Phosphonic acid, P-[2-[[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]amino]-2-oxoethyl]-, diethyl ester

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

January 30 to March 18 2003

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

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Test material

Test material information

Constituent 1

Reference substance name:

diethyl [({4-[(3-chloro-4-fluorophenyl)amino]-7-[(3S)-oxolan-3-yloxy]quinazolin-6-yl}carbamoyl)methyl]phosphonate

EC Number:

928-634-1

Cas Number:

618061-76-0

Molecular formula:

C24 H27 Cl F N4 O6 P

IUPAC Name:

diethyl [({4-[(3-chloro-4-fluorophenyl)amino]-7-[(3S)-oxolan-3-yloxy]quinazolin-6-yl}carbamoyl)methyl]phosphonate

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS:
- male and female rats were obtained from Charles River Deutschland GmbH
-body weight ranges from 169-214 g on Day 1
- age ranges from approx. 7 - 9 weeks on Day 1

CONDITIONS:
- ssniff R/M-H V1530 served as food
- room temperature 22degC +/- 3degC
- relative humidty 55% +/- 15%
- rooms were lit and darkened for periods of 12 hours each
- drinking water in bottles was offered ad libitum

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: 0.5% aqueous hydroxyethylcellulose

Details on oral exposure:

doses were administered orally by gavage according to international guidline.
administration volume is 10 ml/kg b.w.
dose level is 2000 mg/kg b.w

Doses:

2000 mg/kg

No. of animals per sex per dose:

3male and 3 female

Control animals:

no

Details on study design:

- observations were performed before and immediately, 5, 15, 30 and 60 min, as well as 3, 6 and 24 hours after administration
- all surviving animals were observed for a period of 14 days
- during the follow-up period, changes of skin and fur, eyes and mucous membranes, respiratory and the circulatory, autonomic and central nervous system and somatomotor activity as well as behavior pattern were observed at least once a day until all symptoms subsided, thereafter each working day. Attention was also paid to possible tremor, convulsions, salivation, diarrhea, sleep and coma.
- individual body weights were recorded before administration of the test substance and thereafter in weekly intervals up to the end of the study, and a death. Changes in weight were calculated and recorded

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

a singe oral administration of 2000 mg/kg b.w. BIBW2993MA2/CDBB0250BS/kg b.w to rats caused the death of 1 of 3 female animals

Clinical signs:

other: 1 female rat died prematurely on test day 4

Gross pathology:

none

Applicant's summary and conclusion

Interpretation of results:

other: not classified according to CLP

Conclusions:

Under the present test conditions, a single oral administration of 2000 mg/kg b. w. BIBW2992MA2/CDBB0250BS/kg b.w. to rats caused the death
of 1 of 3 female animals. None of the 3 male rats died. No further signs of toxicity were noted. The surviving animals gained the expected weight
throughout the whole study period.
No autopsy findings were noted.
LD50 (14 days): > 2000 mg/kg b.w.