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Repeated dose toxicity: oral

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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 guideline
Principles of method if other than guideline:
- European Community (EC) Council Directive 96/54/EC, Annex
IV.D, replacing EC Directive 67/548/EEC, Part B : Methods
for the Determination of Toxicity and other Health Effects;
B.7: "Repeated Dose (28 days) Toxicity (oral)". Official
Journal of the European Communities No. L248, September

- Organisation for Economic Co-operation and Development
(OECD), OECD Guidelines for Testing of Chemicals, Section 4,
Health Effects, No. 407: "Repeated Dose 28-day Oral
Toxicity Study in Rodents", Paris Cedex, 27 July 1995.

- United States Environmental Protection Agency (EPA).
Health Effects Test Guidelines, OPPTS 870.3050, Repeated
dose 28-day oral toxicity study in rodents. Office of
Prevention, Pesticides and Toxic Substances (7101), EPA 712-
C-00-366, July 2000.
GLP compliance:
Limit test:

Test animals

other: Rat: Crl:WI(Han)

Administration / exposure

Route of administration:
oral: unspecified
propylene glycol
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 50 mg/kg bw/day
Male: 5 animals at 150 mg/kg bw/day
Male: 5 animals at 500 mg/kg bw/day
Female: 5 animals at 50 mg/kg bw/day
Female: 5 animals at 150 mg/kg bw/day
Female: 5 animals at 500 mg/kg bw/day

Results and discussion

Results of examinations

Details on results:
Clinical observations:
A total of four animals at 500 mg/kg/day did not survive
their scheduled treatment period. One male and one female at
500 mg/kg/day were found dead on days 15 and 4,
respectively. Another male and female at this dose level
were sacrificed in extremis on days 14 and 22, respectively.

Clinical signs noted among most animals at 500 mg/kg/day
that did not survive until their scheduled termination:
hunched posture, breathing difficulties, piloerection, a
lean appearance and ptosis. A hunched posture was also noted
among all surviving females at 500 mg/kg/day.

No clinical signs were noted among control animals, and
males at 50 mg/kg/day.

Laboratory findings:

No toxicologically relevant changes occurred in
haematological parameters of surviving rats.

Clinical biochemistry:

The following (statistically significant) changes in
clinical biochemistry parameters distinguished treated
animals from control animals:

- Increased ALAT in one male at 500 mg/kg/day, and in
females at 500 mg/kg/day,

- Increased ALP in females at 500 mg/kg/day and also in
three females at 150 mg/kg/day and 1 female at 50 mg/kg/day.

- Increased glucose levels in two males at 500 mg/kg/day,
and in females at 500 mg/kg/day,

- Increased cholesterol levels in females at 500 mg/kg/day
(not statistically significant, but showing a dose-related

- Reduced sodium levels in males at 150 and 500 mg/kg/day,

- Reduced chloride levels in males at 500 mg/kg/day, and in
one female at 500 mg/kg/day,

- Increased potassium levels in males at 150 and 500
mg/kg/day (not statistically significant at 500 mg/kg/day),
and in females at 500 mg/kg/day,

Effects in organs:
Macroscopic examination:

Findings among animals at 500 mg/kg/day that did not survive
until their scheduled termination consisted of an emaciated
appearance, a stage of beginning autolysis, a gastro-
intestinal tract distended with gas, red discolouration of
the lungs, enlargement of the liver, red foci on the thymus,
and fluid in the body cavity. No such findings were present
among the surviving animals at 500 mg/kg/day.

No macroscopic abnormalities were noted among control
animals, males at 50 mg/kg/day and males and females at 150

Organ weights:

Spleen and thymus weight (absolute and relative weights) of
surviving females at 500 mg/kg/day were slightly reduced (no
level of statistical significance was achieved).

Microscopic examination:

There were no microscopic findings recorded which could be
attributed specifically to treatment with the test
substance. Thymic atrophy and in one case necrosis in the
animals dying or killed in extremis during the study was
considered to be indicative of general health status rather
than a specifc effect of the test substance.

Effect levels

Dose descriptor:
Effect level:
150 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