Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Meets the criteria for classification as Reliable without restriction according to Klimisch et al (1997)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1997

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Version / remarks:
Annex V
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
other: Rat (CD)
Sex:
male/female

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
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 1.5, 15, 150 mg/kg/day
Basis:
other:
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
Control animals:
yes, concurrent vehicle

Results and discussion

Results of examinations

Details on results:
Clinical observations:
There were no deaths. Purple/black staining of the cage tray
paper was seen throughout the treatment period in animals
receiving 15 or 150 mg/kg/day. Dark faecal pellets were seen
in animals receiving 150 mg/kg/day.

Bodyweight gain in animals receiving 150 mg/kg/day was lower
than that of controls (35 and 15% lower in males and females
respectively). Amongst females receiving 15 mg/kg/day, a
slight reduction in weight gain was seen during the first
two weeks of treatment only.

Food consumption in males receiving 15 or 150 mg/kg/day was
lower than that of the controls (7 and 25% lower than
control values for males receiving 15 or 150 mg/kg/day
respectively).

In comparison with the controls overall water cosumption in
females receiving 15 mg/kg/day and males and females
receiving 150 mg/kg/day was 16-32% higher than that of the
controls.

Laboratory findings:
Statistically significantly reduced packed cell volumes,
haemoglobin concentration (13-21%), erythrocyte counts
(7-22%) and mean cell haemoglobin concentration (3%) were
seen in both sexes receiving 150 mg/kg/day; the effect was
less marked in males than females. In addition, slightly but
not statistically significant higher mean cell volumes were
seen in females receiving 150 mg/kg/day; occasional animals
from other treated groups also had high mean cell volumes.
These changes were accompanied by changes in the
morphological appearance of the erythrocytes including
anisocytosis, polychromasia and in one male macrocytes. High
platelet counts were seen in both males and females
receiving 150 mg/kg/day which reached statistical
significance in females only (31% higher than controls).
These haematological changes may be due to induction of
methaemoglobincienua at 150 mg/kg. There was no evidence of
any clear effect on the haematological parameters in other
treated groups. Statistically significantly elevated plasma
bilirubin concentrations (2-3 fold increase) were seen in
both males and females receiving 150 mg/kg/day.
Statistically significantly increased (6-10%) total plasma
protein concentrations were sen in males and females
receiving 150 mg/kg/day and to a less marked degree, in
females receiving 15 mg/kg/day; this was assiciated with
slight increases in plasma albumin and B-globulin
concentrations at 15 and for 150 mg/kg. High plasma
cholesterol concentrations were seen in males and females
receiving 150 mg/kg/day. In females, low plasma glucose and
urea concentrations were seen in all treated groups. Low
alkaline phosphatase and aspartate aminotransferase
activities were seen in males and females receiving 150
mg/kg/day, although this type of change is considered to
have no toxicological significance.

Effects in organs:
Absolute liver weights were increased in males and females
receiving 150 mg/kg/day (12% and 39% respectively), reacting
statistical significance in females only. Spleen weight was
increased (38%) in females receiving 150 mg/kg/day; a
similar effect in respect of bodyweight relative spleen
weights only was seen in males receiving this dosage. High
thyroid weights was seen in 1 female receiving 150 mg/kg/day
(55% above controls) although the increase was not
statistically significant. A dose related increase in kidney
weight in all treated female groups did not reach
statistical significance; at 150 mg/kg, kidney weight was
15% higher than control. Macroscopic abnormalities related
to treatment were confined to observations of dark thyroids
in almost all animals given 150 mg/kg/day.

Amongst animals treated at 150 mg/kg/day, the following
microscopic changes were seen: periacinar hepatocytic
hypertrophy of the liver (all animals), proximal tubular
vacuolation and necrosis of the kidney (3 females only);
increased haemosiderin (all males and females) and
conjestion (all femalesonly) in the spleen and follicular
cell hyperplasia and brown pigment in the follicular cells
and for colloid of the thyroid (all animals). No
toxicologically significant treatment-related macroscopic or
microscopic changes were seen in animals at 1.5 or 15 mg/kg.

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:
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: Xn - harmful