4-Bromo-2-fluoro-N-methylbenzamide

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 2015-12-01 to 2015-12-24

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2016

Report date:

2016

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

2001

Deviations:

yes

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Version / remarks:

May 2008

Deviations:

yes

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Version / remarks:

2002

Deviations:

yes

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147

Version / remarks:

November 2000

Deviations:

not specified

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

4-Bromo-2-fluoro-N-methylbenzamide

EC Number:

808-257-8

Cas Number:

749927-69-3

Molecular formula:

C8H7BrFNO

IUPAC Name:

4-Bromo-2-fluoro-N-methylbenzamide

Test material form:

solid: particulate/powder

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: M15BD0474
- Expiration date of the lot/batch: 2017-01-15
- Appearance: White powder with lumps
- Purity: 99.8% (w/w)
- Purity test date: 2015-09-11

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature
- Analysis of stability, homogeneity and concentration of the test item under test conditions was not performed as part of this study.

OTHER SPECIFICS
- Correction factor: 1
- pH (1% in water, indicative range): 5.7 – 6.0 (determined by WIL Research Europe)

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: 6 female rats, Wistar strain Crl:WI (Han) (outbred, SPF-Quality) from Charles River Deutschland, Sulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: approx.. 8-9 weeks old
- Weight at study initiation: 155-179 grams
- Fasting period before study: animals were deprived of food overnight (for a maximum of 20 hours) prior to dosing and until 3-4 hours after administration of the test item. Water was available.
- Housing: Group housing of 3 animals per cage in labeled Makrolon cages (MIV type; height 18 cm.) containing sterilized sawdust as bedding material (Lignocel S 8-15, JRS -
J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) and paper as cageenrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom).
- Diet (e.g. ad libitum): ad libitum, free access to pelleted rodent diet t (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water (e.g. ad libitum): ad libitum, free access to tap water.
- Acclimation period: at least 5 days before the commencement of dosing.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24 °C
- Humidity (%): 40-70%
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 2015-12-01 To: 2015-12-24

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Remarks:

specific gravity 1.036

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: The vehicle was selected based on trial preparations performed at WIL Research Europe and on test item data supplied by the Sponsor. The vehicle was chosen from (in order of preference): water (Elix) (test item did not dissolve), 1% aq. carboxymethyl cellulose (test item did not dissolve), propylene glycol (spec.gravity 1.036) (solution), polyethylene glycol 400 (spec. gravity 1.125) and corn oil (spec. gravity 0.92).


MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

DOSAGE PREPARATION:
- Test item dosing formulations (w/w) were homogenized to visually acceptable levels at appropriate concentrations to meet dose level requirements.
The dosing formulations were kept at room temperature until dosing. The dosing formulations were stirred until and during dosing. No correction was made for purity of the test item.

Doses:

2000 mg/kg (single dosage)

No. of animals per sex per dose:

3 females per dose, 2 groups in total

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days (until day 15)
- Frequency of observations and weighing:
mortality/moribundity: twice daily, in the morning and at the end of the working day. Animals were not removed from cage during observation, unless necessary for identification or confirmation of possible findings. Animals showing pain, distress or discomfort, which was considered not transient in nature or was likely to become more severe, were sacrificed for humane reasons based on OECD guidance document on humane endpoints (ENV/JM/MONO/ 2000/7). The time of death was recorded as precisely as possible;
body weights: days 1 (pre-dose), 8 and 15. A fasted weight was recorded on the day of dosing;
clinical signs: at periodic intervals on the day of dosing (at least three times) (day 1) and once daily thereafter. The observation period was 14 days. All the animals were examined for reaction to dosing. The onset, intensity and duration of these signs was recorded (if appropriate). Signs were graded for severity and the maximum grade was predefined at 3 or 4. Grades were coded as slight (grade 1), moderate (grade 2), severe (grade 3) and very severe (grade 4). For certain signs, only its presence (grade 1) or absence (grade 0) was scored.
- Necropsy of survivors performed: yes, the moribund animals and animals surviving to the end of the observation period were sacrificed by oxygen/carbon dioxide procedure. All animals assigned to the study were subjected to necropsy and descriptions of all internal macroscopic abnormalities recorded.

Statistics:

No statistical analysis was performed.

Results and discussion

Effect levels

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 2500 mg/kg body weight.

Mortality:

Two animals were sacrificed for humane reasons on Day 2 and 3, respectively. No further mortality occurred.

Clinical signs:

other:

Body weight:

other body weight observations

Remarks:

The body weight gain shown by the surviving animals over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain

Gross pathology:

No abnormalities were found at macroscopic post mortem examination of all animals.

Any other information on results incl. tables

Number of dead animals in each test group with 3 animals each:

Females 2000 mg/kg: 1/3

Females 2000 mg/kg: 1/3

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The oral LD50 value of JNJ-61789975-AAA (T003669) in Wistar rats was established to exceed 2000 mg/kg body weight. According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 2500 mg/kg body weight.

Based on these results:
- according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2011) (including all amendments), JNJ-61789975-AAA (T003669) should be classified as: may be harmful if swallowed (Category 5) for acute toxicity by the oral route;
- according to the Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures (including all amendments), JNJ-61789975-AAA (T003669) does not have to be classified and has no obligatory labelling requirement for oral toxicity.