Registration Dossier

Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
July 05 2018 - 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:
other: "Acute Dermal Toxicity" (TG 402) published by the Ministry of Environmental Protection of People's Republic of China (2013)
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity: Fixed Dose Procedure)
Deviations:
no
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
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

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
Justification of Test System: Rats are the preferred species of choice as historically used for the safety evauluations studies and are specified in the appropriate test guidelines.

11.2 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-ROlOOO 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.

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
water
Details on dermal exposure:
Justification for the Route of Administration
The dermal route was chosen to assess the safety by a possible dermal exposure.

Testing Strategy
To investigate if the test material has dermal-irritation potential, an in vivo test in rabbits was conducted in a sequential way.
Initial Test: The test was performed initially using one animal with one control patch and one test patch for an exposure period of 4 hours.
Confirmatory Test: No irritant effects were observed in the initial test within 24hours after patch removal of the test item, a confirmatory test was conducted by exposing two additional animals simultaneously. Each animal received application of one control patch and one test patch for an exposure period of 4 hours.

Dose Design
Based on the Guidelines for the testing of chemicals "Acute Dermal Irritation/Corrosion Test" (TG 404) published by the Ministry of Environmental Protection of People's Republic of China in the year of 2013, 0.5 g oftest item was applied to the test site of skin.

Test Item Preparation and Dosage
0.5 g oftest item was weighed ahd moistened with vehicle, and then was applied to the gauze patch for the test site.

Preparation of Animals
Approximately 24 hours before the test, the back and flanks of each animal were clipped free· of fur. Care was taken to avoid abrading the skin, and only animals with healthy, intact skin by gross observation were used for the study.
Depilated area was approximately 6 cm x 6 cm for each side of the mid-line of each animal. The site (about 2.5cmx2.5cm) of depilated area below the suprascapular on each side was selected. Site A was for the control patch served as a control site, and Site B was for the test patch, both for an exposure period of 4 hours.

Administration Method
Dosing: A dose 0.5 g of the test item was applied to the gauze patch (2.5cm x 2.5cm), which was on no-irritating adhesive tape covered by medical film. 0.8 mL vehicle was dripped into the test item and modulated into a paste for uniform distribution of the substance, and which was served as test patch. The untreated gauze patch (2.5cm x 2.5cm) on no-irritating adhesive tape covered by medical film was served as control patch. The test and control patches were applied to the appointed and depilated skin, all animals were wrapped using elastic bandage and medical paper tape to form a semi-occlusive dressing, by which there was a good contact with skin and prevented animals from ingestion or inhalation of the test item. One control patch and one test patch were applied to each animal for an exposure period of 4 hours. Site A was covered with the control patch and Site B was covered with the test patch, removed after 4 hours.
Removal of Residual Test Item: Patches were removed at the end of the exposure period. The residual test substance was gently wiped off the application site by cotton moistened with tepid water. Care was taken not to alter the existing response or the integrity of the epidermis.
Dosing Frequency: Each animal was dosed once.
Dosing Time: Morning
The time interval between initial and confirmatory tests was 1 day.
Duration of exposure:
24 hours
Doses:
2000 mg/kg b.w.
No. of animals per sex per dose:
Dose 1 - 5 males
Dose 2 - 5 females
Control animals:
no
Details on study design:
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
Swnmary 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.

Results and discussion

Effect levelsopen allclose all
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
no indication of skin irritation up to the relevant limit dose level
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
no indication of skin irritation up to the relevant limit dose level
Mortality:
No deaths or moribund status were observed during the test.
Clinical signs:
There were no abnormal findings in all animals during the test.
Body weight:
The results indicated that most of the body weight gains of animals showed growth.
Gross pathology:
Not specified

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
According to the GHS's classification criteria of acute dermal toxicity, the test item was classified as "Category 5" or "Unclassified". However, since category 5 is not implemented in the EU, GHS critieria was considered to be not met.