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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:
supporting study
Study period:
From 11 NOV 1970 to 16 DEC 1970
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Does not meet important criteria of today standard methods (e.g. no clinical biochemistry, no detailed clinical observations, no functional observations, only 4-5 days post observation period, no reporting of individual/mean data, especially on food consumption and body weight development)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1971
Report Date:
1971

Materials and methods

Principles of method if other than guideline:
Testing of toxicity after repeated oral application
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: in house breeding; SPF
- Weight at study initiation: males: mean 112 g (96 g - 126 g); females: mean 100 g (90 g - 112 g)
- Fasting period before study: no
- Housing: 5 animals/sex/cage
- Diet: Standard diet Altromin R (Altromin GmbH, Lage, Germany), ad libitum
- Water: tap water, ad libitum
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-25
- Humidity (%): 35-60


Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): once at the beginning of the study
- Mixing appropriate amounts with standard diet using a "Lödige-Präzisions-Minuten-Mischer Modell M 20 E"
- Preparation of pellets using a "Templewood-Mischfutterpresse"
- Storage temperature of food: no data
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
30 days
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
5.0%, 1.0%, 0.2%
Basis:
nominal in diet
No. of animals per sex per dose:
10
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: no lethality was observed after single oral application of 15000 mg/kg bw; pretest (10 days feeding study) with rats receiving feed with 5%, 1% and 0.2% of the test item
Positive control:
none

Examinations

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

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined: YES
- mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

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: No data

WATER CONSUMPTION AND COMPOUND INTAKE: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: before the beginning and at the end of the experiment
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: from each animal
- Parameters examined: haemoglobin concentration, erythrocyte count, leucocyte count, differential blood count, appearance of Heinz bodies

CLINICAL CHEMISTRY: No

URINALYSIS: Yes
- Time schedule for collection of urine: before the beginning and at the end of the experiment
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters examined: appearance, colour, protein, glucose, bilirubin, specific weight (urine collected from 5 animals), sediment


NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (heart, lung, liver, spleen, adrenals, kidney)
Other examinations:
ORGAN WEIGHTS:
- heart, lung, liver, spleen, adrenals, kidney

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:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
not examined
Urinalysis findings:
no effects observed
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:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
- no effects

BODY WEIGHT AND WEIGHT GAIN
- no differences between treated animals and controls

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
-no effects


HAEMATOLOGY
- no pathological findings


URINALYSIS
- no test item related effects
- at the end of the study male rats excreted protein in the urine which was judged to be normal in adult male rats


ORGAN WEIGHTS
- no effects

GROSS PATHOLOGY
- no effects

HISTOPATHOLOGY: NON-NEOPLASTIC
- no effects

Effect levels

Dose descriptor:
NOAEL
Effect level:
50 000 mg/kg diet
Sex:
male/female
Basis for effect level:
other: no toxic effects were observed (50000 mg/kg diet correspond to 2000 mg/kg bw in male rats and 2500 mg/kg bw in female rats, calculated according to Guidance on information requirements R.8)

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

The test item was excreted via faeces.

Applicant's summary and conclusion

Conclusions:
The test item did not reveal any substance related toxic effects under the conditions tested. The NOAEL in this subacute oral feeding study was 5% in the diet (corresponding to 2500 mg/kg bw in females and 2000 mg/kg bw in males). Although the study design and reporting does not fulfil todays standard requirements (e.g. no clinical biochemistry, no detailed clinical observations, no functional observations, only 4-5 days post observation period, partially limited reporting of the results), these data indicate that the test substance is not toxic after repeated oral exposure and supports the findings of the key study.
Executive summary:

Male and female Wistar rats were exposed to 5%, 1% and 0.2% test item in the diet for 30 days and observed for another 4-5 days. Cage side observations, food consumption, body weight development, haematology, urine analysis, macroscopic investigations and histopathology of selected organs did not reveal any substance related toxic effects. The NOAEL in this study was 5% in the diet (corresponding to 2500 mg/kg bw in females and 2000 mg/kg bw in males).