7,8,9,10-Tetrahydro-8-(trifluoroacetyl)-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

25 October - 26 November 2001

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2003

Report date:

2003

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

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:

2,2,2-trifluoro-1-{5,8,14-triazatetracyclo[10.3.1.0²,¹¹.0⁴,⁹]hexadeca-2,4,6,8,10-pentaen-14-yl}ethan-1-one

EC Number:

810-682-9

Cas Number:

230615-70-0

Molecular formula:

C15H12F3N3O

IUPAC Name:

2,2,2-trifluoro-1-{5,8,14-triazatetracyclo[10.3.1.0²,¹¹.0⁴,⁹]hexadeca-2,4,6,8,10-pentaen-14-yl}ethan-1-one

Test material form:

solid: particulate/powder

Details on test material:

Buff coloured solid or pale brown powder depending on which batch
Storage conditions: room temperature. in the dark

Specific details on test material used for the study:

Buff coloured solid
Storage conditions: room temperature. in the dark
Batch No: 53650-10-11

Test animals

Species:

rat

Strain:

other: Sprague-Dawley CD (Cri: CDa (SD) IGS BR)

Sex:

male/female

Details on test animals or test system and environmental conditions:

The animals were randomly allocated to cages. The females were nulliparous and non-pregnant. After an acclimatisation period of at
least five days the animals were selected at random and given a unique number. At the start of the study the animals weighed 205 to 348g. and were approximately eight weeks of age. The animals were housed in groups of three by sex in solid-floor polypropylene cages furnished with woodflakes. With the exception of an overnight fast immediately before dosing and for approximately three to four hours after dosing, free access to mains drinking water and food was allowed throughout the study. The temperature and relative humidity were set to achieve limits of 19 to 25°C and 30 to 70%
respectively.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

arachis oil

Details on oral exposure:

A group of three fasted females was treated with the test material at a dose level of 2000 mg/kg bodyweight. Based on the results from this dose level further groups of fasted animals were treated at a dose level of 200 mg/kg bodyweight. Dosing was performed sequentially.

Doses:

2,000 mg/kg (concentration 200 mg/ml & dose volume 10 ml/kg) - 3 females
200 mg/kg (concentration 20 mg/ml & dose volume 10 ml/kg) - 3 females
200 mg/kg (concentration 20 mg/ml & dose volume 10 ml/kg) - 3 males

No. of animals per sex per dose:

3 females at 2,000 mg/kg
3 females at 200 mg/kg
3 males at 200 mg/kg

Control animals:

no

Details on study design:

All animals were dosed once only by gavage, using a metal cannula attached to a graduated syringe. The volume administered to each animal was calculated according to the fasted bodyweight at the time of dosing. Treatment of animals was sequential. Sufficient time was allowed between each sex and each dose level to confirm the survival of the previously dosed animals. The animals were observed for deaths or overt signs of toxicity IA, 1. 2 and 4 hours after dosing and subsequently once daily for up to fourteen days. Morbidity/mortality checks were made twice daily during normal working days and once daily at weekends and public holidays. Individual bodyweights were recorded prior to dosing and seven and fourteen days after treatment or at death. At the end of the observation period the surviving animals were killed by cervical dislocation. All animals were subjected to gross necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities for examination of major organs. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

approximate LD50

Effect level:

200 mg/kg bw

Based on:

test mat.

Remarks on result:

other: LD50 in the range of 200 - 2,000 mg/kg bw

Mortality:

All animals treated with 2000 mg/kg were found dead four hours or one day after dosing. No deaths were noted at a dose level of 200 mg/kg.

Clinical signs:

other: Signs of systemic toxicity noted in animals treated with 2000 mg/kg were hunched posture. ataxia. tiptoe gait. lethargy. decreased respiratory rate. laboured respiration, ptosis. occasional body tremors and increased lachrymation. Hunched posture was note

Other findings:

Necropsy
Abnormalities noted at necropsy of animals that died during the study were haemorrhaeic lungs. dark liver, dark kidneys. haemorrhage or sloughing of the gastric mucosa, haemorrhage of the non-glandular region of the stomach and haemorrhagic small intestine. No abnormalities were noted at necropsy of animals that were killed at the end of the study.

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The acute oral median lethal dose (LD50) of CP-548,507 in the Sprague-Dawley CD (Cri: CD (SD) IGS BR) strain rat was estimated to be in the range of 200 - 2000 mg/kg body-weight.

Executive summary:

CP-548,507 was classified as HARMFUL and the symbol -Xn” and risk phrase R 22 -HARMFUL IF SWALLOWED- are required according to EU labelling regulations Commission Directive 93/21 /EEC. This risk phrase translates to the GHS classification of acute tox. category 4, H-302: "Harmful if swallowed."