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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:
2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016
Report Date:
2016

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
2012
Deviations:
yes
Remarks:
Deviations from the maximum level daily mean relative humidity occurred. Evaluation: Laboratory historical data do not indicate an effect of the deviations. The study integrity was not adversely affected by the deviation.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Batch No. 605803
- Expiration date of the lot/batch: 23 October 2016

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

FORM AS APPLIED IN THE TEST (if different from that of starting material): Unchanged test article was applied

Test animals / tissue source

Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Charles River France, L’Arbresle, France
- Age at study initiation: Between 12 and 13 weeks
- Weight at study initiation: Average 2.49 kg
- Housing: Animals were individually housed in labeled cages with perforated floors (Ebeco, Germany, dimensions 67 x 62 x 55 cm) and shelters (Ebeco, Germany, dimensions 40 x 32 x 23 cm).
- Diet (e.g. ad libitum): Pelleted diet for rabbits (Global Diet 2030 from Harlan Teklad®, Mucedola, Milanese, Italy) approximately 100 grams per day. Hay (TecniLab-BMI BV, Someren, The Netherlands) and wooden sticks (Swedish aspen wood, Bioservices, Uden, The Netherlands) were available during the study period.
- Water (e.g. ad libitum): Free access to tap water.
- Acclimation period: Acclimatization period was at least 5 days before start of treatment under laboratory conditions.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 24°C
- Humidity (%): 40 to 70%
- Air changes (per hr): At least 10 air changes/hour
- Photoperiod (hrs dark / hrs light): 12:12 hour light:dark cycle

IN-LIFE DATES: From: 09 June 2016 To: 11 July 2016

Test system

Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 96.2 mg (range 95.8 – 96.7 mg) of the test item (a volume of approximately 0.1 mL)
Duration of treatment / exposure:
24 hours
Observation period (in vivo):
14 days
Number of animals or in vitro replicates:
3 males
Details on study design:
SCORING SYSTEM: The irritation was assessed according to the following numerical scoring system. At each
observation, the highest scores given were recorded:

CORNEAL IRRITATION
Opacity: degree of density (area most dense taken for reading)
No ulceration or opacity (may include slight dulling of normal luster) .......................................................................0
Scattered or diffuse areas of opacity, details of iris clearly visible .........................................................................1
Easily discernible translucent area, details of iris slightly obscured ........................................................................2
Nacreous area, no details of iris visible, size of pupil barely discernible .................................................................3
Opaque cornea, iris not discernible through the opacity ..........................................................................................4

Area of cornea involved:
No ulceration or opacity ............................................................................................................................................0
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
Normal ...................................................................................................................................................................0
Markedly deepened rugae, congestion, swelling, moderate circumcorneal hyperaemia, or injection, any of
these or combination thereof, iris still reacting to light (sluggish reaction is positive) ..........................................1
No reaction to light, hemorrhage, gross destruction (any or all of these) ............................................................2

CONJUNCTIVAL IRRITATION
Redness (refers to palpebrae and sclera, excluding cornea and iris):
Blood vessels normal ..............................................................................................................................................0
Some blood vessels definitely hyperaemic (injected) .............................................................................................1
Diffuse, crimson color, individual vessels not easily discernible ............................................................................2
Diffuse beefy red ....................................................................................................................................................3

Chemosis (refers to lids and/or nictitating membranes):
No swelling ………………………………………… ...............................................................................................0
Any swelling above normal (includes nictitating membranes) ..............................................................................1
Obvious swelling with partial eversion of lids ......................................................................................................2
Swelling with lids about half closed ......................................................................................................................3
Swelling with lids more than half closed ...............................................................................................................4

Discharge:
No discharge (may include small amounts observed in inner canthus of normal animals) ....................................0
Any amount different from normal and/or lacrimation ............................................................................................1
Discharge with moistening of the lids and hairs just adjacent to lids ..............................................................,......2
Discharge with moistening of the lids and hairs (considerable area around the eye) ...........................................3

TOOL USED TO ASSESS SCORE: Where standard lighting was considered inadequate for observing minor effects, eye examinations were
performed using an ophthalmic examination lamp.

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
other: mean 24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
other: mean 24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
other: mean 24/48/72 h
Score:
0.7
Max. score:
1
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
iris score
Basis:
animal #1
Time point:
other: mean 24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #2
Time point:
other: mean 24/48/72 h
Score:
0.3
Max. score:
1
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
iris score
Basis:
animal #3
Time point:
other: mean 24/48/72 h
Score:
0.3
Max. score:
1
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
other: conjunctivae redness
Basis:
animal #1
Time point:
other: mean 24/48/72 h
Score:
1.7
Max. score:
2
Reversibility:
fully reversible within: 14 days
Irritation parameter:
other: conjunctivae redness
Basis:
animal #2
Time point:
other: mean 24/48/72 h
Score:
0.7
Max. score:
1
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
other: conjunctivae redness
Basis:
animal #3
Time point:
other: mean 24/48/72 h
Score:
1.7
Max. score:
2
Reversibility:
fully reversible within: 14 days
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
other: mean 24/48/72 h
Score:
0.3
Max. score:
1
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
other: mean 24/48/72 h
Score:
0.3
Max. score:
1
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
other: mean 24/48/72 h
Score:
2
Max. score:
3
Reversibility:
fully reversible within: 7 days
Irritant / corrosive response data:
Instillation of approximately 96 mg of MTDID 15670 (a volume of approximately 0.1 mL) into one eye of each of three rabbits resulted in effects on the cornea, iris and/or conjunctivae. The irritation of the conjunctivae consisted of redness (max. grade 2), chemosis (max. grade 3) and discharge (max. grade 2). The irritation had completely resolved within 72 hours after instillation in one animal and within 14 days in the other two animals. The corneal injury was apparent in one animal only and consisted of opacity (grade 1) and epithelial damage (30%) and resolved within 72 hours. Iridial irritation (grade 1) was observed in two animals and resolved within 72 hours.

There was no evidence of ocular corrosion. Remnants of the test item were present on the outside of the eyelids on Day 1 in one animal.
Other effects:
No signs of systemic toxicity were observed in the animals during the test period and no mortality occurred.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Based on the results of the study, the instillation of approximately 96 mg of MTDID 15670 was not irritating and not corrosive to the eyes of rabbits.
Executive summary:

The primary ocular irritation/corrosion potential of the test material, MTDID 15670, was evaluated in three male New Zealand White rabbits. The study was based on OECD 405 (2012) and was certified GLP. The study was performed in a stepwise manner and was started by treatment of a single animal (sentinel) and the other two were treated in a similar manner 10 days later after considering the degree of eye irritation in the first animal. Approximately 96.2 mg (approximately 1 mL) unchanged test material was instilled to the conjunctival sac of one eye by gently pulling the lower eyelid away from the eye; the other eye of each animal served as a control. Eyes were held together gently for approximately one second to prevent loss of the test item. The treated eye of each animal was examined for irritation of the cornea, iris, and conjunctivae at 1, 24, 48 and 72 hours and/or 7 and 14 days post exposure. After the 24-hour observation, a solution of 2% fluorescein in water was instilled into both eyes of each animal to quantitatively determine corneal epithelial damage; this was repeated to assess recovery. After the final observation, the animals were sacrificed by intra-venous injection of Euthasol®. Additional observations for mortality/viability (twice daily), toxicity (at least once daily), and body weight (day 1 prior to exposure and after final observation) were recorded.  

 

Instillation of approximately 96 mg of MTDID 15670 (approximately 0.1 mL) into one eye of each of three rabbits resulted in effects on the cornea, iris and/or conjunctivae. Mean (24, 48, and 72 hours) corneal capacity scores for the three animals were 0.0, 0.0 and 0.7. Mean (24, 48, and 72 hours) iritis scores for the three animals were 0.0, 0.3 and 0.3. Mean (24, 48, and 72 hours) conjunctival redness scores for the three animals were 1.7, 0.7, and 1.7. Mean (24, 48, and 72 hours) conjunctival chemosis scores for the three animals were 0.3, 0.3 and 2.0. The irritation had completely resolved within 72 hours after instillation in one animal and within 14 days in the other two animals. Corneal injury and iridial irritation resolved within 72 hours. There was no evidence of ocular corrosion. Remnants of the test item were present on the outside of the eyelids on Day 1 in one animal. No signs of systemic toxicity were observed in the animals during the test period and no mortality occurred. Based on the results of the study, the instillation of approximately 96 mg of MTDID 15670 was not irritating and not corrosive to the eyes of rabbits.