Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
June 09 - July 07, 1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: done under GLP and OECD method

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1999
Report Date:
1999

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Version / remarks:
Directive 96/54
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Qualifier:
according to
Guideline:
other: Annex V of EEC Directive 92/32 (7th amendment)
GLP compliance:
yes
Remarks:
OECD[C(81)30 final]
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
other: Sprague DawleyCrl:CD(SD)BR
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Italia S.p.A. CALCO (Lecco) Italy
- Age at study initiation: approx. 4 weeks
- Weight at study initiation: males; 75-85g, females; 60-70g.
- Housing: wire cages.
- Diet: 4 RF 21 GLP Top Certificate.
- Water: ad libitum
- Acclimation period: 3 weeks approx.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2
- Humidity: 55±10%
- 20 air changes per hour
- Photoperiod (hrs dark / hrs light):12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.2% Hydroxypropyl methylcellulose in water.
Details on oral exposure:
Method of administration:
Gavage
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
C.o.A. provided by supplier indicate contents of diet were ±5% of the declared contents.
Duration of treatment / exposure:
Test duration: 28 days
Frequency of treatment:
Dosing regime: once daily, 7 days/week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0 mg/kg
Basis:
other: gavage
Remarks:
Doses / Concentrations:
50mg/kg
Basis:
other: gavage
Remarks:
Doses / Concentrations:
150mg/kg
Basis:
other: gavage
Remarks:
Doses / Concentrations:
500mg/kg
Basis:
other: gavage
No. of animals per sex per dose:
Male: 5 animals at 0 mg/kg bw/day
Male: 5 animals at 50 mg/kg bw/day
Male: 5 animals at 150 mg/kg bw/day
Male: 5 animals at 500 mg/kg bw/day

Female: 5 animals at 0 mg/kg bw/day
Female: 5 animals at 50 mg/kg bw/day
Female: 5 animals at 150 mg/kg bw/day
Female: 5 animals at 500 mg/kg bw/day
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on acute oral toxicity testing results
Positive control:
n/a

Examinations

Observations and examinations performed and frequency:
All rats observed twice daily during treatment for mortality.
Daily observations for physical appearance, behavior and clinical signs were also performed.
At week 4 of treatment the animals were also examined for signs of neurological changes.

Formulation of different test concentrations were prepared for each dosage level so that all rats received a constant volume of 10mg/kg, adjusted weekly on the basis of the most recently determined body weights.

BODY WEIGHT:
- Time schedule for examinations: The day before dosing commenced and then at weekly intervals.
Sacrifice and pathology:
At the end of the 4 week dosing period, the body weight of each animal that had been fasted overnight (about 16 hrs) was recorded before the animal was sacrificed for pathology investigation (organ weight, gross pathology and histology).

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
No deaths or clinical abnormalities were seen at any dose.
Mortality:
no mortality observed
Description (incidence):
No deaths or clinical abnormalities were seen at any dose.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No treatment related effects were found.
Ophthalmological findings:
no effects observed
Description (incidence and severity):
No modification was seen
Haematological findings:
no effects observed
Description (incidence and severity):
No treatment related effects were found.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No treatment related effects were found.
Urinalysis findings:
no effects observed
Description (incidence and severity):
No treatment related effects were found.
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No treatment related modifications were observed.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No treatment related changes were seen.
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No treatment related effects were observed
Details on results:
CLINICAL SIGNS:

MORTALITY: No animals died during the study

Effect levels

Dose descriptor:
NOEL
Effect level:
500 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: after 4 weeks of daily dosing

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The no-toxic-effect level ws considered to be 500mg /kg/day in this study.
Executive summary:

Abbott-164220.0 when given to Sprague Dawley rats by oral route for 4 consecutive weeks at dosages of 50, 150 and 500mg/kg/day, was well tolerated up to and including the highest dosage tested, inducing no signs of toxicity.

The dosage of 50mg/kg/day of Abbott-164220.0 may be considered the NOEL in rats after 4 weeks of consecutive daily administrations.