Trimethoxy(methyl)silane

Endpoint summary

Description of key information

The key study for acute oral toxicity in rat reports an LD50 value of 11685 mg/kg in rat (Mellon Institute, 1963; rel 2). Clinical signs of toxicity were sluggishness and unsteady gait post-dosing. At necropsy, gross examination revealed congested lungs, mottled livers with prominent acini and some haemorrhage and congestion of the gastrointestinal tract. The study was well documented and meets generally accepted scientific principles, but was not conducted in compliance with GLP.

The key acute inhalation study reports an LC50 value of >42.1 mg/L (Dow Corning Corporation 2006; rel 1). Clinical signs were urine staining, discoloured urine, fecal staining, head and muzzle soiling. Necropsy findings included urinary bladder calculi and kidney foci in both sexes, an enlarged kidney in one male, and abscessed prostrate glands in two males. The study was conducted according to the appropriate OECD test guideline, and in compliance with GLP.

The key acute dermal LD50 is >9500 mg/kg (Mellon Institute, 1963; rel 2). There were no clinical signs of toxicity and no abnormalities were detected at necropsy. The study was well documented and meets generally accepted scientific principles, but was not conducted in compliance with GLP.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1963

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

Method: 6 male rats were dosed at 6 and 18 ml/kg by peroral intubation of the undiluted test substance. The observation period was 14 days.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: Carworth Farms-Eliss

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS

- Source: The rats were reared at the Mellon Institute

- Age at study initiation: 5-6 weeks

- Weight at study initiation: 90-120g

- Fasting period before study: no

- Diet: Rockland complete rat diet

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 1.9ml

Doses:

16 and 8 ml/kg

No. of animals per sex per dose:

5M

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days

- Necropsy of survivors performed: yes

Statistics:

The method of moving average was used for calculating the median effective dose (LD50)

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

12.3 mL/kg bw

Based on:

test mat.

Remarks on result:

other: (9.98 to 15.3) ml/kg, undiluted.

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

11 685 mg/kg bw

Based on:

test mat.

Remarks on result:

other: calculated using density = 0.95

Mortality:

Most deaths occurred within the first several hours after dosing.

Clinical signs:

other: The animals were sluggish and unsteady in gait soon after dosing.

Gross pathology:

At autopsy, gross examination revealed congested lungs, mottled livers with prominent acini and some haemorrhage and congestion of the gastrointestinal tract.

Table 1: Number of animals dead and time range within which mortality occurred

 

Dose (ml/kg bw)	Mortality (# dead/total)			Time range of deaths (days)
	Male	Female	Combined
16.0	4/5	-	4/5	0,1
8.0	0/5	-	0/5	-

 

Interpretation of results:

GHS criteria not met

Conclusions:

The acute oral LD50 of 12.3 ml/kg (11685 mg/kg) was determined for male rats in a reliable study conducted according to generally accepted scientific principles.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

11 685 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS

- Source: Charles River Laboratories, 401 S. New Hope rd., Raleigh, NC 27610

- Age at study initiation: ca. 9 weeks

- Weight at study initiation: Females: 218.2-226.2 g, Males: 311.9-351.7 g

- Housing: Individually housed in suspended wire-mesh cages during quarantine/acclimation period and during the in-life portion of the study.

- Diet: Certified Rodent Chow #5002, ad libitum, except during exposure

- Water: Municipal water, further purified by reverse osmosis, ad libitum, except during exposure

- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS

- Temperature (°C): 19-25

- Humidity (%): 30-70

- Air changes (per hr): 10-15

- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: not applicable

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION

- Exposure apparatus: A Rochester - type, stainless steel and glass, whole body chamber.

- Exposure chamber volume: 450 litres

- Method of holding animals in test chamber: The animals were positioned in stainless steel exposure caging (two levels of 10 wire mesh cages).

- Source and rate of air: The source of air was a Nash Air Compressor (Model/size AL-574) The test article was metered from a reservoir under nitrogen head space, into the J tube using a Fluid Metering Incorporated pump. Compressed air flowed through the J-tube at a controlled rate of ca 30L/min. The carrier/vapour mixture passed from the J-tube to the inlet port at the top of the exposure chamber. Just prior to entering the exposure chamber, the carrier/vapour mixture combined with chamber supply air (dilution air) and was diluted to the target chamber concentration as it enters the exposure chamber.

- Method of conditioning air: The compressed air which acted as a carrier, was passed through a series of filters to remove contaminants prior to use in test atmosphere generation. Conditioned building air was passed through HEPA and activated charcoal filetrs before delivery to the chamber. Moisture was added as necessary to maintain relative humidity within the required range.

- System of generating particulates/aerosols: Generation of test article vapour concentration was performed using a heated stainless steel J-tube containing a column of stainless steel beads.


- Temperature, humidity, pressure in air chamber: The exposure chamber was operated under dynamic conditions with regard to airflow, temperature, relative humidity and pressure. Chamber temperature was maintained within the range of 21.9-26.4°C, humidity within 37.5-60%. Each exposure chamber contained a temperature/humidity sensor, which was monitored.


TEST ATMOSPHERE

- Brief description of analytical method used: The test article reservoir weight was determined pre- and post-exposure. These data, along with the chamber airflow rate and the vapour generation time, were used to calculate a nominal chamber concentration of test article. In the presence of moisture, methyltrimethoxysilane has the potential to hydrolyze, leading to the formation of methyl alcohol. Therefore, actual chamber concentrations of both test article and methyl alcohol were analyzed using a Varian 3400 gas chromatograph equipped with a flame ionization detector. The concentration of test article and methyl alcohol in the chamber atmosphere during the exposure period was evaluated approximately once every 30 minutes.

- Samples taken from breathing zone: yes



CLASS METHOD (if applicable)

- Rationale for the selection of the starting concentration: The limit test concentration was selected based on the lower explosive level of the material.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

6 h

Concentrations:

8000 ppm (nominal), 7605 ppm (analytical)

No. of animals per sex per dose:

5M/ 5F

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: Observations were carried out daily and body weights were recorded just prior to exposure on day 1, again on day 8 and prior to terminal sacrifice on day 15.

- Necropsy of survivors performed: yes

- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: Signs of toxicity including, but not limited to, changes in the skin and fur, eyes and mucous membranes, respiratory system, circulatory system, autonomic and central nervous systems, motor activity and behaviour pattern. Particular attention was directed to observations of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma. All animals were euthanized on day 15 and subjected to a complete gross pathology examination (no tissues were saved).

Statistics:

The mean chamber concentration of the test substance was calculated along with the standard deviation. Additionally, chamber environmental conditions, including temperature, humidity and airflow were monitored continuously and recorded ca. every 30 min. Mean and standard deviation were calculated for each of these parameters.

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 7 605 ppm

Based on:

test mat.

Exp. duration:

6 h

Mortality:

No mortalities reported.

Clinical signs:

other: Urine staining, discoloured urine, fecal staining, head and muzzle soiling, with all females returning to normal by post exposure day 4. Four of the 5 males were reported normal by post exposure day 5, and all males were normal by post exposure day 10.

Body weight:

Body weights and body weight gains were within normal limits over the duration of the study for all females. Two of the five males demonstrated weight loss during the first week post-exposure, with a return to normal weight gain during the second week.

Gross pathology:

Necropsy findings included urinary bladder calculi and kidney foci in both sexes, an enlarged kidney in one male, and abcessed prostrate glands in two males. Urinary tract and prostate disease was attributed to urolithiasis of uncertain primary aetiology; a direct role for the test article in the formation of urinary calculi could neither be confirmed nor denied as a result of this study.

Other findings:

No other effects reported.

.

Interpretation of results:

GHS criteria not met

Conclusions:

The acute inhalation LC50 value of > 7605 ppm (42.1 mg/L) for rats was determined in a reliable study conducted according to a test appropriate protocol, and in compliance with GLP.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

42.1 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1963

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

occlusive dressings used

Principles of method if other than guideline:

Method: other

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Species:

rabbit

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS

- Source: 'produced locally'

- Age at study initiation: 3 to 5 months

- Weight at study initiation: 2.5kg

- Diet: Rockland rabbit ration

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE

- Type of wrap if used: vinylite or polyethylene sheeting

Duration of exposure:

24 hours

Doses:

10 ml/kg

No. of animals per sex per dose:

4

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days

Statistics:

None

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

> 10 mL/kg bw

Based on:

test mat.

Mortality:

No animals died (0/4).

Clinical signs:

other: Little skin irritation was observed but some desquamation was found after 14 days.

Gross pathology:

None reported.

Other findings:

None reported.

10 ml/kg is calculated to be 9500 mg/kg using the formula

ml/kg = mg/kg*density*1000, where density = 0.95

Interpretation of results:

GHS criteria not met

Conclusions:

The acute dermal LD50 value of >10 ml/kg (>9500 mg/kg) for rabbits was reported in a reliable study conducted according to appropriate protocol. The study was not compliant with GLP.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

9 500 mg/kg bw

Additional information

The acute oral LD50 of 12.3 ml/kg (equivalent to 11685 mg/kg) was determined for male rats in a reliable study conducted according to generally accepted scientific principles, but not in compliance with GLP (Mellon Institute, 1963). The animals were sluggish and unsteady in gait soon after dosing. At autopsy, gross examination revealed congested lungs, mottled livers with prominent acini and some haemorrhage and congestion of the gastrointestinal tract.

A supporting study reporting an LD50 value of 7000mg/kg bw in mouse was also available (Societe des Usines Chimiques Rhone-Poulenc, 1972). The study was conducted according to a protocol equivalent to current guideline, but not in compliance with GLP. At lethal doses (4, 6, 9 and 13.5 g/kg bw) the mice were unreactive, with loss of reflexes and dyspnea, and died within the first 15 minutes post administration. At the non-lethal dose of 2.6 g/kg, the symptoms were similar but alleviated within 2 hours.

A second supporting study was also available for acute oral toxicity, reporting an acute oral LD50 value of >9500 mg/kg bw in rat which was determined in a reliable study conducted according to an appropriate test protocol, but not in compliance with GLP (Hazelton Laboratories, 1966). There were no deaths at any dosage level tested. Signs of toxicity were observed at 10 ml/kg body weight and included depression, laboredlaboured respiration, ataxia, and excessive urination. These signs had completely resolved by day 4 post-dosing. There were no findings at necropsy.

The study by Mellon Institute (1963) was chosen as the key study for acute oral toxicity instead of the more recent report by Societe des Usines Chimiques Rhone-Poulenc (1972) because the newer report used mouse instead of rat as the test species.

The current guideline recommends the use of rat for acute oral toxicity studies. Both studies were reliability 2 and equivalent to current guideline. The choice of key study therefore does not affect classification, as the LD50 values of all studies are well above the cut off point for classification. For the acute dermal and inhalation toxicity, the most recent and high reliability sources available were selected as key. The key study for acute inhalation determined an LC50 value of > 7605 ppm (42.1 mg/L) for rats in a reliable study conducted according to current guideline, and in compliance with GLP (Dow Corning Corporation, 2006). No mortalities were reported. Clinical signs included urine staining, discoloured urine, fecal staining, head and muzzle soiling, with all females returning to normal by post exposure day 4. Four of the 5 males were reported normal by post exposure day 5, and all males were normal by post exposure day 10. Body weights and body weight gains were within normal limits over the duration of the study for all females. Two of the five males demonstrated weight loss during the first week post-exposure, with a return to normal weight gain during the second week. Necropsy findings included urinary bladder calculi and kidney foci in both sexes, an enlarged kidney in one male, and abscessed prostrate glands in two males. Urinary tract and prostate disease was attributed to urolithiasis of uncertain primary aetiology; a direct role for the test article in the formation of urinary calculi could neither be confirmed nor denied as a result of this study. A supporting study was also available for acute inhalation, reporting an LC50 value of >26,000 ppm in rat, which was determined in a reliable study conducted according to an appropriate test protocol but not in compliance with GLP (Mellon Institute 1963). In this study, one group of 6 rats (sex not specified) was exposed to concentrated vapor generated at 22,000 to 27,000 ppm with the following results; 8 hours killed 5 of 6 animals, 4 hours killed 3 of 6 animals and 2 hours killed 1 of 6 animals. All animals appeared to be anaesthetized when removed from the inhalation chambers and most deaths occurred within the ensuing 24-hour period. However, several animals had died before termination of the inhalation period. At autopsy, the victims had diffuse hemorrhage of the lungs. Most of the survivors gained weight during the subsequent 2-week observation period and had no gross pathology evident at sacrifice on the 14th day. A second group of 6 rats (sex not specified) was exposed to metered concentrations for 4 hours, where 26,000 ppm killed 0 of 6 animals. Metered concentration at either 26000ppm or 24000 ppm caused no mortality after a 4-hour inhalation period. The animals appeared to be anesthetized when removed from the chambers but most gained weight (at a normal rate) during the ensuing 2-week observation period. Gross pathology was minimal at sacrifice on the 14th day. A third inhalation toxicity study is available (Dow Corning Corporation, 1982) which has been deemed not reliable. The key study for acute dermal toxicity reports an LD50 value of >10 ml/kg (equivalent to >9500 mg/kg) for rabbits in a reliable study conducted according to an appropriate protocol, but not in compliance with GLP (Mellon Institure, 1963). There were no mortalities. Little skin irritation was observed but some desquamation was found after 14 days. Necropsy findings were not reported.  

Justification for classification or non-classification

Based on the available data trimethoxy(methyl)silane does not require classification for acute toxicity according to Regulation (EC) No. 1272/2008.