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EC number: 948-052-1
CAS number: -
study was designed to investigate the systemic toxicity of the test
substance, KOMAD 710, following repeated dosing. The
assessment of repeated dose toxicity was made as part of a Combined
Repeated Dose Toxicity Study with the Reproduction/ Developmental
Toxicity Screening Test which also assessed potential adverse effects of
the test item on reproduction. The
study was designed to be compatible with the requirements of the OECD
Guidelines for Testing of Chemicals No. 422 “Combined Repeated Dose
Toxicity Study with the Reproduction/ Developmental Toxicity Screening
Test” (adopted 29 July 2016).
groups of ten male and ten female rats received the test substance at
doses of 100, 330 or 750 mg/kg/day by oral gavage administration. Males
were treated daily for two weeks before pairing and up to necropsy after
a minimum of four consecutive weeks. Females
were treated daily for two weeks before pairing, throughout pairing,
gestation and until Day 13 of lactation. Females
were allowed to litter, rear their offspring and were killed on Day 13
of lactation. The
F1 generation received no direct administration of the test item; any
exposure was in utero or via the milk. A
similarly constituted Control group received the vehicle, propylene
the same relative treatment period.
the study, clinical condition, detailed physical examination and arena
observations, sensory reactivity observations, grip strength, motor
activity, body weight, food consumption, hematology (peripheral blood),
blood chemistry, estrous cycles, pre-coital interval, mating
performance, fertility, gestation length, organ weight and macroscopic
pathology and histopathology investigations were undertaken.
Day 9 of treatment, one female receiving 330 mg/kg/day
was killed for welfare reasons.
Day 23 of gestation, a second female receiving 330 mg/kg/day
(3F No. 96) was killed for welfare reasons.
Day 8 of lactation, a Group 4 female receiving 750 mg/kg/day was
terminated early due to total litter loss.
Day 9 of lactation, a third female receiving 330 mg/kg/day was
terminated early due to total litter loss.
Day 25 of gestation, three Group 4 females receiving 750 mg/kg/day
were killed due to having surpassed the designated gestational time.
were no clinical signs observed following dose administration or signs
at routine clinical examination that were considered to be associated
were no treatment-related changes in the behavioural parameters observed
during the study.
were no inter-group differences in sensory reactivity scores that were
considered to be related to treatment.
body weight gains for males given 750 mg/kg/day were moderately low and
slightly low for males given 100 or 330 mg/kg/day. During
the two-week pre-pairing period the females receiving 750 mg/kg/day body
weight gain was higher than Controls. During
the gestation and lactation periods body weight gain was slightly or
moderately low for females receiving 330 or 750 mg/kg/day. For
females receiving 100 mg/kg/day, body weight gain was slightly low
during the lactation period, only.
food intake for males receiving 750 mg/kg/day was generally slightly
lower compared to Control throughout the treatment period. Mean
food consumption during gestation was low for females receiving
750 mg/kg/day and following parturition was low for females receiving
330 or 750 mg/kg/day. Mean
food consumption for males receiving 100 or 330 mg/kg/day and for
females receiving 100 or 330 mg/kg/day was generally similar to Controls
throughout the dosing period, with exception of the lactation period for
females at 330 mg/kg/day.
haematological examinations at scheduled termination revealed, when
compared with Controls, a reduction in red cell mass amongst males and
females receiving 330 or 750 mg/kg/day. Mean
cell haemoglobin and mean cell volume were slightly lower than that of
Controls for males receiving 330 or 750 mg/kg/day.
chemistry investigations after five weeks of treatment revealed
statistically significant changes in the liver enzymes for
males at all dose levels where alkaline phosphatase activity was higher
compared to Controls and alanine aminotransferase activity was lower
compared to Controls. A
dose dependent response was observed for alkaline phosphatase only. Liver
enzymes changes were observed in females with lower alkaline phosphatase
and alanine aminotransferase activity at all dose levels compared to
dose dependent response was observed for alanine aminotransferase levels
levels were high for males at 330 and 750 mg/kg/day when compared to
Controls although there was no dose-response evident. Bilirubin
and bile acids concentrations for males receiving 750 mg/kg/day were
higher compared to Controls. Mean
albumin concentrations were slightly high at all dose levels in males
and in females receiving 750 mg/kg/day, a dose relationship was only
apparent in males.
in organ weights consisted of slightly lower body weight adjusted
seminal vesicles with coagulating gland and LABC weights in males
receiving 750 mg/kg/day, adjusted prostate weights were also low in
males receiving 330 or 750 mg/kg/day. In
males, at all dose levels slightly high body weight adjusted kidney
weights were seen. Slightly
high body weight adjusted liver weights were evident amongst males at
330 or 750 mg/kg/day and in females given 330 mg/kg/day. In
addition, group mean adjusted thymus weights were moderately high for
females given 100, 330 or 750 mg/kg/day.
examination of the adult males and females revealed abnormally pale
colouration of the livers in all males given 750 mg/kg/day, abnormally
pale areas in the lungs of four males and six females given
750 mg/kg/day and two females receiving 330 mg/kg/day. Thickening
of the non-glandular region of the stomach was also observed in two
females receiving 750 mg/kg/day and one male receiving 330 mg/kg/day.
evaluation of retained tissues revealed treatment related changes in the
kidneys, lungs, stomach, mammary gland and liver. In
the kidneys, vacuolation of the tubular epithelium was present in all
males given 750 mg/kg/day and there was single cell necrosis of the
tubular epithelium in three females given 330 mg/kg/day and all females
given 750 mg/kg/day. Minimal
to slight alveolar macrophage aggregates were distributed at the
terminal bronchioles and/or perivascular within the subpleural region
affecting all males and females given 750 mg/kg/day and in four females
and two males receiving 330 mg/kg/day. This
was accompanied by acicular
clefting and neutrophilic infiltrate and associated type 2
epithelialisation (particularly for females at750
and/or hyperkeratosis were present in the mucosa of the non-glandular
region of the stomach affecting a single male and female given
750 mg/kg/day and this was accompanied by minimal single erosion of the
non-glandular mucosa at the limiting ridge in the male given
750 mg/kg/day; this was associated with gross thickening in some animals. The
mammary tissue showed decreased secretory activity in four females
receiving 750 mg/kg/day and one female given 330 mg/kg/day. Minimal
to slight increase of rarefaction was present in the liver of all males
given 330 or 750 mg/kg/day and the majority of females given
750 mg/kg/day and two females given 330 mg/kg/day. Centrilobular
hypertrophy was observed in one male and in two females dosed with
There was no effect of treatment on the
circulating levels of thyroxine (T4) in adult males or in the Day 13
male and female offspring.
Based on the results of this study it was
concluded that the No Observed Adverse Effect Level (NOAEL) for general
systemic toxicity was 100 mg/kg/day due to the histopathological changes
in the kidneys and lungs.
Adverse findings included minimal increases
of single cell necrosis of the tubular epithelium in females given 330
or 750 mg/kg/day and alveolar macrophages at the bronchioloalveolar
junction with the associated inflammatory cell infiltrates of
polymorphonuclear cells, acicular clefting and type 2 epithelialisation
was observed in females and one male given 750 mg/kg/day.
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