Registration Dossier

Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2001.06.11 to 2001.07.16
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001
Report date:
2001

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
yes

Test material

Constituent 1
Test material form:
other: liquid

Test animals

Species:
rat
Strain:
other: HanBrl:WIST (SPF)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: RCC Ltd.
- Age at study initiation: 6 weeks
- Weight at study initiation: males 143-160g females 112-130g
- Housing: five per cage in Makrolon type-4 cages with wire mesh tops and standard softwood bedding (Lignocel)
- Diet: Pelleted standard Provimi Kliba rat maintenance diet (batch 07/00) ad libitum
- Water: Community tap water ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+/-3
- Humidity (%): 30-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To: 11 June to 16 July 2001

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
peanut oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Prepared daily, Y-15167 weighed into a tared glass beaker and vehicle added. Mixture prepared using a magnetic stirrer and used at room temperature.

VEHICLE
- Concentration in vehicle: 0, 10, 40, 200 mg/mL
- Amount of vehicle (if gavage): 5mL/kg
- Lot/batch no.: 9.3.01 SCO / 7.3.01 SCO
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentration, homogeneity and stability (after 2 hours) were determined at teh start of the study. Concentration and homogeneity also determined during Week 3 (according to NMR method)
Duration of treatment / exposure:
28 days
Frequency of treatment:
Once daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
200 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on results of non-GLP 5-day dose range finding study
- Rationale for animal assignment: random (computer-generated algorithm)

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily days 1-3, once daily thereafter

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Week 4
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: All
- Parameters checked in table No. 1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Week 4
- Animals fasted: Yes
- How many animals: All
- Parameters checked in table No.2 were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Week 4
- Dose groups that were examined: All
- Battery of functions tested: sensory activity, grip strength, motor activity
Sacrifice and pathology:
ORGANS WEIGHTS: Yes (see table 3)
GROSS PATHOLOGY: Yes (see table 4)
HISTOPATHOLOGY: Yes (see table 4)
Statistics:
The following statistIcal methods were used to analyze the body weight, organ weights and ralios. as well as clinical laboratory data:
• The Dunnett-test (many to one t-test) based on a pooled variance estimate was applied if the variables could be assumed to follow a normal distribution for the comparison of the treated groups and the control groups for each sex.
• The Steel-test (many-one rank test) was applied insteadof the Dunnett-test when the data could not be assumed to follow a normal distribution.
• Student's t-test was applied to grip strength and locomotor activity.
• Fisher's exact-test was applied to the macroscopic findings.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Description (incidence):
A male at 1000 mg/kg/day was found dead on Day 4. The cause of death was considered to be a dosing error.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
Reduced locomotor activity was noted at 1000 mg/kg/day, most clearly seen in males.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
Necrotic tracheitis was noted in the 1000 mg/kg/day male which died on Day 4 and was considered consistent with a dosing error.
Histopathological findings: neoplastic:
no effects observed

Effect levels

Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Reduced motor activity was noted at 1000 mg/kg bw/day

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Oral administration to Wistar rats at 0, 50, 200 or 1000 mg/kg bw/day for 28 days resulted in no test item-related mortality (a sinlge male died from suspected dosing error), no clinical signs during daily observations or weekly behavioural observations, no findingsduring functional observation battery observations, no effects upon haematology or clinical chemistry parameters, no changes in absolute or relative organ weights and no macro- or microscopic changes.
Treatment-related changes were noted for locomotor activity which was slightly reduced at 1000 mg/kg/day.
Based on the results of this study the NOAEL was concluded to be 200 mg/kg bw/day.