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Key value for chemical safety assessment

Effects on fertility

Description of key information

There are no reproductive toxicity data on 3-chloropropyl(dimethoxy)methylsilane or its hydrolysis product, 3-chloropropyl(methyl)silanediol.

Reliable data for the related substance 3-chloropropyl(trimethoxy)silane (CAS 2530-87-2) have been used to assess the reproductive toxicity of 3-chloropropyl(dimethoxy)methylsilane to allow interim risk characterisation.

3-Chloropropyl(trimethoxy)silane was tested in an inhalation study conducted according to OECD 422 and in compliance with GLP (RCC Ltd., 2005), up to and including the highest concentration of 100 ppm. In this study there were no signs of adverse effects on reproduction. Therefore, based on these results the NOAEC was established to be at least 100 ppm (813 mg/m3). In addition, the OECD 413 test on 3-chloropropyltrimethoxysilane did not reveal any adverse findings relating to the reproductive organs. Therefore, reproductive toxicity testing is not triggered for the registered substance.

This conclusion will be re-evaluated if the testing proposal for an OECD 408 test on the registered substance is approved by ECHA.

Link to relevant study records
Reference
Endpoint:
one-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Rats were obtained from Charles River Deutschland GmbH
Animals were a minimum of 8 weeks of age at delivery. Males were 309-377 grams and females were 204-248 grams. Animals were acclimated for 7 days prior to treatment, under test conditions with an evaluation of the health status. Animals rooms were air conditioned with 10-15 air changes per hour; the environment was monitored continously with recordings of temperature and relative humidity, 12 hours artificial fluorescent light/12 hours dark with background music played at a centrally defined low volume for at least 8 hours during the light period. Animals were housed in Makrolon (R) cages with wire mesh tops and standard granulated softwood bedding. Pelleted standard rat/mouse maintenance diet was available ad libitum. Tap water from Fullinsdorf in bottles was available ad libitum.
Route of administration:
inhalation
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
The vapor generation system consisted of a round bottomed flask that was placed in a heating device set at 30 °C. Compressed air was
supplied into the glass flasks and allowed the liquid test item to equilibrate with the temperature of the walls of the container. The vapor
produced passed through a pipe and was then mixed and diluted with filtered air and conveyed to the inlet of the whole-body exposure
chamber. After set-up of the definitive generation system the chamber concentration and stability of CPTMO over the duration of 6 hours
was determined on two occasions prior to the start of the animal exposures.
Details on mating procedure:
During the pairing period, rats were housed overnight with one male and one female in Makrolon pairing cages. The female was placed with the same male until mating occurred or two weeks elapsed.
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
The nominal atmosphere concentration was determined once daily by weighing the test item container before and after each exposure.
The weight of the test item used was divided by the total air flow volume to give the nominal concentration. The test atmosphere
concentration in each chamber was determined daily, 5 times per hour per chamber during each hour of exposure.
Duration of treatment / exposure:
Exposure period: 28 days Premating exposure period (males): 14 days Premating exposure period (females): 14 days Duration of test: until the individual day 19 post coitum

3-chloropropyl(trimethoxy)silane was administered for 6 hours daily by  whole-body vapour inhalation to male rats for 28 days and to female rats  throughout the 14-day pre-pairing, pairing and gestation period until the  individual day 19 post coitum. 
Frequency of treatment:
daily
Details on study schedule:
Premating exposure period (males): 14 days
Premating exposure period (females): 14 days
Duration of test: until the individual day 19 post coitum

3-chloropropyl(trimethoxy)silane was administered for 6 hours daily by  whole-body vapour inhalation to male rats for 28 days and to female rats  throughout the 14-day pre-pairing, pairing and gestation period until the  individual day 19 post coitum. 
Dose / conc.:
5 ppm (nominal)
Dose / conc.:
25 ppm (nominal)
Dose / conc.:
100 ppm (nominal)
No. of animals per sex per dose:
10/sex/dose
Control animals:
yes, concurrent no treatment
Details on study design:
The animals were exposed to the following mean test item concentrations:
Group 1: 0 ppm (air control)
Group 2: 5 ppm
Group 3: 25 ppm
Group 4: 100 ppm
Control animals were exposed to air only under the same conditions as animals exposed to the test item.
P generation males were sacrificed after they had been treated for 28 days, P generation females and pups were sacrificed on day 4 post partum.
Parental animals: Observations and examinations:
Animals were observed twice daily for mortalities and clinical signs. Detailed clinical observations were performed once per week. A Functional Observational battery (modified Irwin screen test) was performed once during the test (males: shortly before sacrifice; females: on day 3 post-partum). Body weights and food consumption was recorded.
Litter observations:
The litters were examined for litter size, live birth, stillbirth and any gross anomalies. The sex ratio of the pups were recorded. Pups were weighed individually on day 0, 1 and 4 post partum. The pups were observed daily for survival and behavioral abnormalities in nesting and nursing. Dead pups and pups killed on day 4 post partum were examined macroscopically.
Postmortem examinations (parental animals):
Parental generation males were sacrificed after they had been treated for  28 days, parental generation females were sacrificed on day 4  post partum.
A complete gross necropsy was performed on all adult animals.
ORGAN WEIGHTS From all adult males and females the following organs were taken, trimmed and weighed: liver, heart, adrenals*, overies*,
thymus, uterus, kidneys*, testes*, spleen, epididymides*, seminal vesicles, with coagulating glands and their fluids(as one unit), lungs, prostate,
brain * = paired weights
TISSUE PRESERVATION The following tissues were collected from all adult males and females and preserved in neutral phosphate buffered
4% formaldehyde solution (except for testes and epididymides, which were fixed in Bouin's fixative): gross lesions, uterus, heart, brain,
thymus, spinal cord, thyroid, small and large intestines (incl. Peyers Patches), trachea and lungs (preserved by inflation with fixative and then
immersion), stomach, urinary bladder, liver, lymph nodes (mediastinal and mesenteric), kidneys, sciatic nerve, adrenals, bone marrow, spleen,
testes, ovaries, epididymides, uterus, prostate, seminal vesicles with coagulation glands
Full histopathology was carried out on the preserved organs and tissues of the control and high dose group animals.Examinations were extended to lower dose group animals if treatment related changes were seen in the high dose group.
For perganant females, the number of corora lutea and the number of impantation sites were recorded. Mated females that did not deliver were sacrificed on gestation day 24-27. Histological exam of ovaries and uterus was carried out onany females that did not give birth. Microscopic exam of the reproductive organs of all infertile males was made if necessary.
Postmortem examinations (offspring):
Pups were sacrificed on day 4  post partum.The litters were examined for litter size, live birth, stillbirth and any gross anomalies.
Statistics:
Statistical Methods: Mean and standard deviation of data were calculated. Univariate one-way analysis of variance was used to assess the
significance of intergroup differences. If the variables were assumed to follow a normal distribution, the Dunnett t-test, based on a pooled variance estimate, was used for intergroup comparisons. The Steel test (rank test) was applied when the data could not be assumed to follow a normal distribution. Fisher's Exact test for 2x2 tables was applied if the variables could be dichotomized without loss of information.
Reproductive indices:
Fertlity and mating performance
Duration of gestation
Implantation rate and Post-implantation loss
Litter size at first litter check
Postnatal loss day 0 - 4 post partum
Offspring viability indices:
Abnormal findings at first litter check and during lacatation to weaning
Sex ratios
Pup weights to day 4 post partum
Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
The fertility rate was high resulting in at least 9 litters per group for  evaluation of reproduction data. At all concentrations, there were 
no  treatment-related effects on precoital time, fertility indices, mean  duration of gestation, number of implantations, post-implantation 
loss through to scheduled sacrifice on  day 4 post partum. The mean number of corpora lutea per dam (determined at necropsy) was  
similar in all groups and gave no indication of a test item-related effect. There were no findings, which distinguished test item-treated 
animals  from controls. In particular, no treatment-related histopathological  findings were observed in the reproductive organs of either 
sex from the  parental generation. The assessment of the integrity of the  spermatogenetic cycle did not provide any evidence of impaired  
spermatogenesis.
Key result
Dose descriptor:
NOAEC
Effect level:
>= 100 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed.
Critical effects observed:
no
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
At all concentrations, there were no  treatment-related effects on pup survival or litter size from birth through to scheduled sacrifice on  
day 4 post partum.

No abnormal findings were noted for pups at first litter check or during  the first 4 days post partum. Sex ratios at first litter check and on day  4 post partum were unaffected by treatment with the test item.  Mean pup weights on day 0 and day 1 post partum were unaffected by  treatment with the test item. Mean pup weight development during the  first 4 days post partum lactation was unaffected by treatment with the  test item. 
Key result
Dose descriptor:
NOAEC
Generation:
F1
Effect level:
>= 100 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed.
Critical effects observed:
no
Reproductive effects observed:
no

Exposure to 3 -chloropropyl(trimethoxy)silane up to and including the high concentration of 100 ppm did not result in any signs of

general or reproductive toxicity of the test item.

Based on these results the NOEC (no observed effect concentration) was established as >=100 ppm.

Conclusions:
Exposure to 3-Chloropropyl(trimethoxy)silane up to and including the high concentration of 100 ppm did not result in any signs of
general or reproductive toxicity of the test item. Based on these results the NOEC (no observed effect concentration) was established as >=100 ppm.
Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
813 mg/m³
Study duration:
subacute
Species:
rat
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

There are no reproductive toxicity data on 3-chloropropyl(dimethoxy)methylsilane or its hydrolysis product, 3-chloropropyl(methyl)silanediol, so reliable data for the related substance 3-chloropropyl(trimethoxy)silane (CAS 2530-87-2) have been used to assess the reproductive toxicity of 3-chloropropyl(dimethoxy)methylsilane to allow interim risk characterisation.

For read-across justification see RAAF report in Section 13 of IUCLID.

Effects on developmental toxicity

Description of key information

There are no developmental toxicity data on 3-chloropropyl(dimethoxy)methylsilane or its hydrolysis product, 3-chloropropyl(methyl)silanediol.

A prenatal developmental toxicity test according to OECD 414 is being conducted with the registered substance as requested in an ECHA final decision.

Reliable data for the related substance 3-chloropropyl(triethoxy)silane (CAS 5089 -70 -3) have been used to assess the developmental toxicity of 3-chloropropyl(dimethoxy)methylsilane to allow interim risk characterisation. The NOAEL from a reliable oral OECD 414 test on 3-chloropropyl(triethoxy)silane gave a NOAEL of 300 mg/kg bw/day for maternal and developmental toxicity (BSL, 2014).

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
Rats were obtained from Charles River Deutschland GmbH
Animals were a minimum of 8 weeks of age at delivery. Males were 309-377 grams and females were 204-248 grams. Animals were acclimated for 7 days prior to treatment, under test conditions with an evaluation of the health status. Animals rooms were air conditioned with 10-15 air changes per hour; the environment was monitored continously with recordings of temperature and relative humidity, 12 hours artificial fluorescent light/12 hours dark with background music played at a centrally defined low volume for at least 8 hours during the light period. Animals were housed in Makrolon (R) cages with wire mesh tops and standard granulated softwood bedding. Pelleted standard rat/mouse maintenance diet was available ad libitum. Tap water from Fullinsdorf in bottles was available ad libitum.

Route of administration:
inhalation
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
(3-Chloropropyl)trimethoxysilane was administered for 6 hours daily by  whole-body vapour inhalation to male rats for 28 days and to female rats  throughout the 14-day pre-pairing, pairing and gestation period until the  individual day 19 post coitum. 
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
The nominal atmosphere concentration was determined once daily by weighing the test item container before and after each exposure.
The weight of the test item used was divided by the total air flow volume to give the nominal concentration. The test atmosphere
concentration in each chamber was determined daily, 5 times per hour per chamber during each hour of exposure.
Details on mating procedure:
During the pairing period, rats were housed overnight with one male and one female in Makrolon pairing cages. The femlae was placed with the same male until mating occurred or two weeks elapsed.

Duration of treatment / exposure:
Exposure period: 28 days
Premating exposure period (males): 14 days
Premating exposure period (females): 14 days
Duration of test: until the individual day 19 post coitum

3-chloropropyl(trimethoxy)silane was administered for 6 hours daily by whole-body vapour inhalation to male rats for 28 days and to female rats throughout the 14-day pre-pairing, pairing and gestation period until the individual day 19 post coitum.
Frequency of treatment:
daily
Dose / conc.:
5 ppm (nominal)
Dose / conc.:
25 ppm (nominal)
Dose / conc.:
100 ppm (nominal)
No. of animals per sex per dose:
10/sex/dose
Control animals:
yes, concurrent no treatment
Details on study design:
The animals were exposed to the following mean test item concentrations:
Group 1: 0 ppm (air control)
Group 2: 5 ppm
Group 3: 25 ppm
Group 4: 100 ppm
Control animals were exposed to air only under the same conditions as animals exposed to the test item.
P generation males were sacrificed after they had been treated for 28 days, P generation females and pups were sacrificed on day 4 post partum.
Maternal examinations:
Animals were observed twice daily for mortalities and clinical signs. Detailed clinical observations were performed once per week. A Functional Observational battery (modified Irwin screen test) was performed once during the test (on day 3 post-partum). Body weights and food consumption was recorded.
Ovaries and uterine content:
For pregnant females, the number of corpora lutea and the number of impantation sites were recorded, mated females that did not deliver were sacrificed on gestation day 24-27. Histological exam of ovaries and uterus was carried out on any females that did not give birth.
Fetal examinations:
Pups were sacrificed on day 4 post partum.The litters were examined for litter size, live birth, stillbirth and any gross anomalies.
Statistics:
Statistical Methods: Mean and standard deviation of data were calculated. Univariate one-way analysis of variance was used to assess the
significance of intergroup differences. If the variables were assumed to follow a normal distribution, the Dunnett t-test, based on a pooled variance estimate, was used for intergroup comparisons. The Steel test (rank test) was applied when the data could not be assumed to follow a normal distribution. Fisher's Exact test for 2x2 tables was applied if the variables could be dichotomized without loss of information.
Indices:
Reproductive indices
Fertlity and mating performance
Duration of gestation
Implantation rate and Post-implantation loss
Litter size at first litter check
Postnatal loss day 0 - 4 post partum


Offspring viability indices
Abnormal findings at first litter check and during lacatation to weaning
Sex ratios
Pup weights to day 4 post partum
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
The fertility rate was high resulting in at least 9 litters per group for evaluation of reproduction data. At all concentrations, there were
no treatment-related effects on precoital time, fertility indices, mean duration of gestation, number of implantations, post-implantation
loss through to scheduled sacrifice on day 4 post partum. The mean number of corpora lutea per dam (determined at necropsy) was
similar in all groups and gave no indication of a test item-related effect. There were no findings, which distinguished test item-treated
animals from controls. In particular, no treatment-related histopathological findings were observed in the reproductive organs of either
sex from the parental generation.
Key result
Dose descriptor:
NOAEC
Effect level:
>= 100 ppm (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Abnormalities:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No abnormal findings were noted for pups at first litter check or during  the first 4 days post partum. Sex ratios at first litter check and on day  4 post partum were unaffected by treatment with the test item.  Mean pup weights on day 0 and day 1 post partum were unaffected by  treatment with the test item. Mean pup weight development during the  first 4 days post partum lactation was unaffected by treatment with the  test item. 
No test item-related findings were noted at macroscopical examination of  pups.
Key result
Dose descriptor:
NOAEC
Effect level:
>= 100 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: teratogenicity
Abnormalities:
no effects observed
Developmental effects observed:
no
Conclusions:
Exposure to (3-Chloropropyl)trimethoxysilane up to and including the high concentration of 100 ppm did not result in any signs of general or reproductive toxicity of the test item.
Based on these results the NOEC (no observed effect concentration) was established as >=100 ppm.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
813 mg/m³
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

There are no developmental toxicity data on 3-chloropropyl(dimethoxy)methylsilane or its hydrolysis product, 3-chloropropyl(methyl)silanediol, so reliable data for the related substance 3-chloropropyl(triethoxy)silane (CAS 5089 -70 -3) have been used to assess the developmental toxicity of 3-chloropropyl(dimethoxy)methylsilane to allow interim risk assessment.

Administration of 3-chloropropyl(triethoxy)silane at doses of 0, 100, 300 or 1000 mg/kg bw/day by oral gavage to pregnant female Wistar rats from gestation days 5 to 19 resulted in lower body weight, body weight gain and food consumption at 1000 mg/kg bw/day and were considered to be adverse. Lower terminal body weight, uterus weight and mean total litter weight were also noted at this dose. Increased incidences of skeletal findings such as delayed ossification and lower litter weight recorded at 1000 mg/kg bw/day were considered to be attributable to the maternal effects and not adverse. An increased incidence of wavy ribs and bent scapula was also noted at this dose and these findings are recognised as part of chondrodystrophy syndrome in rats and have been demonstrated to be post-natally reversible and therefore also not adverse. However, the increased incidence of skeletal variations noted together with the lower litter weight was considered to be adverse at 1000 mg/kg bw/day. Therefore, the maternal and foetal NOAEL were both considered to be 300 mg/kg bw/day.

3-Chloropropyl(trimethoxy)silane (CAS 2530 -87 -2) was tested in an inhalation study conducted according to OECD 422 and in compliance with GLP (RCC Ltd., 2005), up to and including the highest concentration of 100 ppm. In this study there were no signs of adverse effects on development of pups. Therefore, based on these results the NOAEC was established to be at least 100 ppm (813 mg/m3).

For read-across justification see RAAF report in Section 13 of IUCLID.

Justification for classification or non-classification

Based on the available read across data 3-chloropropyl(dimethoxy)methylsilane is not classified for reproductive or developmental toxicity according to Regulation (EC) No 1272/2008.