Bis(triethoxysilylpropyl)amine

Endpoint summary

Description of key information

Oral (OECD 401), rat: LD50 = 3657 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:

18 Jan - 27 June 1988

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

adopted 1981

Deviations:

no

GLP compliance:

not specified

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: Winkelmann Versuchstierzucht, Borchen, Germany
- Age at study initiation: 7-8 weeks (males), 9-10 weeks (females)
- Weight at study initiation: 130-178 g (males), 132-162 g (females)
- Fasting: 16 h prior to dosing
- Housing: individual housing in Makrolon cages (type II)
- Diet: ssniff R, (ssniff Spezialdiäten GmbH, Soest, Germany), ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2
- Humidity (%): 55±15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 12.1 ml/kg bw

Doses:

2506, 5395, 11616 mg/kg bw (2.61, 5.62, 12.1 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 (for 21 days for animal no. 6)
- Frequency of observations and weighing: The rats were observed for 4-8 h post-dose on day of appplication and once (clinical signs) or twice (mortality) daily thereafter. Body weights were obtained on the day of treatment and on day 7 and 14 (and 21 for animal 6).
- Necropsy of survivors performed: yes (major organ systems of the thoracic and abdominal cavities were examined for all animals)
- Histopathology of macroscopic findings was performed (fixation in formalin)

Statistics:

Probit analysis for LD50 calculation

Sex:

male/female

Dose descriptor:

LD50

Effect level:

4 580 mg/kg bw

Based on:

test mat.

95% CL:

3 288 - 6 325

Sex:

male

Dose descriptor:

LD50

Effect level:

3 657 mg/kg bw

Based on:

test mat.

95% CL:

1 333 - 7 287

Sex:

female

Dose descriptor:

LD50

Effect level:

6 106 mg/kg bw

Based on:

test mat.

95% CL:

3 167 - 12 716

Mortality:

2506 mg/kg bw: 1/5 males (day 3) and 0/5 females
5395 mg/kg bw: 4/5 males (day 1-2) and 2/5 females (day 1-4)
11616 mg/kg bw: 5/5 males (day 1-3) and 5/5 females (day 1)

Clinical signs:

other: 2506 mg/kg bw: Males: reduced locomotor activity, shivering of the head, reduction of muscle tone, nasal discharge, salivation, piloerection, cyanosis, labored breathing, abnormal gait, cavernous flanks, reduction of body weight Females: reduced locomotor

Gross pathology:

2506 mg/kg bw: mottled liver (1 animal)
5395 mg/kg bw: red coloured glandular stomach (focal erosion) and intestinal mucosa, mottled liver, pale kidney with punctual spots
11616 mg/kg bw (1 animal): red coloured glandular stomach (focal erosion) and intestinal mucosa, mottled liver, pale kidney with punctual spots

Other findings:

2506 mg/kg bw: tubular hyperplasia in 3/5 animals (in one animal: tubular dilatation, necrosis, hypertrophy, interstitial fibroplasia, secondary glomerulonephrosis and protein cylinder)
5395 mg/kg bw (1 animal): liver necrosis with liver cell hypertrophy and focal pigment deposits, necrosis in the kidney and deposits of basophile material
11616 mg/kg bw (1 animal): cell degeneration and necrosis in the liver, oval cell hyperplasia, necrosis in the kidney and deposits of basophile material

Interpretation of results:

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

Conclusions:

In an acute oral toxicity study conducted according to OECD 401, a LD50 of 3657 mg/kg bw was derived in rats. In the low dose group 1/5 males and 0/5 females were found dead. Treatment with 5395 mg/kg bw led to 4/5 dead males and 2/5 dead females within day 1-2 and 1-4, respectively. All animals were found dead after treatment with 11616 mg/kg bw on days 1-2. In conclusion, a combined LD50 of 4580 mg/kg bw was calculated. The LD50 for males and females were 3657 and 6106 mg/kg bw, respectively.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

3 657 mg/kg bw

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 2), 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

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size

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

Study period:

18 Nov 2008 - 29 Jan 2009

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 (incl. QA statement)

Remarks:

Freie und Hansestadt Hamburg, Behörde für Arbeit, Gesundheit uns Soziales, Germany

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: Crl:CD (SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sulzfeld, Germany
- Age at study initiation: 50 days (males), 64 days (females)
- Weight at study initiation: 218-240 g (males), 205-222 g (females)
- Fasting: 16 h prior to dosing
- Housing: individual housing in Makrolon cages (type III plus)
- Diet: ssniff R/M-H V1534, ssniff Spezialdiäten GmbH, Soest, Germany, ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3
- Humidity (%): 55±15
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: 5 cm x 6 cm
- % coverage: 10% of total body surface
- Type of wrap if used: gauze bandaging (8 layers) covered with a plastic sheet and secured with adhesive plaster

REMOVAL OF TEST SUBSTANCE
- Washing: at the end of the exposure period no residual test item had to be removed

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw, 2.07 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 before and immediately, 5, 15, 30, and 60 min as well as 3, 6, and 24 h post-dose (clinical signs and mortality). Body weights were obtained before treatment and weekly thereafter.
During the follow-up period, changes of skin and fur, eyes and mucous membranes, respiratory and circulatory function, autonomic and central nervous system and somatomotor activity as well as behaviour pattern, were observed at least once a day until all symptoms subsided, thereafter each working day. Attention was also paid to possible tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.

- Necropsy of survivors performed: yes (At the end of the experiments, all animals were sacrificed, dissected and inspected macroscopically. All gross pathological changes were recorded. No histopathology was carried out as no macroscopical findings were noted at autopsy.)
- Dermal observations: application sites were examined for erythema, oedema and other dermal findings once daily until the end of the observation period.

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: No clinical signs of toxicity were observed.

Gross pathology:

The macroscopic examination did not reveal any changes.

Other findings:

- Other observations: No skin reactions were observed at the application site in any animals at any time point.

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	226.6	299±32	337.6±49
2000	female	212.4	248.2±16.9	258.6±21.8

Interpretation of results:

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

Conclusions:

In an acute dermal toxicity study conducted according to OECD 402 and in compliance with GLP, a LD50 of > 2000 mg/kg bw was derived for rats. No mortality and no clinical signs of toxicity were observed. The body weight gain was not influenced by the test item administration. The macroscopic examination did not reveal any changes. No skin reactions were observed at the application site in any animal at any time point.

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

Acute toxicity: oral

An acute oral toxicity is available with 3-(triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine (CAS 13497-18-2), which was conducted according to OECD 401 (ASTA Pharma AG, 1988). Five male and female Wistar rats were treated with 2506, 5395, and 11616 mg/kg bw by oral gavage. The test substance was applied undiluted (2.41, 5.62, 12.1 ml/kg). The rats were observed for 4-8 h post-dose on day of appplication (day 0) and once daily thereafter for clinical signs and twice daily for mortality. Body weights were obtained at the day of treatment and on day 7 and 14 (and day 21 for animal no. 6). Necropsy of survivors was performed and major organ systems of the thoracic and abdominal cavities were examined for all animals. Histopathology of macroscopic findings was performed.

In the low dose group 1/5 males and 0/5 females were found dead. Treatment with 5395 mg/kg bw led to 4/5 dead males and 2/5 dead females within day 1-2 and 1-4, respectively. All animals were found dead after treatment with 11616 mg/kg bw on days 1-2. Clinical signs observed in the 2506 mg/kg bw dose group included reduced locomotor activity, shivering of the head, reduction of muscle tone, nasal discharge, salivation, piloerection, cyanosis, labored breathing, abnormal gait, cavernous flanks, cyanosis and salivation. In the 5395 and 11616 mg/kg bw dose groups the clinical signs observed included: clonic and tonic convulsions, reduction of muscle tone, loss of startle reflexes, mydriasis, body cool to touch, nasal discharge and loss of pinna reflex (only in high dose males). Body weight loss was observed in 1 male of each dose group and in 1 female of the mid-dose group. Necropsy findings included a mottled liver in 1 animal of the 2506 mg/kg bw dose group as well as red coloured glandular stomach (focal erosion) and intestinal mucosa, mottled liver, pale kidney with punctual spots in the 5395 and 11616 mg/kg bw dose groups. Histology findings in the kidney included tubular hyperplasia and tubular dilatation, necrosis, hypertrophy, interstitial fibroplasia, secondary glomerulonephrosis and protein cylinder (in 1 animal each) in the low dose group. In the other dose groups necrosis in the kidney and deposits of basophile material were observed in 1 animal each. In the liver partial autolysis and the occurrence of microgranulomes were observed in the low dose group. Furthermore, microgranulomes (mid dose) and partial autolysis and necrosis (high dose) were observed in the surviving animals. In conclusion, a combined LD50 of 4580 mg/kg bw was calculated. The LD50 for males and females were 3657 and 6106 mg/kg bw, respectively.

 

Acute toxicity: inhalation

No data on acute inhalation toxicity is available.

Acute toxicity: dermal

An acute dermal toxicity study is available with 3-(triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine (CAS 13497-18-2), which was conducted according to OECD 402 and in compliance with GLP (LPT, 2009). Five male and female Crl:CD (SD) rats were treated with the limit dose of 2000 mg/kg bw by occlusive dermal application for 24 h. The test substance was applied undiluted (2.07 ml/kg) to the back of the animals covering 10% of the total body surface. At the end of the exposure period no residual test item had to be removed. The rats were observed before and immediately, 5, 15, 30, and 60 min as well as 3, 6, and 24 h post-dose, thereafter at least once daily (clinical signs and mortality). Body weights were obtained on the day of treatment and weekly thereafter. Necropsy of survivors was performed at the end of the experiment. The application sites were examined for erythema, oedema and other dermal findings once daily until the end of the observation period. Skin reactions were determined using the Draize scoring system. No mortality and no clinical signs of toxicity were observed. The body weight gain was not influenced by the test item administration. The macroscopic examination did not reveal any changes. No skin reactions were observed at the application site in any animal at any time point. 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 and dermal 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 are available for acute inhalation toxicity.