Forum for Nordic Dermato-Venereology Nr 4, 2019 | Page 16

Dissertation
Analytical Methodologies for Common Skin Allergens – Organic Thioureas,
Isothiocyanates and Fragrance Hydroperoxides in Everyday Life Products
A hmed R amzi , P h D
Analytical chemist. E-mail: [e-mail]
On 22 March 2018 Ahmed Gamal Ramzi defended his thesis ”Analytical methodologies for common skin
allergens – Organic thioureas, isothiocyanates and fragrance hydroperoxides in everyday life products” at
the Department of Environmental Science and Analytical Chemistry, Stockholm University. Professor Anneli
Julander from Karolinska Institute was opponent, Professor Ulrika Nilsson, Stockholm University, was main
supervisor and Professor Lina Hagvall, Sahlgrenska Academy at University of Gothenburg, acted as co-supervisor.
The thesis describes analytical methodologies for the determi-
nation of important skin-sensitizing chemicals in two types of
commercial items: chloroprene rubber and fragrance products,
which are both well-known to be associated with contact allergy.
Chloroprene rubber (neoprene ® ) is widely used in different
applications and products, such as bags, gloves, wetsuits, brac-
es, mouse pads etc. Exposure to chloroprene rubber materials
has resulted in numerous cases of allergic contact dermatitis.
Organic thioureas have been considered the main culprits, even
though they at the same time have been classified as weak or
non-sensitizers in the murine local lymph node assay (LLNA).
Previous findings indicate that a possible reason for sensitization
is that organic thioureas are being metabolized in the skin to
strong haptens, such as isothiocyanates and isocyanates, after
skin exposure. In this thesis, chemical ana­lyses of a number of
chloroprene products from the Swedish open market showed
the presence of diethylthiourea in all analyzed items, while
other organic thioureas could not be detected. The levels of
diethylthiourea varied, with the highest at 158 µg/cm in a
used back support that had previously caused allergic contact
dermatitis in a patient. Furthermore, it was discovered that
all the examined items emitted ethyl isothiocyanate. LLNA
showed that ethyl isothiocyanate is a strong skin sensitizer, as
has been shown earlier for other tested isothiocyanates. Isothi-
ocyanates were shown to be thermally formed from diethyl-,
diphenyl- and dibutylthiourea at a temperature as low as 35°C,
i. e. around skin temperature. Altogether, the results from these
experiments, patch tests and chemical analyses reveal that
isothiocyanates are important haptens in contact allergy to
chloroprene rubber.
Fragrances constitute one of the main causes of contact allergy,
next to nickel and preservatives. The most widespread fragranc-
es in cosmetics and perfumes on the market are monoterpe-
noid compounds, such as linalool and limonene, which at air
exposure easily oxidize to hydroperoxides, that are strongly
skin-sensitizing and the main haptens. Despite this, there is
so far no EU regulation concerning fragrance hydroperoxides
in products, which probably is due to lack of reliable analyti-
cal methods. Presented in this thesis is a toolbox of different
analytical methods, applied on essential oils, shampoo, patch
test preparations and different types of perfumes. Furthermore,
126
Ahmed Ramzi with the Supervisor Ulrika Nilsson.
one of the studies elucidated the first case (to my knowledge)
of allergic contact dermatitis as being associated with fragrance
hydroperoxides in a commercial product. The product inves-
tigated was a shampoo, heavily fragranced with linalool and
shown to contain linalool hydroperoxides.
Taken together, the thesis shows the importance of developing
analytical methods to be able to identify, measure and detect
important haptens in contact allergy.
L ist
of original publications
1. Ramzy AG, Hagvall L. Pei MN, Samuelsson K, Nilsson U. Inves-
tigation of diethylthiourea and ethyl isothiocyanate as potent
skin allergens in chloroprene rubber. Contact Dermatitis 2015;
72: 139–146.
2. Ramzy AG, Lammintausta K, Matura M, Bråred Christensson J,
Nilsson U, Hagvall L. Isothiocyanates are important as haptens
in contact allergy to chloroprene rubber. Br J Dermatol 2017;
177: 522–530.
3. Rudbäck J, Ramzy A, Karlberg A-T, Nilsson U. Determination of
allergenic hydroperoxides in essential oils using gas chromatog-
raphy with electron ionization mass spectrometry. J Sep Sci 2014;
37: 982–989.
4. Elliot JF, Ramzy A, Nilsson U, Moffat W, Suzuki K. Severe intractable
eyelid dermatitis probably caused by exposure to hydroperoxides
of linalool in a heavily fragranced shampoo. Contact Dermatitis
2017; 76: 114–115.
5. Ramzi A, Ahmadi H, Sadiktsis I, Nilsson U. A two-dimensional
non-comprehensive reversed/normal phase high-performance
liquid chromatography/tandem mass spectrometry system for
determination of limonene and linalool hydroperoxides. J Chro-
matography A 2018; 1566: 102–110.
Forum for Nord Derm Ven 2019, Vol. 24, No. 4