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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2009-11-24 to 2009-12-18
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted in compliance with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results. The study report was conclusive and done to a valid guideline.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010
Report date:
2010

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
1-Propanesulfonamide, N-[3-[[5-bromo-1-(2,6-dichlorobenzoyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-
EC Number:
806-756-5
Cas Number:
1262985-24-9
Molecular formula:
C24 H16 Br Cl2 F2 N3 O4 S
IUPAC Name:
1-Propanesulfonamide, N-[3-[[5-bromo-1-(2,6-dichlorobenzoyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-
Test material form:
other: solid
Details on test material:
Purity >99% (w/w)

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
On receipt the animals were selected by hand and not using a computer generated randomization program. After an acclimatisation period of at least six days the animals selected were without any visible signs of illness. At the start of treatment the animals were ten weeks of age. The bodyweights were in the range 179.8-191.3 g at the start of treatment. The animals were housed in groups of three in Makrolon type-4 cages with wire mesh tops and standard softwood bedding. 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 diet and drinking water were routinely analysed.
Standard Laboratory Conditions. Air-conditioned with 10-15 air changes per hour, and continuously monitored environment with ranges for room
temperature 22 +/- 3 C and for relative humidity between 30-70% (values above 70% during cleaning process possible), automatically controlled light
cycle of 12 hours light and 12 hours dark, music during the daytime light period

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
PEG300
Details on oral exposure:
The dose formulations were prepared shortly before each dosing occasion using a magnetic stirrer and an Ultra-Turrax as homogenizers. The test item was weighed into a tared glass beaker on a suitable precision balance and the vehicle was added (weight:volume). The glass beaker was wrapped with aluminium foil to protect the test item solution against light. The formulations were prepared using a magnetic stirrer and a spatula as homogenizers. The preparation of dose formulations was conducted under yellow light. Homogeneity of the test item in the vehicle was maintained during administration using a magnetic stirrer. The preparation was protected from direct light exposure with aluminium foil.
Observations for Mortality: Daily during the acclimatization period, within the first 30 minutes and at approximately I, 2, 3 and 5 with the clinical signs) and twice daily during days 2-15.
Clinical signs:Daily during the acclimatization period, within the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1, depending on the occurrence of clinical signs of toxicity. Once daily during days 2- 15.
Doses:
The animals received a single dose of the test item by oral gavage administration at 2000 mg/kg body weight after being fasted for approximately 16 to 18 hours (access to water was permitted). Food was provided again approximately 3 hours after dosing. The dosing volume was 10 mL/kg body weight.
No. of animals per sex per dose:
3 females per group. Two groups were dosed at 2000 mg/kg bw.
Control animals:
not specified
Details on study design:
Individual bodyweights were recorded prior to dosing, Day 1, and on Days 8 and 15. At the end of the observation period the surviving animals were killed by carbon dioxide asphyxiation and discarded after macroscopic examinations were performed. An external examination and opening of the abdominal and thoracic cavities for examinations of major organs were performed. No organs or tissues were retained.
Statistics:
No statistical analysis was performed

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No intercurrent deaths occurred during the course of the study.
Clinical signs:
No clinical signs were recorded throughout the entire observation period.
Body weight:
The body weight of the animals was within the range commonly recorded for this strain and age.
Gross pathology:
No macroscopic findings were recorded at necropsy.

Applicant's summary and conclusion

Interpretation of results:
study cannot be used for classification
Remarks:
Migrated information
Conclusions:
The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was > 2000 mg/kg bodyweight
Executive summary:

Introduction. Two groups, each consisting of thee female RccHan:WIST (SPF) rats, were treated the test item by oral gavage administration at a dosage of 2000 mg/kg body weight.

Method: The test item was formulated in PEG 300 at a concentration of 0.2 g/mL and administered at a dosing volume of 10 mL/kg. The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical sign within the first 30 minutes and approximately 1,2, 3 and 5 hours after treatment on day 1 and once daily during test days 2-15. Mortality/viability was recorded within the first 30 minutes and approximately 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15. Body weights were recorded on day 1 (prior to administration) and on days 8 and 15. All animals were necropsied and examined macroscopically.

Results: All animals survived until the end of the study period. No clinical signs were recorded throughout the entire observation period. The body weights of the animals were within the range commonly recorded for this strain and age. No macroscopic findings were recorded at necropsy. The median lethal dose of the test item after single oral administration to female rats, observed over a period of 14 days, is: LD50 (female rat): greater than 2000 mg/kg body weight.

Conclusion. Based upon the referred classification criteria (Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008), the test item is not classified with respect to acute oral toxicity in the rat.