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: 92/69/EWG, B.7; OECD 407 (1981) (siehe Bemerkung)
GLP compliance:
yes
Limit test:
no

Test animals

Species:
other: rat, Wistar

Administration / exposure

Route of administration:
oral: unspecified
Details on oral exposure:
Method of administration:
Futter
Duration of treatment / exposure:
Test duration: 28 days
Frequency of treatment:
Dosing regime: 7 days/week
No. of animals per sex per dose:
Male: 5 animals at 0 mg/kg bw/day
Male: 5 animals at 28.8 mg/kg bw/day
Male: 5 animals at 123.6 mg/kg bw/day
Male: 5 animals at 479 mg/kg bw/day
Female: 5 animals at 0 mg/kg bw/day
Female: 5 animals at 31 mg/kg bw/day
Female: 5 animals at 130.8 mg/kg bw/day
Female: 5 animals at 569.4 mg/kg bw/day

Results and discussion

Results of examinations

Details on results:
Clinical observations:
No mortality occurred during the study period.

There were no treatment-related clinical signs in any dose
group and no effect on food and water consumption.

Laboratory findings:
There were no treatment-related effects on hematology and
urinalysis which could be considered of biological
significance.

Clinical biochemistry revealed the liver as target organ.
There were increases in the activity of plasma aline
aminotransferase of male and female rats at 1,200 and 4,800
ppm. An increase of aline aminotransferase was also noted in
females at 300 ppm. However, that was not corroborated by
findings of the additional study. In addition at 1,200 and
4,800 ppm, an increased activity of alkaline phosphatase was
observed in animals of both sexes. There was also an
increase of alkaline phosphatase in male rats at 300 ppm,
while this finding was not confirmed in the opposite sex,
neither in the main study nor in the additional study. It
was considered incidental.

In the hepatic tissue, an increase of the activity of the
N-Demythylase and of Cytochrom P-450 was found in males
treated at 4,800 ppm. This effect is taken as evidence for a
mild induction of the mixed-function oxidases.

Effects in organs:
At 4,800 ppm female rats showed an increase in relative
liver weight when compared with controls.

Histopathology revealed an increased eosinophilia of
centrolobular hepatocytes in 2 of 5 male rats at 4,800 ppm.
Such findings are known to be an adaptive phenomenon as a
result of enzyme induction.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
28.8 mg/kg bw/day (nominal)
Basis for effect level:
other: original NCD unit is mg/kg/day.
Dose descriptor:
NOEL
Effect level:
28.8 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: Not classified