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Acetophenone Azine

Raison-Peyron, Nadia MD; Sasseville, Denis MD, FRCPC

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doi: 10.1097/DER.0000000000000697
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Beginning in 2016, a small number of publications have described the occurrence of approximately a dozen cases of severe allergic contact dermatitis secondary to shin pads or footwear.1–6 A common characteristic of the responsible objects was the presence of cushioning foam made of ethyl vinyl acetate (EVA), a largely used thermoplastic, elastomeric copolymer of ethylene and vinyl acetate.


The first reported case was a 13-year-old boy who wore shin pads when playing soccer. He developed a contact dermatitis that was initially located on both shins (Fig. 1) but eventually became progressively more severe and widespread (Fig. 2). Comprehensive patch testing was carried out in multiple sessions with the European baseline series, rubber series, plastics/glues series, and shavings from the EVA foam lining the inner side of the shin guards. The only positive reaction was to the EVA foam. Chemical analysis of this material by high-performance liquid chromatography revealed the presence of acetophenone azine. The chemical was bought from Sigma-Aldrich (St Louis, MO) and was diluted in water and acetone to prepare stock solutions at 1.0% wt/vol. The patient was then tested with serial dilutions of these stock solutions, which gave positive reactions down to a concentration of 0.1% in water and 0.001% in acetone (Fig. 3).1

Figure 1
Figure 1:
Case 1. Contact dermatitis localized to the area covered by shin pads. Reproduced with permission from John Wiley & Sons A/S.
Figure 2
Figure 2:
Case 1. Widespread extension of the initial dermatitis.
Figure 3
Figure 3:
Case 1. Results of patch tests with dilutions of acetophenone azine in water and acetone. Reproduced with permission from John Wiley & Sons A/S.

Additional reports have described similar cases, mostly in young patients wearing not only shin pads but also sports shoes or flip-flops, either de novo or after sensitization from shin pads.2–6 When secondary to footwear, the dermatitis presented either as dyshidrosiform, vesiculobullous eczema, sometimes accompanied by palmar lesions, or as plantar hyperkeratotic dermatitis. Widespread dissemination was also often seen in these cases. Some patients healed with scarring and marked postinflammatory hypopigmentation.2,4

These patients were all children or teenagers, except for a 29-year-old male hockey player who developed contact dermatitis to his shin pads and subsequently to his sneakers.3 All patients were Europeans, with the exception of a Canadian soccer-playing child who became sensitized to his shin pads and thereafter reacted to 2 brands of sports shoes.6 Chemical analysis revealed a higher amount of acetophenone azine in shin pads than in footwear.3 This, coupled with friction and sweating, a wider area of exposure over thinner skin than the sole of the foot, probably explains why most subjects became sensitized from their shin pads. We believe that primary sensitization from other EVA-containing items will ultimately be reported.


The chemical formula of acetophenone azine is C16H16N2, and its CAS is 729-43-1 (Fig. 4). It is also known as 1-phenylethan-1-one (1-phenylethylidene), hydrazone, or methylphenyl ketazine. Whereas ketazines in general may be used as industrial biocides,7 acetophenone azine most of the time is used as an intermediate in organic synthesis. As found on the Internet, section 11 of its Material Safety Data Sheet clearly mentions that “prolonged or repeated exposure may cause allergic reactions in certain sensitive individuals. The preceding data, or interpretation of data, was determined using Quantitative Structure Activity Relationship (QSAR) modeling.”8

Figure 4
Figure 4:
Molecular structure of acetophenone azine.

The presence of this compound in sports equipment and footwear is poorly explained. It is likely not intentionally added to EVA but is believed to be generated during the manufacturing process, probably from reactions between other additives. It is hypothesized that acetophenone arises from the degradation of the initiator dicumylperoxide and hydrazine from the foaming agent azodicarbonamide.2


Acetophenone azine is not currently available from suppliers of patch testing materials and needs to be obtained from distributors of chemical products. Based on the available publications, a concentration of 0.1% in acetone or petrolatum is recommended, the latter vehicle potentially conferring greater stability to the preparation. From the clinical presentation of the reported cases, acetophenone azine seems to be a potent allergen, likely present in numerous items such as sneakers, flip-flops, ski boots, insoles, shin pads and other protective sports equipment, swimming goggles, bicycle saddles, and so on (Table 1). With the COVID-19 pandemic, EVA is liable to be found in some personal protective equipment, such as the headband of face shields.9 Given the recent discovery of this allergen, it is presumed that cases of allergic contact dermatitis would have been missed and labeled irritant contact dermatitis or dyshidrosis. The inclusion of acetophenone azine in shoe series, or in any plastics and glues series, seems highly desirable.

TABLE 1 - Summary of Published Cases
Reference Country of Origin Age Sex Source Test Materials Concentration, % Vehicle Patch Tests Results
D2 D3/D4
Raison-Peyron et al1 France 13 M Shin pads Shin pads 100 Aqua ++ +++
Shin pads 100 Acetone ++ +++
Shin pads 100 Ethanol ++ +++
AA 1 Aqua ++ ++
AA 0.1 Aqua + +
AA 0.01 Aqua
AA 0.001 Aqua
AA 0.0001 Aqua
AA 1 Acetone ++ ++
AA 0.1 Acetone ++ ++
AA 0.01 Acetone +? +
AA 0.001 Acetone +?
AA 0.0001 Acetone
Raison-Peyron et al2 France 11 M Shin pads Shin pads 100 Aqua ++ ++
Shin pads 100 Acetone ++ ++
Shin pads 100 Ethanol ++ ++
Flip-flops 100 Aqua ++ ++
Flip-flops Flip-flops 100 Acetone ++ ++
Flip-flops 100 Ethanol ++ ++
AA 0.1 Acetone ++ ++
AA 0.01 Acetone ++ ++
12 M Sneakers Sneakers 100 Aqua ++ ++
Sneakers 100 Acetone + +
Sneakers 100 Ethanol
AA 0.1 Acetone ++ ++
AA 0.01 Acetone ++ ++
De Fré et al3 Belgium 29 M Shin pads Shin pads 100 Acetone + ++
Sports shoes Sports shoes 100 Acetone + ++
AA 0.1 Acetone ++ ++
AA 0.01 Acetone + +
Koumaki et al4 United Kingdom 17 M Shin pads Shin pads 100 Aqua ++ +
AA 0.1 Acetone ++ ++
AA 0.01 Acetone +
AA 0.001 Acetone +
AA 0.0001 Acetone
AA 0.00001 Acetone
Darrigade et al5 France and Belgium 7 M Shin pads Shin pads 100 As is +
AA 0.1 Petrolatum +
12 M Shin pads Shin pads 100 As is ++ ++
Flip-flops Flip-flops 100 As is ++ ++
AA 0.1 Petrolatum ++ ++
12 M Shin pads Shin pads 100 As is ++ ++
Sneakers Sneakers 100 As is ++ ++
AA 0.1 Petrolatum ++ ++
14 M Shin pads Shin pads 100 As is ? ++
Sneakers Sneakers 100 As is ? ++
Flip-flops Flip-flops 100 As is ? ++
AA 0.1 Petrolatum ++
13 M Shin pads Shin pads 100 As is + +
AA 0.1 Petrolatum +
13 M Shin pads Nike Shin pads Puma 100 Aqua ++ ++
Shin pads Puma Shin pads Nike 100 Aqua ++ ++
Sneakers Sneakers 100 Aqua ? +
Sneakers Sneakers 100 Aqua + ++
AA 0.1 Petrolatum +++ +++
Besner Morin et al6 Canada 6 M Shin pads Shin pads 100 Aqua + +
Sneakers Adidas cleats 100 Aqua +
Soccer cleats AA 1 Petrolatum + +
AA 0.1 Petrolatum + +
Before application for patch testing, some pieces of shin pads, sneakers, flip-flops, or cleats were moistened either with water (aqua), acetone, or ethanol.
AA, acetophenone azine; D2, day 2; D3/D4, day 3/day 4; M, male.

A study published in 2018 by ANSES (a French agency for food, environmental, and occupational health and safety), entitled “Assessment of the Skin Sensitizing/Irritant Effects of Chemicals Found in Footwear and Textile Clothing,” revealed that 14% of sampled footwear contained acetophenone azine.10 Recently, the French authorities have filed a request to the European Chemicals Agency to register acetophenone azine as a cutaneous sensitizer in the Registration, Evaluation, Authorization and Restriction of Chemicals regulation.


The discovery of acetophenone azine as a potent, previously unrecognized allergen is another example of the beneficial results of fruitful collaboration between dermatologists and chemists. Given the wide use of EVA foam, especially in sports equipment, the suppliers of patch testing materials should make acetophenone azine 0.1% petrolatum rapidly available to the dermatology community.


1. Raison-Peyron N, Bergendorff O, Bourrain JL, et al. Acetophenone azine: a new allergen responsible for severe contact dermatitis from shin pads. Contact Dermatitis 2016;75:106–110.
2. Raison-Peyron N, Bergendorff O, Du-Thanh A, et al. Two new cases of severe allergic contact dermatitis caused by acetophenone azine. Contact Dermatitis 2017;76:380–381.
3. De Fré C, Bergendorff O, Raison-Peyron N, et al. Acetophenone azine: a new shoe allergen causing severe foot dermatitis. Contact Dermatitis 2017;77:416–417.
4. Koumaki D, Bergendorff O, Bruze M, et al. Allergic contact dermatitis to shin pads in a hockey player: acetophenone is an emerging allergen. Dermatitis 2019;30:162–163.
5. Darrigade AS, Raison-Peyron N, Courouge-Dorcier D, et al. The chemical acetophenone azine: an important cause of shin and foot dermatitis in children. J Eur Acad Dermatol Venereol 2020;34:e61–e62.
6. Besner Morin C, Stanciu M, Miedzybrodzki B, et al. Allergic contact dermatitis from acetophenone azine in a Canadian child. Contact Dermatitis 2020;83:41–42.
7. Permachem Asia, Ltd, Japan. Ketazins as industrial microbiocides. Patent Jpn. Kokai Tokkyo Koho JP 55147202 A 19801117, 1980.
8. Acetophenone azine. Molbase. Available at: 729-43-1-moldata-294392.html. Accessed July 20, 2020.
9. SinaLite adds face shield to product selection. Printing impressions. Available at: Accessed August 6, 2020.
10. Assessment of the skin sentising/irritant effects of chemicals found in footwear and textile clothing. ANSES. Available at Accessed July 20, 2020.
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