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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:
Tetsing was conducted between 21st February 2018 and 2nd April 2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Reaction mass of 4,4'-methylenediphenol and 2,2'-methylenediphenol and o-[(4-hydroxyphenyl)methyl]phenol
EC Number:
908-912-9
Cas Number:
1333-16-0
Molecular formula:
C39H36O6
IUPAC Name:
Reaction mass of 4,4'-methylenediphenol and 2,2'-methylenediphenol and o-[(4-hydroxyphenyl)methyl]phenol
Test material form:
solid
Specific details on test material used for the study:
Name Bisphenol-F(Reaction mass of 2,2’-methylenediphenol and 4,4’-methylenediphenol and o-[(4-hydroxyphenyl)methyl]phenol)
Lot No. KZ517047
CAS No. 1333-16-0
Appearance Light pink or light yellow solid
Purity 97.4%
Expiration date Jun. 30, 2018
Storage condition: Room temperature (measurement value: 18.7–20.7°C, permissible range: 15−25°C)
Handling instruction: Wear a mask, clothing, gloves and goggle
Supplier:
Name KUKDO Chemical Co., Ltd.
Address 345-35, Kasan-dong, Kumchon-gu, Seoul, 08588,
Republic of Korea
Date of receipt Dec. 1, 2017

Test animals / tissue source

Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source:
Producer: YONAM COLLEGE, Yonam Laboratory Animal
Supplier: ORIENTBIO INC., Republic of Korea
- Age at study initiation: 10 - 11 weeks old
- Weight at study initiation: 1.69 - 2.08 kg
- Housing: Stainless wire mesh cages, 450W×600D×360H (mm)
One animal per age during the quarantine, acclimation and observation periods.
- Diet (e.g. ad libitum): Purina experimental diet for rabbit 38302AF
- Water (e.g. ad libitum): Public tap water in Cheongju-si was filtered and irradiated by ultraviolet light and provided ad libitum.
- Acclimation period:
Upon receipt, all animals were subjected to the clinical examination. Body weights were recorded (CP12001S, Sartorius, Germany).
During the quarantine-acclimation period, all animals were observed for clinical signs once daily for 8 days in the initial test and for 10 days in the confirmatory test.
On the last day of the quarantine-acclimation period, the measurement of body weights and examination of health condition were conducted and the results were recorded by a responsible person. All animals were judged to be healthy and acceptable for use in the study.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 24 deg C
- Humidity (%): 39.8 - 63.2 %
- Air changes (per hr): 10 - 15 per hour
- Photoperiod (hrs dark / hrs light): 12 hours light/dark (light between 7am and 7pm)
Lighting: 150 - 300 Lux

IN-LIFE DATES: From: 26th February To: 7th March

Test system

Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1g
- Concentration (if solution):

VEHICLE
- Amount(s) applied (volume or weight with unit):
- Concentration (if solution):
- Lot/batch no. (if required):
- Purity:
Duration of treatment / exposure:
In the initial test, irritation effects were shown from one hour after test substance application. After the initial 8-hour post-test substance application, buprenorphine at 0.01 mg/kg SC was administered every 12 hours, in conjunction with meloxicam at
0.5 mg/kg SC every 24 hours, until the terminate of experiment at 48 hours.
Observation period (in vivo):
The response scores of the cornea, iris and conjunctival were recorded at 1, 24 and 48 hours after application according to the evaluation of eye response (Method of Draize: 1959)1) by visual observations and using a slit lamp (Kowa SL-15, KOWA Co., Ltd., Japan).
Duration of post- treatment incubation (in vitro):
Not applicable
Number of animals or in vitro replicates:
Initial test - 1 animal
Confirmatory test - 2 animals
Details on study design:
Use of topical anesthetic and systemic analgesics:
Sixty minutes prior to test substance application, buprenorphine at 0.01 mg/kg was administered by subcutaneous injection (SC) to provide a therapeutic level of systemic analgesia.
Five minutes prior to test substance application, one drop of 0.5% proparacaine hydrochloride was applied to the right and left eyes.
In the initial test, irritation effects were shown from one hour after test substance application. After the initial 8-hour post-test substance application, buprenorphine at 0.01 mg/kg SC was administered every 12 hours, in conjunction with meloxicam at 0.5 mg/kg SC every 24 hours, until the terminate of experiment at 48 hours.

Method of administration:
0.1 g of the test substance (100% test substance) was instilled into the conjunctival sac of the right eye of animal after gently pulling over the lower eyelid away from the eyeball using a spatula. The eyelid was gently held together for approximately one second in order to prevent the loss of the test substance. The left eye was untreated and served as control In the initial test, corrosive effect was not observed after test substance application.
Therefore, a confirmatory test was conducted using two rabbits.

Observation of eye irritation:
The response scores of the cornea, iris and conjunctival were recorded at 1, 24 and 48 hours after application according to the evaluation of eye response (Method of Draize: 1959)1) by visual observations and using a slit lamp (Kowa SL-15, KOWA Co., Ltd., Japan).
Test animals were evaluated for signs of pain and distress immediately after test substance application, at each observation time and prior to administration of systemic analgesics throughout the study.
At 24 hours after test substance application of initial test, the eye of animal was examined for cornea injury by fluorescein paper strips (Lot No.: 1626). Irreversible damage (corrosive) of grade 4 corneal opacity was observed in the initial and confirmatory tests, thus the experiment was terminated (initial test: Day 2, confirmatory test: Day 0). Representative photographs of the application site of an animal were taken at each interval up to 48 hours after application.

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
cornea opacity score
Remarks:
Animal 1101
Basis:
animal #1
Time point:
24/48 h
Score:
3.5
Max. score:
4
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Remarks:
Study terminated after 24 hours, due to the severe corrosive effects.
Irritation parameter:
cornea opacity score
Remarks:
Animal 1102
Basis:
animal #2
Time point:
other: 1 hour
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Remarks:
Study terminated, due to the severe corrosive effects
Irritation parameter:
cornea opacity score
Remarks:
Animal 1103
Basis:
animal #3
Time point:
other: 1 hour
Score:
3
Max. score:
4
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Remarks:
Study terminated, due to the severe corrosive effects
Irritation parameter:
chemosis score
Remarks:
Animal 1101
Basis:
mean
Time point:
24/48 h
Score:
2
Max. score:
4
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Irritant / corrosive response data:
Initial test:
Corneal opacity (score 2), area of the opacity (score 4), congestion of the iris (score 1), redness of the conjunctival (score 1), chemosis of the conjunctival (score 2) and discharge (score 1) were observed at one hour after application.
Corneal opacity (score 3), area of the opacity (score 4), congestion of the iris (score 1), redness of the conjunctival (score 1), chemosis of the conjunctival (score 2) and discharge (score 3) were observed at 24 hour after application. Also, corneal damage was examined using a fluorescein paper strip at 24 hours after application. As a result, fluorescein sodium dye spots were observed in the cornea and the range of dyeing was the whole area.
Corneal opacity (score 4), area of the opacity (score 4), congestion of the iris (score 1), redness of the conjunctival (score 1), chemosis of the conjunctival (score 2) and discharge (score 3) were observed at 48 hour after application.
No reactions on the conjunctival, cornea and iris were observed in the control eye during the observation period.

Confirmatory test:
Corneal opacity (score 4), area of the opacity (score 4), congestion of the iris (score 1), redness of the conjunctival (score 1), chemosis of the conjunctival (score 2) and discharge (score 1) was observed in one animal at one hour. Corneal opacity (score 3), area of the opacity (score 4), congestion of the iris (score 1), redness of the conjunctival (score 1), chemosis of the conjunctival (score 2) and discharge (score 1) was observed in another animal.
No reactions on the conjunctival, cornea and iris were observed in the control eye during the observation period.
The corneal opacity of score 4 is an ocular lesion that is not reversible before the end of the scheduled 21 days observation period, thus the experiment was terminated from a humane endpoints.

In both the initial and confirmatory tests, an irreversible lesion (corneal opacity of score 4) was observed, the test substance was judged to be corrosive to rabbit’s eye.
Other effects:
Clinical signs: No abnormal signs or symptoms were observed in any animal throughout the course of the study.
Clinical Signs of Pain and Distress: No abnormal signs of pain and distress were observed in three animals on Day 0. Excessive tearing (ET) was observed at the time of observation and before the administration of analgesic on Day 1 and 2 in the initial test.

Applicant's summary and conclusion

Interpretation of results:
Category 1 (irreversible effects on the eye) based on GHS criteria
Conclusions:
In conclusion, the test substance, Bisphenol-F(Reaction mass of 2,2’-methylenediphenol and 4,4’-methylenediphenol and o-[(4-hydroxyphenyl)methyl]phenol), was considered to be corrosive to rabbits’ eyes under the conditions of this study.
Executive summary:

This study was conducted to evaluate the potential eye irritation/corrosion after a single application of the test substance, Bisphenol-F(Reaction mass of 2,2’-methylenediphenol and 4,4’-methylenediphenol and o-[(4-hydroxyphenyl) methyl]phenol), in three 11-week-old male New Zealand White rabbits.

In the initial test, 0.1 g of pulverized test substance was instilled to the conjunctival sac of the right eye of one animal. A corrosion effect was not observed after application. Therefore, a confirmatory test was conducted using two additional animals. Eye irritation was observed in the cornea, iris and conjunctival, and scored according to the grade of eye irritation of Draize’s method1)at 1, 24 and 48 hours in the initial test and one hour in the confirmatory test after application of the test substance. In the initial and confirmatory tests, corneal opacity (score 4) was observed at 48 hours and one hour after application, respectively. This lesion was generally regarded as irreversible damage (corrosive). Thus the initial and confirmatory tests were terminated at 48 hours and one hour after application of the test substance, respectively.

 

In the initial test, corneal opacity (score 2-4), area of the opacity (score 4), congestion of the iris (score 1), redness of the conjunctival (score 1), chemosis of the conjunctival (score 2) and discharge (score 1 and 3) were observed from one to 48 hours after application.

In the confirmatory test, corneal opacity (score 3-4), area of the opacity (score 4), congestion of the iris (score 1), redness of the conjunctival (score 1), chemosis of the conjunctival (score 2) and discharge (score 1) were observed at one hour after application.

 

Topical anesthetic and systemic analgesics were used to avoid or minimize pain and distress in eye irritation/corrosion testing procedures. 

During the observation period, no abnormal clinical signs or body weight gain was observed in any animal. Also, in the initial test, clinical signs of pain and distress (excessive tearing) were observed.

 

Based on the result of this study, the test substance, Bisphenol-F(Reaction mass of 2,2’-methylenediphenol and 4,4’-methylenediphenol and o-[(4-hydroxy phenyl) methyl]phenol), was considered to be corrosive to rabbits’ eyes under the conditions of this study.