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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
March - July 1998
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: core guideline, MDA11 has a comparable composition on dry matter and salt free dry matter

Data source

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

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
there were no clinical examinations
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
dark brown powder
Total solids 98.2%
Protein 52.8%
Salt 10.9%
Total glutamic acid <1%
Fat 3.6%

Test animals

Species:
rat
Strain:
other: Wistar Crl(WI) WUBR
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Sulzfeld, Germany
- Age at study initiation: 5-6 weeks
- Weight at study initiation: 138-180 g for males and 114-134 g for females
- Fasting period before study: no
- Housing: in groups of five in suspended, stainless steel cages with wire mesh floors
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 14 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-25
- Humidity (%): 35-70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 hrs dark/ 12 hours light
IN-LIFE DATES: From: 18 March, 1998 To: 30 June, 1998

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: tap water containing 1% methyl cellulose
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: daily
VEHICLE
- Justification for use and choice of vehicle (if other than water): not applicable
- Concentration in vehicle: 0, 20, 62.5 or 200 mg/ml
- Amount of vehicle (if gavage): 10 ml/kg bw/day
- Lot/batch no. (if required): 034632
- Purity: not indicated
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
Dose: 0, 200, 625 or 2000 mg/kg/day
Basis:
nominal in water
No. of animals per sex per dose:
10 males & 10 females
Control animals:
yes
Details on study design:
- Dose selection rationale: based on a 14-day range-finding study
- Rationale for animal assignment (if not random): not applicable
- Rationale for selecting satellite groups: not applicable
- Post-exposure recovery period in satellite groups: not applicable
- Section schedule rationale (if not random): not applicable
Positive control:
not included

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily on working days, daily on Saturdays and Sundays and public holidays

DETAILED CLINICAL OBSERVATIONS: No
- Time schedule: not applicable

BODY WEIGHT: Yes
- Time schedule for examinations: at start of dosing, weekly, thereafter, an on day of scheduled necropsy

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each cage determined and mean daily diet consumption calculated as g per rat per day
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not applicable (gavage study)

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: in week 1, 6 and 12

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to the start of treatment and towards the end of treatment
- Dose groups that were examined: all rats; week 13: control and high dose

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at autopsy
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: No
- How many animals: all rats
- Parameters checked in table [No.?] were examined. Standard parameters

CLINICAL CHEMISTRY: Yes / No / No data
- Time schedule for collection of blood:
- Animals fasted: Yes / No / No data
- How many animals:
- Parameters checked in table [No.?] were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: at the end of treatment period on day 86-87
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked in table [No.?] were examined. Standard parameters

NEUROBEHAVIOURAL EXAMINATION: No
- Time schedule for examinations: not applicable
- Dose groups that were examined: not applicable
- Battery of functions tested: sensory activity / grip strength / motor activity / other: not applicable

OTHER: The concentrating ability of the kidneys was investigated on day 86-87 by measuring the urinary volume and density in individual samples
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table)
HISTOPATHOLOGY: Yes (see table)
Statistics:
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):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
not examined
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
general condition and behaviour not affected. No mortality

BODY WEIGHT AND WEIGHT GAIN
No significant differences between groups

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
no treatment-related changes

FOOD EFFICIENCY
no treatment-related changes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
occasionally increased in high dose males and females

OPHTHALMOSCOPIC EXAMINATION
no treatment-related changes

HAEMATOLOGY
no treatment-related changes

CLINICAL CHEMISTRY
no treatment-related changes

URINALYSIS
increased urinary density and brownish yellow urine, observed in high-dose females, were not considered to be adverse effects

NEUROBEHAVIOUR
not examined

ORGAN WEIGHTS
no treatment-related changes

GROSS PATHOLOGY
no treatment-related changes

HISTOPATHOLOGY: NON-NEOPLASTIC
no treatment-related changes

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
no treatment-related changes

HISTORICAL CONTROL DATA (if applicable)
not applicable

OTHER FINDINGS
none

Effect levels

Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day (nominal)
Sex:
female
Basis for effect level:
other: urinalysis: increased urinary density and brownish yellow urine, observed in high-dose females were not considered to be adverse effects

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Oral administration of MDA 11 at levels up to 2000 mg/kg body weight/day for 13 weeks did not induce adverse effects in rats