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Analytical methodologies for common skin allergens: Organic thioureas, isothiocyanates and fragrance hydroperoxides in everyday life products
Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes analytical methodologies for the determination 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, braces, mouse pads et c. 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 into more reactive electrophiles, such as isothiocyanates and isocyanates, after skin exposure. In this thesis, chemical analyses of a number of chloroprene products from the European 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-2 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. Isothiocyanates 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 revealed 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 fragrances in cosmetics and perfumes on the market are monoterpenes, such as linalool and limonene, which at air exposure easily oxidize to hydroperoxides, which are strongly skin sensitizing compounds and the main haptens. Despite this, there is so far no EU regulation concerning fragrance hydroperoxides in products, which may be due to lack of analytical methods which can reliably measure them in fragrances. 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, one of our studies elucidated the first case (to my knowledge) of allergic contact dermatitis as being correlated to a product that contains a fragrance hydroperoxide.

Taken together, the thesis shows the importance of developing analytical methods for the identification, measurement and detection of important haptens in contact allergy. 

Place, publisher, year, edition, pages
Stockholm: Department of Environmental Science and Analytical Chemistry, Stockholm University , 2018. , p. 79
Keywords [en]
Chemical analysis, contact allergy, chloroprene rubber, diethyl thiourea, ethyl isothiocyanate, fragrance hydroperoxides
National Category
Analytical Chemistry
Research subject
Analytical Chemistry
Identifiers
URN: urn:nbn:se:su:diva-152640ISBN: 978-91-7797-149-8 (print)ISBN: 978-91-7797-150-4 (electronic)OAI: oai:DiVA.org:su-152640DiVA, id: diva2:1180486
Public defence
2018-03-22, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 5: Manuscript.

Available from: 2018-02-27 Created: 2018-02-05 Last updated: 2018-02-27Bibliographically approved
List of papers
1. Investigation of diethylthiourea and ethyl isothiocyanate as potent skin allergens in chloroprene rubber
Open this publication in new window or tab >>Investigation of diethylthiourea and ethyl isothiocyanate as potent skin allergens in chloroprene rubber
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2015 (English)In: Contact Dermatitis, ISSN 0105-1873, E-ISSN 1600-0536, Vol. 72, no 3, p. 139-146Article in journal (Refereed) Published
Abstract [en]

Background

Exposure to chloroprene rubber has resulted in numerous cases of allergic contact dermatitis, attributed to organic thiourea compounds used as vulcanization accelerators. However, thiourea compounds are not considered to be strong haptens.

Objectives

To analyse common commercial chloroprene materials for their contents of diethylthiourea (DETU), dibutylthiourea (DBTU), diphenylthiourea (DPTU), and their degradation products, isothiocyanates; and to investigate the sensitization potencies of possible degradation products of the mentioned thiourea compounds.

Methods

Liquid chromatography/mass spectrometry (MS) was used for quantification of organic thiourea compounds in chloroprene products, such as medical, sports and diving gear; isothiocyanates were measured by solid-phase microextraction/gas chromatography/MS. Sensitization potencies were determined with the murine local lymph node assay (LLNA).

Results

DETU was identified at concentrations of 2.7-9.4 mu g/cm(2) in all samples, whereas neither DBTU nor DPTU was detected. At 37 degrees C, degradation of DETU in the materials to ethyl isothiocyanate (EITC) was detected. EITC and ethyl isocyanate showed extreme and strong sensitization potencies, respectively, in the LLNA.

Conclusions

DETU can act as a prehapten, being degraded to EITC when subjected to body temperature upon skin contact. EITC could thus be the culprit behind allergic contact dermatitis caused by chloroprene rubber.

Keywords
chloroprene, contact dermatitis, diethylthiourea, ethyl isothiocyanate, exposure analysis, local lymph node assay, neoprene, rubber chemicals
National Category
Dermatology and Venereal Diseases Analytical Chemistry
Research subject
Analytical Chemistry
Identifiers
urn:nbn:se:su:diva-116000 (URN)10.1111/cod.12318 (DOI)000349965800002 ()25532938 (PubMedID)
Note

AuthorCount:5;

Available from: 2015-04-10 Created: 2015-04-08 Last updated: 2018-02-12Bibliographically approved
2. Isothiocyanates are important as haptens in contact allergy to chloroprene rubber
Open this publication in new window or tab >>Isothiocyanates are important as haptens in contact allergy to chloroprene rubber
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2017 (English)In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 177, no 2, p. 522-530Article in journal (Refereed) Published
Abstract [en]

Background Contact allergy to chloroprene rubber products is well known. Thiourea compounds are considered the cause of allergy. Diethylthiourea commonly occurs in this type of product and can decompose to the sensitizer ethyl isothiocyanate. Objectives To investigate the clinical importance of degradation products and metabolites from organic thioureas in contact allergy to chloroprene rubber with a focus on isothiocyanates and isocyanates. Methods Patients with contact allergy to diphenylthiourea were patch tested with phenyl isothiocyanate and phenyl isocyanate. Patients with known contact allergy to diethylthiourea were retested with diethylthiourea, while chemical analyses of their chloroprene rubber products were performed. The stability of diethylthiourea, diphenylthiourea and dibutylthiourea in patch-test preparations was investigated. Liquid chromatography/mass spectrometry and solid-phase microextraction/gas chromatography were used for determination of organic thioureas and isothiocyanates. Results All patients allergic to diphenylthiourea reacted to phenyl isothiocyanate, two of eight reacted to phenyl isocyanate and six of eight reacted to diphenylthiourea. Four patients allergic to diethylthiourea reacted at retest; diethylthiourea was detected in all chloroprene rubber samples, with levels of 2-1200 nmol cm(-2). At 35 degrees C, ethyl isothiocyanate was emitted from all samples. Patch-test preparations of diethylthiourea, diphenylthiourea and dibutylthiourea all emitted the corresponding isothiocyanate, with diethylthiourea showing the highest rate of isothiocyanate emission. Conclusions Thiourea compounds are degraded to isothiocyanates, which are generally strong or extreme sensitizers, thus acting as prehaptens. This process occurs in both chloroprene rubber products and patch-test preparations. Positive reactions to phenyl isocyanate indicate cutaneous metabolism, as the only known source of exposure to phenyl isocyanate is through bioactivation of diphenylthiourea.

National Category
Chemical Sciences
Research subject
Analytical Chemistry
Identifiers
urn:nbn:se:su:diva-147115 (URN)10.1111/bjd.15444 (DOI)000407994100038 ()28295200 (PubMedID)
Available from: 2017-10-09 Created: 2017-10-09 Last updated: 2018-02-12Bibliographically approved
3. Determination of allergenic hydroperoxides in essential oils using gas chromatography with electron ionization mass spectrometry
Open this publication in new window or tab >>Determination of allergenic hydroperoxides in essential oils using gas chromatography with electron ionization mass spectrometry
2014 (English)In: Journal of Separation Science, ISSN 1615-9306, E-ISSN 1615-9314, Vol. 37, no 8, p. 982-989Article in journal (Refereed) Published
Abstract [en]

Fragrance monoterpenes are widely used commercially due to their pleasant scent. In previous studies, we have shown that air-exposed monoterpenes form hydroperoxides that are strong skin sensitizers. Methods for detection and quantification of the hydroperoxides in essential oils and scented products are thus desirable. Due to thermolability and low UV absorbance, this is a complicated task. We have recently developed a sensitive LC-ESI-MS method, but with limited structural information and separation efficiency for positional isomers and stereoisomers. In the present study, we investigated derivatization with a trimethyl silyl reagent and subsequent GC with electron ionization MS for the determination of monoterpene hydroperoxides. All investigated monoterpene hydroperoxides could be chromatographed as thermostable trimethyl silyl derivatives and yielded the fragment m/z 89 ([OSi(CH3)(3)](+)) at a higher extent compared to corresponding alcohols. Limonene-2-hydroperoxide and four other hydroperoxide isomers of limonene were separated and detected in sweet orange oil autoxidized for two months. The concentration of limonene-2-hydroperoxide isomers was found to be 19 g/mg in total. Also isomers of linalyl acetate hydroperoxide and linalool hydroperoxide were detected in autoxidized petitgrain oil (two months). The presented GC-MS method showed concentrations in the same order as previous LC-MS/MS analysis of the same type of oils.

Keywords
Contact allergy, Essential oils, GC-MS, Monoterpene hydroperoxides, Trimethyl silyl derivatives
National Category
Chemical Sciences
Research subject
Analytical Chemistry
Identifiers
urn:nbn:se:su:diva-103977 (URN)10.1002/jssc.201300843 (DOI)000334059900012 ()
Note

AuthorCount:4;

Available from: 2014-06-05 Created: 2014-05-27 Last updated: 2018-02-12Bibliographically approved
4. Severe intractable eyelid dermatitis probably caused by exposure to hydroperoxides of linalool in a heavily fragranced shampoo
Open this publication in new window or tab >>Severe intractable eyelid dermatitis probably caused by exposure to hydroperoxides of linalool in a heavily fragranced shampoo
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2017 (English)In: Contact Dermatitis, ISSN 0105-1873, E-ISSN 1600-0536, Vol. 76, no 2, p. 114-115Article in journal (Other academic) Published
Keywords
allergic contact dermatitis, case report, eyelid dermatitis, fragrances, hydroperoxides of linalool, linalool oxidation products, liquid chromatography–mass spectrometry, patch testing, static headspace gas chromatography–mass spectrometry
National Category
Chemical Sciences
Research subject
Analytical Chemistry
Identifiers
urn:nbn:se:su:diva-151909 (URN)10.1111/cod.12738 (DOI)
Available from: 2018-01-20 Created: 2018-01-20 Last updated: 2018-02-12Bibliographically approved
5. A two-dimensional reversed and normal phase high-performance liquid chromatography/tandem mass spectrometry system for determination of linalool and limonene hydroperoxides.
Open this publication in new window or tab >>A two-dimensional reversed and normal phase high-performance liquid chromatography/tandem mass spectrometry system for determination of linalool and limonene hydroperoxides.
(English)Manuscript (preprint) (Other academic)
National Category
Chemical Sciences
Research subject
Analytical Chemistry
Identifiers
urn:nbn:se:su:diva-152639 (URN)
Available from: 2018-02-05 Created: 2018-02-05 Last updated: 2018-02-12Bibliographically approved

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