Registration Dossier

Administrative data

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
June 06, 2018 to November 03, 2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

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

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
"Acute Eye Irritation/Corrosion Test" (TG 405) published by the Ministry of Environmental Protection of People's Republic of China 2013
Deviations:
no
Principles of method if other than guideline:
In the study plan, animals will be individually raised in suspended, stainless steel cages (W40 cmxLSO cmxH40 cm) on cage racks (1167 cmxW70 cmxHI 71 cm) during the study. But in fact they were individually raised in stainless steel cages (W70 cmxL80 cmxH75 cm) without cage racks. Because the cage racks used were larger than the planned ones, this deviation was considered not to affect the quality and integrity of the study
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
(2-fluoro-3-methoxyphenyl)boronic acid
EC Number:
609-099-0
Cas Number:
352303-67-4
Molecular formula:
FC6H3(OCH3)B(OH)2
IUPAC Name:
(2-fluoro-3-methoxyphenyl)boronic acid
Test material form:
solid: particulate/powder

Test animals / tissue source

Species:
rabbit
Strain:
other: Japanese White (Albino)
Details on test animals or tissues and environmental conditions:
Test System Species: Albino rabbit
Strain: Japanese White
Grade: Conventional Laboratory Animals
Supplier: Qingdao Kangda Biological Technology Limited Company · License No.: SCXK (Lu) 20160002
Qualification No.: 37003900000708
Justification: Rabbits are the preferred species of choice as historically used for the safety evaluations studies and are specified in the appropriate test guidelines.
Number: 3
Sex: Male
Age: Young adult, 84 days at receipt and 94-95 days at dosing.
Body Weight Range: 1962.5-2055.6 g at receipt and 2262.1-2418.7 g at dosing
Physical Check-up and Acclimatization: Physical checksup was made to all animals on arrival. Healthy young adult animals were acclimatized to the laboratory conditions and housed individually for 10- 11 days prior to dosing, during which clinical observations were performed daily and all animals showed no abnormality. All animals were weighed and marked by the special animal markers beginning from No. 1100 to 1102 and number written on cage cards in 24 hours after arrival.

Test Conditions
Husbandry
Animals were housed in building A115 at start of the study. Animals were individually raised in stainless steel cages (W70 cmxL80 cmxH75 cm) during the study.

Environmental Condition
Temperature and humidity were controlled automatically and daily recorded. The values in the animal room were 17~23°C for temperature, and 40%~70% for humidity. The lighting sequence was 12 hours light, 12 hours dark.

Diet and Water
Animals were provided with rabbit maintenance feed supplied by Beijing Keaoxieli Feed Co., Ltd.. Analysis reports of diet were .supplied by the supplier. All the nutrition components and contaminants were within the permitted limits described in the national standard (GB14924.3-2010 and GB14924.2-2001).
Drinking water was purified by the HT-R0l000 purity system. Water analysis was conducted routinely analyzed (annually), and all parameters were within the permitted limits described in the national standard (OB5749-2006}.
Diet and drinking water were considered not to .contain any contaminants that could reasonably be expected to affect the result, purpose and integrity of the study.
Diet and drinking water were available to the animals ad libitum during the test.

Animal Welfare
All procedures in this protocol were in accordance with the national animal welfare laws and regulations, Instructive Notions with Respect to Caring for Laboratory Animals (2006, PRC Ministry of Science). The animal care and use activities required for conduct of this study were reviewed and approved by the testing facility Animal Care and Use Committee (IACUC).
To avoid or minimize pain and distress in ocular safety testing procedures, a local anesthetic (tetracaine hydrochloride: 0.5%, 1 drop/animal eye five minutes prior to test substance application) was used at the discretion of the study director. Both eyes were similarly anesthetized. The identity and .use of local anesthetic were documented in the study data.
The survival animals were humanely killed by 10% KC! injection application (1.5 mL/kg) after anesthesia by Zoletil (5 mg/kg) at the end of the study. Their corpse treatments were entrusted to specialized agencies.

Test system

Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
0.1g of the test item
Duration of treatment / exposure:
1 second
Observation period (in vivo):
3 days
Number of animals or in vitro replicates:
3 males
Details on study design:
Justification for the Route of Administration
The eye route was chosen to assess the safety by a possible eye exposure.

Testing Strategy
To investigate if the test material had eye-irritation potential, an in vivo test in rabbits was conducted in a sequential way.
Initial Test: Testing was initially conducted in one animal.
Confirmatory Test: A corrosive or severe irritant effect was not observed in the initial test, the confirmatory test was conducted using two additional animals simultaneously. The time interval between initial and confirmatory test was 1 day.

Dose Design
Based on the Guidelines for the testing of chemicals "Acute Eye Irritation/Corrosion Test" published by the Ministry of Environmental Protection of People's Republic of China in the year of 2013, 0.1 g of the test item was applied to eye for each animal.

Test Item Preparation and Dosage
0.1 oftest item was weighed, and then was applied to the test eye.

Preparation of Animals
Approximately 24 hours prior to dosing, both eyes of each animal were examined with binocular loupe and 2% aqueous of sodium fluorescein (vehicle: physiological saline) in the slit lamp. One drop of 2% aqueous of sodium fluorescein was placed in the conjunctivae sac of both eyes, and then eyes were washed using physiological saline after 15 seconds. Corneas of both eyes were examined in the slit lamp to see whether there was fluorescein detention in the cornea or not.

Administration Method
Dosing: The rabbits were held firmly but gently until quiet. 0.1 g of the test item was placed in the conjunctiva! sac of right eye of each animal after gently pulling the lower lid away from the eyeball. The lids were gently held together for approximately one second in order to prevent loss of the material. The left eye remained untreated and served as a control.
Dosing Frequency: Each animal was dosed once.
Dosing Time: In the morning.

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
0.22
Max. score:
0.33
Remarks on result:
no indication of irritation

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Based on the above results, FMPBA could produce slight eye irritant reactions in rabbit, and was classified as "unclassified" according to GHS's classification criteria for the eye irritation.