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Key value for chemical safety assessment

Effects on fertility

Description of key information

(3-Chloropropyl)trimethoxysilane was tested in a combined repeated dose toxicity study with the reproduction / developmental toxicity screening test) via the inhalation route of exposure, conducted according to OECD Test Guideline 422 and in compliance with GLP (RCC, 2005). The NOAEC for reproduction toxicity was considered to be at least 100 ppm (813 mg/m3) based on no reproductive toxicity observed at the highest concentration tested.

Link to relevant study records
Reference
Endpoint:
one-generation reproductive 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
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 or test system 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 vapour 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 vapour 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)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. 
Frequency of treatment:
daily
Details on study schedule:
Premating exposure period (males): 14 days
Premating exposure period (females): 14 days
Duration of test: until day 19 post coitum

(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 day 19 post coitum. 
Dose / conc.:
0 ppm (nominal)
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:
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 was recorded. Pups were weighed individually on day 0, 1 and 4 post partum. The pups were observed daily for survival and behavioural 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*, ovaries*,
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 pregnant females, the number of corpora lutea and the number of implantation 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. 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:
Fertility 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 lactation to weaning
Sex ratios
Pup weights to day 4 post partum
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
not specified
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
In particular, no treatment-related histopathological  findings were observed in the reproductive organs of either sex from the parental generation. 
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
The assessment of the integrity of the  spermatogenetic cycle did not provide any evidence of impaired spermatogenesis.
Reproductive performance:
no effects observed
Description (incidence and severity):
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.
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
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not examined
Anogenital distance (AGD):
not specified
Nipple retention in male pups:
not specified
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
Other effects:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
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)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.

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 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
Quality of whole database:
Klimisch 1 score
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

The OECD 422 study is the only study available for the reproductive toxicity endpoint.

(3-Chloropropyl)trimethoxysilane was tested in a combined repeated dose toxicity study with the reproduction / developmental toxicity screening test) via the inhalation route of exposure, conducted according to OECD Test Guideline 422 and in compliance with GLP (RCC, 2005). In the study rats were treated with the test substance via whole-body inhalation exposure up to and including the highest concentration of 100 ppm. No adverse effects on reproduction were observed. Based on the results the NOAEC for reproduction was concluded to be at least 100 ppm (813 mg/m3), the highest concentration tested.

Effects on developmental toxicity

Description of key information

(3-Chloropropyl)trimethoxysilane was tested in a combined repeated dose toxicity study with the reproduction / developmental toxicity screening test) via the inhalation route of exposure, conducted according to OECD Test Guideline 422 and in compliance with GLP (RCC, 2005).  The NOAEC for developmental toxicity was concluded to be at least 100 ppm (813 mg/m3) based on no effects at the highest concentration tested.

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
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 or test system 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 female 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 day 19 post coitum

(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 day 19 post coitum.
Frequency of treatment:
daily
Dose / conc.:
0 ppm
Remarks:
air control
Dose / conc.:
5 ppm
Dose / conc.:
25 ppm
Dose / conc.:
100 ppm
No. of animals per sex per dose:
10/sex/dose
Control animals:
yes, concurrent no treatment
Details on study design:
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 implantation 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.
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
One male animal had eyes with crust during all detailed weekly clinical observations, one female had a mass i the right hip/flank region from day 6 of the pre-pairing period until day 4 of lactation.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One animal was found dead, however, in the histopathological examination, this dead depended on myeloid leukaemia.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
A tendency towards slightly higher food consumption in the groups exposed to the test item. This higher food consumption was considered to be incidental and of no toxicological relevance.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
A marginally, however, statistically significant lower absolute heart weight was noted. Nevertheless, this was not statistically significantly decreased and not considered of toxicological relevance. Mean uterus weight was marginally, however, statistically significantly lower in groups 2 and 4 than in the vehicle control.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Enlarged liver, renal pelvic dilation, testes and epididymides reduced in size, spleen enlarged and discoloured mediastinal lymph node(s). However, this was not related to the test-item.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
not examined
Number of abortions:
not specified
Pre- and post-implantation loss:
effects observed, non-treatment-related
Description (incidence and severity):
In one of the dose groups, an incidentally although statistically significant lower incidence of post-implantation loss was noted.
Total litter losses by resorption:
effects observed, non-treatment-related
Description (incidence and severity):
Due to the incidentally lower incidence of post-implantation loss the mean number of live pups per litter was statistically significantly higher in group 2 than in the vehicle control.
Early or late resorptions:
not specified
Dead fetuses:
not specified
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
not specified
Other effects:
not examined
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.
Key result
Dose descriptor:
NOAEC
Effect level:
>= 100 ppm (nominal)
Based on:
test mat.
Basis for effect level:
other: No adverse effects observed
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
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. 
Reduction in number of live offspring:
not specified
Changes in sex ratio:
no effects observed
Description (incidence and severity):
Sex ratios at first litter check and on day 4 post partum were unaffected by treatment with the test item.
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
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. 
Changes in postnatal survival:
not specified
External malformations:
no effects observed
Description (incidence and severity):
No abnormal findings were noted for pups at first litter check or during the first 4 days post partum. No test item-related findings were noted at macroscopical examination of pups.
Skeletal malformations:
no effects observed
Description (incidence and severity):
No abnormal findings were noted for pups at first litter check or during the first 4 days post partum. No test item-related findings were noted at macroscopical examination of pups.
Visceral malformations:
no effects observed
Description (incidence and severity):
No abnormal findings were noted for pups at first litter check or during the first 4 days post partum. No test item-related findings were noted at macroscopical examination of pups.
Other effects:
not examined
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
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:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
813 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
Klimisch 1 score
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

The OECD 422 study is the only study available for the developmental toxicity endpoint.

(3-Chloropropyl)trimethoxysilane was tested in a combined repeated dose toxicity study with the reproduction / developmental toxicity screening test) via the inhalation route of exposure, conducted according to OECD Test Guideline 422 and in compliance with GLP (RCC, 2005). In the study rats were treated with the test substance via whole-body inhalation exposure up to and including the highest concentration of 100 ppm. No adverse effects on development were reported. Based on the results the developmental NOAEC was concluded to be at least 100 ppm (813 mg/m3), the highest concentration tested.

Justification for classification or non-classification

Based on the available information, (3-chloropropyl)trimethoxysilane is not classified for reproductive and developmental toxicity according to Regulation (EC) No 1272/2008.

Additional information

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