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Diss Factsheets

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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report date:
2012

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
of 2002
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Version / remarks:
of 2008
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
Version / remarks:
of 1998
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japanese MAFF Test Data for Registration of Agricultural Chemicals, Eye Irritation (2-1-5), 12 Nohsan No. 8147, Agricultural Production Bureau, November 24, 2000.
Deviations:
no
GLP compliance:
yes (incl. QA statement)

Test material

Test animals / tissue source

Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS

- Stock supply of healthy adult rabbits
- Number and Sex: 3 females
- Age on day of dosing (Day 1): 41 weeks
- Weight prior to dosing (Day 1): Minimum 3.95 kg, maximum 4.16 kg
- Housing: Individual housing in plastic cages with peforated floor
- Environmental enrichment: Small soft white untreated wood blocks
- Diet : Standard laboratory rabbit diet (125 g/animal/day). In addition, dietary supplement of hay
replaced by a supplement of wholemeal bread as from 2 days prior to dose instillation.
- Water: Drinking water, ad libitum
- Acclimation period: 29 or 30 weeks prior to study start under laboratory conditions.

Routine analysis of the batch of diet used for nutrients, possible contaminants and microorganisms and of the drinking water were conducted or available at the testing facility.


ENVIRONMENTAL CONDITIONS

Air conditioned animal room set at:
- Temperature (°C): 18 ± 2°C
- Relative Humidity (%): 40 to 70%
- Photoperiod: 12 hrs artificial light per 24 hrs

Test system

Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
0.1 mL of undiluted test substance was administered into the conjunctival sac of one eye per rabbit (right eye). The contralateral eye (left eye) remained untreated to serve as a control.
Duration of treatment / exposure:
The eyes were not rinsed after treatment, but in two of the three animals (#1 and #3) the treated eye was flushed with saline at 24 and 48 hours after treatment. For the other animal (#2) flushing of the eye with saline was not reported.
Observation period (in vivo):
21 days for two animals, the other animal (# 3) was killed at 9 days after instillation for humane reasons.
Number of animals or in vitro replicates:
3 adult female rabbits
Details on study design:
EYE EVALUATION:

Before treatment start both eyes of each animal were investigated to ensure that there was no pre-existing corneal damage, iridial inflammation or conjunctival irritation.

One animal (the sentinel # 1) was initially treated and in the absence of a severe effect the remaining two animals were committed to the study.

Eyes were evaluated at approximately 1, 24, 48 and 72 hours and 7, 14 and 21 days after test substance instillation adopting the numerical scoring system listed in Table 1 in the field below. The animal killed for humane reasons at 9 days after instillation (Day 10) had a final check for ocular lesions on this day. As from 24 h post treatment staining with fluorescein supported the recognition of corneal lesions.O

Equipment used for eye evaluation: Ophthalmoscope or pencil beam torch

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
over 3 animals and 3 time points
Time point:
other: 24, 48, 72 h
Score:
1.9
Max. score:
4
Reversibility:
not reversible
Remarks:
as in one animal (# 3) area of pannus at 9 days after instillation
Irritation parameter:
cornea opacity score
Basis:
animal #1
Remarks:
mean over 3 time points
Time point:
other: 24, 48, 72 h
Score:
1.3
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
cornea opacity score
Basis:
animal #2
Remarks:
mean over 3 time points
Time point:
other: 24, 48, 72 h
Score:
1.7
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
cornea opacity score
Basis:
animal #3
Remarks:
mean over 4 time points
Time point:
other: 48 h, 72 h, 7 days, 9 days
Score:
3
Max. score:
4
Reversibility:
not reversible
Remarks:
as area of pannus at 9 days after instillation
Remarks on result:
other: Animal killed at 9 days after instillation for humane reasons
Irritation parameter:
other: Area of corneal opacity
Basis:
mean
Remarks:
over 3 animals and 3 time points
Time point:
other: 24, 48, 72 h
Score:
1.9
Max. score:
4
Reversibility:
other: Corneal ulceration or opacity were not evident
Irritation parameter:
iris score
Basis:
mean
Remarks:
over 3 animals and 3 time points
Time point:
other: 24, 48, 72 h
Score:
1
Max. score:
2
Reversibility:
not reversible
Remarks:
within 9 days in one animal (#3)
Irritation parameter:
iris score
Basis:
animal #1
Remarks:
mean over 3 time points
Time point:
other: 24, 48, 72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 14 days
Irritation parameter:
iris score
Basis:
animal #2
Remarks:
mean over 3 time points
Time point:
other: 24, 48, 72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 7 days
Irritation parameter:
iris score
Basis:
animal #3
Remarks:
mean over 3 time points
Time point:
other: 24, 48, 72 h
Score:
1
Max. score:
2
Reversibility:
not reversible
Remarks:
within 9 days
Remarks on result:
other: Animal killed at 9 days after instillation for humane reasons
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
mean
Remarks:
over 3 animals and 3 time points
Time point:
other: 24, 48, 72 h
Score:
2.8
Max. score:
3
Reversibility:
not fully reversible within: 9 days in one animal (#3)
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #1
Remarks:
mean over 3 time points
Time point:
other: 24, 48, 72 h
Score:
2.7
Max. score:
3
Reversibility:
fully reversible within: 14 days
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #2
Remarks:
mean over 3 time points
Time point:
other: 24, 48, 72 h
Score:
2.7
Max. score:
3
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #3
Remarks:
mean over 3 time points
Time point:
other: 24, 48, 72 h
Score:
3
Max. score:
3
Reversibility:
not fully reversible within: 9 days
Remarks on result:
other: Animal killed at 9 days after instillation for humane reasons.
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
over 3 animals and 3 time points
Time point:
other: 24, 48, 72 h
Score:
2.6
Max. score:
4
Reversibility:
not fully reversible within: within 9 days in one animal (#3)
Irritation parameter:
chemosis score
Basis:
animal #1
Remarks:
mean over 3 time points
Time point:
other: 24, 48, 72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritation parameter:
chemosis score
Basis:
animal #2
Remarks:
mean over 3 time points
Time point:
other: 24, 48, 72 h
Score:
2.3
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
animal #3
Remarks:
mean over 3 time points
Time point:
other: 24, 48, 72 h
Score:
3.3
Max. score:
4
Reversibility:
not fully reversible within: 9 days
Remarks on result:
other: Animal killed at 9 days after instillation for humane reasons
Irritation parameter:
other: discharge
Basis:
mean
Remarks:
over 3 animals and 3 time points
Time point:
other: 24, 48, 72 h
Score:
2.3
Max. score:
4
Reversibility:
fully reversible within: 14 days
Remarks on result:
other: often mucoid discharge
Irritant / corrosive response data:
In two animals corneal opacity (grade 1 or 2), iritis (grade 1), conjunctival redness (grades 1, 2 and/or 3), chemosis (grades 1 to 2 in one animal and grades 1 to 4 in the other animal) and discharge (grades 1 to 3) were seen until 72 hours or 7 days after instillation. One of these animals was entirely free from ocular findings by 7 days after instillation the other animal by 14 days after instillation.

However, the third animal was more severely affected, in particular regarding corneal and conjunctival findings: Translucent and nacreous areas of corneal opacity were evident from 48 hours after instillation and nine days after instillation an area of pannus formation was apparent. Due to the irreversible nature of these corneal findings, this animal was humanely sacrificed immediately after the examination at nine days after instillation. In addition, an ulcer under the top eyelid was evident at nine days after instillation.
Other effects:
Observation of the animals for defined behavioural criteria led to the conclusion that instillation of the test substance induced practically no initial pain response. Any other signs of systemic toxicity or ill health were not evident.

Signs of reaction to treatment comprised the head of all animals being held slightly to the right on the day of administration, the right periorbital area being sensitive to touch 24 hours after instillation in one animal (#2), and hairloss on the right upper eye lid in two animals (#1 and #3) nine days after instillation or from fourteen days after instillation.

Applicant's summary and conclusion

Interpretation of results:
Category 1 (irreversible effects on the eye)
Remarks:
Migrated information Criteria used for interpretation of results: EU