Registration Dossier

Administrative data

Endpoint:
repeated dose toxicity: oral
Adequacy of study:
other information

Data source

Reference
Reference Type:
other: Body responsible for the test
Title:
Unnamed

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD 407, EEC B7
GLP compliance:
yes
Limit test:
no

Test animals

Species:
other: Rat, Spraque Dawley

Administration / exposure

Route of administration:
oral: unspecified
Vehicle:
other: 0.5 % aqueous methylcellulose
Details on oral exposure:
Method of administration:
Gavage
Duration of treatment / exposure:
Test duration: 28 days
No. of animals per sex per dose:
Male: 5 animals at 0 mg/kg bw/day
Male: 5 animals at 17.5 mg/kg bw/day
Male: 5 animals at 175 mg/kg bw/day
Male: 5 animals at 1000 mg/kg bw/day
Female: 5 animals at 0 mg/kg bw/day
Female: 5 animals at 17.5 mg/kg bw/day
Female: 5 animals at 175 mg/kg bw/day
Female: 5 animals at 1000 mg/kg bw/day

Results and discussion

Results of examinations

Details on results:
Clinical observations:
There were no toxicologically meaningful clinical signs or
behavioral abnormalities at 17.5 and 175 mg/kg/day. At the
highest dose level of 1000 mg/kg/day, animals exhibited
treatment-related clinical signs from week 4 of the study.
They consisted mainly of hypersalivation in all animals and
pilo-erection and general pallor in a majority of female
animals. Marked reduced motor activity was also noted in two
females and one female exhibited tremors and prostration.

Laboratory findings:
In hematology no significant changes were observed. In
clinical chemistry treated at 1000 mg/kg/day triglycerides,
bilirubin, urea and albumin concentrations were increased in
females, cholesterol and protein concentrations were
increased in both sexes. In addition, lower glucose
concentration was noted in females.

Effects in organs:
At necropsy, enlarged livers were noted in all males and
females treated at 1000 mg/kg/day. A dose-related higher
liver weight (absolute and relative) was noted at 175 and
1000 mg/kg/day in both sexes. Kidney weight (relative) was
increased in both sexes at 175 and 1000 mg/kg/day and
absolute kidney weight was also noted in males at 175
mg/kg/day.

In microscopic examination revealed in the liver a marked
centrilobular hypertrophy, bile duct hyperplasia,
centrilobular necrosis and fibrosis and periportal
basophilia in males and females treated at 175 and 1000
mg/kg/day. At 1000 mg/kg/day proximal tubular
microvacuolation and cytoplasmic eosinophilia was observed
in both sexes. Chronic cardiomyopathy was noted in a
proportion of male and female rats and increased cortical
vacuolation of the adrenal gland was noted in males treated
at the two highest dose levels.

Effect levels

Dose descriptor:
NOAEL
Effect level:
17.5 mg/kg bw/day (nominal)
Basis for effect level:
other: original NCD unit is mg/kg/day.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Classified as: Xn - harmful