Registration Dossier

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
July 05, 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 guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: TG 436
Version / remarks:
"Acute Inhalation Toxicity" (TG 436) published by the Ministry of Enviornmental Protection of the People's Republic of China in the year of 2013.
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
no

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

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
Test System
Species: Rat
Strain: Sprague Dawley Grade: SPF
Supplier: Beijing Vital River Laboratory Animal Technology Co., Ltd. Animal Production License: SCXK. (Jing) 2016-0006
Animal Certificate No.: 11400700321610
Number of Animals: 18 animals (9 males and 9 females) were ordered and 6 of them were used. The females were nulliparous and non,-pregnant.
Age and Body Weight: The age was between 56-62 days, and the ·body weights were between 246-248 g for male rats and 206-216 g for female rats at the commencement of dosing, respectively.
Physical Examination and Acclimatization: A physical examination, weighing and marking on the hair and cage card identifying was made in 24 hours after animals' arrival. After the physical examination a 7-day acclimatization period started. Animals were acclimated to the restraining tubes twice prior to dosing in order to minimize stress and uncomfortableness about restraining tubes. First pre-adaption was about 1 h. Second pre-adaption was about 2 h. No abnormalities were found during both restraining.

Test conditions:
Husbandry: Animals were housed in Room Al20-1 of the facility. Animals were raised in suspended, stainless steel cages (132.0cm xW28.0cmxH20.0cm) on cage racks (L167.0cmxW70.0cmxH171.0cm). There were 10 cages per layer, and 4 layers per rack. Animals were housed individually during the test.
Environmental Controls: The temperature and humidity were automatically controlled and recorded. The animal room temperature was 19-25°C, the relative humidity was 40%-70% and light cycle was 12 hour light and 12 hour dark.
Food and Water: Animals were provided with SPF rodent maintenance feed supplied by Beijing Keaoxieli Feed CO., LTD. Analysis report of diet was provided by the supplier. Water was purified using the HT-R0l000 purity system. Drinking water was routinely analyzed. Diet and drinking water were considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study.. During the test, diet and water were available to the animals ad libitum except restraining periods.
Animal Welfare: The animal use for this study complies 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). The spare animals were euthanized by CO2.
Active Ingredient (a.i.): (2-fluoro-3-methoxyphenyl) boronic acid Batch No.: 18051400

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
snout only
Vehicle:
other: fumed silica
Mass median aerodynamic diameter (MMAD):
ca. 1.65 µm
Geometric standard deviation (GSD):
ca. 1.55
Remark on MMAD/GSD:
Aerosol Instrument for Aerodynamic Particle Sizer 3321 was used to assess the particle size distribution of the test atmosphere.
The average aerodynamic particle size less than 4 micron (mass %) for a two-time measurement was 97.66%.
Details on inhalation exposure:
Test Equipment and Administration Method

Equipment: HOPE-MED 8052H dynamic snout only aerosol inhalation instrument was used.

Atmosphere Generation System: The test item was aerosolized using a stainless steel aerosol generation system. There is a pump with a rotating baffle which drives test item to a rotating round plate where the test item is mixed with compressed air. Target concentration was achieved by adjusting air flow rate and pump infusion velocity.

Method: Before exposure, restrain each rat in a confined transparent polycrylic tube. The exposure tubes were installed in the portholes of the inhalation chamber and quantitative test item and aerosol was sent to exposure chamber. The moving speed and exposure airflow rate was adjusted as appropriated. The aerosol was continuously generated from generation system on the top of the chamber with an aerosol producer. The exhausted air was removed from the outlet at the bottom ·of the chamber to absorption unit.

Concentration Trial: Before exposure, test item trial was conducted (without animals) using the inhalation system. After two successive concentrations' error fell within ±20% of target concentration, exposure was conducted.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
5070 mm/m^3
No. of animals per sex per dose:
First Dose: 3 males
Second Dose: 3 females
Control animals:
no
Details on study design:
Clinical Observations
Clinical observations were performed once during the exposure, and once when and 1 h after the animals' removing from the confined tubes on the exposure day. Observations on death or dying were performed twice (both in the morning and afternoon) from the first day after exposure day to the end of observation period except that they were performed once (in the morning) on necropsy days, weekends and public holidays.
Observations and records were conducted including animal fur changes, eyes and mucousmembranes, and also respiratory,. circulatory, autonomic and central nervous systems, and somatomotor activity· and . behavior patterns. Attention was directed to tremors, convulsions, salivation, diarrhea, lethargy, sleep and coma. It was determined by the toxic reactions, time of onset and length of recovery period, and might thus be extended when considered necessary. Animals' poisoning symptoms were observed and the time of their onset, duration and disappearance were recorded.

Body Weights
The animals were weighed on the day of exposure (day 0, prior to exposure), and on day 1, day 3, day 7 and day 14.·

Necropsy
All surviving animals were dissected at the end of the study after anesthetizing with ether and killed by bloodletting. Nose, eyes, pharynx, larynx, trachea and lung were examined. The necropsy included following examinations such as the external features of the carcass, external body orifices, the abdominal, thoracic arid their contents of all animals, and the location, size, hardness and the color. All the changes at necropsy were recorded. Due to no abnormalities were observed in target organs at necropsy, the histopathological examination was not performed.

Evaluation of Data
Animal number, sex,. bodyweight, necropsy and histopathology abnormal findings were summed up. The mean and standard deviations of body weight at different times were calculated.
The inhalation toxicity LCso range was found. According to GHS criteria for the acute inhalation toxicity (as shown in Table 3 below) the test item category was given. Because unit of LCso was mg/m3, the LCso divided by 1000 was converted to mg/L units when test item classification was conducted.

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5 070 mg/m³ air
Based on:
test mat.
Mortality:
No deaths of animals under test were observed after exposure till the end of the test.
Clinical signs:
other: no signs of abnormality
Body weight:
The body weights of the animals under test showed an increasing trend.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Based on above results, the acute inhalation LC50 (4 h) in rats for FMPBA is more than 5070 mg/m3 and the cut-off value of LC50 (4h) is- infinity mg/L. According to GHS's classification criteria of acute inhalation toxicity, the test item is classified as "Unclassified".