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EC number: 924-669-1
CAS number: -
combined repeated dose toxicity study with the
reproduction/developmental toxicity screening test according to OECD TG
422 was performed to obtain initial information on the toxic potential
of Reaction product of Hexamethylene diisocyanate, oligomers with
Mercaptopropyltrimethoxysilane and its possible effects on male and
female reproductive performance such as gonadal function, mating
behavior, conception, pregnancy, parturition as well as development of
the F1 offspring from conception to day 13 post- partum when repeatedly
administered orally (by gavage) to parental animals at doses of 30 mg/kg
bw/day, 100 mg/kg bw/day and 300 mg/kg bw/day compared to control
animals. Four groups of Han:WIST rats (n=12/sex/group) were administered
with the test item orally (by gavage) once a day at 0 (vehicle), 30, 100
and 300 mg/kg bw/day doses corresponding to concentrations of 0, 6, 20
and 60 mg/mL. The application volume was 5 mL/kg bw. Control animals
received the vehicle, Polyethylene glycol 400 (PEG 400). The suitability
of the vehicle at the intended concentrations of the test item was
analytically verified up front. The concentration of the test item in
the dosing formulations was checked two times during the study. Reaction
product of Hexamethylene diisocyanate, oligomers with
Mercaptopropyltrimethoxysilane concentrations in the dosing formulations
varied in the acceptable range between 101 % and 109 % of the nominal
values confirming the proper dosing. All animals of the parent (P)
generation were dosed prior to mating (14 days) and throughout mating.
In addition, males received the test item or vehicle after mating up to
the day before the necropsy (altogether for 50 days). Females were
additionally exposed through the gestation period and up to lactation
days 12-16 (altogether for 50-55 days). Observations included mortality,
clinical signs, body weight, food consumption, mating, pregnancy and
delivery process, as well as development of offspring. Five dams and the
male mating partners were randomly selected from each group to examine
further signs of toxicity such as functional observations, hematology,
clinical chemistry, gross necropsy, organ weighing and histopathology.
Estrous cycle was monitored by examining vaginal smears before the
treatment for two weeks and for two weeks from the beginning of the
treatment period (two weeks pre-mating period) and during the mating
period until evidence of mating. The dams were allowed to litter, and
rear their offspring up to day 13 postpartum. Litters were weighed and
offspring were observed for possible abnormalities and were euthanized
on post-natal day 13 or shortly thereafter. Blood samples were collected
for possible determination of serum levels of thyroid hormones (T4, TSH)
from at least two pups per litter (where it was feasible) on post-natal
day 4, from all dams and at least two pups per litter at termination on
post-partum/post-natal day 13 and from all parent male animals at
parental animals were subjected to gross pathology one day after the
last treatment. The body weight, brain weight, weight of the testes,
epididymides and prostate and seminal vesicles with coagulating glands
as a whole of all adult male animals were determined. Histopathology
examination was performed on reproductive organs (testes, epididymides,
uterus and ovaries) in the control and high dose groups. Additionally,
full histopathology was performed on the organs and tissues of parental
animals (male and female) selected for general toxicological
examinations in the control and high dose groups. Based on macroscopic
and histopathology findings at 300 mg/kg bw/day, pancreas of selected
animals administered with 30 and 100 mg/kg bw/day doses were also
processed and examined histologically. In addition, organs showing
macroscopic findings at necropsy were also processed and examined
histologically in single animals at 100 mg/kg bw/day (kidneys, pancreas
and seminal vesicle and uterus). The results were interpreted comparing
treatment groups with respect to controls, which were treated
concurrently with vehicle (PEG 400) only. Historical control data were
was no mortality at 30, 100 or 300 mg/kg bw/day groups during the course
clinical signs of systemic toxicity related to the test item were not
detected at any dose level at the daily or detailed weekly clinical
observations or at the terminal functional observations. The behavior
and physical condition of animals was not affected by the test item at
any dose level (30, 100 or 300 mg/kg bw/day) during the entire
observation period. Soft stool was detected in the bedding material in
each cage of male and female animals of control, 30, 100 and 300 mg/kg
weight and body weight gain
item related adverse changes in the body weight or body weight gain were
not detected. The body weight development was not disturbed and it was
comparable in the control and test item treated groups.
mean daily food consumption was not affected by the test item in male or
female animals at 30, 100 and 300 mg/kg bw/day during the entire study
(pre-mating, post-mating, gestation and lactation periods).
test item influence on the estrous cycle was not found at any dose level
(30, 100 and 300 mg/kg bw/day).
were no test item related differences between the control and test item
treated groups in the reproductive performance of male and female
data of dams
were no toxicologically relevant differences between the control and
test item treated groups (30, 100 and 300 mg/kg bw/day) in the evaluated
delivery parameters of dams.
were no test item related adverse changes in the examined hematological
parameters in male or female animals at 30, 100 or 300 mg/kg bw/day.
alterations related to test item effect were not detected in the
examined clinical chemistry parameters at any dose level (male or
female; 30, 100 or 300 mg/kg bw/day).
were no test item related changes in the serum thyroid hormone (T4, TSH)
levels at any dose (parental male animals or PN13 offspring).
macroscopic alterations related to the effect of the test item were not
found in the reproductive organs of male or female animals at 30, 100 or
300 mg/kg bw/day at the necropsy. Enlargement or paleness of pancreas
was observed at 100 and 300 mg/kg bw/day in male animals in accordance
with histopathological findings.
were no test item related adverse changes in the weights (absolute and
relative to body or brain weights) of selected organs in the animals at
any dose level.
examinations of the investigated reproductive organs (ovaries, uterus,
vagina, testes, epididymides, prostate and seminal vesicles with
coagulating gland) did not reveal any test item related changes at 300
mg/kg bw/day. Increased amount of zymogen granules and flattened and
basophilic acinar cells were observed in the pancreas in 1/1 male animal
at 100 mg/kg bw/day and in 5/5 male and 3/5 female animals at 300 mg/kg
bw/day. The cytomorphology of pancreas was normal in the selected
animals of the low and mid dose groups. These findings might be
indicative of a disorder in synthesis and secretion of the digestive
enzymes and are associated with test item treatment.
offspring’s development was not adversely influenced at any dose level.
the conditions of the present study, Reaction product of Hexamethylene
diisocyanate, oligomers with Mercaptopropyl- trimethoxysilane did not
adversely influence the fertility or reproductive performance (gonad
function, mating behavior, conception, parturition) in parental male and
female Han:WIST rats at 30, 100 and 300 mg/kg bw/day doses administered
by oral gavage. 300 mg/kg bw/day induced pancreatic changes: enlargement
and pale color in male animals, increased amount of zymogen granules and
flattened and basophilic acinar cells in male and female animals. The
morphological change in the pancreas was considered test item related
but its toxicological significance is equivocal because no related
changes were detected in any of the examined parameters. Since neither
inflammation, necrosis or apoptosis were observed nor an increase in
severity over time compared to the 14 day-Dose Range-Finder study,
reversibility of these exocrine pancreatic observations can be
considered as very likely. The endocrine pancreas was not affected and
cytomorphology of Langerhans-islets was normal in all cases. At 100
mg/kg bw/day, pancreatic changes (increased amount of zymogen granules
and flattened and basophilic acinar cells) were observed in only one
male animal. In
conclusion, all observations in the pancreas are interpreted as
were no test item related changes in other animals administered with 100
mg/kg bw/day. There were no test item related changes in animals
administered with 30 mg/kg bw/day.
development of the F1 offspring was not impaired at any dose level from
birth to post-natal day 13 after repeated oral administration of dams.
The NOAEL for systemic toxicity of male/female rats was 300 mg/kg
bw/day, the NOAEL for reproductive performance of male/female rats was
300 mg/kg bw/day and the NOAEL for F1 Offspring was 300 mg/kg bw/day,
the highest dose tested.
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