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Administrative data

Description of key information

No reliable repeated-dose toxicity data are available for (3-chloropropyl)triethoxysilane (CAS 5089-70-3). A 90-day repeated dose toxicity study by the oral route with the registered substance according to OECD Test Guideline 408 and in compliance with GLP is proposed.

Good quality data from the analogous substance (3-chloropropyl)trimethoxysilane (CAS 2530-87-2) is included and used as read-across for interim risk assessment. After approval by ECHA and once the results from the OECD Test Guideline 408 are available, the DNELs will be revised.


In a 90-day inhalation study in rats with (3-chloropropyl)trimethoxysilane, 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 (Dow Corning Corporation, 1993).


In a combined repeated dose toxicity study with the reproduction / developmental toxicity screening test with (3-chloropropyl)trimethoxysilane, conducted according to OECD Test Guideline 422 and in compliance with GLP, by the inhalation route, whole-body in rats, the NOAEC was established to be at least 100 ppm (813 mg/m³) based on no observed toxicity (RCC, 2005).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available (further information necessary)

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:
supporting 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 periods 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 time, 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
Remarks on result:
other: equivalent to 813 mg/m³
Critical effects observed:
no
Conclusions:
In a 90-day inhalation study (reliability score 1) conducted according to OECD Test Guideline 413 and in compliance with GLP with the analogue substance (3-chloropropyl)trimethoxysilane (CAS 2530-87-2), the NOAEC for male and female rats was reported to be 100 ppm (equivalent to 813 mg/m³).
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
813 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
Klimisch score 1

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:
supporting 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 periods 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 time, 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
Remarks on result:
other: equivalent to 813 mg/m³
Critical effects observed:
no
Conclusions:
In a 90-day inhalation study (reliability score 1) conducted according to OECD Test Guideline 413 and in compliance with GLP with the analogue substance (3-chloropropyl)trimethoxysilane (CAS 2530-87-2), the NOAEC for male and female rats was reported to be 100 ppm (equivalent to 813 mg/m³).
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

No adequate repeated-dose toxicity data are available for (3-chloropropyl)triethoxysilane (CAS 5089-70-3).

A 90-day repeated dose toxicity study by the oral route according to OECD Test Guideline 408 and in compliance with GLP is proposed.

For interim risk assessment, good quality inhalation data for the analogous substance (3-chloropropyl)trimethoxysilane (CAS 2530-87-2) have been read-across.

Both registered and read-across substances share a common hydrolysis product, (3-chloropropyl)silanetriol, with the other hydrolysis products being ethanol and methanol respectively. Since neither methanol nor ethanol would contribute to general systemic toxicity effects in rodents at the dose levels tested, it is considered that the observed toxicological effects are due to the action of the (3-chloropropyl)silyl moiety, although the specific toxicological mechanism cannot be determined from the available information. Both substances have log Kow in the range that is favourable for absorption across the respiratory tract (ethoxy log Kow= 3.13 and methoxy log Kow= 2.0). No acute inhalation toxicity data are available for either substance, but acute oral and dermal LD50 values for both substances in rats are >2000 mg/kg. It is therefore considered valid to read-across the results for the trimethoxy analogue to fill data gaps for the registered substance.

There are two reliability score 1 studies for repeated inhalation of (3-chloropropyl)trimethoxysilane, a subchronic (90-day) repeated dose toxicity study in accordance with OECD Test Guideline 413 (Dow Corning Corporation, 1993) and a subacute combined repeated dose and reproductive/developmental screening study in accordance with OECD Test Guideline 422 (RCC, 2005).

In the 90-day inhalation study, microscopic examinations did not reveal any adverse findings in females exposed to 0.5 or 5 ppm 3-(chloropropyl)trimethoxysilane. 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 is 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 histologic 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).

(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. 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) (RCC, 2005).

In a 21-day repeated dose toxicity dermal study with registered substance (3-chloropropyl)triethoxysilane, the test material was found slightly irritating to the rabbit skin (Laboratorium Für Pharmakologie und Toxikologie, 1977). However, the purpose of this test was to determine irritation effects following repeated exposure, and did not meet the requirements for a repeated dose toxicity test.

Justification for classification or non-classification

Based on the current available read-across data from 3-chloropropyl(trimethoxysilane), (3-chloropropyl)triethoxysilane does not require classification for specific 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.