Registration Dossier

Toxicological information

Repeated dose toxicity: inhalation

Currently viewing:

Administrative data

sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
19.08.1993 to 06.01.1995
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: 2b The study was conducted according to an appropriate OECD test guideline, with acceptable restrictions. The restrictions were that low exposure concentrations were used, an exposures were only on five days per week.

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guideline
equivalent or similar to guideline
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Low exposure concentrations and exposure 5 days/week
GLP compliance:
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Details on test material:
- Name of test material (as cited in study report): Trimethoxysilane
- Substance type: Silane
- Physical state: Clear, colourless liquid
- Expiration date of the lot/batch: No data
- Stability under test conditions: No data
- Storage condition of test material: Ambient temperature

Test animals

Details on test animals or test system and environmental conditions:
- Source: Harlan Sprague Dawley Inc
- Age at study initiation: approximately 47 days
- Weight at study initiation: Males: 197.2-240.1 g; Females: 129.7-186.1 g
- Fasting period before study: No data
- Housing: Individually in stainless steel, wire mesh cages.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: two weeks

- Temperature (°F): 66-77
- Humidity (%): 40-70
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 20.09.1993 To: 23.12.1993

Administration / exposure

Route of administration:
Type of inhalation exposure:
whole body
other: unchanged (no vehicle)
Details on inhalation exposure:
The inhalation chambers, constructed from stainless steel with glass windows for animal observation, were rectangular (213 x 98 x 207 cm) in shape. The volume of each chamber was approximately 4320 litres.
- Method of holding animals in test chamber: No data
- Source and rate of air: No data
- Method of conditioning air: No data
- Temperature, humidity, pressure in air chamber: Mean temperature of approximately 23oC, humidity of approximately 45. No data on pressure.
- Air flow rate: 1000 l/min
- Air change rate: 13-14 air changes/hour
- Treatment of exhaust air: No data

- Brief description of analytical method used: Sampling done with impingers and a double beam spectrophotometer.
- Samples taken from breathing zone: yes, the distribution of TMS vapour was measured at five positions for each individual chamber distribution test. Each chamber was tested once prior to the initiation of the study. The distribution tests simulated actual animal exposures including the use of similar animal cages, cage carriers with collection trays and airflow rates. No animals were present in the exposure chambers.
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
The concentration of TMS vapour in the exposure chamber atmosphere was monitored throughout the 66 days of exposure by sampling with impingers. The impingers contained a solution of acidic ammonium molybdate and sodium bisulfite. TMS reacted with the molybdate and formed a blue coloured product. The absorbance of the solution was measured at 620 nm with a double-beam spectrophotometer.
Duration of treatment / exposure:
90 days
Frequency of treatment:
6 hr/day, 5 day/wk
Doses / concentrations
Doses / Concentrations:
0.02, 0.1, and 0.5 ppm

No. of animals per sex per dose:
10 with an additional 5 rats/sex in the control and high exposure groups
Control animals:
other: yes, filtered air only
Details on study design:
- Dose selection rationale: Based on dose range-finding study
- Rationale for animal assignment (if not random): Random
- Rationale for selecting satellite groups: To investigate the reversibility of any effects
- Post-exposure recovery period in satellite groups: Five animals/sex in the control and 0.5 ppm groups were maintained for a 4-week recovery period. 
Positive control:


Observations and examinations performed and frequency:
- All animals were individually observed for signs of toxic effects except during the exposures. During the exposures, observations were recorded on a group basis. Preceding and following each exposure, observations were recorded for animals exhibiting overt signs. At the time of body weight measurement and just prior to sacrifice, detailed observations were performed on all animals. On nonexposure days, the animals were observed once per day for overt clinical signs and twice per day for mortality.


- Time schedule for examinations: On the morning prior to initiation of the first exposure, weekly throughout the study, and immediately preceding sacrifice.

FOOD CONSUMPTION: Yes, measured weekly during the study and recovery period.

- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION: Yes, measured weekly during the study and recovery period.

- Time schedule for examinations: Prior to the first exposure, during week 14 of the study, and after the four week recovery period.
- Dose groups that were examined: All

- Time schedule for collection of blood: Weeks 6 and 14
- Anaesthetic used for blood collection: Yes, methoxyflurane
- Animals fasted: No
- How many animals: 10/group/sex
- Parameters checked in table No.1 were examined.

- Time schedule for collection of blood: Weeks 6 and 14
- Anaesthetic used for blood collection: Yes, methoxyflurane
- Animals fasted: No
- How many animals: 10/group/sex
- Parameters checked in table No.1 were examined

- Time schedule for collection of urine: Following the fourth exposure week, during week 13, and during week 18 (control and high concentrations)
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No
- Parameters checked in table No.1 were examined.

Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table 2)
HISTOPATHOLOGY: Yes (see table 2)
The data for quantitative, continous variables were intercompared for the three exposure groups and the control group by use of Levene's test for equality of variances, analysis of variance (ANOVA), and t-tests. Nonparametric data were statistically evaluated using the Kruskal-Wallis test followed by the Mann-Whitney U-test. Incidence data were compared using Fisher's Exact test. For all statistical tests the probability value of <0.05 (two-tailed) was used as the critical level 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):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
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:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY: The exposure regimen produced no mortality or exposure-related clinical signs. There were some signs due to procedural trauma, in all groups including the controls.

BODY WEIGHT AND WEIGHT GAIN: No exposure-related effects.

FOOD CONSUMPTION: No exposure-related effects.

WATER CONSUMPTION: No exposure-related effects. There were sporadic significant increases in water consumption observed in all exposure groups, but there was no trend and they were therefore not considered an adverse effect of treatment.

OPHTHALMOSCOPIC EXAMINATION: No exposure-related effects. There were signs of trauma caused by the bleeding procedure. There were also sporadic occurrences of conjunctivitis in all groups including the controls. The authors suggested that such occurrences in animals exposed to TMS could have been a sign of mild irritation, but there was no concentration response trend.

HAEMATOLOGY: No exposure-related effects. In females at week 6 there was a significant increase in hemoglobin (intermediate and high) and hematocrit (all exposure groups) observed. There were no sifnificant differences at week 14. Due to the lack of a concentration-related response the described differences were not believed to be exposure-related.

CLINICAL CHEMISTRY: No exposure-related effects. Total and direct bilirubin values were significantly decreased in low and high group males, and low and intermediate group females at week 6. Calcium was significantly lower in intermediate group females at week 6. At week 14, potassium was significantly lower in low group males. No significant clinical chemistry findings were noted at week 14. Due to the lack of a concentration-related response the described differences were not believed to be exposure-related.

URINALYSIS: No exposure-related effects. Significant decreases in urine creatinine were observed in males (low group) at weeks 5 and 13, and week 18 (high group). Males had significant decreases in alpha2u-globulin (low group) and urine total protein (all groups) at week 13. Females from the low and high group had increased urine total protein at week 13. Males had decreased alpha2u-globulin at week 18. Low group males had increased urine total volume at week 13. Due to the lack of a concentration-related response the described differences were not believed to be exposure-related.

ORGAN WEIGHTS: No exposure-related effects. In males, absolute thyroid gland weight was significantly increased at week 14 (low and intermediate groups). No other differences in absolute or relative organ weights were observed in males from any exposure group during the exposure or recovery phases of the study. In females, absolute ovary weight, ovary and spleen weights as a percent of final body weight were significantly lower, and brain weight was significantly higher at week 18 (high group), However, these are not believed to be exposure related since the effects were observed at the end of the recovery period only.

GROSS PATHOLOGY: No exposure-related findings.

HISTOPATHOLOGY: No exposure-related findings. Microscopic diagnosis in males sacrificed at week 14 revealed significant increases in sinus erythrocytosis ( intermediate group), and hemorrhage of the thymic region (intermediate group). However, these findings are not believed to be exposure related. No significant differences in microscopic diagnoses were observed in females sacrificed at weeks 14 and 18.

Effect levels

Dose descriptor:
Effect level:
>= 0.51 ppm

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

In a good quality 90-day inhalation study (reliability score 2) conducted in a study comparable to OECD 413 and GLP, the NOAEL for trimethoxysilane was greater than 0.51 ppm (the highest dose tested) in rats exposed six hours/day, five days/week, followed by a four-week recovery period.
Executive summary:

In a good quality 90-day inhalation study (reliability score 2) conducted in a study comparable to OECD 413 and GLP, Sprague-Dawley rats (10 with an additional 5 rats/sex in the control and high exposure groups) were exposed to trimethoxysilane vapor for 90 days over a l3-week period for 6 hours/day, 5 days/week, followed by a 4-week recovery period. Mean exposure concentrations of 0.02, 0.99 and 0.51 ppm were achieved. This exposure regimen did not produce any exposure-related effects upon clinical signs, body weight and body weight gains, food and water consumption, ophthalmic evaluations, hematology, clinical chemistry, serum protein fractions, urine chemistry, urinalysis, absolute and relative organ and tissue weights, or gross and microscopic evaluations of organs and tissues. Therefore, the NOAEL was determined to be at least 0.51 ppm under the conditions of this study.