Triethoxysilane

Endpoint summary

Description of key information

Oral (OECD TG 422, RA from CAS 1185-55-3), rat: NOAEL 60.5 mg/kg bw
Inhalation - systemic (similar to OECD TG 413, RA from CAS 2487-90-3), rat: NOAEC=3.35 mg/m³
Inhalation - local (similar to OECD TG 412, RA from CAS 2487-90-3), rat: NOAEC=1.34 mg/m³
Dermal: No data available.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

19.11.2003 to 19.05.2005

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The study was conducted according to the appropriate OECD guideline and in compliance with GLP and is therefore considered to be reliability 1. Read-across of the study itself is considered to be reliability 2. Further information on read-across is given in the endpoint summary.

Justification for type of information:

Please refer to the attached justification below and the overall justification for grouping of substances attached in IUCLID Section 13.

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Qualifier:

according to guideline

Guideline:

other: USEPA OPPTS 870.3650

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: Crl:CD®(SD)IGS BR VAF/Plus®

Sex:

male/female

Details on test animals or test system and environmental conditions:

ANIMAL RECEIPT AND ACCLIMATION
Ninety female and forty five male Crl:CD®(SD)IGS BR VAF/Plus® rats were received from Charles River Laboratories, Portage, MI. The animals were 9 weeks old. Upon receipt, each animal was inspected by animal resource personnel and animals judged to be in good health and suitable as test animals were quarantined for six days. During the quarantine period animal resource personnel observed each animal at least once daily. The attending veterinarian examined all animals before release from quarantine and documented the general state of animal health.

ANIMAL HOUSING
Animals were individually housed in suspended wire-mesh cages elevated over Bed-O’Cobs Alf-a’ bedding, during quarantine and throughout the course of the study, with the following exceptions. During cohabitation, reproductive group females were paired 1 to 1 with a male from the same treatment group in suspended wire-mesh cages elevated over Bed-O’Cobs Alf-a’ bedding. The animals were paired in the home cage of the male. On day 0 of gestation, reproductive group females were moved into shoebox cages containing Bed-O’ Cobs Combination bedding and remained there throughout the remainder of the study. The results of the manufacturer’s periodic analysis of the Bed-O’ Cobs Combination bedding were reviewed to ensure that there were no contaminants present at levels that would be expected to affect the outcome of the study. The cages, bedding/fecal pans were routinely cleaned, consistent with good husbandry practices.

DIET, DRINKING WATER AND MAINTENANCE
PMIcertified Rodent Diet #5002, manufactured by PMI Nutritional International, St. Louis, MO, was offered ad libitum except during functional observational battery assessment period. Males and toxicity group females were fasted prior to necropsy by removing food on the evening of the day before necropsy. The results of the manufacturer’s periodic analyses of the certified feed were reviewed to ensure that heavy metals and pesticides were not present in concentrations that would be expected to affect the outcome of the study.

Municipal water, further purified by reverse osmosis was available ad libitum except during performance of functional observational battery testing. The drinking water was monitored on at least a semi-annual basis to determine compliance with the U.S.E.P.A. drinking water standards. The most recent analysis was reviewed and there were no contaminants in the water known to be present at levels expected to interfere with the integrity of the study.

ENVIRONMENTAL CONDITIONS
Animals were housed in an environmentally controlled animal room (12-hour fluorescent light/dark cycle, 68.3-72.5 oF, 36.0-62.0% relative humidity, 10-15 air changes per hour) throughout the in-life phase of the study. Temperature and humidity were continuously monitored. The most recent air change verification was reviewed by the study director.

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

The vehicle and test article formulations were administered orally by gavage, via a 3-4 inch, 15-18 gauge, animal feeding needle and syringe once daily. Volume administrations did not exceed 3 mL/kg of body weight except for a few instances. The volume administered was based upon the most recent body weight.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The concentration of methyltrimethoxysilane (MTMS) in corn oil dosing solutions was determined prior to the beginning of the definitive study.

Preparation of Solvent Standards: Stock solvent standards of MTMS in toluene were prepared under a nitrogen atmosphere by weighing an amount of MTMS and mixing with a known volume of toluene. Aliquots of the stock solution were then further diluted with toluene to cover the standard range from approximately 100 µg MTMS/ml toluene to approximately 1000 µg/ml. New solvent standards were prepared with each dosing solution analysis. An aliquot of each solvent standard was placed in an autosampler vial and analyzed.

Preparation of Dosing Solutions for Analysis of Concentration Verification: Aliquots of dosing formulations were volumetrically measured into volumetric flasks, diluted to volume with toluene and mixed well. Aliquots of the diluted dosing solutions were placed in autosampler vials and were analyzed with the solvent standards for determination of the concentration of MTMS.

Gas Chromatography Analysis: A set of solvent standards comprising of at least five concentrations was used to establish a calibration curve. Trendlines and their mathematical equations were generated by linear regression analysis of the peak areas resulting from the analysis of the solvent standards using Microsoft Excel 2000 (Version 9.0). The dosing solution verifications were performed by comparing the target concentration of the dose solutions to the mean observed test substance concentration found by refitting the peak areas resulting from the dosing solution dilution samples to the standard curve. The limit of quantitation was set at the level of the lowest standard analyzed and was equal to 5 mg MTMS/ml dosing solution. The conditions used were as follows:
Injection: 1 µl, split 50:1
Injector Temp: 160 oC
Carrier Gas: Helium
Column Flow: 1.3 ml/min
Hydrogen Flow: 30 ml/min
Air Flow: 400 ml/min
Combined Flow: 25 ml/min (constant column + make-up flow)
Column: HP-5MS, 30 m x 0.25 mm, 0.25 µm film thickness
Oven Temp: 70 oC for 3 min to 210 oC at 17 oC/min
Detector: Flame Ionization Detector (FID)
Detector Temp: 300 oC

Homogeneity and Stability: Homogeneity and stability of MTMS in corn oil dosing solutions was performed as part of the pilot study with MTMS. The dosing solutions were found to be homogeneous and stable up to 15 days if aliquoted into separate vials for daily usage.

Concentration Verification: Verification of each dosing concentration was conducted following each new preparation. New dosing solutions were prepared at least every 15 days in order to stay within the stability timeframe established in the pilot study.

Results: Dose solution analysis for concentration determined that each batch of 50, 250 and 1000 mg/kg/day dose solution was within 95-07%, 95-97% and 99-100% of the target concentration, respectively.

Duration of treatment / exposure:

Test substance was administered once daily by oral gavage, seven days per week at approximately the same time each day. Dose levels of methyltrimethoxysilane (MTMS) were 0 (control), 50, 250 and 1000 mg MTMS/kg/day. MTMS, dissolved in corn oil, was administered by oral gavage once each day for up to 51 consecutive days. Females in each dose level were divided into a toxicity (10 animals/group) and a reproductive group (10 animals/group). A single group of males (10 animals/group) were used for both the toxicity and reproductive phases of the study. Toxicity group females and males were treated for 28 and 29 days, respectively. Reproductive group females were treated for 14 days prior to the mating period, during the mating period, and then up to and including post partum day 3, for a total of up to 51 days.

Frequency of treatment:

daily

Remarks:

Doses / Concentrations:
0 (corn oil), 50, 250, and 1000 mg/kg bw/day
Basis:

No. of animals per sex per dose:

10/sex/dose

Control animals:

yes, concurrent vehicle

Details on study design:

Males and toxicity group females were sacrificed after they had been  treated for 28 days.  Reproductive group females and pups were sacrificed  
on day 4 postpartum.  A functional observational battery (FOB) evaluation  for signs of neurobehavioral effects was performed on all adult males 
and  all toxicity group females prior to the start of dosing and during the  last week of dosing.  Body weights and food consumption were recorded  
weekly.  From all males and all toxicity group females, blood samples  were obtained on the day of scheduled necropsy for hematology and  
clinical chemistry parameters evaluations.  Animals were subjected to a  complete gross necropsy.  Many tissues and organs were collected for  
histological examination and were weighed.  

Positive control:

Not required

Observations and examinations performed and frequency:

Mortality/Morbidity: Animals were observed at least twice daily in their cages for moribundity and mortality throughout the in-life phase of the study.
Clinical observations:
Daily Observations: General clinical examinations were made at lease once a day and were conducted immediately after dosing. The examinations included, but were not limited to, changes in the skin, fur, eyes, mucous membranes, respiratory, circulatory, autonomic and central nervous system functions, motor activity and behavior patterns. Findings were recorded for individual animals. General clinical examinations were not performed on days when detailed physical examinations were performed.

Detailed Physical Examinations: All animals received a detailed physical examination once before the first dose administration (to allow for within-subject comparisons), and weekly thereafter. Examinations were made outside the home cage in a standard arena at approximately the same time each day. Observations were detailed and carefully recorded. Examinations included, but were not limited to, changes in skin, fur eyes, mucous membranes, occurrence of secretions and excretions, and autonomic activity. Changes in gait, posture and response to handling as well as the presence of clonic or tonic movement, stereotypies, difficult or prolonged parturition or bizarre behavior were recorded. The presence or absence of findings was recorded for individual animals.

Body weights and food consumption were recorded weekly. Additional body weights for reproductive group females were obtained on gestational day 0, 7, 14, and 20, and within 24 hours of parturition, and on postnatal day 4. Individual food consumption was determined for each group following group specific schedules. In addition, detailed clinical observations (functional observational battery [FOB] conducted out of the home cage) and locomotor activity were evaluated for all adult male and toxicity phase females once prior to the start of test article administration (baseline evaluations) and again during the last week of the test article administration. Blood samples were collected from males and toxicity group females on the day of scheduled termination for analysis of hematology and serum chemistry parameters.

Sacrifice and pathology:

Complete necropsies were performed on the males and the toxicity group females and selected organs were weighed (adrenals, brain, heart, kidneys, liver, lungs, spleen, thymus, uterus, ovaries, testes, prostate, seminal vesicles, and epididymides). Microscopic examination was performed on protocol-specified tissues from all animals in the control and high dose group males and toxicity group females. Microscopic examination of the liver, thyroid, jejunum and duodenum was extended to males and toxicity group females in the 50 and 250 mg/kg dose groups. In addition, the adrenal gland from these middle dose groups was evaluated for the toxicity group females.

Statistics:

All data analyses were carried out using SAS version 8.2. Statistically significant probabilities were reported for /-values of <0.05, <0.02 and <0.01.

Body weight, body weight changes, organ weight, organ to body weight ratios, food consumption, hematology data, clinical chemistry and prothrombin times were analyzed using a one-way Analysis of Variance (ANOVA) if the data satisfied the requirements of normality of the residuals and homogeneity of variance as determined using the Shapiro-Wilk test for normality and Levene’s test for homogeneity of variance. If the data did not satisfy the parametric requirements, a Kruskal-Wallis test was used. If the ANOVA or Kruskal-Wallis test was significant, pair-wise comparisons of the dosed groups to control were made using the Dunnett’s Test or a Wilcoxon test, respectively.

The red blood morphology findings in the hematology data that were reported by severity grade; polychromasia, anisocytes, poikilocytosis, and ananthocytes were analyzed using a Cochran-Armitage trend test to indicate an increasing incidence trend regardless of grade with Fisher’s Exact tests used to indicate increased incidence (non-grade specific) over the control. To determine shifts in severity, analysis using the Kruskal-Wallis test was performed on the graded data only if there was at least once incidence of severity grade seen in the controls group. If the overall Kruskall-Wallis test was significant, pair wise comparisons of the graded animals between the control and treated groups was done using the Kruskal-Wallis.

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Details on results:

There were two unscheduled deaths (one female each at 0 and 50 mg/kg  bw/day); both were related to dosing errors.  Clinical signs included  
transient inactivity or salivation following dosing.  Statistically  significant decreases in body weight gain and food consumption were noted  
for 1000 mg/kg bw/day group males.  Increased liver weight was observed  for male and female animals at 250 and 1000 mg/kg bw/day.  
Exposure to  MTMS was associated with organ weight and/or histomorphological changes  in males (liver, thymus, thyroid, duodenum,
 jejunum, and red blood cell)  and females (liver, thyroid, duodenum, jejunum, and adrenal gland) at  dose levels at or above 250 mg/kg bw/day.  
A marked increase in  prothrombin time was observed for males at 250 and 1000 mg/kg bw/day  whereas females were unaffected.  Exposure 
was also associated with  increased blood platelet concentration for males and females at 1000  mg/kg bw/day.  The NOAEL for systemic 
toxicity was 50 mg/kg bw/day.

Key result

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Organ weight and/or histomorphological changes  in males (liver, thymus, thyroid, duodenum,  jejunum)  and females (liver, thyroid, duodenum, jejunum, and adrenal gland) at  dose levels at or above 250 mg/kg bw/day.  

Critical effects observed:

no

Toxic Response/Effects by Dose Level:

50 mg/kg bw/day Methyltrimethoxysilane:
Males: None
Females:  None

250 mg/kg bw/day Methyltrimethoxysilane:
Males: 
Increased liver weight (absolute(relative): 19%* (25%*)
Thyroid gland follicular cell hyperplasia/hypertrophy: (incidence 6*/10)
Decreased thymus weight (absolute(relative): 28%*(24%*)
Increased prothrombin time: 2-fold*

Females:
Increased liver weight (absolute(relative): 37%* (41%*)
Centrilobular hepatocellular hypertrophy (incidence 5*/10)
Periportal vacuolation (incidence 10*/10)
Thyroid gland follicular cell hyperplasia/hypertrophy:
(incidence 10*/10)

1000 mg/kg bw/day Methyltrimethoxysilane:
Males:  
Increased liver weight (absolute(relative): 33%* (47%*) 
Diffuse hepatocellular hypertrophy (incidence 10*/10)
Thyroid gland follicular cell hyperplasia/hypertrophy: (incidence 10*/10)
Mucosal lipidosis: duodenum  (incidence 4*/10)
Mucosal lipidosis: jejunum (incidence 7*/10)
Decreased thymus weight (absolute(relative): 35%*(29%*)
Ancanthocytosis (incidence 5*/10)
Increased red blood cell concentration: 16%*
Increased prothrombin time: 2-fold*
Increased serum alanine aminotransferase (48%*)
Increased blood platelet concentration: 16*

Females (Toxicity Phase):
Increased liver weight (absolute(relative)): 197%* (200%*)
Centrilobular hepatocellular hypertrophy (incidence 10*/10)
Periportal vacuolation (incidence 8*/10)
Thyroid gland follicular cell hyperplasia/hypertrophy:(incidence 10*/10)
Adrenal gland hyperplasia/hypertrophy (incidence 10*/10)
Adrenal gland apoptosis (incidence 9*/10)
Adrenal gland lymphocytic infiltration: zona reticularis:(incidence 5*/10)
Mucosal lipidosis: duodenum  (incidence 5*/10)
Mucosal lipidosis: jejunum (incidence 5*/10)
Increased blood platelet concentration: 21%*

Where "*" denotes statistically different from control
(p<0.05)

Conclusions:

Exposure to methyltrimethoxysilane was associated with organ weight and/or histomorphological changes in males (liver,
thymus, thyroid, duodenum, jejunum, and red blood cell) and females (liver, thyroid, duodenum, jejunum, and adrenal
gland) at dose levels at or above 250 mg/kg bw/day. A marked increase in prothrombin time was observed for males at 250
and 1000 mg/kg bw/day whereas females were unaffected. Exposure was also associated with increased blood platelet
concentration for males and females at 1000 mg/kg bw/day. These data support a NOAEL for the toxicity phase of the
study of 50 mg/kg bw/day.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

60.5 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The study was conducted according to the appropriate OECD guideline and in compliance with GLP and is therefore considered to be reliability 1. Read-across of the study itself is considered to be reliability 2.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

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:

19.08.1993 to 06.01.1995

Reliability:

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.

Justification for type of information:

Please refer to the attached justification below and the overall justification for grouping of substances attached in IUCLID Section 13.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

Deviations:

yes

Remarks:

Low exposure concentrations and exposure 5 days/week

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- 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


ENVIRONMENTAL CONDITIONS
- 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

Route of administration:

inhalation

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
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


TEST ATMOSPHERE
- 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:

yes

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

Remarks:

Doses / Concentrations:
0.02, 0.1, and 0.5 ppm
Basis:

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:

None

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- 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.


DETAILED CLINICAL OBSERVATIONS: No data


BODY WEIGHT: Yes
- 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.


FOOD EFFICIENCY:
- 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.


OPHTHALMOSCOPIC EXAMINATION: Yes
- 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


HAEMATOLOGY: Yes
- 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.


CLINICAL CHEMISTRY: Yes
- 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


URINALYSIS: Yes
- 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.


NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see table 2)
HISTOPATHOLOGY: Yes (see table 2)

Statistics:

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.

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):

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.

Dose descriptor:

NOAEC

Effect level:

>= 0.51 ppm

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Dose descriptor:

NOAEC

Effect level:

>= 2.5 mg/m³ air

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Critical effects observed:

no

Conclusions:

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 13-week period for 6 hours/day, 5 days/week, followed by a 4-week recovery period. Mean exposure concentrations of 0.02, 0.10 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 NOAEC was determined to be at least 0.51 ppm under the conditions of this study.

Reference 2

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

No data

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: 4b The result is sourced from secondary literature (IUCLID 2000 data set). The original reference was not available for review and no further information is available.

Justification for type of information:

Please refer to the attached justification below and the overall justification for grouping of substances attached in IUCLID Section 13.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

Deviations:

yes

Remarks:

Range finding study only

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

inhalation

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

9 days

Frequency of treatment:

6 hr/day, 5 day/wk

Remarks:

Doses / Concentrations:
0.2, 1 and 5 ppm
Basis:

No. of animals per sex per dose:

10/sex/group
Five additional animals/sex were in the control and 5 ppm groups for a l4-day recovery group.

Control animals:

yes, concurrent no treatment

Details on study design:

Three groups, consisting of 10 male and 10 female Sprague Dawley rats, were exposed 6 hours/day, 5 days/week, for 9 days to trimethoxysilane vapor at target concentrations of 0.2, 1, and 5 ppm. A control group was exposed to filtered air alone. Five additional animals/sex were in the control and 5 ppm groups for a l4-day recovery group. 

Observations and examinations performed and frequency:

 Monitors for toxic effects included clinical observations, ophthalmic examinations, body weights, food and water consumption

Sacrifice and pathology:

 Monitors for toxic effects included hematology, serum clinical chemistry evaluations, serum protein fraction evaluation, urinalysis and urine chemistry, organ weights (including uterine and testes weights), necropsy, and histopathology.

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Haematological findings:

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Details on results:

The analytical mean exposure concentrations (+/- SD) of trimethoxysilane vapor were 0.2 (+/- 0.05), 0.9 (+/- 0.12), and 4.9 (+/- 0.35) ppm. 

Clinical observations in the 5 ppm group males and females included perinasal encrustation, cold extremities, blepharospasm, salivation, nasal discharge, prostration, labored respiration, audible respiration, and gasping. In females from the 5 ppm group, dehydration, hunched posture, rapid respiration, swollen periocular tissue, emaciation, and urine stains or urogenital wetness were observed. Tremors were observed in 1 male from this group. Fourteen males and 12 females in the 5 ppm group died between the eighth and twelfth study day. These deaths resulted in the cancellation of the recovery period.  No significant signs were seen in the 0.2 and 1 ppm groups. Both the male and female body weight values and the body weight gains were decreased from Day 2 through Day 12 in the 1 and 5 ppm groups. For the males, the absolute and relative (as percentages of body and brain weights) lung weights in the 1 and 5 ppm groups were increased. The absolute and relative (as percentages of body and brain weights) spleen weights in the 5 ppm group were decreased. For the females, the absolute and relative (as percentages of body and brain weights) lung weights in the 1 and 5 ppm groups were increased.  The absolute and relative (as percentages of body and brain weights) spleen weights in the 5 ppm group were decreased.  Mean corpuscular volume decreased in the males from the 1 ppm group. Serum potassium increased in the males from the 1 ppm group. Necropsy observations in the male and female animals from the 5 ppm group demonstrated decreased spleen size and discoloration of the lungs. Inflammation, degeneration/necrosis of epithelia, squamous metaplasia, and airway fibrosis in the bronchioles in the 5 ppm group of animals were severe and extensive. In the 1 ppm group, lesions included inflammation of the respiratory tract (rhinitis, laryngitis, tracheitis, perivascular infiltrates, and bronchopneumonia) and squamous metaplasia of the nasal mucosa. Within the 5 ppm group, lymphoid depletion in the spleens and lymph nodes and lymphoid necrosis in the thymuses were evident. In the female animals from the 1 ppm group, lymphoid depletion was present in the lymph nodes. These lymphoid tissue effects may have resulted from the stress of exposure to a highly irritant chemical.

Dose descriptor:

LOAEL

Effect level:

1 ppm

Based on:

test mat.

Sex:

male/female

Dose descriptor:

NOEL

Effect level:

0.2 ppm

Based on:

test mat.

Sex:

male/female

Critical effects observed:

yes

The analytical mean exposure concentrations (+/- SD) of trimethoxysilane vapor were 0.2 (+/- 0.05), 0.9 (+/- 0.12), and 4.9 (+/- 0.35) ppm. Clinical observations in the 5 ppm group males and females included perinasal encrustation, cold extremities, blepharospasm, salivation, nasal discharge, prostration, labored respiration, audible respiration, and gasping. In females from the 5 ppm group, dehydration, hunched posture, rapid respiration, swollen periocular tissue, emaciation, and urine stains or urogenital wetness were observed. Tremors were observed in 1 male from this group. Fourteen males and 12 females in the 5 ppm group died between the eighth and twelfth study day. These deaths resulted in the cancellation of the recovery period. No significant signs were seen in the 0.2 and 1 ppm groups. Both the male and female body weight values and the body weight gains were decreased from Day 2 through Day 12 in the 1 and 5 ppm groups. For the males, the absolute and relative (as percentages of body and brain weights) lung weights in the 1 and 5 ppm groups were increased. The absolute and relative (as percentages of body and brain weights) spleen weights in the 5 ppm group were decreased. For the females, the absolute and relative (as percentages of body and brain weights) lung weights in the l and 5 ppm groups were increased. The absolute and relative (as percentages of body and brain weights) spleen weights in the 5 ppm group were decreased. Mean corpuscular volume decreased in the males from the 1 ppm group. Serum potassium increased in the males from the 1 ppm group. Necropsy observations in the male and female animals from the 5 ppm group demonstrated decreased spleen size and discoloration of the lungs. Inflammation, degeneration/necrosis of epithelia, squamous metaplasia, and airway fibrosis in the bronchioles in the 5 ppm group of animals were severe and extensive. In the 1 ppm group, lesions included inflammation of the respiratory tract (rhinitis, laryngitis, tracheitis, perivascular infiltrates, and bronchopneumonia) and squamous metaplasia of the nasal mucosa. Within the 5 ppm group, lymphoid depletion in the spleens and lymph nodes and lymphoid necrosis in the thymuses were evident. In the female animals from the 1 ppm group, lymphoid depletion was present in the lymph nodes. These lymphoid tissue effects may have resulted from the stress of exposure to a highly irritant chemical.

Conclusions:

In a IUCLD 2007 summary of an inhalation range-finding study (reliability score 4) conducted using a protocol similar to OECD 412, and to GLP, trimethoxysilane vapor at 5 ppm was lethal, with death probably being a consequence of respiratory tract injury. Based on the body weights, organ weights, the clinical pathology, and the necropsy and histopathologic observations, the NOAEL for trimethoxysilane in rats exposed for 9 days was 0.2 ppm.

Executive summary:

In a IUCLID 2007 summary of an inhalation range-finding study (reliability score 4) conducted using a protocol similar to OECD 412, and to GLP, trimethoxysilane vapor at 5 ppm was lethal, with death probably being a consequence of respiratory tract injury. At 5 ppm exposure level, observations at necropsy included decreased spleen size, discoloration of lungs, inflammation and degeneration/necrosis of epithelia, squamous metaplasia and airway fibrosis in the bronchioles. These effects were severe and extensive. At 1 ppm, observed effects were inflammation of respiratory tract, squamous metaplasia of nasal mucosa. Also at 5 ppm, lymphoid depletion in spleens and lymph nodes, and lymphoid necrosis in thymus were observed. These effects may have resulted from stress of exposure to a highly irritant substance. Based on the body weights, organ weights, the clinical pathology, and the necropsy and histopathologic observations, the NOAEL for trimethoxysilane in rats exposed for 9 days was 0.2 ppm.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

3.35 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

The study was conducted according to an appropriate OECD test guideline, with acceptable restrictions.

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Reference 1

Endpoint:

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:

19.08.1993 to 06.01.1995

Reliability:

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.

Justification for type of information:

Please refer to the attached justification below and the overall justification for grouping of substances attached in IUCLID Section 13.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

Deviations:

yes

Remarks:

Low exposure concentrations and exposure 5 days/week

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- 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


ENVIRONMENTAL CONDITIONS
- 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

Route of administration:

inhalation

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
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


TEST ATMOSPHERE
- 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:

yes

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

Remarks:

Doses / Concentrations:
0.02, 0.1, and 0.5 ppm
Basis:

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:

None

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- 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.


DETAILED CLINICAL OBSERVATIONS: No data


BODY WEIGHT: Yes
- 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.


FOOD EFFICIENCY:
- 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.


OPHTHALMOSCOPIC EXAMINATION: Yes
- 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


HAEMATOLOGY: Yes
- 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.


CLINICAL CHEMISTRY: Yes
- 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


URINALYSIS: Yes
- 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.


NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see table 2)
HISTOPATHOLOGY: Yes (see table 2)

Statistics:

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.

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):

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.

Dose descriptor:

NOAEC

Effect level:

>= 0.51 ppm

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Dose descriptor:

NOAEC

Effect level:

>= 2.5 mg/m³ air

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Critical effects observed:

no

Conclusions:

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 13-week period for 6 hours/day, 5 days/week, followed by a 4-week recovery period. Mean exposure concentrations of 0.02, 0.10 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 NOAEC was determined to be at least 0.51 ppm under the conditions of this study.

Reference 2

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

No data

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: 4b The result is sourced from secondary literature (IUCLID 2000 data set). The original reference was not available for review and no further information is available.

Justification for type of information:

Please refer to the attached justification below and the overall justification for grouping of substances attached in IUCLID Section 13.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

Deviations:

yes

Remarks:

Range finding study only

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

inhalation

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

9 days

Frequency of treatment:

6 hr/day, 5 day/wk

Remarks:

Doses / Concentrations:
0.2, 1 and 5 ppm
Basis:

No. of animals per sex per dose:

10/sex/group
Five additional animals/sex were in the control and 5 ppm groups for a l4-day recovery group.

Control animals:

yes, concurrent no treatment

Details on study design:

Three groups, consisting of 10 male and 10 female Sprague Dawley rats, were exposed 6 hours/day, 5 days/week, for 9 days to trimethoxysilane vapor at target concentrations of 0.2, 1, and 5 ppm. A control group was exposed to filtered air alone. Five additional animals/sex were in the control and 5 ppm groups for a l4-day recovery group. 

Observations and examinations performed and frequency:

 Monitors for toxic effects included clinical observations, ophthalmic examinations, body weights, food and water consumption

Sacrifice and pathology:

 Monitors for toxic effects included hematology, serum clinical chemistry evaluations, serum protein fraction evaluation, urinalysis and urine chemistry, organ weights (including uterine and testes weights), necropsy, and histopathology.

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Haematological findings:

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Details on results:

The analytical mean exposure concentrations (+/- SD) of trimethoxysilane vapor were 0.2 (+/- 0.05), 0.9 (+/- 0.12), and 4.9 (+/- 0.35) ppm. 

Clinical observations in the 5 ppm group males and females included perinasal encrustation, cold extremities, blepharospasm, salivation, nasal discharge, prostration, labored respiration, audible respiration, and gasping. In females from the 5 ppm group, dehydration, hunched posture, rapid respiration, swollen periocular tissue, emaciation, and urine stains or urogenital wetness were observed. Tremors were observed in 1 male from this group. Fourteen males and 12 females in the 5 ppm group died between the eighth and twelfth study day. These deaths resulted in the cancellation of the recovery period.  No significant signs were seen in the 0.2 and 1 ppm groups. Both the male and female body weight values and the body weight gains were decreased from Day 2 through Day 12 in the 1 and 5 ppm groups. For the males, the absolute and relative (as percentages of body and brain weights) lung weights in the 1 and 5 ppm groups were increased. The absolute and relative (as percentages of body and brain weights) spleen weights in the 5 ppm group were decreased. For the females, the absolute and relative (as percentages of body and brain weights) lung weights in the 1 and 5 ppm groups were increased.  The absolute and relative (as percentages of body and brain weights) spleen weights in the 5 ppm group were decreased.  Mean corpuscular volume decreased in the males from the 1 ppm group. Serum potassium increased in the males from the 1 ppm group. Necropsy observations in the male and female animals from the 5 ppm group demonstrated decreased spleen size and discoloration of the lungs. Inflammation, degeneration/necrosis of epithelia, squamous metaplasia, and airway fibrosis in the bronchioles in the 5 ppm group of animals were severe and extensive. In the 1 ppm group, lesions included inflammation of the respiratory tract (rhinitis, laryngitis, tracheitis, perivascular infiltrates, and bronchopneumonia) and squamous metaplasia of the nasal mucosa. Within the 5 ppm group, lymphoid depletion in the spleens and lymph nodes and lymphoid necrosis in the thymuses were evident. In the female animals from the 1 ppm group, lymphoid depletion was present in the lymph nodes. These lymphoid tissue effects may have resulted from the stress of exposure to a highly irritant chemical.

Dose descriptor:

LOAEL

Effect level:

1 ppm

Based on:

test mat.

Sex:

male/female

Dose descriptor:

NOEL

Effect level:

0.2 ppm

Based on:

test mat.

Sex:

male/female

Critical effects observed:

yes

The analytical mean exposure concentrations (+/- SD) of trimethoxysilane vapor were 0.2 (+/- 0.05), 0.9 (+/- 0.12), and 4.9 (+/- 0.35) ppm. Clinical observations in the 5 ppm group males and females included perinasal encrustation, cold extremities, blepharospasm, salivation, nasal discharge, prostration, labored respiration, audible respiration, and gasping. In females from the 5 ppm group, dehydration, hunched posture, rapid respiration, swollen periocular tissue, emaciation, and urine stains or urogenital wetness were observed. Tremors were observed in 1 male from this group. Fourteen males and 12 females in the 5 ppm group died between the eighth and twelfth study day. These deaths resulted in the cancellation of the recovery period. No significant signs were seen in the 0.2 and 1 ppm groups. Both the male and female body weight values and the body weight gains were decreased from Day 2 through Day 12 in the 1 and 5 ppm groups. For the males, the absolute and relative (as percentages of body and brain weights) lung weights in the 1 and 5 ppm groups were increased. The absolute and relative (as percentages of body and brain weights) spleen weights in the 5 ppm group were decreased. For the females, the absolute and relative (as percentages of body and brain weights) lung weights in the l and 5 ppm groups were increased. The absolute and relative (as percentages of body and brain weights) spleen weights in the 5 ppm group were decreased. Mean corpuscular volume decreased in the males from the 1 ppm group. Serum potassium increased in the males from the 1 ppm group. Necropsy observations in the male and female animals from the 5 ppm group demonstrated decreased spleen size and discoloration of the lungs. Inflammation, degeneration/necrosis of epithelia, squamous metaplasia, and airway fibrosis in the bronchioles in the 5 ppm group of animals were severe and extensive. In the 1 ppm group, lesions included inflammation of the respiratory tract (rhinitis, laryngitis, tracheitis, perivascular infiltrates, and bronchopneumonia) and squamous metaplasia of the nasal mucosa. Within the 5 ppm group, lymphoid depletion in the spleens and lymph nodes and lymphoid necrosis in the thymuses were evident. In the female animals from the 1 ppm group, lymphoid depletion was present in the lymph nodes. These lymphoid tissue effects may have resulted from the stress of exposure to a highly irritant chemical.

Conclusions:

In a IUCLD 2007 summary of an inhalation range-finding study (reliability score 4) conducted using a protocol similar to OECD 412, and to GLP, trimethoxysilane vapor at 5 ppm was lethal, with death probably being a consequence of respiratory tract injury. Based on the body weights, organ weights, the clinical pathology, and the necropsy and histopathologic observations, the NOAEL for trimethoxysilane in rats exposed for 9 days was 0.2 ppm.

Executive summary:

In a IUCLID 2007 summary of an inhalation range-finding study (reliability score 4) conducted using a protocol similar to OECD 412, and to GLP, trimethoxysilane vapor at 5 ppm was lethal, with death probably being a consequence of respiratory tract injury. At 5 ppm exposure level, observations at necropsy included decreased spleen size, discoloration of lungs, inflammation and degeneration/necrosis of epithelia, squamous metaplasia and airway fibrosis in the bronchioles. These effects were severe and extensive. At 1 ppm, observed effects were inflammation of respiratory tract, squamous metaplasia of nasal mucosa. Also at 5 ppm, lymphoid depletion in spleens and lymph nodes, and lymphoid necrosis in thymus were observed. These effects may have resulted from stress of exposure to a highly irritant substance. Based on the body weights, organ weights, the clinical pathology, and the necropsy and histopathologic observations, the NOAEL for trimethoxysilane in rats exposed for 9 days was 0.2 ppm.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

1.34 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

The result is sourced from secondary literature (IUCLID 2000 data set). The original reference was not available for review and no further information is available.

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 data available for triethoxysilane (CAS 998-30-1), however, reliable repeated dose toxicity studies by the oral and inhalation routes are available for the structural analogue substances trimethoxymethylsilane (CAS 1185-55-3) and trimethoxysilane (CAS 2487-90-3). All three substances have the ability to hydrolyse in contact with water to produce structural analogue silanol hydrolysis products, silanetriol and methylsilanetriol.The Si-C bond is stable under physiological conditions; the methyl moiety is thus firmly bound to the silanol group. The latter renders both molecules very polar and ready for rapid excretion via urine. It is therefore considered that read-across between the substances is appropriate. 

The molecular weight difference between target and source chemical is following:

RA from CAS 1185-55-3: 164.28/136.22=1.21

RA from CAS 2487-90-3: 164.28/122.20=1.34

Repeated dose toxicity: oral

In the available key study (DCC, 2005), conducted according to the OECD TG 422, and compliance with GLP, trimethoxymethylsilane (CAS 1185-55-3) in corn oil was administered to Crl:CD®(SD)IGS BR VAF/Plus® rats once daily by oral gavage, seven days per week at approximately the same time each day. Dose levels of methyltrimethoxysilane (MTMS) were 0 (control), 50, 250 and 1000 mg/kg bw/day. MTMS, dissolved in corn oil, was administered by oral gavage once each day for up to 51 consecutive days. Females in each dose level were divided into a toxicity (10 animals/group) and a reproductive group (10 animals/group). A single group of males (10 animals/group) were used for both the toxicity and reproductive phases of the study. Toxicity group females and males were treated for 28 and 29 days, respectively. Reproductive group females were treated for 14 days prior to the mating period, during the mating period, and then up to and including post-partum day 3, for a total of up to 51 days. Males and toxicity group females were sacrificed after they had been treated for 28 days. A functional observational battery (FOB) evaluation for signs of neurobehavioral effects was performed on all adult males and all toxicity group females prior to the start of dosing and during the last week of dosing. Body weights and food consumption were recorded weekly. From all males and all toxicity group females, blood samples were obtained on the day of scheduled necropsy for haematology and clinical chemistry parameters evaluations. Animals were subjected to a complete gross necropsy. Many tissues and organs were collected for histological examination and were weighed. Exposure to MTMS was associated with organ weight and/or histomorphological changes in males (liver, thymus, thyroid, duodenum, jejunum, and red blood cell) and females (liver, thyroid, duodenum, jejunum, and adrenal gland) at dose levels at or above 250 mg/kg bw/day. A marked increase in prothrombin time was observed for males at 250 and 1000 mg/kg bw/day whereas females were unaffected. Exposure was also associated with increased blood platelet concentration for males and females at 1000 mg/kg bw/day. These data support a NOAEL for the toxicity phase of the study of 50 mg/kg bw/day.

The NOAEL for the target chemical is 60.5 mg/kg bw/day.

Repeated dose toxicity: inhalation

Repeated exposure of rats to trimethoxysilane vapour (CAS 2487-90-3) in a 9-day range finding study (BRRC, 1994), conducted similar to the OECD TG 412, and in compliance with GLP, resulted in lethal effects at 5 ppm (0.025 mg/l), attributed to respiratory tract injury. The LOAEC in this study was 1 ppm (5 mg/m³), and the NOAEC was 0.2 ppm (1 mg/m³). The NOAEC for the target chemical is 1.34 mg/m³.

In a subsequent key subchronic vapour inhalation study (BRRC, 1995) with trimethoxysilane vapour (CAS 2487-90-3), conducted similar to the OECD TG 413, and in compliance with GLP, 10 Sprague-Dawley rats per sex per dose (with an additional 5 rats/sex in the control and high exposure groups) were treated with 0.02, 0.099 and 0.51 ppm of unchanged test material in a whole body inhalation system for 6 h/day and 5 days/week for 90 days. The choice of such a low exposure concentration for the repeat-dose studies was determined by the need to minimise suffering of the test animals due to severe respiratory tract injury following exposure to vapour. The control animals were treated with filtered air only. The exposure period wasfollowed by a 4-week recovery period. 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 NOAEC for both local and systemic effects was 0.51 ppm (equivalent to 2.5 mg/m³). The NOAEC for the target chemical is 3.35 mg/m³.

Since the effects observed in the available inhalation studies were a result of the local corrosive effects of trimethoxysilane, there is no proposed classification for systemic effects following repeated exposure.

Repeated dose toxicity: dermal

No data available.

Justification for classification or non-classification

The available data are reliable and suitable for classification. Based on this data, classification for systemic toxicity after repeated exposure according to 67/584/EEC and EC/1272/2008 is not warranted.