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EC number: 448-260-8 | CAS number: 379268-96-9
Skin sensitisation
Administrative data
- Endpoint:
- skin sensitisation: in vivo (non-LLNA)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 21 July - 10 Oct 2003
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP - Guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 003
- Report date:
- 2003
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 406 (Skin Sensitisation)
- Version / remarks:
- adopted 1992
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.6 (Skin Sensitisation)
- Version / remarks:
- adopted 1996
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.2600 (Skin Sensitisation)
- Version / remarks:
- adopted 2003
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), november 2000, including the most recent partial revisions
- Deviations:
- no
- GLP compliance:
- yes
- Type of study:
- guinea pig maximisation test
Test material
Reference
- Name:
- Unnamed
- Type:
- Constituent
- Test material form:
- solid: particulate/powder
- Remarks:
- migrated information: powder
- Details on test material:
- - Name of test material (as cited in study report): UM-235
- Physical state: white powder
- Lot/batch No.: #SI-1
- Expiration date of the lot/batch: 01 Jan 2005
- Storage condition of test material: at room temperature in the dark
In vivo test system
Test animals
- Species:
- guinea pig
- Strain:
- Dunkin-Hartley
- Sex:
- female
- Details on test animals and environmental conditions:
- TEST ANIMALS
- Source: Charles River Deutschland, Kisslegg, Germany
- Age at study initiation: approximately 5 weeks old
- Weight at study initiation: control group I (mean) - 377 g ± 12 g, control group II (mean) - 342 g ± 6 g, experimental group I (mean) - 373 g ± 19 g, experimental group II (mean) - 320 g ± 8 g
- Housing: group housing of maximal 5 animals per cage containing purified sawdust bedding material
- Diet: standard guinea pig diet including asorbic acid (1000 mg/kg) (Charles River Breeding and Maintenance Diet for Guinea Pigs, Altromin), ad libitum and pressed hay twice a week
- Water: tap-water, ad libitum
- Acclimation period: at least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18.6 - 23.9 (actual range)
- Humidity (%): 38 - 96 (actual range)
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 / 12
Study design: in vivo (non-LLNA)
Inductionopen allclose all
- Route:
- intradermal and epicutaneous
- Vehicle:
- corn oil
- Concentration / amount:
- Induction:
2% intradermal, 50% epicutaneous
Challenge:
50% epicutaneous
Challengeopen allclose all
- Route:
- epicutaneous, occlusive
- Vehicle:
- corn oil
- Concentration / amount:
- Induction:
2% intradermal, 50% epicutaneous
Challenge:
50% epicutaneous
- No. of animals per dose:
- 10 (control), 20 (in test group)
- Details on study design:
- RANGE FINDING TESTS:
A preliminary irritation study was conducted, the selection of concentrations was based on the following criteria:
- the concentrations are well-tolerated systemically
- for induction exposure: the highest possible concentration that produced mild to moderate irritation (grades 2-3)
- for challenge exposure: the maximum not-irritant exposure
Series of test substance concentrations were tested. Practical feasibility of administration determined the highest starting concentration for each route. The starting and subsequent concentrations were taken from a series of dilutions: 100, 50, 20, 10, 5, 2, 1% and if needed further lower concentrations. The system and procedure were the same as used in the main study. The 4 animals used were between 4 and 9 weeks old.
Intradermal injections:
A series of test substance concentrations was used, the highest concentration being the maximum concentration that could technically be injected. Each of two animals received two different concentrations in duplicate (0.1 mL/site) in the clipped scapular region. Assessment for irritation was done 24 and 48 hours after treatment.
Epidermal application:
A series of test substance concentrations was used, the highest being the maximum concentration that could technically be applied. Two different concentrations were applied (0.5 mL each) per animal to the clipped flank. The animals receiving intradermal injections were treated with the lowest concentrations and two additional animals with the highest concentrations. After 24 hours the dressing was removed and the skin cleaned of residual test substance using water. The treated skin area was assessed for irritation 24 and 48 hours after exposure ended.
MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 2 (intradermal and epicutaneous, respectively)
- Exposure period: single injection (intradermal), 48 hours (epicutaneous)
- Test groups:
Intradermal (pairs of 3 injections):
Injection 1) 1:1 w/w mixture of Freunds' Complete Adjuvant with water for injection
Injection 2) test substance at 2 % concentration in vehicle
Injection 3) 1:1 w/w mixture of Freunds' Complete Adjuvant and the test substance at 4% concentration
Epicutaneous:
- Test substance in vehicle (50%)
- Control group:
Intradermal (3 injections):
Injection 1) 1:1 w/w mixture of Freunds' Complete Adjuvant with water for injection
Injection 2) vehicle
Injection 3) 1:1 w/w mixture of Freunds' Complete Adjuvant and vehicle
Epicutaneous:
- vehicle
- Site: scapular region (intradermal and epicutaneous)
- Frequency of applications: on Day 1 and Day 8
- Duration: Days 0-8
- Concentrations: intradermal 2%, epicutaneous 50%
B. CHALLENGE EXPOSURE
- No. of exposures: 1 challenge
- Day(s) of challenge: Day 21
- Exposure period: 24 h
- Test groups: test substance in vehicle only
- Control group: test substance in vehicle only
- Site: flank
- Concentrations: 50%
- Evaluation (hr after challenge): 48 and 72 h
OTHER:
To clarify the results of the main study, the study was extended using another set of 10 experimental and 5 control animals that were treated using the procedures described for the first set of animals. On Day 7 10% SDS was applied to one topical application site to induce skin irritation. - Challenge controls:
- The control group is actually a challenge control.
- Positive control substance(s):
- yes
- Remarks:
- Alpha-Hexylcinnamicaldehyde (tested in a reliability check which was conducted regularly, last check 6 months before start of test with test substance, induction: intradermal 20%, epicutaneous undiluted; challenge: 20%)
Results and discussion
- Positive control results:
- The skin reactions in 6 of 10 experimental animals (at 24 h reading) were considered indicative of sensitisation, based on the absence of any response in control animals. These result lead to a sensitisation rate of 60%.
In vivo (non-LLNA)
Resultsopen allclose all
- Reading:
- 1st reading
- Hours after challenge:
- 48
- Group:
- other: test group I
- Dose level:
- induction: 2%; challenge: 50%
- No. with + reactions:
- 2
- Total no. in group:
- 10
- Remarks on result:
- other: Reading: 1st reading. . Hours after challenge: 48.0. Group: other: test group I. Dose level: induction: 2%; challenge: 50%. No with. + reactions: 2.0. Total no. in groups: 10.0.
- Reading:
- 1st reading
- Hours after challenge:
- 48
- Group:
- other: control I (negative)
- Dose level:
- induction: 2%; challenge: 50%
- No. with + reactions:
- 0
- Total no. in group:
- 5
- Remarks on result:
- other: Reading: 1st reading. . Hours after challenge: 48.0. Group: other: control I (negative). Dose level: induction: 2%; challenge: 50%. No with. + reactions: 0.0. Total no. in groups: 5.0.
- Reading:
- 2nd reading
- Hours after challenge:
- 72
- Group:
- other: test group I
- Dose level:
- induction: 2%; challenge: 50%
- No. with + reactions:
- 2
- Total no. in group:
- 10
- Remarks on result:
- other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: other: test group I. Dose level: induction: 2%; challenge: 50%. No with. + reactions: 2.0. Total no. in groups: 10.0.
- Reading:
- 2nd reading
- Hours after challenge:
- 72
- Group:
- other: control I (negative)
- Dose level:
- induction: 2%; challenge: 50%
- No. with + reactions:
- 0
- Total no. in group:
- 5
- Remarks on result:
- other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: other: control I (negative). Dose level: induction: 2%; challenge: 50%. No with. + reactions: 0.0. Total no. in groups: 5.0.
- Reading:
- 1st reading
- Hours after challenge:
- 48
- Group:
- other: test group II
- Dose level:
- induction: 2%; challenge: 50%
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Remarks on result:
- other: Reading: 1st reading. . Hours after challenge: 48.0. Group: other: test group II. Dose level: induction: 2%; challenge: 50%. No with. + reactions: 0.0. Total no. in groups: 10.0.
- Reading:
- 1st reading
- Hours after challenge:
- 48
- Group:
- other: control II (negative)
- Dose level:
- induction: 2%; challenge: 50%
- No. with + reactions:
- 0
- Total no. in group:
- 5
- Remarks on result:
- other: Reading: 1st reading. . Hours after challenge: 48.0. Group: other: control II (negative). Dose level: induction: 2%; challenge: 50%. No with. + reactions: 0.0. Total no. in groups: 5.0.
- Reading:
- 2nd reading
- Hours after challenge:
- 72
- Group:
- other: test group II
- Dose level:
- induction: 2%; challenge: 50%
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Remarks on result:
- other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: other: test group II. Dose level: induction: 2%; challenge: 50%. No with. + reactions: 0.0. Total no. in groups: 10.0.
- Reading:
- 2nd reading
- Hours after challenge:
- 72
- Group:
- other: control II (negative)
- Dose level:
- induction: 2%; challenge: 50%
- No. with + reactions:
- 0
- Total no. in group:
- 5
- Remarks on result:
- other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: other: control II (negative). Dose level: induction: 2%; challenge: 50%. No with. + reactions: 0.0. Total no. in groups: 5.0.
Any other information on results incl. tables
The erythema seen after the topical induction exposure was considered to be enhanced by the SDS treatment. The first test with 5 control and 10 test animals showed two animals with positive reactions at the 48 and 72 h reading time points. This result was not sufficient to exclude a skin sensitising potential. Therefore, the study was extended using another 15 animals.
Table 1: Induction readings (first experiment)
| Animal | Intradermal injection (Day 3) |
Epidermal exposure (Day 10) |
||||||
number |
A |
B |
C |
D |
||||
Control |
E |
N |
E |
N |
E |
N |
E |
N |
16 |
2 |
0 |
0 |
0 |
2 |
0 |
0 |
0 |
17 |
1 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
18 |
2 |
0 |
0 |
0 |
2 |
0 |
0 |
0 |
| 19 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| 20 | 2 | 0 | 0 | 0 | 2 | 0 | 0 | 0 |
| Experimental | E | N | E | N | E | N | E | N |
| 21 | 3 | 0 | 3 | 0 | 3 | 0 | 3 | 0 |
| 22 | 3 | 0 | 3 | 0 | 3 | 0 | 3 | 0 |
| 23 | 3 | 0 | 3 | 0 | 3 | 0 | 3 | 0 |
| 24 | 3 | 0 | 3 | 0 | 3 | 0 | 3 | 0 |
| 25 | 3 | 0 | 3 | 0 | 3 | 0 | 3 | 0 |
| 26 | 3 | 0 | 3 | 0 | 3 | 0 | 3 | 0 |
| 27 | 3 | 0 | 3 | 0 | 3 | 0 | 3 | 0 |
| 28 | 3 | 0 | 3 | 0 | 3 | 0 | 3 | 0 |
| 29 | 3 | 0 | 3 | 0 | 3 | 0 | 3 | 0 |
| 30 | 3 | 0 | 3 | 0 | 3 | 0 | 3 | 0 |
Table 2: Induction readings (second experiment)
| Animal | Intradermal injection (Day3) |
Epidermal exposure (Day10) |
||||||
number |
A |
B |
C |
D |
||||
Control |
E |
N |
E |
N |
E |
N |
E |
N |
331 |
3 |
0 |
2 |
0 |
2 |
0 |
1 |
0 |
332 |
3 |
0 |
1 |
0 |
2 |
0 |
2 |
0 |
333 |
3 |
0 |
2 |
0 |
3 |
0 |
1 |
0 |
| 334 | 2 | 0 | 1 | 0 | 2 | 0 | 0 | 0 |
| 335 | 3 | 0 | 2 | 0 | 2 | 0 | 1 | 0 |
| Experimental | E | N | E | N | E | N | E | N |
| 336 | 3 | 0 | 3 | 0 | 3 | 0 | 1 | 0 |
| 337 | 3 | 0 | 3 | 0 | 3 | 0 | 2 | 0 |
| 338 | 3 | 0 | 3 | 0 | 3 | 0 | 2 | 0 |
| 339 | 3 | 0 | 3 | 0 | 2 | 0 | 1 | 0 |
| 340 | 3 | 0 | 3 | 0 | 3 | 0 | 1 | 0 |
| 341 | 3 | 0 | 3 | 0 | 3 | 0 | 2 | 0 |
| 342 | 3 | 0 | 3 | 0 | 3 | 0 | 2 | 0 |
| 343 | 3 | 0 | 3 | 0 | 3 | 0 | 2 | 0 |
| 344 | 3 | 0 | 2 | 0 | 2 | 0 | 3 | 0 |
| 345 | 3 | 0 | 3 | 0 | 3 | 0 | 1 | 0 |
A = 1:1 mixture of FCA and water for injection
B = 2% test substance concentration (experimental) or vehicle (control)
C = 1:1 mixture of FCA and a 4% test substance concentration (experimental) or vehicle (control)
D = 50% test substance concentration (experimental) or vehicle (control)
skin effects intradermal injections:
E = Erythema
N = signs of necrosis (mm in diameter)
Applicant's summary and conclusion
- Interpretation of results:
- not sensitising
- Remarks:
- Migrated information Criteria used for interpretation of results: EU
- Conclusions:
- CLP: not classified
DSD: not classified
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