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: Annex V
GLP compliance:
yes

Test animals

Species:
other: Rat (Sprague-Dawley)

Administration / exposure

Route of administration:
oral: unspecified
Vehicle:
other: 1% w/v methylcellulose in water
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: 5 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: 5 animals at 1000 mg/kg bw/day
Female: 5 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: 5 animals at 1000 mg/kg bw/day

Results and discussion

Results of examinations

Details on results:
Clinical observations:
There were no unscheduled deaths and no treatment related
clinical signs. Sensory reactivity observations, grip
strength, motor activity, bodyweight and food consumption
were considered to be unaffected by treatment.

Laboratory findings:
Lower than control group mean haematocrit, haemoglobin and
mean cell haemoglobin values and evidence of hyperchromasia
were recorded for both sexes receiving 1000 mg/kg/day.

Lower than control red blood cell and mean cell haemoglobin
concentration values were present for females receiving 1000
mg/kg/day and a lower than control group mean mean cell
volume was recorded for males receiving 1000 mg/kg/day.
Females at 1000 mg/kg/day showed higher than control mean
lymphocyte, total white blood cell and platelet counts.

Higher than control group mean blood urea values were
evident for both sexes receiving 1000 mg/kg/day. Higher than
control aspartate amino-transferase and glucose values were
recorded for males receiving 1000 mg/kg/day and higher than
control cholesterol values were recorded for females
receiving 1000 mg/kg/day. In addition a higher than control
mean albumin, total protein and A/G ratio were recorded for
males receiving 1000 mg/kg/day.

Effects in organs:
An increased incidence of liver enlargement and heavier than
control group mean liver weights were recorded for both
sexes receiving 1000 mg/kg/day and females receiving

150 mg/kg/day with a dose relationships observed for the
females. Heavier than control group mean kidney and spleen
weights were recorded for females receiving 1000 mg/kg/day.

Generalised hepatocyte hypertrophy/eosinophilia was seen in
the liver of both sexes receiving 1000 mg/kg/day. Follicular
cell hypertrophy was seen in the thyroid and a slight
increase in the severity of extramedullary haemopoiesis was
seen in the spleen of females receiving

1000 mg/kg/day.

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