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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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to the OECD TG 406 and followed GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1988
Report date:
1988

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
(1981)
Deviations:
no
GLP compliance:
yes
Type of study:
guinea pig maximisation test

Test material

Constituent 1
Reference substance name:
A mixture of: N,N-diethylpropane-1,3-diamine 6-methyl-2-(4-(2,4,6-triaminopyrimidin-5-ylazo)phenyl)benzothiazole-7-sulfonate; 2,2-iminodiethanol 6-methyl-2-(4-(2,4,6-triaminopyrimidin-5-ylazo)phenyl)benzothiazole-7-sulfonate; 2-methylaminoethanol 6-methyl-2-(4-(2,4,6-triaminopyrimidin-5-ylazo)phenyl)benzothiazole-7-sulfonate
EC Number:
403-410-1
EC Name:
A mixture of: N,N-diethylpropane-1,3-diamine 6-methyl-2-(4-(2,4,6-triaminopyrimidin-5-ylazo)phenyl)benzothiazole-7-sulfonate; 2,2-iminodiethanol 6-methyl-2-(4-(2,4,6-triaminopyrimidin-5-ylazo)phenyl)benzothiazole-7-sulfonate; 2-methylaminoethanol 6-methyl-2-(4-(2,4,6-triaminopyrimidin-5-ylazo)phenyl)benzothiazole-7-sulfonate
Cas Number:
114565-65-0
Molecular formula:
C18 H16 N8 O3 S2 . x C7 H18 N2 . x C4 H11 N O2 . x C3 H9 N O
IUPAC Name:
(3-aminopropyl)diethylamine; 2-(methylamino)ethan-1-ol; 2-[(2-hydroxyethyl)amino]ethan-1-ol; 6-methyl-2-{4-[2-(triaminopyrimidin-5-yl)diazen-1-yl]phenyl}-1,3-benzothiazole-7-sulfonic acid
Details on test material:
- Name of test material (as cited in study report): FAT 11'184/B
- Physical state: powder
- Analytical purity: No data mentioned in the report. However, in an Ames test report (CCR 124312, see IUCLID chapter 7.6.1) using the same batch of test substance the analytical purity was given as 89.6%.
- Lot/batch No.: Op. 1 BD 823/8
- Expiration date of the lot/batch: January, 1993
- Stability under test conditions: test substance in dilution is stable for at least 2 hours

In vivo test system

Test animals

Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Designation: Dunkin-Hartley albino guinea pigs (DUHA KFM)
- Source: Kleintierfarm Madoerin AG, CH 4414 Fuellinsdorf / Switzerland
- Age at pretest: 8 weeks
- Weight at study initiation: 321-521 g
- Housing: Individually in Makrolon type-3 cages with standard softwood bedding
- Diet: Pelleted standard Kliba 342, Batches 42/88 guinea pig breeding/maintenance diet, ad libitum
- Water: Tap water, ad libitum
- Acclimation period: one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 40 - 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 and epicutaneous
Vehicle:
physiological saline
Concentration / amount:
The concentrations used for testing were selected on the basis of the results of a pretest.
For the intradermal induction, the test article was used at a concentration of 3% in vehicle.
For the epicutaneous induction, the test article was used at a concentration of 25% in vehicle.
For challenge, the test article was used at a concentration of 10% in vehicle.
Challengeopen allclose all
Route:
epicutaneous, occlusive
Vehicle:
physiological saline
Concentration / amount:
The concentrations used for testing were selected on the basis of the results of a pretest.
For the intradermal induction, the test article was used at a concentration of 3% in vehicle.
For the epicutaneous induction, the test article was used at a concentration of 25% in vehicle.
For challenge, the test article was used at a concentration of 10% in vehicle.
No. of animals per dose:
The thirty females were allocated in the following 2 groups:
- 10 animals in the control group (group 1)
- 20 animals in the test group (group 2)
Details on study design:
RANGE FINDING TEST
The aim of the pretest was to identify irritant test article concentrations suitable for the induction phase of the main study. In addition, a suitable non-irritant concentration of the test article, by the topical route of administration, was identified for the challenge application. The procedure applied for these investigations was as follows:
Intradermal injections:
Intradermal injections (0.1 ml/site) were made into the clipped flank of two animals at concentrations of 0.1, 0.3, 0.5, 1, 3 and 5% the test article in physiological saline. The resulting dermal reactions were assessed 24 hours later.
Epidermal applications:
Patches of filter paper (2 x 2 cm) were saturated with concentrations of 3, 5, 10 and 25% of the test article in physiological saline and applied to the clipped and shaved flanks of each of four animals. The patches were covered by a strip of aluminium foil and firmly secured by elastic plaster wound round the trunk and covered with impervious adhesive tape (occlusive conditions). This procedure ensured intensive contact of the test article with the guinea pig skin. The dressings were removed after an exposure period of 24 hours and the reaction sites were assessed for erythema and edema; further examination of the sites was performed 24 and 48 hours after removal of the dressings.

MAIN STUDY
A. INDUCTION EXPOSURE
A.1-Intradermal injection
An area of dorsal skin from the scapular region (approximately 6 x 8 cm) was clipped free of hair. Three pairs of intradermal injections (0.1 ml/site) were made as follows in the test group:
1) Freunds' complete adjuvant 50:50 with physiological saline.
2) The test article, diluted to 3% with physiological saline.
3) The test article diluted to 3% with physiological saline, emulsified in a 50:50 mixture of Freunds' complete adjuvant and physiological saline
The control group was treated similarly however with the omission of test article.

A.2- Epicutaneous application
One week after the injections, the scapular area (approximately 6 x 8 cm) was again clipped and shaved free of hair. A 4 x 4 cm patch of filter paper was saturated with the test article (25% in physiological saline) and placed over the injection sites of the test animals. The patch was covered by aluminium foil and firmly secured by an elastic plaster wound round the trunk of the animal and secured with impervious adhesive tape. The dressings were left in place for approximately 48 hours. The animals of the control group were treated as described above with the omission of test article. The reaction sites were assessed for erythema and edema immediately, 24 and 48 hours after removal of the dressing.

B. CHALLENGE EXPOSURE
The test and control animals were challenged two weeks after the epidermal induction application. Hair was clipped and shaved from a 5 x 5 cm area on the left and right flank of each animal. Two patches (2 x 2 cm) of filter paper were saturated with a) non-irritant concentration of the test article (10 % in physiological saline), and b) with the vehicle only and applied to the left (a) flank and right (b) flank respectively using the same method as for the epidermal application. The dressings were removed approximately 24 hours later. The sites were assessed for erythema and edema immediately, 24 and 48 hours after removal.
The control animals were treated in the same way as described above.

C- RECHALLENGE
A second challenge was performed 2 weeks after the first challenge. The method for the animals of the test article-treated group was equal to that described for the first challenge with the exception that the flanks of all the guinea-pigs were changed (a - vehicle; b - test article dilution). The control animals were treated with the vehicle alone.

SCORING OF ERYTHEMA AND EDEMA FINDINGS
Prior to the first reading of the reactions, the skin was flushed with the vehicle to clean the application site from staining, produced by the test
article, so that the reactions (erythema) were clearly visible at that time.
Erythema and edema were assessed using the following numerical grading system:
Erythema and eschar formation:
- No erythema 0
- Slight erythema (barely perceptible) 1
- Well-defined erythema 2
- Moderate erythema 3
- Severe erythema (beet redness) to slight eschar formation (injuries in depth) 4
Edema formation:
- No edema 0
- Slight edema (barely perceptible) 1
- Well-defined edema (edges of area well-defined by definite raising) 2
- Moderate edema (raised approximately 1 millimeter) 3
- Severe edema (raised more than 1 millimeter and extending beyond the area of exposure) 4

GRADING OF THE SENSITIZATION RATE
Based upon the percentage of animals sensitized (24-hour reading), the test article was assigned to one of the following five grades of allergenic potency, ranging from weak to extreme:
Sensitization rate (%) - Grade - Classification
0 to 8% - 1 - weak
9 to 28 - 2 - mild
29 to 64 - 3 - moderate
65 to 80 - 4 - strong
81 to 100 - extreme

FURTHER EXAMINATIONS
In addition to the sensitizing reactions, mortality and clinical symptoms were checked daily, whereas body weights were recorded at acclimatization start, start of application and at test ending. All surviving animals were sacrificed at test ending and discarded.
Positive control substance(s):
yes
Remarks:
Tests for contact hypersensitivity in the albino guinea pig with dinitro-chloro-benzol (DNCB) as positive control were regularly conducted in the testing facilities. The latest experimental run (March 1988) revealed clear positive results (100%)

Results and discussion

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
vehicle only
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: vehicle only. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
10% test article in vehicle
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 10% test article in vehicle. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
vehicle only
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: vehicle only. No with. + reactions: 0.0. Total no. in groups: 20.0.
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
10% test article in vehicle
No. with + reactions:
16
Total no. in group:
20
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 10% test article in vehicle. No with. + reactions: 16.0. Total no. in groups: 20.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
vehicle only
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: vehicle only. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
10% test article in vehicle
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 10% test article in vehicle. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
vehicle only
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: vehicle only. No with. + reactions: 0.0. Total no. in groups: 20.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
10% test article in vehicle
No. with + reactions:
14
Total no. in group:
20
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 10% test article in vehicle. No with. + reactions: 14.0. Total no. in groups: 20.0.
Reading:
rechallenge
Hours after challenge:
24
Group:
negative control
Dose level:
vehicle only
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 24.0. Group: negative control. Dose level: vehicle only. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
rechallenge
Hours after challenge:
24
Group:
test chemical
Dose level:
vehicle only
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 24.0. Group: test group. Dose level: vehicle only. No with. + reactions: 0.0. Total no. in groups: 20.0.
Reading:
rechallenge
Hours after challenge:
24
Group:
test chemical
Dose level:
10% test article in vehicle
No. with + reactions:
12
Total no. in group:
20
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 24.0. Group: test group. Dose level: 10% test article in vehicle. No with. + reactions: 12.0. Total no. in groups: 20.0.
Reading:
rechallenge
Hours after challenge:
48
Group:
negative control
Dose level:
vehicle only
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: negative control. Dose level: vehicle only. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
rechallenge
Hours after challenge:
48
Group:
test chemical
Dose level:
vehicle only
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: test group. Dose level: vehicle only. No with. + reactions: 0.0. Total no. in groups: 20.0.
Reading:
rechallenge
Hours after challenge:
48
Group:
test chemical
Dose level:
10% test article in vehicle
No. with + reactions:
11
Total no. in group:
20
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: test group. Dose level: 10% test article in vehicle. No with. + reactions: 11.0. Total no. in groups: 20.0.

Applicant's summary and conclusion

Interpretation of results:
sensitising
Remarks:
Migrated information Criteria used for interpretation of results: EU