Imidazo[5,1-f][1,2,4]triazin-4(1H)-one, 2-[2-ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]phenyl]-5-methyl-7-propyl-

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

April 2000

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2000

Report date:

2000

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 (Acute Toxicity (Oral))

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

2-{2-ethoxy-5-[(4-ethylpiperazin-1-yl)sulfonyl]phenyl}-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(1H)-one

EC Number:

607-088-5

Cas Number:

224785-90-4

Molecular formula:

C23 H32 N6 O4 S

IUPAC Name:

2-{2-ethoxy-5-[(4-ethylpiperazin-1-yl)sulfonyl]phenyl}-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(1H)-one

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Winkelmann GmbH, Borchen, Germany
- Strain: Hsd Cpb:WU (SPF)
- Age at study initiation: 8-9 weeks
- Mean weight at study initiation: 210-217 g (males) or 154-162 g (females)
- Housing: in groups of 3 animals
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 55 +/- 5
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: formulated in demineralized water with the aid of Cremophor EL 2% (v/v)

Details on oral exposure:

- Application volume: 10 mL/kg bw

- Rationale for the selection of the starting dose:
As described in the flow charts of Annex 2, OECD guideline 423, the starting dose level should be that which is most likely to produce mortality in
some of the dosed animals. Therefore, the limit dose 2000 mg/kg bw was chosen as starting dose.

Doses:

2000 mg/kg

No. of animals per sex per dose:

3

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: at least once daily (clinical signs, mortality) or once weekly (weight gain)
- Necropsy of survivors performed: yes

Statistics:

none (limit test)

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

other: LD50 cut-off

Effect level:

> 2 500 mg/kg bw

Based on:

test mat.

Mortality:

One female died on day 2 after administration of 2000 mg/kg bw. The other 5 animals survived the treatment.

Clinical signs:

other: At 2000 mg/kg bw in males and females the motility and reactivity were decreased, the animals showed narrowed palpebral fissures, and the breathing was labored. Additionally, in females piloerection and a uncoordinated gait were observed. The signs observ

Gross pathology:

No gross pathological findings were observed at the end of the post-treatment observation period. In the female animal that died during the observation period a pale discoloration of kidneys was detected.

Other findings:

none

Applicant's summary and conclusion

Interpretation of results:

practically nontoxic

Remarks:

Migrated information

Executive summary:

The acute oral toxicity of Bay 38-7268 was low with a LD50 exceeding 2500 mg/kg bw in rats (cut-off value) according to OECD TG 423. At the limit-dose 2000 mg/kg one female animal died and in both genders clinical signs were observed up to day 5 after administration. The main clinical findings were decreased motility, decreased reactivity, uncoordinated gait, narrowed palpebral fissures, piloerection and labored breathing.

Administration was tolerated without effects on body weight gain and gross pathological findings.