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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
Study period:
03 November 2008 - 13 November 2008
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2009
Report date:
2009

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
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147, November 2000, including the most recent partial revisions
Deviations:
no
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Test material form:
solid
Details on test material:
- Appearance/physical state: Black lumps
- Storage conditions: 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 France SARL, Gannat, France.
- Conditions: Controlled environment, in which optimal conditions were considered to be approximately 15 air changes per hour, a temperature of 21 +/- 3C, a relative humididty of 30-70% and 12 hours artificial fluorescent light and 12 hours darkness per day.
- Housing: Individually in labelled cages with perforated floors (Ebeco, Germany) dimensions 67 x 62 x 55 cm and shelters (Ebeco, Germany) dimensions 40 x 32 x 23 cm.
- Acclimatisation: At least five days before the start of treatment under laboratory conditions.
- Diet: Pelleted diet for rabbits (K-H from SSNIFF Spezialdiatenj GmbH, Soest, Germany (approximately 100 g per day) and hay (TecniLab-BMI BV, Someren, The Netherlands) was provided at least three times a week.
- Water: Free access to tap water.
- Results of analysis for each batch of diet (nutrients and contaminants), hay and water were assessed and did not reveal any findings that were considered to have affected the integrity of the study.

Test system

Vehicle:
unchanged (no vehicle)
Controls:
other: The other eye remained untreated and served as the reference control.
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml
- Concentration (if solution): Undiluted
- Amount(s) applied (volume or weight with unit): 62.1 mg (range 61.8-62.2 mg) of the test substance (a volume of approximately 0.1 mL)


Duration of treatment / exposure:
72 hours in one animal (sentinel) and 24 hours in the other two animals.
Observation period (in vivo):
approximately 1, 24, 48, and 72 hours after instillation
Number of animals or in vitro replicates:
3 Males
Details on study design:
STUDY DESIGN
- An in vitro study was considered but a negative result was anticipated and this would need to have been confirmed by an in vivo study.
- The study was performed in a stepwise manner and was started by treatment of a single rabbit (sentinel).
- The two other animals were treated in a similar manner one wek later after considering the degree of eye irritation observed in the first animal.

TREATMENT
- Animals were treated by instillation of 62.1 to 62.2 mg test substance (0.1 mL) into the conjunctival sac of one of the eyes after gently pulling the lower lid away from the eyeball.
- The lids were then gently held together for about one second to prevent loss of the test substance.
- The other eye remained untreated and served as the reference control.
- Immediately after the 24 -hour observation, a solution of 2 % fluorescein (Merck, Darmstadt, Germany) in water (adjusted to pH 7.0) was instilled into both eyes of each animal to quantitatively determine corneal epithelial damage.
- Immediately after fluorescein examination on Day 2, the treated eye of two animals was rinsed with tepid tap water (approximately 50 mL) to remove residual test substance using a velocity of flow which did not affect the eye.
- For reference control the other eye was also rinsed.
- After the final observation, the animals were sacrificed by intravenous injection of phenobarbital (Euthesate; Ceva Sante Animale BV, Naaldwijk, The Netherlands).

OBSERVATIONS
- Mortality/viability: Twice daily
- Toxicity: At least once daily
- Body weight: Day of treatment (prior to instillation) and at termination
- Irritation: The eyes of each animal were examined at approximately 1, 24, 48 and 72 hours after instillation of the test substance. Irritation scores according to the attached scheme were recorded together with a description of other (local effects).

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
cornea opacity score
Basis:
animal #1
Remarks:
mean score
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: Animal 955
Irritation parameter:
iris score
Basis:
animal #1
Remarks:
mean score
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
other: not applicable
Remarks on result:
other: Animal 955
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #1
Remarks:
mean score
Time point:
24/48/72 h
Score:
0
Max. score:
3
Reversibility:
other: not applicable
Remarks on result:
other: Animal 955
Irritation parameter:
chemosis score
Basis:
animal #1
Remarks:
mean score
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: Animal 955
Irritation parameter:
cornea opacity score
Basis:
animal #2
Remarks:
mean score
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: Animal 3
Irritation parameter:
iris score
Basis:
animal #2
Remarks:
mean score
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
other: not applicable
Remarks on result:
other: Animal 3
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #2
Remarks:
mean score
Time point:
24/48/72 h
Score:
0.33
Max. score:
3
Reversibility:
fully reversible within: 48 h
Remarks on result:
other: Animal 3
Irritation parameter:
chemosis score
Basis:
animal #2
Remarks:
mean score
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: Animal 3
Irritation parameter:
cornea opacity score
Basis:
animal #3
Remarks:
mean score
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: Animal 4
Irritation parameter:
iris score
Basis:
animal #3
Remarks:
mean score
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
other: not applicable
Remarks on result:
other: Animal 4
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #3
Remarks:
mean score
Time point:
24/48/72 h
Score:
0.33
Max. score:
3
Reversibility:
fully reversible within: 48 h
Remarks on result:
other: Animal 4
Irritation parameter:
chemosis score
Basis:
animal #3
Remarks:
mean score
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: Animal 4
Irritant / corrosive response data:
- Individual eye irritation scores are presented in Table 1 (attached).
- Instillation of approximately 62 mg of test item (0.1 mL) into one eye of each of three rabbits resulted in irritation of the conjuntivae (redness in one animal which resolved within 24 hours and redness and discharge in the other two animals which resolved within 48 hours).
- No iridial irritation or corneal opacity was observed and treatment of the eyes with 2 % fluorescein 24 hours after test substance instillation revealed no corneal epithelial damage.
- There was no evidence of ocular corrosion.

Any other information on results incl. tables

- No staining of (peri) ocular tissues by the test substance was observed. Remnants of the test substance were present in the eye and on the outside of the eyelids in all animals on Day 1. On Day 2, test substance remnants were still present in the eye in two animls and on the outside of the eyelids in one animal.

- No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occurred.

Applicant's summary and conclusion

Interpretation of results:
not irritating
Conclusions:
Instillation of approximately 62 mg of test item (a volume of approximately 0.1 mL) into the eye of each of three rabbits resulted in irritation of the conjunctivae which consisted of redness in one animal which resolved within 24 hours and redness and discharge in the other two animals which resolved within 48 hours. No iridial or corneal opacity was observed, and treatment of the eyes with 2% fluorescein 24 hours after test substance instillation revealed no corneal epithelial damage. Based on these results the test item does not have to be classified for eye irritation according to EC criteria (Council Directive 67/548/EEC) or the Globally Harmonized System of Classification and Labeling of Chemicals (GHS) of the United Nations (2007).
Executive summary:

GUIDELINE

The study was conducted in accordance with OECD No 405 (2002) "Acute Eye Irritation/Corrosion", EU No Method B.5 (2008) "Acute Toxicity: Eye Irritation/Corrosion", EPA OPPTS 870.2400 (1998) "Acute Eye Irritation" and JMAFF guidelines (2000) including the most recent revisions.

METHODS

Animals were treated by instillation of 62.1 to 62.2 mg test substance (0.1 mL) into the conjunctival sac of one of the eyes after gently pulling the lower lid away from the eyeball. The lids were then gently held together for about one second to prevent loss of the test substance. The other eye remained untreated and served as the reference control. Immediately after the 24 -hour observation, a solution of 2 % fluorescein in water (adjusted to pH 7.0) was instilled into both eyes of each animal to quantitatively determine corneal epithelial damage. Immediately after fluorescein examination on Day 2, the treated eye of two animals was rinsed with tepid tap water (approximately 50 mL) to remove residual test substance using a velocity of flow which did not affect the eye. For reference control the other eye was also rinsed. After the final observation, the animals were sacrificed by intravenous injection of phenobarbital.

RESULTS

Instillation of approximately 62 mg of test item (a volume of approximately 0.1 mL) into the eye of each of three rabbits resulted in irritation of the conjunctivae which consisted of redness in one animal which resolved within 24 hours and redness and discharge in the other two animals which resolved within 48 hours. No iridial or corneal opacity was observed, and treatment of the eyes with 2% fluorescein 24 hours after test substance instillation revealed no corneal epithelial damage.

CONCLUSION

Based on study results the test item does not have to be classified for eye irritation according to EC criteria (Council Directive 67/548/EEC) or the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2007).