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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:
key study
Study period:
04-07-2005 to 26-08-2005
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005
Report date:
2005

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
other: CTFA Safety Testing Guidelines
Version / remarks:
The Cosmetic, Toiletry and Fragrance Association, Inc., Washington, D. C. 20036; "Guidelines for Evaluating Photodermatitis", 1991.
Qualifier:
according to guideline
Guideline:
other: Klecak G., Geleick H. and Frey J.R. (1977). Screening of fragrance materials for allergenicity in the guinea pig. J. Soc. Cosmet. Chem. 28: 53-64.
Deviations:
not specified
Qualifier:
according to guideline
Guideline:
other: DERMATOTOXICOLOGY, Ed. F.N. Marzulli & H.l. Maibach, 1982. Hemisphere Publ. Co., Chapter 9, Author: G. Klecak. pp. 213-219
Deviations:
not specified
GLP compliance:
yes (incl. QA statement)
Remarks:
inspected: November 2002 ; signature: March 2003
Type of study:
open epicutaneous test
Justification for non-LLNA method:
Study conducted prior to Regulation (EC) 1907/2006 and/or Regulation (EC) 1272/2008 publication and implementation.

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
460-490-0
EC Name:
-
Cas Number:
477218-42-1
Molecular formula:
C18H32O3
IUPAC Name:
2-[(1S)-1-[(1R)-3,3-dimethylcyclohexyl]ethoxy]-2-methylpropyl cyclopropanecarboxylate; 2-[(1S)-1-[(1S)-3,3-dimethylcyclohexyl]ethoxy]-2-methylpropyl cyclopropanecarboxylate
Test material form:
liquid
Details on test material:
Physical state: Liquid
- Storage condition of test material: at room temperature (range of 20 ± 5 °C), light protected.
- Other: colourless liquid

In vivo test system

Test animals

Species:
guinea pig
Strain:
Dunkin-Hartley
Remarks:
CRL:(HA)BR, SPF
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Recognised supplier
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: 5-6 weeks.
- Weight at study initiation: 336 – 372 g
- Housing: individually in stainless steel suspended cages
- Diet (e.g. ad libitum): Standard maintenance/breeding diet for guinea pigs from a recognised supplier (details in the full study report).
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: The acclimatization period was at least 5 days before the start of treatment under laboratory conditions; identical to the test. One group (group 4) had no acclimatisation.

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

IN-LIFE DATES: From: To: 29-06-2005 to 04-08-2005

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
epicutaneous, open
Vehicle:
polyethylene glycol
Concentration / amount:
- Topical: 0% test material (control group)
Day(s)/duration:
Day 1 - 26
Route:
epicutaneous, open
Vehicle:
polyethylene glycol
Concentration / amount:
- Topical: 25% test material
Day(s)/duration:
Day 1 - 26
Adequacy of induction:
highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
Route:
epicutaneous, open
Vehicle:
polyethylene glycol
Concentration / amount:
- Topical: 50% test material
Day(s)/duration:
Day 1 - 26
Adequacy of induction:
highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
Route:
epicutaneous, open
Vehicle:
polyethylene glycol
Concentration / amount:
- Topical: 75% test material
Day(s)/duration:
Day 1 - 26
Adequacy of induction:
highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
Route:
epicutaneous, open
Vehicle:
unchanged (no vehicle)
Concentration / amount:
- Topical: 100%
Day(s)/duration:
Day 1 - 26
Adequacy of induction:
highest technically applicable concentration used
Challengeopen allclose all
No.:
#1
Route:
epicutaneous, open
Vehicle:
polyethylene glycol
Concentration / amount:
- Challenge: 5%
Day(s)/duration:
day 29
No.:
#2
Route:
epicutaneous, open
Vehicle:
polyethylene glycol
Concentration / amount:
- Challenge: 10%
Day(s)/duration:
day 29
No.:
#3
Route:
epicutaneous, open
Vehicle:
polyethylene glycol
Concentration / amount:
- Challenge: 15%
Day(s)/duration:
day 29
No.:
#4
Route:
epicutaneous, open
Vehicle:
polyethylene glycol
Concentration / amount:
- Challenge: 25%
Day(s)/duration:
day 29
Adequacy of challenge:
highest non-irritant concentration
No. of animals per dose:
Test group: 6 ; Control group: 6
Details on study design:
RANGE FINDING TESTS:
A preliminary irritation study was conducted in order to select test substance concentrations to be used in the main study. By cutaneous route: Tested concentrations: 100%, 75%, 50%, and 25% (w/w). Cutaneous reactions were evaluated approximately 24 and 48 hours after the application.
At 24 and 48 hours: No non-irritating dose was observed. The minimal irritating concentration of the concentrations tested was 25%. Final concentrations for definitive testing based on preliminary irritation study:
- Induction: 0.1 mL of test item, undiluted (100%) and diluted to 25%, 50% and 75% in PEG 300.
- Control: 0.1 mL PEG 300 only.
- Challenge: All animals previously treated in induction, as well as control animals, were treated in the same procedure as the induction period, but with a 5%, 10%, 15% or 25% solution in PEG 300.

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: epidermal, daily (5 times per week) for 4 weeks.
- Exposure period: Days 1-26.
- Test groups: I: Control group (PEG 300); II: Test Group 1 (induced with 25% solution); III: Test Group 2 (induced with 50% solution); IV: Test Group 3 (induced with 75% solution); V: Test Group 4 (induced with undiluted test item).
- Control group: PEG 300 (vehicle only).
- Site: epidermal application (clipped right flank);
- Frequency of applications:
- Duration: Daily application (5 days/week) over days 1-26.
- Concentrations: Topical induction: 0.1 mL test item, undiluted and diluted to 25%, 50% and 75% in PEG 300.
The control group were treated as described for the experimental group except that, instead of the test item, the vehicle was administered.

B. CHALLENGE EXPOSURE
- No. of exposures: 1 initial challenge
- Day(s) of challenge: day 29 (topical challenge)
- Exposure period: Days 1-26 (induction) ; Day 29 (topical challenge). The treated sites were assessed for challenge reactions 24, 48 and 72 hours after challenge procedure.
- Test groups: 1 control group, and 4 test groups, all challenged.
- Control group: 1; vehicle only application instead of induction with test item.
- Site: One flank (clipped)
- Concentrations: 5%, 10%, 15%, 25% in PEG 300.
- Evaluation (hr after challenge): 24, 48 and 72 hours after challenge (Day 30, 31, 32).
The control group were treated as described for the experimental group except that induction exposure had been with the vehicle rather than the test item.

OTHER: Mortality, toxicity and body weights along with irritation were examined as part of the study
Challenge controls:
negative control group consisting of 6 females, consistent with the main study (the difference being that instead of the test item only the vehicle was administered during induction)
Positive control substance(s):
yes
Remarks:
Alpha-hexylcinnamaldehyde (HCA)

Results and discussion

Positive control results:
A reliability check was performed (presented in the full study report) to check the sensitivity of the test system and the reliability of the experimental techniques used. The study used the same conditions as the main study using alpha-hexylcinnamaldehyde (induced topically with 5%, 10% and 15% solutions in PEG 300, and challenged with 0.1 - 10% challenge concentrations) as positive control.
The highest challenge concentration of 10% chosen as well as the concentration of 5% were irritant as revealed by the positive challenge results obtained with the control group. The threshold for induction of skin sensitisation was approximately 5%. No sensitisation was induced with 1%, 0.3% and 0.1%. The challenge threshold was dependent on the induction concentration used. The declining frequency of positives indicated that the threshold was achieved at 3%.

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
1st reading
Hours after challenge:
72
Group:
negative control
Dose level:
0% (control group); challenge concentration 5%
No. with + reactions:
0
Total no. in group:
6
Clinical observations:
No clinical observations noted.
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
72
Group:
negative control
Dose level:
0% (control group); challenge concentration 10%
No. with + reactions:
0
Total no. in group:
6
Clinical observations:
No clinical observations noted.
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
72
Group:
negative control
Dose level:
0% (control group); challenge concentration 15%
No. with + reactions:
0
Total no. in group:
6
Clinical observations:
No clinical observations noted.
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
72
Group:
negative control
Dose level:
0% (control group); challenge concentration 25%
No. with + reactions:
0
Total no. in group:
6
Clinical observations:
No clinical observations noted.
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
72
Group:
test chemical
Dose level:
induction concentration 25%; challenge concentration 5%
No. with + reactions:
2
Total no. in group:
6
Clinical observations:
No clinical observations noted.
Reading:
1st reading
Hours after challenge:
72
Group:
test chemical
Dose level:
induction concentration 25%; challenge concentration 10%
No. with + reactions:
4
Total no. in group:
6
Clinical observations:
No clinical observations noted.
Reading:
1st reading
Hours after challenge:
72
Group:
test chemical
Dose level:
induction concentration 25%; challenge concentration 15%
No. with + reactions:
3
Total no. in group:
6
Clinical observations:
No clinical observations noted.
Reading:
1st reading
Hours after challenge:
72
Group:
test chemical
Dose level:
induction concentration 25%; challenge concentration 25%
No. with + reactions:
5
Total no. in group:
6
Clinical observations:
No clinical observations noted.
Reading:
1st reading
Hours after challenge:
72
Group:
test chemical
Dose level:
induction concentration 50%; challenge concentration 5%
No. with + reactions:
2
Total no. in group:
6
Clinical observations:
No clinical observations noted.
Reading:
1st reading
Hours after challenge:
72
Group:
test chemical
Dose level:
induction concentration 50%; challenge concentration 10%
No. with + reactions:
2
Total no. in group:
6
Clinical observations:
No clinical observations noted.
Reading:
1st reading
Hours after challenge:
72
Group:
test chemical
Dose level:
induction concentration 50%; challenge concentration 15%
No. with + reactions:
3
Total no. in group:
6
Clinical observations:
No clinical observations noted.
Reading:
1st reading
Hours after challenge:
72
Group:
test chemical
Dose level:
induction concentration 50%; challenge concentration 25%
No. with + reactions:
2
Total no. in group:
6
Clinical observations:
No clinical observations noted.
Reading:
1st reading
Hours after challenge:
72
Group:
test chemical
Dose level:
induction concentration 75%; challenge concentration 5%
No. with + reactions:
3
Total no. in group:
6
Clinical observations:
No clinical observations noted.
Reading:
1st reading
Hours after challenge:
72
Group:
test chemical
Dose level:
induction concentration 75%; challenge concentration 10%
No. with + reactions:
3
Total no. in group:
6
Clinical observations:
No clinical observations noted.
Reading:
1st reading
Hours after challenge:
72
Group:
test chemical
Dose level:
induction concentration 75%; challenge concentration 15%
No. with + reactions:
5
Total no. in group:
6
Clinical observations:
No clinical observations noted.
Reading:
1st reading
Hours after challenge:
72
Group:
test chemical
Dose level:
induction concentration 75%; challenge concentration 25%
No. with + reactions:
5
Total no. in group:
6
Clinical observations:
No clinical observations noted.
Reading:
1st reading
Hours after challenge:
72
Group:
test chemical
Dose level:
induction concentration 100%; challenge concentration 5%
No. with + reactions:
2
Total no. in group:
5
Clinical observations:
One animal was humanely terminated on day 1, due to emaciation and diarrhoea. No clinical observations were noted in the survivors
Reading:
1st reading
Hours after challenge:
72
Group:
test chemical
Dose level:
induction concentration 100%; challenge concentration 10%
No. with + reactions:
2
Total no. in group:
5
Clinical observations:
One animal was humanely terminated on day 1, due to emaciation and diarrhoea. No clinical observations were noted in the survivors
Reading:
1st reading
Hours after challenge:
72
Group:
test chemical
Dose level:
induction concentration 100%; challenge concentration 15%
No. with + reactions:
4
Total no. in group:
5
Clinical observations:
One animal was humanely terminated on day 1, due to emaciation and diarrhoea. No clinical observations were noted in the survivors
Reading:
1st reading
Hours after challenge:
72
Group:
test chemical
Dose level:
induction concentration 100%; challenge concentration 25%
No. with + reactions:
5
Total no. in group:
5
Clinical observations:
One animal was humanely terminated on day 1, due to emaciation and diarrhoea. No clinical observations were noted in the survivors
Reading:
2nd reading
Hours after challenge:
72
Group:
positive control
Dose level:
PC induction concentration 10%; PC challenge concentration 10%
No. with + reactions:
5
Total no. in group:
6
Remarks on result:
positive indication of skin sensitisation

Any other information on results incl. tables

Applicant's summary and conclusion

Interpretation of results:
Category 1B (indication of skin sensitising potential) based on GHS criteria
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of this study, the test item was found to be a skin sensitiser.
Executive summary:

The study was performed using an Open Epicutaneous Test method under GLP. The method was consistent with Klecak G. et. al., (1977). Screening of fragrance materials for allergenicity in the guinea pig. J. Soc. Cosmet. Chem. 28: 53-64, test to assess the skin sensitisation potential of the test item. The concentrations selected for the main study were based on the results of a preliminary study. In the main study, induction was via daily topical application of the test item diluted with polyethylene glycol to 0% (control), 25%, 50%, 75%, and 100% for 5 days/week between days 1 -26. A treatment group of 6 per concentration and a control group of 6, respectively were on day 26, challenged with 5%, 10%, 15% or 25% test item in PEG 300 vehicle. Skin reactions were evaluated 24 to 72 hours after challenge treatment. No clinical signs were reported, with the exception of one animal in the 100%-induction group, which was euthanised on day 1 due to emaciation and diarrhoea. Bodyweight gain in the treated group was comparable to controls, and all survivors gained bodyweight during the study. The maximum score in control was zero. All test groups showed positive results in at least 2 animals. Under the conditions of this study, the test item is considered to be a contact skin sensitiser.