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EC number: 629-765-4
CAS number: 1226892-44-9
Accuracy of preparation: The
concentrations analysed in the formulations for the 10, 30 and 100 mg/kg dose
groups were in agreement with target concentrations (i.e. mean
accuracies between 90% and 110%). A small response at the retention time
of the test substance was observed in the chromatograms of the control formulations.
It was considered to derive from carry over since a similar response was
obtained in the analytical blanks.
Homogeneity: The formulations
of Group 2 and Group 4 were homogeneous (i.e. coefficient of variation = 10%).
Stability: Formulations at the
entire range were stable when stored under nitrogen in a refrigerator
for at least 8 days.
Tall oil diethylenetriamine imidazoline was
administered by daily oral gavage to groups of 10 male and 10 female
Wistar Han rats for 90 days at dose levels of 0, 10, 30 and 100
mg/kg/day. The study was performed under GLP and based
on OECD TG 408.
Chemical analyses of formulations
preparations; clinical signs daily; functional observation tests in Week
12; body weight and food consumption weekly; ophthalmoscopy at pretest
and in Week 13; estrous cycle determination; clinical pathology and
macroscopy at termination; organ weights and histopathology (including
spermatogenesis staging) on a selection of tissues.
Formulation analyses confirmed that
formulations of test substance in propylene glycol were prepared
accurately and homogenously, and were stable over at least 8 days.
All animals survived up until scheduled
termination. No toxicologically significant clinical signs were noted
during the observation period.
The treatment-related lower motor activity
of males at 100 mg/kg, and a trend towards lower motor activity for
females at 30 and 100 mg/kg were considered not to represent an adverse
effect on neurobehaviour. These results were not supported by clinical
observations or other functional observation tests, were slight in
nature (within the normal range for rats of this age and strain), and
had no supportive morphological correlates in examined neuronal tissues.
Males at 30 and 100 mg/kg showed a lower
mean body weight and body weight gain with lower food intake,
essentially during the second half of the treatment period, with a
slightly lower body weight and body weight gain of females at 100 mg/kg
during the last week of treatment.
No treatment-related ophthalmology findings,
changes in haematological parameters or macroscopic findings were noted.
Test item-related microscopic findings
foamy macrophages in the lamina propria of the small intestines (males
and females starting at 10 mg/kg/day),
- foamy macrophages in the mesenteric lymph
nodes (females starting at 10 mg/kg/day, males starting at 30
- increased incidence and severity of
pigmented macrophage foci in the mesenteric lymph nodes (males and
females starting at 30 mg/kg/day),
- increased incidence and severity of
alveolar (mainly foamy) macrophage aggregations in the lung (females at
macrophages in the glomeruli of the kidneys (males and females at 100
The findings in the lamina propria of the
small intestines were considered to have caused reduced protein uptake,
and to correlate with lower total protein and albumin levels in males
and females at 100 mg/kg.
Other treatment-related changes in clinical
biochemistry parameters at 100 mg/kg consisted of higher alanine and
aspartate aminotransferase activity in males and females, higher total
bilirubin and glucose levels in males, lower urea levels in males (with
a trend towards an increase among female dose groups), higher bile acid
levels in females, and lower calcium levels in females at 100 mg/kg
(possibly secondary to the lower albumin levels).
The lower liver, thymus and spleen weights
in males at 100 mg/kg (with a decreasing trend across other male groups)
had no histopathological correlates, and were therefore ascribed to the
lower terminal body weights for these males. As such, these changes were
considered to be of no toxicological relevance.
One male at 100 mg/kg showed various
microscopic (and correlating macroscopic and organ weight) changes in
reproductive organs including undeveloped testes (correlating to absence
of all spermatogenesis stages) with reduced sperm content in the
epididymides and immature prostate, and a difference in cell size in the
periportal-centrilobular area of the liver. In addition, this animal
showed a lower weight gain during treatment, and blood analyses showed a
lower glucose value and a higher bile acid and inorganic phosphate
level. Since these findings were confined to this single animal, these
were considered unrelated to treatment with the test substance.
There were no indications of possible
reproductive toxicity based on the parameters determined in this study.
No treatment related changes in estrous cycle length were noted across
the dose groups during the period in which estrous cycle length was
determined (Day 72 up to and including Day 92), and histopathological
examination of the male and female reproductive organs (including
spermatogenesis staging) did not show treatment-related lesions.
The first effects to occur is the presence
of foamy macrophages in the lamina propria of the small intestines and
mesenteric lymph nodes. These effects are considered to represent a
local, porte d’entrée related effect due to the route of application,
rather than a systemic effect.
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