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EC number: 221-117-5
CAS number: 3007-53-2
An unintentional intratracheal application might have been the cause for
the effects in the lungs (severe bronchopneumonia in no. B 915/group III
and acute edema in no. B 944/group III) leading to premature sacrificing
or death of these two animals.
To assess the subchronic toxicity of confidential substance namea
subchronic test according toOECD Guideline for Testing of Chemicals No.
409 "Subchronic Oral Toxicity - Non rodent", adopted 12th of May 1981
Therefore Groups of 4 male and 4 female beagle dogs per dosage
were treated once daily by gavage over a period of 13 weeks with
following daily oral doses:
Control group: 0 mg/kg b.w.
Group I : 40 mg/kg b.w.confidential substance name
Group II : 200 mg/kg b.w.confidential substance name
Group III : 1000 mg/kg b.w.confidential substance name
From the second day of the study onwards, 1000 mg/kg were reduced
to 800 mg/kg, and from the 4th day of the study onwards, 800 mg/kg were
reduced to 500 mg/kg due to a markedly reduced health status of some
The official result in the report was:
Tests of the reflexes, body temperatures, pulse rates, blood
pressure, and heart rates showed no changes up to and including group
III. The same holds true for the electrocardiograms . The nutritional
state, feed intake, and body weight gain also yielded no adverse effects
up to and including group III. Clinical observations evidenced repeated
vomiting and salivation from group II upwards. Additional effects in
group III consisted of uncoordinated movements, nasal discharge,
lateral/prone position, and trembling. All these effects from group II
upwards are considered to be due to treatment with the test compound.
Animal no. B 915/group III had to be sacrificed on day 3 of the study
showing lateral position, flat breathing, and bloody faeces before
sacrificing, and animal no. B 944/group III died in week 7 of the study
exhibiting lateral position, bloody nasal and oral discharge before
death. Due to the lung findings observed in the histopathological
investigations, these two events might be associated with an
unintentional intratracheal application.
Ophthalmoscopy showed a lens cataract in one animal of group III.
This effect is seen to be treatment-related. Haematology and
Differential blood counting showed no changes up to and including group
III. Clinical chemistry evidenced a substance-related elevation of
APh-values in group III. Increased N-Demethylase values from group II
upwards and increased Cytochrome P450-values in group III are seen as
treatment-related effects giving evidence for an increased metabolic
activity in the liver. In this context the increased liver weights in
males of group III are also considered to be treatment-related.
Urinalyses showed no changes up to and including group III. Necropsy and
histopathological examination did not reveal toxicologically relevant
effects up to and including group III. Besides increased liver weights
in males of group III (see above), no changes in organ weights were
detected up to and including group III.
The author followed that based on the reported effects it can be
concluded that 40 mg/kg Testsubstance administered orally by gavage to
beagle dogs daily over a period of 13 weeks were tolerated without
In contrast to this conclusion the applicant assessed the effects
observed as follow:
The NOEL at 40 mg/kg bw/d (0.4%) reported is based on local
effects caused by oral application of the test substance at irritating
concentrations (≥2%). At 200 mg/kg bw/d clinical chemistry revealed only
slightly increased N-DEM values in the absence of any other finding. The
increase of this parameter is an indication for a minimal liver enzyme
induction but not for an adverse effect.Therefore the NOAEL is
established at 200 mg/kg bw/d
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