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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
February - July 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study according to GLP

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012

Materials and methods

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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
other: liquid

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Wistar rat, Crl: WI(Han) (SPF), Charles River, Germany
- Age at study initiation: 7-8 weeks (males); 7-8 weeks (females)
- Weight at study initiation: 132-178 g (males); 123-138 g (females)
- Fasting period before study: over night
- Housing: individual housing in IVC cages, type III H
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3 °C
- Humidity (%): 55 +/- 10 %
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 hourd light / dark

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
7 days/week, for 28 days
Frequency of treatment:
once daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0 mg/kg
Basis:
actual ingested
Remarks:
Doses / Concentrations:
12 mg/kg
Basis:
actual ingested
Remarks:
Doses / Concentrations:
30 mg/kg
Basis:
actual ingested
Remarks:
Doses / Concentrations:
75 mg/kg
Basis:
actual ingested
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on 14 day dose-range finder
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: n.a.
- Post-exposure recovery period in satellite groups: 14 days
- Section schedule rationale (if not random): random

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: at beginning of treatment and weekly thereafter

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations:before tretament, last week of treatments, end of recovery period
- Dose groups that were examined: all animals

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after last administration
- Anaesthetic used for blood collection: No
- Animals fasted: No
- How many animals: all surviving animals

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after last administration
- Animals fasted: No
- How many animals: all surviving animls

URINALYSIS: Yes
- Time schedule for collection of urine: prior to sacrifice
- Metabolism cages used for collection of urine: No
- Animals fasted: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: once before first exposure and in forth week of exposure
- Dose groups that were examined: all animals
- Battery of functions tested: sensory activity / grip strength / motor activity / other: Functional observation battery
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
No mortality and no clinically signs

BODY WEIGHT AND WEIGHT GAIN
no effects on body weight development

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
no effect on food consumption and/or water intake

FOOD EFFICIENCY
n.a.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
n.a.

OPHTHALMOSCOPIC EXAMINATION
no ophthalmoscopic findings

HAEMATOLOGY
no changes in haematological parameters

CLINICAL CHEMISTRY
all changes noted within range of historical controls

URINALYSIS
no changes in urinary parameters

NEUROBEHAVIOUR
no effects in FOB parameters noted

ORGAN WEIGHTS
no treatment related changes in organ weights

GROSS PATHOLOGY
no macroscopic findings

HISTOPATHOLOGY: NON-NEOPLASTIC
no treatment or test substance related histopathological changes

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
n.a.

HISTORICAL CONTROL DATA (if applicable)
n.a.

Effect levels

Dose descriptor:
NOAEL
Effect level:
>= 75 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Based on the data of the present study, the no observed adverse effect level (NOAEL) of the test substance is equal or greater 75 mg/kg body weight per day.
Executive summary:

The test item was orally administered in graduated doses of 0, 12, 30 and 75 mg/kg body weight per day to 3 groups of male and female Wistar rats by oral gavage. One group receiving the vehicle sterile water served as control. The volume of application was 5 mL/kg body weight and the animals were dosed 7 days per week for a period of 28 days. No mortality and no clinical signs were recorded in any of the dose groups during the treatment period of this study. Additionally, no effects with clinical relevance were observed in any of the parameters of the functional battery testing and no ophthalmoscopic findings were noted. Body weight development and food intake were not affected. No relevant differences were found for haematological and blood coagulation parameters. Slight deviations in the clinical biochemistry parameters glucose, total protein, cholesterol and sodium in male or female treatment groups were within the range of historical controls. Additionally, deviation observed for relative weight (to terminal body weight) of kidney in female high dose group animals were not associated with histopathological findings and hence, were unlikely to be related to treatment. Based on the data generated the no observed adverse effect level (NOAEL) of Genamin CH 020 is considered to be equal or greater 75 mg/kg body weight per day.