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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
November 23 to December 09, 1998
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study was conducted according to OECD and in accordance with GLP. The study material is well characterize

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1998
Report date:
1999

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
GLP compliance:
yes
Remarks:
OECD ENV/MC/CHEM(98)17
Test type:
acute toxic class method

Test material

Constituent 1
Chemical structure
Reference substance name:
2,5-anhydro-4-{[4-(4-{4-[({1-[(2S,3S)- 2-(benzyloxy)pentan-3-yl]hydrazino}carbonyl)amino]phenyl}piperazin1-yl)phenoxy]methyl}-1,3,4-trideoxy-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-
EC Number:
701-059-1
Cas Number:
345217-03-0
Molecular formula:
C43H50F2N8O4
IUPAC Name:
2,5-anhydro-4-{[4-(4-{4-[({1-[(2S,3S)- 2-(benzyloxy)pentan-3-yl]hydrazino}carbonyl)amino]phenyl}piperazin1-yl)phenoxy]methyl}-1,3,4-trideoxy-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-
Test material form:
other: WHITE SOLID
Details on test material:
STORAGE AT ROOM TEMPERATURE IN THE DARK.

Test animals

Species:
rat
Strain:
other: Sprague-Dawley CD (Crl: CD(SD) IGS BR)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: CHARLES RIVER (UK) Ltd, Margate, Kent, UK.
- Age at study initiation: 8 - 12 weeks
- Weight at study initiation: 204 to 227 g- male; 200 to 220 g-females
- Fasting period before study: overnight
- Housing: 3 per same sex in solid floor polypropylene cages furnished with wood flakes stainless steel cage
- Diet: free access to Rat and Mousse Expanded diet No.1
- Water: fre access to mains drinking water
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19° - 21°
- Humidity (%): 44-66
- Air changes (per hr): 15 approx
- Photoperiod (hrs dark / hrs light): 12 hrs continous light and 12 hrs dark.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Remarks:
suspension
Details on oral exposure:
Using all available information on the toxicity of the test material, 2000 mg/kg bodyweight was chosen as the starting dose.
concentration: 200 mg/ml
Therefore, Dose volume = 10ml/kg
Doses:
dose level: 2000 mg/kg ( males), 2000 mg/kg ( females)
No. of animals per sex per dose:
3 females/males per dose
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 was calculated according to the fasted bodyweight at the time of dosing. Treatment of animals was sequential. Sufficient time was allowed between each group to confirm the survival of the previously dosed animals. The animals were observed for deaths or overt signs of toxicity ½, 1, 2 and 4 hours after the final dose and subsequently once daily for fourteen days. Individual body weights were recorded prior to dosing and seven and fourteen days after dosing. At the end of the observation period the animals were killed by cervical dislocation. All animals were subjected to gross pathological observations. This consisted of external examination and opening of the abdominal and thoracic cavities for examination of major organs. The appearance of any macroscopic abnormalities were recorded. No tissues were retained.

Results and discussion

Effect levelsopen allclose all
Sex:
male
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths.
Clinical signs:
Hunched posture was commonly noted. All males appeared normal two days after treatment whilst females appeared normal four to nine days after treatment.
Body weight:
All animals showed expected gains in bodyweight over the study period.
Gross pathology:
No abnormalities were noted at necropsy.

Applicant's summary and conclusion

Conclusions:
The acute oral median lethal dose (LD50) of the test material in the Sprague-Dawley CD strain rat was estimated to be greater than 2500 mg/kg bodyweight.
Executive summary:

The acute oral median lethal dose (LD50) of the test material in the Sprague-Dawley CD strain rat was estimated to be greater than 2500 mg/kg bodyweight.

No mortalities were noted at 2000 mg/kg bodyweight.