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Sensitisation data (human)

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Administrative data

Endpoint:
sensitisation data (humans)
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2002 to 2003
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
A skin sensitiser is an agent that will lead to an allergic response in susceptible individuals following skin contact. Human experimental studies are not recommended to fulfil REACH Annex VII information requirements. However, all existing available information should be evaluated, including any available human data. The human patch test is a confirmatory test in the safety evaluation of skin sensitisers involving the repeat exposure of small patches of skin to the test item. Whilst the CLP regulation does not contain clear criteria for classification for skin sensitisation based on human data, the studies can substantiate no-effect levels and ensure that matrix effects are not making an unexpected contribution to sensitising potency.

Data source

Reference
Reference Type:
publication
Title:
Selected oxidized fragrance terpenes are common contact allergens
Author:
Matura M, Sköld M, Börje A, Andersen KE, Bruze M, Frosch P, Goossens A, Johansen JD, Svedman C, White IR, Karlberg AT
Year:
2005
Bibliographic source:
Contact Dermatitis, 52, 320–328

Materials and methods

Type of sensitisation studied:
skin
Study type:
study with volunteers
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Inclusion/exclusion criteria: Patients with known and/or suspected fragrance allergy and patients with hand eczema without known adverse reactions to fragrances were included.
- Principle of test: Dermatitis patients were tested with the maximal non-irritant test item concentrations at the participating dermatology clinics of Copenhagen, Dortmund, Leuven, London, Malmö and Odense during 2002–2003. A questionnaire about clinical data (i.e. localisation of symptoms, history of atopy and occupation) was filled out before testing. An additional two step targeted study was performed in Odense and Leuven including patients with fragrance hypersensitivity without hand eczema, and patients with hand eczema but without adverse reaction to fragrances.
- Short description of test conditions: Patch test materials were applied in small (8 mm) Finn Chambers on Scanpor tape. Readings were taken twice, on days 2 and 4 (exceptionally on day 3) in Leuven, London and Dortmund, and on days 3 and 6/7 in the other
centres, and scored according to the ICDRG standard recommendations.
- Parameters analysed / observed: Positive / negative reactions
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Caryophyllene
EC Number:
201-746-1
EC Name:
Caryophyllene
Cas Number:
87-44-5
Molecular formula:
C15H24
IUPAC Name:
(1R,4E,9S)-4,11,11-trimethyl-8-methylidenebicyclo[7.2.0]undec-4-ene

Method

Type of population:
other: dermatitis patients
Ethical approval:
confirmed and informed consent free of coercion received
Subjects:
- Number of subjects exposed: 1151
- Demographic information: Participants undertook testing in Copenhagen, Dortmund, Leuven, London, Malmö and Odense
Clinical history:
- History of allergy or casuistics for study subject or populations: The irritation test was performed with dermatitis patients. The targeted study was performed with patients with fragrance hypersensitivity without hand eczema, and patients with hand eczema but without adverse reaction to fragrances.
- Exposure history: The patients with fragrance allergy (n = 21) were partly recruited for retesting among previously tested individuals who had shown positive reactions to fragrance allergy markers and own perfumes, and partly chosen from consecutive dermatitis patients who had a certain history of adverse reactions to fragrances. In the two-step-targeted study, there were 66 patients with hand eczema and no history for adverse reaction to fragrances.
Controls:
None reported
Route of administration:
dermal
Details on study design:
TYPE OF TEST(S) USED: patch test (epicutaneous test)

ADMINISTRATION
- Description of patch: Patch test materials were applied in small (8 mm) Finn Chambers on Scanpor tape (Epitest, Tuusula, Finland).
- Vehicle / solvent: Non-stabilised white petrolatum
- Concentrations: The irritation study and targeted test were performed with 3.0% (w/w) oxidation mixture of β-caryophyllene and 3.9% (w/w) caryophyllene oxide. Oxidized β-caryophyllene contained 25% β-caryophyllene and 35% caryophyllene oxide.
- Volume applied: 20 µL
- Testing/scoring schedule: Readings were taken twice, on days 2 and 4 (exceptionally on day 3) in Leuven, London and Dortmund, and on days 3 and 6/7 in the other centres.
- Other: To mimic the oxidation that takes place during handling and storage, β-caryophyllene was air exposed in an Erlenmeyer flask, covered with aluminium foil to prevent contamination, and stirred for 1 h, 4 times a day. An oxidised sample of β-caryophyllene (air-exposed for 10 weeks) was stored under nitrogen at –20°C until test preparations were made.

EXAMINATIONS
- Grading/Scoring system: ICDRG standard recommendations
- Statistical analysis: Chi-square test was used for the analysis of concomitant positive reactions.

Results and discussion

Results of examinations:
Testing with oxidation mixture of caryophyllene gave positive reactions in 8/1511 patients (0.5%), of whom 2 also reacted to caryophyllene oxide. In the two-step-targeted study, the oxidation mixture of caryophyllene gave 1 reaction.

Any other information on results incl. tables

Table 1. Positive patch test reactions to oxidized terpenes and oxidation fractions in 1511 consecutive dermatitis patients at 6 dermatological centres

 Test item  Dortmund (n = 223)  Gentofte (n = 230)  Leuven (n = 200)  London (n = 302)  Malmö (n = 294)  Odense (n = 262)  Total (n = 1511)
 Oxidation mixture of caryophyllene 3.0% pet.  2 (0.9%)  0  1 (0.5%)  2 (0.7%)  0  3 (1.1%)  8 (0.5%)
 Caryophyllene oxide 3.9% pet.  1 (0.4%)  0  0  0  0  1 (0.4%)  2 (0.1%)

Table 2. Questionable and positive patch test reactions to oxidized and non-oxidized terpenes, oxidation compounds and fractions in the targeted study of patients with hand eczema or fragrance hypersensitivity in Odense and Leuven

 Test item  Concentration  Fragrance hypersensitivity patients (n = 21)     Hand eczema patients (n = 66)   
     Questionable  Positive  Questionable  Positive
 Caryophyllene oxide  3.9%  2  0  1  0
 Oxidation mixture of caryophyllene  3%  0  1 (++)  0  0

Applicant's summary and conclusion

Conclusions:
About 0.5% of the patients (n = 1511) reacted to oxidised caryophyllene and 0.1% of patients reacted to caryophyllene oxide. Caryophyllene oxide gave positive reactions in only 2 out of 8 patients also reacting to the mixture of oxidized caryophyllene.
Executive summary:

Consecutive dermatitis patients (n = 1511) in 6 European dermatology centres were patch tested with 3.0% oxidation mixture of caryophyllene (containing 25% β-caryophyllene and 35% caryophyllene oxide) or 3.9% caryophyllene oxide in non-stabilised white petrolatum (2005). About 0.5% of the patients reacted to oxidized caryophyllene and 0.1% of patients reacted to caryophyllene oxide. Caryophyllene oxide gave positive reactions in only 2 out of 8 patients also reacting to the mixture of oxidized caryophyllene. This study is reliable with restrictions (Klimisch 2) as it is a large clinical study reported in a peer-reviewed journal and meets generally accepted scientific principles.

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