4-Quinazolinamine, N-(3-chloro-4-fluorophenyl)-6-nitro-7-(phenylsulfonyl)-

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2005 - 2007

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted in GLP compliance and according to an OECD guideline.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2007

Report date:

2007

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

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

7-(benzenesulfonyl)-N-(3-chloro-4-fluorophenyl)-6-nitroquinazolin-4-amine

EC Number:

620-069-6

Cas Number:

945553-94-6

Molecular formula:

C20 H12 Cl F N4 O4 S

IUPAC Name:

7-(benzenesulfonyl)-N-(3-chloro-4-fluorophenyl)-6-nitroquinazolin-4-amine

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

Test item: BIBW 2992 Sulfon (intermediate of BIBW 2992 MA2)
Appearance: yellow - crystalline powder
Batch number: V12SRE00198
Purity: 99.7 area % (HPLC, method: AF10_LC3_BIBWSulfon_LM_MS)
Certificate of analysis: dated 13 June 2005
Stability: confirmed until May 2006 (to be retested)
Manufacturer: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach/Riss, Germany
Storage conditions: at room temperature, protected from light

Test animals

Species:

rat

Strain:

other: Crl: WI(Han)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS:
- Species, number of animals: 9 rats, 3 males (M) and 6 females (F)
- Strain: Crl: WI(Han), SPF quality
- Supplier/Source: Charles River Deutschland GmbH, Sulzfeld, Germany via Biological Laboratory Services, Boehringer Ingelheim Pharma GmbH & Co. KG
- Age (Day 1): approximately 8 weeks
- Body weight range at study initiation (Day 1): males 207 g-221 g, females 130 g-148 g
- Housing: a barrier-protected system under standardized air conditions (They were kept in groups of up to three animals of one gender per cage (Noryl, type V))
- Diet (e.g. ad libitum): pelleted dry food (Kliba No. 3438.9.25, Provimi Kliba SA, Kaiseraugst, Switzerland) ad libitum
- Water (e.g. ad libitum): municipal tap drinking water (Stadtwerke Biberach) ad libitum via drinking bottles
- Acclimation period: 5- to 8-day pretest period

ENVIRONMENTAL CONDITIONS
- Room number: 35, building N81
- Temperature (°C): 22 +/- 2
- Relative Humidity (%): 45 - 75
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12:12 hrs, illumination period: 6:00 - 18:00, average illumination: approximately 60 lx (depending on the cage position; during work in the room the intensity is raised to approximately 450 lx)

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: 0.5% aqueous hydroxyethylcellulose (Natrosol® 250 HX)

Details on oral exposure:

Directly before administration, the appropriate amount of test item was weighed into a tared glass beaker, was brought to volume with vehicle and was thoroughly mixed using an Ultra-Turrax homogenizer.

VEHICLE
- Test: Concentration: 200 and 2000 mg/kg test item per kg bw were mixed in 0.5% aqueous hydroxyethylcellulose (Natrosol® 250 HX).
- Amount of vehicle (if gavage): 20 mL/kg in each group

- MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg bw

Doses:

200 and 2000 mg/kg bw
single dose, 20 ml/kg bw

No. of animals per sex per dose:

3 female animals at 200 mg/kg
3 per sex at 2000 mg/kg

Control animals:

no

Details on study design:

- Duration of observation period following administration: 15 days
- Frequency of weighing: 24 h after arrival, prior to first application (day -1) and on day 1, 2, 8 and 15
- Frequency of clinical observations: twice a day on the working days and once a day per non-working day
- Necropsy of survivors performed: yes (gross pathology)

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

other: ALD

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

In rats, no mortality was observed subsequent to a single oral administration of 200 mg/kg and 2000 mg/kg, respectively.

Clinical signs:

other: dose: 200 mg/kg (3 females) - Piloerection was seen at Day 1 (1 to 6 h post administration). All females returned to normal at Day 1 (8.0 h p.a.). - No further clinical signs were recorded. dose: 2000 mg/kg (males and females) - No clinical signs were no

Gross pathology:

No necropsy findings were noted in females treated with 200 mg/kg, as well as in rats of both genders subsequent to administration of 2000 mg/kg.

Other findings:

Clinical signs during the study were restricted to females which showed piloerection at both dose levels up to 6 h post administration.

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

No mortality was seen in rats subsequent to oral administration of 200 mg/kg or 2000 mg/kg BIBW 2992 Sulfon.
Thus, the approximate lethal dose (ALD) for BIBW 2992 Sulfon, an intermediate of BIBW 2992 MA2, is set above 2000 mg/kg.