Registration Dossier

Administrative data

Description of key information

Based on the results from both the skin irritation/corrosion and eye irritation studies, there was no indication of irritation or corrosion.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin 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
Qualifier:
according to guideline
Guideline:
other: TG 404
Version / remarks:
"Acute Dermal Irritation/Corrosion Test" published by the Ministry of Environmental Protection of People's Republic of China 2013
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
Seventh revised edition, 2017, United Nations
Deviations:
no
Principles of method if other than guideline:
In the study plan, animals will be individually raised in suspended, stainless steel cages (W40 cmxL50 cmxH40 cm) on cage. racks (1167 cmxW70 .cmxHl 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
Species:
rabbit
Strain:
other: Japanese White(Albino)
Details on test animals or test system 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.: 37003900000709
Justification of Test System: 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 animals
Sex: Male
Age: Young adult, 84 days at arrival and 89~90 days at dosing.
Body Weight Range: 2037.4-2355.0 g at receipt and 2117.3-2690.9 g at dosing.
Physical Check-up and Acclimatization: Physical check-up was made to all animals on arrival. Healthy young adult animals were acclimatized to the laboratory conditions and housed individually for 5~6days 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 within 24 hours after arrival.

Test Conditions
Husbandry
Animals were housed in Room A115 of the facility. Animals were individually raised in stainless steel cages (W70 cmxL80cmxH75 cm) during the study.

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

Food 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.
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.
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
Animal use comply with national animal welfare laws and regulations (instructive notions with respect to caring for laboratory aninJals) (2006, Ministry of Science, P.R.C.).The aninJal care and use activities required for conduct of this study were reviewed and approved by the testing facility Animal Care and Use Committee (IACUC).

The surviving animals were humanely killed by 10% KCl injection application (1.5 mL/kg) after anesthetized by Zoletil (5 mg/kg) at the end of the study. Their corpse treatments were entrusted to specialized agencies.
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
water
Controls:
yes, concurrent no treatment
Amount / concentration applied:
0.5 g/ test site
Duration of treatment / exposure:
4 hours
Observation period:
24 hours between initial and confirmatory tests.
Number of animals:
3 males
Details on study design:
Observation, Measurement and Examination Clinical Observations
All animals were observed for clinical signs once daily throughout the study.

Skin Reactions Examination
The skin sites after patch removal were examined and recorded for dermal irritation (erythema/eschar, oedema and all local toxic effects of skin) and corrosion (ulcers, bleeding, bloody scabs, etc., by the end of observation).
The skin sites of each animal were examined and recorded for signs of skin reaction immediately, at approximately 1, 24, 48 and 72 hours after patch removal.

Grading of Skin Reactions
Dermal reactions for erythema/eschar or oedema of test sites of each animal were scored and recorded at approximately 1, 24, 48 and 72 hours after patch removal according to the grades in Table2 below.

Body Weights
Individual animal body weight was recorded within 24 hours after arrival, on the day of dosing and on the completion day of the final observations of dermal irritant symptoms.

Histopathological Examination
Histopathological examination was not conducted because there were no equivocal responses.

Evaluation of Data
Summary data in tables covered animal ID, gender, dosage, clinical observations, skin reactions examination, grading of skin reactions and body weights.
Mean scores for erythema/eschar and oedema at 24, 48 and 72 hours after patch removal of the test item for each animal were calculated to assess the degree of dermal irritation/corrosion of the test item in conjunction with the nature and severity of lesions, and their reversibility or lack of reversibility.
The test item was classified according to GHS criteria for the Acute Dermal Irritation/Corrosion.
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Interpretation of results:
GHS criteria not met
Conclusions:
Based on above results, FMPBA was considered to have no irritations to skins of rabbits, and was classified as "unclassified" according to GHS's classification criteria for the skin irritation.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
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
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
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.
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.
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
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.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification