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EC number: 203-052-4
CAS number: 102-77-2
Homogeneity ± 7 % was regared as acceptable, investigation of
formulation stability under laboratory conditions showed a small but
acceptable decrease in concentration over a 28 day period.
Analysis of the formulations before the feeding phase showed
satisfactory homogeneity and stability under suitable conditions of use.
anaylsis of formulations during the feeding phase showed a satisfactory
agreement between the nominal and actual concentrations of Santocure MOR.
General observations and mortality:
The physical condition of the treated rats did not differ from controls.
Changes which were seen were those commonly seen in ageing CD rats. In
the period between weeks 58 and 85 the male medium and high dose groups
experienced a greater mortality rate than did the control group. There
was also strong evidence of a trend with dose (p<0.01). Significant
excess mortality was seen in the mid and high dose group (p<0.01). The
differences then declined and at termination there was no effidence of a
treatmant-related trend in mortality. In the latter part of the study
the female medium and high dose group mortality rate was lower than that
of the control group.
Body weight gain
High dose group males gained less weight than controls from the very
early part of the study so that at termination there was a difference
between the groups of about 22 %. A simular less pronounced trend was
seen in the male medium dose group, a difference from the control group
of about 7 % being seen at termination. This trend was also seen in
treated females. At termination high dose group females weighed about 28
% less than controls and medium dose group about 10 % less. There was
also a small differences (about 5 %) between low dose females and
controls, but this did not begin to develop until week 65.
Male and females rats given the high and medium doses gained less weight
than controls throughout study.
(Study termination body weights conpared to control, males: 100 %, 98 %,
93% and 78 at 0, 5, 50, 400 mg/kg bw/d; females: 100 %, 95%, 90 % and 72
% at 0, 5, 50 and 400 mg/kg bw/d)
The reduced weight gain was associated with slight reductions in food
consumption. High dose males ate slightly less than controls. This
pattern was also evident in female of the mid and high dose groups. The
differences were of the order of 5%. Low and mid dose group males and
low dose females had similar food consumption patterns to the controls.
Test article intake:
The overall mean test article intakes, unadjusted for the formulation
analysis, were in very good agreement with the nominal values. The
analysis of diet bin residues suggested that the actual doses were
slightly below the nominal concentrations, perhaps up to 10 % lower.
Palpable subcutaneous masses were identified in a proportion of the
animals in all groups in the course of the study. The masses were of the
type commonly seen in the CD rat and were most frequently seen in the
axillae and mammary glands. The time to first mass was not affected by
treatment. Male groups 3 (mid dose) and 4 (high dose) showed a
statistically significant increase in palpable masses, whereas the
corresponding female groups showed a reduced incidence. The microscopic
pathology data did not indicate this to be an oncogenic response.
No changes were seen in haematological parameters to suggest an effect
of treatment with the test article.
Considerable variation within groups was seen in some parameters,
notably some plasma enzyme activities and bilirubin concentrations. The
male and female high dose animals did, however, trend to have lower
plasma LDH activities than controls. No statistically significant
differences were seen between control and test groups.
(No test substance-related biologically relevant effects on GOT values
during the study)
Male rats given high dose Santocure MOR tended to have more urinary
reducing substances than controls. The differences were, however, small
and did not appear to be due to glycosuria. Microscopic examination of
urinary deposits showed no trends to suggest an effect of treatment.
Interim kill (week 54)
The absolute kidney weight of group 4 (high dose) males was
statistically significant greater than that of the control group. The
relative (organ to body weight) weights of the livers and kidneys of
group 4 males (high dose group), the relative kidney weight of group 3
females (mid dose group) and the relative heart weight of the group 4
females (high dose group) exceeded the control values to a statistically
The relative brain,liver, heart, gonad
(males only), adrenal (females only), kidney, spleen (females
only) and lung weights of group 4 animals (high dose group) were greater
than control values. The intergroup variation was, however,
considerable, although in some instances the differences were
Slight changes were seen in the
absolute and relative weights of certain organs at necropsy. The changes
in the kidney and liver weights suggest a slight response to treatment.
The changes in the weights of other organs are considered to be a
secondary effect of treatment, refecting the interference with the
normal growth pattern.
Gross and microscopic
No consistent pattern of changes
was seen to suggest a response to treatment.
There was no differences in the
total incidence of morbidity or mortality from all causes between
control groups and highest dose group animals. In females most of the
preterminal morbidity and mortality was associated with neoplasia, a
less clear pattern being seen in males. The total incidence of
neoplastic cause of demise in high dose group males was slightly higher
than in controls; wheras the reverse occured in females. This was due
mainly to losses due to mammary neoplasia in control group females.
A variety of non-neoplastic
conditions was found in both sexes. These did not, however, appear to be
influenced, in terms of incidence or severity, by treatment.
There was no apparent difference
between control and high dose group in the incidence of tumor-bearing
animals or in the incidence of animals with tumors of single or multiple
Histopathology from all control animals and all animals from the highest
dose group (400 mg/kg bw and day) was performed. The reproductive organs
(ovaries, testes, prostate, and uterus) were evaluated. No adverse
effects of the test substance MBS on these organs was indicated in
treated animals (400 mg/kg bw and day). However, a significant increase
in relative gonad weights (146 %, p< 0.01) was indicatives for males of
the highest dose group, but this change was considered to be a secondary
Therefore, for MBS the NOAEL (400 mg/kg bw and day) from the chronic
toxicity study (Monsanto Co. 1982) could be used for DNEL derivation.
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