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Diss Factsheets

Administrative data

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2007-11-12 to 2007-12-10
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2008
Report date:
2008

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:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Chemical structure
Reference substance name:
[(3R)-3-[2-hydroxy-5-(hydroxymethyl)phenyl]-3-phenylpropyl]bis(propan-2-yl)azanium (2R)-2-(acetyloxy)-2-phenylacetate
EC Number:
929-947-6
Molecular formula:
C22H31NO2 • C19H10O4
IUPAC Name:
[(3R)-3-[2-hydroxy-5-(hydroxymethyl)phenyl]-3-phenylpropyl]bis(propan-2-yl)azanium (2R)-2-(acetyloxy)-2-phenylacetate
Test material form:
solid
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and batch No.of test material: Sponsor and E010005910

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature in the dark

Test animals / tissue source

Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source:Harlan, The Netherland
- Age at study initiation: twelve to twenty weeks old
- Weight at study initiation: 2.0 to 2.37 kg
- Housing: Suspended cage
- Diet (e.g. ad libitum): Certified Rabbit Diet ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: >5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 - 23
- Humidity (%): 30 - 70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Test system

Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied: 0.1 ml
Duration of treatment / exposure:
1 second
Observation period (in vivo):
14 days
Number of animals or in vitro replicates:
3
Details on study design:
SCORING SYSTEM:
Modified Draize Scale for Scoring Ocular Irritation

1. CONJUNCTIVAE
(A) Redness (refers to palpebral and bulbar conjunctivae excluding cornea and iris)
Vessels normal 0
Vessels definitely injected above normal 1
More diffuse, deeper crimson red, individual vessels not easily discernible 2
Diffuse beefy red 3

(B) Chemosis
No swelling 0
Any swelling above normal (includes nictitating membrane) 1
Obvious swelling with partial eversion of lids 2
Swelling with lids about half closed 3
Swelling with lids half closed to completely closed 4

(C) Discharge
No discharge 0
Any amount different from normal (does not include small amounts observed in inner canthus of normal animals) 1
Discharge with moistening of the lids and hairs just adjacent to lids 2
Discharge with moistening of the lids and hairs a considerable area around the eye 3
THE TOTAL SCORE = (A + B + C) x 2
MAXIMUM TOTAL = 20

2. IRIS
(D) Values
Normal 0
Folds above normal, congestion, swelling, circumcorneal injection (any or all of these or combination of any thereof) iris still reacting to light (sluggish reaction is positive) 1
No reaction to light, haemorrhage, gross destruction (any or all of these) 2
THE TOTAL SCORE = D x 5
MAXIMUM TOTAL =10

3. CORNEA
(E) Degree of Opacity (most dense area used)
No opacity 0
Scattered or diffuse areas, details of iris clearly visible 1
Easily discernible translucent areas, details of iris slightly obscured 2
Opalescent areas, no details of iris visible, size of pupil barely discernible 3
Opaque, iris not discernible through the opacity 4

(F) Area of Cornea Involved
One quarter (or less) but not zero 1
Greater than one quarter but less than half 2
Greater than half but less than three quarters 3
Greater than three quarters, up to whole area 4
TOTAL SCORE = (E x F) x 5
MAXIMUM TOTAL = 80

MAXIMUM TOTAL SCORE POSSIBLE = 110

TOOL USED TO ASSESS SCORE: standard opthalmoscope

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
other: 1 hr
Score:
ca. 0
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24 h
Score:
ca. 10
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
48 h
Score:
ca. 5
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
72 h
Score:
ca. 0
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
7 d
Score:
ca. 0
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
other: 1 hr
Score:
ca. 0
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48 h
Score:
ca. 10
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
72 h
Score:
ca. 5
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
7 d
Score:
ca. 5
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
14 d
Score:
ca. 0
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
other: 1 hr
Score:
ca. 0
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24 h
Score:
ca. 10
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
48 h
Score:
ca. 5
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
72 h
Score:
ca. 5
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
7 d
Score:
ca. 5
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
14 d
Score:
ca. 0
Irritation parameter:
iris score
Basis:
animal #1
Time point:
other: 1 hr
Score:
ca. 5
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48 h
Score:
ca. 5
Irritation parameter:
iris score
Basis:
animal #1
Time point:
72 h
Score:
ca. 0
Irritation parameter:
iris score
Basis:
animal #1
Time point:
7 d
Score:
ca. 0
Irritation parameter:
iris score
Basis:
animal #2
Time point:
other: 1 hr
Score:
ca. 5
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
ca. 5
Irritation parameter:
iris score
Basis:
animal #2
Time point:
7 d
Score:
ca. 0
Irritation parameter:
iris score
Basis:
animal #2
Time point:
14 d
Score:
ca. 0
Irritation parameter:
iris score
Basis:
animal #3
Time point:
other: 1 hr
Score:
ca. 5
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
ca. 5
Irritation parameter:
iris score
Basis:
animal #3
Time point:
7 d
Score:
ca. 0
Irritation parameter:
iris score
Basis:
animal #3
Time point:
14 d
Score:
ca. 0
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
other: 1 hr
Score:
ca. 10
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24 h
Score:
ca. 12
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
48 h
Score:
ca. 8
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
72 h
Score:
ca. 8
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
7 d
Score:
ca. 0
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
other: 1 hr
Score:
ca. 12
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48 h
Score:
ca. 12
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
72 h
Score:
ca. 8
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
7 d
Score:
ca. 2
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
14 d
Score:
ca. 0
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
other: 1 hr
Score:
ca. 0
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24 h
Score:
ca. 12
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
48 h
Score:
ca. 10
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
72 h
Score:
ca. 8
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
7 d
Score:
ca. 2
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
14 d
Score:
ca. 0
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
other: 1 hr
Score:
ca. 2
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24 h
Score:
ca. 2
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
48 h
Score:
ca. 1
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
72 h
Score:
ca. 1
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
7 d
Score:
ca. 0
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
other: 1 hr
Score:
ca. 2
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48 h
Score:
ca. 2
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
72 h
Score:
ca. 1
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
7 d
Score:
ca. 0
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
14 d
Score:
ca. 0
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
other: 1 hr
Score:
ca. 2
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24 h
Score:
ca. 2
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
48 h
Score:
ca. 1
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
72 h
Score:
ca. 1
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
7 d
Score:
ca. 0
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
14 d
Score:
ca. 0
Irritant / corrosive response data:
-Scattered or diffuse corneal opacity was noted in all treated eyes at the 24 and 48-hour observations and in two treated eyes at the 72-hour and 7-day observations.
-Iridial inflammation was noted in all treated eyes one hour after treatment and at the 24 and 48-hour observations and in two treated eyes at the 72-hour observation.
-Moderate conjunctival irritation was noted in all treated eyes one hour after treatment and at the24, 48 and 72-hour observations with minimal conjunctival irritation noted in two treated eyes at the 7-day observation.
-Petechial haemorrhage covering the whole of the nictitating membrane was noted in two treated eyes at the 24, 48 and 72-hour observations.
-One animal appeared normal at the 7-day observation and the remaining two animals appeared normal at the 14-day observations.
Other effects:
-All animals showed expected gain in bodyweight.
-Off white-coloured residual test material was noted in two treated eyes at the 1-hour observation.

Applicant's summary and conclusion

Interpretation of results:
Category 2A (irritating to eyes) based on GHS criteria
Conclusions:
This study indicates the test material would be classified as Category 2A (irritating to eyes) under the Globally Harmonised System (GHS).