Registration Dossier

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993
Report Date:
1993

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
no
Principles of method if other than guideline:
OECD Guideline 407 adopted 1981; also according to Guideline of the EEC Commission 84/449 of April 1984.
GLP compliance:
yes
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Purity >= 98.4%
- Storage condition of test material: room temperature
- test substance, stability of the test substance, and solution of the test substance (stability, homogeneity) were analysed

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
- 38 days old Wistar rats received from Karl Thomae, Biberach, Germany
- acclimatization period 4 days
HOUSING AND DIET
- rats singly housed
- temperature 20-24°C, relative humidity 30-70%, day/night rythm 12h/12h
- room desinfected before use
- food (Kliba 343 feed) and water ad libitum
ANALYSIS
- food and drinking water analysed, no contamination
TEST ORGANISMS at initiation of experiment
- Age: 42 days
- Weight at study initiation: males 164-169 g, females 138-155 g

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: bidistilled water
Details on oral exposure:
- Vehicle:
bidistilled water
- Concentration in vehicle:
0 or 100 mg/ml
- Volume applied:
all animals received 10 ml/kg bw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
- test substance, stability of the test substance, and solution of the test substance (stability, homogeneity) were analysed by GC methods
- analytical check confirmed the correct concentration and stability/homogeneity
Duration of treatment / exposure:
28 days
Frequency of treatment:
once daily, 5 days per week
Doses / concentrations
Remarks:
Doses / Concentrations:
0 or 1000 mg/kg bw/d
Basis:
actual ingested
No. of animals per sex per dose:
5 males and 5 females per group
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: 3 days
Positive control:
No

Examinations

Observations and examinations performed and frequency:
CLINICAL EXAMINATIONS:
- Clinical signs and mortality checked twice daily
- Body weight determined on day 0 and then in weekly intervals
- Food consumption determined weekly (over a period of 7 d)
- Samples for hematology and clinical chemistry: Blood sampling on day 31 (sampling in a randomized sequence) from retroorbital venous plexus
- Hematological parameters: leukocytes, erythrocytes, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelets, differential blood count, blood clotting analysis
- Clinical chemistry parameters: Enzymes: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, serum-gamma-glutamyltransferase; blood chemistry: Na, K, Cl, Ca, Mg, inorganic phosphate, urea, creatinine, glucose, total bilirubin, total protein, albumin, globulins, triglycerides, cholesterol; hormones: total triiodothyronine (T3), total thyroxine (T4)
Sacrifice and pathology:
ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC):
- according to OECD guideline 407 (1981)
Other examinations:
no
Statistics:
- for clinical examinations, hematology and clinical chemistry analysis done via the MANN-WHITNEY-U-Test, marked level of significance p < 0.05

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:
no effects observed
Urinalysis findings:
not examined
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:
TOXIC RESPONSE/EFFECTS
- No significant effects were observed (exceptions see below) at any parameter listed in Materials and Methods.
- Exceptions: a) in males significant decrease in red blood cell counts, hemoglobin level and hematocrit; effect within the range of variation, values in control males unusually high; effect considered to be incidental b) in males significant decrease in bilirubin and albumin concentrations; effect within the range of variation (laboratory historical control), clinical and histopathological examinations revealed no findings in accordance with these changes; effects considered to be of no toxicological significance
- Pathology: no changes related to the treatment

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: general toxicity

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
In a sub-acute oral study (limit test) no changes were observed related to the test substance administered. NOAEL = 1000 mg/kg bw/day.
Executive summary:

GLP guideline study.

In a subacute study Wistar rats (n=5 per dose per sex) received once daily (5 days per week) for 28 days 0 or 1000 mg/kg bw (limit test). Rats were sacrificed 3 days after the end of the exposure period. No clinical signs were detected and no effects on body weight gain or food consumption. Hematology and clinical chemistry (blood sampling 3 days after termination of the exposure period) did not show any treatment related effects. No effects were detected at necropsy including organ weights. No treatment related effects at histopathological examinations.

Conclusion: In a sub-acute oral study (limit test) no changes were observed related to the test substance administered. NOAEL = 1000 mg/kg bw/day.