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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:
From 1997-04-30 to 1997-05-30
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study performed according to OECD test guideline No. 406 and in compliance with GLP
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1997
Report date:
1997

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
yes
Remarks:
temperature of animal room was outside the range; age of animals at study initiation not reported
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. QA statement)
Type of study:
guinea pig maximisation test

Test material

Constituent 1
Chemical structure
Reference substance name:
Pentadecan-15-olide
EC Number:
203-354-6
EC Name:
Pentadecan-15-olide
Cas Number:
106-02-5
Molecular formula:
C15H28O2
IUPAC Name:
1-oxacyclohexadecan-2-one
Test material form:
solid: crystalline
Details on test material:
- Physical state: White crystalline
- Storage condition of test material: Stored in the refrigerator at 2-8 °C

In vivo test system

Test animals

Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Mollegaard Breeding and Research Centre A/S, Lille Skensved, Denmark
- Weight at study initiation: 299-361 g
- Housing: Animals were housed two or three per cage in polycarbonate (macrolone type IV, floor area 1800 cm^2) cages.
- Diet: Pelleted diet ("3113 Altromin", from Chr. Petersen A/S, Ringsted, Denmark), ad libitum
- Water: Vitamin C enriched domestic quality water acidified to pH 2.5 with Hydrochloric acid, ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 3 °C
- Humidity: 55 ± 15 %
- Air changes: 10/h
- Photoperiod: 12 h dark / 12 h light

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
other: intradermal and topical induction
Vehicle:
other: Sesame oil and Ethanol/diethyl phthalate 1:1
Concentration / amount:
Preliminary study (irritancy study):
- Intradermal irritancy: 1.25, 2.5, 5, 10 and 25 % w/w in sesame oil
- Topical irritancy: 12.5, 25, 50 and 100 % w/w in Ethanol/diethyl phthalate 1:1

Main study:
- Intradermal induction exposure: 10 % w/w in sesame oil
- Topical induction exposure: 50 % w/w in Ethanol/diethyl phthalate 1:1
- Topical challenge exposure: 25 % w/w in Ethanol/diethyl phthalate 1:1
- Topical rechallenge exposure: 12.5 % w/w in Ethanol/diethyl phthalate 1:1
Challengeopen allclose all
Route:
other: topical challenge
Vehicle:
other: Sesame oil and Ethanol/diethyl phthalate 1:1
Concentration / amount:
Preliminary study (irritancy study):
- Intradermal irritancy: 1.25, 2.5, 5, 10 and 25 % w/w in sesame oil
- Topical irritancy: 12.5, 25, 50 and 100 % w/w in Ethanol/diethyl phthalate 1:1

Main study:
- Intradermal induction exposure: 10 % w/w in sesame oil
- Topical induction exposure: 50 % w/w in Ethanol/diethyl phthalate 1:1
- Topical challenge exposure: 25 % w/w in Ethanol/diethyl phthalate 1:1
- Topical rechallenge exposure: 12.5 % w/w in Ethanol/diethyl phthalate 1:1
No. of animals per dose:
Sighting study: 2 animals used for intradermal and topical induction
Main study: 10 and 20 animals for control and treatment group, respectively
Details on study design:
PRELIMINARY STUDY:
- Intradermal irritancy: Guinea pigs received intradermal injections of test material at concentrations of 1.25, 2.5, 5, 10 and 25 % w/w in sesame oil and evaluated for local reactions at 24 and 48 h after termination of exposure.
- Topical irritancy: Two guinea pigs were applied topically with test substance at 12.5, 25, 50 and 100 % w/w in Ethanol/diethyl phthalate 1:1 and evaluated for dermal reactions at 24 and 48 h after termination of exposure.

MAIN STUDY
A. INDUCTION EXPOSURE: INTRADERMAL
- No. of exposures: One
- Test groups: Intradermally injected with 3 pairs of injections (0.1 mL each) of Freund's complete adjuvant (FCA) emulsified 1:1 in sterile water, 10 % (w/w) test article in sesame oil and 10 % (w/w) test article formulated in a 1:1 mixture (w/w) of FCA and sesame oil, on Day 1.
- Control group: Intradermally injected with 3 pairs of injections (0.1 mL each) of Freund's complete adjuvant (FCA) emulsified 1:1 in sterile water, sesame oil, distilled water and FCA in the ratio 1:1 (w/w), on Day 1.
- Site: Shoulder region
- Duration: Days 1-7

Day 7 - Sodium lauryl sulphate exposure: Six days after the injections, the same injected area was applied with 0.5 g sodium lauryl sulphate (10 % in petrolatum) to provoke a mild inflammatory reaction for topical exposure of test item.

B. INDUCTION EXPOSURE: TOPICAL
- No. of exposures: One
- Exposure period: 48 h
- Test groups: Filter paper patch (Whatman No.3 MM, 2 x 4 cm) was saturated with 0.25 mL of 50 % test article in Ethanol/diethyl phthalate 1:1, applied topically via occlusive dressing, on Day 8.
- Control group: Filter paper patch (Whatman No.3 MM, 2 x 4 cm) was saturated with 0.25 mL of Ethanol/diethyl phthalate 1:1, applied topically via occlusive dressing, on Day 8.
- Site: Same intradermally injected area of shoulder region
- Frequency of applications: Single application
- Duration: Days 8-20

C. CHALLENGE EXPOSURE: TOPICAL
- No. of exposures: One
- Day of challenge: Day 21
- Exposure period: 24 h
- Test groups: Filter paper patch (Whatman No. 3 MM, 2 x 2 cm) was saturated with about 0.1 mL of 25 % (w/w) test article in Ethanol/diethyl phthalate 1:1 or vehicle (Ethanol/diethyl phthalate 1:1) and placed on the left anterior flank and left posterior flank, respectively via occlusive dressing.
- Control group: Filter paper patch (Whatman No. 3 MM, 2 x 2 cm) was saturated with about 0.1 mL of 25 % (w/w) test article in Ethanol/diethyl phthalate 1:1 and placed on the left posterior flank, via occlusive dressing.
- Evaluation (h after removal of challenge patch): 24 and 48 h

D. RECHALLENGE EXPOSURE: TOPICAL
- No. of exposures: One
- Day of challenge: Day 29
- Exposure period: 24 h
- Test groups: Filter paper patch (Whatman. No. 3 MM, 2 x 2 cm) was saturated with about 0.1 mL of 12.5 % (w/w) test article in Ethanol/diethyl phthalate 1:1 or vehicle (Ethanol/diethyl phthalate 1:1) and placed on the right anterior flank and right posterior flank, respectively via occlusive dressing.
- Control group: Filter paper patch (Whatman. No. 3 MM, 2 x 2 cm) was saturated with about 0.1 mL of 12.5 % (w/w) test article in Ethanol/diethyl phthalate 1:1 and placed on the right posterior flank via occlusive dressing.
- Evaluation (h after removal of challenge patch): 24 and 48 h

OTHER:
Health and body weight:
- Animals were observed at least once a day for signs of ill health and reaction to treatment.
- Animals were weighed on the day of the first induction and at termination of the study.
Challenge controls:
- Challenge control: 25 % (w/w) test article in Ethanol/diethyl phthalate 1:1 was placed on the left posterior flank of control group.

- Rechallenge control: 12.5 % (w/w) test article in Ethanol/diethyl phthalate 1:1 was placed on the right posterior flank of control group.
Positive control substance(s):
yes
Remarks:
Historical data (1996): Formaldehyde

Study design: in vivo (LLNA)

Concentration:
Not applicable
No. of animals per dose:
Not applicable
Details on study design:
Not applicable
Statistics:
Not applicable

Results and discussion

Positive control results:
Historical data (1996): Incidence of sensitisation for formaldehyde was 90 % and classified as a sensitiser to guinea pig skin.

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
25 % (w/w) in Ethanol/diethyl phthalate 1:1
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
none
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 25 % (w/w) in Ethanol/diethyl phthalate 1:1. No with. + reactions: 0.0. Total no. in groups: 20.0. Clinical observations: none.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
25 % (w/w) in Ethanol/diethyl phthalate 1:1
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
none
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 25 % (w/w) in Ethanol/diethyl phthalate 1:1. No with. + reactions: 0.0. Total no. in groups: 20.0. Clinical observations: none.
Reading:
rechallenge
Hours after challenge:
24
Group:
test chemical
Dose level:
12.5% (w/w) in Ethanol/diethyl phthalate 1:1
No. with + reactions:
0
Total no. in group:
19
Clinical observations:
none; one animal died on Day 30
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 24.0. Group: test group. Dose level: 12.5% (w/w) in Ethanol/diethyl phthalate 1:1. No with. + reactions: 0.0. Total no. in groups: 19.0. Clinical observations: none; one animal died on Day 30.
Reading:
rechallenge
Hours after challenge:
48
Group:
test chemical
Dose level:
12.5% (w/w) in Ethanol/diethyl phthalate 1:1
No. with + reactions:
0
Total no. in group:
19
Clinical observations:
none; one animal died on Day 30
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: test group. Dose level: 12.5% (w/w) in Ethanol/diethyl phthalate 1:1. No with. + reactions: 0.0. Total no. in groups: 19.0. Clinical observations: none; one animal died on Day 30.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
0
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 0. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
0
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 0. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
rechallenge
Hours after challenge:
24
Group:
negative control
Dose level:
0
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 24.0. Group: negative control. Dose level: 0. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
rechallenge
Hours after challenge:
48
Group:
negative control
Dose level:
0
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: negative control. Dose level: 0. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.

In vivo (LLNA)

Resultsopen allclose all
Parameter:
SI
Remarks on result:
other: Not applicable
Parameter:
other: disintegrations per minute (DPM)
Remarks on result:
other: Not applicable

Any other information on results incl. tables

Induction of test and negative control groups

- Intradermal injections of Freund's complete adjuvant mixed with vehicle or test article elicited irritation.

- Slight erythema was observed in the test group on Day 3.

- No other skin reactions were observed following the induction with either vehicle or test article.

 

Challenge of test and negative control groups

Control group: Left posterior flank - HR 97/660539 (25 %)

- Slight or discrete erythema was observed in 1 animal at the examination after 48 h. Apart from that no other skin reactions were observed in any animal after 24 or 48 h.

 

Test group: Left anterior flank - HR 97/660539 (25 %)

- Slight or discrete erythema was observed in 8 animals at the examination after 24 h and in 2 animals after 48 h.

Test group: Left posterior flank - Ethanol/diethyl phthalate 1:1

- No skin reactions were observed in any animal after 24 or 48 h.

 

Rechallenge of test and negative control groups

Control group: Right posterior flank - HR 97/660539 (12.5 %)

- No skin reactions were observed in any animal after 24 or 48 h.

Test group: Right anterior flank - HR 97/660539 (12.5 %)

- Slight or discrete erythema was observed in 7 animals at the examination after 24 h and in 2 animals after 48 h.

Test group: Right posterior flank - Ethanol/diethyl phthalate 1:1

- Slight or discrete erythema was observed in 2 animals at the examination after 24 h and in one animal after 48 h.

 

- One animal died on Day 30. As necropsy showed no signs related to the study, this is not considered to affect the results of the study. Other animals showed no signs of ill health.

- Bodyweight gains of guinea pigs in the test group, between Days 1 and 24 and Days 1 and 32 were comparable to those observed in the control group animals over the same period.

 

Applicant's summary and conclusion

Interpretation of results:
not sensitising
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under these test conditions, test item HR 97/660539 is not classified as skin sensitiser according to the Annex VI of the Directive 67/548/EEC and of the Regulation (EC) N° 1272-2008 (CLP).
Executive summary:

In a Magnusson & Kligman maximisation study (GPMT) performed according to OECD Guideline 406 and in compliance with GLP, 20 female Dunkin-Hartley guinea pigs were induced with three pairs of intradermal injections (0.1 mL each) of Freund's complete adjuvant (FCA) emulsified 1:1 in sterile water, 10 % (w/w) test item, HR 97/660539 in sesame oil and 10 % (w/w) test article formulated in a 1:1 mixture (w/w) of FCA and sesame oil, on Day 1 on three different sites on each side of the mid-line on shoulder region. Control group of 10 females was intradermally induced with 0.1 mL each of Freund's complete adjuvant (FCA) emulsified 1:1 in sterile water, sesame oil, distilled water and FCA in the ratio 1:1 (w/w), on Day 1. On Day 8, the same area was topically induced with 50 % test article in Ethanol/diethyl phthalate 1:1 via occluded filter paper patch for 48 h for the treated group. Control group was patched with filter paper saturated with Ethanol/diethyl phthalate 1:1. On Day 21, challenge filter paper patch of 25 % (w/w) test article in Ethanol/diethyl phthalate 1:1 or vehicle (Ethanol/diethyl phthalate 1:1) was applied on the left anterior flank and left posterior flank, respectively. Challenge control group was applied with 25 % (w/w) test article in Ethanol/diethyl phthalate 1:1 on the left posterior flank. On Day 29, a rechallenge filter paper patch of 12.5 % (w/w) test article in Ethanol/diethyl phthalate 1:1 or vehicle (Ethanol/diethyl phthalate 1:1) was applied on the right anterior flank and right posterior flank, respectively. Rechallenge control group was applied with 12.5 % (w/w) test article in Ethanol/diethyl phthalate 1:1 on the right posterior flank. The test concentrations for the main study were determined from a sighting study using two animals per exposure.

Slight or discrete erythema was observed at the rechallenge sites of test group animals at 24 and 48 h observations. Test substance HR 97/660539 produced a 0 % (0/19) sensitisation rate and was considered to be a non-sensitiser to guinea pig skin. Historical data on positive control, formaldehyde exhibited evidence of sensitisation.

Under these test conditions, test item HR 97/660539 is not classified as skin sensitiser according to the Annex VI of the Directive 67/548/EEC and of the Regulation (EC) N° 1272-2008 (CLP).