Registration Dossier

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 in GLP compliance and in accordance with several internationally established guidelines (OECD, EEC, EPA guidelines, see below).

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2006
Report date:
2006

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Qualifier:
according to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2600 (Skin Sensitisation)
GLP compliance:
yes (incl. QA statement)
Type of study:
guinea pig maximisation test

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
480-420-2
EC Name:
-
Cas Number:
144702-27-2
Molecular formula:
C33 H29 N5
IUPAC Name:
4'-{[4-methyl-6-(1-methyl-1H-1,3-benzodiazol-2-yl)-2-propyl-1H-1,3-benzodiazol-1-yl]methyl}-[1,1'-biphenyl]-2-carbonitrile
Test material form:
other: solid
Details on test material:
- Name of test material (as cited in study report): BIBR 277 Nitril
- Physical state: solid
- Analytical purity: 99.7 %
- Purity test date: 17 October 2005
- Lot/batch No.: T02/03
- Expiration date of the lot/batch: April 2006
- Storage condition of test material: at room temperature , dark and dry

In vivo test system

Test animals

Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
not specified
Details on test animals and environmental conditions:
TEST ANIMALS
-Source: LAB-ALL, Bt. Budapest, 1174 Hunyadi u. 7.
- Weight at study initiation: 313-349 g
- Housing: al animals were housed in Macrolon cages, size III, with 2-3 animals per cage.
- Diet (e.g. ad libitum): PURISTAR standard diet for rabbit ad libitum
- Water (e.g. ad libitum): tap water ad libitum, with 50 mg/100 mL ascorbic acid.
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 3°C
- Humidity (%): 30 - 70% (relative humidity)
- Air changes (per hr): 8-12 per hour by central air-condition system
- Photoperiod (hrs dark / hrs light): 12 hours light daily from 6 am - 6pm (artificial light).

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal and epicutaneous
Vehicle:
other: methyl cellulose (1%)
Concentration / amount:
BIBR 277 Nitril was formulated in methyl cellulose (1%). the mixture was stirred using a magnetic stirrer before and during the treatment


For intra-dermal exposure test: BIBR 277 Nitril was adminstrated at concentrations of 0.1%
For dermal induction: BIBR 277 Nitril was applied at concentrations of 75%
For the challenge exposure: BIBR 277 Nitril was applied at concentrations of 50% in vehicle (methyl cellulose (1% ))
Control animals were treated with vehicle methyl cellulose ( 1%)
Challengeopen allclose all
Route:
epicutaneous, occlusive
Vehicle:
other: methyl cellulose (1%)
Concentration / amount:
BIBR 277 Nitril was formulated in methyl cellulose (1%). the mixture was stirred using a magnetic stirrer before and during the treatment


For intra-dermal exposure test: BIBR 277 Nitril was adminstrated at concentrations of 0.1%
For dermal induction: BIBR 277 Nitril was applied at concentrations of 75%
For the challenge exposure: BIBR 277 Nitril was applied at concentrations of 50% in vehicle (methyl cellulose (1% ))
Control animals were treated with vehicle methyl cellulose ( 1%)
No. of animals per dose:
10 test animals, 5 control animals per test.

Details on study design:
RANGE FINDING TESTS: a preliminary dose-finding study was performed
Test item was applied at concentrations of 0.01 and 0.1 % (w/v) for intra-dermal injection and 10, 25, 50 and 75% (w/v) for dermal application.

MAIN STUDY
A. INDUCTION EXPOSURE

- No. of exposures: 6 injections per animal for intra-dermal induction test, 1 per animal for dermal induction test.
- Exposure period: 24h (intradermal), 48h (epicutaneous)
-day(s) of challenge: day 8 after first induction test
- Test groups: 1 group, 10 animals per group
- Control group: 1 group, 5 animals per group
- Evaluation (hr after challenge): 24 or intra-dermal induction test and 1, 24, 48 and 72 hours after exposure



B. CHALLENGE EXPOSURE
- No. of exposures: 1 (epicutaneous)
- Day(s) of challenge: day 22 after first induction test
- Exposure period: 24 hours
- Test groups: 1 group, 10 animals per group
- Control group: 1 group, 5 animals per group
- Evaluation (hr after challenge): 24 and 48 hrs after exposure


Challenge controls:
Challenge controls were treated with the test substance at c=50%.

Positive control substance(s):
yes
Remarks:
Reliability studies are carried out twice a year, using items that are known to have moderate skin sensitisation properties. Latest check: 16 feb-12 March 2012 . Results are available.

Results and discussion

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
0.1%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 0.1%. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
none
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: none. No with. + reactions: 0.0. Total no. in groups: 5.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
75%
No. with + reactions:
0
Total no. in group:
19
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 75% . No with. + reactions: 0.0. Total no. in groups: 19.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
vehicle only
No. with + reactions:
0
Total no. in group:
5
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: 5.0.

Applicant's summary and conclusion

Interpretation of results:
not sensitising
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Challenge with the test item BIBR 277 Nitril caused no signs of sensitisation in test animals previously sensitised. At the same time, none of the control animals showed signs of skin sensitisation. The net response value was thus 0%, as no indications for adverse skin reactions were noted.
The test item was classified as a non-senisitiser, based on this guinea pig test and according to current EU-regulations.