Registration Dossier

Administrative data

Description of key information

In the acute oral toxicity study, conducted according to OECD Test Guideline 401 but not in compliance with GLP, the concluded LD50 values for male and female rats were 7.34 ml/kg and 7.46 ml/kg ( equivalent to 6899 and 7012 mg/kg bw based on relative density of 0.94 g/cm3), respectively (Bushy Run Research Centre, 1984a).

In the acute inhalation toxicity study, conducted according to OECD Test Guideline 403 but not in compliance with GLP, an acute inhalation LC50 value of 2773 ppm (16.8 mg/L) was determined for rats (Bushy Run Research Centre, 1986).

In the acute dermal toxicity study, conducted according to a protocol similar to OECD Test Guideline 402 but not in compliance with GLP, LD50 (rabbit) values of 3.36 ml/kg bw for females and 4 ml/kg bw for males (equivalent to 3158 and 3760 mg/kg bw, respectively, based on relative density of 0.94 g/cm3) were determined (Bushy Run Research Centre, 1984b).

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:
1984
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
The GLP status of the study is uncertain.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
not specified
Remarks:
Although a statement regarding GLP was not available with the study report, it is known that this laboratory conducted studies in compliance with GLP at this time.
Test type:
other: LD50
Limit test:
no
Species:
rat
Strain:
Wistar
Remarks:
Hilltop Wistar albino
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS

- Weight at study initiation: 200- 300g
Route of administration:
other: intubation
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: not reported

Doses:
16.0, 8.0, 4.0, 2.0 and 1.0 ml/kg bw in males; 16.0, 8.0, 4.0 and 2.0 ml/kg bw in females
No. of animals per sex per dose:
45
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: Body weights were recorded on days 0, (before dosing), 7 and 14 (prior to termination).

- Necropsy of survivors performed: yes.

- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: At necropsy, each animal was subjected to gross pathologic evaluation.
Statistics:
LD50 with 95% confidence limits; males 7.34 (4.61 to 11.7) ml/kg; females 7.46 (5.16 to 10.8) ml/kg. LD50 slopes; males 3.67, females 4.22.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
ca. 7.34 - ca. 7.46 mL/kg bw
Based on:
test mat.
Remarks on result:
other: Equivalent to 6899 and 7012 mg/kg bw based on relative density of 0.94 g/cm3
Mortality:
Deaths occurred at 2.5 hours to 4 days.
Clinical signs:
Sluggishness, red to brown discharge (around nose, eyes and anus), lacrimation, piloerection, unkempt appearance, prostation, emaciation and unsteady gait were amongst the signs of toxicity observed. Survivors recovered at one to 5 days. With the exception of an enlarged kidney in one female animal in the 8.0 ml/kg bw dose group, there were no remarkable gross lesions in animals that survived to study termination.   
Body weight:
Males dosed 1 ml/kg gained from the mean of 90g to the mean of 125g, at 2 ml/kg from the mean of 84g to 132g, at 4ml/kg from 68g to 111g and at 8ml/kg from 50g to 90g. Females dosed 2 ml/kg gained from the mean of 39g to 61g, 4 ml/kg from 49g to 63g, at 8ml/kg from 26g to 59g.
Gross pathology:
At necropsy, there were several instances of dark red kidney section among victims.

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

 

Dose
(ml/kg)

Mortality (# dead/total)

Time range of deaths (days)

Male

Female

Combined

16

 5/5

 5/5

 10/10

 0 and 1

8

 3/5

 3/5

 6/10

 1,2,3,4

4

 0/5

 0/5

 0/10

 

2

 1/5

 0/5

 1/10

 3

1

 0/5

 0/5

 0/10

 

 

Interpretation of results:
GHS criteria not met
Conclusions:
The acute oral toxicity study, conducted according to OECD Test Guideline 401 with uncertain GLP status, the concluded LD50 values for male and female rats were 7.34 ml/kg and 7.46 ml/kg (equivalent to 6899 and 7012 mg/kg bw based on relative density of 0.94 g/cm3), respectively.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
6 899 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:
1986
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
The restrictions being that there was no report of whether the study was in compliance with GLP.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS

- Source: Charles River Breeding Laboratories, Inc., Kingston, NY

- Age at study initiation: 53 -56 days

- Housing: Two or three animals per cage were housed in in 23.5x20x18cm high stainless steel wire mesh cages on carriers .

- Diet: Pelleted feed (Certified Rodent Chow 5002, Relaton Purina Co., St. Louis, MO) was available ad libitum except during the exposure.

- Water: ad libitum, except during the exposure.




ENVIRONMENTAL CONDITIONS

- Temperature (°F): 66-76

- Humidity (%): 31-52

- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: none
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION

- Exposure apparatus: A piston pump (Fluid Metering Inc., Oyster Bay, NY)

- Exposure chamber volume: ca. 1330 litres

- Method of holding animals in test chamber: The animals were in wire mesh cages inside the test chamber.

- Source and rate of air: No information available

- Temperature, humidity, pressure in air chamber: The temperature and relative humidity in the animal housing rooms were recorded continuously with a seven day recording hygrothermograph (Cole Parmer Instruments, Chicago, IL). During the exposure the temperature was monitored with an airguide Humidity Indicator (Airguide Instrument Co., Chicago, IL).


TEST ATMOSPHERE

- Brief description of analytical method used: A Perkin-Elmer Model 3920B gas chromatograph equipped with a flame ionization detector was used to monitor the A-171 vapor concentrations in the chambres. A Spectra-Physics Series 4000 central processor, a data interface, and a Perkin-Elmer automatic gas sampling system (station and valve programmer units and a gas sampling valve) were used for the analyses.

- Samples taken from breathing zone: Yes

- The test material originated from a heated evaporator similar in design to that described by Carpenter et al., 1975


Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
1981, 2335, 2798, 3547, and 5372 ppm (analytical). (Target concentrations of 2000, 2400, 2750, 3500 and 5000 ppm)
No. of animals per sex per dose:
5/sex (50 total)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: The animals were weighed prior to exposure and on post-exposure days seven and fourteen.

- Necropsy of survivors performed: yes

- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: The animals were sacrificed following methoxyflurane anesthesis. The rats were exsanguinated by severing the brachial blood vessels and a complete necropsy was performed. Any abnormal tissues were placed in a fixative and saved for possible future histologic examination.
Statistics:
The mean and standard deviations of the body weights, body weight changes and exposure concentrations were calculated. No statistical comparisons were made. The LC50 was determined by the moving averages method of Thompson's (1947) using the 3547, 2798 and 2335 ppm exposure groups.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
2 773 ppm
Exp. duration:
4 h
Mortality:
Mortalities occurred at the 5372, 3547 and 2798 ppm concentrations in both male and female animals (see table 1).
Clinical signs:
other: Clinical signs included perinasal, encrustation, unkempt fur, hypoactivity, blepharospasm, lacrimation, respiratory difficulties (mouth breathing, audible respiration, decreased respiration rate), ataxia, prostration, tremors, distended stomachs, a negati
Body weight:
Depressed mean body weight gains were observed for both sexes of the 1981 and 2335 ppm groups and males of the 2798 ppm group during the first week of the post exposure period, when compared to mean body weight gains observed during the second postexposure week.
Gross pathology:
Two males and four females of the 5372 exposure group had eye opacities with three males and five females also having gas-filled stomachs. There were no other gross lesions in any of the other exposure groups.
Other findings:
No other findings reported.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The acute inhalation toxicity study, conducted according to OECD Test Guideline 403 with uncertain GLP status, an acute inhalation LC50 value of 2773 ppm (16.8 mg/l) was determined for rats.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
16 800 mg/m³

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:
1984
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
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:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS

- Weight at study initiation: 2-3kg
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE

- Area of exposure: clipped, intact skin of the trunk

REMOVAL OF TEST SUBSTANCE

- Washing (if done): After the contact period, excess fluid was removed.
Duration of exposure:
24 hours
Doses:
8.0, 4.0 and 2.0 ml/kg bw
No. of animals per sex per dose:
5/sex/dose, except only 3 females dosed at 8.0 ml/kg bw (due to insufficient amount of test article)
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days

- Frequency of observations and weighing:  Observations for skin reaction were made at one hour, 7 days and 14 days after the contact period. Body weights were recorded on day 0 (before application), 7 and 14 (prior to termination). 

- Necropsy of survivors performed: yes

- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other:  At necropsy, each animal was subjected to gross pathologic evaluation.
Statistics:
LD50's were calculated by the moving average method (Thompson, 1947) and are based on a 14-day observation period.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
3.36 mL/kg bw
Based on:
test mat.
Remarks on result:
other: equivalent to 3158 based on relative density of 0.94 g/cm3
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
4 mL/kg bw
Based on:
test mat.
Remarks on result:
other: equivalent to 3760 mg/kg bw based on relative density of 0.94 g/cm3
Mortality:
Most deaths occurred at one to 5 days (one rabbit died at 8 days).   
Clinical signs:
FEMALES: 8 ml/kg bw : sluggishness, unsteady gait at 3 minutes; marked sluggishness at 15 minutes; prostration at 2 hours. 4 ml/kg bw: Sluggishness, unsteady gait, lacrimation at 17 minutes; unkempt appearance, brown perianal discharge at 1 day. Survivors recovered at 2 days. Prostration in one at 2 days. 2 ml/kg bw: sluggishness at 3.5 hours; unkempt appearance, mild red perinasal discharge at 1 day. Recovery at 2 days.

MALES: 8 ml/kg bw : Immediate signs of discomfort (intense struggling, vocalization); sluggishness to prostration at 1 day. Recovery of survivor at 3 days. 4 ml/kg bw: immediate signs of discomfort; sluggishness, unsteady gait at 1 day. Recovery of survivors at 2 to 3 days. 2 ml/kg bw; immediate signs of discomfort; unsteady gait at 1 days. recovery in 2 days. Emaciation in 1 at 7 days (dead at 8 days).
Body weight:
No data available.
Gross pathology:
At necropsy, lungs appeared red and mottled in animals that died.  A few livers were mottled or had red or white foci in animals that died.  No remarkable findings were noted in survivors.  
Other findings:
- Other observations: Skin reaction included erythema, ecchymosis and desquamation. Discomfort, sluggishness, unsteady gait, and prostration were observed.  Survivors recovered at 2 to 3 days.

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

 

Dose
(mg/kg
bw)

Mortality (# dead/total)

Time range of deaths (days)

Male

Female

Combined

8

 4/5

 3/3

 7/8

 1,2,3

4

 2/5

 3/5

5/10 

 3,4,5

2

 2/5

 1/5

 3/10

 3,8

 

Interpretation of results:
GHS criteria not met
Conclusions:
In the acute dermal toxicity study, conducted according to a protocol similar to OECD Test Guideline 402 without information about GLP compliance, an LD50 (rabbit) values of 3.36 ml/kg bw for females and 4 ml/kg bw for males (equivalent to 3158 and 3760 mg/kg bw, respectively, based on relative density of 0.94 g/cm3) were determined.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
3 158 mg/kg bw

Additional information

In the acute oral toxicity study, conducted according to OECD Test Guideline 401 but not in compliance with GLP, the concluded LD50 values for male and female rats were 7.34 ml/kg and 7.46 ml/kg (equivalent to 6899 and 7012 mg/kg bw based on relative density of 0.94 g/cm3), respectively (Bushy Run Research Centre, 1984a). 5 male and 5 female rats were administered single oral gavage dose of undiluted trimethoxy(vinyl)silane at doses of 16.0, 8.0, 4.0, 2.0 and 1.0 ml/kg bw for males and 16.0, 8.0, 4.0 and 2.0  ml/kg bw for females. Following administration, the animals were observed for 14 days. Body weights and clinical signs were recorded on a regular basis. At the end of the study period, the animals were sacrificed and subject to macroscopic examination. All rats treated with 16 ml/kg bw and 3 male and 3 female rats treated with 8 ml/kg bw died. One male rat treated with 2 ml/kg bw also died. Deaths occurred at 2.5 hours to 4 days post-dosing. Clinical signs included sluggishness, red to brown discharge, lacrimation, piloerection, unkempt appearance, prostration, emaciation and unsteady gait. At necropsy, dark red kidney sections were observed in animals that died at 16 and 8 ml/kg bw. There were no gross necropsy findings in animals that survived to the end of the study.

Several supporting studies were also available for acute oral toxicity.

An acute oral toxicity study conducted in accordance with OECD Test Guideline 423 (acute toxic class method) and in compliance with GLP, determined the LD50 value to be between 300 and 2000 mg/kg bw (Hashima Laboratories, 2005). Based on weight of evidence from several other available acute oral toxicity studies which report LD50s well above the limit dose, the result of this study is considered not to be representative of the acute toxicity of the test material.

An LD50 value of 11.3 ml/kg bw (equivalent to 10961 mg/kg bw) was determined in a reliable study conducted according to OECD Test Guideline 401, but not in compliance (Mellon Institute, 1962).

The LD50 value of 8.2 ml/kg bw (equivalent to 7954 mg/kg bw) was determined in a reliable study conducted according to OECD Test Guideline 401, but not in compliance with GLP (Consultox Laboratories, 1976).

In addition, two reliability 4 sources were also available which are in line with the results of the reliable studies (Smyth et al., 1969, Dow Corning Corporation, 1973).

In the acute inhalation toxicity study, conducted according to OECD Test Guideline 403 but not in compliance with GLP, an acute inhalation LC50 value of 2773 ppm (16.8 mg/L) was determined for rats (Bushy Run Research Centre, 1986). In the study, 5 male and 5 female rats per group were exposed to the vapours of the undiluted test material, trimethoxy(vinyl)silane, at concentrations of 1981, 2335, 2798, 3547, and 5372 ppm via single whole body inhalation for 4 hours. Following exposure, the animals were observed for 14 days. Body weights and clinical signs were recorded on a regular basis. At the end of the study period, the animals were sacrificed and subject to macroscopic examination. Mortalities occurred at the 5372 ppm (all animals died), 3547 ppm (all animals died) and 2798 ppm (2/5 males; 5/5 females) concentrations in both male and female animals Clinical signs included perinasal, encrustation, unkempt fur, hypoactivity, blepharospasm, lacrimation, respiratory difficulties (mouth breathing, audible respiration, decreased respiration rate), ataxia, prostration, tremors, distended stomachs, a negative surface and air righting reflex, and negative toe and tail pinch reflex. Two males and four females of the 5372 ppm exposure group had eye opacities with three males and five females also having gas-filled stomachs. There were no other gross lesions in any of the other exposure groups.

Three reliability 4 studies were also available which support the key findings (Dow Corning Corporation 1973; Bushy Run Research Center, 1984; Smyth, 1969).

In the acute dermal toxicity study, conducted according to a protocol similar to OECD Test Guideline 402 but not in compliance with GLP, an LD50 (rabbit) values of 3.36 ml/kg bw for females and 4 ml/kg bw for males ( equivalent to 3158 and 3760 mg/kg bw, respectively, based on relative density of 0.94 g/cm3) were determined (Bushy Run Research Centre, 1984b). In the study, doses of 8.0, 4.0 and 2.0 ml/kg bw undiluted test material, trimethoxy(vinyl)silane, were applied onto the skin of male and female rabbits under occlusive dressing for 24 hours. Following application, the animals were observed for 14 days. Body weights and clinical signs were recorded on a regular basis. At the end of the study period, the animals were sacrificed and subject to macroscopic examination. Deaths occurred in 4/5 males and 3/3 females at 8 ml/kg bw; 2/5 males and 3/5 females at 4 ml/kg bw; 2/5 males and 1/5 females at 2 ml/kg bw. Most deaths occurred at one to 5 days (one rabbit died at 8 days).   

Signs of local dermal irritation were reported, and clinical signs of toxicity included discomfort, sluggishness, unsteady gait and prostration. At necropsy, lungs were red and mottled, and some livers were mottled with hard red of white foci.

An acute dermal LD50 value of 3.54 ml/kg bw (equivalent to 3434 mg/kg bw) was determined for rabbits in a study which did not meet current guideline requirements for OECD and which was not in compliant with GLP) (Mellon Institute, 1962).

A reliability 4 study was also available (Witco, 1996), which supports the key findings.


Justification for classification or non-classification

Based on the available data trimethoxy(vinyl)silane requires classification for acute inhalation toxicity as Acute Toxicity Category 4 (vapour): H332: Harmful if inhaled, according to Regulation (EC) No 1272/2008. Classification for acute oral and dermal toxicity is not required.