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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: 96/54/EG, B.7; OECD 407
GLP compliance:
yes
Limit test:
no

Test animals

Species:
other: rat, Wistar HsdCpb:Wu

Administration / exposure

Route of administration:
oral: unspecified
Vehicle:
other: 2 % aqueous Cremophor EL
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 100 mg/kg bw/day
Male: 5 animals at 500 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 100 mg/kg bw/day
Female: 5 animals at 500 mg/kg bw/day
Female: 5 animals at 1000 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 effects reported in clinical observations
(including open field), body weight development and food
intake.

Detailed behavioural investigation (FOB) showed reduced
number of rearing in males at 1000 mg/kg bw/d, which was
caused by individually low values in 4/5 animals. In 1000
mg/kg bw/d females both mean and individual motor and
locomotor activity were increased compared to control.

Laboratory findings:
Haematology did not reveal toxicologically relevantly
treatment-related changes on parameters on red and white
blood and on blood coagulation.

Clinical biochemistry revealed statistically significant
increase of triglyceride concentrations in males at 500 and
1000 mg/kg bw/d and in females at 1000 mg/kg bw/d. Total
bilirubin was decreased in males and in females
(statistically significant) at 1000 mg/kg bw/d.

Urinalysis revealed increased volumes at 500 mg/kg bw/d and
above in males (not dose-dependent) as well as at 1000 mg/kg
bw/d in females.

Effects in organs:
In females the relative liver weights were statistically
significantly increased at 500 mg/kg bw/d and above (up to
11 %) and in males absolute spleen weight at 1000 mg/kg bw/d
(23 %).

Necropsy showed dilation of stomach and cecum in males at
500 and 1000 mg/kg bw/d and dilation of the cecum in one
female at 1000 mg/kg bw/d possibly due to motility
disturbances in the gastrointestinal tract; and deformation
of the liver in one male at 500 mg/kg bw/d and in 3/5 males
at 1000 mg/kg bw/d. Furthermore, discoloured popliteal lymph
nodes were observed in males at 500 and 1000 mg/kg bw/d and
in females at all dose groups.

Microscopy revealed a minimal increase of inflammatory cells
in the gastric mucosa in males and females at 500 and 1000
mg/kg bw/d. This cellular reaction should primary regarded
as an enhanced immunological response of the gastric mucosa,
without adverse impact and a high chance of reversibility.
In the liver, inflammatory infiltration with portal fibrosis
and pigment deposits was seen in 3/5 males at 1000 mg/kg
bw/d. The finding was mostly located under the liver capsule
or at liver edges, leading to constriction of the liver
surface. Therefore, the liver deformation in these animals
is discussed to be of traumatic origin and was not
considered to be related by treatment with the test
substance. The liver deformation in one male at 500 mg/kg
bw/d was based on cystic dilation of a hepatic vein. In
females, hepatocellular glycogen deposits were increased at
1000 mg/kg bw/d. In the testes, spermatic exfoliation,
tubular atrophy and spermatic giant cells were observed at
500 and 1000 mg/kg bw/d, partly leading to spermatic debris
or oligospermia in the epididymides beyond 500 mg/kg bw/d.
In the popliteal nodes, pigment deposits were found in males
beyond 500 mg/kg bw/d, while in females they occurred in all
dose groups. These findings are supposed to be caused by
blood removal from the caudal vein.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Basis for effect level:
other: original NCD unit is mg/kg/day.
Dose descriptor:
NOEL
Effect level:
100 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