N-[3-(triethoxysilyl)propyl]ethylenediamine

Endpoint summary

Description of key information

Oral (OECD 401), rat: LD50 >2000 mg/kg bw
Inhalation (OECD 403), rat: LC50 = 1.1 mg /l (male)/1.18 mg/l (female)

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:

3 Nov - 21 Dec 1995

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted according to an appropriate OECD test guideline, and in compliance with GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

Federal Department Of Home Affairs, Bern, Switzerland

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: HanIbm:WIST

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: BRL, Biological Research Laboratories Ltd., Füllinsdorf, Switzerland
- Age at study initiation: 8 weeks (males), 10 weeks (females)
- Weight at study initiation: 193.8 - 211.9 g (males), 167.4 - 186.7 g (females)
- Fasting period before study: overnight fasting prior to application
- Housing: 5 animals per cage (Makrolon type-4)
- Diet: Pelleted standard Kliba 343 (Batch 80/94, 81/94, 82/94), Klingentalmuehle AG, Kaiseraugst, Switzerland
- Water: tap water, ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20±1
- Humidity (%): 58± 12
- Photoperiod (hrs dark / hrs light): 12/12
- Air changes (per hr): 10-15

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 100, 150, 200 mg/ml
- Amount of vehicle (if gavage): 10 ml/kg bw

MAXIMUM DOSE VOLUME APPLIED: 10 ml

Doses:

1000, 1500, 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:
Mortality/Viability/Clinical signs: 4-5 times at test day and daily for surviving animals during days 2-15
Body weights: On test day (before administration), and on day 8 and 15
- Necropsy of survivors performed: yes

Statistics:

LOGIT-Model (COX, Analysis of binary data, 1977): mean lethal dose calculation

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality was observed after treatment with 1000 mg/kg bw. After treatment with 1500 mg/kg bw 0/5 males and 2/5 females were found dead. Treatment with 2000 mg/kg bw led to 1/5 death males and females, each. Mortalities occurred on day 1 or 2, respectively.

Clinical signs:

1000 mg/kg bw no clinical signs observed
1500 and 2000 mg/kg bw: sedation, spasms, dyspnea, ruffled fur, and diarrhea (reversible within 1 or 2 days for females and males, respectively)

Body weight:

No effect on body weight gain was observed.

Gross pathology:

No organ abnormalities were observed at necropsy.

Interpretation of results:

GHS criteria not met

Conclusions:

In an acute oral toxicity study conducted according to OECD 401 and in compliance with GLP, a LD50 >2000 mg/kg bw was observed in rats. No mortality was observed after treatment with 1000 mg/kg bw. After treatment with 1500 mg/kg bw 0/5 males and 2/5 females were found dead. Treatment with 2000 mg/kg bw led to 1/5 death males and females, each. Mortalities occurred on day 1 or 2, respectively. Clinical signs of toxicity at 1500 and 2000 mg/kg bw were sedation, spasms, dyspnea, ruffled fur, and diarrhea (reversible within 1 or 2 days for females and males, respectively). No effects on bw gain and no abnormalities after necropsy have been observed.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

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

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

19 Aug - 21 Nov 1991

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted according to an appropriate OECD test guideline, and in compliance with GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hoechst AG, Kastengrund, Germany
- Age at study initiation: 8-10 weeks
- Weight at study initiation: 185-223 g (males), 184-221 g (females)
- Fasting period before study: no data
- Housing: 5 animals per cage (Makrolon type-4)
- Diet: Rattendiaet Altromin 1324, Altromin GmbH, Lage/Lippe, Germany
- Water: tap water, ad libitum
- Acclimation period: at least 5 days

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

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

clean air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: stainless steel/glass exposure chamber
- Exposure chamber volume: 60 l
- Method of holding animals in test chamber: animals are placed in plastic tubes (only nose exposed to the exposure chamber)
- Source and rate of air: clean air at 800 l/h
- System of generating particulates/aerosols: The test substance is injected in a two component nozzle. Primary aerosol was produced in a round bottom flask. Secondary aerosol reached the inhalation chamber through an ascending pipe.
- Method of particle size determination: Anderson-Kaskadenimpaktor Mark III, Anderson Samplers INC, Atlanta, USA
- Treatment of exhaust air: Aerosol in the inhalation chamber was aspirated through an A2-respiratory protection filter, a washing bottle filled with methanol, a washing bottle with water, a Bühlerfilter and a CaCl2 bottle. Substance leaking from the exposure chamber was aspirated and neutralized by a gas cleaning plant.
- Temperature, humidity, pressure in air chamber: 20.7 - 22.4°C; 12.2 - 30.3%, negative pressure

TEST ATMOSPHERE
- Brief description of analytical method used:
Gravimetric analysis: Atmosphere was aspirated through a gas meter and glass- and membrane filters (0.65 µm) every 15 minutes (Flow rate: 1.25 m/s). Filters were weighed before and after every measurement.
- Samples taken from breathing zone: yes

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: 100% of the particles had a diameter <10.3 µm. 5% to 22% of the particles were <0.6 µm (see table 2)
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 0.9-1.4 / 1.6-2.2

Analytical verification of test atmosphere concentrations:

yes

Remarks:

gravimetric

Duration of exposure:

4 h

Concentrations:

0.23, 0.83, 1.78, 5.06 mg/l (analytical)

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: Behaviour was checked during exposure and twice daily until day 15. Weight was determined at day 8 and 15.
- Necropsy of survivors performed: yes

Statistics:

LC50 derivation: Probit method

Sex:

male

Dose descriptor:

LC50

Effect level:

1.1 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Sex:

female

Dose descriptor:

LC50

Effect level:

1.18 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

0.23 mg/l: 1/5 (male), 0/5 (female)
0.83 mg/l: 1/5 (male), 1/5 (female)
1.78 mg/l: 3/5 (male), 4/5 (female)
5.06 mg/l: 5/5 (male), 5/5 (female)

Clinical signs:

other: 0.23 mg/l: male: panting, irregular respiration, coat bristling, uncoordinated gait, nasal discharge (blood coloured) were observed at the day of exposure and day 2. Sneezing was observed from day 2 to 4. From day 5 no abnormalities were observed. female:

Body weight:

Slightly reduced body weight gain was observed in the week after dosing with a dose-response relationship (see table 1).

Gross pathology:

Animals that died showed some abnormalities of the lung (except in the high dose group): red coloured lungs, emission of foam on dissection (males), plethoric (males), patchy dark red
Animals that survived until the end of the study showed no abnormalities.

Other findings:

Irregular respiration was observed immediately after start of exposure at any concentration tested. Nasal discharge (blood coloured) was observed in all dose groups, but the onset was concentration dependent starting 3 h after start of exposure in the low concentration group and after 30 min in the 1.78 mg/l group. In the high dose group no nasal discharge was observed, which was based on the fact that the animals of the 5.06 mg/l group died within 0.5 and 2.5 h. The effects observed indicate that the substance induces respiratory irritation including cytotoxic effects. These effects are concentration dependent and were observed before mortality occurred. Based on the clinical signs and the pathology findings in the lung it can be assumed that the local effects are accountable for the mortality.

Table 1: Body weights and body weight gain of the animals in the acute inhalation study.

Dose group [mg/l]		Bodyweight ±SD [g]			Bodyweight gain ±SD [g]
		day 1	day 8	day 15	day 1-8	day 1-15
0.23	male	219.4±3.8	254.8±3.4	291.5±4.8	35.8±3.4	72.5±3.1
	female	208.4±8.6	216.0±6.5	227.6±8.3	7.6±6.3	19.2±7.8
0.83	male	191.8±4.8	206.5±20.9	262.3±17.6	14.3±25.7	70.0±22.1
	female	191.6±3.6	196.0±8.9	220.5±6.5	4.0±10.5	28.5±8.8
1.78	male	215.0±4.2	194.0±11.3	243.5±20.5	-23.0±18.4	26.5±27.6
	female	196.2±3.6	196.0±0.0	214.0±0.0	-1.0±0.0	17.0±0.0
5.06	male	198.8±5.8	-	-	-	-
	female	192.0±6.3	-	-	-	-

Table 2: Cumulative particle size distribution (2 measurements per exposure group) of the acute inhalation toxicity study.

Particle size [µm]	Dose [mg/l]
	0.23		0.83		1.78		5.06
	1st	2nd	1st	2nd	1st	2nd	1st	2nd
<0.6	22.4	19.56	16.56	17.53	10.26	13.37	5.34	13.74
0.6-0.8	47.4	46.37	44.58	49.13	32.22	35.46	19.96	39.62
0.8-1.5	76.95	79.18	83.13	85.35	70.88	76.16	55.73	80.51
1.5-3.0	100	100	100	100	98.33	100	91.50	95.53
3.0-4.8	-	-	-	-	100	-	97.03	96.81
4.8-7.0	-	-	-	-	-	-	99.40	97.77
7.0-10.3	-	-	-	-	-	-	100	100

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

In an acute inhalation toxicity study conducted according to OECD 403 and in compliance with GLP, a LD50 of 1.1 and 1.18 mg/l (aerosol) was observed in male and female Wistar rats. The MMAD was 0.9-1.4 µm with a GSD of 1.6-2.2 µm with 97% of the particles having a diameter smaller than 5 µm. Mortality was observed in all exposure groups. 1/5 males was found dead in the 0.23 mg/l group. 1/5 males and females, each died in the 0.82 mg/l group. 3/5 males and 4/5 females animals were found dead in the 1.78 mg/l exposure group. In the high dose group all animals died. Clinical signs as panting, irregular respiration, coat bristling, uncoordinated gait, nasal discharge (blood coloured) were observed in all dose groups, mainly at the day of exposure and the day thereafter. Slightly reduced body weight gain was observed in the week after dosing with a dose-response relationship. Animals that died showed some abnormalities of the lung (red coloured lungs, emission of foam on dissection (males), plethoric (males), patchy dark red). Animals that survived until the end of the study showed no abnormalities.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

1 100 mg/m³

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.

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute toxicity: oral

A key study is available with N-[3-(triethoxysilyl)propyl]ethylenediamine (CAS 5089-72-5), which was conducted according to OECD 401 and in compliance with GLP (RCC, 1995a). Groups of 5 male and 5 femlae animals per group were treated with 1000, 1500, and 2000 mg test substance per kg bodyweight. No mortality was observed after treatment with 1000 mg/kg bw. After treatment with 1500 mg/kg bw 0/5 males and 2/5 females were found dead. Treatment with 2000 mg/kg bw led to 1/5 death males and females, each. Mortalities occurred on day 1 or 2, respectively. No clinical signs were observed at 1000 mg/kg bw. At 1500 and 2000 mg/kg bw sedation, spasms, dyspnea, ruffled fur, and diarrhea (reversible within 1 or 2 days for females and males, respectively) were observed. No effect of treatment on body weight was observed. Necropsy revealed no organ abnormalities in any dose group. In conclusion a LD50 >2000 mg/kg bw was derived.

 

Acute toxicity: inhalation

For the inhalation route a study according to OECD 403 (in compliance with GLP) was conducted with N-[3-(triethoxysilyl)propyl]ethylenediamine (Hoechst, 1992). Five male and female Wistar rats per group were exposed to aerosol concentrations of 0.23, 0.83, 1.78, 5.06 mg/l (analytical) N-[3-(triethoxysilyl)propyl]ethylenediamine for 4 h (nose only). The MMAD was 0.9-1.4 µm with a GSD of 1.6-2.2 µm with 97% of the particles having a diameter smaller than 5 µm. Mortality was observed in all exposure groups. 1/5 males was found dead in the 0.23 mg/l group. 1/5 males and females, each died in the 0.82 mg/l group. 3/5 males and 4/5 females animals were found dead in the 1.78 mg/l exposure group. In the high dose group all animals died. Clinical signs as panting, irregular respiration, coat bristling, uncoordinated gait, nasal discharge (blood coloured) were observed in all dose groups, mainly at the day of exposure and the day thereafter. Sneezing was also observed throughout the dose groups and occurred over a longer period of time (up to 15 days). In addition, at higher doses signs as gasping, crackling rales, squatting posture, trembling, decreased spontaneous activity were observed. Slightly reduced body weight gain was observed in the week after dosing with a dose-response relationship. Animals that died showed some abnormalities of the lung (red coloured lungs, emission of foam on dissection (males), plethoric (males), patchy dark red). In the high dose group these effects were not observed, probably due to the fact that the animals died within 1 and 4 h of the exposure period. Animals that survived until the end of the study showed no abnormalities. Based on the mortalities observed a LC50 of 1.1 and 1.18 mg/l was derived for male and female animals, respectively.

 

Acute toxicity: dermal

According to Regulation (EC) No. 1907/2006, Annex VIII, Column 2, 8.5.3, an acute dermal toxicity study is required only if inhalation of the substance is unlikely and skin contact in production and/or use is likely and the physicochemical and toxicological properties suggest potential for a significant rate of absorption through the skin. As an inhalation study is available, a low toxicity was observed in an acute oral study and the physico-chemical properties suggest a low dermal absorption, there is no need to perform an acute dermal toxicity study, also accounting for animal welfare.

Justification for classification or non-classification

For the inhalation route, it is not considered appropriate to classify for acute toxicity as the observed effects are due to exposure to aerosol droplets rather than to systemic availability of the test substance.

The available data on acute toxicity of the test substance do not meet the criteria for classification according to Regulation (EC) No. 1272/2008, and are therefore conclusive but not sufficient for classification.

No data on acute dermal toxicity are available.