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
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 15 mg/kg bw/day
Male: 5 animals at 150 mg/kg bw/day
Male: 5 animals at 300 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 300 mg/kg bw/day

Results and discussion

Results of examinations

Details on results:
Clinical observations:
There were no unscheduled deaths.


Clinical signs of toxicological importance comprised

partially closed eyelids, hunched posture and piloerection,

which were observed in both sexes receiving 300 mg/kg/day

and underactive behaviour which was observed in females

receiving 300 mg/kg/day.



300 mg/kg/day had a higher than control food intake.

Laboratory findings:
Hindlimb grip strength values for males and females

receiving 300 mg/kg/day were low when compared with

controls.



When compared with controls lower motor activity was

recorded for both sexes receiving 300 mg/kg/day and males

receiving 150 mg/kg/day.



Lower overall bodyweight gains and food intake were evident

for males at 300 mg/kg/day, whilst females at 150 or 300

mg/kg/day showed higher weight gains and females dosed with
300 mg/kg/day had a higher than control food intake.



Lower than control creatinine values and higher than control

glucose values were recorded for all treated male groups.

Mean creatinine values for females receiving 300 mg/kg/day

were also lower than controls. Lower than control group mean

cholesterol values were recorded for both sexes receiving

300 mg/kg/day. In addition lower than control total protein

(due to both a lowering in albumin and globulin) was

recorded for females receiving 300mg/kg/day, with lower
globulin also being apparent in males at this dose level.

Effects in organs:
Heavier than control group bodyweight-adjusted mean kidney

weights were recorded for both sexes receiving 150 or 300

mg/kg/day. Males at this dose level also showed elevated
bodyweight-adjusted mean liver weight compared with

controls. Heavier than control mean adrenal weight was

recorded for both sexes receiving 300 mg/kg/day.



The macroscopic examination performed at termination

revealed a higher incidence of enlargement in the adrenals

of female rats treated with 300 mg/kg/day.



Treatment with 300 mg/kg/day was associated with cortical

hypertrophy and hyperplasia in the adrenals of female rats,

an increased degree of aggregations of foamy alveolar
macrophages in the lungs of male and female rats and
extramedullary haemopoiesis in spleen of female rats.

Treatment with 150 mg/kg/day was associated with cortical

hypertrophy in the adrenals and extramedullary haemopoiesis

in the spleen of female rats. Treatment with 15 mg/kg/day

was associated with cortical hypertrophy in the adrenals of

female rats.

Effect levels

Dose descriptor:
NOAEL
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