4-Ethoxy-2,3-difluorphenylboronic acid

Endpoint summary

Description of key information

The LD50 value for the test item is expected to be between 300 - 2000 mg/kg bw after single oral administration in rats.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

April 12, 2016 - July 25, 2016

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga GmbH, Sulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at start of study: 9 weeks
- Weight at study initiation: 157- 179g
- Fasting period before study: 17 hours before until up to 4 hours after treatment
- Housing: separately in type III Makrolon cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.5 - 23.4°C
- Humidity (%): 45.1-76.5%
- Photoperiod (hrs dark / hrs light): 12 hour light - 12 hour dark regime

IN-LIFE DATES: From: day 1 To: day 15

Route of administration:

oral: gavage

Vehicle:

methylcellulose

Remarks:

Methocel K4M Premium solution

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 and 30 g/L
- Amount of vehicle (if gavage): 10 ml/kg
- Justification for choice of vehicle: well tolerated and established standard vehicle

Doses:

300 and 2000 mg/kg bw

No. of animals per sex per dose:

2000 mg/kg: 3 (f)
300 mg/kg: 6 (f)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: daily
- Frequency of weighing: day 1, 2, 4, 6, 8, 11, 13 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross pathology

Statistics:

Standard statistical methods have been applied for data processing.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 300 - < 2 000 mg/kg bw

Based on:

test mat.

Mortality:

All rats treated with 2000 mg/kg were killed three hours after treatment in a moribund state. No mortality was seen in the rats treated with 300 mg/kg.

Clinical signs:

other: All rats treated with 2000 mg/kg showed locomotor disturbance and incomplete eyelid closure 15 minutes after treatment until they were killed. Additionally, piloerection and hunched position occurred 2 hours after treatment in all rats treated with 2000 m

Gross pathology:

All surviving rats were sacrificed at the end of the experimental part and all rats in moribund conditions were sacrificed by an air carbon dioxide mixture and exsanguination after opening the abdominal vessels (Vena cava caudalis, Aorta abdominalis). All rats were subjected to a gross pathological examination and macroscopic findings were noted manually on a necropsy protocol.
On decision of the responsible pathologist, the liver of animal no 4, 5 and 6 (prematurely killed rats dosed with 2000 mg/kg) were fixed in a 4% formaldehyde solution, processed to HE-stained slides and were subjected to histopathology. Histopathology findings were noted manually on the necropsy protocol.
The gross pathological examination revealed in prematurely killed rats dosed with 2000 mg/kg, a beige discoloration of the liver (animal no. 4, 5 and 6). Histopathology revealed no treatment-related lesions in the liver. No histomorphological findings that could be related to the beige discoloration were found. All other animals showed no macroscopic findings.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

Under the conditions of the present study, the LD50 value for the test item is expected to be between 300 - 2000 mg/kg after single oral administration in rats.

Executive summary:

Study Design

The study was started with 300 mg/kg in 3 female rats and continued stepwise with further 3 females treated with 2000 mg/kg and 3 females treated with 300 mg/kg.Mortality and clinical signs were monitored for at least 6 hours after administration and then daily. All animals were weighed before treatment (day 1) and on days 2, 4, 6, 8, 11, 13, and 15. At the end of the observation period, all surviving rats were sacrificed and subjected to a detailed necropsy. 

 

Results

All rats treated with 2000 mg/kg were killed three hours after treatment in a moribund state. No mortality was seen in the rats treated with 300 mg/kg.

All rats treated with 2000 mg/kg showed locomotor disturbance and incomplete eyelid closure 15 minutes after treatment until they were killed. Additionally, piloerection and hunched position occurred 2 hours after treatment in all rats treated with 2000 mg/kg. No clinical signs of toxicity were observed in the rats treated with 300 mg/kg.

The body weight development was inconspicuous throughout the study.

The gross pathological examination revealed in prematurely killed rats dosed with 2000 mg/kg a beige discoloration of the liver (animal no. 4, 5 and 6). Histopathology revealed no treatment-related lesions in the liver. No histomorphological findings that could be related to the beige discoloration were found. All other animals showed no macroscopic findings.

 

Conclusion

Under the conditions of the present study, the LD50 value for the test item is expected to be between 300 - 2000 mg/kg bw after single oral administration in rats.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

300 mg/kg bw

Quality of whole database:

Guideline study under GLP conditions

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute oral toxicity study

The study was started with 300 mg/kg in 3 female rats and continued stepwise with further 3 females treated with 2000 mg/kg and 3 females treated with 300 mg/kg.Mortality and clinical signs were monitored for at least 6 hours after administration and then daily. All animals were weighed before treatment (day 1) and on days 2, 4, 6, 8, 11, 13, and 15. At the end of the observation period, all surviving rats were sacrificed and subjected to a detailed necropsy. 

Under the conditions of the present study, the LD50 value for the test item is expected to be between 300 - 2000 mg/kg bw after single oral administration in rats.

Justification for classification or non-classification

Based on the data provided, the test item is classified for acute oral toxicity category 4 and labelled with H302 according to Regulation (EC) No 1272/2008.