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EC number: 695-748-3
CAS number: 65286-55-7
Discussion of the results
The administration of the test substance to rats at 20, 60 and 100 mg/kg
bw/day resulted in statistically significant reductions in body weight
development throughout the treatment period for both males and females
treated with 60 or 100 mg/kg bw/day compared to controls. A reduction in
food consumption for these animals was also apparent throughout the
treatment period and with no visible effects on water intake. No such
effects were detected in animals of either sex treated with 20 mg/kg
bw/day. There were no clinical observations of true systemic toxicity
and only sporadic instances of noisy respiration from isolated
Statistically significant differences in males and females treated with
60 or 100 mg/kg bw/day were noted in comparison to controls for the
hematological and blood chemical parameters measured. Due to the effects
apparent at histological examination an association with treatment
cannot be discounted for the majority of these differences.
The evaluation of Thyroxine (T4) in adults and male/female offspring
(Day 13 of age) did not identify any treatment-related findings in the
offspring. However, the adults did show a dose related reduction
attaining statistical significance for adult males treated with 60 and
100 mg/kg bw/day. This could be an associated effect due to the
histopathological changes to the thyroid gland.
Mating performance and fertility were unaffected by treatment. However,
offspring from 60 or 100 mg/kg bw/day litters showed a reduction (p<0.05
- p<0.001) in body weight, body weight gain and cumulative gains which
resulted in statistically significantly lower litter weights at 100
mg/kg bw/day (p<0.05 - p<0.01). No such effects were noted for
offspring from 20 mg/kg bw/day litters.
Vacuolation was observed in numerous tissues for both sexes treated at
60 or 100 mg/kg bw/day, with vacuolation and hypertrophy of the choroid
plexus being apparent within the brain. Macrophage vacuolation was also
apparent within the spleen, thymus at these dosages and uterus at 100
mg/kg bw/day. The exact cause of the vacuolation could not be
determined, but where this vacuolation occurred alone, with no
degenerate changes and at a minimal level, it may be considered to be
non-adverse. As vacuolation is seen as part of a degeneration process
and vacuolar degeneration of hepatocytes was observed in the liver of
both sexes at 60 or 100 mg/kg bw/day, the study director considered this
effect to be toxicologically significant and adverse. This
interpretation is complemented by an expert statement prepared by the
sponsor. The vacuoles observed are considered transient and non-adverse
based on scientific peer-reviewed literature regarding weakly basic
aliphatic amines (which can be primary, secondary or tertiary amines)
and supporting evidence from similar compounds within the same chemical
family of aliphatic amines (Smith et al., 2019, internal document). With
regards to degeneration of hepatocytes in the liver for males and
females, there are no other parameters within the study that supports
this observation as being adverse or progressive (i.e., clinical
pathology or hematology/clinical blood chemistry). Cytoplasmic
vacuolization is a well-known morphological phenomenon observed in
mammalian cells after exposure to bacterial or viral pathogens as well
as to various natural and artificial low-molecular-weight compounds.
Vacuolization often accompanies cell death. Hence, the vacuolization
observed in the numerous tissues from the study was considered to be
excessive and of potential toxicological concerns due to the number of
tissues where the pathological findings was observed.
It can be demonstrated that aliphatic amines, such as the test item
induce clear cytoplasmic vacuoles. That the induced vacuolization is
most likely the result of osmotic effects associated with disturbed
ionic balance in the organelles rather than an impact on proteins
controlling cellular functions. These osmotic effects are considered to
be transient in nature and thus non-adverse.
Reduced hematopoiesis in the spleen was present in all males and females
treated with the test substance. The significance of this finding is
unclear but unlikely to be significant. A further male treated with the
test substance at 100 mg/kg bw/day had cellular depletion.
Atrophy of the thymus was present in two males and one female treated
with 100 mg/kg bw/day.
To conclude, within this study, the oral administration of the test item
to rats at dose levels of 60 or 100 mg/kg bw/day was associated with
vacuolation in numerous tissues, vacuolation and hypertrophy of the
choroid plexus of the brain and macrophage vacuolation within the
spleen, thymus and uterus. The significance of the vacuolation for many
of these tissues is unclear, and can be attributed to the test item
characteristics. The NOAEL for systemic toxicity is considered to be 100
The results indicate that the prepared formulations were within 98 -104%
of the nominal concentration.
Summary of the results from the 14day repeated dose oral (gavage)
range-finding toxicity study
In this study, effects on body weight development and reduced dietary
intake was observed for animals treated with 250 and 125 mg/kg bw/day.
Due to the severity of the body weight loss for animals of either sex
treated with 250 mg/kg bw/day, these animals were terminated early on
Day 8 of the study. At 75 mg/kg bw/day, effects on body weight
development were considered not to represent an adverse effect of
The mean concentrations of the test item in test formulations were analyzed during the study and these are the results:
The mean concentrations of all test item formulations analyzed for the study were within +/- 20% of nominal concentrations, confirming accurate formulation.
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