N-[3-(trimethoxysilyl)propylcyclohexylamine]

Endpoint summary

Description of key information

Acute oral toxicity (OECD 401, rat): LD50 >2000 mg/kg bw
Acute inhalation toxicity (OECD 403, rat): LC50 = 2 mg/L air (combined males/females)
Acute dermal toxicity: no data 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:

04 - 21 Aug 1998

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:

(1987)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Version / remarks:

(1992)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Winkelmann, Borchen, Germany
- Age at study initiation: 6 - 10 weeks
- Weight at study initiation: 203 - 219 g (males), 174 - 193 g (females)
- Fasting period before study: animals were fasted from about 16 h before to 3 - 4 h after treatment.
- Housing: animals were housed in fully air-conditioned rooms in macrolon cages (type 4) on soft wood granulate in groups of 5 animals.
- Diet: ssniff R/M-H (V 1534), ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 50 ± 20
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

other: sesame oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg/mL (20% solution)
- Amount of vehicle: 10 mL/kg bw

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

Doses:

2000 mg/kg bw (main study)
500, 1000 and 2000 mg/kg bw (range finding study)

No. of animals per sex per dose:

5 (main study)
1 (range finding study)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical signs were recorded twice daily (in the morning and afternoon) and once daily on weekends and public holidays. The animals were weighed at weekly intervals.
- Necropsy of survivors performed: yes

Preliminary study:

In a dose range finding study groups of one rat of each sex were administered the test material at dose levels of 500, 1000 and 2000 mg/kg bw via oral gavage as a 20% solution in sesame oil. The animals were observed for clinical signs of toxicity for 14 days. No mortality and no clinical signs of toxicity were recorded during the study period up to and including the highest dose tested. Body weight gain was within the expected range and no abnormalities were observed at necropsy.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: no mortality and no clinical signs of toxicity were observed

Mortality:

No mortality occurred during the study period.

Clinical signs:

No clinical signs of toxicity were observed during the study period.

Body weight:

Body weight gain was within the expected range during the study period.

Gross pathology:

Gross pathology revealed no abnormalities.

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 according to OECD guideline 401 and in compliance with GLP, no mortality and no clinical signs of toxicity were observed at 2000 mg/kg bw. In conclusion, a LD50 >2000 mg/kg bw was derived.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises an adequate and reliable study, and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, 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:

20 Aug - 08 Oct 1991

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

(1981)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Version / remarks:

(1984)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: Hoe:WISKf(SPF71)

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: 198 - 212 g (males), 186 - 212 g (females)
- Housing: animals were housed in fully air-conditioned rooms in macrolon cages (type 4) on soft wood granulate in groups of 5 animals.
- Diet: rodent diet Altromin 1324 (Altromin-GmbH, Lage, Germany), ad libitum
- 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/head 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 hold in cylindrical plastic cages and are exposed to a defined aerosol concentration via nose only inhalation.
- Source and rate of air: filtered air at 0.8 m³/h
- System of generating aerosols: the test material was injected in a nozzle via permanent infusion device with a constant rate. Primary aerosol formation occurred in a glass flask. Smaller aerosol particles (secondary aerosol) were piped in the exposure chamber via a standpipe.
- Method of particle size determination: Anderson-Kaskadenimpaktor Mark III followed by Probit analysis
- Treatment of exhaust air: exhausted air/aerosol is removed and filtered via a methanol, water and cotton wool wash bottle followed by a buehlerfilter and a calciumchloride wash bottle.
- Temperature and humidity in air chamber: 21.1 - 22.9 °C, 13.2 - 34.7%

TEST ATMOSPHERE
- Brief description of analytical method used: gravimetric measurements were performed for determination of test material concentration (15 min interval).
- Samples taken from breathing zone: yes

VEHICLE
- Composition of vehicle: filtered clean air
- Concentration of test material in vehicle: 1.59, 1.65, 0.89, 3.17 mg/L

TEST ATMOSPHERE
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 0.7 - 1.1 / 1.6 - 1.9

Analytical verification of test atmosphere concentrations:

yes

Remarks:

The test substance was absorbed in gas washing bottles. The samples were diluted in n-hexane. The determination of the test substance was performed by gaschromatography using an FID as detector.

Duration of exposure:

4 h

Concentrations:

Group 1: 1.59 mg/L air (nominal concentration)
Group 2: 1.65 mg/L air (nominal concentration)
Group 3: 0.89 mg/L air (nominal concentration)
Group 4: 3.17 mg/L air (nominal concentration)

No. of animals per sex per dose:

5 (Group 1 - 3)
5 females (Group 4)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 21 days (Group 1), 14 days (Group 2, 3), 28 days (group 4)
- Frequency of observations and weighing: Clinical signs were observed twice daily and once daily on weekends and public holidays. Body weights were recorded in weekly intervals.
- Necropsy of survivors performed: yes

Sex:

female

Dose descriptor:

LC50

Effect level:

2.3 mg/L air (nominal)

Based on:

test mat.

Exp. duration:

4 h

Sex:

male

Dose descriptor:

LC50

Effect level:

1.6 mg/L air (nominal)

Based on:

test mat.

Exp. duration:

4 h

Sex:

male/female

Dose descriptor:

LC50

Effect level:

2 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: combined LC50 for males/females

Mortality:

5/10, 4/10, 0/10 and 3/5 animals died during the study period when exposed to 1.59, 1.65, 0.89 and 3.17 mg/L air, respectively.

Clinical signs:

other: Animals exposed with 0.89 mg/L air of the test material showed fitful and cracking breathing, ataxic/staggering movements, reddish rhinorrhea, sneezing and piloerection. Animals exposed to higher concentrations of the test material additionally showed cli

Body weight:

With the exception of one female all animals showed body weight gain until study termination.

Gross pathology:

Gross pathology of animals died during the study revealed discoloured lungs and liver, spotted lungs, inflated intestine and foam withdrawal from dissected lungs.

Table 1: Mortality data

Animals Group	Target Concentration [mg/L air]	Mortality	Clinical Signs
		N	N
Males
1	1.59	3/5	5/5
2	1.65	2/5	5/5
3	0.89	0/5	5/5
Females
1	1.59	2/5	5/5
2	1.65	2/5	5/5
3	0.89	0/5	5/5
4	3.17	3/5	5/5

N= Number of animals/number of animals used

Interpretation of results:

other: CLP/EU GHS Category 4 (H332) according to Regulation (EC) No 1272/2008

Conclusions:

In an acute inhalation toxicity study according to OECD guideline 403 and in compliance with GLP, a combined LC50 of 2 mg/L air was derived for male and female rats resulting in category 4 classification.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

2 000 mg/m³

Quality of whole database:

The available information comprises an adequate and reliable study, and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute toxicity: oral

A reliable acute oral toxicity study with N-[3-(trimethoxysilyl)propylcyclohexylamine] (CAS 3068-78-8) is available and was performed according to OECD TG 401 and in compliance with GLP (Hoechst, 1998). In this limit test five fasted Sprague-Dawley rats of each sex were administered a single dose of 2000 mg/kg bw of the test substance in sesame oil (vehicle) via oral gavage. The animals were observed for 14 days after administration. No mortality and no clinical signs of toxicity were recorded during the study period. Body weight gain was within the expected range and no abnormalities were observed at necropsy. Thus, the acute oral LD50 value for males/females was calculated to be greater than 2000 mg/kg bw.

 

Acute toxicity: inhalation

A reliable acute inhalation toxicity study was performed with N-[3-(trimethoxysilyl)propylcyclohexylamine] (CAS 3068-78-8) according to OECD TG 403 and in compliance with GLP (Hoechst, 1991). In this study five Hoe:WISKf rats of each sex were exposed to an aerosol with nominal concentrations of 1.59, 1.65 and 0.89 mg/L air (Groups 1-3) for 4 hours in an nose/head-only inhalation exposure chamber. Five additional female rats were exposed to an aerosol concentration of 3.17 mg/L air (Group 4) via the same procedure. The animals were observed for 21 (Group 1), 14 (Group 2, 3) and 28 (Group 4) days after exposure, respectively. In summary, 5/10, 4/10, 0/10 and 3/5 animals died during the study period when exposed to 1.59, 1.65, 0.89 and 3.17 mg/L air of the test material, respectively. Animals exposed to 0.89 mg/L air of the test material showed fitful and cracking breathing, ataxic/staggering movements, reddish rhinorrhea, sneezing and piloerection. Animals exposed to higher concentrations of the test material additionally showed clinical signs such as crouch/abdominal position, tremor, reduced activity, crusty noses and alopecia. Clinical signs were still recorded at study termination in some animals. With the exception of one female all animals showed body weight gain until study termination. Gross pathology of animals which died during the study revealed discoloured lungs and liver, spotted lungs, inflated intestine and foam withdrawal from dissected lungs. Therefore, the acute inhalation LC50 values were calculated to be 1.6 and 2.3 mg/L air for males and females, respectively.

 

Acute toxicity: dermal

According to Regulation (EC) No 1907/2006, Annex VIII, Section 8.5.3, Column 2, testing by the dermal route does not need to be conducted if the substance does not meet the criteria for classification as acutely toxic by the oral route and no systemic effects have been observed in in vitro studies with dermal exposure (e.g. skin irritation and skin sensitisation) or no systemic effects after dermal exposure are predicted on the basis of non-testing approaches (e.g. read across, QSAR studies). An acute oral toxicity study was performed with the registered substance N-[3-(trimethoxysilyl)propylcyclohexylamine] (CAS 3068-78-8) according to OECD TG 401 indicating no signs of systemic toxicity and thus, a LD50 value >2000 mg/kg bw was derived. Furthermore, in vivo studies on skin irritation and skin sensitisation are available with the registered substance N-[3-(trimethoxysilyl)propylcyclohexylamine] (CAS 3068-78-8) performed according to the appropriate OECD TG. No mortality and no systemic effects were observed either in the skin irritation or in the skin sensitisation study. Thus, with respect to the animal welfare, the conduct of an acute dermal toxicity study would be scientifically unjustified.

Justification for classification or non-classification

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