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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:
09 November 1998 - 21 December 1998
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
GLP study following test guideline OECD406. The study can be used to draw a conclusion on the non sensitizing properties to skin of the tested substance, which differs slightly from the registered substance. The report does not include the compostion of the test substance.

Data source

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

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
1992
GLP compliance:
yes (incl. QA statement)
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The Murine Local Lymph Node Assay (LLNA) is the first-choice method for in vivo testing according to the REACH Regulation. However, this reliable GPMT test was performed before entry into force of the REACH Regulation.

Test material

Constituent 1
Reference substance name:
Benzene, 1,1'-oxybis[methyl-, sulfonated, ammonium salts
EC Number:
278-188-0
EC Name:
Benzene, 1,1'-oxybis[methyl-, sulfonated, ammonium salts
Cas Number:
75314-26-0
Molecular formula:
C14H13O4S . NH4 - C70H60O19S6 . 2NH4
IUPAC Name:
Benzene, 1,1'-oxybis[methyl-, sulfonated, ammonium salts
Constituent 2
Chemical structure
Reference substance name:
Urea
EC Number:
200-315-5
EC Name:
Urea
Cas Number:
57-13-6
Molecular formula:
CH4N2O
IUPAC Name:
urea
Constituent 3
Chemical structure
Reference substance name:
Water
EC Number:
231-791-2
EC Name:
Water
Cas Number:
7732-18-5
Molecular formula:
H2O
IUPAC Name:
Oxidane
Test material form:
liquid
Details on test material:
Description : brown viscous liquid
Storage conditions: room temperature in the dark
Specific details on test material used for the study:
Date received : 02 November 1998

In vivo test system

Test animals

Species:
guinea pig
Strain:
Dunkin-Hartley
Remarks:
Albino animals
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: David Hall Limited, Burton-on-Trent, Staffordshire, UK
- Females nulliparous and non-pregnant: not specified
- Age at study initiation: eight to twelve weeks old
- Weight at study initiation: 311 to 357g
- Housing: singly or in pairs in solid-floor polypropylene cages furnished with woodflakes.
- Diet: Guinea Pig FD1 Diet, Special Diets Services Limited, Witham, Essex, UK ad libitum
- Water: tap water ad libitum
- Acclimation period: at least 5 days
- Indication of any skin lesions:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 22°C
- Humidity (%): 44 to 51%
- Air changes (per hr): Approx. 15 changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal
Vehicle:
water
Concentration / amount:
1% w/v
Adequacy of induction:
highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
Route:
epicutaneous, occlusive
Vehicle:
unchanged (no vehicle)
Concentration / amount:
Filter paper patch WHATMAN No.4 approximate size 20 mm x 20 mm, saturated with the undiluted test material
Day(s)/duration:
48 hours
Adequacy of induction:
highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
Challenge
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
unchanged (no vehicle)
Concentration / amount:
Filter paper patch WHATMAN No.4, approximate size 20 mm x 20 mm, saturated with the undiluted test material and 75% v/v in distilled water
Day(s)/duration:
24 hours
Adequacy of challenge:
highest non-irritant concentration
No. of animals per dose:
10 test animals, 5 control animals
Details on study design:
RANGE FINDING TESTS:
1 - Selection of Concentration for lntradermal lnduction
Two concentrations of test material were investigated (5% and 1% w/v in distilled water). A total of two 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 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.
2 - Selection of Concentration for Topical lnduction
Two guinea pigs (intradermally injected with Freund's Complete Adjuvant eleven days earlier) were treated with the undiluted test material and three preparations of the test material (75%, 50% and 25% vlv in distilled water). 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.
3 - Selection of Concentration for Topical Challenge
The undiluted test material and three preparations of the test material (75%,50% and 25% v/v in distilled water) 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. INDUCTION EXPOSURE
lnduction 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 1% w/v formulation of the test material in distilled water
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 (ie. injection site b) 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 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 tape (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

lnduction of the Control Animals: lntradermal 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) distilled water
c) a 50% w/v formulation of distilled water in Freund's Complete Adjuvant/distilled water 1 : 1
Approximalely 24 and 48 hours after intradermal injection the degree of efihema at the vehicle injection sites (ie injection site b) was evaluated.
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.


B. CHALLENGE EXPOSURE
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), saturated with the undiluted test material 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 75% v/v in distilled water 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 distilled water 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.

Challenge controls:
Approximately 24 and 48 hours after challenge dressing removal, the degree of erythema and oedema was quantified
Positive control substance(s):
no

Results and discussion

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:
10
Clinical observations:
none
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:
10
Clinical observations:
none
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
75 %
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
75%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
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:
5
Clinical observations:
none
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:
5
Clinical observations:
none
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
75 %
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
none
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:
5
Clinical observations:
none
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
other: project no. 039/163
Group:
positive control
Dose level:
10% of 2-Mercaptobenzothiazole in arachis oil BP (intradermal) / 50% of 2-Mercaptobenzothiazole in acetone:PEG400 70:30 (topical) / 50% and 25% of 2-Mercaptobenzothiazole in acetone:PEG400 70:30 (challenge)
No. with + reactions:
7
Total no. in group:
10
Remarks on result:
positive indication of skin sensitisation
Key result
Reading:
other: report no. 039/239
Group:
positive control
Dose level:
10% of 2-Mercaptobenzothiazole in arachis oil BP (intradermal) / 50% of 2-Mercaptobenzothiazole in acetone:PEG400 70:30 (topical) / 50% and 25% of 2-Mercaptobenzothiazole in acetone:PEG400 70:30 (challenge)
No. with + reactions:
9
Total no. in group:
10
Remarks on result:
positive indication of skin sensitisation
Key result
Reading:
other: report no. 039/249
Group:
positive control
Dose level:
10% of 2-Mercaptobenzothiazole in arachis oil BP (intradermal) / 50% of 2-Mercaptobenzothiazole in acetone:PEG400 70:30 (topical) / 50% and 25% of 2-Mercaptobenzothiazole in acetone:PEG400 70:30 (challenge)
No. with + reactions:
7
Total no. in group:
10
Remarks on result:
positive indication of skin sensitisation
Key result
Reading:
other: report no. 039/258
Group:
positive control
Dose level:
10% of 2-Mercaptobenzothiazole in arachis oil BP (intradermal) / 50% of 2-Mercaptobenzothiazole in acetone:PEG400 70:30 (topical) / 50% and 25% of 2-Mercaptobenzothiazole in acetone:PEG400 70:30 (challenge)
No. with + reactions:
9
Total no. in group:
10
Remarks on result:
positive indication of skin sensitisation
Key result
Reading:
other: report no. 039/284
Group:
positive control
Dose level:
10% of 2-Mercaptobenzothiazole in arachis oil BP (intradermal) / 50% of 2-Mercaptobenzothiazole in acetone:PEG400 70:30 (topical) / 50% and 25% of 2-Mercaptobenzothiazole in acetone:PEG400 70:30 (challenge)
No. with + reactions:
10
Total no. in group:
10
Remarks on result:
positive indication of skin sensitisation
Key result
Reading:
other: report no. 413/26
Group:
positive control
Dose level:
0.1% of 2,4-Dinitrochlorobenzene in arachis oil BP (intradermal) / 0.75% of 2,4-Dinitrochlorobenzene in 80% aqueus ethanol (topical) / 0.25% and 0.1% of 2,4-Dinitrochlorobenzene in 80% aqueus ethanol (challenge)
No. with + reactions:
10
Total no. in group:
10
Remarks on result:
positive indication of skin sensitisation

Any other information on results incl. tables

Skin Reactions Observed After lntradermal lnduction:

Well-defined or moderate to severe erythema was noted at the intradermal injection sites of test group animals at the 24 and 48-hour observations.

lncidents of very slight erythema were noted at the intradermal injection sites of control group animals.

Skin Reactions Observed After Topical lnduction:

Very slight or well-defined erythema and incidents of very slight or slight oedema were noted at the topical induction sites of all test group animals at the 1-hour observation and eight test group animals at the 24-hour observation.

lncidents of bleeding from the intradermal injection sites were noted in test and control group animals at the 1-hour observation.

No skin reactions were noted at the topical induction sites of control group animals at the 1 and 24-hour observations.

Skin Reactions Observed After Topical Challenge:

Undiluted As Supplied: No skin reactions were noted at the challenge sites of the test or control group animals at the 24 or 48-hour observations.

75% v/v in Distilled Water: 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.

Evidence of Systemic Toxicity:

There was no evidence of systemic toxicity.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
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 the regulation 1272/2008/EC after reinterpretation of the raw data.
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 86 of Commission Directive 92/69/EEC (which constitutes Annex V of Council Directive 67/548/EEC).

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

2. 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 follows:

lntradermal lnduction: 1% w/v in distilled water

Topical lnduction: undiluted as supplied

Topical Challenge: undiluted as supplied and 75% v/v in distilled water

3. The test material produced a 0% (0/10) sensitisation rate and was classified as a nonsensitiser to guinea pig skin. The test material did not meet the criteria for classification as a sensitiser according to the regulation 1272/2008/EC after reinterpretation of the raw data.