N-[3-(trimethoxysilyl)propyl]aniline

Endpoint summary

Description of key information

Acute toxicity:
Oral (OECD 401), rat: LD50 = 704 mg/kg bw
Dermal (OECD 402), rat: LD50 > 2000 mg/kg bw
Inhalation: no study available

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:

24 Feb 1994 - 15 Dec 1994

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: CDF(F-344)Crl:BR VAF/PLUS

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Portage, MI, USA
- Age at study initiation: young adult
- Weight at study initiation: 144-175 g
- Fasting: 18-20 h prior to dosing until 3-4 h after dosing
- Housing: individual housing in wire-mesh cages
- Diet: Purina Certified Rodent Chow #5002, ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.5±1.5
- Humidity (%): 20-66
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 1.92 mL/kg

Doses:

500, 1000, 2000 mg/kg bw (0.48, 0.96, 1.92 mL/kg)

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: The rats were observed 1, 3, and 4 h post-dose on day of appplication (day 0) and once daily thereafter. Body weights were obtained on the day before treatment, the day of treatment and on days 7 and 14.
- Necropsy of survivors performed: yes (major organ systems of the cranial, thoracic and abdominal cavities were examined for all animals)

Sex:

male/female

Dose descriptor:

LD50

Effect level:

809 mg/kg bw

Based on:

test mat.

95% CL:

590 - 1 109

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

704 mg/kg bw

Based on:

test mat.

95% CL:

499 - 993

Sex:

female

Dose descriptor:

LD50

Effect level:

969 mg/kg bw

Based on:

test mat.

95% CL:

831 - 1 130

Mortality:

500 mg/kg bw: 1/5 males (day 2) and 0/5 females
1000 mg/kg bw: 4/5 males (day 1-3) and 3/5 females (day 2-3)
2000 mg/kg bw: 5/5 males (day 1) and 5/5 females (day 1-2)

Clinical signs:

other: 500 mg/kg bw: Males: wet yellow urogenital staining (1/5) Females: hypoactivity (2/5), wet yellow urogenital staining (3/5) 1000 mg/kg bw: Males: hypoactivity (5/5), ataxia (4/5), ocular discharge (3/5), tremors (4/5), prostration (2/5), hypothermia (2/

Gross pathology:

Animals that were found dead:
Gastrointestinal abnormalities were observed for the majority of the rats that died during the study. Reddened kidneys and/or reddened/white renal cortico-medullary junctions were observed. Five rats had reddened or dark red adrenal glands. Hemorrhages in the thymus glands were noted. Other findings at a low incidence included an oedematous abdominal cavity and congenital accessory splenic tissue. Various external surface mattings were observed.

Animals sacrificed at end of study:
White areas in the kidneys (1/5 males, 500 mg/kg bw) and dark red lungs (1/5 females, 1000 mg/kg bw)

Table 1: Body weights of the animals in the acute oral toxicity study.

Dose group [mg/kg bw]		BW±SD [g]
		day -1	day 0	day 7	day 14
2000	male	178±9	156±7	-	-
	female	159±3	145±2	-	-
1000	male	187±2	171±3	206±0	220±0
	female	165±3	155±3	161±1	173±1
500	male	173±5	152±4	179±23	210±15
	female	165±4	149±4	161±6	168±4

Table 2: Clinical signs of the male animals in the acute oral toxicity study.

Clinical findings (number out of 5 animals)	Males
	500 mg/kg bw	1000 mg/kg bw	2000 mg/kg bw
Found dead	1	4	5
Hypoactive	0	5	5
Clear ocular discharge	0	3	5
Wet brown urogenital staining	0	1	2
Labored respiration	0	1	2
Body cool to touch	0	2	1
Ataxia	0	4	5
Prostrate	0	2	2
White frothy salivation	0	0	3
Dried brown urogenital staining	0	0	1
Convulsions	0	0	1
Tremors	0	4	2
Wet yellow urogenital staining	1	0	1
Dried red material around nose	0	1	1
Dried red material around mouth	0	2	1
Clear wet matting around mouth	0	3	1

Table 3: Clinical signs of the female animals in the acute oral toxicity study.

Clinical findings (number out of 5 animals)	Females
	500 mg/kg bw	1000 mg/kg bw	2000 mg/kg bw
Found dead	0	3	5
Hypoactive	2	5	5
Clear ocular discharge	0	4	5
Wet brown urogenital staining	0	5	3
Labored respiration	0	2	5
Body cool to touch	0	3	5
Ataxia	0	5	5
Prostrate	0	3	5
White frothy salivation	0	1	3
Dried brown urogenital staining	0	4	4
Tremors	0	1	0
Wet yellow urogenital staining	3	4	0
Dried red material around nose	0	5	0
Dried red material around mouth	0	3	3
Clear wet matting around mouth	0	1	0

Table 4: Necropsy findings of the male and female animals in the acute oral toxicity study.

Necropsy findings (number out of 5 animals)	Males			Females
	500 mg/kg bw	1000 mg/kg bw	2000 mg/kg bw	500 mg/kg bw	1000 mg/kg bw	2000 mg/kg bw
Adrenal Glands - reddened - dark red	0 0	1 1	2 0	0 0	1 0	0 0
Intestine - dark red contents	0	2	5	0	3	4
Kidneys - reddened cortico-medullary junction - reddened - white cortico-medullary junction	0   0 0	0   2 1	2   3 0	0   0 0	1   0 0	2   2 0
Lungs - mottled	0	0	4	0	0	1
Spleen - accessory	0	1	0	0	0	0
Stomach - dark red area - dark red content	0 0	1 2	1 0	0 0	1 3	3 0
Thymus gland - hemorrhagic	0	1	0	0	0	3
External surface - yellow matting - red matting - brown matting - clear matting - green matting	0 0 0 0 0	0 2 0 1 0	4 5 2 0 0	0 0 0 0 0	1 2 2 0 1	1 2 1 1 1
Abdominal cavity - oedematous	0	0	0	0	0	0

Interpretation of results:

other: CLP/EU GHS criteria are met, Category 4 classification required according to Regulations (EC) No 1272/2008

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

704 mg/kg bw

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.6, of Regulation (EC) No 1907/2006.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

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:

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:

other: Crl:CD BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Portage, MI, USA
- Age at study initiation: young adult
- Weight at study initiation: 220-267 g
- Fasting: 18-20 h prior to dosing until 3-4 after dosing
- Housing: individual housing in mesh-bottom cages
- Diet: Purina Certified Rodent Chow #5002, ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.1±0.2
- Humidity (%): 39.1-44.0
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- % coverage: 14-18% of total body surface
- Type of wrap if used: gauze bandaging secured with non-irritating tape

REMOVAL OF TEST SUBSTANCE
- Washing (if done): application sites were wiped with disposable paper towels moistened with deionized water
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw, 1.92 mL/kg

Duration of exposure:

24 h

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: The rats were observed 1, 3, and 4 h post-dose on day of appplication (day 0) and once daily (clinical observation) or twice daily (mortality) thereafter. Body weights were obtained on the day of treatment and on days 7 and 14.
- Necropsy of survivors performed: yes (major organ systems of the cranial, thoracic and abdominal cavities were examined for all animals)
- Dermal observations: application sites were examined for erythema, oedema and other dermal findings 30-60 minutes after bandage removal and daily thereafter for thirteen days. The rats were clipped to facilitate dermal observations on study days 7 and 14.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: No mortality was observed.

Mortality:

No mortality was observed.

Clinical signs:

other: Clinical findings were limited to dried red material around the eye(s) and/or nose for seven rats and wet and dried yellow urogenital staining for five rats. These findings are typically noted in association with the bandage/collar application procedures

Gross pathology:

Reddened seminal vesicles and multiple calculi in the kidneys, ureter(s) and urinary bladder were noted in one male at the terminal necropsy. These are common, spontaneous findings in rats of this age and strain and were unrelated to the test material. One female had scabbing on the application site. There were no other gross necropsy findings for all examined tissues.

Other findings:

- Other observations:
The test material induced very slight to severe erythema, very slight edema and eschar on one animal. Desquamation was present on six animals. There were no other dermal findings. With the exception of one male and female with severe erythema, slight edema, eschar and/or desquamation, all dermal irritation completely subsided by day 11 or earlier. Skin reactions were determined using the Draize scoring system.

Table 1: Body weights of the animals in the acute dermal toxicity study.

Dose group [mg/kg bw]		BW±SD [g]
		day 0	day 7	day 14
2000	male	262±4	304±12	343±23
2000	female	225±4	225±5	235±6

Table 2: Dermal observations of the males in the acute dermal toxicity study.

Rat No. (males)	1		2		3		4		5
Observation time [day no]	Erythema	Edema	Erythema	Edema	Erythema	Edema	Erythema	Edema	Erythema	Edema
1	0d	0	0d	0	0	0	0	0	0	0
2	0d	0	0	0	0	0	0	0	0	0
3	0d	0	0	0	0	0	0	0	0	0
4	0d	0	0d	0	0	0	0	0	0d	0
5	0d	0	0d	0	0	0	0	0	0d	0
6	0d	0	0	0	0	0	0	0	0	0
7	0d	0	0	0	0d	0	0	0	0	0
8	0d	0	0	0	0d	0	0	0	0	0
9	0d	0	0	0	0d	0	0	0	0	0
10	0d	0	0	0	0d	0	0	0	0	0
11	0d	0	0	0	0	0	0	0	0	0
12	0d	0	0	0	0	0	0	0	0	0
13	0d	0	0	0	0	0	0	0	0	0
14	0d	0	0	0	0	0	0	0	0	0

d: desquamation

Table 3: Dermal observations of the females in the acute dermal toxicity study.

Rat No. (females)	1		2		3		4		5
Observation time [day no]	Erythema	Edema	Erythema	Edema	Erythema	Edema	Erythema	Edema	Erythema	Edema
1	0	0	0	0	0	0	0	0	0	0
2	0	0	0	0	0	0	0	0	0	0
3	0	0	0d	0	0	0	0	0	0	0
4	0	0	0d	0	0	0	0	0	0d	0
5	0	0	1d	0	0	0	0	0	0	0
6	0	0	1d	0	0	0	0	0	0	0
7	0	0	2d	0	0	0	0	0	0	0
8	0	0	2d	0	0	0	0	0	0	0
9	0	0	3d	1	0	0	0	0	0	0
10	0	0	3d	1	0	0	0	0	0	0
11	0	0	4de	1	0	0	0	0	0	0
12	0	0	4de	1	0	0	0	0	0	0
13	0	0	4de	1	0	0	0	0	0	0
14	0	0	4de	1	0	0	0	0	0	0

d: desquamation

e: eschar

Interpretation of results:

other: CLP/EU GHS criteria are not met, no classification required according to Regulations (EC) No 1272/2008

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.6, of Regulation (EC) No 1907/2006.

Additional information

A key study is available with N-[3 -(trimethoxysilyl)propyl]aniline (CAS 3068 -76 -6), which was conducted according to OECD 401 and in compliance with GLP (WIL, 1994). Five male and female Fischer rats were treated with 500, 1000, and 2000 mg/kg bw by oral gavage. The test substance was applied undiluted (0.48, 0.96, 1.92 mL/kg).

The rats were observed 1, 3, and 4 h post-dose on day of appplication (day 0) and once daily thereafter for clinical signs and mortality. Body weights were obtained on the day before treatment, the day of treatment and on days 7 and 14. Necropsy of survivors was performed and major organ systems of the cranial, thoracic and abdominal cavities were examined for all animals.

In the low dose group 1/5 males and 0/5 females were found dead. Treatment with 1000 mg/kg bw led to 4/5 dead males and 3/5 dead females within day 1 -3 and 2 -3, respectively. All animals were found dead after treatment with 2000 mg/kg bw on days 1 -2. There were no remarkable changes or differences observed in body weights. Clinical signs mainly observed in the 1000 and 2000 mg/kg bw dose groups included hypoactivity, ataxia, ocular discharge, tremors, prostration, hypothermia, labored respiration, wet/dried brown urogenital staining, salivation, dried red material around the nose/mouth. All surviving animals appeared normal by day 4 or earlier. Necropsy findings included gastrointestinal abnormalities for the majority of the rats that died during the study. Reddened kidneys and/or reddened/white renal cortico-medullary junctions were observed. Five rats had reddened or dark red adrenal glands. Hemorrhages in the thymus glands were noted. Other findings at a low incidence included an oedematous abdominal cavity and congenital accessory splenic tissue. Various external surface mattings were observed. In conclusion, a combined LD50 of 809 mg/kg bw was calculated. The LD50 for males and females were 704 and 969 mg/kg bw, respectively.

 

Supporting data are available from another acute oral toxicity study with N-[3 -(trimethoxysilyl)propyl]aniline (CAS 3068 -76 -6), which was conducted according to OECD 401 and in compliance with GLP (WIL, 1996). Crj: CD (SD) rats (5 per sex) were treated with 500, 980, 1921, 2689 (only females), and 3765 (only females) mg/kg bw test substance by oral gavage. The test substance was dosed in corn oil at a maximum dose of 5 mL/kg bw.

The rats were observed 1, 3, and 4 h post-dose on day of appplication (day 0) and twice daily thereafter for clinical signs and mortality. Body weights were obtained on the day before treatment, the day of treatment and on days 7 and 14. Necropsy of survivors was performed and major organ systems of the cranial, thoracic and abdominal cavities were examined for all animals.

In the low dose group no mortality was observed. Treatment with 980 and 1921 mg/kg bw led to 1/10 and 4/10 dead animals within day 2 -3, respectively. As only males were affected, two further groups of 5 females were dosed with 2689 and 3765 mg/kg bw and mortality was observed in 1/5 and 5/5 animals within 3 and 0-2 days, respectively.

Clinical findings were noted in all dose groups. Twenty-three rats had wet and/or dried yellow urogenital, ventral abdominal and/or ventral thoracic staining. Hypoactivity and tremor was noted in the two high dose groups. Various dried red material around the eye(s), mouth, forelimb(s) and/or nose and abnormal excretion (mucoid faeces, soft stool, decreased defecation and/or urination) were observed for nine animals each. Six rats (two high-dose groups) had labored respiration. Clear wet matting around the mouth and hypothermia (body cool to touch) were noted for four rats each. Two animals of the two high dose groups (females) showed hair loss on the ventral abdominal and/or thoracic area, clear ocular discharge and prostration. Lacrimation in the right eye was noted for a single female. There were no other clinical findings. With the exception of hair loss on the ventral abdominal and/or thoracic area(s) for two rats, all animals appeared normal by day 9 or earlier and throughout the remainder of the study. There were no remarkable changes or differences observed in body weights.

Necropsy findings included dark red or mottled lungs in three out of eleven rats that were found dead. Two animals each had gastrointestinal abnormalities (dark red area(s) in the stomach or dark red intestinal contents) and reddened adrenal glands. A single male had opacity in the right eye. Various external matting (red and/or brown matting around the eyes, nose, mouth, anogenital and/or urogenital area) were noted for six out of eleven animals that died during the study. There were no other gross necropsy findings for all other animals found dead. Internal findings noted at the terminal necropsy were limited to a dilated renal pelvis (right) for a single male. Two females had hair loss on the ventral abdominal area. There were no other gross necropsy findings for all other surviving animals.

In conclusion, LD50 for males and females were 1379 and 2843 mg/kg bw, respectively.

 

A key study is available with N-[3 -(trimethoxysilyl)propyl]aniline (CAS 3068 -76 -6) for the dermal route, which was conducted according to OECD 402 and in compliance with GLP (WIL, 1995). Five male and female Crl:CD BR rats were treated with the limit dose of 2000 mg/kg bw by semi-occlusive dermal application for 24 h. The test substance was applied undiluted (1.97 mL/kg) to the back of the animals covering 14-18% of the total body surface. The application sites were wiped with disposable paper towels moistened with deionized water after 24 h.

The rats were observed 1, 3, and 4 h post-dose on day of appplication (day 0) and once or twice daily thereafter for clinical signs and mortality, respectively. Body weights were obtained on the day of treatment and on days 7 and 14. Necropsy of survivors was performed and major organ systems of the cranial, thoracic and abdominal cavities were examined for all animals. The application sites were examined for erythema, oedema and other dermal findings 30-60 minutes after bandage removal and daily thereafter for thirteen days. The rats were clipped to facilitate dermal observations on study days 7 and 14.

No mortality was observed. Clinical findings were limited to dried red material around the eye(s) and/or nose for seven rats and wet and dried yellow urogenital staining for five rats. These findings are typically noted in association with the bandage/collar application procedures and were not a result of test material application. There were no other clinical findings. All animals appeared normal by day 3 or earlier and throughout the remainder of the study. Two females lost 1-3 % of body weight and one female had zero gain from day 0 to day 7. Slight losses or lower gains in body weight are common in animals which have been bandaged and collared for 24 hours. The two females which had losses recovered and surpassed their initial (day 0) weights by termination (day 14). There were no other remarkable changes or differences in body weights. Reddened seminal vesicles and multiple calculi in the kidneys, ureter(s) and urinary bladder were noted in one male at the terminal necropsy. These are common, spontaneous findings in rats of this age and strain and were unrelated to the test material. One female had scabbing on the application site. There were no other gross necropsy findings for all examined tissues. The test material induced very slight to severe erythema, very slight edema and eschar on one animal. Desquamation was present on six animals. There were no other dermal findings. With the exception of one male and female with severe erythema, slight edema, eschar and/or desquamation, all dermal irritation completely subsided by day 11 or earlier. Skin reactions were determined using the Draize scoring system.

In conclusion, a dermal LD50 of >2000 mg/kg bw was derived for male and female animals.

Justification for classification or non-classification

The available data on acute oral toxicity of the registered substance meet the criteria for classification as “Harmful if swallowed (H302)” according to Regulation (EC) 1272/2008.

The available data on acute dermal toxicity of the registered substance do not meet the criteria for classification according to Regulation (EC) 1272/2008 and according to Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.

No data are availabe for the inhalation route.