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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
Study period:
26th January - 22nd March 1998
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1998
Report date:
1998

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
no
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The LLNA does not need to be conducted because adequate data from a guinea pig maximisation test are available.

Test material

Constituent 1
Reference substance name:
Pentaerythritol mixed esters with 2-methyl butyric acid, n-pentanoic acid, n-heptanoic acid, 3,5,5-trimethylhexanoic acid, n-octanoic acid, n-decanoic acid
Cas Number:
141686-49-9
IUPAC Name:
Pentaerythritol mixed esters with 2-methyl butyric acid, n-pentanoic acid, n-heptanoic acid, 3,5,5-trimethylhexanoic acid, n-octanoic acid, n-decanoic acid
Constituent 2
Reference substance name:
Trimethylol propane mixed esters with 2-methyl butyric acid, n-pentanoic acid, n-heptanoic acid, 3,5,5-trimethylhexanoic acid, n-octanoic acid, n-decanoic acid
Cas Number:
141686-50-2
IUPAC Name:
Trimethylol propane mixed esters with 2-methyl butyric acid, n-pentanoic acid, n-heptanoic acid, 3,5,5-trimethylhexanoic acid, n-octanoic acid, n-decanoic acid
Test material form:
liquid
Details on test material:
Identification: Hatcol ® 1772
Appearance/physical state: Clear colorless liquid
Purity: 100% (no solvent present)
Composition: 70% pentaerythritol esters described by CAS# 141686-49-9; 30% trimethylolpropane esters described by CAS# 141686-50-2

In vivo test system

Test animals

Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
male
Details on test animals and environmental conditions:
ANIMAL INFORMATION
Thirty-eight 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 301 to 441 g, 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.

ANIMAL CARE AND 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.

The animal room was maintained at a temperature of 20 to 21°C and relative humidity of 34 to 66%. 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
Vehicle:
arachis oil
Concentration / amount:
25% w/v
Challenge
Route:
epicutaneous, occlusive
Vehicle:
arachis oil
Concentration / amount:
75% v/v
Day(s)/duration:
24 hours
Adequacy of challenge:
highest non-irritant concentration
No. of animals per dose:
Dose selection: 8
Induction/challenge: 20
Challenge control: 10
Details on study design:
SELECTION OF CONCENTRATIONS FOR MAIN STUDY (SIGHTING TESTS)
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. The procedures were as follows:

SELECTION OF CONCENTRATION FOR INTRADERMAL INDUCTION
Four concentrations of test material were investigated (1%, 5%, 10% and 25% w/v in arachis oil BP). A total of four guinea pigs were used, each guinea pig receiving four 0.1 ml injections of only one concentration of test material. The degree of erythema at the injection sites was assessed approximately 24, 48 and 72 hours and up to 7 days after injection according to the Draize scale. The degree of oedema was not evaluated. Any evidence of systemic toxicity was also recorded. The highest concentration that caused only mild to moderate skin irritation, and which was well tolerated systemically, was selected for the intradermal induction stage of the main study.

SELECTION OF CONCENTRATION FOR TOPICAL INDUCTION
Two guinea pigs (intradermally injected with Freund's Complete Adjuvant 17 days earlier) were treated with the undiluted test material and three preparations of the test material (75%, 50% and 25% v/v in arachis oil BP). Applications were made to the clipped flanks under occlusive dressings for an exposure period of 48 hours. The degree of erythema and oedema was evaluated approximately 1, 24 and 48 hours after dressing removal. The highest concentration producing only mild to moderate dermal irritation was selected for the topical induction stage of the main study.

SELECTION OF CONCENTRATION FOR TOPICAL CHALLENGE
The undiluted test material and three preparations of the test material (75%, 50% and 25% v/v in arachis oil BP) were applied to the clipped flanks of two guinea pigs under occlusive dressings for an exposure period of 24 hours. These guinea pigs did not form part of the main study but had been treated identically to the control animals of the main study, up to Day 14. The degree of erythema and oedema was evaluated approximately 1, 24 and 48 hours after dressing removal. The highest non-irritant concentration of the test material and one lower concentration were selected for the topical challenge stage of the main study.

MAIN STUDY
A group of thirty guinea pigs was used for the main study, twenty test and ten 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) a challenge of that response.

INDUCTION
INDUCTION OF THE TEST ANIMALS: 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 25% w/v formulation of the test material in arachis oil BP
c) a 25% 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 (i.e. injection site b) was evaluated according to the Draize scale.

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 undiluted test material. A filter paper patch (WHATMAN No. 4: approximate size 40 mm x 20 mm), saturated with the undiluted test material was applied to the prepared skin and held in place with a strip of surgical adhesive (BLENDERM: approximate size 50 mm x 30 mm) covered with an overlapping length of aluminium foil). The patch and foil were further secured with a strip of elastic adhesive bandage (ELASTOPLAST: approximate size 250 mm x 35 mm) 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 twenty-four hours following removal of the patches using the Draize scale. Any other reactions were also recorded.

INDUCTION OF THE 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) a 50% w/v formulation of arachis oil BP in Freund's Complete Adjuvant/distilled water 1:1

Approximately 24 and 48 hours after intradermal injection the degree of erythema at the vehicle injection sites (i.e. injection site b) was evaluated according to the Draize scale. The topical applications followed the same procedure as for the test animals except that nothing was applied to the filter paper. Skin reactions were quantified as for the test animals.

EVALUATION OF SKIN REACTIONS
Approximately 24 and 48 hours after challenge dressing removal, the degree of erythema and oedema was quantified using the Draize scale. Any other reactions were also recorded.

INTERPRETATION OF RESULTS
The percentage of test animals that showed a more severe reaction at the test material challenge site than the most severe reaction seen in the control animals, was compared with the following scale:

Percentage of animals sensitised Classification of sensitisation potential
0 non-sensitiser
> 0 - 8 weak sensitiser
> 8 - 28 mild sensitiser
> 28 - 64 moderate sensitiser
> 64 - 80 strong sensitiser
> 80 - 100 extreme sensitiser
Positive control substance(s):
no
Remarks:
No concurrent positive control group was included in this study. Positive control studies performed by the laboratory every 6 months in order to demonstrate satisfactory sensitisation responses using known sensitisers.

Results and discussion

Positive control results:
No concurrent positive control group was included in this study. Positive control studies performed by the laboratory every 6 months in order to demonstrate satisfactory sensitisation responses using known sensitisers. See attachment for the summary of positive control data.

In vivo (non-LLNA)

Resultsopen allclose all
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
100%
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
100%
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
75% v/v
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
75% v/v
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
100%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
100%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
75% v/v
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
75%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The test material produced a 0% (0/20) 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 risk phrase is required.
Executive summary:

Introduction

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 92/69/EEC (which constitutes Annex V of Council Directive 67/548/EEC) and the US EPA Health Effects Test Guidelines OPPTS 870.2600 (draft).

Method

Twenty test and ten 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 follows:

Intradermal induction: 25% w/v in arachis oil BP

Topical induction: undiluted as supplied

Topical challenge: undiluted as supplied and 75% v/v in arachis oil BP

Conclusion

The test material produced a 0% (0/20) 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 risk phrase is required.