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Diss Factsheets

Toxicological information

Skin sensitisation

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Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
Between 07 November 2005 and 10 February 2006.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP study conducted in compliance with OECD Guideline No. 406. However, age at study initiation, housing and feeding conditions not reported.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2006
Report date:
2006

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
17 July 1992
Deviations:
yes
Remarks:
age at study initiation, housing and feeding conditions are not reported.
Qualifier:
according to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
Version / remarks:
30 July 1996.
Deviations:
yes
Remarks:
age at study initiation, housing and feeding conditions are not reported.
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. QA statement)
Remarks:
Inspected on 2005-10-03 / Signed on 2005-12-13.
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
According to REACH regulation, in vivo skin sensitisation studies that were carried out or initiated before May 2017 shall be considered appropriate to address this standard information requirement.

Test material

Constituent 1
Chemical structure
Reference substance name:
(5R)-5-pentyloxan-2-one
Molecular formula:
C10 H18 O2
IUPAC Name:
(5R)-5-pentyloxan-2-one
Constituent 2
Chemical structure
Reference substance name:
(5S)-5-pentyloxan-2-one
Molecular formula:
C10 H18 O2
IUPAC Name:
(5S)-5-pentyloxan-2-one
Test material form:
liquid
Details on test material:
- Physical state: Liquid
- Storage condition of test material: room temperature.

In vivo test system

Test animals

Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Centre de production animale (F-45160 Olivet).
- Weight at study initiation: 329 - 484 g
- Housing: no data
- Diet: Guinea pigs breeding diets
- Water: no data
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 17-25 °C. A temperature of 17°C was registered instead of 19°C. A relative humidity of 25% was registered instead of 30% (minimal limit). These deviations did not, in any case, influence the results of the study.
- Humidity: 25-50 %
- Air changes: no data
- Photoperiod: no data

IN-LIFE DATES: From 07 November 2005 to 10 February 2006.

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal
Vehicle:
olive oil
Concentration / amount:
6.25% for the 1st induction
Day(s)/duration:
Day 0 - 6.
Adequacy of induction:
other: 1st induction - intradermal injection at the maximal non necrosing concentration of 6.25%
Route:
epicutaneous, occlusive
Vehicle:
paraffin oil
Concentration / amount:
100% for the 2nd induction
Day(s)/duration:
Day 7 - 10.
Adequacy of induction:
other: 2nd induction by maximal non-irritant concentration of 100%
Challenge
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
paraffin oil
Concentration / amount:
topical application at 50% and 100%.
Day(s)/duration:
Day 20 - 21
Adequacy of challenge:
other: 100% (MNIC) and at 50% (1/2 MNIC).
No. of animals per dose:
MAIN STUDY:
Group 1 (negative control): 10 males and 2 females.
Group 2 (treated): 16 males and 6 females.

Details on study design:
PRELIMINARY STUDIES:
- Maximum Non Necrotizing Concentration (M.N.N.C.) determination by intradermal injection: 2 male guinea pigs were used. The test item was injected by intradermal route at the following concentrations: 100%, diluted at 50%, 25%, 12.5%, 6.25% and 3.125% in olive oil. No necrosis has been observed, since the concentration of 6.25%, the first induction has been carried out by intradermal injection at the same concentration.

- Pre-Maximum Non Irritant Concentration (Pre-M.N.I.C.) determination by topical application: 2 male guinea pigs were used. The test item was applied under an occlusive dressing during 24 hours, at the following concentrations 100%, diluted at 50%, 25% and 12.5% in paraffin oil. 24 hours after the removal of the occlusive dressings, no cutaneous reaction was recorded whatever the tested concentration. In view of these results, the concentration selected was 100% for the 2nd induction of the main study and the MNIC determination began at this concentration of 100%

- Maximum Non Irritant Concentration (M.N.I.C.) determination by topical application: 3 female guinea pigs were used. After induction by intradermal injection with olive oil and by topical application with paraffin oil and a 17-day rest phase, the challenge phase under occlusive dressing for 24 hours consists in a single topical application of the test item at the following concentrations: 100% diluted at 50%, 25%, 12.5% in paraffin oil. 24 hours after removal of the occlusive dressings, no cutaneous reaction was recorded. In view of this result, the concentrations selected were 100% (MNIC) and 50% (1/2 MNIC) for the challenge phase.

MAIN STUDY
Induction phase: The induction phase was performed by intradermal injection at D0 with the test item at 6.25% and by topical application at D7 with the test item at 100% during 48 hours, 24 hours after brushing with a solution of sodium lauryl sulfate.
A. INDUCTION EXPOSURE (INTRADERMAL - 1st induction: Day 0)
- No. of exposures: One
- 2 intradermal injections of the test item diluted at 6.25%; 2 intradermal injections of Freund’s Complete Adjuvant diluted at 50% in isotonic sodium chloride; 2 intradermal injections of a mixture with equal volumes - Freund’s Complete Adjuvant at 50% and the test item at 12.5%.
- Site: Each side of the mid-line on scapular zone
- Exposure period: Day 0-6
- Duration: 6 days
Day 6: The scapular zone of all the animals in each group, shorn beforehand, was brushed with a solution of sodium lauryl sulfate at 10% in thick vaseline, in order to create a local irritation.

B. INDUCTION EXPOSURE (TOPICAL - 2nd induction: Day 7)
- No. of exposures: One
- Topical application, on the same zone, with the test item at 100%, 24 hours after brushing with 0.5 mL of a solution of Sodium lauryl sulfate at 10%.
- Test groups: 0.5 mL of the test item at 100%
- Control group: 0.5 mL of paraffin oil
- Site: Same intradermally injected area of scapular zone
- Frequency of applications: Single application
Day 10: Occlusive dressing removal

REST PHASE
- The animals of both groups were left for 10 days.

C. CHALLENGE EXPOSURE - FIRST CHALLENGE
- No. of exposures: One
- Day(s) of challenge: Day 20
- Exposure period: 24 h
- Day 21: Occlusive dressing removal
- The experimental procedure of this phase was identical for both negative control and treated groups submitted to this experimentation: on the previously shorn dorso-lumbar zone, an application on either side of the spine, under occlusive dressing, was performed during 24 hours:
- 1 sample cup containing the test item at 12.5% (MNIC) and at 6.25% (1/2 MNIC).
- Evaluation (h after removal of challenge patch): 24, 48 and 72 h
Positive control substance(s):
yes
Remarks:
α-Hexylcinnamaldehyde

Results and discussion

Positive control results:
α-Hexylcinnamaldehyde induced skin sensitisation indicating the validity of the study.

In vivo (non-LLNA)

Resultsopen allclose all
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
100%
No. with + reactions:
10
Total no. in group:
22
Clinical observations:
None
Remarks on result:
positive indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
100%
No. with + reactions:
6
Total no. in group:
22
Clinical observations:
None
Remarks on result:
positive indication of skin sensitisation
Key result
Reading:
other: 3rd reading
Hours after challenge:
72
Group:
test chemical
Dose level:
100%
No. with + reactions:
1
Total no. in group:
22
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
100%
No. with + reactions:
0
Total no. in group:
12
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
100%
No. with + reactions:
0
Total no. in group:
12
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
other: 3rd reading
Hours after challenge:
72
Group:
negative control
Dose level:
100%
No. with + reactions:
0
Total no. in group:
12
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
50%
No. with + reactions:
7
Total no. in group:
22
Clinical observations:
None
Remarks on result:
positive indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
50%
No. with + reactions:
3
Total no. in group:
22
Clinical observations:
None
Remarks on result:
positive indication of skin sensitisation
Key result
Reading:
other: 3rd reading
Hours after challenge:
72
Group:
test chemical
Dose level:
50%
No. with + reactions:
1
Total no. in group:
22
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
50%
No. with + reactions:
1
Total no. in group:
12
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
50%
No. with + reactions:
0
Total no. in group:
12
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
other: 3rd
Hours after challenge:
72
Group:
negative control
Dose level:
50%
No. with + reactions:
0
Total no. in group:
12
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
100 and 50%
No. with + reactions:
10
Total no. in group:
10
Clinical observations:
None
Remarks on result:
positive indication of skin sensitisation

Any other information on results incl. tables

Sensitising potential assessment:

It was recorded a slight erythema, respectively in 45% (10/22), 27% (6/22) and 5% (1/22) of the animals from the treated group, 24, 48 and 72 hours after the challenge phase, on the treated area at 100%. It was noted a slight to moderate erythema, respectively in 24%, 14% and 5% of the animals from the treated group, 24, 48 and 72 after the challenge phase, on the treated area at 50%.

No cutaneous intolerance reaction was recorded in animals from the negative control group. In effect, it was only noted a slight erythema, in only one animal (1/12) on the treated area at 50%, at the reading time 24 hours.

Weight evolution:

Not any abnormality was recorded in the weight growth of both groups, except for one treated animal for which a decrease of the body weight (-5%) was registered during the test.

Mortality: No mortality occurred during this study.

Applicant's summary and conclusion

Interpretation of results:
Category 1B (indication of skin sensitising potential) based on GHS criteria
Conclusions:
Under the test conditions, the test material is classified as skin sensitser in Category 1B according to the Regulation (EC) No. 1272/2008 (CLP) and to the GHS.
Executive summary:

In a Magnusson & Kligman maximisation study (GPMT) performed according to OECD Guideline 406 and in compliance with GLP, test item was assessed for skin sensitization in male and female Dunkin-Hartley Guinea pigs. After induction (intradermal injection at 6.25% and topical application at 100%) of 22 Guinea pigs of treated group with the test item and a 17-day rest phase, the challenge phase, under occlusive dressing for 24 hours, consisted of a single topical application of the test item at 100%, diluted at 50% in paraffin oil and of a negative control (liquid paraffin). Control group of 2 females and 10 males treated in similar manner. The test concentrations for the main study were determined from a preliminary study.

It was recorded a slight erythema, respectively in 45% (10/22), 27% (6/22) and 5% (1/22) of the animals from the treated group, 24, 48 and 72 hours after the challenge phase, on the treated area at 100%. It was noted a slight to moderate erythema, respectively in 24%, 14% and 5% of the animals from the treated group, 24, 48 and 72 after the challenge phase, on the treated area at 50%.

No cutaneous intolerance reaction was recorded in animals from the negative control group. In effect, it was only noted a slight erythema, in only one animal (1/12) on the treated area at 50%, at the reading time 24 hours.

The sensitivity of the guinea-pig was checked with known sensitiser i.e., α-Hexylcinnamaldehyde indicating the validity of the study.

Under these experimental conditions, the test material is classified as skin sensitiser in category 1B (H317: May cause an allergic skin reaction) according to the Regulation (EC) No. 1272 /2008 (CLP) and to the GHS.

This study is considered as acceptable and satisfies the requirement for skin sensitisation endpoint.