Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
23 September 1996
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1996
Report Date:
1996

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Version / remarks:
7 days study "in the sense of the OECD 407 directive"
Deviations:
yes
Remarks:
7 days instead of 28 days study
GLP compliance:
yes (incl. certificate)
Remarks:
quality assurance statement included

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Test material form:
solid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
Male and female, approximately 45 days old, male weight 200-220 g and female weight 160-180 g
Sex:
male/female
Details on test animals and environmental conditions:
Acclimatization for 7 days; air-conditionned room; temperature of 20°C and humidity of 55%; regulated light/dark cycle (lighting from 7 a.m to 7 p.m).
Drinking water ad libitum and sterilized food pellets.

Administration / exposure

Route of administration:
oral: gavage
Details on route of administration:
intubation
Vehicle:
water
Remarks:
deionized water
Details on oral exposure:
gastric intubation
20 mL/kg administered volume using 5 or 10 mL syringues fitted with a stainless steel cannula
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
7 days
Frequency of treatment:
Daily
Doses / concentrations
Dose / conc.:
3 750 mg/kg bw/day (nominal)
No. of animals per sex per dose:
5 per sex, 1 dose
Control animals:
yes
Details on study design:
similar with OECD 407 protocol
Positive control:
no

Examinations

Observations and examinations performed and frequency:
Observations twice daily for 7 days, especially for the 6 hours following the administration, except on saturday and sunday:
Body weight, food and water consumption, clinical signs (symptoms, lethality), haemtology and blood chemistry, post mortem observations (organ weight, liver and kidney micropical anatomy examination)
Sacrifice and pathology:
Animals were killed 24 hours after the last treatment by exsanguination.
Other examinations:
not specified
Statistics:
ANOVA (variance analysis) and DUNNET's test if necessary to test the homogeneity of body weights before treatment, body weight values, clinical biology and organ weights values.

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):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
In males, urea was significantly lower in treated animals when compared with control group but was considered of no clinical significance.
In females, treated animals exhibited a glycemia significantly lower than that of controls, this difference was very weak and remained in a physiological range.
Urinalysis findings:
not examined
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
The only abnormality consisted in gastric ulcer like lesions found in several control and treated animals.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Hepatic microgranulomas were observed in 9 control animals and 10 treated animals.
Periportal inflammation was associated with hepatic microgranulomas in 1 male control and in 2 female treated animals.
Test substance as the cause of this alteration could not be ascertained.
Histopathological findings: neoplastic:
not examined
Other effects:
not specified
Details on results:
Results comparable between treated animals and controls.
Most parameters of treated animals were unchanged, remained in a physiological range or were modified in a similar way as in controls.

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
ca. 3 750 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: highest dose tested

Target system / organ toxicity

Key result
Critical effects observed:
no
Lowest effective dose / conc.:
3 750 mg/kg bw/day (actual dose received)
System:
hepatobiliary
Organ:
liver
kidney
Treatment related:
no
Dose response relationship:
no
Relevant for humans:
yes

Applicant's summary and conclusion

Conclusions:
The test substance was non toxic after repeated exposure by oral route during 7 days at 3750 mg/kg bw/d (only dose tested).
Executive summary:

Non toxic in male and female rats after repeated exposure by oral route during 7 days at 3750 mg/kg bw/d, only dose tested, protocol similar to OECD 407