Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Nov 2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2004
Report Date:
2004

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: Single dose acute toxicity testing for pharmaceuticals: Revised guideline. Federal Register, August 26. 1998. p 43934-43935
Version / remarks:
Chengelis 1995
GLP compliance:
yes
Test type:
acute toxic class method

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
3 males and 3 females/ group ( Groups 1 - 4)
5 males and 5 females/group (Group 5)


Room temperature: 18° to 26°C
Room relative humidity: 30 to 70%
Lighting cycle: Artificial light for a 12-hour light/12-hour dark cycle
Animal caging: In stainless steel wire cages in compliance with the NRC
(National Research Council) Guide for the Care and Use of Laboratory Animals.
Diet: Teklad Certified LM-485 Rodent Diet #7012C ad libitum. except approximately 4 hours prior to dose (fast) until approximately 2 hours post-dose.
Analysis of diet: The lot number(s) and specifications of each lot used are archived at Calvert.
Water was provided to the animals ad libitum
Periodic analyses of the water were performed and the results are archived at Calvert.

Animals were housed individually and in compliance with the National Research Council
"Guide for the Care and Use of Laboratory Animals". Temperature and relative humidity
were monitored daily. Calvert is USDA registered and a fully accredited AAALAC facility.

There were no known contaminants in the diet or water which, at the levels detected.
interfered with the purpose, conduct or outcome of the study.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.5% (w/v) sodium carboxymethylcellulose [CMC] (high viscosity 1500-3000 cps)
Details on oral exposure:
Route and frequency: Oral, once to each rat
Dose volume: 20 mL/kg
AI-IU377 in 0.5% (w/v) sodium carboxymethylcellulose (0.5% CMC). The actual dose preparation procedures were documented in the raw data and presented as follows:
The amount of AHU3 77 required for each batch was based on the batch size.
Dosing formulations were prepared by gradual addition of 0.5% CMC to the calculated amount of test article, using a mortar and pestle. The suspensions were transferred to an appropriate HPDE container and the mortar and pestle were rinsed with vehicle. A stir bar was added and the mixture was thoroughly mixed for over an hour. The contents were then transferred to a graduated cylinder and the remaining vehicle was added. The formulations were then transferred
back into the HOPE container. The following preparations reflect the total amounts used to make each final dosing formulation.
Doses:
Five groups consisting of five animals per sex per group were allocated to the study. Four groups consisting of three animals per sex per group were dosed at 0. 50. 250 and 1000 mg/kg on Day I. Since neither lethality nor other relevant clinical signs were observed. the remaining two animals per sex of Groups 1 thru 4 were not dosed and all animals allocated to Group 5 (5/sex) were dosed at 2000 mg/kg.
No. of animals per sex per dose:
Five groups consisting of five animals per sex per group were allocated to the study. Four groups consisting of three animals per sex per group were dosed at 0. 50. 250 and 1000 mg/kg on Day I. Since neither lethality nor other relevant clinical signs were observed. the remaining two animals per sex of Groups 1 thru 4 were not dosed and all animals allocated to Group 5 (5/sex) were dosed at 2000 mg/kg.
Control animals:
yes
Details on study design:
Pretest period: A minimum of at least 5 days was allowed between animal receipt and the start of dosing to acclimate animals to the laboratory environment and to observe them for the development of infectious disease.
Study period: Fifteen days
The test article dosing preparations were administered once to each rat orally. Each animal received 20 mL/kg via a syringe (5 cc) and a 16 g gavage needle. The dosing formulations were shaken then stirred via a magnetic stir plate and stir bar prior to dosing and continued during dosing. Unused portions of dosing formulations were discarded at the end of each dosing day.

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
other: no-effect level
Effect level:
2 000 mg/kg bw
Based on:
test mat.
Mortality:
There was no mortality
Clinical signs:
No clinical signs were observed in any animals receiving the vehicle formulation or the test
article at 50, 250, 1000 and 2000 mg/kg during the study with the exception of soft feces in
one animal at the 6 hour observation at the 2000 mg/kg dose level.
Body weight:
Body weights were recorded as per protocol. No biologically significant differences were
observed.
Gross pathology:
There were no gross necropsy findings in any of the animals receiving the vehicle formulation
or the test article at 50, 250, 1000 or 2000 mg/kg.

Applicant's summary and conclusion

Interpretation of results:
other: no-effect level was identified at 2000 mg/kg.
Conclusions:
Single oral administration of AHU377 at 50, 250, 1000 and 2000 mg/kg to rats revealed no clinical signs with an absence of mortality. Under the conditions of this study, a no-effect level was identified at 2000 mg/kg.