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Toxicological information

Eye irritation

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Administrative data

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2001-09-25 to 2001-10-18
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001
Report date:
2001

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
Adopted 1987-02-24
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Version / remarks:
Adopted 1992-07-31
Deviations:
no
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Chemical structure
Reference substance name:
rel-(4aR,8aR)-1-bromo-3-methoxy-4a,5,9,10,11,12-hexahydro-6H-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-one hydrochloride (1:1)
EC Number:
700-867-1
Molecular formula:
C16H16BrNO3.HCl
IUPAC Name:
rel-(4aR,8aR)-1-bromo-3-methoxy-4a,5,9,10,11,12-hexahydro-6H-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-one hydrochloride (1:1)
Test material form:
solid
Details on test material:
- Name of test material (as cited in study reports): T002102
- Physical state: solid
- Appearance: white (SDS)
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: RT002102G4A311
- Expiration date of the lot/batch: 2002-03-25 (retest date)
- Purity test date: no data
- Purity: 99.4%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: in the original container, at room temperature (range 17-23°C), away from direct sunlight.
- Stability under test conditions: stable under storage conditions
- Solubility and stability of the test substance in the solvent/vehicle: not applicable
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: not applicable

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: none

Test animals / tissue source

Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Elevage Scientifique des Dombes, F-01400 Chatillon sur Chalaronne, France
- Age at start of treatment: 14-15 weeks (males); 15-16 weeks (females)
- Weight at day of treatment: 2872 g (male), 2705-2736 g (females)
- Housing: Individually in stainless steel cages equipped with feed hoppers, drinking water bowls, with wood and haysticks for gnawing.
- Diet (e.g. ad libitum): ad libitum, pelleted standard Provimi Kliba 3418 rabbit maintenance diet (batch no. 92/01)
- Water (e.g. ad libitum): ad libitum, community tap water from Füllinsdorf
- Acclimation period: 2001-09-25 to 2001-09-30, under laboratory conditions after health examination

ENVIRONMENTAL CONDITIONS
- Temperature (deg C): 20+-3 °C
- Humidity (%): 30-70%
- Air changes (per hr): 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs fluorescent light, music played during the light period

IN-LIFE DATES: From 2001-10-01 To 2001-10-18

Test system

Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied: 0.1 g/animal (left eye only)
- Concentration: no data
Duration of treatment / exposure:
single application, the treated eyes were not rinsed after instillation.
Observation period (in vivo):
17 days
Scoring: 1, 24, 48, and 72 hours, as well as 7, 10, 14 and 17 days after administration
Number of animals or in vitro replicates:
3 animals (1 male; 2 females)
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): no. The treated eyes were not rinsed after instillation.
- Time after start of exposure: not applicable.

SCORING SYSTEM:
The ocular reaction was assessed according to the numerical scoring system listed in the EEC Commission directive 92/69/EEC at approximately 1, 24, 48 and 72 h, as well as 7, 14 and 21 days after administration. When present, corrosion of and/or staining of sclera and cornea by the test article were recorded and reported. Eye examinations were made with Varta Cliptrix diagnostic lamp (A. Riegger, Basel, Switzerland).
The primary irritation score was calculated by totaling the mean cumulative scores at 24, 48 and 72 hours and then divided by the number of data points.

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
overall irritation score
Remarks:
primary eye irritation
Basis:
mean
Remarks:
cumulative scores at 24, 48, and 72 hours and then divided by the number of data points.
Time point:
24/48/72 h
Score:
3
Reversibility:
fully reversible within: 17 days
Irritation parameter:
cornea opacity score
Remarks:
opacity
Basis:
mean
Remarks:
male 10
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Irritation parameter:
cornea opacity score
Remarks:
opacity
Basis:
mean
Remarks:
female 11
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
cornea opacity score
Remarks:
opacity
Basis:
mean
Remarks:
female 12
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Irritation parameter:
cornea opacity score
Remarks:
area
Basis:
mean
Remarks:
male 10
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Irritation parameter:
cornea opacity score
Remarks:
area
Basis:
mean
Remarks:
female 11
Time point:
24/48/72 h
Score:
3.33
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
cornea opacity score
Remarks:
area
Basis:
mean
Remarks:
female 12
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Irritation parameter:
iris score
Basis:
mean
Remarks:
male 10
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
other: not applicable
Irritation parameter:
iris score
Basis:
mean
Remarks:
female 11
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
other: not applicable
Irritation parameter:
iris score
Basis:
mean
Remarks:
female 12
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
other: not applicable
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
mean
Remarks:
male 10
Time point:
24/48/72 h
Score:
2
Max. score:
3
Reversibility:
fully reversible within: 14 days
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
mean
Remarks:
female 11
Time point:
24/48/72 h
Score:
2
Max. score:
3
Reversibility:
fully reversible within: 14 days
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
mean
Remarks:
female 12
Time point:
24/48/72 h
Score:
1.67
Max. score:
3
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
male 10
Time point:
24/48/72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
female 11
Time point:
24/48/72 h
Score:
1.33
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
female 12
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritant / corrosive response data:
- primary irritation score of 3.0
- eye reaction (mean values from 24 to 72 h) consisted:
cornea opacity 0.33
iris lesions 0.0
redness of the conjunctivae 1.89
chemosis of the conjunctivae 0.85.
- A slight corneal opacity, effecting up to the whole area of the cornea, was observed in one animal from 1 to 48 hours after treatment. This opacity was still present at the 72-hour reading (effecting up to half of the cornea) but was no longer apparent 7 days after treatment.
-No abnormal findings were observed in the iris of any animal at any reading during the observation period.
-Slight to moderate reddening of the conjunctivae was noted in two animals from 1 hour to 10 days after treatment and in the other animal from 1 to 72 hours after treatment.
-Swelling of the conjunctivae, with lids about half closed, was evident in all animals at the 1-hour reading. The severity of the swelling decreased at the 24-hour reading and gradually diminished to clear in all animals by the 7-day reading.
-A slight to moderate watery discharge was observed in all animals 1 hour after treatment and persisted in one animal up to the 24-hour reading.
-Assessment of the sclera was not possible 1 hour after treatment due to swelling of the conjunctivae, however, moderate reddening was evident in all animals at the 24-hour reading. Slight to moderate reddening persisted in one animal up to the 72-hour reading, up to the 7 -day reading in another animal and up to the 14-day reading in the remaining animal.
-No abnormal findings were observed in the treated eye of any animal at the final 17-day reading.
-No corrosion of the cornea was observed at any of the reading times. No abnormal effects were observed in the treated eyes of any animal 17 days post-exposure.
Other effects:
- No mortality occurred.
- No clinical signs of systemic toxicity
- No staining from the test substance was observed.
- No remnants of the test item in the eye or conjunctival sac were observed.
- Animal number 10 showed a very slight body weight loss (1 %) during the acclimatization period. This weight loss is considered to be incidental. The body weights of all other rabbits were considered to be within the normal range of variability.

Any other information on results incl. tables

Table 1. Eye irritation scores-mean values after 24, 48 and 72 hours.

Animal Number

Sex

Corneal Opacity

N

Iris

N

Conjunctivae

Primary Eye Irritation Score

Redness

N

chemosis

N

10

M

0.00

3

0.00

3

2.00

3

0.67

3

3.00

11

F

1.00

3

0.00

3

2.00

3

1.33

3

12

F

0.00

3

0.00

3

1.67

3

0.33

3

Mean Score

0.33

0.00

1.89

0.78

 

 N= number of available data points

Applicant's summary and conclusion

Interpretation of results:
Category 2 (irritating to eyes) based on GHS criteria
Conclusions:
The test substance is considered to be "not irritating" to the rabbit eye based on the referred classification criteria (EEC Commission Directive 93/21/EEC of April 27, 1993). However, based on the results of this study and the criteria of the CLP Regulation, the substance should be classified as eye irritant category 2.