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
Limit test:
no

Test animals

Species:
other: Rat (Wistar)

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: 5 animals at 0 mg/kg bw/day
Male: 5 animals at 1.5 mg/kg bw/day
Male: 5 animals at 15 mg/kg bw/day
Male: 5 animals at 150 mg/kg bw/day
Female: 5 animals at 0 mg/kg bw/day
Female: 5 animals at 1.5 mg/kg bw/day
Female: 5 animals at 15 mg/kg bw/day
Female: 5 animals at 150 mg/kg bw/day

Results and discussion

Results of examinations

Details on results:
Clinical observations:
All animals dosed with 150 mg/kg were killed on days 16 or
17 on humane grounds due to severe reductions in bodyweight
gain (Bodyweight 14-25% of control on days 16 or 17).

Signs of toxicity observed in this group were hunched
posture and piloerection. One male animal also showed tiptoe
gait. There were no treatment-related clinical effects in
animals in the 15 or 1.5 mg/kg/day dose groups.


Food consumption was also decreased in animals treated with
150 mg/kg/day (males - 15% and fenales -8%). There was no
significant difference in food consumption observed in
animals treated with 15 mg/kg/day or less.


No treatment-related effects or motor activity in the
functional observation bathing were observed.

Laboratory findings:
There were reductions observed in both males and females
dosed with 150 mg/kg/day in plasma glucose (45% and 32%)
total protein (25% and 27%) and albumin (22% and 28%). There
were increases in plasma bilirubin (200 and 850%), alkaline
phosphatase (51% and 224%), aspartate amino transferase
(133% and 177%) and creatine kinase (88% and 114%).


At 15 mg/kg/day there were reductions in plasma glucose (21%
and 17%), albumin (6% and 9%) and total protein (10% and
12%). There were increases in plasma bilirubin (70% and
167%), alkaline phosphate (10% and 50%) and apartate amino
transferase (52% and 177%). These changes were statistically
significant in both sexes.


There were increases in haemoglobin concentrations,
haematocrit, red cell count and total and differential white
cell counts, seen in both sexes at 150 mg/kg. These changes
were considered to be a secondary consequence of weight loss
and dehydration and not a direct toxicological effect.


There were no toxicologically significant haematological
effects observed in the 15 and 1.5 mg/kg dose group.

Effects in organs:
Minimal to slight adrenal corticol vacuolation and apoptosis
was noted in the 150 mg/kg treated males. Slight
hypertrophy/hyperplasia of the kidney collecting duct
epithelium, accompanied by slight or moderate tubular
dilation was observed in 3 males at this dose. Splenic red
pulp depleted of blood was also observed in 4 males. Minimal
to moderate panlobular hepatocellular degeneration was
observed in all animals at this dose, with minimal to
moderate biliary epithelial hyperplasia also being observed.
Minimal degenerative cardiomyopathy was also noted.


Microscopic changes: Minimal/slight biliary epithelial
hyperplasia was observed in all animals at 15 mg/kg. All
animals of this dose group also showed slight or moderate
panlobular hepatocellular degeneration. Slight to moderate
red pulp blood depletion was seen in 4 males at 15 mg/kg,
and minimal degenerative cardiomyopathy was present in 3
males at this dose. No changes were observed in the testis
at 15 or 150 mg/kg. No treatment-related liver changes were
seen in animals at 1.5 mg/kg.

Effect levels

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