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EC number: 221-336-6
CAS number: 3069-29-2
are no reproductive toxicity data on
N-(3-dimethoxymethylsilyl)propyl)ethylenediamine (CAS No. 3069-29-2, EC
No. 221-336-6) or its hydrolysis product,
N-[3-(dihydroxymethylsilyl)propyl]ethylenediamine (CAS / EC Nos. not
are no reproductive toxicity data on
N-(3-dimethoxymethylsilyl)propyl)ethylenediamine or its hydrolysis
product, N-[3-(dihydroxymethylsilyl)propyl]ethylenediamine. Reliable
data for the related substance
N-(3-(trimethoxysilyl)propyl)ethylenediamine are used as supporting
information only to support the read-across justification for the
genetic toxicity endpoint using this analogue substance.
has been evaluated in an oral combined repeated dose toxicity study with
the reproduction / developmental toxicity screening test, conducted
according to OECD Test Guideline 422 and in compliance with GLP (Dow
Corning Corporation, 2002, reliability score 1).
were three unscheduled deaths during the conduct of the study. None of
the unscheduled deaths were attributed to the test substance. Clinical
findings attributed to test substance included clear perioral soiling in
several high dose animals and either increased nasal sounds, laboured
respiration, or soft vocalizations in approximately half of the high
dose females and one high dose male. These signs were not seen in the
control animals and infrequently seen in either of the two lower dose
groups. Observations recorded at dosing indicated a dose-related
resistance to dosing. Evaluating all 30 animals/dose (males, female
toxicity and female reproductive groups) over the entire dosing period,
the incidence of resistance was 3, 5, 27 and 62 for the controls, 25,
125 and 500 mg/kg bw/day dose groups, respectively. Similar incidence
patterns were noted for salivation just prior to dosing, wetness around
the mouth at dosing, and wetness around the mouth 5-30 minutes following
dosing. There were no test substance-related effects on body weight or
food consumption for any of the dose groups. No test substance-related
changes on FOB and motor activity parameters were observed in the male
and female toxicity animals evaluated. There were no test
substance-related changes in haematology and serum chemistry parameters
for these animals. No test substance-related effects were observed at
the macroscopic examinations for any of the animals (males, females
toxicity, female reproductive or the pups). There were no effects on
mean organ weights or organ to body weight ratios attributable to the
test substance for the selected organs evaluated (adrenal glands, brain,
heart, kidneys, liver, spleen, thymus, uterus, ovaries, testes,
epididymides, prostate, and seminal vesicles) in the male and toxicity
thorough histopathological examination performed on all gross lesions,
selected tissues and organs for control and high dose toxicity group
animals demonstrated no microscopic findings directly attributable to
test substance treatment. No test substance-related effects were
observed in any of the reproductive parameters evaluated. Two high dose
(500 mg/kg bw/day) and one low dose (25 mg/kg bw/day) reproductive group
females that did not produce litters had positive evidence of
copulation. Six of the eight surviving high dose reproductive group
females produced litters that were similar in all respects to control
systemic was observed in this study and therefore the NOAEL for
N-(3-(trimethoxysilyl)propyl)ethylenediamine was concluded to be greater
than or equal to 500 mg/kg bw/day. The reproductive NOAEL would likewise
be greater than or equal to 500 mg/kg bw/day, based on the absence of
effects on reproductive parameters or organs.
a study conducted according to OECD Test Guideline 414 and in compliance
with GLP (BSL Bioservice Scientific Laboratories, 2021, reliability
score 1), pregnant Wistar Han rats were administered
N-[3-(dimethoxymethylsilyl)propyl]ethylenediamine (CAS No. 3069-29-2, EC
No. 221-336-6) at 0, 100, 600, and 750/1000 mg/kg bw/day via oral gavage
(dried and deacidified corn oil vehicle) during days 5 through 19 of
gestation. The maternal systemic NOAEL was 100 mg/kg bw/day, based on
test item-related adverse findings (mortality, clinical signs, decreased
body weight gain / food consumption, and gross pathology) at 600 and/or
750/1000 mg/kg bw/day. No effects were observed on mating or maternal
prenatal parameters. The developmental NOAEL was identified as 750 mg/kg
bw/day based on the absence of test item-related foetal effects up to
750/1000 mg/kg bw/day.
maternal endpoints with test
a summary results table will be provided upon completion of the final
OECD Test Guideline 414 study report.
was evaluated in a study conducted according to OECD Test Guideline 414
and in compliance with GLP (BSL Bioservice Scientific Laboratories,
2021, reliability score 1). Pregnant Wistar Han rats were administered
the test item at 0, 100 (LD), 600 (MD), and 750/1000 (HD) mg/kg bw/day
via oral gavage (dried and deacidified corn oil vehicle) during days 5
through 19 of gestation. During the study, the HD was reduced from 1000
to 750 mg/kg bw/day due to severe clinical signs and subsequent
morbidity. Observations and examinations were conducted per OECD Test
Guideline 414. Maternal systemic parameters included mortality, clinical
observations, body weight, food consumption, gross pathology, and
thyroid/parathyroid endpoints (serum T3, T4, and TSH levels, organ
weight, and histopathology). Uterine examination consisted of pregnancy
status and, for pregnant females, gravid uterine weight, numbers of
corpora lutea, pre- and post-implantations, early and late resorptions,
and live and dead foetuses. In addition, foetal / litter weight, sex and
sex ratios, anogenital distance (AGD) and, in male foetuses, testicular
descent were determined. Detailed foetal examinations included external,
visceral, craniofacial, and skeletal.
the maternal animals, no effects on the thyroid endpoints (serum T3, T4,
and TSH levels, organ weight, and histopathology), mating, or the
prenatal (uterine) parameters were observed up to the HD. As discussed
below, several systemic effects (maternal mortality, clinical signs,
decreased body weight gain / food consumption, and gross pathology) were
considered test item-related and adverse.
to reducing the HD, one MD animal and four HD animals were moribund
sacrificed. After reducing the HD from 1000 to 750 mg/kg bw/day, no
mortality was observed during the study and all other animals survived
until the end of the study.
item-related adverse clinical signs were observed in all animals at the
MD and HD, with the severity of signs occurring in a dose-dependent
manner. The predominant clinical signs these groups included: increased
salivation (slight, moderate/severe; MD-10/23, HD-20/26), moving the
bedding (MD-21/23, HD-25/26), abnormal breathing (MD-6/23, HD-11/26),
piloerection (MD-3/23, HD-7/26), and spontaneous reduced activity
(slight/moderate/severe; MD-2/23, HD-2/26). No test item-related
clinical signs were observed at the LD.
item-related adverse slight decrease in mean body weight gain on GDs
5-20 (9.52% below control) and food consumption on GDs 5-20 (7.77% below
control) were observed at the HD, but without statistical significance
for body weight gain. No test item-related effect on mean body weight
gain and food consumption was observed at the LD or MD when compared to
the control group. No test item-related effect was identified for mean
body weight at any dose.
item-related adverse macroscopic lesions were observed in moribund
sacrificed animals of the MD group (one animal) and HD group (four
animals). These findings were primarily related to the gastrointestinal
tract (gas-filled stomach, duodenum, jejunum, ileum and/or caecum in the
MD animal and three of the HD animals; red foci in the stomach and
stomach glandular mucosa in one HD animal). In addition, one HD animal
had an enlarged thymus and enlarged hindlimb, while another HD animal
had a small thymus. The macroscopic findings seen in the
gastrointestinal tract were most likely due to the irritating properties
of the test item and, hence, considered test item-related and adverse.
No test item-related macroscopic lesions were observed in the LD group.
the foetuses, no test item-related effects were observed for the foetal
parameters (foetal / litter weight, sex ratios, AGD, testicular descent)
up to the HD. Test item-related effects also were not identified based
on the detailed foetal external, skeletal, visceral, and craniofacial
examinations. The latter are briefly discussed below.
were no external findings observed in any of the foetuses of test
item-treated groups or the control group.
the visceral exam, a range of findings were observed in the treated
groups and the control group. Visceral findings observed in the treated
groups were at frequencies generally comparable to or in some cases
slightly higher or lower in frequency compared to the control group.
Higher litter incidences were observed for umbilical artery,
malpositioned (76.2% in LD compared to 63.2% in the control group) and
abdomen internal haemorrhage (66.7%, 68.2% and 78.9% in the LD, MD and
HD groups, respectively, compared to 63.2% in the control group). As the
observed findings were either minor variations and/or lacked dose
dependency, they were considered spontaneous in nature and unrelated to
test item treatment. All litter incidences from the treated groups were
statistically insignificant when compared to the control group, and well
within the historical control range.
craniofacial exam, midbrain, haematoma, subdural was observed in the MD
and HD groups (13.6% and 10.5%, respectively) and control group (21.1%).
However, this finding was considered spontaneous in nature and not
related test item treatment. Statistical analysis revealed no
statistical significance for any of the findings in the treated groups,
and all values were within the historical control range.
examination revealed a range of findings in all groups including the
control group. Observed ossification-related findings in the treated
groups were observed at lower or higher incidences when compared to the
control group. At gestation day 20, incomplete ossification was seen in
several bones of litters in all treated groups and the control group.
Mostly, bones of the skull, sternum, paws, limbs and vertebra were
affected by variations in ossification, described as incomplete
ossification, irregular ossification, unossified or increased
ossification, throughout all experimental groups. However, no dose
dependency and no trend towards a treatment-related ossification effect
were observed. With one exception, statistical analysis revealed no
statistical significance for any of the ossification findings. A slight
but statistically significant lower foetal incidence of skull frontal,
incomplete ossification was seen in the LD, MD and HD groups (0%) when
compared to the control group (2.14%) but this finding was considered
incidental in nature and not a test item-related effect. There were
slightly higher or lower litter incidences of other skeletal findings in
the treated groups, but they did not show any dose dependency or
statistical significance and were not considered related to test item
summary, the maternal systemic NOAEL for
N-[3-(dimethoxymethylsilyl)propyl]ethylenediamine in the Wistar Han rat
was identified as 100 mg/kg bw/day, based on systemic findings
considered to be test item-related and adverse (mortality, clinical
signs, decreased body weight gain / food consumption, and gross
pathology) at 600 and/or 750/1000 mg/kg bw/day. No effects were observed
on mating or maternal prenatal parameters. The developmental NOAEL was
identified as 750 mg/kg bw/day based on the absence of test item-related
foetal effects up to 750/1000 mg/kg bw/day.
a developmental toxicity range finding study conducted in compliance
with GLP (BSL Bioservice Scientific Laboratories, 2020, reliability
score 2), Wistar Han rats were administered
N-[3-(dimethoxymethylsilyl)propyl]ethylenediamine at 0, 100, 600, and
1000 mg/kg bw/day via oral gavage (dried and de-acidified corn oil
vehicle) on gestation days 5-19. Maternal endpoints assessed included:
mortality, clinical observation, body weight, food consumption, gross
pathology, and reproductive parameters (pregnancy status and uterine
content). Foetal evaluations included: body weight, sex, and detailed
external exam. No signs of systemic toxicity up to 1000 mg/kg bw/day
(HD) were found in the females. There may have been a slight local
effect of the test item at the HD leading to increased appearance of
clinical signs like increased salivation and moving the bedding.
However, these reactions of the animals could also be attributed to
general discomfort directly after test item administration. No signs of
foetal toxicity were seen based on the prenatal data or external
examination findings up to the HD. Thus,
the maternal / developmental NOAELs are considered to be 1000 mg/kg
findings were used for the initial dose selection (0, 100, 600, and 1000
mg/kg bw/day) for the main developmental toxicity study.
supporting developmental toxicity test for the analogue substance
N-(3-(trimethoxysilyl)propyl)ethylenediamine (CAS No. 1760-24-3, EC No.
217-164-6) is included only to support the read-across justification for
the genetic toxicity endpoint currently using this analogue substance.
prenatal developmental toxicity study conducted with the analogue
according to OECD Test Guideline 414 and
in compliance with GLP (Charles River, 2016, reliability score 1), the
substance was administered orally by gavage to bred Crl:CD(SD) rats. No
evidence of maternal or developmental toxicity was noted at 100, 500, or
750 mg/kg bw/day. Test substance-related effects were limited to
increased incidences of rales, clear material around the mouth, and/or
salivation prior to dosing at 500 and 750 mg/kg bw/day. However, in the
absence of any other signs of maternal toxicity at these dosage levels,
the clinical observations were not considered to be adverse. Based on
these results, a dosage level of 750 mg/kg bw/day, the highest dose
tested, was considered the NOAEL for maternal toxicity and embryo/foetal
Based on the reliable data available,
N-[3-(dimethoxymethylsilyl)propyl]ethylenediamine is not classified for
effects on reproduction and development according to Regulation (EC) No.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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