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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:
June 7th to August 2nd, 2002
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2003
Report date:
2003

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Version / remarks:
96/54/EC
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Qualifier:
according to guideline
Guideline:
other: Japanese Guideline for Screening, Toxicity Testing of chemicals
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Reference substance name:
Red LF 6339
IUPAC Name:
Red LF 6339

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, Biotechnology and animal breeding division, CH-4414 Fullindsorf, Switzerland
- Age at study initiation: 6 weeks
- Weight at study initiation: 129.6 - 158.5 g (mean 145.3 g) for males, 112.8-134.0 g (mean 124.8 g) for females
- Housing: in groups of five in Makrolon type-4 cages with wire mesh tops and standardised softwood bedding
- Diet (e.g. ad libitum): pelleter standard Provini Kliba 3433, ad libitum
- Water (e.g. ad libitum): community tap water, ad libitum
- Acclimation period: 7 days. under test conditions after health examination. Only animals without any visible signs of illness were used for the study.

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

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Remarks:
bidistilled
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
HPLC - dose formulations taken during week 3 of treatment
Duration of treatment / exposure:
Exposure: 28 days
Recovery: 14 days
Frequency of treatment:
7 days/week
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
50 mg/kg bw/day (nominal)
Dose / conc.:
200 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
Male: 10 animals at 0 mg/kg bw/day
Male: 5 animals at 50 mg/kg bw/day
Male: 5 animals at 200 mg/kg bw/day
Male: 10 animals at 1000 mg/kg bw/day
Female: 10 animals at 0 mg/kg bw/day
Female: 5 animals at 50 mg/kg bw/day
Female: 5 animals at 200 mg/kg bw/day
Female: 10 animals at 1000 mg/kg bw/day
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on results of a non-GLP 5-day dose range finding test

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes / No / Not specified
- Time schedule: one before administration, twice daily on days 1-3, once daily on days 4-28 and once daily during days 29-42 (recovery)

MORTALITY/VIABILITY
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS:
- Time schedule: once weekly

BODY WEIGHTS
- Time schedule for examinations: weekly during pretest, treatment and recovery and before necropsy

FOOD CONSUMPTION AND COMPOUND INTAKE
- Time schedule for examinations: once during pretest and weekly thereafter

FUNCTIONAL OBSERVATIONAL BATTERY
- Grip strength
- Locomotor activity

HAEMATOLOGY: Yes

CLINICAL CHEMISTRY:
- Time schedule for collection of blood: after 4 and 6 weeks
- Animals fasted: Yes. 18 hrs before blooed sampling
- How many animals: from all animals

URINALYSIS:
- Time schedule for collection of urine: after 4 and 6 weeks
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes. 18 hrs before blooed sampling
- How many animals: from all animals
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
sacrifice after 4 and 6 weeks. all macroscopic abnormalities were recorded
absolute and relative organ weights were determined

HISTOPATHOLOGY and HISTOTECHNIQUE: Yes. on organs and tissues from all control and high dose animals
Statistics:
Dunnett-test, Steel-test, Fischer's exact test, Armitage/Cohran Trend test

Results and discussion

Results of examinations

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
slightly bent tail and slight red scab
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The mean body weights and the mean body weight gain compared well with those of the controls.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
The mean daily and relative food consumption of the test item-treated animals compared well to those of the control animals.
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related changes in parameters of hematology were noted in males or females after four or six weeks when compared with controls.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related changes in parameters of clinical biochemistry were noted in males or females after four or six weeks when compared with controls.
Urinalysis findings:
effects observed, non-treatment-related
Description (incidence and severity):
There were no toxicologically relevant changes to urine analysis parameters.
Behaviour (functional findings):
effects observed, non-treatment-related
Description (incidence and severity):
GRIP STRENGTH: No test item-related changes in fore- or hind-limb grip strength were observed.
LOCOMOTOR ACTIVITY: It could not be excluded that the decrease of locomotor activity, seen in rats treated with 1000 mg/kg/day was test item-related, but in the absence of clear changes in the rats treated with 200 mg/kg/day, the changes seen at 50 mg/kg/day were considered to be incidental.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related changes in the relative or absolute organ weights were noted when compared with the controls.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
The continuous, daily, administration of the test item to Wistar rats at doses of 50, 200 and 1000 mg/kg/day, for 28 days produced no treatment-related histopathological findings at terminal or recovery necropsy. At terminal necropsy all of the animals given 1000 mg/kg/day were noted to have red discolouration. This change was not observed in animals given 50 or 200 mg/kg/day. Red discolouration was confined to the kidneys of all the animals given 1000 mg/kg/day at recovery necropsy.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
behaviour (functional findings)
Dose descriptor:
NOEL
Effect level:
50 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
behaviour (functional findings)

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
NOAEL = 200 mg/kg bw/day
NOEL = 50 mg/kg bw/day
Executive summary:

Oral administration of the test item to Wistar rats at doses of 50, 200 and 1000 mg/kg/day, for 28 days resulted in no effects upon:

Mortality, clinical signs (daily, weekly), grip strength, hematology, clinical biochemistry or urinalysis, changes in absolute or relative organ weights, macroscopic or microscopic changes which were related to test item treatment.

It could not be excluded that the decrease of locomotor activity, seen in rats treated with 1000 mg/kg/day was test item-related, but in the absence of clear changes in the rats treated with 200 mg/kg/day, the changes seen at 50 mg/kg/day were considered to be incidental.

Based on the results of this study, 50 mg/kg body weight/day of the substance was established as the no-observed-effect-level (NOEL) and 200 mg/kg body weight/day of the test item as the no-observed-adverse-effect-level (NOAEL).