Dihydroxypyrimidine

Repeated dose toxicity: oral

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 (1995)

GLP compliance:

yes

Limit test:

no

Test animals

Species:

other: rat, Wistar Hsd Cpb:WU

Administration / exposure

Route of administration:

oral: unspecified

Vehicle:

other: 2 % cremophor in water

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 20 mg/kg bw/day
Male: 5 animals at 100 mg/kg bw/day
Male: 5 animals at 500 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 100 mg/kg bw/day
Female: 5 animals at 500 mg/kg bw/day

Results and discussion

Results of examinations

Details on results:

Clinical observations:
There were no test substance related deaths. One male
treated at 500 mg/kg bw/d died shortly after blood sampling
(for laboratory study) on day 28 of the study without
clinical signs prior to death. The cause of death was
considered to be due to the blood sampling procedure.
Treatment with 500 mg/kg bw/d resulted in clinical findings
in male rats. There were piloerection (3/5), decreased
motility (2/5), closed eyes (1/5), discolored feces (1/5).
In male rats partly statistically significant decrease in
body weights was noted at 500 mg/kg bw/d (-10 % at the end
of the study).

There were no test substance-related effects during
functional observational battery including functional
observations, open field observations, reflex testing and
grip strength measurements.

Laboratory findings:
Hematology revealed statistically significant decreased
counts of erythrocytes, leukocytes, and basophils; and
atypical cells in males at 500 mg/kg bw/d. A trend to lower
leukocyte and lymphocyte counts was observed also in female
rats at >= 100 mg/kg bw/d.

Clinical biochemistry revealed statistically significant
(but not dose-related) increase of aspartate
aminotransferase in females at 20 and 100 mg/kg bw/d; and
decreased concentrations in creatinine and protein in males
and females at 500 mg/kg bw/d, and additional in albumin in
females, respectively.

No effects on the activity of enzymes and on the content of
cytochrome P-450 in liver tissue samples were detected.

Effects in organs:
The absolute and relative weights of testes were
statistically significant decreased at 100 mg/kg bw/d

(-13 %) and 500 mg/kg bw/d (-60 %).

At necropsy treatment-related changes were recorded from the
male sex organs. The testes were diminished in size, and
discolored at >= 100 mg/kg bw/d, and epididymides, prostate,
and seminal vesicle were diminished in size at 500 mg/kg
bw/d.

At microscopy treatment-related changes were seen in several
organs: spleen, Payer's patches, testes, epididymides,
prosta/seminal vesicles, ovaries and thyroid gland. In the
spleen a dose-related increased atrophy (lymphocytic
depletion) of the marginal zone of the white pulp was
observed in rats of either sex at >= 100 mg/kg bw/d, and an
increased extramedullary hematopoiesis in male rats given
500 mg/kg bw/d. Minimal lymphoid depletion of the Payer's
patches was present in 4/5 males and 3/5 females treated at
500 mg/kg bw/d.

Corresponding to the macroscopic findings in male sexual
organs minimal to marked degeneration of the testicular
epithelium was observed in males treated at >= 100 mg/kg
bw/d. Minor changes such as vacuolation of the germinal
epithelium were observed at 100 mg/kg bw/d. The testicular
changes were accompanied by aspermia, oligospermia and an
increase of spermatic debris in the epididymides at

>= 100 mg/kg bw/d. One male treated at 500 mg/kg bw/d had an
atrophy of the prostate and the seminal vesicles. In the
ovaries central necrosis of the corpora lutea was observed
in 1/5 females at 100 mg/kg bw/d and in 3/5 females at

500 mg/kg bw/d. An effect on the estrous cycle was not
visible. A stimulation of the follicular cells of the
thyroid gland (follicular cell hypertrophy of minimal
severity score) was observed in higher frequency in males at
500 mg/kg bw/d.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

20 mg/kg bw/day (nominal)

Basis for effect level:

other: original NCD unit is mg/kg/day.

2

Dose descriptor:

NOEL

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

Conclusions:

Classified as: Xn - harmful