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Repeated dose toxicity: oral

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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
Guideline:
other: OECD-Guideline No. 407
GLP compliance:
yes
Limit test:
no

Test animals

Species:
other: rat, Wistar (SPF

Administration / exposure

Route of administration:
oral: unspecified
Vehicle:
other: Isotonic saline 0.9%
Details on oral exposure:
Method of administration:
by garage
Duration of treatment / exposure:
Test duration: 90 days
Frequency of treatment:
Dosing regime: 7 days/week
No. of animals per sex per dose:
Male: 6 animals at 40 mg/kg bw/day
Male: 6 animals at 200 mg/kg bw/day
Male: 6 animals at 1000 mg/kg bw/day
Male: 6 animals at 0 mg/kg bw/day
Female: 6 animals at 40 mg/kg bw/day
Female: 6 animals at 200 mg/kg bw/day
Female: 6 animals at 1000 mg/kg bw/day
Female: 6 animals at 0 mg/kg bw/day

Results and discussion

Results of examinations

Details on results:
Clinical observations:
1000 mg/kg: flat-footed gait (2 m) diminshed muscular tone
(4 m, 3 f), slightly increased sialorrhea (2 m, 1 f).
Decrease in mean food consumption. Decrease in body weight
gain. Failure in balancing test. Failure in placing reaction
test(4 m)

200 mg/kg: Decrease in body weight gain.

Laboratory findings:
1000 mg/kg: Slight increase in urinary volume with slight
decrease in specific gravity (f, day 23). Slight increase in
serum calcium (f), slight decrease in alpha-globulins and
gama-globulins (m,f). Shortening of thrombin time (m,f),
shortening of activated partial thromboplastin time (m)

200 mg/kg: slight decrease in alpha-globulins (m)

Effects in organs:
1000 mg/kg: Decrease in absolute spleen weights (m,f).
Decrease in absolute thymus weights (m,f). Decrease in
absolute testes weights, siminal vesicles and epididymides.
Decrease in absolute uterus weights. Reduction in absolute
weights of adrenal glands (f). Decrease in absolute and
relative weights of the pituitary gland (f,m). Increase in
relative weights of kidneys (m,f), liver (m,f), lung (m,f),
brain (m,f), pancreas (f), testes (m), thyroid gland (m),
heart (m), adrenal glands (m,f).

Maturation arrest with hypospermatogenesis associated with
oligospermia (3 m), cellular debris in the epididymides (6
m), reduced secretory activity in the seminal vesicles (2
m). Thymic atrophy (5 m, 2 f), pyknosis and phagocytosis of
lymphocytes (6 m,6 f), slight lymphoid atrophy in the spleen
(1 m,1 f).

Effect levels

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Dose descriptor:
NOAEL
Effect level:
40 mg/kg bw/day (nominal)
Basis for effect level:
other: original NCD unit is mg/kg/day.
Dose descriptor:
NOEL
Effect level:
40 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