Triethoxy(3-isocyanatopropyl)silane

Endpoint summary

Description of key information

In the key acute oral toxicity study, conducted according to OECD Test Guideline 423 and in compliance with GLP, an LD50 value in the range of 300 and 500 mg/kg bw was concluded for triethoxy(3-isocyanatopropyl)silane (Safepharm Laboratories, 2003).

In the key acute dermal toxicity study, which pre-dated GLP but was conducted according to a guideline similar to OECD Test Guideline 402, an LD50 value of 1261 mg/kg bw was concluded (Chem Hygiene Fellowship, 1973c).

An acute inhalation study with the registered substance was included as weight of evidence (Chem Hygiene Fellowship, 1973b). Although the acute inhalation study is reliability 4 it is included because the effects seen are consistent with the severe local effects on the respiratory tract noted in the repeat dose sutdy with a similar read-across isocyanatosilane substance and support the proposed classification for acute inhalation toxicity.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

8 July 2003 to 21 August 2003

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)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Ltd, Margate, Kent, UK
- Age at study initiation: 8 to 12 weeks
- Weight at study initiation: within 20% of the mean of the initial bodyweight of the first treated group
- Fasting period before study: overnight before dosing, and approximately 3 to 4 hours after dosing
- Housing: groups of 3
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25 °C
- Humidity (%): 30 to 70%
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 15 July 2003 To: 16 July 2003 [report gives this date as "necropsy", although animals in the first and second tested groups (at 300 mg/kg bw) were observed for 14 days prior to necropsy]

Route of administration:

oral: gavage

Vehicle:

arachis oil

Remarks:

BP

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 30 mg/ml or undiluted
- Amount of vehicle (if gavage): 10 or 2 ml/kg bw
- Justification for choice of vehicle: no data available
- Lot/batch no. (if required): no data available
- Purity: no data available

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg bw

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: "all available information on the toxicity of the test material"

Doses:

300 and 2000 mg/kg bw

No. of animals per sex per dose:

3 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observed 1/2, 1, 2 and 4 hours after dosing, then once daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

Not applicable

Sex:

female

Dose descriptor:

LD50

Effect level:

>= 300 - <= 500 mg/kg bw

Based on:

test mat.

Remarks on result:

other: Mortality: 0/3 in two 300 mg/kg bw groups; 3/3 in 2000 mg/kg bw group

Mortality:

0/6 animals given 300 mg/kg bw died
3/3 animals given 2000 mg/kg bw died (between 30 minutes and 4 hours after dosing)

Clinical signs:

other: In animals given 300 mg/kg bw, there were no signs of systemic toxicity In animals given 2000 mg/kg bw, hunched posture, ataxia, decreased breathing rate, diarrhoea, diuresis, lethargy and pilo-erection were noted in two animals during the day of dosing

Gross pathology:

In animals given 300 mg/kg bw, no abnormalities were noted at necropsy
In animals given 2000 mg/kg bw, no abnormalities were noted at necropsy for one rat, while abnormally red lungs, dark liver and kidneys, and slight haemorrhage of the gastric mucosa were noted in the other two animals

Other findings:

No data available

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

In an acute oral toxicity study, performed according to OECD Test Guideline 423 and in compliance with GLP, triethoxy(3-isocyanatopropyl)silane was harmful to rats when given as a single oral gavage administration at up to 2000 mg/kg bw. The LD50 value was estimated to be in the range of 300 to 500 mg/kg bw.

Executive summary:

A GLP acute oral study was carried out in female Sprague-Dawley rats exposed to triethoxy(3-isocyanatopropyl)silane by gavage, according to OECD Test Guideline 423 (acute oral toxicity – acute toxic class method).

A group of three females was given a single oral gavage administration of triethoxy(3-isocyanatopropyl)silane at 300 mg/kg bw (in arachis oil BP) and observed for 14 days. No deaths or clinical signs were observed, and no abnormalities were seen upon gross necropsy. The same results were reported for another group of three females treated in the same way.

A further group was treated at a higher dose level of 2000 mg/kg bw (undiluted). All three of the females treated by gavage at this dose level died within four hours of dosing. Clinical effects (hunched posture, ataxia, decreased breathing rate, diarrhoea, diuresis, lethargy and pilo-erection) were noted in two of these animals. Abnormalities seen at necropsy for these two animals included red lungs, dark liver and kidneys, and slight haemorrhage of the gastric mucosa.

Triethoxy(3-isocyanatopropyl)silane was harmful to rats when given as a single oral gavage administration at up to 2000 mg/kg bw. The LD50 value was estimated to be in the range of 300 to 500 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

300 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:

weight of evidence

Study period:

no data available

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

abstract

Remarks:

Although the study was conducted according to a protocol similar to a current guideline test atmosphere concentrations were not verified.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

yes

Remarks:

(insufficient detail to judge compliance with test guideline (study procedure D))

Principles of method if other than guideline:

Two study procedures were followed, A and D. Study procedure A was a non-guideline study from which the LT50 value, the median lethal time (i.e. the length of exposure to "substantially saturated vapor" needed to kill 50% of treated animals), was calculated. Study procedure D was probably similar to OECD guideline 403.

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: no data available
- Age at study initiation: no data available
- Weight at study initiation: no data available
- Fasting period before study: no data available
- Housing: no data available
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: no data available

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data available
- Humidity (%): no data available
- Air changes (per hr): no data available
- Photoperiod (hrs dark / hrs light): no data available

IN-LIFE DATES: no data available

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: glass exposure chamber
- Exposure chamber volume: 9 L
- Method of holding animals in test chamber: no data available
- Source and rate of air: gas washing bottle at 2.5 L/min
- Method of conditioning air: procedure A: dried air was passed through a fritted glass disc immersed to a depth of at least 1.5 inches in test material; procedure D: vapour was generated by feeding the liquid at a constant rate down the inside of a spirally corrugated surface of a minimally-heated one-inch Pyrex tube, through which metered air was passed. Resultant vapour was delivered as in procedure A.
- Treatment of exhaust air: no data available
- Temperature, humidity, pressure in air chamber: no data available

TEST ATMOSPHERE
- Brief description of analytical method used: procedure A: mean vapour calculated from loss in weight of liquid or estimated from the vapour pressure at the actual temperature of the chemical during aeration; procedure D: not checked analytically
- Samples taken from breathing zone: no data available

CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration: no data available

Analytical verification of test atmosphere concentrations:

no

Duration of exposure:

>= 4 - <= 8 h

Remarks on duration:

in procedure D, animals were only exposed for 4 hours, whereas both durations were used in procedure A

Concentrations:

Procedure A: "substantially saturated vapor"
Procedure D: 15, 30 and 60 ppm

No. of animals per sex per dose:

6 animals/dose (sex not specified)

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: no data available
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

No data available

Preliminary study:

No data available

Sex:

not specified

Dose descriptor:

LC50

Effect level:

ca. 33.7 ppm

Based on:

test mat.

95% CL:

15.2 - 74.8

Exp. duration:

4 h

Remarks on result:

other: 33.7 ppm = 0.36 (0.16-0.80) mg/litre; 3/6 deaths at 60 ppm, 4/6 deaths at 30 ppm, 0/6 deaths at 15 ppm

Sex:

not specified

Dose descriptor:

other: LT50

Effect level:

5.3 other: h

Based on:

test mat.

95% CL:

4.3 - 6.5

Remarks on result:

other: LT50 = median lethal time (i.e. the length of exposure to "substantially saturated vapor" needed to kill 50% of treated animals); 6/6 deaths at 8 hours; 1/6 deaths at 4 hours

Mortality:

Procedure A:
1/6 animals exposed to "substantially saturated vapor" for 4 hours died (on day 14)
6/6 animals exposed to "substantially saturated vapor" for 8 hours died (4 on day 0, 2 on day 2)

Procedure D:
0/6 animals exposed to 15 ppm died
4/6 animals exposed to 30 ppm died (on days 2, 8, 10 and 13)
3/6 animals exposed to 60 ppm died (on days 1, 2 and 9)

Clinical signs:

other: Procedure A: In animals exposed to "substantially saturated vapor" for 4 hours, irritated eyes and slight body jerks were noted within 30 min and irregular breathing and apparent listlessness were noted in all rats within 60 min In animals exposed to "sub

Body weight:

Procedure A:
In animals exposed to "substantially saturated vapor" for 4 hours, weight changes of -26 to +37 were reported
In animals exposed for 8 hours, weight change was not recorded [presumably due to mortality]

Procedure D:
In animals exposed to 15 ppm, weight changes of -7 to +69 were reported
In animals exposed to 30 ppm, weight changes of -26 to -2 were reported
In animals exposed to 60 ppm, weight changes of -12 to +6 were reported

Gross pathology:

Procedure A:
Victim exposed for 4 hours: lungs mostly haemorrhaged and scattered areas of pneumonia. Mostly autolysed
Survivors exposed for 4 hours: various degrees of pneumonia
Victims exposed for 8 hours: all had froth in the trachea, scattered haemorrhage in all lobes of lungs, fluid in pleural cavity and yellow intestines. Two had pneumonia

Procedure D:
Survivors exposed to 15 ppm: various degrees of pneumonia in 5/6 animals, one appeared normal
Victims exposed to 30 ppm: three completely autolysed and cannibalised, the fourth partially autolysed with lungs 50% haemorrhaged
Survivors exposed to 30 ppm: scattered areas of pneumonia in three rats [although report also states that only two rats survived at this dose]
Victims exposed to 60 ppm: one completely autolysed and cannibalised, lungs mostly haemorrhaged in others
Survivors exposed to 60 ppm: scattered pneumonia in all lobes of lungs

Other findings:

No data available

Interpretation of results:

Category 1 based on GHS criteria

Conclusions:

In a study probably similar to that described by OECD Test Guideline 403, triethoxy(3-isocyanatopropyl)silane was extremely toxic to rats following acute inhalation exposure, as described in two summary reports. A 4-hour inhalation LC50 of 33.7 ppm (0.36 mg/litre) was derived.

Executive summary:

Two summary reports describe an acute inhalation toxicity study in rats, probably similar to that described by OECD Test Guideline 403 (acute inhalation toxicity), with triethoxy(3-isocyanatopropyl)silane.

Groups of six rats were exposed by inhalation to triethoxy(3-isocyanatopropyl)silane for four hours (whole-body) at 15, 30 or 60 ppm. (In a supplementary procedure, two further groups of six rats were exposed to “substantially saturated vapor” for four or eight hours.) Rats were observed for 14 days for mortality and clinical signs of toxicity, before sacrifice and necropsy to identify any gross pathological changes.

Three and four rats in the top and middle dose groups respectively died. (Of the rats exposed to saturated vapour, all those exposed for eight hours died, and one exposed for four hours.) Pathological changes included pneumonia in animals from all treatment groups and lung haemorrhage (as well as yellow intestines and fluid in the pleural cavity in rats exposed to saturated vapour for eight hours). Clinical signs such as eye irritation, jerky movement and changes to breathing (irregular or laboured breathing and gasping) were noted.

Triethoxy(3-isocyanatopropyl)silane was extremely toxic to rats following acute inhalation exposure, as described in two summary reports. A 4-hour inhalation LC50 of 33.7 ppm (0.36 mg/litre) was derived (and an LT50 (median lethal time, i.e. the length of exposure to "substantially saturated vapor" needed to kill 50% of treated animals) of 5.3 hours).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

360 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

No data available

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

(4 animals per dose group (at least 5 recommended), 2 doses (at least 3 recommended), immobilisation not recommended, occlusive application (semi-occlusive recommended), insufficient details to further judge compliance with test guideline)

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

other: albino

Sex:

male

Details on test animals or test system and environmental conditions:

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

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data available
- Humidity (%): no data available
- Air changes (per hr): no data available
- Photoperiod (hrs dark / hrs light): no data available

IN-LIFE DATES: no data available

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: no data available
- % coverage: no data available
- Type of wrap if used: impervious sheeting

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no data available
- Time after start of exposure: no data available

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 1 or 2 ml/kg bw [980 or 1970 mg/kg bw]
- Constant volume or concentration used: no data available

Duration of exposure:

24 Hours

Doses:

1 or 2 ml/kg bw [980 or 1970 mg/kg bw]

No. of animals per sex per dose:

4 males

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: no data available
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, skin irritation

Statistics:

No data available

Preliminary study:

No data available

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

1.26 mL/kg bw

Based on:

test mat.

95% CL:

>= 0.772 - < 2.06

Remarks on result:

other: Density 1.0007 g/ml; 1.26 ml/kg bw is equivalent to 1261 mg/kg bw; 4/4 deaths at 2 ml/kg bw, 1/4 deaths at 1 ml/kg bw

Mortality:

1/4 animals given 1 mlkg died (on day 2)
4/4 animals given 2 ml/kg died (on day 1)

Clinical signs:

other: No clinical signs were reported for animals given 1.0 ml/kg bw In animals given 2 ml/kg bw, rapid breathing and irritability were noted within the first few hours of treatment

Gross pathology:

Congestion of the lungs
Spleens, livers and kidneys pale
Livers and kidneys mottled

Other findings:

- Other observations: skin erythema and oedema were reported in animals given 1 ml/kg bw. Skin erythema and ecchymosis were reported in animals given 2 ml/kg bw

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

In a study probably similar to that described by OECD Test Guideline 402, triethoxy(3-isocyanatopropyl)silane was harmful to male rabbits following a 24-hour acute dermal administration. An acute dermal LD50 of 1.26 ml/kg bw [1261 mg/kg bw] was derived.

Executive summary:

Two summary reports described an acute dermal toxicity study in rabbits, probably similar to that described by OECD Test Guideline 402 (acute dermal toxicity), with triethoxy(3-isocyanatopropyl)silane.

Groups of four male albino rabbits were exposed to undiluted triethoxy(3-isocyanatopropyl)silane at 1 or 2 ml/kg bw under occlusion for 24 hours. Rabbits were observed for 14 days for mortality and clinical signs of toxicity, before sacrifice and necropsy to identify any gross pathological changes.

One and four animals died in the low and high dose groups respectively. Congestion was noted in the lungs, as well as paleness and mottling in livers and kidneys, and pale spleens. Irritability and rapid breathing were noted in animals from the top dose group within the first few hours of treatment. Skin erythema was seen in all treated animals, while ecchymosis [haemorrhagic spots] was seen in animals treated with 2 ml/kg bw, and oedema in animals given 1 ml/kg bw.

Triethoxy(3-isocyanatopropyl)silane was harmful to male rabbits and an acute dermal LD50 of 1.26 ml/kg bw [1240 mg/kg bw] was derived.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 261 mg/kg bw

Additional information

In the key acute oral toxicity study, conducted according to OECD Test Guideline 423 and in compliance with GLP, (SafePharm, 2003) there were no deaths noted at 300 mg/kg bw, but at 2000 mg/kg bw all animals were found dead between 30 minutes and 4 hours after dosing. In decedent animals clinical signs indicative of poor clinical condition were noted and at necropsy discolouration (red or dark) of some internal organs was noted in 2 animals. Based on the mortalities the oral LD₅₀ was estimated to be between 300 and 500 mg/kg bw. In a supporting acute oral study (Chem Hygiene Fellowship, 1973) groups of up to 5 male rats were given undiluted triethoxy(3-isocyanatopropyl)silane by oral gavage at doses of 500, 1001 or 4003 mg/kg bw and resulted in 1/5, 4/5 and 3/3 deaths respectively. Pathological changes were noted in the stomach, intestines, kidneys and adrenals. Clinical signs included piloerection, prostration, heavy breathing, salivation and nose rubbing. Based on these findings an oral LD₅₀ of 707 mg/kg bw was derived.

In a reliability 4 acute inhalation study (Chem Hygiene Fellowship, 1973) exposure of rats to triethoxy(3-isocyanatopropyl)silane at metered concentrations of 60, 30 or 15 ppm for 4 hours resulted in 3/6, 4/6 and 0/6 deaths respectively. The LC₅₀ for the 4 hour exposure period was calculated as 33.7 ppm (360 mg/m3). Signs of toxicity and gross pathological findings included respiratory difficulty and severe lung edema.

In the key acute dermal toxicity study, which pre-dates GLP, but was conducted according to a guideline similar to OECD Test Guideline 402 (Chem Hygiene Fellowship, 1973), application of undiluted triethoxy(3-isocyanatopropyl)silane at 1 or 2 ml/kg to the skin of male rabbits under an impervious covering for 24 hours resulted in the death of all animals at the high dose and 1/4 animals at the low dose. Congestion was noted in the lungs, as well as paleness and mottling in livers and kidneys, and pale spleens. Irritability and rapid breathing were noted in animals from the high dose group within the first few hours of treatment. Skin erythema was seen in all treated animals, while ecchymosis [haemorrhagic spots] was seen in animals treated with 2 ml/kg bw, and oedema in animals given 1 ml/kg bw.

Data for the hydrolysis product, 3-aminopropyl(triethoxy)silane (CAS 919-30-2), have been added to the dataset as supporting information for completeness, but are not used in the assessment as the parent substance has reliable data.

Justification for classification or non-classification

Based on the available data triethoxy(3-isocyanatopropyl)silane requires classification for acute oral toxicity Category 4, H302: "Harmful if swallowed", acute inhalation toxicity Category 1, H330: "Fatal if inhaled" and acute dermal toxicity Category 4, H312: "Harmful in contact with skin" according to Regulation (EC) No 1272/2008.