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Diss Factsheets

Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2011-10-04 to 2011-12-23
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study according to OECD test guideline 406

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report date:
2012

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
(1993)
Qualifier:
according to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
Version / remarks:
(2008)
GLP compliance:
yes
Type of study:
guinea pig maximisation test

Test material

Constituent 1
Chemical structure
Reference substance name:
4-(3-methylbut-2-en-1-yl)phenol
EC Number:
686-822-6
Cas Number:
1200-09-5
Molecular formula:
C11H14O
IUPAC Name:
4-(3-methylbut-2-en-1-yl)phenol
Test material form:
other: liquid

In vivo test system

Test animals

Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories B. V., Kreuzelweg 53, 5961 NM Horst/The Netherland
- Age at study initiation: 4 - 6 weeks
- Weight at study initiation: at beginning of acclimatization period: pretest groups 321.2 - 451.9g and test and control groups 320.7 - 439.5g
- Housing: In groups of up to 10 animals in stainless steel cages with standard softwood bedding
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 weeks for test group and control group I, 1 week for control group 2

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +- 3°C
- Humidity (%): 30 - 70%
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12/12

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal
Vehicle:
polyethylene glycol
Concentration / amount:
- Intradermal induction: 3%
- Epidermal induction: 25%
- Challenge: 10%
Challengeopen allclose all
Route:
epicutaneous, occlusive
Vehicle:
polyethylene glycol
Concentration / amount:
- Intradermal induction: 3%
- Epidermal induction: 25%
- Challenge: 10%
No. of animals per dose:
10 test animals
2 x 5 control animals
Details on study design:
RANGE FINDING TESTS:
A. INTRADERMAL INJECTION

- Intradermal Injections I:
Four intradermal injections (0.1 mL/site) of a 1:1 (v/v) mixture of Freund's Complete Adjuvant/physiological saline were made into the shaved neck of one guinea pig (no. 1). One week later, three intradermal injections (0.1 mL/site) were made into the clipped flank of the same guinea pig at concentrations of A = 50%, B = 25% and C = 10% of the test item in PEG 300. Dermal reactions were assessed 24 hours later.

- Intradermal Injections II
Due to necrosis at the injection site being observed at all concentrations tested, a second intradermal pretest was carried out in the same manner as the first intradermal pretest, using concentrations of H=3%, I=1% and J=0.3%. Dermal reactions were assessed 24 hours later.

B. EPIDERMAL APPLICATION

- Epidermal application I:
Four intradermal injections (0.1 mL/site) of a 1:1 (v/v) mixture of Freund's Complete Adjuvant/physiological saline were made into the shaved neck of two guinea pigs (nos. 2-3). One week later, four patches of filter paper (3 x 3 cm) were saturated with the test item at D = 25% E = 10%, F = 5% and G = 1% in PEG 300 and applied to the shaved flanks of the same guinea pigs. The volume of test item preparation applied was approximately 0.2 mL. The occlusive dressings were left in place for 24 hours. Dermal reactions were assessed 24 hours later.

- Epidermal application II:
As no skin irritation was observed at any concentration tested, a second intradermal pretest was carried out on two animals in the same manner as the first, using concentrations of K=75% and L=50%. Dermal reactions were assessed 24 hours later.

MAIN STUDY
A. INDUCTION EXPOSURE

1.) Intradermal Injection

- Day of application: Day 1
- Application volume: 0.1 mL
- Application site: Scapular area (left and right), clipped free of hair
- Number of applications: Total 6; each injection per site: 1) 1:1 (v/v) mixture of Freund's Complete Adjuvant (FCA) and physiological saline, 2) The test item at 3% in PEG 300, 3) The test item at 3% in a 1:1 (v/v) mixture of FCA and physiological saline
- Control group I: Identical treatment, without test item

2.) Epidermal application

- Day of application: Day 8
- Application site: Injection sites (scapular area (left and right), clipped, shaved free of hair)
- Pretreatment of application site: 0.5 mL of 10% sodium laurylsulfate (SLS) in paraffinum perliquidum massaged into the skin on day 7
- Route of application: Occlusive patch
- Duration of application: 48 h
- Patch material: Patch of filter paper (2 x 4 cm)
- Concentration: 25% in PEG 300
- Amount applied: approximately 0.3 mL
- Number of application: 1
- Fixation of Patch material: patch covered with aluminium foil and secured by an elastic plaster wrapped around the trunk of the animal and secured with impervious adhesive tape
- Evaluation (hr after challenge): approximately 24 and 48 hours after removal of the test item
- Control group I: Identical treatment, without test item


B. CHALLENGE EXPOSURE

1.) First challenge

- Day of application: Day 22
- Route of application: Epidermal (occlusive patch)
- Duration of application: 24 hours
- Patch material: Patch of filter paper (3 x 3 cm)
- Concentration: 10%
- Application volume: approximately 0.2 mL
- Application site: Left flank (test item), right flank (vehicle)
- Evaluation (hr after challenge): 24 hours and 48 hours after removal of the test item
- Control group I: Identical treatment, without test item

2.) Second challenge

- Day of application: Day 43
- Route of application: Epidermal (occlusive patch)
- Duration of application: 24 hours
- Patch material: Patch of filter paper (3 x 3 cm)
- Concentration: 10%
- Application volume: approximately 0.2 mL
- Application site: Right flank (test item), left flank (vehicle)
- Evaluation (hr after challenge): 24 hours and 48 hours after removal of the test item
- Control group II: naive control group, identical treatment, without test item

Challenge controls:
First challenge:
- Control group I: identical treatment as the test group, without test item

Second challenge:
- Control group II: naive animals, identical treatment as the test group, without test item
Positive control substance(s):
yes
Remarks:
alpha-hexylcinnamaldehyde

Results and discussion

Positive control results:
The results from the most recent positive control test (Harlan Laboratories Study D24531, performed from 29-Mar-2011 to 20-May-2011) confirm alpha-hexylcinnamaldehyde as skin sensitizer, as it produced allergic contact dermatitis in >30% of the test animals.

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
other: 1st reading of the first challenge
Hours after challenge:
24
Group:
other: control group I, vehicle treatment (right flank)
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
no
Remarks on result:
other: Reading: other: 1st reading of the first challenge. . Hours after challenge: 24.0. Group: other: control group I, vehicle treatment (right flank). No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: no.
Reading:
other: 2nd reading of the first challenge
Hours after challenge:
48
Group:
other: control group I, vehicle treatment (right flank)
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
no
Remarks on result:
other: Reading: other: 2nd reading of the first challenge. . Hours after challenge: 48.0. Group: other: control group I, vehicle treatment (right flank). No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: no.
Reading:
other: 1st reading of the first challenge
Hours after challenge:
24
Group:
other: control group I, test item (left flank)
Dose level:
10%
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
no
Remarks on result:
other: Reading: other: 1st reading of the first challenge. . Hours after challenge: 24.0. Group: other: control group I, test item (left flank). Dose level: 10%. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: no.
Reading:
other: 2nd reading of the first challenge
Hours after challenge:
48
Group:
other: control group I, test item (left flank)
Dose level:
10%
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
no
Remarks on result:
other: Reading: other: 2nd reading of the first challenge. . Hours after challenge: 48.0. Group: other: control group I, test item (left flank). Dose level: 10%. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: no.
Reading:
other: 1st reading of the first challenge
Hours after challenge:
24
Group:
other: test group, vehicle treatment (right flank)
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
no
Remarks on result:
other: Reading: other: 1st reading of the first challenge. . Hours after challenge: 24.0. Group: other: test group, vehicle treatment (right flank). No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: no.
Reading:
other: 2nd reading of the first challenge
Hours after challenge:
48
Group:
other: test group, vehicle treatment (right flank)
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
no
Remarks on result:
other: Reading: other: 2nd reading of the first challenge. . Hours after challenge: 48.0. Group: other: test group, vehicle treatment (right flank). No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: no.
Reading:
other: 1st reading of the first challenge
Hours after challenge:
24
Group:
other: test group, test item (left flank)
Dose level:
10%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
no
Remarks on result:
other: Reading: other: 1st reading of the first challenge. . Hours after challenge: 24.0. Group: other: test group, test item (left flank). Dose level: 10%. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: no.
Reading:
other: 2nd reading of the first challenge
Hours after challenge:
48
Group:
other: test group, test item (left flank)
Dose level:
10%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
no
Remarks on result:
other: Reading: other: 2nd reading of the first challenge. . Hours after challenge: 48.0. Group: other: test group, test item (left flank). Dose level: 10%. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: no.
Reading:
other: 1st reading of the second challenge
Hours after challenge:
24
Group:
other: control group II, vehicle treatment (left flank)
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
no
Remarks on result:
other: Reading: other: 1st reading of the second challenge. . Hours after challenge: 24.0. Group: other: control group II, vehicle treatment (left flank). No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: no.
Reading:
other: 2nd reading of the second challenge
Hours after challenge:
48
Group:
other: control group II, vehicle treatment (left flank)
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
no
Remarks on result:
other: Reading: other: 2nd reading of the second challenge. . Hours after challenge: 48.0. Group: other: control group II, vehicle treatment (left flank). No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: no.
Reading:
other: 1st reading of the second challenge
Hours after challenge:
24
Group:
other: control group II, test item (right flank)
Dose level:
10%
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
no
Remarks on result:
other: Reading: other: 1st reading of the second challenge. . Hours after challenge: 24.0. Group: other: control group II, test item (right flank). Dose level: 10%. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: no.
Reading:
other: 2nd reading of the second challenge
Hours after challenge:
48
Group:
other: control group II, test item (right flank)
Dose level:
10%
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
no
Remarks on result:
other: Reading: other: 2nd reading of the second challenge. . Hours after challenge: 48.0. Group: other: control group II, test item (right flank). Dose level: 10%. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: no.
Reading:
other: 1st reading of the second challenge
Hours after challenge:
24
Group:
other: test group, vehicle treatment (left flank)
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
no
Remarks on result:
other: Reading: other: 1st reading of the second challenge. . Hours after challenge: 24.0. Group: other: test group, vehicle treatment (left flank). No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: no.
Reading:
other: 2nd reading of the second challenge
Hours after challenge:
48
Group:
other: test group, vehicle treatment (left flank)
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
no
Remarks on result:
other: Reading: other: 2nd reading of the second challenge. . Hours after challenge: 48.0. Group: other: test group, vehicle treatment (left flank). No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: no.
Reading:
other: 1st reading of the second challenge
Hours after challenge:
24
Group:
other: test group, test item (right flank)
Dose level:
10%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
no
Remarks on result:
other: Reading: other: 1st reading of the second challenge. . Hours after challenge: 24.0. Group: other: test group, test item (right flank). Dose level: 10%. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: no.
Reading:
other: 2nd reading of the second challenge
Hours after challenge:
48
Group:
other: test group, test item (right flank)
Dose level:
10%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
no
Remarks on result:
other: Reading: other: 2nd reading of the second challenge. . Hours after challenge: 48.0. Group: other: test group, test item (right flank). Dose level: 10%. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: no.

Any other information on results incl. tables

Pretest:

- Intradermal Injections: Necrosis of the injection site was observed at all three concentrations tested, therefore a second intradermal pretest was performed.

- Epidermal applications: No signs of skin irritation were observed in the first epidermal application test at any of the concentrations tested (25%, 10%, 5%, 1%). At the second epidermal application test necrosis were observed at both concentration tested (75% and 50%).

-Based on the results of the pretests, the test item concentrations were selected for the main study.

Results:

Viability / Mortality

- No intercurrent deaths occurred during the course of the study.

Clinical Signs

- No clinical signs of systemic toxicity were observed throughout the study.

Skin Reactions

Skin Reactions in the Intradermal Induction:

- Expected common findings were observed in the test and control groups after the different injections using FCA intradermally. These findings consisted of erythema, oedema, necrotizing dermatitis, encrustation and exfoliation of encrustation.

No detailed description of the skin reactions is given in the report as these FCA effects are well-known.

Skin Reactions in the Epidermal Induction:

- After pretreatment with SLS prior to the application of PEG 300 only, four of five animals of control group 1 showed skin reactions ranging from discrete or patchy erythema to moderate and confluent erythema accompanied by crusts.

After pretreatment with SLS prior to the application of the test item at 25% in PEG 300, all animals of the test group showed skin reactions ranging from discrete or patchy erythema to intense erythema and swelling accompanied by crusts, fissures or scales, indicating sufficient skin irritation to induce a potential sensitisation.

Skin Reactions in the First Challenge:

- No skin reactions were observed in control group 1 or the test group after the first challenge with 10% test item in PEG 300 or PEG 300 alone.

Skin Reactions in the Second Challenge:

- No skin reactions were observed in control group 2 or the test group after the second challenge with 10% test item in PEG 300 or PEG 300 alone, thus confirming the results of the first challenge.

Body Weights

- The body weight of the animals was within the range commonly recorded for animals of this strain and age.

Pathology

- No intercurrent deaths occurred during the course of the study, hence no necropsy was performed.

Applicant's summary and conclusion

Interpretation of results:
not sensitising
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on the above mentioned findings in an adjuvant sensitisation test (M&K-test) in guinea pigs, the substance is not considered to be a skin sensitizer according to Regulation (EC) No 1272/2008.