4’-(2-Propyl-4-methyl-6-(1-methylbenzimidazolyl-2-yl)-benzimidazol-1-ylmethyl)biphenyl-2-carbonsäure Hydrochlorid

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

24 January - 23 March 2006

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 guidelines, see below).

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2006

Report date:

2006

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2400 (Acute Eye Irritation)

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

485-140-4

EC Name:

-

Cas Number:

515815-48-2

Molecular formula:

C33 H30 N4 O2 x HCl

IUPAC Name:

4’-(2-Propyl-4-methyl-6-(1-methylbenzimidazolyl-2-yl)-benzimidazol-1-ylmethyl)biphenyl-2-carbonsäure Hydrochlorid

Test material form:

other: solid

Details on test material:

- Name of test material (as cited in study report): BIBR 277 CL
- Molecular formula (if other than submission substance): C33H30N4O2*HCl
- Molecular weight (if other than submission substance): 514.6 + 36.5 g/mol
- Structural formula attached as image file (if other than submission substance): see reference substance
- Physical state: solid; sligh grey
- Analytical purity: 99.8 %
- Purity test date: 17. october 2005
- Lot/batch No.: 9
- Expiration date of the lot/batch: april 2006
- Storage condition of test material: at room temperature, dark and dry

Test animals / tissue source

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Ferenc Sandor breeder, Kartal, Hungary
- Age at study initiation: young adult rabbits, 10 weeks old
- Weight at study initiation: from 2940 to 34 18 g
- Housing: housed individually in metal cages
- Diet (e.g. ad libitum): Puristar rabbit diet ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: 24 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 3°C
- Humidity (%): 30 - 70%
- Air changes (per hr): 8-12 per hour
- Photoperiod (hrs dark / hrs light): 12 hrs each

Test system

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

A total volume of 0.1g of the test item was used for the study in pure state, in a single dose. The test item was instilled into the conjunctival sac of the left eye of each animal. The eyelids were held closed gently for several seconds to prevent the loss of the test item. The contralateral eye served as control. The eyes of the test animals were not washed out after test item application.

Duration of treatment / exposure:

72 hours (single dose)

Observation period (in vivo):

1, 24, 48 and 72 hours after start of the treatment.

Number of animals or in vitro replicates:

3

Details on study design:

SCORING SYSTEM:
The eye irritation scored were evaulated according to the scoring system by Draize (1959) and OECD 405 ( 24 April 2002).

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

iris score

Basis:

mean

Time point:

other: 1, 24, 48 and 72 hours

Score:

0

Max. score:

0

Results 2

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

mean

Time point:

other: 1, 24, 48 and 72 hours

Score:

0.11

Max. score:

2

Reversibility:

fully reversible

Results 3

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

other: 1, 24, 48 and 72 hours

Score:

0.44

Max. score:

4

Reversibility:

fully reversible

Any other information on results incl. tables

One hour after treatment in all animals the vessels were more diffuse (score 2), with obvious conjunctival swelling with partial eversion of the lids (score 2) and the discharge with moistening of the lids and hairs on considerable area around the were found (score 3). In these animals diffuse areas of opacity were observed on the cornea involved was greater than three quarters, up to the whole area (score 4). Iris alterations were not recorded throughout the study period.

24 hours after treatment in one animal some hyperaemic blood vessels occurred (score 1). Chemosis and increased discharge excretion were not found by this time. In two animals the degree and extension of cornea opacity did not change when compared to the previous observation (score 1, 4). One animal was free of irritation symptoms at 24 hours after the treatment.

48 hours after the treatment irritation of conjunctivae was not found in the treated animals. In two animals the degree and extension of cornea opacity did not change when compared to the previous observation (1, 4).

72 hours after treatment all animals were free of irritation symptoms.

72 hours after treatment the study was terminated, with animals free of symptoms of irritation.

Applicant's summary and conclusion

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

BIBR 277 CL, applied to the rabbit's eye mucosa caused conjunctival and corneal irritant effects, fully reversible within 72 hours. According to EC criteria for classification and labelling requirements for dangerous substances and preparations, the test item does not have to be classified and has no obligatory labelling requirement for eye irritation.