Registration Dossier

Administrative data

Description of key information

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

A sub-chronic toxicity test according to OECD 408 will be conducted with the registered substance after approval from ECHA.

Reliable data for the related substance 3-chloropropyl(trimethoxy)silane (CAS 2530-87-2) have been used to assess the general systemic toxicity of 3-chloropropyl(dimethoxy)methylsilane in order to perform interim risk characterisation. In a 90-day inhalation study (DCC, 1993) in rats, conducted in accordance with OECD 413, the NOAEC for 3-chloropropyl(trimethoxy)silane was determined to be ≥100 ppm (813 mg/m3).

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:
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 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 initaition 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 concentratlona 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 vertfy 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)
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 vapors 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
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
The actual overall mean exposure concentration for the test groups were 0.5, 5, 99 and 189 ppm. 
No mortality or apparent treatment-related signs of toxicity were observed in any of the test animals. 
No statistically significant differences were observed in mean body weights or food consumption between the test and control groups. 
There were no statistically significant differences in the hematology values of male or female rats. Sporadic increases in sodium,
potassium and chloride were observed only in male rats.
There were no statistically significant differences in male or female organ weights among the groups.  
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.  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 inlcuded in the test protocol, therefore it is not possible to determine if the observed effects were reversible.
Dose descriptor:
NOAEC
Effect level:
>= 100 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Critical effects observed:
not specified

Target concentrations of 0, 0.5, 5, and 100 ppm and 200 ppm = 0, 4, 41,  

and 814 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: 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:
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 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 initaition 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 concentratlona 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 vertfy 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)
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 vapors 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
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
The actual overall mean exposure concentration for the test groups were 0.5, 5, 99 and 189 ppm. 
No mortality or apparent treatment-related signs of toxicity were observed in any of the test animals. 
No statistically significant differences were observed in mean body weights or food consumption between the test and control groups. 
There were no statistically significant differences in the hematology values of male or female rats. Sporadic increases in sodium,
potassium and chloride were observed only in male rats.
There were no statistically significant differences in male or female organ weights among the groups.  
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.  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 inlcuded in the test protocol, therefore it is not possible to determine if the observed effects were reversible.
Dose descriptor:
NOAEC
Effect level:
>= 100 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Critical effects observed:
not specified

Target concentrations of 0, 0.5, 5, and 100 ppm and 200 ppm = 0, 4, 41,  

and 814 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 no repeated dose 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 general systemic toxicity of 3 -chloropropyl(dimethoxy)methylsilane in order to perform interim risk characterisation.

There are several reliability score 1 studies for repeated inhalation of 3-chloropropyl(trimethoxy)silane. The 90-day study was selected as the key study as it tested over the longest duration (Dow Corning Corporation, 1993).

In the key study (Dow Corning Corporation, 1993), microscopic examinations did not reveal any adverse findings in females exposed to 0.5 or 5 ppm of the test material. Eight of ten 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 ten 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 histopathologic 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. There is no evidence for genotoxicity of 3-chloropropyl(trimethoxy)silane. Therefore it is highly unlikely that the minimal/mild proliferative changes of the bladder are caused by a urinary bladder genotoxic carcinogen. Based on the fact that the hyperplasia of the bladder was mild /minimal and associated with a minimal inflammation (cystitis) it can presumed that if the stimulus for the inflammation 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 reversible effect is not adverse. Therefore the NOAEC is ≥100 ppm (≥813 mg/m3).

An additional dose group at 200 ppm was used for a micronucleus assay, reported in Section 5.7. Hyperplasia was not observed in the second supporting repeated dose toxicity study, an OECD 422 study (RCC Ltd, 2005) on 3-chloropropyl(trimethoxy)silane, in which animals were exposed for about 28 days to concentrations up to 100 ppm.

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

Justification for classification or non-classification

Based on the fact that the urinary bladder effects observed in the read across data were minimal and are expected to be reversible,

3-chloropropyl(dimethoxy)methylsilane is not classified for specific target organ toxicity following repeated exposures according to Regulation (EC) No 1272/2008.