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Diss Factsheets

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
from 14 March 2000 to 24 July 2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: guidance test with GLP compliance

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2000
Report date:
2000

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
other: Directive 96/54/ EC, B. 7. "Repeated dose (28 days) toxicity (oral)", September 30, 1996.
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japanese Guidelines for Screening, Toxicity Testing of Chemicals : Testing Methods for new Substances, enacted July 13, 1974，amended December 5, 1986
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
Identification: FAT41'029/A
Batch number: ARL 123/PP 1/99 UL
Purity: approx. 98 %
Color / Physical form: orange red to brown powder
Stability of test article: Stable under storage conditions
Expiry date: 04-NOV-2005
Storage conditions: In the original container, at room temperature (range of 20 ± 3 °C), away from direct sunlight
Safety precautions: Routine hygienic procedures were used to ensure the health and safety of the personnel

Test animals

Species:
rat
Strain:
other: HanIbm: WIST (SPF)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST SYSTEM
Test system: Rat, HanIbm: WIST (SPF)
Source: RCC Ltd Biotechnology & Animal Breeding Division CH-4414 Füllinsdorf / Switzerland
Number of animals: 30 males and 30 females
Age at delivery: 6 weeks
Body weight range at acclimatization: males: 110-174 grams (mean 132 grams); females: 95-145 grams (mean 119 grams)
Acclimatization: Under test conditions after health examination. Only animals without any visual signs of illness were used for the study.

HUSBANDRY
Conditions
Standard Laboratory Conditions:
Air-conditioned with 10-15 air changes per hour and continuously monitored environment with a range for room temperature of 22±3 °C, and for relative humidity between 40-70 %. The animals were provided with a 12-hour light, 12-hour dark cycle. Music was played during the light period.
Accommodation: In groups of five in Makrolon type-4 cages with wire mesh tops and standardized softwood bedding.
Diet: Pelleted standard Provimi Kliba 3433 (batch no. 43/99) rat maintenance diet was available ad libitum.
Water: Community tap-water.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
PEG 300
Details on oral exposure:
Daily dose levels: Group 1: 0 mg/kg body weight
Group 2: 50 mg/kg body weight
Group 3: 200 mg/kg body weight
Group 4: 1000 mg/kg body weight
Duration of recovery: 15 days
Dose volume: 5 ml/kg body weight
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentration, homogeneity and stability (after 2 hours and 7 days) of the dose formulations were determined in samples taken during acclimatization. Concentration and homogeneity of the dose formulations were determined in samples taken during week 3 of the treatment.
Duration of treatment / exposure:
28 days
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50, 200 and 1000 mg/kg body weight
Basis:
other:
No. of animals per sex per dose:
Groups 1 and 4: 10 males; 10 females
Groups 2 and 3: 5 males; 5 females
Control animals:
yes, concurrent vehicle
Positive control:
none

Examinations

Observations and examinations performed and frequency:
MORTALITY / VIABILITY: Observations for mortality/viability were recorded twice daily.
GENERAL CAGESIDE OBSERVATIONS (DAILY): The animals were observed for clinical signs once before commencement of administration; twice daily on days 1-3; as well as once daily on days 4-28, and once daily during days 29-42 (recovery).
DETAILED CLINICAL OBSERVATIONS (WEEKLY): The animals were observed in their home cages, outside their home cages in a standard arena and in the hand. These observations were performed in random sequence once before commencement of administration and once weekly (weeks 1-3) thereafter.
FOOD CONSUMPTION: The food consumption was recorded once during the pretest period and weekly thereafter.
BODY WEIGHTS: Body weights were recorded weekly during pretest, treatment and recovery and before necropsy.
FUNCTIONAL OBSERVATIONAL BATTERY: During week 4, relevant parameters from a modified Irwin screen test were evaluated in all animals.
Sacrifice and pathology:
PATHOLOGY AND NECROPSY
After 4 and 6 weeks. All animals were weighed and necropsied. Descriptions of all macroscopic abnormalities were recorded. Necropsies were performed by experienced prosectors supervised by an experienced veterinary pathologist. All animals surviving to scheduled necropsy were anesthesized by intraperitoneal injection of sodium pentobarbitone and killed by exsanguination.
Other examinations:
CLINICAL LABORATORY INVESTIGATIONS
Blood samples for hematology and clinical biochemistry were collected from all animals under light anesthesia. The animals were fasted in metabolism cages for approximately 18 hours before blood sampling but allowed access to water ad libitum. Blood samples were collected early in the working day to reduce biological variation caused by circadian rhythms. Blood samples were drawn from the retro-orbital plexus using a micro-hematocrit glass capillary tube. Urine was collected during the 18-hour fasting period into a specimen vial.
Statistics:
The following statistical methods were used to analyze grip strength, locomotor activity, body weights, organ weights and all ratios, 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 instead of the Dunnett-test when the data could not be assumed to follow a normal distribution.
Student’s T-Test was applied to locomotor activity and grip strength.
Fisher's exact-test was applied to macroscopic findings.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
No clinical signs of toxicity were evident during daily observations in any animal treated with the test article. All animals survived until scheduled necropsy.
Mortality:
no mortality observed
Description (incidence):
No clinical signs of toxicity were evident during daily observations in any animal treated with the test article. All animals survived until scheduled necropsy.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The mean daily food consumption and body weight development of the test article-treated animals were unaffected during the treatment and recovery periods.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
The mean daily food consumption and body weight development of the test article-treated animals were unaffected during the treatment and recovery periods.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
The hematological parameters of the test article-treated animals were generally similar to those of the control animals after the treatment and recovery periods.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
The clinical biochemistry parameters of the test article-treated animals were generally similar to those of the control animals after the treatment and recovery periods.
Urinalysis findings:
no effects observed
Description (incidence and severity):
No test article-related differences in urinalysis were observed when compared with the controls after the treatment and recovery periods.
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
The absolute and relative organ weights did not show test article-related differences when compared with those of the controls.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No test article related macroscopic or microscopic findings were recorded.
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No test article-related macroscopic or microscopic findings were recorded.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
The absolute and relative organ weights did not show tst article-related differences when compared with those of the controls.
Details on results:
DETAILED CLINICAL OBSERVATIONS (WEEKLY)
No test article-related abnormalities were noted during weekly observation (weeks 1-3).
FUNCTIONAL OBSERVATIONAL BATTERY
No test article-related differences to the control animals were noted during the functional observational battery (week 4).
Grip Strength
The mean fore- and hindlimb grip strength of all test article-treated animals compared favorably with those of the control animals.
Locomotor Activity
The mean locomotor activity of the males and females treated with 1000 mg/kg/day was significantly (p<0.05) less than that of the controls. Although the differences were slight and no clear dose-response relationship was seen, a relationship with the test article could not be eliminated.

Effect levels

open allclose all
Dose descriptor:
NOEL
Effect level:
200 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Based on the test results, 200 mg/kg body weight/day was established as the no-observed-effect-level (NOEL) and 1000 mg/kg body weight/day as the no-observed-adverse-effect-level (NOAEL).
Executive summary:

Oral administration of FAT 41’029/A to Wistar rats at doses of 50, 200 and 1000 mg/kg/day, for 28 days resulted in no deaths, no test article-related clinical signs (following daily and weekly observation), no effects upon the parameters of the functional observation battery (including grip strength), no changes in body weight and food consumption, and no effects upon hematology or clinical biochemistry parameters, or organ weights. No test article-related macroscopic or microscopic changes were evident at necropsy.

Test article-related changes included slightly decreased locomotor activity at 1000 mg/kg/day, only.

Based on the results of this study, 200 mg/kg body weight/day was established as the no-observed-effect-level (NOEL) and 1000 mg/kg body weight/day as the no-observed-adverse-effect-level (NOAEL).