5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 2015-06-04 to 2015-07-03

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well documented study performed according to OECD guideline 423, EU method B1 tris and EPA OPPTS guideline 870.1100, in compliance with GLP. No deviations were noted.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2015

Report date:

2015

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

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:

5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one

EC Number:

258-771-6

EC Name:

5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one

Cas Number:

53786-28-0

Molecular formula:

C12H14ClN3O

IUPAC Name:

5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one

Test material form:

solid: particulate/powder

Details on test material:

- Name of test material (as cited in study reports): T000990
- Physical state: solid (powder)
- Appearance: slight beige powder

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: A14JB3414
- Expiration date of the lot/batch: 2015-10-01 (retest date)
- Purity test date: 2014-12-22

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at room temperature
- Stability under test conditions: No data
- Solubility and stability of the test substance in the solvent/vehicle: No data

OTHER SPECIFICS:
correction factor: 1

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: 9 female rats (nulliparous and non-pregnant), Wistar strain Crl:WI (Han) (outbred, SPF-Quality); Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approximately 8 weeks old
- Weight at study initiation: 144 - 167 grams
- Fasting period before study: animals were deprived of food overnight prior to dosing and until 3-4 hours after administration of the test item. Water was available ad libitum.
- Housing: group housing of 3 animals per cage in labeled Makrolon cages (MIV type; height 18 cm.) containing sterilized sawdust as bedding material and paper as cage-enrichment
- Diet (e.g. ad libitum): ad libitum, free access to pelleted rodent diet .
- Water (e.g. ad libitum): ad libitum, free access to tap water.
- Acclimation period: at least 5 days before start of treatment under laboratory conditions, health inspection at least prior to dosing. It was ensured that the animals were healthy and without any abnormality that might affect the study integrity.

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

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

1% aqueous CMC

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 30 mg/ml (300 mg/kg body weight) and 200 mg/ml (2000 mg/kg body weight)
- 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 (turbid solution), propylene glycol (spec.gravity 1.036), polyethylene glycol 400 (spec. gravity 1.125) and corn oil (spec. gravity 0.92).
- Lot/batch no. (if required): no data
- Purity: no data

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg

DOSAGE PREPARATION (if unusual):
- The preparations (w/w) were kept at room temperature and were dosed within 4 hours after adding the vehicle to the test item. Homogeneity was assessed by visual inspection of the solutions and the formulations were stirred during dosing, which ensures homogeneity sufficient for these kinds of studies.
- No correction was made for purity of the test item.
- The concentration of the test item in vehicle was varied to allow constant dosage volume in terms of mL/kg body weight.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: the dose level was selected based on toxicity data (e.g. existing human and animal data, literature, substance data supplied by the Sponsor, analysis of structure activity relationships (SAR) and in vitro, ex-vivo and in vivo tests) of the test item (specified and approved by the Study Director in the study files).

Doses:

300 and 2000 mg/kg body weight

No. of animals per sex per dose:

3 females per dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days (until day 15)
- Frequency of observations and weighing:
-mortality/viability: twice daily;
-body weights: days 1 (pre-administration), 8 and 15;
-clinical signs: at periodic intervals on the day of dosing (day 1) and once daily thereafter, until day 15. The signs were graded according to fixed scales and the time of onset, degree and duration were recorded: maximum grade 4: grading slight (1) to very severe (4); maximum grade 3: grading slight (1) to severe (3); maximum grade 1: presence is scored (1).
- Necropsy of survivors performed: yes, the 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:

> 300 - < 2 000 mg/kg bw

Based on:

test mat.

Mortality:

At 300 mg/kg, no mortality occurred.
At 2000 mg/kg, all animals were found dead on day 1.

Clinical signs:

other: At 300 mg/kg, hunched posture, piloerection and/or ptosis were noted for the animals between days 1 and 4. At 2000 mg/kg, hunched posture was noted on day 1.

Body weight:

other body weight observations

Remarks:

The body weight gain shown by most of 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. One animal treated at 300 mg/kg, showed body weight loss between days 1 and 8, but showed a body weight that was considered normal on day 15.

Gross pathology:

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

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The oral LD50 value of JNJ-119743-AAA (T000990) in Wistar rats was established to be within the range of 300-2000 mg/kg body weight.
According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 500 mg/kg body weight.
Based on these results according to the CLP regulation, JNJ-119743-AAA (T000990) should be classified as Category 4 and should be labeled as H302: Harmful if swallowed.