Amino functional alkoxysilanes

Endpoint summary

Description of key information

There are no acute toxicity data for the registered substance, trimethoxy(methyl)silane and its reaction products with 3-aminopropyltriethoxysilane and [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (EC 701 -410 -9). Therefore, existing data for its constituents have been used for the assessment of acute oral, inhalation and dermal toxicity endpoints.

Block A

Trimethoxy(methyl)silane (CAS 1185-55-3)

In the acute oral toxicity study with trimethoxy(methyl)silane, conducted prior to OECD Test Guidelines and GLP, an LD50 value of 12.3 ml/kg (equivalent to 11685 mg/kg bw based on density of 0.95) was determined for male rats (Mellon Institute, 1963).

In the acute inhalation toxicity study with trimethoxy(methyl)silane, conducted according to OECD Test Guideline 403 and in compliance with GLP, the LC50 value was concluded to be >7605 ppm (equivalent to 42.1 mg/l) in rats (Dow Corning Corporation, 2006).

In the acute dermal toxicity study with trimethoxy(methyl)silane, conducted according to a protocol similar to OECD Test Guideline 402 but prior to GLP, the LD50 value was concluded to be >10 ml/kg (equivalent to 9500 mg/kg bw based on density of 0.95) in rabbits (Mellon Institute, 1963).

Triethoxy(methyl)silane (CAS 2031-67-6)

In the acute oral toxicity study with triethoxy(methyl)silane, conducted according to the now-deleted OECD Test Guideline 401 and in compliance with GLP, there was no mortality or marked systemic effect in rats and the LD50 value was concluded to be >2007 mg/kg bw (Hazleton France, 1992a).

In the acute inhalation (aerosol) toxicity study with triethoxy(methyl)silane, conducted according to OECD Test Guideline 403 and in compliance with GLP, the LC50 value was concluded to be >13.5 mg/l (Hoechst, AG., 1991).

In the acute dermal toxicity study with triethoxy(methyl)silane, conducted according to OECD Test Guideline 402 and in compliance with GLP, the LD50 value was concluded to be >2007 mg/kg bw following 24-hour dermal exposure (Hazleton France, 1992b).

Block B

3-Aminopropyl(triethoxy)silane (CAS 919-30-2)

In the acute oral toxicity study with 3-aminopropyl(triethoxy)silane, conducted according to EPA OTS 798.1175 (Acute Oral Toxicity) and in compliance with GLP, the LD50 values for female and male rats were 1.57 and 2.83 ml/kg bw, respectively (equivalent to 1492 and 2689 mg/kg bw based on density of 0.95) (Bushy Run Research Center, 1989).

In the acute inhalation toxicity study with 3-aminopropyl(triethoxy)silane, conducted according to OECD Test Guideline 403 and in compliance with GLP, found no toxicity when male and female rats were exposed for 6 h to the substantially saturated vapour; the mean measured concentrations of the test material (after hydrolysis) were 5 and 16 ppm, for male and female rats, respectively. Therefore, the LC50 values were >5 and 16 ppm, for male and female rats, respectively (Bushy Run Research Center, 1982).

In the acute dermal toxicity study with 3-aminopropyl(triethoxy)silane, conducted according to EPA OTS 798.1100 (Acute Dermal Toxicity) and in compliance with GLP, the LD50 value was 4.29 ml/kg bw in male and female rabbits (equivalent to 4076 mg/kg bw based on density of 0.95) (Bushy Run Research Center, 1989).

3-(Trimethoxysilyl)propylamine (CAS 13822-56-5)

In the acute oral toxicity study with 3-(trimethoxysilyl)propylamine, conducted according to a protocol similar to the now-deleted OECD Test Guideline 401 but pre-GLP compliance, the LD50 value was 2.97 ml/kg bw (equivalent to 3030 mg/kg bw based on density of 1.02) (Bushy Run Research Center, 1980).

In the acute dermal toxicity study with 3-(trimethoxysilyl)propylamine, conducted according to a protocol similar to OECD Test Guideline 402 and in compliance with GLP, the LD50 value was 11.3 ml/kg bw in male and female rabbits (equivalent to 11526 mg/kg bw based on density of 1.02) (Bushy Run Research Center, 1980).

Trimethoxy(methyl)silane and its reaction products with [3-(2,3-epoxypropoxy)propyl]trimethoxysilane and 3-(trimethoxysilyl)propylamine (EC No. 701 -408 -8)

In the acute oral toxicity study with trimethoxy(methyl)silane and its reaction products with [3-(2,3-epoxypropoxy)propyl]trimethoxysilane and 3-(trimethoxysilyl)propylamine conducted according to the now-deleted OECD Test Guideline 401 and in compliance with GLP, the LD50 value was concluded to be >2000 mg/kg bw (Dow Corning Corporation, 1990a).

In the acute dermal toxicity study with trimethoxy(methyl)silane and its reaction products with [3-(2,3-epoxypropoxy)propyl]trimethoxysilane and 3-(trimethoxysilyl)propylamine conducted according to OECD Test Guideline 402 and in compliance with GLP, the LD50 was concluded to be > 2000 mg/kg bw (Dow Corning Corporation, 1990b).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

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)

Sex:

male

Dose descriptor:

LD50

Effect level:

12.3 mL/kg bw

Based on:

test mat.

95% CL:

>= 9.98 - < 15.3

Remarks on result:

other: equivalent to 11685 mg/kg bw based on density of 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:

In the acute oral toxicity study with trimethoxy(methyl)silane, conducted prior to OECD Test Guidelines and GLP, an LD50 value of 12.3 ml/kg ( equivalent to 11685 mg/kg bw based on density of 0.95) was determined for male rats.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

16.09.1991 to 13.03.1992

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral 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: Iffa-Crédo, FRANCE
- Age at study initiation: 5-7 wk
- Weight at study initiation: 136-228 g
- Fasting period before study: 17-18 hr
- Housing: 5/cage (separate sexes), polycarbonate cages
- Diet: standard diet ad libitum
- Water: drinking water ad libitum
- Acclimation period: at least 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 30-70
- Air changes (per hr): at least 8
- Photoperiod (hrs dark / hrs light): 12 h/12 h

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

VEHICLE
none

MAXIMUM DOSE VOLUME APPLIED: 2.23 ml/kg bw

Doses:

main study: 2007 mg/kg bw
preliminary study: 504, 1008, 2007 mg/kg bw

No. of animals per sex per dose:

main study: 5
preliminary study: 2

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days (changes to skin and fur, eyes, mucous membranes, respiratory system, circulatory system, autonomic and central nervous system, as well as somato-motor activity and behaviour. Shivering, convulsions, salivation, diarrhoea, lethargy, sleeping and coma were noted with particular attention.)
- Frequency of observations and weighing: deaths and abnormal clinical signs were noted 15 minutes after administration, then 1, 2 and 4 h then daily for 14 days; weighed on day before treatment (day -1), immediately prior to administration of the test substance (day 1), and on Days 8 and 15.
- Necropsy of survivors performed: yes, after the 14 day observation period (Day 15), with particular attention paid to the following organs: liver, heart, kidneys and lungs.

Statistics:

The body weights of the animals were evaluated for each sex. The mean, standard deviation and coefficient of variation were calculated. There were no deaths so an LD50 could not be calculated.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 007 mg/kg bw

Based on:

test mat.

Remarks on result:

other: No deaths at any dose.

Sex:

male/female

Dose descriptor:

LD0

Effect level:

> 2 007 mg/kg bw

Based on:

test mat.

Mortality:

No deaths throughout the study.

Clinical signs:

other: Main study (2007 mg/kg bw) Subdued behaviour in all treated animals at 1, 2 and 4 h, no overt clinical effects at Day 2.

Gross pathology:

No remarkable macroscopic findings.

Table 1: Number of animals dead

 

Dose (mg/kg bw)	Mortality (dead/total)
	Male	Female	Combined
504^a	0/2	0/2	0/4
1008^a	0/2	0/2	0/4
2007^a	0/2	0/2	0/4
2007^b	0/5	0/5	0/10

a. preliminary study

b. main study

Interpretation of results:

GHS criteria not met

Conclusions:

In the acute oral toxicity study with triethoxy(methyl)silane, conducted in according to the now-deleted OECD Test Guideline 401 and in compliance with GLP, there was no mortality or marked systemic effect in rats and the LD50 value was concluded to be 2007 mg/kg bw.

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

No follow up study in females; limited detals of clinical examinations and pathology,

GLP compliance:

no

Test type:

standard acute method

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: no details
- Age at study initiation: 3-4 wk
- Weight at study initiation: 90-120 g
- Fasting period before study: no details
- Housing: no details
- Diet: standard diet ad libitum
- Water: drinking water ad libitum
- Acclimation period: no details

ENVIRONMENTAL CONDITIONS
no details

IN-LIFE DATES: no details

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 5 ml/kg bw (neat test substance)

Doses:

1.25, 2.5, 5.0 ml/kg bw

No. of animals per sex per dose:

5 males/dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: weighed at days 0 and 14; no details on frequency of observations
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

Moving average method.

Sex:

male

Dose descriptor:

LD50

Effect level:

2.97 mL/kg bw

Based on:

test mat.

95% CL:

>= 1.67 - < 5.28

Remarks on result:

other: equivalent to 3030 mg/kg bw based on density of 1.02

Mortality:

See table 1.

Clinical signs:

other: See table 1.

Gross pathology:

Among the survivors at 2.5 ml/kg bw, the rat with weight loss (see table 1) had pus in the lungs. No other remarkable findings in survivors. Those that died had purple colouration in the glandular stomach.

Table 1: Number of animals dead [and with evident toxicity] [and time range within which mortality occurred]

Dose (ml/kg bw)	Mortality (dead/total)	Time range of deaths (days)	Overt toxicity	Weight change (g)
	Male
1.25	0/5	-	-	75 to 107 (mean 95)
2.5	2/5	0,5	Sluggish @ 10 mins; one death @ 15 mins.	-31 to 108 (mean 61)
5.0	4/5	0,0,0,5	Sluggish and unsteady gait @ 2 mins; salivation @ 10 mins; death of 3 @ 6 min-2.5 h.	125

 

Interpretation of results:

GHS criteria not met

Conclusions:

In the acute oral toxicity study with 3-(trimethoxysilyl)propylamine, conducted according to a protocol similar to the now-deleted OECD Test Guideline 401 but pre-GLP compliance, the concluded LD50 value was 2.97 ml/kg bw (equivalent to 3030 mg/kg bw based on density of 1.02).

Reference 4

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Remarks:

This relatively comprehensive report does not provide all the information that would be required by current guidelines; information on the duration of acclimatization and housing conditions would also be required.

Qualifier:

according to guideline

Guideline:

EPA OTS 798.1175 (Acute Oral Toxicity)

Version / remarks:

(as stated in SIAR, 2003, not evident from study report seen by this reviewer)

GLP compliance:

not specified

Remarks:

SIAR (2003) notes that this laboratory was certified at the date of this study

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: no details given
- Age at study initiation: no details given
- Weight at study initiation: 200-300 g
- Fasting period before study: overnight
- Housing: no details given
- Diet: standard diet ad libitum
- Water: drinking water ad libitum
- Acclimation period: no details given

ENVIRONMENTAL CONDITIONS
no details given

IN-LIFE DATES: no details given

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

VEHICLE
n/a

MAXIMUM DOSE VOLUME APPLIED: 4 ml/kg bw

Doses:

4, 2, and 1 ml/kg bw in males; 2, 1.41 and 1 ml/kg bw in females

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations daily, weighing weekly
- Necropsy of survivors performed: yes;  No microscopic exam was conducted on animals dosed at 1 ml/kg. Kidneys and urinary bladders from 5 animals (3 females, 2 males) dosed at 2 ml/kg bw, and 2 males dosed at 4 ml/kg bw were examined histologically.
- Other examinations performed: clinical signs, body weight, histopathology (kidney and urinary bladder of: 2 males at 4 ml/kg bw; 2 males and 3 females at 2 ml/kg bw.

Statistics:

Moving Average Method (Thompson, 1974; Weil, 1983)

Sex:

male

Dose descriptor:

LD50

Effect level:

2.83 mL/kg bw

Based on:

test mat.

95% CL:

>= 1.61 - < 4.98

Remarks on result:

other: equivalent to 2689 mg/kg bw based on density of 0.95

Sex:

female

Dose descriptor:

LD50

Effect level:

1.57 mL/kg bw

Based on:

test mat.

95% CL:

>= 1.34 - < 1.85

Remarks on result:

other: equivalent to 1492 mg/kg bw based on density of 0.95

Mortality:

Deaths at 1.41 and 2 ml/kg bw in females and at 4 and 2 ml/kg bw in males. No deaths in either sex at 1 ml/kg bw. See table 1.

Clinical signs:

other: See table 1

Gross pathology:

See table 2

Other findings:

- Histopathology: examination of the kidneys and urinary bladders of a selected group revealed tubular necrosis in those that died and some evidence of lesser kidney damage in those that survived (see table 2).
- Potential target organs: kidney

Table 1: Number of animals that died, time range for mortality, body weight change and overt toxicity

Dose (ml/kg bw)	Mortality (dead/total)			Time range of deaths (days)	Mean body weights (days 0/7/14) (g)		Overt toxicity
	Male	Female	Combined		Male	Female	Male	Female
1.00	0/5	0/5	0/10	-	238/278/304	211/231/241	None.	Sluggishness, recovery at 2 days.
1.41	-	1/5	-	1	-	212/227/234	-	Sluggishness, periurogenital staining (positive for blood), red encrusted fur around nose; survivors recovered at 2 days.
2.00	1/5	5/5	6/10	2-4	234/251/302	223/-/-	Sluggishness, unkempt appearance, periurogenital brown staining, red encrusted fur around nose and eyes, closed eyelids, emaciation and diarrhoea. Survivors recovered at 5 to 9 days.	Sluggishness, lacrimation, unkempt appearance, red encrusted fur around nose and eyes and diarrhoea.
4.00	4/5	-	-	1-2	244/254/283	-	Sluggishness, lacrimation, kyphosis (curvature of the thoracic spine), piloerection and red encrusted fur around nose. Survivor recovered at 3 days.	-

 

Table 2: Gross and microscopic examinations

Dose (ml/kg bw)	Gross examination		Microscopic examination of kidneys and urinary bladder
	Male	Female	Male	Female
1.00	Nothing remarkable.	Nothing remarkable.	-	-
1.41	-	Victim: lungs dark red; stomach (glandular) white to dark red; intestine filled with yellow liquid. Survivors: nothing remarkable.	-	-
2.00	Victim: bright red lungs; dark red (glandular) stomachs filled with light brown liquid. Survivors: nothing remarkable.	Victims: lungs bright pink; stomachs (glandular) dark red or mottled; stomachs and intestines filled with light brown liquid; intestines of one yellow; kidneys dark red.	Examined 2 survivors: moderate renal tubular hyperplasia (indicative of prior necrosis) and mild tubular mineralization in 1; no urinary bladder lesions	Examined 3 victims: moderate tubular necrosis; mild to moderate tubular mineralization; moderate kidney congestion; no urinary bladder lesions
4.00	Victims: dark red, mottled lungs; dark red (glandular) stomachs; stomachs and intestines filled with yellow liquid; spleen mottled, dark red. Survivor: nothing remarkable.	-	Examined 2 victims: moderate tubular necrosis; marked kidney congestion; epithelial necrosis in the urinary bladder (only 1 rat examined).	-

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

In the acute oral toxicity study with 3-aminopropyl(triethoxy)silane, conducted according to EPA OTS 798.1175 (Acute Oral Toxicity) and in compliance with GLP, the concluded LD50 values for female and male rats were 1.57 and 2.83 ml/kg bw, respectively.

Reference 5

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

02 August 1990 to 22 October 1990

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

1987

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: not specified
- Stability under test conditions: not specified
- Solubility and stability of the test substance in the solvent/vehicle: The test substance was administered undiluted.
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: not applicable

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: not specified
- Preliminary purification step (if any): not specified
- Final dilution of a dissolved solid, stock liquid or gel: not applicable
- Final preparation of a solid: not applicable

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Michigan
- Females (if applicable) nulliparous and non-pregnant: not specified
- Age at study initiation: young adults
- Weight at study initiation: 205-267 g
- Fasting period before study: 16 hours
- Housing: Housed individually in conventional design stainless steel, wire mesh bottom cages.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): not specified
- Humidity (%): not specified
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): not specified

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: not specified

DOSAGE PREPARATION: undiluted

CLASS METHOD
- Rationale for the selection of the starting dose: standard method used

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observed frequently on the day of dosing and twice a day thereafter. Animals were weighed prior to dosing, then at 24 hours after dosing and on days 7 and 14 thereafter.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, organ weights

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

One female died spontaneously. No other deaths were recorded.

Clinical signs:

other: No clinical signs of systemic toxicity were noted in any of the animals.

Gross pathology:

The female that died spontaneously showed gross tissue changes consistent with acute gastritis with regurgitation and inspiration of test material. No such lesions were reported in the rest of the animals. Therefore, this change was considered to be due to gavage treatment. No gross macroscopic changes were noted in the rest of the animals.

Other findings:

- Organ weights: not examined
- Histopathology: not examined
- Potential target organs: not examined

Interpretation of results:

GHS criteria not met

Conclusions:

In the acute oral toxicity study, conducted according to the now-deleted OECD Test Guideline 401 and in compliance with GLP, an LD50 value of >2000 mg/kg bw was concluded.

Reference 6

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2001

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: RCC Ltd., Switzerland
- Age at study initiation: males, 8 weeks, females 10 weeks
- Fasting period before study: 16-20 hours
- Housing: Groups of 3/sex, in Makrolon type-4 cages with standard softwood bedding
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 'Under laboratory conditions, after health examination. Only animals without any visible signs were used for thhhe study.'

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 /- 3
- Humidity (%): 30-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 2 ml/kg bw

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

3 males, 3 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: Mortality and viability were observed once daily during acclimatization period and 1, 2, 3 and 5 hours after test item administration on test day 1 and twice daily during days 2-15. Each animal was examined for changes in appearance and behaviour once daily during the acclimatization phase. 1, 2, 3 and 5 hours after test item administration on test day 1, and once daily during days 2-15. All abnormalities were recorded.

- Necropsy of survivors performed: yes

Statistics:

No statistical analysis was used.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No death occurred during the study.

Clinical signs:

other: In one female, ruffled fur and hunched posture were noted on test day 1. No clinical signs were evident from test day 2 until the end of the observation period.

Gross pathology:

No macroscopic findings were observed at necropsy.

Other findings:

None reported.

Interpretation of results:

GHS criteria not met

Conclusions:

The acute oral toxicity study with N-ethyl-3-trimethoxysilyl-2-methyl-propanamine, conducted according to OECD Test Guideline 423 and in compliance with GLP, the LD50 value was concluded to be >2000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

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.

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 7 605 ppm

Based on:

test mat.

Exp. duration:

6 h

Remarks on result:

other: equivalent to 42.1 mg/L

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:

In the acute inhalation toxicity study with trimethoxy(methyl)silane, conducted according to OECD Test Guideline 403 and in compliance with GLP, the concluded LC50 value was >7605 ppm (equivalent to 42.1 mg/L) in rats.

Reference 2

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

from 3 Sept to 17 Sept 1991

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:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hoechst AG, SPF-Zucht, GERMANY
- Age at study initiation: 8-10 wk
- Weight at study initiation: males 188 (184-191) g; females 190 (185-200) g
- Housing: 1/plastic cage
- Diet: standard diet ad libitum
- Water: drinking water ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 50 +/- 20
- Photoperiod (hrs dark / hrs light): 12h/ 12 h

IN-LIFE DATES: From: 1991-09-03 To: 1991-09-17

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
[from report in German]
- Exposure apparatus: cylindrical plastic cages housed in stainless steel inhalation chamber
- Exposure chamber volume: total volume 60 L
- Method of holding animals in test chamber: rats were fitted into test tubes with a coned end reaching into the test chamber
- Source and rate of air: 800 L/h
- Method of conditioning air: air was led at a constant pressure of 4 bar into a nozzle and through separators and filters
- System of generating particulates/aerosols: test substance was injected contineously into the air flow in the nozzle, primary aerosol built in a four-necked round-bottom flask, through a riser-pipe secondary arosol (smaller particle size) reached the test chamber
- Method of particle size determination: determination not possible

TEST ATMOSPHERE
- Brief description of analytical method used: gas chromatography with FID detector
- Samples taken from breathing zone: yes


TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: not given
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): not given

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

13.5 mg/L

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations 2/day; weights on Days 0, 7 and 14
- Necropsy of survivors performed: yes
- Other examinations performed: no other examinations

Statistics:

Single exposure concentration - no statistics presented.

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 13 500 mg/m³ air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

1/5 males; 0/5 females

Clinical signs:

other: Ataxia, irregular respiration, stupor, altered gait, prostration, tonic convulsions, trembling and reduced spontaneous activity were seen in both sexes during the 14-day observation period.

Body weight:

No treatment-related effect identified.

Gross pathology:

1/5 males had dark red, patchy lungs. [The extent of examination is unclear.]

Table 1: Concentration and mortality per animals treated

Analytical Conc. (mg/L)	Mortality (dead/total)
	Males	Females	Combined
13.5	1/5	0/5	1/10

Interpretation of results:

GHS criteria not met

Conclusions:

In the acute inhalation (aerosol) toxicity study with triethoxy(methyl)silane, conducted according to OECD Test Guideline 403 and in compliance with GLP, the concluded LC50 value was 13.5 mg/L.

Reference 3

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

[as stated in SIAR, 2003, not evident from the study report seen by this reviewer

GLP compliance:

not specified

Remarks:

SIAR (2003) notes that this laboratroy was GLP certified at the date of this study

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: "Hilltop Wistar" - no further details given
- Age at study initiation: not stated
- Weight at study initiation: 200-300 g
- Fasting period before study: no details
- Housing: no details
- Diet: standard diet ad libitum
- Water: drinking water ad libitum
- Acclimation period: no details

ENVIRONMENTAL CONDITIONS
- Temperature (°C): mean chamber concentration 25
- Humidity (%): no details
- Air changes (per hr): no details
- Photoperiod (hrs dark / hrs light): no details

IN-LIFE DATES: no details

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: dynamic
- Exposure chamber volume: 9 l
- Method of holding animals in test chamber: not stated
- Source and rate of air: 2.5 l air/min passed through neat sample at 19 deg C then through test chamber
- Method of conditioning air: air passed through neat sample of test material at 19 deg C
- Temperature, humidity, pressure in air chamber: test chamber 25 deg C, no further details

TEST ATMOSPHERE
- Brief description of analytical method used: gas chromatography
- Samples taken from breathing zone: yes, taken from exposure chambers

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: -
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): -

Analytical verification of test atmosphere concentrations:

yes

Remarks:

gas chromatography

Duration of exposure:

6 h

Remarks on duration:

OECD 403 recommends exposure for 4 h

Concentrations:

"Substantially saturated vapour", measured concentration 5 (+/-2) ppm (males) and 16 (+/-5.8) ppm (females) test material in the test chambers.
The test material concentration in vapour passing to the female test chamber was 90 ppm. Reaction with moisture in the test chambers (from exhaled air and urine) resulted in extensive hydrolysis to ethanol and unspecified other products. Ethanol concentrations of 380 and 490 ppm were reported for test chambers containing the males and females, respectively. [16 ppm would be equivalent to around 145 mg/m3.]

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: daily observations, body weights on days 0, 7, 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

None

Sex:

male

Dose descriptor:

LC50

Effect level:

> 5 ppm

Exp. duration:

6 h

Sex:

female

Dose descriptor:

LC50

Effect level:

> 16 ppm

Exp. duration:

6 h

Mortality:

None (see table 1).

Clinical signs:

other: None (see table 1). Full data are not presented.

Body weight:

See table 1

Gross pathology:

None (see table 1). Full data are not presented.

Other findings:

None

Table 1: Concentrations, mortality or evident toxicity

Sex	Analytical Conc. (ppm)	Mortality (No./total)	Mean body weight change (g) 0-7 days	Mean body weight change (g) 0-14 days	Number with overt toxicity	Number with remarkable gross pathology
males	5 (+/- 2)	0/5	51 (36-61)	71 (62-79)	0/5	0/5
females	16 (+/- 5.8)	0/5	10 (5-14)	18 (9-27)	0/5	0/5

LT50 (median lethal time)
Males: > 6.0 h
Females: > 6.0 h

Interpretation of results:

GHS criteria not met

Conclusions:

In the acute inhalation toxicity study with 3-aminopropyl(triethoxy)silane, conducted according to OECD Test Guideline 403 and in compliance with GLP, found no toxicity when male and female rats were exposed for 6 h to the substantially saturated vapour; the mean measured concentrations of the test material (after hydrolysis) were 5 and 16 ppm, for male and female rats, respectively. Therefore, the concluded LC50 values were >5 and 16 ppm, for male and female rats, respectively.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1963

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

occlusive dressings used

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

Sex:

not specified

Dose descriptor:

LD50

Effect level:

> 10 mL/kg bw

Based on:

test mat.

Remarks on result:

other: equivalent to 9500 mg/kg bw based on density of 0.95.

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

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

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 but prior to GLP, the concluded LD50 value was >10 ml/kg (equivalent to 9500 mg/kg bw based on density of 0.95) in rabbits.

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

16.09.1991 to 10.03.1992

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

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: Iffa-Crédo, FRANCE
- Age at study initiation: 6-8 wk
- Weight at study initiation: 212-259 g (variability within sex <20%)
- Fasting period before study: none specified
- Housing: 1/F1 polycarbonate cage
- Diet: standard diet ad libitum
- Water: drinking water ad libitum
- Acclimation period: at least 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 30-70
- Air changes (per hr): at least 8
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 1991-11-18 To: 1991-12-03

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: back and flanks
- % coverage: approx 10%
- Type of wrap if used: semi-occlusive (perforated adhesive band/elastic crepe bandage)

REMOVAL OF TEST SUBSTANCE
- Washing (if done): wiped with Codex absorbant gauze
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2007 mg/kg bw (2.23 mL/kg bw)
- Concentration (if solution): neat liquid

Duration of exposure:

24 h

Doses:

2007 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observation at 0 and 15 mins, 1, 2 and 4 h, then daily until study completion at 15 days; weighting on Days 0, 8 and 15. The daily observations performed, amongst others, included changes in the fur, in the treated skin, the eyes, mucous membranes, respiratory system, circulatory system, autonomic and central nervous systems, as well as somato-motor activity and behaviour. Shivering, convulsions, salivation, diarhoea, lethargy, sleeping and coma were noted with particular attention.
- Necropsy of survivors performed: yes, on Day 15 all rats were killed and necropsied. Particular attention was paid to liver, heart, kidneys, lungs and skin of application site.
- Other: Cutaneous lesions were evaluated daily for each rat from Days 2 to 15, according to a scale equivalent to that of Draize.

Statistics:

The body weights of the animals were evaluated for each sex, calculating the mean of the values obtained, the standard deviation, the coefficient of variation which indicates the homogeneity of the data.

As no deaths were observed an LD50 could not be calculated.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 007 mg/kg bw

Based on:

test mat.

Mortality:

0/10

Clinical signs:

other: No effects reported.

Gross pathology:

No abnormal observations.

Other findings:

No local effects (erythema or oedema).

Table1. Number of animals dead and with evident toxicity

Dose (mg/kg bw)	Mortality dead/total)			Number with evident toxicity (/total)
	Male	Female	Combined	Male	Female	Combined
2007	0/5	0/5	0/10	0/5	0/5	0/10

 

Interpretation of results:

GHS criteria not met

Conclusions:

In the acute dermal toxicity study with triethoxy(methyl)silane, conducted according to OECD Test Guideline 402 and in compliance with GLP, the concluded LD50 value was >2007 mg/kg bw following 24-hour dermal exposure.

Reference 3

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

Ony 4 males tested at each dose; no follow-up assessment in females. Occlusive covering. Limited detail of clinical examinations and pathology.

GLP compliance:

no

Test type:

standard acute method

Species:

rabbit

Strain:

New Zealand White

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: no details
- Age at study initiation: 3-5 months
- Weight at study initiation: no details
- Fasting period before study: no details
- Housing: no details
- Diet (e.g. ad libitum): no details
- Water (e.g. ad libitum): no details
- Acclimation period: no details

ENVIRONMENTAL CONDITIONS
no details

IN-LIFE DATES: no details

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: no details
- % coverage: no details
- Type of wrap if used: polyethylene

REMOVAL OF TEST SUBSTANCE
- Washing (if done): test substance 'removed' after exposure
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 4, 8 and 16 ml/kg bw (no further details).
- Concentration (if solution): neat

Duration of exposure:

24 h

Doses:

4, 8 and 16 ml/kg bw

No. of animals per sex per dose:

4 males/dose

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: no details
- Necropsy of survivors performed: apparently yes - very limited details given
- Other examinations performed: body weight - very limited details given

Sex:

male

Dose descriptor:

LD50

Effect level:

11.3 mL/kg bw

Based on:

test mat.

95% CL:

>= 5.19 - < 24.7

Remarks on result:

other: equivalent to 11526 mg/kg bw based on density of 1.02

Mortality:

See table 1.

Clinical signs:

other: None reported.

Gross pathology:

See table 1; no further details given.

Other findings:

- Organ weights: not measured
- Histopathology: see table 1
- Potential target organs: insufficient detail available

Table 1: Number of animals dead and with evident toxicity, and time range within which mortality occurred

Dose (ml/kg bw)	Mortality (# dead/total)	Time range of deaths (days)	Local skin effects	Pathology	Body weight change (g) [as reported – initial body weight not given]
4	0/2	-	Scabbing in1 of 2 on day 14	In fatalities: discoloured liver  (mottled red and tan, white spots) and kidneys (tan). In survivors: discoloured livers (dark red) and kidneys (mottled tan and red).	4; 61
8	1/4	9	Erythema, oedema, desquamation and necrosis; full details not presented.		-784 to 239 (mean 239)
16*	3/4	1, 2, 4	Erythema, oedema, desquamation, necrosis and fissuring in the survivor; full details not presented.		59

* two different samples of test substance used for 2 rabbits in each case

Interpretation of results:

GHS criteria not met

Conclusions:

In the acute dermal toxicity study with 3-(trimethoxysilyl)propylamine, conducted according to a protocol similar to OECD Test Guideline 402 and in compliance with GLP, the concluded LD50 value was 11.3 ml/kg bw in male and female rabbits (equivalent to 11526 mg/kg bw based on density of 1.02).

Reference 4

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Qualifier:

according to guideline

Guideline:

EPA OTS 798.1100 (Acute Dermal Toxicity)

Version / remarks:

[as stated in SIAR, 2003; not evident from study report seen by this reviewer]

GLP compliance:

not specified

Remarks:

SIAR (2003) notes that this laboratory was GLP certified at the date of this study

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
- Source: no details given
- Age at study initiation: no details given
- Weight at study initiation: 2-3 kg
- Fasting period before study: no
- Housing: no details given
- Diet: standard diet ad libitum
- Water: drinking water ad libitum
- Acclimation period: not stated

ENVIRONMENTAL CONDITIONS
no details given

IN-LIFE DATES: no details given

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: no details
- Type of wrap if used: impervious wrap covered by Vetrap bandage tape

REMOVAL OF TEST SUBSTANCE
excess liquid removed - no further details
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied: 1, 2, 4 or 8 ml/kg bw
- Concentration: neat
- Constant volume: no

Duration of exposure:

24 h

Doses:

8, 4, 2, and 1 ml/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations daily for 14 days; body weights on days 0, 7 and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, microscopic examination of limited range of tissues

Statistics:

Moving average method (Thompson, 1947; Weil, 1983)

Sex:

male/female

Dose descriptor:

LD50

Effect level:

4.29 mL/kg bw

Based on:

test mat.

95% CL:

>= 2.9 - < 6.34

Remarks on result:

other: equivalent to 4076 mg/kg bw based on density of 0.95

Mortality:

Among groups of males and groups of females, 5/5 and 2/5 died at 8 and 4 ml/kg bw, respectively. There were no deaths at the lower doses of 1 and 2 ml/kg bw. See table 1.

Clinical signs:

other: General signs of toxicity included sluggishness, prostration and diarrhoea. Blood loss around the rectal and urogenital areas were also widespread. See table 1.

Gross pathology:

Treatment-related chages were detected in the following organs: kidney, lungs, liver, stomach, urinary bladder and urethra (see table 2). The kidney was identified as the target organ.

Other findings:

Microscopic examinations (on 2 rabbits/sex for the upper dose groups, 1/sex for the lower dose groups) identified acute renal necrosis in those that died (at 8 and 4 ml/kg bw) with accompanying tubular proteinosis and necrosis or other changes to gastric mucosa. Only mild kidney changes were reported in those of the 4 ml/kg bw groups that survived. No clear treatment-related effects were identified in the urinary bladder. Skin changes were seen in all treated groups, from acute necrotic changes in those that died to inflammation and vascular changes in survivors.

Table 1: Number of animals dead and with evident toxicity, and time range within which mortality occurred

Dose (ml/kg bw)	Mortality (dead/total)			Time range of deaths (days)	Number with evident toxicity
	Male	Female	Combined		Male	Female
1	0/5	0/5	0/10	-	1/5: substantial bleeding around rectal area on day 1, recovery on day 2	1/5: diarrhoea on day 1, recovery on day 2
2	0/5	0/5	0/10	-	1/5: substantial bleeding around rectal area on day 1, recovery on day 4	2/5: substantial bleeding around rectal area on day 1. 1/5: sluggishness on day 1. Recovery on day 2
4	2/5	2/5	4/10	2-3	Victims: 2/2 sluggish, unsteady gait; 1/2 mucus around rectal area, mucus and blood clots under cage on day 2 Survivors: sluggish on day 1. 2/3 had rectal blood loss on day 1. Recovery on days 2-3.	Victims: 2/2 sluggish, blood loss around rectal and vaginal areas on day 1. 1/2 unsteady gait, diarrhoea on day 2 Survivors: sluggishness and blood loss from rectum on day 1. Blood under cage on day 2. 1/3 was emaciated on day 7. Recovery of 2 survivors on day 3.
8	5/5	5/5	10/10	1-2	Sluggishness, prostration, blood loss from urogenital or rectal areas, or salivation.	Sluggishness, prostration, unsteady gait or perianal discharge.

 

Table 2: Effect on body weight and gross pathology

Dose (ml/kg bw)	Mean body weight (kg) (days 0/7/14)		Gross Pathology
	Male	Female	Male	Female
1	2.5/2.6/2.8	2.5/2.6/2.8	No remarkable findings	No remarkable findings
2	2.7/2.6/2.8	2.4/2.4/2.6	Lungs (2/5) dark red or pink	No remarkable findings
4	2.6/2.2/2.4	2.8/2.3/2.6	Victims: lungs (1/2) dark red; stomach (2/2) discoloured; kidney (1/2) haemorrhaged; bladder (1/2) dark red clots; liver (1/2) mottled tan Survivors: lungs mottled or with dark red foci	Victims: lungs (1/2) bright red; stomach (1/5) areas adhered to walls; kidneys haemorrhaged; Urinary bladder (2/2) filled with red liquid; urethra (1/2) haemorrhaged; Survivors: lungs dark red or mottled
8	2.4/-/-	2.4/-/-	Lungs (2/5) bright red, mottled; livers mottled tan; stomachs with haemorrhage (1/5) or mucus (2/5); kidneys haemorrhaged (1/5) or tan (2/5); urinary bladder (2/5) filled with red liquid.	Lungs mottled red or pink; livers (2/5) mottled tan; stomachs with mucus; kidneys (1/5) tan.

Interpretation of results:

GHS criteria not met

Conclusions:

In the acute dermal toxicity study with 3-aminopropyl(triethoxy)silane, conducted according to EPA OTS 798.1100 (Acute Dermal Toxicity) and in compliance with GLP, the concluded LD50 value was 4.29 ml/kg bw in male and female rabbits (equivalent to 4076 mg/kg bw based on density of 0.95).

Reference 5

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

14 August 1990 to 28 August 1990

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

1987

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: not specified
- Stability under test conditions: not specified
- Solubility and stability of the test substance in the solvent/vehicle: The test substance was administered undiluted.
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: not applicable

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: not specified
- Preliminary purification step (if any): not specified
- Final dilution of a dissolved solid, stock liquid or gel: not applicable
- Final preparation of a solid: not applicable

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Langshaw Farms, Augusta, Michigan
- Females (if applicable) nulliparous and non-pregnant: not specified
- Age at study initiation: young, no further information given
- Weight at study initiation: 2.2 - 2.6 kg
- Fasting period before study: none
- Housing: Housed individually in clean, stainless steel cages.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): not specified
- Humidity (%): not specified
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): not specified

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: dorsal area
- % coverage: 10%
- Type of wrap if used: porous gauze dressing

REMOVAL OF TEST SUBSTANCE
- Washing (if done): washed with tap water
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw, volume not specified
- Constant volume or concentration used: yes

Duration of exposure:

24 hours

Doses:

2000 mg/kg kg/bw

No. of animals per sex per dose:

5

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed frequently after dosing, then twice daily thereafter. All rabbits were weighed at 1, 7 and 14 days after the application of the test material.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

Not used.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No deaths occurred during the study period.

Clinical signs:

other: No clinical signs of toxicity occurred during the study period.

Gross pathology:

All animals had changes in skin and changes were not uniformly distributed in the dermal test site. The distribution of skin changes strongly suggest causation by mechanical trauma of handling and/or restrained of the animals.

Other findings:

- Organ weights: not examined
- Histopathology: not examined
- Potential target organs: not examined
:

Interpretation of results:

GHS criteria not met

Conclusions:

In the acute dermal toxicity study, conducted according to OECD Test Guideline 402 and in compliance with GLP, an LD50 value of greater than 2000 mg/kg bw was concluded.

Reference 6

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2001

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: RCC Ltd., Switzerland
- Age at study initiation: males 9 weeks, females 12 weeks
- Fasting period before study: not reported
- Housing: During acclimation, in groups of 5/sex in Makrolon type 4 cages. Individually in Makrolon type-3 cages during treatment and observation.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 'Under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for htis study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/-3
- Humidity (%): 30-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: the back
- % coverage: 10
- Type of wrap if used: Semi-occlusive dressing was wrapped around the abdomen, and fixed with an elastic adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2 ml/kg bw

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5 males, 5 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: Mortality and viability were observed once daily during acclimatization period and 1, 2, 3 and 5 hours after test item administration on test day 1 and twice daily during days 2-15. Each animal was examined for changes in appearance and behaviour once daily during the acclimatization phase. 1, 2, 3 and 5 hours after test item administration on test day 1, and once daily during days 2-15. All abnormalities were recorded. Body weights were recorded on days 1, 8 and 15.

- Necropsy of survivors performed: yes

Statistics:

No statistical analysis was used.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No deaths occurred during the study.

Clinical signs:

other: Reversible slight to moderate reddening (maculated), scaling, and scabbing were noted at the application in 6, 2 and 3 animals respectively. All dermal reactions subsided by day 10. No other clinical signs were observed during the observation period.

Gross pathology:

No macroscopic findings were observed at necropsy.

Other findings:

None reported.

Interpretation of results:

GHS criteria not met

Conclusions:

In the acute dermal toxicity study, conducted according to OECD Test Guideline 402 and in compliance with GLP, the concluded LD50 value was >2000 in male and female rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Additional information

The registered substance trimethoxy(methyl)silane and its reaction products with 3-aminopropyltriethoxysilane and [3-(2,3-epoxypropoxy)propyl]trimethoxysilane is a UVCB substance. The identity and concentration range of the constituents have been determined by GC analysis. A detailed description of the composition can be found in Section 1.2 of IUCLID. There are no acute toxicity data for the registered substance, therefore, data for its constituents have been used for acute oral, inhalation and dermal toxicity endpoints (summarised in Table 1) making it possible to determine the appropriate classification of the substance based on the rules for mixtures specified in Regulation (EC) No 1272/2008.

Table 1 Summary of acute toxicity data for constituents of the registered substance

Block	Chemical Name	CAS Number	Acute oral LD50 (mg/kg bw/day)	Acute inhalation LC50 (mg/l)	Acute dermal LD50 (mg/kg bw/day)
A	Trimethoxy(methyl)silane	1185-55-3	11685	>42.1	>9500
A	Triethoxy(methyl)silane	2031-67-6	>2007	>13.5	>2007
B	3-Aminopropyl(trimethoxy)silane	13822-56-5	3030	-	11526
B	3-Aminopropyl(triethoxy)silane	919-30-2	1490-2690	-	4080
701 -408 -8	Trimethoxy(methyl)silane and its reaction products with [3-(2,3-epoxypropoxy)propyl]trimethoxysilane and 3-(trimethoxysilyl)propylamine	None	>2000		>2000
HP for D	N-ethyl-3-trimethoxysilyl-2-methyl-propanamine	227085-51-0	>2000	-	>2000

Block A

Trimethoxy(methyl)silane (CAS 1185-55-3)

In the acute oral toxicity study with trimethoxy(methyl)silane, conducted prior to OECD Test Guidelines and GLP, an LD50 value of 12.3 ml/kg (equivalent to 11685 mg/kg bw based on density of 0.95) was determined for male rats (Mellon Institute, 1963). In the study 5 male rats were given a single oral gavage administration of 16 and 8 ml undiluted test material/kg. Following administration, the animals were observed for 14 days for signs of toxicity. At the end of the 14-day observation period, necropsy was performed on the surviving animals. Most deaths occurred within the first several hours after dosing. Clinical signs of toxicity were sluggishness and unsteady gait post-dosing. All surviving animals showed body weight gains. At necropsy, gross examination revealed congested lungs, mottled livers with prominent acini and some haemorrhage and congestion of the gastrointestinal tract.

In the acute inhalation toxicity study with trimethoxy(methyl)silane, conducted according to OECD Test Guideline 403 and in compliance with GLP, the LC50 value was >7605 ppm (equivalent to 42.1 mg/l) in rats (Dow Corning Corporation, 2006). In the study 5 male and 5 female rats were exposed for 6 hours to the test material vapours at concentration of 7605 ppm (analytical) by whole body inhalation. Following exposure, the animals were observed for 14 days for signs of toxicity. At the end of the 14-day observation period, necropsy was performed on the surviving animals. No mortality was observed during the observation period. Clinical signs of toxicity included urine staining, discoloured urine, faecal staining, head and muzzle soiling, with all females returning to normal by post exposure day 4. Necropsy findings included urinary bladder calculi and kidney foci in both sexes, an enlarged kidney in one male, and abscessed prostate glands in two males. Urinary tract and prostate disease were 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 disproven as a result of this study.

In the acute dermal toxicity study with trimethoxy(methyl)silane, conducted according to a protocol similar to OECD Test Guideline 402 but prior to GLP, the LD50 value was >10 ml/kg (equivalent to 9500 mg/kg bw based on density of 0.95) in rabbits (Mellon Institute, 1963). In the study 4 rabbits (sex unspecified) were subject to a single 24-hour dermal application of 10 ml/kg bw undiluted test material under occlusive dressing. The animals were observed for signs of toxicity for 14 days. Necropsy was performed at the end of the study. No deaths occurred throughout the observation period. Little skin irritation was observed but some desquamation was found after 14 days. There were no findings at necropsy.

The substance is a part of Block A. It also shares a common silanol hydrolysis product, methylsilanetriol, with the second Block A constituent triethoxy(methyl)silane (CAS 2031-67-6).

Triethoxy(methyl)silane (CAS 2031-67-6)

In the acute oral toxicity study with triethoxy(methyl)silane, conducted in according to the now-deleted OECD Test Guideline 401 and in compliance with GLP, there was no mortality or marked systemic effect in rats and the LD50 value was concluded to be 2007 mg/kg bw (Hazleton France, 1992a). In the study male and female rats were given a single oral gavage administration of 2007 mg undiluted test material/kg bw. Following administration, the animals were observed for 14 days for signs of toxicity. At the end of the 14-day observation period, necropsy was performed on the surviving animals. No deaths occurred throughout the study. Subdued behaviour in all treated animals was observed at 1, 2 and 4 hours post-dosing and no overt clinical effects were observed at Day 2. There were no remarkable macroscopic findings.

In the acute inhalation (aerosol) toxicity study with triethoxy(methyl)silane, conducted according to OECD Test Guideline 403 and in compliance with GLP, the LC50 value was >13.5 mg/l (Hoechst, AG., 1991). In the study 5 male and 5 female rats were subject to a single 4-hour nose only inhalation exposure to the test substance aerosol at concentration of 13.5 mg/l. Following exposure, the animals were observed for 14 days for clinical signs of toxicity. Necropsy was performed at the end of the observation period. Only one male rat died, while all the other animals survived until the end of the study period. Ataxia, irregular respiration, stupor, altered gait, prostration, tonic convulsions, trembling and reduced spontaneous activity were seen in both sexes during the 14-day observation period. Dark red and patchy lungs were seen in the one male rat that died.

In the acute dermal toxicity study with triethoxy(methyl)silane, conducted according to OECD Test Guideline 402 and in compliance with GLP, the LD50 value was >2007 mg/kg bw (Hazleton France, 1992b). In the study male and female rats were subject a single 24-hour dermal application of 2007 mg undiluted test material/kg bw. Following the application, the animals were observed for 14 days for signs of toxicity. At the end of the 14-day observation period, necropsy was performed on the surviving animals. No deaths occurred throughout the study. There were no clinical signs of toxicity. There were no abnormal macroscopic findings.

The substance is a part of Block A. It also shares a common silanol hydrolysis product, methylsilanetriol, with the first Block A constituent trimethoxy(methyl)silane (CAS 1185-55-3).

Block B

3-Aminopropyl(triethoxy)silane (CAS 919-30-2)

In the acute oral toxicity study with 3-aminopropyl(triethoxy)silane, conducted according to EPA OTS 798.1175 (Acute Oral Toxicity) and in compliance with GLP, the LD50 values for female and male rats were 1.57 and 2.83 ml/kg bw, respectively (Bushy Run Research Center, 1989). In the study 5 male and 5 female rats were given a single oral gavage administration of undiluted test material at 4, 2, and 1 ml/kg bw in males and 2, 1.41 and 1 ml/kg bw in females. Following administration, the animals were observed for 14 days for signs of toxicity. At the end of the 14-day observation period, necropsy was performed on the surviving animals. Deaths occurred at 1.41 (1/5) and 2 ml/kg bw (5/5) in females and at 4 (4/5) and 2 ml/kg bw (1/4) in males. No deaths occurred in either sex at 1 ml/kg bw. Sluggishness, lacrimation, kyphosis (curvature of the thoracic spine), piloerection and red encrusted fur around nose was seen in males at 4 ml/kg bw. Survivor recovered at 3 days. Sluggishness, unkempt appearance, periurogenital brown staining, red encrusted fur around nose and eyes, closed eyelids, emaciation and diarrhoea were seen in males at 2 ml/kg bw. Survivors recovered at 5 to 9 days. All females that died at 2 ml/kg bw showed signs of sluggishness, lacrimation, unkempt appearance, red encrusted fur around nose and eyes and diarrhoea. The females at 1.41 ml/kg bw showed signs of sluggishness, periurogenital staining (positive for blood), red encrusted fur around nose; survivors recovered at 2 days. Females at 1 ml/kg bw showed only signs of sluggishness post-dosing, but fully recovered by day 2. Gross and microscopic examination revealed kidney damage, particularly in decedents.

In the acute inhalation toxicity study with 3-aminopropyl(triethoxy)silane, conducted according to OECD Test Guideline 403 and in compliance with GLP. The LC50 values were >5 and 16 ppm, for male and female rats, respectively (Bushy Run Research Center, 1989). In the study 5 male and 5 female rats were subject to a single 6-hour whole body inhalation exposure to the saturated vapour concentration of the test material. The mean measured concentrations of the test material (after hydrolysis) were 5 and 16 ppm, for male and female rats, respectively. Following exposure, the animals were observed for 14 days for signs of toxicity. At the end of the 14-day observation period, necropsy was performed on the surviving animals. No death occurred during the study. No clinical signs were evident during the 14-day study period. No macroscopic findings were observed at necropsy.

In the acute dermal toxicity study with 3-aminopropyl(triethoxy)silane, conducted according to EPA OTS 798.1100 (Acute Dermal Toxicity) and in compliance with GLP, the LD50 value was 4.29 ml/kg bw in male and female rabbits (equivalent to 4076 mg/kg bw based on density of 0.95) (Bushy Run Research Center, 1989). In the study 5 male and 5 female rabbits were subject to a single 24-hour dermal application of undiluted test material at doses of 8, 4, 2, and 1 ml/kg bw. Following application, the animals were observed for 14 days for signs of toxicity. At the end of the 14-day observation period, necropsy was performed on the surviving animals. Among the males and females, 5/5 and 2/5 died at 8 and 4 ml/kg bw, respectively. There were no deaths at the lower doses of 1 and 2 ml/kg bw. General signs of toxicity included sluggishness, prostration and diarrhoea. Blood loss around the rectal and urogenital areas were also widespread. Treatment-related changes at necropsy were detected in the following organs: kidney, lungs, liver, stomach, urinary bladder and urethra. The kidney was identified as the target organ.

The substance is a minor constituent of the registered substance, part of Block B. It also shares a common silanol hydrolysis product, 3-aminopropylsilanetriol, with the other Block B constituent 3-(trimethoxysilyl)propylamine (CAS 13822-56-5).

3-(Trimethoxysilyl)propylamine (CAS 13822-56-5)

In the acute oral toxicity study with 3-(trimethoxysilyl)propylamine, conducted according to a protocol similar to the now-deleted OECD Test Guideline 401 but pre-GLP compliance, the LD50 value was 2.97 ml/kg bw (equivalent to 3030 mg/kg bw based on density of 1.02) (Bushy Run Research Center, 1980). In the study 5 male rats were given a single oral gavage administration of 1.25, 2.5, 5.0 ml undiluted test material/kg bw. Following administration, the animals were observed for 14 days for signs of toxicity. At the end of the 14-day observation period, necropsy was performed on the surviving animals. Deaths occurred at 5 ml/kg bw (4/5) and 2.5 ml/kg bw (2/5). No animals died at 1.25 ml/kg bw. The observed clinical signs included sluggishness and unsteady gait. Among the survivors at 2.5 ml/kg bw, pus in the lungs was seen in one animal. No other remarkable findings were noted in the survivors. The animals that died had purple colouration in the glandular stomach.

In the acute dermal toxicity study with 3-(trimethoxysilyl)propylamine, conducted according to a protocol similar to OECD Test Guideline 402 and in compliance with GLP, the LD50 value was 11.3 ml/kg bw in male and female rabbits (equivalent to 11526 mg/kg bw based on density of 1.02) (Bushy Run Research Center, 1980). In the study 4 male rabbits were subject to a single 24-hour dermal application of undiluted test material at doses of 4, 8 and 16 ml/kg bw. Following application, the animals were observed for 14 days for signs of toxicity. At the end of the 14-day observation period, necropsy was performed on the surviving animals. At 16 ml/kg bw 3/4 animals died, while 1/4 died at 8 ml/kg bw. No clinical signs of toxicity were reported, but severe local effects were observed at the higher dose levels of 8 and 16 ml/kg. In fatalities, necropsy findings were discoloured liver (mottled red and tan, white spots) and kidneys (tan). In survivors, discoloured livers (dark red) and kidneys (mottled tan and red).

The substance is a minor constituent of the registered substance, part of Block B. It also shares a common silanol hydrolysis product, 3-aminopropylsilanetriol, with the other Block B constituent 3-aminopropyl(triethoxy)silane (CAS 919-30-2).

Trimethoxy(methyl)silane and its reaction products with [3-(2,3-epoxypropoxy)propyl]trimethoxysilane and 3-(trimethoxysilyl)propylamine (EC No. 701 -408 -8)

In the key acute oral toxicity study with trimethoxy(methyl)silane and its reaction products with [3-(2,3-epoxypropoxy)propyl]trimethoxysilane and 3-(trimethoxysilyl)propylamine, conducted according to the now-deleted OECD Test Guideline 401 and in compliance with GLP, an LD50 value of greater than 2000 mg/kg bw was concluded (Dow Corning Corporation, 1990a). Following a single oral gavage administration of 2000 mg/kg bw undiluted test material to 5 male and 5 female rats, no test substance-related mortality, clinical signs of toxicity or body weight changes occurred. There were no gross macroscopic abnormalities noted. One female died prior to end of the observation period and its death was attributed to the gavage procedure.

 

In the key acute dermal toxicity study with trimethoxy(methyl)silane and its reaction products with [3-(2,3-epoxypropoxy)propyl]trimethoxysilane and 3-(trimethoxysilyl)propylamine, conducted according to OECD Test Guideline 402 and in compliance with GLP, an LD50 value of greater than 2000 mg/kg bw was concluded (Dow Corning Corporation, 1990b). Following a 24-hour dermal application of 2000 mg/kg bw undiluted test material to the dorsal area of 5 male and 5 female rabbits, no test substance-related mortality, clinical signs of toxicity or body weight changes occurred. Additionally, no gross macroscopic abnormalities were noted.

 

This source substance is the methoxy analogue of the registered methoxy/ethoxy substance (target). Acute toxicity studies for this analogue are included to cover Blocks C to G, and unspecified minor constituents, for which there are no acute toxicity data. The only difference between the target and source substances is one of the three starting materials. The source substance has a starting material, 3-aminopropyl(trimethoxy) silane [237-511-5, 13822-56-5] and the target has the starting material that is the triethoxy analogue, 3-aminopropyl(triethoxy)silane [213-048-4, 919-30-2]. Therefore, the target substance has additional ethoxy constituents. However, whether ethoxy or methoxy, the target and source substance constituents hydrolyse to the same respective silanol hydrolysis products. The only difference is the non-silicon hydrolysis product; the target releases methanol and ethanol, whereas the source substance releases methanol only. The small molecule alkoxysilanes of Block A, Block B and those of Block U1 have similar physicochemical properties as the starting materials. Together they constitute about 60-70% of the substance. Blocks C-G and U2 constitute approximately 20-30% of the substances. These are oligomers formed by combination of the monomer starting materials. Under acidic conditions (pH <4) as experienced in the stomach and relevant to oral studies, the hydrolysis of the source and target substances is rapid and will form the same hydrolysis products. 

 

Table 2: Names of the Blocks in the Source substance (Trimethoxy(methyl)silane and its reaction products with [3-(2,3-epoxypropoxy)propyl]trimethoxysilane and 3-(trimethoxysilyl)propylamine; EC No. 701 -408 -8)

Block	Chemical Name	EC	CAS	Mol Wt	Range
A	Trimethoxy(methyl)silane	214-685-0	1185-55-3	136.22	40-60%
B	3-aminopropyl(trimethoxy) silane	237-511-5	13822-56-5	179.29	5-10%
C	Disilyl(cycloalkylamine), penta(methoxy)-	None	None	383.59 to 473.75	10-20%
D	Trisilyl(alkylamine), octamethoxy-methyl-	None	None	519.82 to 609.97	5-15%
E	Tetrasilyl(alkylamine), decamethoxy-methyl-	None	None	724.12	0-5%
F	Pentasilyl(alkylamine), tridecamethoxy-methyl-	None	None	860.34	0-5%
G	Methyl(methoxy) functional disiloxanes	None	None	226.38 to 269.45	0-2%
U1	Unspecified Silane Substances where each constituent is less than 1%	None	None		0-2%
U2	Unspecified Silyl Substances where each constituent is less than 1%	None	None	>500	0-5%
H1	Methanol	67-56-1	200-659-6	32.07	0-10%

 

Table 2: Names of the Blocks in the Target substance (trimethoxy(methyl)silane and its reaction products with 3-aminopropyltriethoxysilane and [3-(2,3-epoxypropoxy)propyl]trimethoxysilane)

Block	Chemical Name	EC	CAS	Mol Wt Range	Range
A	Triethoxy/methoxy(methyl)silane	214-685-0 217-983-9	1185-55-3 2031-67-6	136.22 to 178.31	50-70%
B	3-aminopropyl-tri(ethoxy/methoxy) silane	237-511-5 213-048-4	13822-56-5 919-30-2	179.29 to 207.35	0-10%
C	Disilyl(cycloalkylamine), penta(ethoxy/methoxy)-	None	None	383.59 to 439.70	5-20%
D	Trisilyl(alkylamine), octa(ethoxy/methoxy)-methyl-	None	None	519.82 to 603.98	5-20%
E	Tetrasilyl(alkylamine), deca(ethoxy/methoxy)-methyl-	None	None	738.14 to 780.23	0-5%
F	Pentasilyl(alkylamine), trideca(ethoxymethoxy)-methyl-	None	None	860.34 to 940.47	0-5%
G	Methyl(ethoxy/methoxy) functional disiloxanes	None	None	226.38 to 240.41	0-2%
U1	Unspecified Silane Substances where each constituent is less than 1%	None	None		0-1%
U2	Unspecified Silyl Substances where each constituent is less than 1%	None	None	>500	0-5%
H1	Methanol	67-56-1	200-659-6	32.07	0-10%
H2	Ethanol	64-17-5	200-578-6	46.07	0-5%

 

Block D

N-ethyl-3-trimethoxysilyl-2-methyl-propanamine (CAS 227085-51-0)

The acute oral toxicity study with N-ethyl-3-trimethoxysilyl-2-methyl-propanamine, conducted according to OECD Test Guideline 423 and in compliance with GLP, the LD50 value was concluded to be >2000 mg/kg bw (RCC, 2001a). In the study 3 male and 3 female rats were given a single oral gavage administration of undiluted test material at 2000 mg/kg bw. Following administration, the animals were observed for 14 days for signs of toxicity. At the end of the 14-day observation period, necropsy was performed on the surviving animals. No death occurred during the study. In one female, ruffled fur and hunched posture were noted on test day 1.  No clinical signs were evident from test day 2 until the end of the observation period. The body weight of the animals was within the range commonly recorded for this strain and age. No macroscopic findings were observed at necropsy.

In the acute dermal toxicity study with N-ethyl-3-trimethoxysilyl-2-methyl-propanamine, conducted according to OECD Test Guideline 402 and in compliance with GLP, the LD50 value was >2000 in male and female rats (RCC, 2001b). In the study 5 male and 5 female rats were subject to a single 24-hour dermal semi-occlusive application of the undiluted test material at doses of 2000 mg/kg bw. Following application, the animals were observed for 14 days for signs of toxicity. At the end of the 14-day observation period, necropsy was performed on the surviving animals. No deaths occurred during the study. Reversible slight to moderate reddening (maculated), scaling, and scabbing were noted at the application site in 6, 2 and 3 animals, respectively. All dermal reactions subsided by day 10. No other clinical signs were observed during the observation period. No macroscopic findings were observed at necropsy.

Data on this substance are relevant as its silanol hydrolysis product is an analogue of the hydrolysis product of constituents trisilyl(alkylamine), octa(ethoxy/methoxy)-methyl- in Block D. Therefore, data on this substance are included as supporting data for completeness.

Conclusion for acute toxicity

It can be seen from the data summarised above that the only constituent that meets the criteria for acute toxicity classification is 3-aminopropyl(triethoxy)silane (CAS 919-30-2), which is classified for acute toxicity Category 4 (oral) in Annex VI of Regulation (EC) No 1272/2008.

Given that the concentration of this constituent in the registered substance (0 to 10%), it does not contribute towards the overall classification according to the rules for mixtures specified in Regulation (EC) No 1272/2008.

For other simple alkoxy and aminofunctional alkoxy constituents with no available data, it can be assumed that these are also not classified for acute toxicity based on weight of evidence for a number of alkyl and amino alkoxysilanes for which measured data indicate no significant differences in acute toxicity properties between methoxy and ethoxy analogues containing the same alkyl or amine groups attached to silicon. Further details of the available data are given in supporting reports attached in Section 13 of IUCLID (PFA, 2013t and PFA, 2013v).

For the trisilane and cyclo-trisilane constituents, no measured data are available for the parent materials. However, these hydrolyse very rapidly, particularly following oral exposure (see Section 4.1), to silanols, methanol and ethanol. In view of the high molecular weight of these parent constituents (>500) it is not anticipated that these would be more hazardous than the simple amino alkoxysilanes or corresponding silanols and it is therefore assumed for the purposes of assessment that these would not contribute to the overall classification of the registered substance for acute systemic toxicity. This conclusion is supported by measured data on trimethoxy(methyl)silane and its reaction products with [3-(2,3-epoxypropoxy)propyl]trimethoxysilane and 3-(trimethoxysilyl)propylamine, which is not classified for acute toxicity via any route.

This substance the methoxy analogue of the registered methoxy/ethoxy substance (target). Acute toxicity studies for this analogue are included to cover Blocks C to G, and unspecified minor constituents, for which there are no acute toxicity data.

Justification for classification or non-classification

Based on the available data for the constituents of trimethoxy(methyl)silane and its reaction products with 3-aminopropyltriethoxysilane and [3-(2,3-epoxypropoxy)propyl]trimethoxysilane, no classification for acute oral, dermal or inhalation toxicity is required according to the rules for mixtures specified in Regulation (EC) No 1272/2008.

The only constituent for which any acute toxicity classification is required is 3-aminopropyl(triethoxy)silane (CAS 919-30-2) which is classified for acute toxicity Category 4 (oral) in Annex VI of Regulation (EC) No 1272/2008. At a concentration ranging from 0 to 10 % in the registered substance, this constituent does not contribute towards the overall classification of the substance.

Since methanol is present in the registered substance at concentration ranging from 0 to 10%, classification STOT SE 2 (eyes and central nervous system) is required for the registered substance according to Annex VI of Regulation (EC) No 1272/2008.