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: 96/54/EG, B.7; OECD 407 (1995)
GLP compliance:
yes
Limit test:
no

Test animals

Species:
other: rat, Wistar Rj:WI (IOPS Han.)

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 3 mg/kg bw/day
Male: 5 animals at 25 mg/kg bw/day
Male: 5 animals at 100 mg/kg bw/day
Female: 5 animals at 0 mg/kg bw/day
Female: 5 animals at 3 mg/kg bw/day
Female: 5 animals at 25 mg/kg bw/day
Female: 5 animals at 100 mg/kg bw/day

Results and discussion

Results of examinations

Details on results:
Clinical observations:
No mortality occurred during the study period.

Post-dose salivation between study days 6 and 28 was noted
in animals receiving 25 and 100 mg/kg bw/d. In males treated
with 100 mg/kg bw/d undescended testis was recorded. Body
weights were significantly reduced in males at 25 and

100 mg/kg bw/d (-11, -37 %), and in females at

100 mg/kg bw/d (-16 %). Overall mean body weight gain was
significantly decreased in both sexes at 100 mg/kg bw/d
(m/f: -79 % / -59 %); and in males at 25 mg/kg bw/d

(-23 %). In females, body weight parameters were

unaffected by treatment at 25 mg/kg bw/d. The mean food
consumption was significantly reduced in animals of both
sexes at 100 mg/kg bw/d (m/f: -38 / -29 %).Mean food
consumption was slightly reduced (not significant) in both
males and females.

Neurotoxictiy assessment revealed a tendency towards
decreased mean exploratory locomotor activity in males and
females (-21 % and -22 %, respectively) at 100 mg/kg bw/d,
when compared to controls.

Laboratory findings:
In males and females treated with 100 mg/kg bw/d hematology
revealed statistically significant decreased red blood cell
counts (m/f: -10 / -12 %), hemoglobin (m/f: -14 / -17 %) and
hematocrit values (m/f: -15 % -15 %), and in parallel to
significantly increased absolute and relative reticulocyte
counts for females. Slightly decreased MCH and a tendency
towards decreased MCV were observed in males.

At 25 mg/kg bw/d slightly reduced red blood cell counts

were noted in males and females (-1 / -6 %, not
statistically significant). Statistically significant
decreased hemoglobin and hematocrit values were observed
only in females (-8 % and -7 %, respectively). Mean absolute
and relative reticulocyte counts were elevated in females
when compared to controls.

At the clinical biochemistry assessment, increased mean
total bilirubin concentrations, alanine aminotransferase and
alkaline phosphatase activities were noted in both males and
females at 100 mg/kg bw/d, additionally in 2/5 males
slightly icteric plasma was found. At 25 mg/kg bw/d
increased mean total bilirubin concentration and alkaline
phosphatase activity were observed only in females.
Urinalysis revealed a decreased mean pH value in males
treated with 100 mg/kg bw/d. A tendency towards decreased
protein level was noted in both sexes at 100 mg/kg bw/d and
in females only at 25 mg/kg bw/d, respectively.

Effects in organs:
At 100 mg/kg bw/d mean terminal body weight was
significantly reduced by 38 % and 19 % in males and females,
respectively. The following organ weights were statistically
significant increased when compared with controls: mean
absolute and relative liver weights in animals of both sexes
at 25 and 100 mg/kg bw/d, mean absolute and relative
pituitary gland weights in males and females at

100 mg/kg bw/d, and mean absolute and/or relative adrenal
weights in males and females at 25 and 100 mg/kg bw/d. The
following organ weights were statistically significantly
decreased when compared to controls: mean absolute and
relative thymus weights in males at 100 mg/kg bw/d and in
females at 25 and 100 mg/kg bw/d. Mean absolute male
reproductive organ weights (testis, epididymis, prostate)
were statistically significant decreased at 100 mg/kg bw/d.
In females mean absolute and/or relative ovary weights were
statistically significantly decreased at 100 and

25 mg/kg bw/d, when compared to controls.

At necropsy enlarged liver was observed in both sexes at

100 and 25 mg/kg bw/d. Atrophic/small and/or soft testes,
atrophic/small epididymides, and atrophic/small prostate
were found in all males at 100 mg/kg bw/d, in addition,
atrophic/small vesicles at 100 and 25 mg/kg bw/d,
respectively. In females atrophic/small ovaries were found
at 100 and 25 mg/kg bw/d.

Microscopy revealed adverse test substance-related effects
in the liver, the adrenal gland, the pituitary gland, the
mammary gland and the male and female reproductive system.
In the liver, minimal to marked centrilobular to panlobular
hepatocellular hypertorphy was observed in males and females
at 100 and 25 mg/kg bw/d, and in addition, focal to
multifocal bile duct hyperplasia in both sexes at

100 mg/kg bw/d and in 1/5 females at 25 mg/kg bw/d. In the
adrenal gland, minimal to moderate cortical degeneration
with hemorrhage was noted in both males and females at

100 mg/kg bw/d and in females at 25 mg/kg bw/d. In the
pituitary gland, minimal to slight diffuse non acidophil
cell hypertrophy/hyperplasia was observed in males at

100 mg/kg bw/d. In the mammary gland, minimal to slight
lobular hyperplasia was observed in females at

100 mg/kg bw/d.

Minimal to slight dilated/lactating ducts was seen in both
sexes at 100 mg/kg bw/d. Male rats treated at 100 mg/kg bw/d
showed relevant microscopic findings in the testis,
epididymis, and prostate. In the testis, marked tubular
degeneration/atrophy (5/5 males) and moderate Leydig cell
atrophy (3/5 males) were seen, in the epididymis severe
tubular atrophy with aspermia (5/5 males), and in the
prostate, diffuse severe glandular atrophy (5/5 males),
respectively. Furthermore, minimal to severe glandular
atrophy of the seminal vesicles was noted at 100 mg/kg bw/d
(5/5 males) and 25 mg/kg bw/d (3/5 males). In the ovary,
minimal to moderate interstitial cell atrophy was observed
in all females at 100 and 25 mg/kg bw/d. In the uterus,
minimal to moderate tall columnar epithelium was noted in
all females at 100 25 mg/kg bw/d. Minimal to slight squamous
cell metaplasia was seen in 2/5 females at 100 and

25 mg/kg bw/d. In the vagina, minimal to moderate abnormal
mucification with degeneration was observed at 100 and

25 mg/kg bw/d. In addition, dysregulation of physiological
estrous cycle (with absence of proestrus, estrus, metestrus
or diestrus) was noted in the females at 100 and

25 mg/kg bw/d.

Additionally test substance-related effects were observed in
the kidney, spleen and thymus in animals of both sexes at
100 mg/kg bw/d. Minimal to slight intracellular brown
pigment in cortical tubules was noted in the kidneys. As
this finding was not associated with cellular damage, it was
not considered as an adverse effect. Minimal increased
hemosiderosis was noted in the spleen, and an elevated
severity of diffuse involution/atrophy in the thymus,
respectively.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
25 mg/kg bw/day (nominal)
Basis for effect level:
other: original NCD unit is mg/kg/day.
Dose descriptor:
NOEL
Effect level:
3 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