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Description of key information

In the key acute oral toxicity study, conducted to the now deleted OECD Test Guideline 401 and in compliance with GLP (Bushy Run Research Center, 1995), the LD50 values in male and female rats were >500 and 878 mg/kg bw, respectively for 3-(trimethoxysilyl)propyl isocyanate. There were no clinical signs of toxicity in males given 500 mg/kg bw test substance in corn oil. Signs in females included hypoactivity, diarrhoea, darkened eyes, pale extremities, slow breathing, abdominal breathing, piloerection, lacrimation, hind limb cyanosis (in 1), prostration (in 1), an unkempt appearance (in 1), a brown stain on the perianal fur and a red crust on the perinasal fur. Most affected survivors recovered within 2 hours to 2 days. Two females recovered at 4 or 7 days. 

In the key acute dermal toxicity study, conducted according to a protocol similar to OECD Test Guideline 402 and in compliance with GLP (Bushy Run Research Center, 1995), the LD50 values in male and female rabbits were 1190 and >2000 mg/kg bw, respectively for 3-(trimethoxysilyl)propyl isocyanate. There were signs of skin irritation. Signs of toxicity included hypoactivity, prostration, slow breathing, shallow breathing, an abnormal gait (in 2 ), rapid breathing, diarrhoea (in 1), front limb splay and marked hindlimb splay (in 1 male that died), marked weakness of right hind limb (in 1 male that died), weakened front limbs (in 1 male that died), pallor (in 2), an abnormal tilting of the head (in l), emaciation, iritis (in 1), dehydrated appearance (in 1), discharge or crust (mostly brown) on the perianal fur, and wetness of the perioral and perinasal fur. Most affected survivors recovered at 1 to 4 days. Two rabbits exhibited signs at 13 and/or 14 days.

In the acute vapour inhalation study, conducted according to OECD Test Guideline 403 and in compliance with GLP (WIL Research Laboratories, 2004), the LC50 for a 4-hour exposure to 3-(trimethoxysilyl)propyl isocyanate was 15 ppm (125.95 mg/m3) in rats. Clinical observations and necropsy findings indicated local effects on the respiratory tract.

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:
supporting study
Study period:
14.07.1994 to 09.08.1994
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:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Sprague Dawley, Inc (Indianapolis, IN)
- Age at study initiation: No data
- Weight at study initiation: Males: 265-291 g; Females: 202-263 g
- Fasting period before study: yes, overnight
- Housing: Groups of up to 5 animals in stainless steel cages
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: At least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 40-70
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 14.07.1994 To: 09.08.1994
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: No data
Doses:
Females: 250, 500, 707 and 1000 mg/kg bw
Males: 500 mg/kg bw
No. of animals per sex per dose:
Three males; five females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Dosed animals were observed frequently for signs of toxicity on the first day of the test and twice per day thereafter. Weights were recorded on the day of dosing and at 7 and 14 days after dosing and at death.
- Necropsy of survivors performed: Yes
- Other examinations performed: Macroscopic examination.
Statistics:
No details given.
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
> 500 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No male animals died.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
878 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Death occurred at 2.25 hr to 1 day.
Mortality:
No male animals died after receiving doses of 500 mg/kg bw test substance in corn oil.
Clinical signs:
other: There were no clinical signs of toxicity in males given 500 mg/kg bw test substance in corn oil. Signs in females included hypoactivity, diarrhoea, darkened eyes, pale extremities, slow breathing, abdominal breathing, piloerection, lacrimation, hind limb
Gross pathology:
Necropsy of animals that died revealed red submandibular lymph nodes (in 1), red lungs, hyperinflated lungs, red thymuses, mottled red to dark red livers, dark red kidneys, reddened stomachs (glandular portion), gas-filled cecums and 2 gas-filled colons. Yellow liquid was also present in the stomach and intestines (in 2) and cecum (in 1). In addition, there was a light yellow stain evident on the facial and perineal fur of all rats that died. There were no gross lesions observed for survivors at necropsy except for red livers (caudate lobe) in two males.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
In an acute oral toxicity study conducted to the now deleted OECD 401 and to GLP (reliability score 1) the LD50 values in male and female rats of >500 and 878 mg/kg bw, respectively for 3-(trimethoxysilyl)propyl isocyanate. There were no clinical signs of toxicity in males given 500 mg/kg bw test substance in corn oil. Signs in females included hypoactivity, diarrhoea, darkened eyes, pale extremities, slow breathing, abdominal breathing, piloerection, lacrimation, hind limb cyanosis (in 1), prostration (in 1), an unkempt appearance (in 1), a brown stain on the perianal fur and a red crust on the perinasal fur. Most affected survivors recovered within 2 hours to 2 days. Two females recovered at 4 or 7 days.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
878 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
24.05.2004 to 16.12.2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1300 (Acute inhalation toxicity)
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, North Carolina
- Age at study initiation: 8-10 weeks old
- Weight at study initiation: Males: 272-298 g; Females: 232-257 g.
- Fasting period before study: No data
- Housing: Individual suspended wire-mesh cages
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: Minimum of 7 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22± 3
- Humidity (%): 50± 20
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 09.09.2004 To: 01.10.2004
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:
- Exposure chamber volume:
- Method of holding animals in test chamber:
- Source and rate of air:
- Method of conditioning air:
- System of generating particulates/aerosols:
- Method of particle size determination:
- Treatment of exhaust air:
- Temperature, humidity, pressure in air chamber:

TEST ATMOSPHERE
- Brief description of analytical method used:
- Samples taken from breathing zone: yes/no
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
3.9, 11.0 and 17.8 ppm (actual)
No. of animals per sex per dose:
Five
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations were made following exposure on study day 0 and once daily thereafter for 14 days. Body weights were obtained immediately prior to exposure on study day 0 and on post-exposure days 7 and 14. All animals that died during the study were weighed.
- Necropsy of survivors performed: yes
- Other examinations performed: macroscopic examination.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
15 ppm
Based on:
test mat.
95% CL:
>= 12 - <= 18
Exp. duration:
4 h
Mortality:
Mortality was 0/10, 1/10 and 8/10 animals for the 3.9, 11.0 and 17.8 ppm groups, respectively.
One male in the 11.0 ppm group was found dead on the day following exposure (study day 1). Five males and three females in the 17.8 ppm group were found dead during the study. All deaths were noted within four days of exposure.
Clinical signs:
other: Clinical observations immediately following exposure included rales in all groups; gasping and laboured respiration in the 11.0 and 17.8 ppm groups; and hypoactivity and hypothermia in the 17.8 ppm group. Significant clinical observations for the survivin
Body weight:
Two females in the 3.9 ppm group lost weight during study days 7 and 14 and three males and one female in the 11.0 ppm group lost weight during study days 0 to 7. Both of the surviving females in the 17.8 ppm group lost weight during study days 0 to 7. With the exception of one female in the 3.9 ppm group, all animals surpassed their initial body weight by study day 14 and were considered normal.
Gross pathology:
There were no gross findings for the male found dead in the 11.0 ppm group. For the animals found dead in the 17.8 ppm group, the only internal gross findings were lungs not fully collapsed for one male. At the scheduled necropsy, dark red discolouration of the mandibular lymph node was noted for one female each in the 11.0 and 17.8 ppm groups.
Interpretation of results:
Category 1 based on GHS criteria
Conclusions:
In an acute vapour inhalation study conducted to OECD 403 and to GLP (reliability score 1) the LC50 for a 4-hour exposure to 3-(trimethoxysilyl)propyl isocyanate was 15 ppm (125.95 mg/m3) in rats. Clinical observations immediately following exposure included rales in all groups; gasping and laboured respiration in the 11.0 and 17.8 ppm groups and hypoactivity and hypothermia in the 17.8 ppm group. Significant clinical observations for the surviving animals during the 14-day post-exposure observation period consisted of rales in all groups; decreased defecation/urination, hypothermia and laboured respiration in the 11.0 and 17.8 ppm groups, and gasping and hypoactivity in the 17.8 ppm group. All animals in the 3.9 ppm group were considered normal by study day 2. Surviving animals in the 11.0 and 17.8 ppm groups were considered normal by study days 9 and 7, respectively. There were no gross findings for the male found dead in the 11.0 ppm group. For the animals found dead in the 17.8 ppm group, the only internal gross findings were lungs not fully collapsed for one male. At the scheduled necropsy, dark red discolouration of the mandibular lymph node was noted for one female each in the 11.0 and 17.8 ppm groups.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
125.95 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:
29.06.1994 to 27.09.1994
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
yes
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: HRP, Inc (Denver, PA)
- Age at study initiation: 13-18 weeks
- Weight at study initiation: 2-2.3 kg
- Fasting period before study: No
- Housing: Individually in cages with wire floors
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: At least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16-22
- Humidity (%): 40-60
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 29.06.1994 To: 27.09.1994
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: Dorsal trunk
- % coverage: No data
- Type of wrap if used: Double layer of gauze sheeting was wrapped around the trunk and secured with adhesive tape. To secure the polyethylene, plastic ties/rubber bands were added (at the ends of the trunk). The sheeting was protected from removal or tearing by wrapping the trunk with bandage tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): No

TEST MATERIAL
- Amount(s) applied: 15 mg/cm2 to 40 mg/cm2
Duration of exposure:
24 h
Doses:
Males: 500, 1000, 1400 and 2000 mg/kg bw.
Females: 1000, 1400 and 2000 mg/kg bw.
No. of animals per sex per dose:
Five
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Dosed animals were observed frequently for signs of toxicity on the first day of the test and twice per day thereafter. Weights were recorded on the day of dosing and at 7 and 14 days after dosing and at death.
- Necropsy of survivors performed: Yes
- Other examinations performed: Macroscopic examination.
Sex:
male
Dose descriptor:
LD50
Effect level:
1 190 mg/kg bw
Based on:
test mat.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
In the definitive percutaneous test, 5 female rabbits were dosed with 2000 mg/kg of undiluted test substance (the maximum required dose - limit
test). Substantial signs of toxicity and 1 death resulted. Another 5 females were dosed with 1400 mg/kg of undiluted Y-5187; 1 animal died. None of 5 females died from 500 mg/kg. Most deaths occurred within 1 to 5 days. Three males died at 4 hours, 6 days or 9 days.
Clinical signs:
other: Signs of toxicity included hypoactivity, prostration, slow breathing, shallow breathing, an abnormal gait (in 2 ), rapid breathing, diarrhoea (in 1), front limb splay and marked hindlimb splay (in 1 male that died), marked weakness of right hind limb (in
Gross pathology:
Necropsy of rabbits that died revealed dark red areas on the lungs and single instances of light brown lungs, pale lungs with dark red areas, a dark red thymus, dark red liquid in the bladder and a distended bladder. The tissues of several animals that died were autolyzed upon necropsy. Gross necropsy findings for survivors included 1 dark red thymus and mottled and/or dark red areas on the lungs (in 2). One animal had a small, firm left kidney and a large right kidney.
Other findings:
Skin reactions included erythema, oedema, ecchymosis, ulceration, necrosis, fissuring, desquamation, alopecia and scabs. For most rabbits, the skin of
the dosed area was dry and leather-like at 1 day.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
In an acute dermal toxicity study conducted using a protocol comparable to OECD 402 and to GLP (reliability score 1) the LD50 values in male and female rabbits were 1190 and >2000 mg/kg bw, respectively for 3-(trimethoxysilyl)propyl isocyanate. There were signs of skin irritation. Signs of toxicity included hypoactivity, prostration, slow breathing, shallow breathing, an abnormal gait (in 2 ), rapid breathing, diarrhoea (in 1), front limb splay and marked hindlimb splay (in 1 male that died), marked weakness of right hind limb (in 1 male that died), weakened front limbs (in 1 male that died), pallor (in 2), an abnormal tilting of the head (in l), emaciation, iritis (in 1), dehydrated appearance (in 1), discharge or crust (mostly brown) on the perianal fur, and wetness of the perioral and perinasal fur. Most affected survivors recovered at 1 to 4 days. Two rabbits exhibited signs at 13 and/or 14 days.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 190 mg/kg bw

Additional information

The key study for acute oral toxicity, conducted according to appropriate guideline and in compliance with GLP (reliability score 1) reports LD50 values in male and female rats of >500 and 878 mg/kg bw, respectively for 3-(trimethoxysilyl)propyl isocyanate (Bushy Run Research Center, 1995a). There were no clinical signs of toxicity in males given 500 mg/kg bw test substance in corn oil. Signs in females included hypoactivity, diarrhoea, darkened eyes, pale extremities, slow breathing, abdominal breathing, piloerection, lacrimation, hind limb cyanosis, prostration, an unkempt appearance, a brown stain on the perianal fur and a red crust on the perinasal fur. All affected survivors recovered by day 7.

The key acute inhalation study, conducted according to OECD Test Guideline 403 and in compliance with GLP (reliability score 1) reports an LC50 for a 4-hour (vapour) exposure to 3-(trimethoxysilyl)propyl isocyanate to be 15 ppm (125.95 mg/m3) in rats (WIL Research Laboratories, 2004). Significant clinical observations for the surviving animals during the 14-day post-exposure observation period consisted of rales in all groups; decreased defecation/urination, hypothermia and laboured respiration in the 11.0 and 17.8 ppm groups, and gasping and hypoactivity in the 17.8 ppm group. All animals in the 3.9 ppm group were considered normal by study day 2. Surviving animals in the 11.0 and 17.8 ppm groups were considered normal by study days 9 and 7, respectively. There were no gross findings for the male found dead in the 11.0 ppm group. For the animals found dead in the 17.8 ppm group, the only internal gross finding was lungs not fully collapsed for one male. At the scheduled necropsy, dark red discolouration of the mandibular lymph node was noted for one female each in the 11.0 and 17.8 ppm groups.

Two supporting studies were also available for acute inhalation. In a well-documented, non-guideline acute inhalation study conducted in compliance with GLP no rats died when exposed to a substantially saturated vapour of 3-(trimethoxysilyl)propyl isocyanate for six hours (Bushy Run Research Center, 1995b). Clinical signs of toxicity apparent during exposure included blepharospasm, wetness of the periocular fur and mouth breathing. Following exposure, signs of toxicity included audible breathing, wetness of periocular fur, mouth breathing, an unkempt appearance, crust on the perinasal fur and tremors (in 1). All rats recovered within 2 to 3 days. Several rats lost weight by 7 days; all at least partially recovered by 14 days. No gross lesions were apparent at necropsy for any animal.

The second supporting study for acute inhalation toxicity (TNO, 2013) was also conducted according to an appropriate OECD guideline and in compliance with GLP. A 4-hour LC50 for 3-(trimethoxysilyl)propyl isocyanate was calculated to be between 54 and 108 mg/m3 (6 and 13 ppm) in rats. Local effects on the respiratory tract were observed.

The key study for acute dermal toxicity, conducted according to an appropriate protocol and in compliance with GLP, reports LD50 values in male and female rabbits of 1190 and >2000 mg/kg bw, respectively for 3-(trimethoxysilyl)propyl isocyanate (Bushy Run Research Center, 1995c). Signs of skin irritation were observed. Signs of toxicity included hypoactivity, prostration, slow breathing, shallow breathing, an abnormal gait, rapid breathing and diarrhoea. Most affected survivors recovered at 1 to 4 days. Two rabbits exhibited signs at 13 and/or 14 days.

The acute toxicity data for the hydrolysis product, 3-(trimethoxysilyl)propylamine (CAS 13822-56-5), have been added as supporting information. The acute toxicity is determined by the isocyanate group. The hydrolysis product data support this conclusion as acute oral and dermal toxicity tests do not lead to classification for acute toxicity for the hydrolysis product, which lacks an isocyanide group.

Justification for classification or non-classification

Based on the available data, 3-(trimethoxysilyl)propyl isocyanate is classified for acute oral and dermal toxicity Cat 4, 'H302: Harmful if swallowed', 'H312: Harmful in contact with skin' and acute inhalation toxicity Cat 1 (vapour), 'H330: Fatal if inhaled'according to Regulation (EC) No 1272/2008.