3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2006-03-29 to 2006-05-04

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2006

Report date:

2006

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

GLP compliance:

yes (incl. QA statement)

Remarks:

Certificate from the Swiss GLP monitoring authorities.

Test type:

acute toxic class method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

EC Number:

255-207-0

EC Name:

3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

Cas Number:

41078-70-0

Molecular formula:

C11H11ClN2O

IUPAC Name:

3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

Test material form:

solid: particulate/powder

Details on test material:

- Name of test material (as cited in study report): JNJ-559728-AAA (T001250)
- Physical state: solid (powder)
- Appearance: White powder

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Janssen Pharmaceutical N.V.; 00443418 RT001250G4a661
- Expiration date of the lot/batch: Unknown, excluded from statement of compliance
- Purity: 100%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature (range of 20 +/- 5 C), light protected
- Stability under test conditions: Stable under storage conditions
- Solubility and stability of the test substance in the solvent/vehicle: unknown in Peg 300

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The dose formulations were made shortly before each dosing occassion using a magnetic stirrer, a spatula and an Ultra-Turrax as homogenizers. The test item was weighed into a tared glass beaker on a suitable precision balance and the vehicle added. Homogeneity of the test item in the vehicle was maintained during administration using a magnetic stirrer.

Test animals

Species:

rat

Strain:

other: HanRcc:WIST (SPF)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: RCC Ltd.., Laboratory Animal Services CH-4414 Fullinsdorf / Switzerland
- Age at study initiation: 12 weeks
- Weight at study initiation: 187.7 - 203.9 grams
- Fasting period before study: no data
- Housing: In groups of three in Makrolon type-4 cages with wire mesh tops and standard softwood bedding ('Lignocel' Schill AG, CH-4132 Muttenz/Switzerland).
- Diet (e.g. ad libitum): Pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, batch no. 001/06 (Provimi Kliba AG, CH-4303 Kaiseraugst/Switzerland) ad libitum.
- Water (e.g. ad libitum): community tap water from Fullinsdorf ad libitum
- Acclimation period: 6 to 10 days

ENVIRONMENTAL CONDITIONS
- Temperature (deg C): 22 +/- 3 deg C
- Humidity (%): 30-70%
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12/12, with music played during light cycle

IN-LIFE DATES:
From: 2006-04-05 To: 2006-04-19 (1st 300 mg/kg treatment)
From: 2006-04-11 To: 2006-04-11 (2000 mg/kg treatment)
From: 2006-04-20 To: 2006-05-04 (2nd 300 mg/kg treatment)

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Remarks:

PEG 300

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 0.2 g/mL
- Amount of vehicle (if gavage): 10 mL/kg body weight
- Justification for choice of vehicle: The vehicle was chosen after a non-GLP solubility trial which was performed before the study initiation date.
- Lot/batch no. (if required): 120471944705164

MAXIMUM DOSE VOLUME APPLIED:
- 2000 mg/kg-bw

Doses:

300 and 2000 mg/kg bw

No. of animals per sex per dose:

Three females/group, 9 animals total (3 groups)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 15 days
- Frequency of observations and weighing:
Observation: During the acclimatization period, and the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1
(with the clinical signs) and twice daily during days 2-15.
Weighing: on days 1 (prior to test), 8, and 15
- Necropsy of survivors performed: yes

Statistics:

No statistical analysis was used.

Results and discussion

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

> 300 - < 2 000 mg/kg bw

Mortality:

All animals tested at a concentration dose of 2000 mg/kg died spontaneously or were killed in extremis for ethical reasons approximately 7.5 hours after treatment. All of the animals treated with 300 mg/kg survived until the end of the study period.

Clinical signs:

irregular respiration

salivation

other:

Body weight:

greater than 10% body weight loss

Remarks:

The body weight of all animals treated with 300 mg/kg was found diminished (3% to 17%) one week after treatment. The animals recovered the lost weight until the end of the study.

Gross pathology:

At the unscheduled necropsy, one 2000 mg/kg treated animal had collapsed lungs, a stomach with liquid contents and the duodenum and jejunum were filled with yellowish liquid. The other two animals treated at the same dose showed a stomach with yellowish liquid contents and a distended urinary bladder filled with yellowish urine. No macroscopic findings were recorded in the 300 mg/kg treated groups at the scheduled necropsy.

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The median lethal dose of the test substance after single oral administration to female rats, observed over a period of 14 days was: 300 mg/kg < LD50 (female rat) < 2000 mg/kg body weight.