1990s in household and industrial products and cosmetics in particular.

The preservative was marketed as Euxyl K400 (Schülke and Mayr, Hamburg, Germany), a combination of MDBGN and phenoxyethanol (1:4), which is a weak sensitiser. Methyldibromo glutaronitrile is the INCI name, and it is synonymous with 1,2-dibromo-dicyanobutane. However, dermatology clinics in Europe found increasing numbers of eczema patients sensitised to the chemical [12]. In 2001, patch test data from 16 European clinics showed an increasing average frequency of sensitivity to MDBGN in eczema patients from 0.7 % in 1991 to 3.5 % in 2000 [13]. This epidemic of MDBGN allergic contact dermatitis from consumer products led the EU authorities to ban the use of MDBGN in cosmetics from 2005. Subsequent epidemiological studies from EU countries showed a decrease in MDBGN contact allergy [14]. The effect of this regulation is a prime example of primary prevention. A repeated short-term exposure, such as frequent hand washing with MDBGN-containing liquid soap, was a significant cause of sensitisation and elicitation of allergic contact dermatitis to this preservative [15]. The current patch test concentration is 5000 ppm in petrolatum. It has been chosen based on consideration of rates of contact allergy, doubtful and irritant reactions, as well as information on clinical relevance represented by results of a repeated open application test. However, others have recommended 3000 ppm as the optimal patch test concentration due to increased number of false-positive reactions at 5000 ppm. MDBGN is now included in T.R.U.E. Test at a concentration of 5 μg/cm².

Formaldehyde is a ubiquitous and potent sensitiser, industrially, domestically and medically. Formaldehyde exposure is difficult to estimate because the chemical – besides being manufactured, imported and used as such – is incorporated into a large variety of products and reactants in many chemical processes, including formaldehyde releasers, polymerised plastics, metalworking fluids, medicaments, fabrics, cosmetics and detergents (Table 13.2). Shampoos may contain formaldehyde, but because they are quickly diluted and washed off, only exquisitely formaldehyde-sensitive consumers develop dermatitis on the scalp and face. Nevertheless, hairdressers may get hand dermatitis from similar products due to their more intense exposure, and it is important to note that formaldehyde-releasing preservatives in cosmetics and topical drugs may elicit allergic contact dermatitis in formaldehyde-sensitive consumers [16].

Formaldehyde dermatitis from textiles is rare today because the manufacturers have improved the fabric finish treatment and have reduced the amount of formaldehyde residues in new clothing. Garments made from 100 % acrylic, polyester, linen, silk, nylon and cotton are generally considered to be formaldehyde-free [17]. Formaldehyde sensitivity is not necessarily accompanied by a simultaneous sensitivity to formaldehyde resins and formaldehyde releasers and vice versa [18]. Fifty-three percent of formaldehyde-sensitive patients tested in a UK multicentre study were positive to one or more of the four formaldehyde releasers tested: quaternium-15, imidazolidinyl urea, diazolidinyl urea and 2-bromo-2-nitropropane-1,3-diol [19]. Indeed, some of the formaldehyde releasers might act directly as haptens or be precursors of haptens (the above-mentioned formaldehyde releasers undergo a chemical transformation (hydrolysis)). It depends on the exposure conditions and the actual release of formaldehyde. The frequency of formaldehyde-positive patch tests in consecutive eczema patients is around 2–3 % [3].

Inexplicable positive patch test reactions frequently occur where no clinical relevance is found. A deeper search, however, might often reveal it. Hidden sources of formaldehyde in the home may be a cause of hand eczema in some women with formaldehyde allergy. Occupational formaldehyde allergy is quite common and occurs in metal workers, hairdressers, masseurs and workers using protective creams, detergents and liquid soaps. In certain cases, the positive patch test should be confirmed by a repeated test and by a use test, since false-positive reactions may occur; this may explain why about one-third of allergies reported to formaldehyde, and its releasers can be lost on repeated patch testing, although a lack of reproducibility in patch testing might also account for this phenomenon [20]. In a detailed clinical experiment, the eliciting closed patch test threshold concentration was 10,000 ppm formaldehyde in 10 of 20 formaldehyde-sensitive individuals, 9 reacted to 5000 ppm, 3 reacted to 1000 ppm, 2 reacted to 500 ppm and 1 reacted to 250 ppm. Positive reactions were not observed in non-occluded patch test with a dilution series from 25 to 10,000 ppm or in a repeated open application test (ROAT) with a leave-on cosmetic product containing a formaldehyde releaser (an average of 300 ppm formaldehyde) [21]. Thus, the threshold concentration for occluded patch test to formaldehyde in formaldehyde-sensitive patients seems to be around 250 ppm.

Formaldehyde is widely distributed in the environment and is difficult to avoid because many finished products may contain small amounts of formaldehyde. It may not appear on the label though, as formaldehyde can be present in raw materials that may be released during storage and use. It is a challenge to inform and train formaldehyde-allergic patients how best to avoid exposure to formaldehyde and formaldehyde releasers because there are so many sources in the environment [22].

Immediate reactions from formaldehyde may also occur, both of presumably allergic and nonallergic nature [23].

Formaldehyde releasers used as preservatives in cosmetics and technical products are often concealed by trade names or synonyms (Table 13.3). The epidemiology of formaldehyde sensitisation requires re-evaluation. The patch test concentration has recently been recommended to be increased from 10,000 to 20,000 ppm in aqueous solution, and the T.R.U.E. Test contains 180 μg/cm².