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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:
The study was conducted between 02 March 2015 and 06 April 2015.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study is considered to be a reliability 1 as it has been conducted according to OECD Test Guideline 405 using an in vivo method and in compliance with GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2015
Report date:
2015

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Chemical structure
Reference substance name:
Reaction mass of (5R)-octahydro-1H-4,7-methanoinden-5-ylacetaldehyde and (5S)-octahydro-1H-4,7-methanoinden-5-ylacetaldehyde
EC Number:
940-300-7
Cas Number:
1339119-15-1
Molecular formula:
C12H18O
IUPAC Name:
Reaction mass of (5R)-octahydro-1H-4,7-methanoinden-5-ylacetaldehyde and (5S)-octahydro-1H-4,7-methanoinden-5-ylacetaldehyde
Test material form:
other: Liquid
Details on test material:
Identification (trade name): IFF TM 11-213 (FRET 09-0425)
Chemical (IUPAC) name of multi constituent: Reaction mass of 4,7-Methano-1H-indene-5-acetaldehyde, octahydro- and 4,7-Methano-1H-indene-5-carboxaldehyde, octahydro-6-methyl-
IPC number: 134635
Physical state / Appearance: clear colorless liquid
Storage Conditions: approximately 4 °C in the dark under nitrogen

Constituent 1
IUPAC names of constituents: 4,7-Methano-1H-indene-5-acetaldehyde, octahydro-
CAS number: 1339119-15-1
Concentration of tested sample: 92.6%
Concentration range: 90-100%
Molecular formula: C12H18O
Molecular weight: 178.28

Constituent 2
IUPAC names of constituents: 4,7-Methano-1H-indene-5-carboxaldehyde, octahydro-6-methyl-
CAS number: 1338815-87-4
Concentration of tested sample: 5.7%
Concentration range: 5-15%
Molecular formula: C12H18O
Molecular weight: 178.28

Test animals / tissue source

Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
Three New Zealand White (Hsdlf:NZW) strain rabbits were supplied by Harlan Laboratories UK Ltd., Leicestershire, UK. At the start of the study the animals weighed 2.93 to 3.22 kg and were 12 to 20 weeks old. After an acclimatization period of at least 5 days each animal was given a number unique within the study which was written with a black indelible marker pen on the inner surface of the ear and on the cage label.

The animals were individually housed in suspended cages. Free access to mains drinking water and food (2930C Teklad Global Rabbit diet supplied by Harlan Laboratories UK Ltd., Oxon, UK) was allowed throughout the study. The diet and drinking water were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.

The temperature and relative humidity were set to achieve limits of 17 to 23 °C and 30 to 70% respectively. The rate of air exchange was at least fifteen changes per hour and the lighting was controlled by a time switch to give 12 hours continuous light (06:00 to 18:00) and 12 hours darkness.

The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.


Justification
The rabbit is the preferred species of choice as historically used for irritation studies and is specified in the appropriate test guidelines.

Test system

Vehicle:
unchanged (no vehicle)
Controls:
other: The left eye remained untreated and was used for control purposes
Amount / concentration applied:
0.1 mL of the test item
Duration of treatment / exposure:
The test item was not removed
Observation period (in vivo):
21 days
Number of animals or in vitro replicates:
Three
Details on study design:
Immediately before the start of the test, both eyes of the provisionally selected test rabbits were examined for evidence of ocular irritation or defect with the aid of a light source from a standard ophthalmoscope. Only animals free of ocular damage were used.

Initially, a single rabbit was treated. A subcutaneous injection of buprenorphine 0.01 mg/kg was administered 60 minutes prior to test item application to provide a therapeutic level of systemic analgesia. Five minutes prior to test item application, a pre dose anesthesia of ocular anesthetic (two drops of 0.5% tetracaine hydrochloride) was applied to each eye.

A volume of 0.1 mL of the test item was placed into the conjunctival sac of the right eye, formed by gently pulling the lower lid away from the eyeball. The upper and lower eyelids were held together for about one second immediately after treatment, to prevent loss of the test item, and then released. The left eye remained untreated and was used for control purposes. Immediately after administration of the test item, an assessment of the initial pain reaction was made.

Eight hours after test item application, a subcutaneous injection of post dose analgesia, buprenorphine 0.01 mg/kg and meloxicam 0.5 mg/kg, was administered to provide a continued therapeutic level of systemic analgesia. The treated animal was checked for signs of pain and suffering approximately 12 hours later. No further analgesia was required.

After consideration of the ocular responses produced in the first treated animal, two additional animals were similarly treated.

Assessment of ocular damage/irritation was made approximately 1 hour and 24, 48 and 72 hours following treatment, according to the numerical evaluation.

Any other ocular effects were also noted. Examination of the eye was facilitated by the use of the light source from a standard ophthalmoscope.

Any clinical signs of toxicity, if present, were also recorded.

Additional observations were made on Days 7, 14 and 21 to assess the reversibility of the ocular effects.

Individual body weights were recorded on Day 0 (the day of dosing) and at the end of the observation period.

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
iris score
Remarks:
Male 74958
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
0.33
Max. score:
2
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
iris score
Remarks:
Male 75009
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
0.33
Max. score:
2
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
iris score
Remarks:
Male 75010
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
0.66
Max. score:
2
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
conjunctivae score
Remarks:
Male 74958
Basis:
mean
Remarks:
Redness
Time point:
other: 24, 48 and 72 hours
Score:
2
Max. score:
3
Reversibility:
fully reversible within: 21 days
Irritation parameter:
conjunctivae score
Remarks:
Male 75009
Basis:
mean
Remarks:
Redness
Time point:
other: 24, 48 and 72 hours
Score:
2
Max. score:
3
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Remarks:
Male 75010
Basis:
mean
Remarks:
Redness
Time point:
other: 24, 48 and 72 hours
Score:
2
Max. score:
3
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Remarks:
Male 74958
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 21 days
Irritation parameter:
chemosis score
Remarks:
Male 75009
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Remarks:
Male 75010
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritant / corrosive response data:
Red colored staining of the fur around the treated eye was noted in one animal 1 hour after treatment.

No corneal effects were noted during the study.

Iridial inflammation was noted in all treated eyes 1 and 24 hours after treatment and in one treated eye at the 48 Hour observation.

Moderate conjunctival irritation was noted in all treated eyes 1 hour after treatment and at the 24, 48 and 72 Hour observations. Minimal conjunctival irritation was noted in one treated eye at the 7 and 14 Day observations.

Two treated eyes appeared normal at the 7 Day observation and one treated eye appeared normal at the 21 Day observation.
Other effects:
Body Weight
All animals showed expected gain in body weight during the study.

Any other information on results incl. tables

Individual Scores and Individual Total Scores for Ocular Irritation

Rabbit Number and Sex

74958Male

75009Male

75010Male

IPR= 0

IPR = 0

IPR = 0

Time After Treatment

1
Hr

24
Hr

48
Hr

72
Hr

7
Dy

14
Dy

21
Dy

1
Hr

24
Hr

48
Hr

72
Hr

7
Dy

1
Hr

24
Hr

48
Hr

72
Hr

7
Dy

CORNEA

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

E = Degree of Opacity

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

F = Area of Cornea Involved

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Score (E x F) x 5

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

IRIS

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

D

1

1

0

0

0

0

0

1

1

0

0

0

1

1

1

0

0

Score (D x 5)

5

5

0

0

0

0

0

5

5

0

0

0

5

5

5

0

0

CONJUNCTIVAE

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A = Redness

2

2

2

2

1

1

0

2

2

2

2

0

2

2

2

2

0

B = Chemosis

2

2

2

2

1

1

0

2

2

2

2

0

2

2

2

2

0

C = Discharge

2Sf

2

1

1

0

0

0

2

2

2

1

0

2

2

2

1

0

Score (A + B + C) x 2

12

12

10

10

4

4

0

12

12

12

10

0

12

12

12

10

0

Total Score

17

17

10

10

4

4

0

17

17

12

10

0

17

17

17

10

0

IPR= Initial pain reaction                   

Hr = Hour            

Dy = Days

Sf = Red colored staining of the fur around the treated eye

Individual Total Scores and Group Mean Scores for Ocular Irritation

Rabbit Number
and Sex

Individual Total Scores At:

1
Hour

24
Hours

48
Hours

72
Hours

7
Days

14
Days

21
Days

74958Male

17

17

10

10

4

4

0

75009Male

17

17

12

10

0

-

-

75010Male

17

17

17

10

0

-

-

Group Total

51

51

39

30

4

4

0

Group Mean Score

17.0

17.0

13.0

10.0

1.3

1.3

0.0

- =  Observation not required - considered to be zero for calculation of Group Mean Score

Individual Body Weights and Body Weight Change

Rabbit Number
and Sex

Individual Body Weight (kg)

Body Weight Change (kg)

74958Male

Day 0

Day 21

0.15

2.99

3.14

75009Male

Day 0

Day 7

0.08

3.22

3.30

75010Male

Day 0

Day 7

0.17

2.93

3.10

 

Applicant's summary and conclusion

Interpretation of results:
Category II
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test item produced a maximum group mean score of 17.0 and was classified as a moderate irritant (Class 5 on a 1 to 8 scale) to the rabbit eye according to a modified Kay and Calandra classification system.

The test item was classified as Category 2A (irritating to eyes) according to the Globally Harmonized System of Classification and Labelling of Chemicals.

The test item was also classified as Irritating to eyes (Category 2) according to Regulation (EC) No. 1272/2008, relating to the Classification, Labelling and Packaging of Substances and Mixtures. It is reasonable to assume that the Signal Word “Warning” and the Hazard Statement “H319: Causes serious eye irritation” are therefore required.
Executive summary:

The eye irritation potential of the test substance, TM 11-213, was assessed according to OECD Test Guideline 405 using an in vivo method as classified - Category 2 (irritating to eyes).