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 (Charles River)

Administration / exposure

Route of administration:
oral: unspecified
Vehicle:
other: 1% w/v methyl cellulose
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 15 mg/kg bw/day
Male: 5 animals at 150 mg/kg bw/day
Male: 5 animals at 1000 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 1000 mg/kg bw/day

Results and discussion

Results of examinations

Details on results:
Clinical observations:
There were no treatment related effects. Body weight gains
were satisfactory for all dose groups and sexes.

Laboratory findings:
Treatment resulted in bright yellow urine and staining of
the bedding material among both sexes treated at 150 and
1000 mg/kg/day and a slight increase in food intake among
males treated at 1000 mg/kg/day. Higher than control group
mean liver and kidney weights were recorded for both sexes
treated at 1000 mg/kg/day. An increased incidence of pallor
and enlargement of the kidneys were also observed among both
sexes treated at 1000 mg/kg/day.

Effects in organs:
The microscopic examination revealed changes in the liver,
kidney, stomach, urinary bladder and ileum/Peyer's patch
area of the ileum. Hepatocytic vacuolation was observed in
the liver of animals treated at 1000 mg/kg/day and minimal
vacuolation was also noted in two females treated at 150
mg/kg/day. Crystal formation was mainly involved in kidneys
and stomach of animals treated with 1000 mg/kg/day. Crystal
formation was also found occasionally in ileum/Peyer's patch
and urinary bladder. In the kidneys of animals treated at
1000 mg/kg/day deggenerative/regenerative changes were seen,
including cortical tubular basophillia, tubular dilatation
and vacuolation, and a minimal degree of tubular necrosis
and degeneration. Cortical intratubular hyaline droplets
were observed in the males and corticomedullary
mineralisation in the females. In animals treated at 150
mg/kg/day only males showed these changes, with the majority
of findings being confined to a single animal. In non-
glandular stomach, epithelial hyperplasia of the limiting
ridge was noted in males and females treated at 1000
mg/kg/day; while intracytoplasma eosinophilic inclusions,
crystal formation and submucosal inflammation were noted in
the glandular region of the stomach of these animals.

Effect levels

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