3-aminopropyltriethoxysilane

Endpoint summary

Description of key information

The key acute oral toxicity study, conducted according to a scientifically acceptable protocol but not in compliance with GLP, reports an LD₅₀ value of 1490 mg/kg bw in rat (BRRC, 1981).

The key acute inhalation toxicity study, which was conducted in a manner similar to OECD Test Guideline 403 without information on GLP compliance, reports an LC₅₀ value of >145 mg/m³ (vapour) in rats with no deaths (BRRC, 1982).

The key acute dermal toxicity study, conducted according to a protocol similar to OECD Test Guideline 402 but not in compliance with GLP, reports an LD₅₀ value of 4.29 ml/kg bw (4075 mg/kg bw) (BRRC, 1986).

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study

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
- 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)

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

2.83 mL/kg bw

95% CL:

> 1.61 - < 4.98

Remarks on result:

other: Equivalent to 2690 mg/kg bw

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

1.57 mL/kg bw

95% CL:

> 1.34 - < 1.85

Remarks on result:

other: Equivalent to 1490 mg/kg bw

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

Remarks:

Based on LD50 value for male rats.

Conclusions:

A reliable study conducted very largely in compliance with a standard guideline and probably in accordance with GLP, identified LD50 values of 1.57 and 2.83 ml/kg bw in female and male rats, respectively.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 490 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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

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 laboratory 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

Key result

Sex:

male

Dose descriptor:

LC50

Effect level:

> 5 ppm

Based on:

test mat.

Exp. duration:

6 h

Remarks on result:

other: Equivalent to 45.2 mg/m3 or 0.0452 mg/L

Key result

Sex:

female

Dose descriptor:

LC50

Effect level:

> 16 ppm

Based on:

test mat.

Exp. duration:

6 h

Remarks on result:

other: Equivalent to 145 mg/m3 or 0.145 mg/L

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:

A well reported study, conducted according to generally accepted scientific standards and probably in accordance with GLP, found no toxicity when male and female rats were exposed for 6 h to an atmosphere 'substantially saturated' with the test material. The mean measured concentrations of the test material (after hydrolysis) were 5 and 16 ppm, for male and female rats, respectively.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

> 145 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study

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

95% CL:

> 2.9 - < 6.34

Remarks on result:

other: Equivalent to 4076 mg/kg bw

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 changes 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:

Category 5 based on GHS criteria

Remarks:

Not classified according to Regulation (EC) No 1272/2008

Conclusions:

A reliable study conducted largely in compliance with a standard guideline and probably in accordance with GLP, identified an LD50 of 4.29 ml/kg bw in male and female rabbits (equivalent to 4076 mg/kg bw), with some evidence of toxicity at the lowest tested dose of 1 ml/kg bw.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

4 075 mg/kg bw

Additional information

The key acute oral toxicity study, conducted according to a guideline similar to (the now-deleted) OECD Test Guideline 401 but not in compliance with GLP, involved gavage administration of one of three doses of the neat material to groups male and female rats (BRRC, 1989). An LD₅₀ value of 2.83 and 1.57 ml/kg bw were reported for males and females, respectively (equivalent to 2690 and 1490 mg/kg bw). Gross and microscopic examination revealed kidney damage, particularly in decedents.

A supporting study for acute oral toxicity, with acceptable restrictions and not in compliance with GLP, reported an LD₅₀ value of <2000 mg/kg bw when the test material was administered neat (Rhône-Poulenc Laboratories, 1972). A fairly limited report of an otherwise good study conducted without guideline or GLP compliance, identified an oral LD₅₀ value in the male rat of 7.1 ml/kg bw (equivalent to 6745 mg/kg bw) (Mellon Institute, 1955). Similarly, another supporting study which meets generally accepted scientific principles but was not conducted in compliance with GLP, reports an LD₅₀ of 2.97 ml/kg bw (equivalent to 2822 mg/kg bw) (Bushy Run Research Centre, 1981). A fairly limited report of an otherwise good study conducted without guideline or GLP compliance, identified an oral LD₅₀ value in the rat of 4.2 ml/kg bw (equivalent to 3990 mg/kg bw) (Mellon Institute, 1964). A study conducted without guideline or GLP compliance, identified an oral LD₅₀ value in the rat of 3.65 ml/kg bw (equivalent to 3468 mg/kg bw) (Degussa-Huls AG, 1976). Another non-GLP compliant study conducted according to generally accepted scientific principles is also available for acute oral toxicity study with an LD₅₀ of 1780 mg/kg bw (Mellon Institute, 1956). A well conducted study that predates GLP, identified an oral LD₅₀ value in the male rat of 6.5 ml/kg bw (equivalent to 6175 mg/kg bw) (Mellon Institute, 1960).

The key acute inhalation toxicity study was conducted according to a guideline similar to OECD Test Guideline 403 (limit test) but without information on GLP compliance, reported an LC₅₀ value of >145 mg/m3 (vapour) in rats with no deaths (BRRC, 1982). No overt toxicity was detected in rats of either sex exposed (whole body, 6 h) to the neat substantially saturated vapour. A supporting study, conducted according to OECD Test Guideline 403 supports the key findings with a reported LC₅₀ of 7.35 mg/L (aerosol) (BRRC, 1986). Several reliability 4 studies were also available via the inhalation route, which all support the low acute toxicity of the test material (Mellon Institute, 1956, Mellon Institute, 1960, Mellon Institute, 1964, BRRC, 1989, BRRC, 1981).

In the key acute dermal toxicity study, conducted according to a protocol similar to OECD Test Guideline 402 but not in compliance with GLP, reported that the skin of male and female rabbits was in occluded 24-h contact. An LD₅₀ of 4.29 ml/kg bw (4075 mg/kg bw) was obtained (BRRC, 1986). A supporting study for acute dermal toxicity, conducted according to generally accepted scientific principles but not in compliance with GLP reports an LD₅₀ of 4 ml/kg bw (equivalent to 3800 mg/kg bw) (BRRC, 1981). A second supporting study conducted according to a scientifically acceptable protocol but without GLP, reports the LD₅₀ value in male and female rats of > 8 ml/kg bw and <16 ml/kg bw (equivalent to >7600 and <15200 mg/kg bw) (BRRC, 1989). Similarly, another reliable supporting study reports an acute dermal LD₅₀ of 3.97 ml/kg bw (equivalent to 3772 mg/kg bw) (Mellon Institute, 1960). A reliable study, conducted as a follow-up to the key study of this section and designed to examine renal effects, provided data suggesting that the LD₅₀ in male rabbits would be in excess of 6 ml/kg bw (equivalent to 5700 mg/kg bw). Finally, a reliable study conducted according to a standard guideline but prior to GLP, indicated an LD50 value in male rabbits of 4 ml/kg bw (equivalent to 3800 mg/kg bw) (Mellon Institute, 1955).

Justification for classification or non-classification

Based on the available data, 3-aminopropyl(triethoxy)silane is classified for acute oral toxicity Category 4: H302 "Harmful if swallowed" according to Regulation (EC) No 1272/2008.