Registration Dossier

Administrative data

repeated dose toxicity: oral
Adequacy of study:
other information

Data source

Reference Type:
other: Body responsible for the test

Materials and methods

Test guideline
according to
other: 96/54/EG, B.7; OECD 407 (1995)
GLP compliance:
Limit test:

Test animals

other: rat, Wistar Hsd Cpb:WU

Administration / exposure

Route of administration:
oral: unspecified
other: water/Cremophor EL; 98 %/2 %, v/v
Details on oral exposure:
Method of administration:
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 20 mg/kg bw/day
Male: 5 animals at 125 mg/kg bw/day
Male: 5 animals at 750 mg/kg bw/day
Female: 5 animals at 0 mg/kg bw/day
Female: 5 animals at 20 mg/kg bw/day
Female: 5 animals at 125 mg/kg bw/day
Female: 5 animals at 750 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 treatment-related clinical signs in any dose
group. Daily food consumption and body weight development of
the test animals were unaffected during the treatment

The functional observational battery showed no signs or
symptoms indicating evidence for systemic toxic and
neurotoxic potential. Motor activity measurements exhibited
no test substance-related changes in both sexes at doses of
750 mg/kg bw/d and below.

At the ophthalmoscopic examinations radial waterclefts were
observed on the anterior cortex of the lens in both eyes of
5 males and 4 females at 750 mg/kg bw/d. The changes were of
slight in males and of medium severity in females.

Laboratory findings:
Hematology revealed statistically significant decreases of
hemoglobin and hematocrit values and of leukocyte count for
the 750 mg/kg bw/d females.

At 750 mg/kg bw/d clinical biochemistry revealed
statistically significant increases of alanine
aminotransferase activity in males and females and
additionally of alkaline phosphatase in females,
respectively. The creatinine concentration was significantly
increased in females of all treatment groups and of
triglycerides in males and females at 750 mg/kg bw/d,

Urinalyses revealed statistically significant increases of
protein excretion for the males and females at 750 mg/kg
bw/d and of the protein/creatinine ratio in females,
respectively. The pH-values were statistically significantly
decreased in males at 20 mg/kg bw/d and above and in females
at 125 mg/kg bw/d and above. At microscopy of sediment at
750 mg/kg bw/d bushy aggregates of crystals were observed in
two females and aggregates of acicular, crystals forming
spheres and dumbbells in one male.

Effects in organs:
At 750 mg/kg bw/d absolute and relative liver weights were
statistically significantly increased in males and females
(males: absolute: 16 %, relative: 11 %; females: absolute:
12 %, relative: 18 %).

At necropsy two males and females given 750 mg/kg bw/d
showed distinct lobation of the liver.

Microscopy revealed in the liver of females at 750 mg/kg
bw/d increased incidence of condensed hepatocellular
cytoplasm which is an indication of a reduced glycogen
content. The Oil Red O stain showed an increased periportal
lipid content in females at the same dose level. In the
spleen an increased number and size of germinal centers
which could possibly indicate an adaptive response of the
immune system, were observed in animals of both sexes given
750 mg/kg bw/d. This finding is not estimated as adverse, an
assumption which is supported by the fact that with the
exception of the decreased leukocyte count in females no
test substance-related changes were observed in the other
lymphoid organs up to and including 750 mg/kg bw/d. In the
sciatic nerve, minimal foamy/vacuolated cells were focally
observed in three females at 750 mg/kg bw/d. A relation of
this finding to treatment with the test substance is
debatable since it is known to occur spontaneously and may
be secondary to mechanical trauma. No induced findings were
noted in the brain or spinal cord. In the eyes, a
degeneration of lens fibers was recorded in all animals of
both sexes at 750 mg/kg bw/d. Incipient lens fiber
degeneration was present also in two females treated with
125 mg/kg bw/d.

Effect levels

open allclose all
Dose descriptor:
Effect level:
20 mg/kg bw/day (nominal)
Basis for effect level:
other: original NCD unit is mg/kg/day.
Dose descriptor:
Effect level:
20 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

Classified as: Not classified