Registration Dossier

Diss Factsheets

Administrative data

Description of key information

According to Column 2 of Reach Regulation, the acute oral toxicity study required under Section 8.5.1 of Annex VII, does not need to be conducted as the substance is classified as corrosive to skin.

For inhalation, the key study (BRRC, 1988) was conducted according to a protocol similar to OECD Test Guideline 403 and in compliance with GLP. A series of inhalation exposures were conducted in which five Sprague-Dawley rats/sex were exposed once to trimethoxysilane vapour by static (for 10 or 60 minutes) or dynamic (for 1 or 4 hours) generation methods and then observed for 14 days. The LC50 for the 4-hour exposure was determined to be 60 (45 to 80) ppm (ca. 300 mg/m³ ); there was no significant difference in LC50 values between male and female rats.

In the key dermal acute toxicity study (BRRC, 1988), with no GLP statement page available but conducted according to a protocol similar to OECD Test Guideline 402, rabbits (strain not given) were exposed under occlusive conditions to trimethoxysilane. The dermal LD50 was 7.46 ml/kg bw in male rabbits (ca. 7087 mg/kg bw) and  6.73 ml/kg bw in female rabbits (ca. 6393 mg/kg bw).

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no study available

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:
No data
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
yes
Test type:
standard acute method
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: 51 to 59 days old.
- Weight at study initiation: 136-273 g
- Fasting period before study: No data
- Housing: Five per sex in stainless steel wire-mesh cages
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: No data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-22
- Humidity (%): 40-62
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 27.08.1988 To: 28.09.1988
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: For the static exposure the test substance was placed as received in an open tray at the top of the sealed 120 l chamber and the vapour was allowed to achieve equilibrium. The animals were then placed into the chamber for either a 10 minute or one hour period. For the dynamic exposures, liquid test substance was metered from a syringe pump into a heated evaporator. The resulting vapour was carried into the chamber by an inlet air stream. The animals were then placed into the chamber for either a one or four hour period.
- Exposure chamber volume: 120 litre (static exposure) and 900 litre (dynamic exposure)
- Method of holding animals in test chamber: Animals were housed individually in wire-mesh cages; 26 x 18.5 x 18 cm (static) and 21 x 12.5 x 18 cm(dynamic), inside the larger chamber.
- Source and rate of air:
- Method of conditioning air: No data
- Treatment of exhaust air: No data
- Temperature, humidity, pressure in air chamber: No data


TEST ATMOSPHERE
- Brief description of analytical method used: The concentration of methanol, a reaction product of trimethoxysilane and water, was determined during the exposure. Chamber concentration analysis was assessed by a gas chromatograph equipped with a flame ionization detector to monitor trimethoxysilane and methanol vapor concentrations in the chambers.  The nominal concentrations were determined by dividing the total weight of the test material delivered by the total volume of air which passed through the chamber during the exposure period. 
- Samples taken from breathing zone: No
Analytical verification of test atmosphere concentrations:
yes
Remarks:
gas chromatograph equipped with a flame ionization detector
Duration of exposure:
4 h
Concentrations:
The target concentrations for the static exposures was a saturated vapour. For the one hour dyamic exposure mean concentrations achieved were: 643, 342, 155 and 68 ppm (mean methanol concentrations were 173, 60, 19 and 9 ppm). For the four hour exposure period mean concentrations achieved were 166, 71, 39 and 19 ppm (mean methanol concentrations were 66, 7 and 9 ppm, excluding highest dose level)
No. of animals per sex per dose:
Five
Control animals:
no
Details on study design:
 - Duration of observation period following administration: 14 days
- Frequency of observations and weighing: All animals were observed for signs of toxic and pharmacologic effects on the day of exposure and daily following exposure.  Body weights were recorded prior to exposure and on postexposure Days 7 and 14.
- Necropsy of survivors performed: yes, on all animals
- Other examinations performed: Lungs and livers were collected, fixed and stained, and examined microscopically.
Statistics:
Statistical procedures: The mean and standard deviation of the body weights, body weight changes, and exposure concentrations were calculated.  No statistical comparisons were made.  The 4-hr LC50 value was determined by a modified method of Finney's (1964) probit analysis for males, females, and the combined sexes.
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
60 ppm
95% CL:
>= 45 - <= 80
Exp. duration:
4 h
Key result
Sex:
male
Dose descriptor:
LC50
Effect level:
81 ppm
95% CL:
>= 54 - <= 122
Exp. duration:
4 h
Key result
Sex:
female
Dose descriptor:
LC50
Effect level:
42 ppm
95% CL:
>= 29 - <= 62
Exp. duration:
4 h
Mortality:
Under static conditions all animals died during or within two hours of exposure for 10 minutes or one hour. Under dynamic conditions there were deaths at all concentrations, except 68 ppm (1-hour) and 19 ppm (4-hour) groups. Deaths occurred primarily on post-exposure days six to 13.
Clinical signs:
other: Clinical signs observed during or following the static exposure were: CNS excitation and breathing difficulties, white residue covering eyes, nose and mouth. Under dynamic conditions: 166 ppm: Male - day of exposure: blepharospasm, abdominal breathing, de
Body weight:
Losses in body weight were observed in animals from all one hour and four hour groups during both postexposure weeks.
Gross pathology:
In the static exposure group gross lesions included: mottled red discolouration of the lungs, dark purple discolouration of the liver and clear fluid in the trachea and thoracic cavitiy. Microscopic examination of the lungs from the 10 minute exposure group revealed congestion, oedema and fibrin formation, and in some rats there was exfoliation of the bronchoilar epithelial cells. In the dynamic groups, no gross lesions were reported for either males or females in any groups.  Potential target organs: Lung dysfunction.
Other findings:
The mean (+/- SD) analytical concentrations of trimethoxysilane in the exposure chamber for the 4-hour study were 166 (+/- 14), 71 (+/- 15), 39 (+/- 14), and 19 (+/- 4) ppm.  The mean (+/- SD) methanol concentrations for the 71, 39, and 19 ppm trimethoxysilane exposures were 66 (+/- 54), 7 (+/- 2.5), and 9 (+/- 2) ppm, respectively.  The methanol concentration for the 166 ppm trimethoxysilane exposure was 25 ppm after 51 min of exposure and, thereafter, less than the estimated minimum detection limit of 5 ppm.  The analytical/nominal trimethoxysilane concentrations for these exposures were 0.69, 0.66, 0.49, and 0.84, respectively.  Mean temperature during the 4-hour exposures ranged from 21-24 deg C.  Mean percent relative humidity (+/- SD) during the 4-hour exposures was 37  (+/- 1), 54 (+/- 1), 46 (+/- 2), and 46 (+/1) for 166, 71, 39, and 19 ppm trimethoxysilane, respectively.

Table 1 Summary of mortality data for the dynamic exposure groups.

 Concentration of trimethoxysilane (ppm) Duration (hour)   Sex  Deaths/total
 643  1  5/5
 643  1  F  5/5
 342  1  M  5/5
 342  1  F  5/5
 155  1  M  2/5
 155  1  F  3/5
 68  1  M  0/5
 68  1  F  0/5
 166  4  M  5/5
 166  4  F  5/5
 71  4  M  2/5
 71  4  F  5/5
 39  4  M  0/5
 39  4  F  1/5
 19  4  M  0/5
 19  4  F  0/5

 

Table 2 Summary of mean weight changes in dynamic exposure groups

 Concentration of trimethoxysilane (ppm)*  Mean body weight change (SD) (g)         
      One hour exposure Four hour exposure    
   Day 7  Day 14  Day 7  Day 14
 Males        
1 -55 (7)  -  -63 (8)  -
2  -52 (3)  -27 (7)  -54 (20)
3  -41 (23) -2 (41)   3 (3)  -10 (36)
4  3 (9)  27 (6)  -3 (4)  13 (34)
 Females        
 1  -34 (8)  -  -44 (4)  -
 2  -38 (1)  -  -22 (18)  -
 3  -37 (8)  -42 (25) 2 (2)   -4 (35)
 4  -7 (18)  4 (28)  3 (4)  22 (4)

*One hour exposure: Groups 1, 2, 3, and 4 concentrations of 643, 342, 155 and 68 ppm, respectively.

Four hour exposure: Groups 1, 2, 3, and 4 concentrations of 166, 71, 39 and 19 ppm, respectively.

Interpretation of results:
Category 1 based on GHS criteria
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
In a well conducted acute inhalation toxicity study conducted using a protocol comparable to OECD Test Guideline 403 and in accordance with GLP, the combined LC50 value for the 4-hour exposure was 60 ppm (ca. 300 mg/m3). There was no significant difference in LC50 values between male and female rats.
Executive summary:

In a well conducted acute inhalation toxicity study (reliaility score 1) conducted using a protocol of which elements were comparable to OECD Test Guideline 403 and in accordance with GLP, a series of inhalation exposures was conducted in which five Sprague-Dawley rats/sex were exposed once to trimethoxysilane vapour by static (for 10 or 60 minutes) or dynamic (for 1 or 4 hours) generation methods, and then observed for 14 days. Since the four hour dynamic conditions are most like the OECD test guideline recommendations only results from this part of the study are presented in this summary. The exposure concentrations in this group were 19, 39, 71 and 166 ppm.

There were deaths at all concentrations, except in the 19 ppm groups. Deaths occurred primarily on post-exposure days 6 to 13. Males in the 166 ppm group had blepharospasm, abdominal breathing, decreased motor activity, ataxia,  slow surface-righting reflex on the day of exposure. One rat on postexposure days 9-12 and one on days 11 - 13 had unkempt fur, decreased breathing rate and motor activity. Females in the 166 ppm group had blepharospasm, periocular wetness, decreased breathing and motor activity. Signs during postexposure days 5 -9 included unkempt fur, audible respiration, decreased respiration rate and motor activity. Males of the 71 ppm group had blepharospasm, abdominal breathing, decreased motor activity, ataxia and a slow surface righting reflex on the day of exposure. Signs on post-exposure days 9-13 included unkempt fur, decreased respiration rate and decreased motor activity. In females periocular wetness, abdominal breathing and decreased motor activity were observed during exposure, and unkempt fur and decreased motor activity on postexposure days 10 -14. Similar clinical signs were also observed in the 39 ppm group. Losses in body weight were observed in animals from all one hour and four hour groups during both postexposure weeks. There were no abnormal findings in the gross necropsy examination.

The LC50 for the 4 -hour exposure was determined to be 60 (45 to 80) ppm (ca. 300 mg/m3); there was no significant difference in LC50 values between male and female rats.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
300 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:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
The study was conducted according to a test protocol that is comparable to the appropriate OECD test guideline. It was not compliant with GLP.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Species:
rabbit
Strain:
not specified
Sex:
male/female
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Duration of exposure:
No data
Doses:
4.0, 8.0, and 16.0 ml/kg bw
No. of animals per sex per dose:
4/sex/dose at the  highest dose tested and 5/sex/dose at the two lower doses
Control animals:
no
Details on study design:
The test material was administered by dermal application (under occlusive cover) to three groups of rabbits (4/sex/dose at the  highest dose tested and 5/sex/dose at the two lower doses). The animals  were observed for mortality and toxic effects immediately after dosing  
and daily for a total of 14 days.  At the end of the 14 day observation  period the surviving animals were weighed, sacrificed and necropsied.   
Animals that died during the study were also subjected to a necropsy.
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
7.46 mL/kg bw
95% CL:
>= 5.05 - <= 11.04
Remarks on result:
other: Equivalent to 7087 mg/kg bw based on a density of 0.95
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
6.73 mL/kg bw
95% CL:
>= 3.79 - <= 11.94
Remarks on result:
other: Equivalent to 6393 mg/kg bw based on a density of 0.95
Mortality:
See detail below
Clinical signs:
other: See detail below
Gross pathology:
See detail below
Other findings:
Local cutaneous effects included erythema, edema, necrosis, ecchymosis, fissuring (in one), ulceration, desquamation, scabs and alopecia.

Sluggishness, salivation (in 2), prostration, emaciation and a clear or red discharge around nose (of 2) were among the signs of toxicity observed.  Time to death for most animals ranged from one to 6 days.  One male died at 2 hours.  One affected survivor recovered at 14 days.  Gross pathological findings included bright or dark red lungs, tan to red raised nodules or foci on the lungs, lungs of one with necrotic areas, tan livers, liquid-filled (in one) and intestines (in one) hemorrhaged, white or black foci on stomachs or intestines, cream-colored foci on intestines of one, one with mottled and dark red kidneys and a tan raised mass on the kidney of one.

A few lungs that had tan nodules were subjected to histopathologic evaluation.  These included lungs from 2 males receiving 4.0 ml/kg of test material and one female receiving 8.0 ml/kg.  In addition, a kidney from a female dosed with 4.0 ml/kg was evaluated.  Grossly, this kidney exhibited a tan mass.  Histopathology of the lungs included abscesses, congestion, hemorrhages, edema, alveolar histiocytosis, mononuclear cells and black deposits.  The kidney was found to have interstitial and tubular nephritis resulting from a protozoan infection.

MALES:
Dosage (ml/kg): 16.0
Dead/Dosed: 4/4 (insufficient sample was available for dosing in the usual 5 animals at this dose level; 5/5 mortality ratio assumed for LD50 determination).
Days to Death: 0, 1, 1, 1
Mean Weight, g +/- S.D.:
0 days: 2423 +/- 167
7 days: -
14 days: -
Skin Irritation: Erythema, edema, ecchymosis, necrosis at death 
Signs of Toxicity: Prostration at 1 hr; clear to red discharge on perinasal area of 2 at death. Death of 1 at 2 hr.
Gross Pathology: Lungs dark or bright red; livers tan; stomach of 1 with white foci, lined with pus.

Dosage (ml/kg): 8.0
Dead/Dosed: 3/5
Days to Death: 3, 3, 5
Mean Weight, g +/- S.D.:
0 days: 2333 +/- 73
7 days: 1862 +/- 5
14 days: 1784 +/- 183
Skin Irritation: Erythema, edema, ecchymosis, necrosis at 1 day to death or 14 days; ulceration at death or 14 days; alopecia of 2 at 7 to 14 days; scabs, desquamation on 2 at 14 days.
Signs of Toxicity: Sluggishness at 1 day; salivation in 1 at death (3 days); emaciation at death or 7 days; prostration in 1 at 7 days. 
Gross Pathology: In animals that died, lungs dark red; lungs of 1 with cream-colored foci and necrotic areas; liver of 1 tan; stomach of 1 with black foci; stomach of 1 liquid-filled; intestines hemorrhaged or with white areas.
In survivors, lungs dark red; lungs dark red; lungs of 1 with raised cream-colored areas. 

Dosage (ml/kg): 4.0
Dead/Dosed: 0/5
Days to Death: 
Mean Weight, g +/- S.D.:
0 days: 2709 +/- 236
7 days: 2436 +/- 193
14 days: 2614 +/- 239
Skin Irritation: Erythema, ecchymosis at 1 day; edema at 1 to 14 days; desquamation, necrosis, ulceration, scabs, alopecia at 7 to 14 days.
Signs of Toxicity: Emaciation in 1 at 7 days.  Recovery at 14 days. 
Gross Pathology: Lungs with raised cream-colored areas or dark red foci (lungs of 2 examined microscopically). 

FEMALES:
Dosage (ml/kg): 16.0
Dead/Dosed: 4/4 (insufficient sample was available for
dosing in the usual 5 animals at this dose level; 5/5
mortality ratio assumed for LD50 determination).
Days to Death: 1, 1, 1, 1
Mean Weight, g +/- S.D.:
0 days: 2309 +/- 62
7 days: -
14 days: -
Skin Irritation: Erythema, edema, ecchymosis, necrosis at death
Signs of Toxicity: Prostration at 1 hr; oscillation of eyes of 1 at 1 hr; salivation in 1 at death.
Gross Pathology: Lungs bright to dark red; livers tan; stomachs of 2 with black foci; stomach lining of 1 hemorrhaged; kidneys of 1 mottled dark red.

Dosage (ml/kg): 8.0
Dead/Dosed: 3/5
Days to Death: 3, 3, 6
Mean Weight, g +/- S.D.:
0 days: 2402 +/- 65
7 days: 1930 +/- 156
14 days: 1966 +/- 385
Skin Irritation: Erythema, ecchymosis at 1 day persisting on 2 to death; edema, necrosis at 1 to 14 days or death; desquamation on 2 at 7 to 14 days or death; ulceration on 2 at 7 to 14 days; scabs on 1 at 14 days; alopecia of 1 at 14 days.
Signs of Toxicity: Sluggishness at 1 day; prostration in 1 at 1 day; emaciation at 7 to 14 days or death. 
Gross Pathology: In animals that died, lungs bright to dark red; lungs of 1 with cream-colored foci; intestines with white or cream-colored foci; stomach of 1 liquid-filled.  In survivors, lungs with cream-colored nodules (lungs of 1 examined microscopically); lungs of 1 dark red. 

Dosage (ml/kg): 4.0
Dead/Dosed: 1/5
Days to Death: 4 
Mean Weight, g +/- S.D.:
0 days: 2564 +/- 66
7 days: 2380 +/- 215
14 days: 2530 +/- 183
Skin Irritation: Erythema at 1 day; edema, necrosis at 1 to 14 days; ecchymosis on 2 at 1 day or death; fissuring on 1 at 7 days; ulceration at 7 days or death; scabs, alopecia,
desquamation (on 2) at 7 to 14 days.
Signs of Toxicity: Sluggishness in 1 at 1 day. 
Gross Pathology: In animal that died, lungs bright to dark red.  In survivors, lungs of 2 dark red; kidney of 1 with a raised, cream-colored mass (examined microscopically).

Interpretation of results:
GHS criteria not met
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
In an acute dermal toxicity study (reliability score 2) with no GLP statement page available but conducted using a protocol comparable to OECD Test Guideline 402, the LD50 for trimethoxysilane was 7.46 ml/kg bw in male rabbits (ca. 7087 mg/kg bw) and 6.73 ml/kg bw in female rabbits (ca. 6393 mg/kg bw)
Executive summary:

In an acute dermal toxicity study (reliability score 2) conducted using a protocol comparable to OECD Test Guideline 402 (with no GLP statement page available), trimethoxysilane was administered under an occlusive dressing to the skin of rabbits at doses of 4.0, 8.0, and 16.0 ml/kg bw (4/sex/dose at the highest dose tested and 5/sex/dose at the two lower doses). The LD50 was 7.46 ml/kg bw in male rabbits and 6.73 ml/kg bw in female rabbits. Local cutaneous effects included erythema, oedema, necrosis, echymosis, fissuing (one animal), ulceration, desquamation, scabs and alopecia. Sluggishness, salivation, prostration, emaciation, and a clear or red discharge around the nose were among the clinical findings. Gross pathological findings included bright or dark red lungs, tan to red raised nodules or foci on the lungs, lungs of one with necrotic areas, tan livers, liquid-filled haemorrhaged intestines, white or black foci on stomach or intestines, cream coloured foci on intestines, one with mottled and dark red kidneys and one with tan raised mass on kidney. Histopathology of lungs with tan nodules showed abscesses, congestion, haemorrhages, oedema, alveolar hystiocytosis, mononuclear cells and black deposits. Histopathology of the kidney with raised mass showed effect due to protoaxan infection.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
6 393 mg/kg bw

Additional information

According to Column 2 of Reach Regulation, the acute oral toxicity study required under Section 8.5.1 of Annex VII, does not need to be conducted as the substance is classified as corrosive to skin.

There are five acute oral toxicity studies available for trimethoxysilane, from which 4 reported an LD50 value of > 2000 mg/kg bw and only one reported a value of 1482 mg/kg bw (BRRC, 1988). Therefore, a conclusion on the acute oral classification for the substance could not be made. In addition, the substance is classified as corrosive to skin and the observed macroscopic findings in BRRC (1988) were consistent with the corrosive properties of the test material.  

In the first acute oral toxicity study (BRRC, 1988), with no GLP statement page available but conducted according to a protocol similar to the now deleted OECD Test Guideline 401, trimethoxysilane was administered to rats (strain not given) by oral gavage. Signs of toxicity included sluggishness, distended abdomens, head and body twitches, piloerection, prostration, a moribund appearance, lacrimation, unsteady gait, red crust around nose and eyes, diarrhoea, an unkempt appearance and emaciation. At necropsy the animals that died had gas-filled stomachs and intestines, red and/or thick stomachs, a hard white material in the stomach, red intestines and red liquid-filled abdominal cavities. In survivors, the only macroscopic finding was mottled and tan to dark red appearance of several kidneys. The LD50 was 2337 mg/kg bw in males and 1482 mg/kg bw in females (based on a density of 0.95 g/cm³).

In the second acute oral toxicity study, conducted using a protocol similar to the now-deleted OECD Test Guideline 401 but pre-dating GLP compliance, trimethoxysilane was administered in arachis oil by oral gavage to CD-1 mice (10/sex/dose) at doses of 1.1, 1.7, 2.6, 4.0, 6.0 and 9.0 g/kg body weight using a dose volume of 25 ml/kg body weight. The animals were then observed for 10 days. The number of deaths was 0, 3, 5, 5, 11, 20 for doses of 1.1, 1.7, 2.6, 4.0, 6.0 and 9.0 g/kg body weight, respectively. The LD50 value was concluded to be 5000 mg/kg body weight. Clinical signs included immediate sedation and dyspnoea (Rhole-Poulenc, 1972).

In the third acute oral toxicity study, conducted using a protocol similar to the now-deleted OECD Test Guideline 401 but pre-dating GLP compliance, undiluted trimethoxysilane was administered via oral gavage to Carworth Farms-Elias non-fasted rats (five males/dose). The animals were observed for 14 days then sacrificed for a gross necropsy examination. The animals were sluggish soon after administration. Deaths in the highest dose group occurred within 4 hours of dosing, while most of the deaths in the lower dose groups occurred within 2 days. Necropsy revealed slightly congested lungs, congested kidneys and adrenals, and some gastrointestinal haemorrhage. The livers were mottled and congested with burned areas evident on the surfaces that lay in opposition to stomachs that still contained part of the dose. The LD50 for trimethoxysilane was concluded to be 9.33 (6.69 to 13.0) ml/kg bw (equivalent to 8863 mg/kg bw based on density of 0.95 g/cm³) (Mellon Institute of Industrial Research, 1962).

In the fourth acute oral toxicity study, conducted using a protocol similar to the now-deleted OECD Test Guideline 401 but pre-dating GLP compliance, trimethoxysilane was administered orally by gavage to six groups of five male Sprague-Dawley rats at 0.031, 0.1, 0.316, 1, 3.16, or 10 mL/kg bw (ca. 30, 95, 300, 950, 3002, or 9500 mg/kg bw, density = 0.95 g/cm³) either as a 1% solution in corn oil or undiluted. There were no deaths, clinical signs or adverse necropsy findings at the four lower doses (0.031, 0.1, 0.316, 1.0 ml/kg bw). One animal dosed at 3.16 ml/kg bw died on day 4 post-dosing, but there were no adverse necropsy findings. All animals that received the highest dose of 10 ml/kg bw died within 24 hours of dosing and necropsy findings included congestion of the lungs, kidneys, adrenals, pancreas and spleen, blanching of areas of the liver, and inflammation and gaseous distention of the gastrointestinal tract. Signs of toxicity at the two highest doses included depression, laboured breathing and ataxia. The LD50 for trimethoxysilane was concluded to be 4.47 ml/kg bw (ca. 4246 mg/kg bw) in male rats (Hazleton Laboratories, 1966).

In a brief IUCLID 2007 summary of an acute oral toxicity study (reliability score 4), the LD50 for trimethoxysilane was 6410 mg/kg bw in fasted rats. No further details on the study are available (Raake, 1973).

For inhalation, the key study (BRRC, 1988) was conducted according to a protocol similar to OECD Test Guideline 403 and in compliance with GLP. A series of inhalation exposures were conducted in which five Sprague-Dawley rats/sex were exposed once to trimethoxysilane vapour by static (for 10 or 60 minutes) or dynamic (for 1 or 4 hours) generation methods, and then observed for 14 days. Since the four-hour dynamic conditions are closest to the OECD test guideline recommendations, only results from this part of the study are presented in the endpoint study record. The exposure concentrations in this group were 19, 39, 71 and 166 ppm. Clinical signs were blepharospasm, abdominal breathing, decreased motor activity, ataxia, slow surface-righting reflex, unkempt fur, decreased respiration rate and motor activity.

The LC50 for the 4-hour exposure was determined to be 60 (45 to 80) ppm (ca. 300 mg/m³); there was no significant difference in LC50 values between male and female rats.

The acute inhalation toxicity of trimethoxysilane was investigated in a series of additional supporting studies.

In an acute inhalation toxicity study conducted according to a protocol similar to OECD Test Guideline 403, and in compliance with GLP, groups of five/sex Sprague-Dawley rats were exposed to trimethoxysilane vapour at analytical concentrations of 45, 132, 178, 105 and 232 ppm for 30 minutes. The animals were then observed for 14 days. At the end of the observation period surviving animals were killed and a gross necropsy examination conducted. One male of the 132 ppm group and one male and female of the 232 ppm group died during the observation period. Clinical signs observed immediately after exposure and up to four hours post exposure were increased salivation, rapid and slow breathing, nasal discharge, laboured breathing, red/brown material around the nose, decreased activity and body surface staining. Most of the clinical signs persisted for a few days. In general, group mean body weight losses (except females of the two lowest concentration groups), were observed during the first post exposure week. The 14-day mean body weights exceeded the pretest weights, with the exception of the 105 and 232 ppm group females. At necropsy, the tissues of most animals were normal. Five animals from the two highest exposure groups exhibited mild to moderate red lung discolouration on multiple lobes. The LC50 was greater than the highest concentration of 232 ppm. It was concluded that the NOEL was less than 158 ppm (MPI, 1998, Rel. 1). Others 4-hour studies (reliability score 2) resulted in inhalation LC50s of 31.25 < LC50< 62.5 ppm (ca. 156 < LC50< 312 mg/m³) and 53 ppm (ca. 265mg/m³; nose only) (Mellon Institute, 1962 and Dow Corning Corporation, 1982, respectively).

In the key dermal acute toxicity study (BRRC, 1988), with no GLP statement page available but conducted according to a protocol similar to OECD Test Guideline 402, rabbits (strain not given) were exposed under occlusive conditions to trimethoxysilane. Local skin effects on one or more animals included erythema, edema, necrosis, ecchymosis, fissuring, ulceration, desquamation, scabs and alopecia. Sluggishness, salivation, prostration, emaciation and a clear or red discharge around the nose were among the signs of toxicity observed. The dermal LD50 was 7.46 ml/kg bw in male rabbits (ca. 7087 mg/kg bw) and  6.73 ml/kg bw in female rabbits (ca. 6393 mg/kg bw).

In a supporting dermal acute toxicity study, microscopic examination of the kidneys and urinary bladders, following a 24-hour occluded dermal application of undiluted trimethoxysilane (12.0 and 4.0 ml/kg bw), did not reveal any significant lesions (BRRC, 1991, Rel.2). In another one, trimethoxysilane was applied to the skin of male rabbits for 24 hours using a covered application; the animals were observed for 14 days.  The dermal LD50 from this study was 6.30 mL/kg bw (ca. 5985 mg/kg bw).

Marked erythema of the skin was observed and gross necropsy findings included congested lungs, mottled livers and bright mottled kidneys with prominent markings on the surface.

Justification for classification or non-classification

The evidence suggests that trimethoxysilane does not need be classified for acute oral or dermal toxicity.

Trimethoxyslane is labelled 'Acute toxic Category 1 (vapour) H330: Fatal if inhaled' according to Regulation (EC) No. 1272/2008. This is based on the criteria LC50 = 0.5 mg/L.

In addition, due to the corrosive effects observed in the respiratory tract, the substance is also classified for Specific Target Organ Toxicity (Single Exposure) Category 3 under Regulation (EC) No 1272/2008.