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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:
other: Annex V
GLP compliance:
yes
Limit test:
no

Test animals

Species:
other: Rat (Hsd)

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 50 mg/kg bw/day
Male: 5 animals at 150 mg/kg bw/day
Male: 10 animals at 1000 mg/kg bw/day
Female: 10 animals at 0 mg/kg bw/day
Female: 5 animals at 50 mg/kg bw/day
Female: 5 animals at 150 mg/kg bw/day
Female: 10 animals at 1000 mg/kg bw/day

Results and discussion

Results of examinations

Details on results:
Clinical observations:
No substance related deaths occurred. One top dose male
waskilled on day 24 due to gavage error. During the second
half of the dosing period salivation, staining around the
mouthand urinary incontinence were observed in most top
doseanimals. These effects were not present during
recovery.There were no effects on bodyweight gain or food
consumption and no signs of toxicity were seen in mid dose
or low doseanimals.

Laboratory findings:
Haematology:

Effects were seen in top dose animals only: statistically
significant reductions in haemoglobin, haematocrit, red cell
count and mean cell haemoglobin concentration as well as an
increase in mean cell volume (both sexes) and mean cell
haemoglobin (males only). Maximum change for any parameter
=< 10%. At the end of recovery, only haemoglobin and
haematocrit had returned to normal. High reticulocyte counts
and polychromasia of the blood film were also observed in 3
females.


Clinical Chemistry:

Effects were seen in top dose animals only: a 20-30%
increase in plasma urea in both sexes at theend of treatment
and males at the end of recovery. A slight increase in
gamma glutamyl transferase levels was also seen in females
at the end of treatment and both sexes at the end of
recovery.


Urinalysis:

Effects apparently related to the presence in urine of test
substance or metabolite was a dose related increase in
cloudiness and the presence of crystals and bright red
stained globules in urine sediments. In addition, in most
top dose animals, blood was detected in the urine during
treatment and recovery (visible contamination observed for 2
males and 2 females) and red blood cells were occasionally
observed in urine sediments of some top dose animals and 3
mid dose females. A slight reduction ofspecific gravity and
doubling of protein levels wereobserved in both sexes at the
end of treatment and females at the end of recovery (top
dose only). Also present in urine sediments from both top
and mid dose animals were renal epithelial cells. The
incidence did not correlate with the severity of other
kidney lesions and levels were reduced at the end of
recovery.

Effects in organs:
In top dose animals only, absolute and relative kidney
weights were increased at the end of treatment and of
recovery; relative liver weights were slightly increased at
the end of treatment only.


Macroscopic:

Effects were observed only in top dose animals. In females
kidneys were pale and enlarged, sometimes accompanied by
pelvic dilatation. Similar effects were observed in one male
at the end of recovery. Distention of the ureter was
observed in 4 females and enlarged spleen in 3 females.


Microscopic:

In top dose animals at the end of treatment distal
nephropathy and papillary necrosis with hypertrophy of
collecting ducts were observed. Affected collecting ducts
often contained proteinaceous debris and desquamated cells.
Also observed was hyperplasia of transitional epithelium in
the renal pelvis often with slight pelvic dilatation and
epithelial hyperplasia in the urinary bladder. In mid dose
animals, distal nephropathy and papillary necrosis with
hypertrophy of collecting ducts (one male) and epithelial
hyperplasia of the urinary bladder (all females and 3 males)
were observed.


No treatment related effects were seen in low dose animals.


At the end of recovery distal nephropathy, occasionally with
papillary necrosis, was still present in top dose animals
as was minimal to slight epithelial hyperplasia in the
urinary bladder and an increase in haemosidarin
depositionin the spleen.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (nominal)
Basis for effect level:
other: original NCD unit is mg/kg/day.
Dose descriptor:
NOEL
Effect level:
50 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