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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:
1998-07-8 to 1998-9-9
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
OECD Guideline 405

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1998
Report date:
1998

Materials and methods

Principles of method if other than guideline:
Based on Draize test and similar to OECD Guideline 405 (Acute Eye Irritation/Corrosion)
GLP compliance:
yes (incl. QA statement)
Remarks:
The study meets the requirements of 40 CFR Part 160 with the following exception: stability, cha racterization, identity and verification of the test item concentration as received and tested are the responsbility of the sponsor.

Test material

Constituent 1
Chemical structure
Reference substance name:
1-[2-(allyloxy)ethyl-2-(2,4-dichlorophenyl)-1H-imidazolium hydrogen sulphate
EC Number:
261-351-5
EC Name:
1-[2-(allyloxy)ethyl-2-(2,4-dichlorophenyl)-1H-imidazolium hydrogen sulphate
Cas Number:
58594-72-2
Molecular formula:
C14H14Cl2N2O.H2O4S
IUPAC Name:
1-[2-(2,4-DICHLOROPHENYL)-2-(PROP-2-EN-1-YLOXY)ETHYL]-1H-IMIDAZOLE SULFATE (1:1)
Test material form:
solid: particulate/powder
Details on test material:
- Product names: FUNGAFLOR® 75C / FUNGAFLOR® 75SP / FUNGAZIL® 750SP / FUNGAFLOR® 75PS / FUNGAZIL® 75SP / FUNGAFLOR® 750SP
- Reference number: JNJ-2634372-ABI / R027180 (product code)
- Physical state: solid
- Appearance: beige solid
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: #ZR027180PUE201
- Expiration date of the lot/batch: October 15 2003
- Purity: 75%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Not specified
- Stability under test conditions: Expected to be stable for the duration of testing
- Solubility and stability of the test substance in the solvent/vehicle: Soluble in water (>500 g/l).

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: A 10% w/v solution of the active ingredient in the test substance was prepared by dissolving 13.3 g of the test substance (10g of imazalil) in distilled water.


Test animals / tissue source

Species:
rabbit
Strain:
New Zealand White
Remarks:
Albino
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Davidson's Mill Farm, South Brunswick, NJ
- Age at study initiation: Adult
- Weight at study initiation: Not specified
- Housing: The animals were singly housed in suspended stainless steel caging with mesh floors which conform to the size recommendations in the Guide for the Care and Use of Laboratory Animals DHEW (NIH) no 86.23. Litter paper was palced beneath the cage and was changed at least 3 times/ week.
- Diet (e.g. ad libitum): Pelleted Purina Rabbit Chow #5326
- Water (e.g. ad libitum): Filtered Tap water was supplied ad libitum by automatic water dispensing system.
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16.7 - 21.1 °C
- Humidity (%): Not specified
- Air changes (per hr): Not specified
- Photoperiod (hrs dark / hrs light): Not specified

In Life dates : 8-17 July 1998

Test system

Vehicle:
water
Controls:
yes, concurrent no treatment
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): one tenth of a millimeter of the test solution
- Concentration (if solution):10 %w/v solution of active ingredient in the test substance in distilled water.

Duration of treatment / exposure:
One application
Observation period (in vivo):
7 days
Number of animals or in vitro replicates:
6 (3 males and 3 females)
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): No.

SCORING SYSTEM:
The eye irritation scores were evaluated according to the scoring system by Draize (1944)
- Cornea
a. Opacity-degree of density (Area most dense taken for reading)
No opacity 0
Scattered or diffuse areas details of iris clearly visible 1
Easily discernible translucent area, details of iris slightly obscured 2
Opalescent areas, no details of iris visible, size of pupil barely discernible 3
Opaque iris invisible 4

b. 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

- Iris
a. Values
Normal 0
Folds above normal, congestion, swelling, circumcorneal injection (any or all of these ot combination of any thereof) iris still reacting to light (sluggish reaction is positive) 1
No reaction to light, Hemorrhage, gross destruction 2

- Conjunctivae
a. Redness (Palpebral and bulbar)
Vessels normal 0
Vessels definately 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 about 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, and considerable area around the eye 3

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not reversible
Irritation parameter:
other: Cornea Area score
Basis:
animal #1
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
not reversible
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #1
Time point:
24/48/72 h
Score:
2
Max. score:
3
Reversibility:
not reversible
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
3
Max. score:
4
Reversibility:
not fully reversible within:
Remarks:
the observed period
Irritation parameter:
conjunctivae score
Remarks:
discharge
Basis:
animal #1
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
not fully reversible within:
Remarks:
the observed period
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not reversible
Irritation parameter:
other: Cornea Area score
Basis:
animal #2
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not fully reversible within:
Remarks:
The observed period
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible
Irritation parameter:
conjunctivae score
Remarks:
Redness
Basis:
animal #2
Time point:
24/48/72 h
Score:
2.33
Max. score:
3
Reversibility:
fully reversible
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
conjunctivae score
Remarks:
discharge
Basis:
animal #2
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
not fully reversible within:
Remarks:
The observed period
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1.67
Max. score:
4
Reversibility:
not reversible
Irritation parameter:
other: Cornea area score
Basis:
animal #3
Time point:
24/48/72 h
Score:
2.67
Max. score:
4
Reversibility:
not reversible
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
not reversible
Irritation parameter:
conjunctivae score
Remarks:
Redness
Basis:
animal #3
Time point:
24/48/72 h
Score:
2
Max. score:
3
Reversibility:
not fully reversible within: The observed period
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
conjunctivae score
Remarks:
Discharge
Basis:
animal #3
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
not reversible
Irritation parameter:
cornea opacity score
Basis:
animal #4
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not reversible
Irritation parameter:
other: Cornea area score
Basis:
animal #4
Time point:
24/48/72 h
Score:
3.67
Max. score:
4
Reversibility:
not reversible
Irritation parameter:
iris score
Basis:
animal #4
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible
Irritation parameter:
conjunctivae score
Remarks:
Redness
Basis:
animal #4
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
not fully reversible within:
Remarks:
The observed period
Irritation parameter:
chemosis score
Basis:
animal #4
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
conjunctivae score
Remarks:
Discharge
Basis:
animal #4
Time point:
24/48/72 h
Score:
2.67
Max. score:
3
Reversibility:
not fully reversible within:
Remarks:
The observed period
Irritation parameter:
cornea opacity score
Basis:
animal #5
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not reversible
Irritation parameter:
other: Cornea area score
Basis:
animal #5
Time point:
24/48/72 h
Score:
3
Max. score:
4
Reversibility:
not reversible
Irritation parameter:
iris score
Basis:
animal #5
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible
Irritation parameter:
conjunctivae score
Remarks:
Redness
Basis:
animal #5
Time point:
24/48/72 h
Score:
2
Max. score:
3
Reversibility:
not fully reversible within:
Remarks:
The observed period
Irritation parameter:
chemosis score
Basis:
animal #5
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
conjunctivae score
Remarks:
Discharge
Basis:
animal #5
Time point:
24/48/72 h
Score:
2.67
Max. score:
3
Reversibility:
fully reversible
Irritation parameter:
cornea opacity score
Basis:
animal #6
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not reversible
Irritation parameter:
other: Cornea area score
Basis:
animal #6
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible
Irritation parameter:
iris score
Basis:
animal #6
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible
Irritation parameter:
conjunctivae score
Remarks:
Redness
Basis:
animal #6
Time point:
24/48/72 h
Score:
2
Max. score:
3
Reversibility:
fully reversible
Irritation parameter:
chemosis score
Basis:
animal #6
Time point:
24/48/72 h
Score:
2.33
Max. score:
4
Reversibility:
not fully reversible within:
Remarks:
The observed period
Irritation parameter:
conjunctivae score
Remarks:
Discharge
Basis:
animal #6
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
not fully reversible within:
Remarks:
The observed period
Irritant / corrosive response data:
One hour after test solution instillation, all six treated eyes exhibited corneal opacity, iritis and conjonctivitis. The overall incidence and severity of irritation persisted in all animals through Day 7, with pannus evident in two rabbits. Due to the severity and irreversible nature of irritation, the sponsor authorized termination of the study and the test animals were euthanized on Day 9.
Other effects:
Apart from eye irritation, there were no other signs of gross toxicity, adverse pharmacologic effects or abnormal behavior.

Applicant's summary and conclusion

Interpretation of results:
Category 1 (irreversible effects on the eye) based on GHS criteria
Conclusions:
Based on the classification system used, a 10% w:v solution of the active ingredient (Imazalil) in Fungaflor 75 SP, lot #ZR027180PUE201 in distilled water is classified as severely irritating to the eye. The classification was raised from moderately to severely irritating due to scores greater than 10 for all rabbits at the 24 hour evaluation interval.