4H-Pyrazino[2,1-a]isoquinolin-4-one, 2-acetyl-1,2,3,6,7,11b-hexahydro-

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2004-11-09 to 2005-02-11

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2005

Report date:

2005

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

470-180-7

EC Name:

-

Cas Number:

61196-40-5

Molecular formula:

C14H16N2O2

IUPAC Name:

2-acetyl-1H,2H,3H,4H,6H,7H,11bH-pyrazino[2,1-a]isoquinolin-4-one

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: F. Winkelmann, 33178 Borchen
- Females nulliparous and non-pregnant: not specified
- Age at study initiation: young adult
- Weight at study initiation: 151 - 172 g
- Fasting period before study: yes
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22- 23 °C
- Humidity: 43 - 59 %
- Photoperiod: 12 / 12 hrs dark / hrs light

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

methylcellulose

Remarks:

aqueous Methocel K4M Premium solution

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 30 and 200 g/L
- Amount of vehicle: 10 mL/kg
- Justification for choice of vehicle: meets the formulation standards set by the USP, JP and Ph. Eur.

MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg bw

Doses:

300, 2000 mg/kg body weight

No. of animals per sex per dose:

3 per sex per dose @ 300 mg/kg bw
3 females @ 2000 mg/kg bw

Control animals:

no

Details on study design:

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

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 300 - < 2 000 mg/kg bw

Based on:

test mat.

Mortality:

Male: 300 mg/kg bw; Number of animals: 3; Number of deaths: 0
Female: 300 mg/kg bw; Number of animals: 3; Number of deaths: 0
Female: 2000 mg/kg bw; Number of animals: 3; Number of deaths: 3

Clinical signs:

other: Signs of toxicity related to dose levels: After oral treatment with 300 mg/kg (3 males, 3 females), signs of toxicity were seen in the male and female. They started 1 to 15 minutes after administration and lasted up to 24 hours. They consisted of locomo

Gross pathology:

Effects on organs: For animals treated with 300 mg/kg body weight, no organ alterations were seen at necropsy The female rat (2000 mg/kg bw), which died, showed changes in the gastrointestinal tract. The two other rats, which were sacrified in a moribund state showed no macroscopic abnormalities.

Any other information on results incl. tables

Table 1 Summary of mortalities

Dose (mg/kg bw)	Dead / treated animals
	males	Females
300	0/3	0/3
2000	-	3/3

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

According to the results of this study, the LD50 value of the test material is expected to be between 300 - 2000 mg/kg bw.

Executive summary:

Study design

The acute toxicity of the test material was determined in rats after oral administration of 300 and 2000 mg/kg body weight. Directly before administration the test material was prepared with aqueous Methocel® K4M Premium solution as the vehicle. This study was performed according to the "Acute toxic class method" (ATC) as described in the OECD Guideline 423.

Results

After oral treatment with 300 mg/kg bw (3 males, 3 females), signs of toxicity were seen in the male and female rats. They started 1 to 2 hours after dosing and lasted up to 24 hours. They consisted of locomotor disturbance and dyspnea. All these animals survived the observation period. All rats, which were sacrificed at the end of the study, showed no macroscopic abnormalities.
After oral treatment with 2000 mg/kg bw (3 females), signs of toxicity were seen in the female rats. They started 1 to 15 minutes after administration and lasted up to 24 hours. They consisted of incomplete eyelid closure, abdominal position, respiratory sounds, locomotor disturbance, and dyspnea. One animal died 6 hours after administration. The two other animals were sacrificed in a moribund state 8 hours after administration.
The female rat (2000 mg/kg bw), which died, showed changes in the gastrointestinal tract (liquid contents of the stomach and thickened contents of the cecum). The other two rats, which were sacrificed in moribund state showed no macroscopic abnormalities.

Conclusions

According to the results of this study, the LD50 value of the test material is expected to be between 300 - 2000 mg/kg bw.