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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

sub-chronic toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was carried out in accordance with an appropriate OECD test guideline and in compliance with GLP.

Data source

Reference Type:
study report
Report Date:

Materials and methods

Test guideline
according to
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:
Limit test:

Test material


Test animals

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.

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
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:
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
Doses / concentrations
Doses / Concentrations:
0.5, 5, 100 and 200 ppm
nominal conc.
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.
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.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
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. 
The results of this study demonstrate test article-related histopathologic changes in the urinary bladder and kidneys of animals exposed 
to 100 ppm. The no-observed-effect-concentration (NOEC) for male and female rats was reported to be 5 ppm.   
NOAEC (NOEC): 5 ppm in both male and female rats

No recovery groups were inlcuded in the test protocol, therefore it is not possible to determine if the observed effects were reversible.

Effect levels

open allclose all
Dose descriptor:
Effect level:
5 ppm (nominal)
Based on:
test mat.
Basis for effect level:
other: minimal/mild histopathologic changes in the urinary bladder and species specific histopathologic changes in the kidneys of animals exposed to 100 ppm
Dose descriptor:
Effect level:
100 ppm (nominal)
Based on:
test mat.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

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.

Applicant's summary and conclusion

In a 90-day inhalation study (reliability score 1) conducted according to OECD 413 and GLP, test substance-related mild/minimal histopathologic changes in the urinary bladder and kidneys of animals exposed to 100 ppm were observed. The NOEC for male and female rats was reported to be 5 ppm. However, the NOAEC is considered by the Registrants to be greater than or equal to 100 ppm (see endpoint summary for further details).