Registration Dossier

Toxicological information

Eye irritation

Currently viewing:

Administrative data

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2014-02-10 to 2014-03-10
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2014
Report date:
2014

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
Deviations:
no
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
1-butylpyrrolidin-2-one
EC Number:
222-437-8
EC Name:
1-butylpyrrolidin-2-one
Cas Number:
3470-98-2
Molecular formula:
C8H15NO
IUPAC Name:
1-butylpyrrolidin-2-one
Test material form:
other: liquid
Details on test material:
- Substance type: organic
- Physical state: clear colourless liquid
- Analytical purity: 99.7 % (GC)
- Composition of test material, percentage of components: 0.18 % (water) by coulometry
- Purity test date: 2013-11-07
- Lot/batch No.: 01061301
- Expiration date of the lot/batch: 31 December, 2016
- Stability under test conditions: responsibility of the sponsor
- Storage condition of test material: Kept in a controlled room temperature area

Test animals / tissue source

Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Covance, Denver, PA.
- Age at study initiation: 29 weeks
- Weight at study initiation: between 2.9 kg to 3.2 kg at initiation of dosing
- Housing: individually in suspended stainless steel cages
- Diet (e.g. ad libitum): ad libitum (PMI Nutrition International Certified Rabbit Chow No. 5322)
- Water (e.g. ad libitum): ad libitum (Municipal tap water following treatment by reverse osmosis and ultraviolet irradiation)
- Acclimation period: at least 12 days before the first day of dosing

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 69°F to 72°F (21°C to 22°C)
- Humidity (%): 37 - 43
- Air changes (per hr): Ten or greater air changes per hour with 100% fresh air (no air recirculation) were maintained in the animal rooms.
- Photoperiod (hrs dark / hrs light): 12 /12

IN-LIFE DATES: From: 2013-02-11 To: 2013-03-10

Test system

Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
Duration of treatment / exposure:
single exposure
Observation period (in vivo):
1, 24, 48, and 72 hours and up to 10 days after dosing
Number of animals or in vitro replicates:
3
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): no
SCORING SYSTEM: according to the Ocular Grading System (based on Draize) (see attached pdf)

TOOL USED TO ASSESS SCORE: fluorescein
The eyes were macroscopically examined with the aid of an auxiliary light source for signs of irritation at 1, 24, 48, and 72 hours and up to 10 days after dosing according to the Ocular Grading System presented above which is based on Draize. Following macroscopic observations at the 24-hour scoring interval, the fluorescein examination procedure was repeated on all test and control eyes and any residual test substance was gently rinsed from the eye at that time using physiological saline. If fluorescein findings were noted at 24 hours, a fluorescein exam was conducted on the affected eyes at each subsequent interval until a negative response was obtained and/or until all corneal opacity had cleared.

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2
Max. score:
3
Reversibility:
fully reversible within: 7 days
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 10 days
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 7 days
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 10 days
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
fully reversible within: 10 days
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
2.67
Max. score:
3
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
2
Max. score:
2
Reversibility:
fully reversible within: 10 days
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2
Max. score:
2
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
2
Max. score:
2
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.33
Max. score:
1
Reversibility:
fully reversible within: 48 hours
Irritant / corrosive response data:
Exposure to the test article produced corneal opacity in 1/3 test eyes by the 24-hour scoring interval and complete resolution occurred by the Day 7 scoring interval. Iritis was observed in 1/3 test eyes by the 1-hour scoring interval and in 2/3 test eyes by the 24-hour scoring interval. Complete resolution of the iritis occurred in 1/3 test eyes by the Day 7 scoring interval and in 2/3 test eyes by the Day 10 scoring interval. Conjunctivitis (redness, swelling, and/or discharge) occurred in 3/3 test eyes by the 1-hour scoring interval and complete resolution occurred in 1/3 test eyes by the Day 7 scoring interval and in 2/3 test eyes by the Day 10 scoring interval. An additional ocular finding of neovascularization (2/3 test eyes) was noted during the study.
Other effects:
Decreased faecal output, including reduced faecal size and absence of faeces, was observed in all animals on at least 1 day during the study. Animals were treated with buprenorphine, an opioid, from Days 1 through 5, and opioids are known to cause decreased faecal output. Therefore, the decreased faecal output is likely an effect of the buprenorphine treatment.

Any other information on results incl. tables

Table 1. Individual ocular irritation scores

Animal No. /sex/ body weight (kg)

 

Cornea

Iris

Conjunctivae

Total

Test Eye

Control Eye

Interval

O

A

OxAx5

I

Ix5

R

S

D

(R+S+D) x 2

 

Fluorescein examination

Secondary ocular findings

Fluorescein examination

Secondary ocular findings

5981/M/

3.241

1 hour

0

0

0

0

0

2

3

2

14

14

 

 

 

 

24 hours

2

1

10

1

5

3

2

2

14

29

FAO

 

NFE

 

48 hours

3

1

15

1

5

3

2

2

14

34

FAO

 

 

 

72 hours

1

1

5

1

5

3

2

2

14

24

FAO

 

 

 

day 7

0

0

0

1

5

2

0

0

4

9

 

 

 

 

day 10

0

0

0

0

0

0

0

0

0

0

 

 

 

 

5984/M/

2.861

1 hour

0

0

0

0

0

2

3

2

14

14

 

 

 

 

24 hours

0

0

0

1

5

2

2

1

10

15

NFE

 

NFE

 

48 hours

0

0

0

1

5

3

2

1

12

17

 

VAS-1

 

 

72 hours

0

0

0

1

5

3

2

1

12

17

 

VAS-3

 

 

day 7

0

0

0

0

0

0

0

0

0

0

 

VAS-1

 

 

5985/M/

3.057

1 hour

0

0

0

1

5

2

3

2

14

19

 

 

 

 

24 hours

0

0

0

1

5

2

1

1

8

13

NFE

 

NFE

 

48 hours

0

0

0

1

5

2

0

1

6

11

 

 

 

 

72 hours

0

0

0

1

5

2

0

1

6

11

 

VAS-1

 

 

day 7

0

0

0

1

5

1

0

0

2

7

 

VAS-4

 

 

day 10

0

0

0

0

0

0

0

0

0

0

 

VAS-1

 

 

O - opacity; A - Area of cornea involved; I - Iritis; R - redness; S - swelling; D - discharge;

FAO - Fluorescein dye retention associated with the area of corneal opacity;

NFE - No fluorescein retention was observed;

VAS - 1: Total area of vascularized corneal tissue was < 10 % of corneal surface (neovascularization - very slight);

VAS - 2: Total area of vascularized corneal tissue was > 10 % but < 25 % of corneal surface (neovascularization - mild);

VAS - 3: Total area of vascularized corneal tissue was > 25 % but < 50 % of corneal surface (neovascularization - moderate);

VAS - 4: Total area of vascularized corneal tissue was > 50 % of corneal surface (neovascularization - severe).

Table 2. Mean ocular score

1 hour

15.67

24 hours

19.00

48 hours

20.67

72 hours

17.33

day 7

5.33

day 10

0.00

 

Applicant's summary and conclusion

Interpretation of results:
Category 2 (irritating to eyes) based on GHS criteria
Conclusions:
According to the Kay and Calandra Evaluation Criteria, the test item is considered to be a moderate irritant to the ocular tissue of the rabbit.
The total ocular irritation score for the 24-, 48-, and 72-hour intervals was individually added for corneal opacity, iris lesion, conjunctival redness, and conjunctival oedema. According to the EEC Ocular Evaluation Criteria, the test substance is classified as non-irritant for corneal opacity, irritant for iris lesions, conjunctival redness and oedema. According to the CLP criteria, the test item is classified as a Category 2 irritant to the eye (potential to induce reversible eye irritation).
Executive summary:

The objective of this study was to assess the irritant and/or corrosive effects of the test substance when given as a single ocular administration to rabbits. Each of 3 rabbits received a 0.1 mL dose of the test substance in the conjunctival sac of the right eye. The contralateral eye of each animal remained untreated and served as a control. Test and control eyes were examined for signs of irritation for up to 10 days following dosing.

Exposure to the test article produced corneal opacity in 1/3 test eyes by the 24-hour scoring interval and complete resolution occurred by the Day 7 scoring interval. Iritis was observed in 1/3 test eyes by the 1-hour scoring interval and in 2/3 test eyes by the 24-hour scoring interval. Complete resolution of the iritis occurred in 1/3 test eyes by the Day 7 scoring interval and in 2/3 test eyes by the Day 10 scoring interval. Conjunctivitis (redness, swelling, and/or discharge) occurred in 3/3 test eyes by the 1-hour scoring interval and complete resolution occurred in 1/3 test eyes by the Day 7 scoring interval and in 2/3 test eyes by the Day 10 scoring interval. An additional ocular finding of neovascularization (2/3 test eyes) was noted during the study. Decreased faecal output was observed in all animals. This observation, which is a known pharmacological effect of opioids, was likely due to the buprenorphine treatment that the animals received from Days 0 to 5. According to the Kay and Calandra Evaluation Criteria, the test substance is considered to be a moderate irritant to the ocular tissue of the rabbit. The total ocular irritation score for the 24-, 48-, and 72-hour intervals was individually added for corneal opacity, iris lesion, conjunctival redness, and conjunctival oedema. According to the EEC Ocular Evaluation Criteria, the test substance is classified as indicated below:

Animal No./Sex

Corneal Opacity

Iris Lesion

Conjunctival Redness

Conjunctival Edema

5981/M

2.00

1.00

3.00

2.00

5984/M

0.00

1.00

2.67

2.00

5985/M

0.00

1.00

2.00

0.33

Irritation Rating

Nonirritant

Irritant

Irritant

Irritant

According to the CLP criteria, the test substance is classified as a Category 2 irritant to the eye (potential to induce reversible eye irritation).