[1,1'-Biphenyl]-2-carbonitrile, 4'-[(1,4'-dimethyl-2'-propyl[2,6'-bi-1H-benzimidazol]-1'-yl)methyl]-

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

24 January - 27 January 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, EPA 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)

Deviations:

not specified

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2400 (Acute Eye Irritation)

Deviations:

not specified

Test guideline 3

Qualifier:

according to guideline

Guideline:

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

Deviations:

not specified

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

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%
- Lot/batch No.: T02/03
- 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: 12 weeks
- Weight at study initiation: * 3 kg
- 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: 15 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:

TEST MATERIAL
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, 72 hours

Score:

0

Max. score:

0

Results 2

Irritation parameter:

conjunctivae score

Remarks:

(redness, chemosis, discharge)

Basis:

mean

Time point:

other: 1, 24, 48, 72 hours

Score:

0

Max. score:

0

Results 3

Irritation parameter:

cornea opacity score

Remarks:

cornea opacity

Basis:

mean

Time point:

other: 1h

Score:

1

Max. score:

1

Reversibility:

fully reversible

Remarks on result:

other: Opacity degree of density: 1 (mean); Extension of opaque area: 4 (mean)

Results 4

Irritation parameter:

cornea opacity score

Remarks:

cornea opacity

Basis:

mean

Time point:

other: 24h

Score:

0.33

Max. score:

1

Reversibility:

fully reversible

Remarks on result:

other: Opacity degree of density: 0.33 (mean); Extension of opaque area: 1.33 (mean)

Results 5

Irritation parameter:

cornea opacity score

Remarks:

cornea opacity

Basis:

mean

Time point:

other: 48 and 72 hours

Score:

0

Max. score:

0

Any other information on results incl. tables

One hour after treatment, in all animals some hyperaemic blood vessels occured (score 1), the discharge with moistening of the lids and hairs on a considerable area around the eye (scores 3) was observed.

In all animals, diffuse areas of opacity were observed in the cornea, but the details of the iris were clearly visible (score 1). The are of 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, irritation of conjunctivae was not found in the treated animals. In one animal, the degree and extension of cornea opacity did not change when compare to the previous observation (score 1, 4). The two remaining animals were free of irritation symptoms.

48 hours after the treatment, every animal was free of irritation symptoms.

72 hours after the treatment, the study was terminated, as all animals were free of symptoms or irritation.

Detailed results are attached.

Applicant's summary and conclusion

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

BIBR 277 Nitril, applied to the rabbit's eye mucosa caused conjunctival and corneal irritant effects, fully reversible within 48 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.