Registration Dossier

Administrative data

Description of key information

In the key 90-day repeated dose toxicity study via the inhalation route  (Dow Corning Corporation, 1993) in rats, conducted according to OECD Test Guideline 413 and in compliance with GLP, the systemic NOAEC was determined to be 100 ppm (813 mg/m3) and the local NOAEC was determined to be ≥ 100 ppm (813 mg/m3).

(3-Chloropropyl)trimethoxysilane has also been 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), a NOAEC was established to be at least 100 ppm (813 mg/m3) based on no observed toxicity.

There are no data for the oral and dermal routes.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1993
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
Male and female rats weighing approximately 155-200 grams; age at study initiation: 6-8 weeks. Animals were quarantined for one week prior to initiation of the study. Animals were housed individually in suspended stainless steel, wire mesh bottomed cages. Before each exposure, animals were transferred into cages designed to be placed within the exposure chambers. After each exposure, the animals were returned to their original housing. The animals were fed Purina Certified Rodent Chow and water ad Iibitum except during exposures. The rats were housed during non-exposure periode in a room designed to be maintained at 22 +/- 3 °C temperature and 30-70% relative humidity. A light cycle of alternating 12 hours light and 12 hours dark was maintained.
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
Exposures were conducted in 2 m3 stainless steel whole body exposure chambers. Exposure cage racks were rotated top to bottom and front to back on a weekly basis. All groups were treated concurrently 5 days a week for thirteen weeks. The duration of each exposure period was six hours after equilibration of the chamber concentration. The equilibration tlme, which is a function of chamber air flow, was approximately 25 minutes.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The amount of test material used during the exposure period was determined by pre- and post- measuring the weight of the test material in each syringe or graduated cylinder reservoir. The exposure duration (exposure period and equilibration time), test material used and airflow through the chambers were then used to calculate nominal concentrations.
Actual chamber concentrations were measured a minimum of once an hour by a Varian 34OO Gas chromatograph (GC). The GC was calibrated before the start of the study and one bag standard was prepared and analyzed during each exposure period to verify calibration.
Duration of treatment / exposure:
90 day(s)
Frequency of treatment:
6 hours/day, 5 days/week
Dose / conc.:
0.5 ppm (nominal)
Dose / conc.:
5 ppm (nominal)
Dose / conc.:
100 ppm (nominal)
Dose / conc.:
200 ppm (nominal)
Remarks:
Used for micronucleus test only
No. of animals per sex per dose:
 10/sex/group, In addition, 5 animals/ sex were utilized for micronucleus assay following termination of the study.
Control animals:
yes, concurrent no treatment
Details on study design:
Groups of male and female rats were exposed to target concentrations of 0, 0.5, 5, 100 and 200 ppm of chloropropyltrimethoxysilane vapours for 6 hours a day, 5 days a week for 90 days. After 13 weeks of exposure, rats were sacrificed and examined for changes in blood, serum chemistry, urine, organ weights and gross and histopathology. At 24 and 48 hours post-exposure, bone marrow was collected from the femur of 5 animals in all groups for micronucleus assay. The group of ten male and ten female rats also exposed to a target concentration of 200 ppm were used for a micronucleus assay, performed on this group at 24 and 48 hours post-exposure.
Observations and examinations performed and frequency:
All animals were observed daily following exposure for treatment-related signs of toxicity, mortality, general appearance and any evidence of respiratory, dermal, behavioral, nasal or ocular changes. Eyes of all rats were examined prior to initiation of the study and eyes of rats in the control and 100 ppm groups were also examined at the termination of the study. Body weights and food consumption of all rats were measured weekly.
Sacrifice and pathology:
Clinical pathology parameters were also assessed for all rats. The lungs, liver, heart, kidneys, brain, spleen, adrenals, testes and ovaries were examined and weighed. A complete set of tissues/organs were collected and retained in 10% neutral buffered formalin. All tissues from the control and 100 ppm groups were processed histologically and examined microscopically.  In addition, tissues from the lower exposure groups were examined if treatment related-effects were seen in the 100 ppm group.
Statistics:
Two-sided Welch Trend Test was used to analyze the data. Micronucleus assay data was analyzed by Wilcoxon Rank Sum Test. One-way analysis of Variance (ANOVA), Dunnett's multiple t-test was also used. The 95% (P= 0.05) confidence level was chosen as the criteria of significance.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Description (incidence and severity):
Sporadic increases in sodium, potassium and chloride were observed only in male rats.
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Immunological findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Microscopic histopathological data were collected for both the 0.5 and 5 ppm exposures groups respectively. There were no reported findings for the female animals of either group, N = 10 per exposure concentration. Eight of 10 male animals in the 0.5 ppm exposure group were reported as normal. The two remaining male animals exhibited minimal chronic cystitis of the urinary bladder. Nine of 10 male animals were reported as normal in the 5.0 ppm exposure group. The remaining male animal exhibited minimal chronic cystitis of the urinary bladder.
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Treatment-related histopathologic effects were seen in 100 ppm group animals. Increased incidence of hyperplasia of the urinary bladder epithelium was noted in both sexes of this group (4/10 males and 6/10 females). Urinary bladder hyperplasia did not occur in any other group. The hyperplasia was suggestive of an irritant excreted in the urine. Silicates do not appear to be involved with this process because of the lack of correlation with the urinary silicate data. The agent and mechanism responsible for the hyperplasia is unknown. In addition, an increased incidence and severity of alpha 2u-globulin inclusions (hyaline droplet nephropathy) in the kidney was observed in males. This condition is unique to male rats and has no known implication for human risk. Statistically significant increases in micronucleated cells were observed in females of the 100 ppm group at 48 hours post-exposure. This finding was not considered treatment-related because it lacked a dose-response and there was no increase in micronucleated cells at 24 hours. There were no test article-related microscopic changes in any organs or tissues of the respiratory tract. No recovery groups were included in the test protocol, therefore it is not possible to determine if the observed effects were reversible.
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
Critical effects observed:
no

Target concentrations of 0, 0.5, 5, and 100 ppm and 200 ppm = 0, 4, 41, and 813 and 1627 mg/m3, respectively. The actual overall mean exposure concentrations of 0.5, 5, and 99 and 189 ppm = 4, 41, and 806 and 1537 mg/m3, respectively.

Conclusions:
In a 90-day inhalation study (reliability score 1) conducted according to OECD 413 and GLP, the NOAEC for male and female rats was reported to be 100 ppm.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
813 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
Klimisch 1 score

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1993
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
Male and female rats weighing approximately 155-200 grams; age at study initiation: 6-8 weeks. Animals were quarantined for one week prior to initiation of the study. Animals were housed individually in suspended stainless steel, wire mesh bottomed cages. Before each exposure, animals were transferred into cages designed to be placed within the exposure chambers. After each exposure, the animals were returned to their original housing. The animals were fed Purina Certified Rodent Chow and water ad Iibitum except during exposures. The rats were housed during non-exposure periode in a room designed to be maintained at 22 +/- 3 °C temperature and 30-70% relative humidity. A light cycle of alternating 12 hours light and 12 hours dark was maintained.
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
Exposures were conducted in 2 m3 stainless steel whole body exposure chambers. Exposure cage racks were rotated top to bottom and front to back on a weekly basis. All groups were treated concurrently 5 days a week for thirteen weeks. The duration of each exposure period was six hours after equilibration of the chamber concentration. The equilibration tlme, which is a function of chamber air flow, was approximately 25 minutes.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The amount of test material used during the exposure period was determined by pre- and post- measuring the weight of the test material in each syringe or graduated cylinder reservoir. The exposure duration (exposure period and equilibration time), test material used and airflow through the chambers were then used to calculate nominal concentrations.
Actual chamber concentrations were measured a minimum of once an hour by a Varian 34OO Gas chromatograph (GC). The GC was calibrated before the start of the study and one bag standard was prepared and analyzed during each exposure period to verify calibration.
Duration of treatment / exposure:
90 day(s)
Frequency of treatment:
6 hours/day, 5 days/week
Dose / conc.:
0.5 ppm (nominal)
Dose / conc.:
5 ppm (nominal)
Dose / conc.:
100 ppm (nominal)
Dose / conc.:
200 ppm (nominal)
Remarks:
Used for micronucleus test only
No. of animals per sex per dose:
 10/sex/group, In addition, 5 animals/ sex were utilized for micronucleus assay following termination of the study.
Control animals:
yes, concurrent no treatment
Details on study design:
Groups of male and female rats were exposed to target concentrations of 0, 0.5, 5, 100 and 200 ppm of chloropropyltrimethoxysilane vapours for 6 hours a day, 5 days a week for 90 days. After 13 weeks of exposure, rats were sacrificed and examined for changes in blood, serum chemistry, urine, organ weights and gross and histopathology. At 24 and 48 hours post-exposure, bone marrow was collected from the femur of 5 animals in all groups for micronucleus assay. The group of ten male and ten female rats also exposed to a target concentration of 200 ppm were used for a micronucleus assay, performed on this group at 24 and 48 hours post-exposure.
Observations and examinations performed and frequency:
All animals were observed daily following exposure for treatment-related signs of toxicity, mortality, general appearance and any evidence of respiratory, dermal, behavioral, nasal or ocular changes. Eyes of all rats were examined prior to initiation of the study and eyes of rats in the control and 100 ppm groups were also examined at the termination of the study. Body weights and food consumption of all rats were measured weekly.
Sacrifice and pathology:
Clinical pathology parameters were also assessed for all rats. The lungs, liver, heart, kidneys, brain, spleen, adrenals, testes and ovaries were examined and weighed. A complete set of tissues/organs were collected and retained in 10% neutral buffered formalin. All tissues from the control and 100 ppm groups were processed histologically and examined microscopically.  In addition, tissues from the lower exposure groups were examined if treatment related-effects were seen in the 100 ppm group.
Statistics:
Two-sided Welch Trend Test was used to analyze the data. Micronucleus assay data was analyzed by Wilcoxon Rank Sum Test. One-way analysis of Variance (ANOVA), Dunnett's multiple t-test was also used. The 95% (P= 0.05) confidence level was chosen as the criteria of significance.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Description (incidence and severity):
Sporadic increases in sodium, potassium and chloride were observed only in male rats.
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Immunological findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Microscopic histopathological data were collected for both the 0.5 and 5 ppm exposures groups respectively. There were no reported findings for the female animals of either group, N = 10 per exposure concentration. Eight of 10 male animals in the 0.5 ppm exposure group were reported as normal. The two remaining male animals exhibited minimal chronic cystitis of the urinary bladder. Nine of 10 male animals were reported as normal in the 5.0 ppm exposure group. The remaining male animal exhibited minimal chronic cystitis of the urinary bladder.
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Treatment-related histopathologic effects were seen in 100 ppm group animals. Increased incidence of hyperplasia of the urinary bladder epithelium was noted in both sexes of this group (4/10 males and 6/10 females). Urinary bladder hyperplasia did not occur in any other group. The hyperplasia was suggestive of an irritant excreted in the urine. Silicates do not appear to be involved with this process because of the lack of correlation with the urinary silicate data. The agent and mechanism responsible for the hyperplasia is unknown. In addition, an increased incidence and severity of alpha 2u-globulin inclusions (hyaline droplet nephropathy) in the kidney was observed in males. This condition is unique to male rats and has no known implication for human risk. Statistically significant increases in micronucleated cells were observed in females of the 100 ppm group at 48 hours post-exposure. This finding was not considered treatment-related because it lacked a dose-response and there was no increase in micronucleated cells at 24 hours. There were no test article-related microscopic changes in any organs or tissues of the respiratory tract. No recovery groups were included in the test protocol, therefore it is not possible to determine if the observed effects were reversible.
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
Critical effects observed:
no

Target concentrations of 0, 0.5, 5, and 100 ppm and 200 ppm = 0, 4, 41, and 813 and 1627 mg/m3, respectively. The actual overall mean exposure concentrations of 0.5, 5, and 99 and 189 ppm = 4, 41, and 806 and 1537 mg/m3, respectively.

Conclusions:
In a 90-day inhalation study (reliability score 1) conducted according to OECD 413 and GLP, the NOAEC for male and female rats was reported to be 100 ppm.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
813 mg/m³
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

There are several reliability score 1 studies for repeated inhalation of (3-chloropropyl)trimethoxysilane.

In the key 90-day repeated dose toxicity study via the inhalation route, conducted according to OECD Test Guideline 413 and in compliance with GLP, microscopic examinations did not reveal any adverse findings in females exposed to 0.5 or 5 ppm. Eight of 10 male animals in the 0.5 ppm exposure group were reported as normal. The two remaining male animals exhibited minimal chronic cystitis of the urinary bladder. Nine of 10 male animals were reported as normal in the 5.0 ppm exposure group. The remaining male animals exhibited minimal chronic cystitis of the urinary bladder. Treatment-related histopathological effects were observed in the 100 ppm group animals. Increased incidence of hyperplasia of the urinary bladder epithelium was noted in both sexes of this group.

It is not known whether the urinary bladder was inflated by a fixative before microscopic examination. Without inflation of the urinary bladder the relevance of the hyperplasia would be questionable. Based on the fact that the hyperplasia of the bladder was mild / minimal and in some cases associated with a minimal inflammation (cystitis) it can presumed that if the stimulus for the hyperplastic changes is removed the hyperplasia will resolve within a matter of weeks and the urinary bladder will return to a normal histological appearance. A minimal/mild change of the urinary bladder not associated with any clinical symptoms or changes in urine parameters does not reflect a marked organ dysfunction. Therefore, the mild/minimal hyperplastic effects are not considered as adverse and the NOAEC is 100 ppm (813 mg/ m3) (Dow Corning Corporation, 1993).

(3-Chloropropyl)trimethoxysilane was also 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 signs of general toxicity were observed. Therefore, based on these results the NOAEC was established to be at least 100 ppm (813 mg/m3).

In the available 28-day subacute inhalation repeated dose toxicity study with (3 -chloropropyl)trimethoxysilane, conducted according to OECD Test Guideline 412 and in compliance with GLP,  10 male and 10 female rats per dose were exposed to vapours of (3 -chloropropyl)trimethoxysilane at concentrations of 10, 50, 100 and 200 ppm via whole body inhalation exposure for 6 hours per day, 5 days per week, for a total of 28 days. The animals were observed daily following exposure for treatment-related signs of toxicity, mortality, general appearance and any evidence of respiratory, dermal, behavioural, nasal or ocular changes. Eyes of all rats were examined prior to initiation of the study and eyes of rats in the control and high exposure groups were also examined at the terminal sacrifice. Body weights and food consumption were measured weekly.  

At the end of the study period, the animals were sacrificed and the liver, brain, heart, kidneys, adrenals, testes, ovaries, lungs and spleen were weighed and examined. A complete set of tissues/organs were selected and retained in 10% neutral buffered formalin. All tissues from the control and high exposure groups were processed histologically and examined microscopically. In addition, the lungs, nasal passages, larynx and trachea of all animals in the lower and intermediate exposure groups were examined microscopically.

Statistically significant increases were noted in the absolute and relative weights of adrenal glands of male rats from the 50, 100 and 200 ppm exposure groups and females at 100 and 200 ppm. Statistically significant increases were also observed in liver and kidney weights of males at 200 ppm. The organ weight changes were supported by the findings of microscopic lesions in these organs. Test article-related changes were detected histopathologically in the adrenal glands, kidneys, liver and urinary bladder in some rats from one or more exposure groups.

Histopathologic changes included adrenal cortical hypertrophy in males at 100 ppm and in both sexes at 200 ppm; hyaline droplet nephropathy in males at 50, 100 and 200 ppm; hepatocellular hypertrophy in males at 200 ppm and hyperplasia of urinary bladder epithelium in females at 10 ppm and both sexes at 50, 100 and 200 ppm. Statistically significant increases in micronucleated cells were observed in female rats of the 200 ppm group. There were no test article-related microscopic changes in any of the respiratory tract organs or other tissues examined. No other effects were observed during the study.

A NOAEC for systemic toxicity could not be determined due to the observation of test article-related changes during histopathology in the adrenal glands, kidneys, liver and urinary bladder at 10, 50, 100 and 200 ppm exposure concentrations (Dow Corning Corporation, 1992).

Changes in the adrenal glands, kidneys or liver were not reported in the key inhalation sub-chronic toxicity study in which (3-chloropropyl)trimethoxysilane was tested at concentrations up to 100 ppm (Dow Corning Corporation, 1993). The only effect that was seen in the key study was the increased incidence of hyperplasia of the urinary bladder epithelium in both sexes in the 100 ppm group, which was concluded to be non-adverse. Therefore, since the effects in the adrenal glands, kidneys or liver were not replicated in the 90-day study, they are considered to be incidental and non-adverse.

In a three-week dose range-finding study with (3-chloropropyl)trimethoxysilane, not conducted according to OECD Test Guideline but in compliance with GLP, 10 male and 10 female rats per dose were exposed to the vapours of (3-chloropropyl)trimethoxysilane at concentrations of 0, 50, 100 or 150 ppm via whole body inhalation exposure for 6 hours per day for three weeks (3 exposures during the first week, 5 during the  second week and 3 during the third week). The animals were observed  daily for general appearance, mortality and any evidence of respiratory, dermal, behavioural or ocular changes. Body weights and food consumption were measured weekly. The terminal body weights were determined on the animals at the terminal sacrifice. Gross necropsies were performed on all rats. No treatment-related effects were observed in any of the parameters examined in this study (Dow Corning Corporation, 1990).

Justification for classification or non-classification

Based on the available information, (3-chloropropyl)trimethoxysilane is not classified for target organ toxicity following repeated exposure according to Regulation (EC) No 1272/2008. Urinary bladder effects are considered to be minimal and are expected to be reversible and non-adverse.