Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)

Data source

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

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: 92/69/EEC
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
other: Rat (Sprague-Dawley)

Administration / exposure

Route of administration:
oral: unspecified
Vehicle:
corn oil
Details on oral exposure:
Method of administration:
Gavage
Duration of treatment / exposure:
Test duration: 28 days
Frequency of treatment:
Dosing regime: 7 days/week
No. of animals per sex per dose:
Male: 10 animals at 0 mg/kg bw/day
Male: 5 animals at 15 mg/kg bw/day
Male: 5 animals at 150 mg/kg bw/day
Male: 10 animals at 500 mg/kg bw/day
Female: 10 animals at 0 mg/kg bw/day
Female: 5 animals at 15 mg/kg bw/day
Female: 5 animals at 150 mg/kg bw/day
Female: 10 animals at 500 mg/kg bw/day

Results and discussion

Results of examinations

Details on results:
Clinical observations:
No treatment-related deaths occurred and no signs of
toxicity were observed. 1 female at d15 and one male on d44
died as a result of accidental occurances. Increased
salivation was noted in group 3 and 4 animals throughout the
study.

Higher than control water consumption was noted for female
rats (91%) and to a lesser extent, for male rats (34%) at
the high dose level during week three and was still high for
females (32%) during the second week of recovery.

Laboratory findings:
At week 5 higher than control globulin levels (18%) (and
hence higher total protein and lower A/G ratio) and lower
than control alkaline phosphatase levels (29%) were recorded
for top dose females.

Effects in organs:
Liver weights for male and female rats receiving 500 or 150
mg/kg/day were higher (15 + 39% respectively, for both
sexes) than control at the end of the treatment period.
Following a 2 week recovery period, liver weights (females
11%) and kidney weights (males 18%) were higher for high
dosage group rats than for controls.

Macroscopic pathology:

At termination immediately post-treatment period enlargement
of the liver was noted in 3/5 male and 3/5 female rats
receiving 500 mg/kg/day. These findings were not present
following a 2 week recovery period.

Microscopic pathology:

Treatment related changes in rats receiving 500 or 150
mg/kg/day included centrilobular hepatocyte enlargement in
the liver of male and female rats and renal cortical tubules
with eosinophilic inclusions in male rats at the end of the
treatment period.

Comparable incidences, amongst all males of all groups,
including control group of seminiferous tubular atrophy and
the end of treatment and recovery was observed. Lower
incidences of these changes among rats following a 2 week
recovery period were considered to show partial
reversibility of these changes.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day (nominal)
Basis for effect level:
other: original NCD unit is mg/kg/day.
Dose descriptor:
NOEL
Effect level:
15 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