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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:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1999
Report date:
1999

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
Test perfomed in 1998 for the purposes of a Notification of New Substance (NONS).

Test material

Constituent 1
Reference substance name:
-
EC Number:
434-230-1
EC Name:
-
Cas Number:
144413-22-9
Molecular formula:
Not applicable - the substance is an UVCB
IUPAC Name:
1,4a-dimethyl-7-(propan-2-yl)-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxylic acid; prop-2-enoic acid
Test material form:
other: pale yellow blocks
Details on test material:
- Chemical name: Rosin acid reaction products with acrylic acid hydrogenated

In vivo test system

Test animals

Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
male
Details on test animals and environmental conditions:
ANIMALS
Twenty-one male albino Dunkin Hartley guinea pigs supplied by David Hall Limited, Burton-on-Trent, Staffordshire, UK were used. At the start of the main study the animals weighed 313 to 426g, and were approximately eight to twelve weeks old. After an acclimatisation period of at least five days, each animal was selected at random and given a number unique within the study which was written on a small area of clipped rump using a black indelible marker-pen.

HUSBANDRY
The animals were housed singly or in pairs in solid-floor polypropylene cages furnished with woodflakes. Free access to mains tap water and food (Guinea Pig FD1 Diet, Special Diets Services Limited, Witham, Essex, UK) was allowed throughout the study.

ENVIRONMENTAL CONDITIONS
The animal room was maintained at a temperature of 19 to 22°C and relative humidity of 49 to 62%. The rate of air exchange was approximately fifteen changes per hour and the lighting was controlled by a time switch to give twelve hours continuous light and twelve hours darkness.

Study design: in vivo (non-LLNA)

Induction
Route:
intradermal and epicutaneous
Vehicle:
arachis oil
Concentration / amount:
- Intradermal induction: 1%
- Topical induction: 50%
- Topical challenge: 50% and 25%
Challenge
Route:
epicutaneous, occlusive
Vehicle:
arachis oil
Concentration / amount:
- Intradermal induction: 1%
- Topical induction: 50%
- Topical challenge: 50% and 25%
No. of animals per dose:
MAIN STUDY:
- test group: 10
- negative control group: 5
Details on study design:
PREPARATION

For the purpose of this study the test material was freshly prepared as follows:
- Intradermal Induction: 1% w/v in arachis oil BP; 1% w/v in a mixture of Freund's Complete Adjuvant plus distilled water (1: 1)
- Topical Induction: 50% w/w in arachis oil BP
- Topical Challenge: 50% and 25% w/w in arachis oil BP

Determination by analysis of the concentration, homogeneity and stability of the test material preparations was not appropriate because it was not specified in the Study Plan and is not a requirement of the Test Guideline.

PROCEDURE

The method used for assessing the sensitising properties of the test material was based on the Guinea Pig Maximisation test of Magnusson B & Kligman A M, J. Invest. Dermatol. (1969) 52: 268 - 276.

SIGHTING TEST

The concentrations of test material to be used at each stage of the main study were determined by 'sighting tests' in which groups of guinea pigs were treated with various concentrations of test material (Intradermal induction: 1 and 5%; Topical Induction: 10, 25, 50 and 75%; Topical challenge: 5, 10, 25 and 50%). The highest concentrations producing only mild to moderate skin irritation, were selected for the intradermal and topical induction. For the challenge the highest non-irritant concentration of the test material and one lower concentration were selected.

MAIN TEST

A group of fifteen guinea pigs was used for the main study, ten test and five control. The bodyweight of each animal was recorded at the start and end of the study. Two main phases were involved in the main study; (a) an induction of a response and (b) achallenge of that response.

Induction:
Shortly before treatment on Day 0 the hair was removed from an area approximately 40 mm x 60 mm on the shoulder region of each animal with veterinary clippers. A row of three injections (0.1 mL each) was made on each side of the mid-line. The injections were:
a) Freund's Complete Adjuvant plus distilled water in the ratio 1:1
b) a 1% w/v formulation of the test material in arachis oil BP
c) a 1% w/v formulation of the test material in a 1: 1 preparation of Freund's Complete Adjuvant plus distilled water.
Approximately 24 and 48 hours after intradermal injection the degree of erythema at the test material injection sites was evaluated.
One week later (Day 7), the same area on the shoulder region used previously for intradermal injections was clipped again and treated with a topical application of the test material formulation. A filter paper patch (WHATMAN No.4: approximate size 40 mm x 20 mm), loaded with the test material formulation (50% w/w in arachis oil BP) as a thick, even layer was applied to the prepared skin and held in place with a strip of surgical adhesive tape covered with an overlapping length of aluminium foil. The patch and foil were further secured with a strip of elastic adhesive bandage wound in a double layer around the torso of each animal. This occlusive dressing was kept in place for 48 hours.
The degree of erythema and oedema was quantified one and twentyfour hours following removal of the patches. Any other reactions were also recorded.

Control animals: Intradermal injections were administered using an identical procedure to that used for the test animals, except that the injections were:
a) Freund's Complete Adjuvant plus distilled water in the ratio 1:1
b) arachis oil BP
c) 50% w/w formulation of arachis oil BP in a 1:1 mixture of Freund's Complete Adjuvant/distilled water
Approximately 24 and 48 hours after intradermal injection the degree of erythema at the vehicle injection sites was evaluated.
The topical applications followed the same procedure as for the test animals except that the vehicle alone was applied to the filter paper.
Skin reactions were quantified as for the test animals.

Challenge:
Shortly before treatment on Day 21, an area of approximately 50 mm x 70 mm on both flanks of each animal, was clipped free of hair with veterinary clippers.
A square filter paper patch (WHATMAN No.4: approximate size 20 mm x 20 mm), loaded with a thick, even layer of test material at the maximum non-irritant concentration (50% w/w in arachis oil BP) was applied to the shorn right flank of each animal and was held in place with a strip of surgical adhesive tape (BLENDERM: approximate size 40 mm x 50 mm). To ensure that the maximum non-irritant concentration was used at challenge, the test material at a concentration of 25% w/w in arachis oil BP was similarly applied to a skin site on the left shorn flank. The patches were occluded with an overlapping length of aluminium foil and secured with a strip of elastic adhesive bandage (ELASTOPLAST: approximate size 250 mm x 75 mm) wound in a double layer around the torso of each animal.
After 24 hours, the dressing was carefully cut using blunt-tipped scissors, removed and discarded. The challenge sites were swabbed with cotton wool soaked in diethyl ether to remove residual material. The position of the treatment sites was identified by using a black indelible marker-pen.
Prior to the 24-hour observation the flanks were clipped using veterinary clippers to remove regrown hair.
Positive control substance(s):
not specified

Results and discussion

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
50 %
No. with + reactions:
0
Total no. in group:
10
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
25 %
No. with + reactions:
0
Total no. in group:
10
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
50 %
No. with + reactions:
0
Total no. in group:
10
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
25 %
No. with + reactions:
0
Total no. in group:
10
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
50 %
No. with + reactions:
0
Total no. in group:
5
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
25 %
No. with + reactions:
0
Total no. in group:
5
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
50 %
No. with + reactions:
0
Total no. in group:
5
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
25 %
No. with + reactions:
0
Total no. in group:
5
Reading:
1st reading
Group:
positive control
Dose level:
Intradermal: 10% in arachis oil BP. Topical: 50% in acetone:PEG 400 (70:30). Challenge: 50% and 25% in acetone:PEG 400 (70:30).
No. with + reactions:
15
Total no. in group:
15
Remarks on result:
positive indication of skin sensitisation
Remarks:
039/284

Any other information on results incl. tables

SIGHTING TEST

Based on the results of the individual skin reactions observed in the sighting test, the following concentrations were selected for the main study:

- Intradermal Induction: 1% w/v in arachis oil BP

- Topical Induction: 50% w/w in arachis oil BP

- Topical Challenge: 50% and 25% w/w in arachis oil BP

MAIN STUDY

Skin Reactions Observed After Intradermal Induction

Very slight to well-defined or moderate to severe erythema was noted at the intradermal induction sites of test group animals at the 24 and 48-hour observations.

Very slight erythema was noted at the intradermal induction sites of all control group animals at the 24-hour observation and two control group animals at the 48-hour observation.

Skin Reactions Observed After Topical Induction

Very slight to well-defined erythema and very slight or slight oedema were noted at the 1 and 24-hour observations. A hardened dark brown/black coloured scab was noted at the induction site of one test group animal at the 24-hour observation and prevented an evaluation of the degree of erythema and oedema.

Very slight to well-defined erythema was noted at the induction sites of controI group animals at the 1-hour observation.

Incidents of bleeding were noted in test and control group animals at the 1 -hour observation.

Skin Reactions Observed After Topical Challenge

- 50% w/w in Arachis Oil BP: No skin reactions were noted at the challenge sites of the test or control group animals at the 24 or 48-hour observations.

- 25% w/w in Arachis Oil BP: No skin reactions were noted at the challenge sites of the test or control group animals at the 24 or 48-hour observations.

Bodyweight

Bodyweight gains of guinea pigs in the test group, between Day 0 and Day 24, were comparable to those observed in the control group animals over the same period.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The test material, Arakawa KE-604, produced a 0 % (0/10) sensitisation rate and was classified as non-sensitiser to guinea pig skin. The test material did not meet the criteria for classificationas a sensitiser according to EU labelling regulations. No symbol and risk phrase are required.
Executive summary:

A study was performed to assess the contact sensitisation potential of the test material in the albino guinea pig. The study was performed in compliance with the OECD Guidelines for Testing of Chemicals No. 406 "Skin Sensitisation" (adopted 17 July 1992) and Method B6 of Commission Directive 96/54/EC (which constitutes Annex V of Council Directive 67/548/EEC).

The results may be used as a basis for classification and labelling under Annex VI of Council Directive 67/548/EEC (as adapted to technical progress by Commission Directive 93/21/EEC).

Ten test and five control animals were used for the main study.

Based on the results of sighting tests, the concentrations of test material for the induction and challenge phases were selected as folIows:

- Intradermal Induction: 1% w/v in arachis oil BP

- Topical Induction: 50% w/w in arachis oil BP

- Topical Challenge: 50% and 25% w/w in arachis oil BP

The test material produced a 0% (0/10) sensitisation rate and was classified as a non-sensitiser to guinea pig skin. The test material did not meet the criteria for classification as a sensitiser according to EU labelling regulations. No symbol and risk phrase are required.