2,2,4-trimethyl-1-oxa-4-aza-2-silacyclohexane

Endpoint summary

Description of key information

2,2,4-trimethyl-1-oxa-4-aza-2-silacyclohexane is classified as corrosive, therefore no acute studies by oral, by inhalation or by dermal route are necessary based on Annex VII/VIII of Regulation (EU) 1907/2006 column 2. However, non-guideline studies for acute oral, inhalation and dermal toxicity reported in the year 1969 are available.

-Acute oral toxicity, female/male Wistar rats, oral gavage, doses: 50, 100,250, 500, 1000, 1500, 1750,2000, 2100,2400, 2500 mg/kg bw (males); 250,500, 1000, 1300, 1500,2000, 2250 and 2500 mg kg bw (females); non-guideline study similar to Standard acute method, non-GLP: LD50 (males) = 1890 mg kg bw and LD50 (females) = 1645 mg/kg bw.

- Acute toxicity: Inhalation, female/male Wistar rats, two tests with aerosols/spray mist, hole body exposure,

test 1: 0.064, 0.296, 0.662 mg/L (analysed concentrations, males) 1 x 4 hrs., 0,82 mg/L (analysed concentrations, females) 1 x 4 hours; 0,141, 0.9 mg/L (analysed doses, males) 4 x 4 hrs.

test 2: 0.344 g/L;

Clinical signs were observed at the highest dose in test 1 ; LC0 males >0.662 mg/L, females >0.820 mg/L (1 x 4 hrs.); LC0 males >0.9 mg/L (5 x 4 hrs.); non-guideline study, non GLP, cannot be used for Classification due to methodological deficiencies. LC0males

- Acute toxicity: Inhalation, male Wistar rats/male mice, male guinea pigs, cat and rabbit, exposure to substance vapour ((12.18), 12.35, 48.4, 51.4 mg test substance/L air), 4h, observation 14 days, LC50 (rats) > 48.4 <51.4 mg/L, LC50 (mice) > 12.35 <48.4 mg/L, non-guideline study, non-GLP, used for Classification due to sufficient documented results and generally accepted method.

-Acute toxicity: dermal, male rats, non-guideline study similar to Standard acute method, non-GLP: LD50 (males) > 1000 µl/kg bw (900 mg/kg bw).

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Principles of method if other than guideline:

- Principle of test: similar to standard acute method (not further specified)
- Short description of test conditions: 15 male and 15 female rats were applied by gavage the test substance in doses up to 2500 mg/kg bw
- Parameters analysed / observed: deaths and clinical signs

GLP compliance:

no

Remarks:

study conducted prior to implementation of GLP

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

OTHER SPECIFICS:
Kp. 140°C
technically pure

Species:

rat

Strain:

Wistar

Remarks:

Wistar II

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 170-205 g (males) and 180-200 g (females)
Please note: test results are also available for mouse, cat and dog.

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: not specified
- Amount of vehicle (if gavage): not specified

MAXIMUM DOSE VOLUME APPLIED: 1mL/100g bw

Doses:

50, 100, 250, 500, 1000, 1500, 1750, 2000, 2100, 2400, 2500 mg/kg bw (males)
250, 500, 1000, 1300, 1500, 2000, 2250 and 2500 mg/kg bw (females)

No. of animals per sex per dose:

15

Control animals:

no

Details on study design:

- Duration of observation period following administration: 7 days

Statistics:

The calculation of the average lethal dose was based on LITCHFIELD and WILCOXON, J. Pharmacol. exper. Therap. 96, 99 (1949).

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

1 890 mg/kg bw

Based on:

test mat.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

1 645 mg/kg bw

Based on:

test mat.

Mortality:

Males:
The lowest lethal dose (3 deaths of 15 animals after 1-3 days) was 1750 mg/kg bw. 11 of 15 animals and 13 of 15 animals died at a dose of 2000 (within 1 day) and 2100 mg/kg bw (within 1-4 days), respectively. At doses 2400 and 2500 mg/kg bw all 15 animals in each dose group died within one day.

Females:
The lowest lethal dose (1 death of 15 animals after 1 day) was 1300 mg/kg bw. 4 of 15 animals and 13 of 15 animals died at a dose of 1500 (within 1 day) and 2000 mg/kg bw (within 1 day), respectively. At doses 2250 and 2500 mg/kg bw all 15 animals in each dose group died within one day.

Clinical signs:

Poisoning signs such as breathing disorders, jumping cramps and reduction of the general condition were observed within 10 minutes (males) and 7 minutes (femlales) at a dose above or equal to 250 mg/kg bw and started within 2-3 minutes above or equal to 2000 (males) and 2250 (females) mg/kg bw. In animals, which did not die, clinical signs disappeared after 2-7 days (males) and 3-7 days (females).

Number of animals dead [and with evident toxicity] [and time range within which mortality occurred]
Dose	Mortality (# dead/total)			Time range of deaths (hours)	Number with evident toxicity(#/total)
(mg/kg bw)	Male	Female	Combined		Male	Female	Combined
50	0/15	not tested	n/a	--	0/15	not tested	n/a
100	0/15	not tested	n/a	--	0/15	not tested	n/a
250	0/15	0/15	0/30	--	15/15	15/15	30/15
500	0/15	0/15	0/30	--	15/15	15/15	30/15
1000	0/15	0/15	0/30	--	15/15	15/15	30/15
1300	not tested	1/15	n/a	24	not tested	15/15	n/a
1500	0/15	4/15	4/30	24	15/15	15/15	30/15
1750	3/15	not tested	n/a	24-72	15/15	not tested	n/a
2000	11/15	13/15	24/30	24	15/15	15/15	30/15
2100	13/15	not tested	n/a	24-96	15/15	not tested	n/a
2250	not tested	15/15	n/a	24	not tested	15/15	n/a
2400	15/15	not tested	n/a	24	15/15	not tested	n/a
2500	15/15	15/15	30/30	24	15/15	15/15	30/15

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The oral LD50 of the test substance in male and female rats was 1890 and 1645 mg/kg bw, respectively.

Executive summary:

In an acute oral toxicity study, 15 male and 15 female Wistar II strain rats per dose group were given a single oral dose of the test substance by gavage at a doses of 50, 100, 250, 500, 1000, 1500, 1750, 2000, 2100, 2400 and 2500 mg/kg bw (males) and 250, 500, 1000, 1300, 1500, 2000, 2250 and 2500 mg/kg bw (females) and were observed for 7 days.

Death in males started at a dose of 1750 mg/kg bw with 3/15 dead males within 1-3 days and death in females started at a dose of 1300 mg/kg bw with 1/15 dead female within 1 day. The LD50 was reported to be 1890 mg Aktiv. MO/kg bw (males) and 1645 mg Aktiv. MO/kg bw (females), respectively.

Clinical signs were breathing disorders, jumping cramps and reduction of the general condition within 10 minutes (males) and 7 minutes (females) at a dose above or equal to 250 mg/kg bw. linical signs were breathing disorders, jumping cramps and reduction of the general condition within 10 minutes (males) and 7 minutes (females) at a dose above or equal to 250 mg/kg bw.

The surviving animals had recovered from the symptoms until day 7.

Further results are available for mouse, cat and dog showing LD50 of >1000 mg/kg bw, 500 mg/kg bw and >250 mg/kg bw, respectively. However, the LD50 value for mice and dog are only estimates since the highest concentration used was 1000 mg/kg bw and 250 mg/kg bw. Furthermore, the total number of animals, i.e. 2 cats and 2 dogs, is not sufficient for a reliable dervation of a LD50 value and due to the preference of rats as suitable test animal for classification and labelling according to OECD guideline recommendation, the LD50 values in the present study report obtained with this species were used for classification and labelling according to regulation (EC) 1272/2008 (CLP).

Oral LD50 (rat, males/females) < 2000 mg/kg bw

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 645 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

significant methodological deficiencies

Principles of method if other than guideline:

- Principle of test:
1) Dynamic spray inhalation equipment (NIESSEN et al., 1963)
2) Static spray inhalation
- Short description of test conditions:
1) spraying of test substance mixed with alcohol and lutrol (1:1), absorbent: cotton for absorption of spray mist containing test substance; 3 air concentrations (nominal: 0.25, 0.5, 1, 2.5, 2.5 mg/L, analytical: 0.064, 0.141, 0.296, 0.662, 0.9 mg/L, 5 dose groups), exposure time 4 hours; 2 weeks observation
2) spraying of test substance mixed with alcohol and lutrol (1:1) every 30 min within 4 hours of total exposure; air agitation by use of fan; rabbits, guinea pigs, rats and mice together exposed in respective 2 m³ test chamber; 2 weeks observation

- Parameters analysed / observed:
1) clinical signs; lethal concentration
2) clinical signs

GLP compliance:

no

Remarks:

study conducted prior to implementation of GLP

Test type:

traditional method

Limit test:

no

Specific details on test material used for the study:

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Final dilution of a dissolved solid, stock liquid or gel: Aktivator MO mixed with alcohol and lutrol (1:1)

Species:

rat

Strain:

Wistar

Remarks:

Wistar II

Sex:

male/female

Route of administration:

other: two tests with aerosols/spray mist

Type of inhalation exposure:

whole body

Vehicle:

other: alcohol and lutrol (1:1)

Remark on MMAD/GSD:

MMAD was not determined

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus:test 1: Dynamic spray inhalation equipment (NIESSEN et al., 1963), test 2: static spray inhalation chamber
- Exposure chamber volume: unknown for test 1 (dynamic spray inhalation); 2 m³ test 2 (static spray inhalation)

TEST ATMOSPHERE
- Samples taken from breathing zone: collection of samples for calculation of average concentration in air, but location of sample collection was not reported

VEHICLE
- Composition of vehicle (if applicable): alcohol and lutrol
- Concentration of test material in vehicle (if applicable): unknown

Analytical verification of test atmosphere concentrations:

not specified

Remarks:

Report stated analytical concentration values but neither sample collection method, location and time point of sample collection nor type of analytical verification was reported

Duration of exposure:

4 h

Concentrations:

Test 1 (dynamic spray inhalation, males/females): theoretical concentrations: males: 0.25, 1, 2.5 mg/L (single exposure) and 0.5 and 2.5mg/L (repeated exposure; 5 x), females: 2.5 mg /L; measured concentrations: 0.064, 0.141, 0.296, 0.662, 0.9 mg/L (males), 0,82 mg/L (females)
Test 2 (static spray inhalation, males): theoretical concentration: 1 mg/L, measured concentration: 0.344 mg/L

No. of animals per sex per dose:

Test 1: 20 males per dose for 0.25, 5 x 0.5, 1, 2.5, 5 x 2.5 mg/L; 20 females per dose 2.5 mg/L
Test 2: 10 male rats

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days

Key result

Sex:

male

Dose descriptor:

LC0

Effect level:

2.5 mg/L air (nominal)

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: Result from Test 1

Key result

Sex:

female

Dose descriptor:

LC0

Effect level:

2.5 mg/L air (nominal)

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: Result from Test 1

Key result

Sex:

male

Dose descriptor:

LC0

Effect level:

2.5 mg/L air (nominal)

Based on:

test mat.

Exp. duration:

20 h

Remarks on result:

other: Result from Test 1 repeated 4h exposure (5x)

Key result

Sex:

male

Dose descriptor:

LC0

Effect level:

0.662 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: Result from Test 1

Key result

Sex:

female

Dose descriptor:

LC0

Effect level:

0.82 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: Result from Test 1

Key result

Sex:

male

Dose descriptor:

LC0

Effect level:

0.9 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

20 h

Remarks on result:

other: Result from Test 1; repeated 4h exposure (5 x)

Mortality:

Test 1: none
Test 2: none

Clinical signs:

other: Test 1: clinical signs were observed in all animals only at the highest nominal dose of 2.5 mg/L. Test 2: none

Test 1 (Dynamic spray inhalation)
Species	Concentration in air (mg Aktivator MO/L)		Exposure duration per day	Exposure days	Toxicological findings in 14 days
	theoret.	measured
rat (male)	0.25	0.064	4	1	0/0/20
	1.00	0.296	4	1	0/0/20
	2.50	0.662	4	1	0/20/20
rat (female)	2.50	0.820	4	1	0/20/20
mice (male)	1.00	0.325	4	1	0/20/20
	2.50	0.724	4	1	1/20/20
rat (male)	0.50	0.141	4	5	0/0/20
	2.50	0.900	4	5	0/20/20
*/*/*	deaths/clinical signs/total number of animals
Test 2
no detailed results, species used in this Test: 1 rabbit, 5 guinea pigs, 10 male rats, 20 male mice					No clinical signs or irritation detected for several species

Interpretation of results:

study cannot be used for classification

Conclusions:

For acute toxicity by inhalation only a LC0 was determined. The LC0 for inhalation of the test material in male rats was 2.5 mg/L nominal for both sexes or 0.662 mg/L analytical and in female rats 0.82 mg/L analytical.

Other results are also available for mice, rabbits and guinea pigs from Test 2 (see any other information on results).

Executive summary:

In an acute inhalation toxicity, male and female Wistar II rats were exposed by inhalation route to the test substance in alcohol and lutrol (1:1) in 2 different tests for 4 hours to the whole body at nominal concentrations of 0.25 – 2.5 mg/L. Animals then were observed for 14 days. Due to lack of mortality the LC50 could not be determined.

LC₀Males = 2.5 mg/L (0.662 mg/L)

      Females = 2.5 mg/L (0.820 mg/L)

Other results are also available for mice, rabbits and guinea pigs from Test 2 (see any other information on results).

Reference 2

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Principles of method if other than guideline:

- Principle of test: Vapourisation
- Short description of test conditions: Exposure of test animals (male rats, male mice, male guinea pigs, cat and rabbit) by vapourisation of test substance at 60-100°C in 0.4 m³ test chamber; air agitation by use of fan; exposure time 4 hours; 2 weeks observation
- Parameters analysed / observed: Clinical signs; deaths

GLP compliance:

no

Remarks:

study conducted prior to implementation of GLP

Test type:

traditional method

Specific details on test material used for the study:

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: Aktivator MO was vapourised at temperatures of 60 -100°C.

Species:

rat

Strain:

Wistar

Remarks:

Wistar II

Sex:

male/female

Route of administration:

other: inhalation of vapourised substance

Type of inhalation exposure:

whole body

Vehicle:

not specified

Remark on MMAD/GSD:

MMAD was not determined

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: vapourisation chamber
- Exposure chamber volume: 0.4 m³ (vapour test)

TEST ATMOSPHERE
- Samples taken from breathing zone: not reported

Analytical verification of test atmosphere concentrations:

no

Duration of exposure:

4 h

Concentrations:

Vapourisation test, male rats, mice and guinea pigs: concentrations: 12.35, 48.4, 51.4 mg test substance/L air

No. of animals per sex per dose:

10 male rats
20 mice
5 guinea pigs

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days

Key result

Sex:

male

Dose descriptor:

LC50

Effect level:

> 48.4 - < 51.4 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: Results for male rats

Key result

Sex:

male

Dose descriptor:

LC50

Effect level:

> 12.35 - < 48.4 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: Results for male mice

Mortality:

1/10 rats had died after 14 days for exposure group with vapour concentration 48.4 mg/L air, 7/10 rats had died after 14 days for exposure group with vapour concentration 51.4 mg/L air. At a concentration of 48.4 mg/L 12/20 male mice had died at the end of the observation period. 2/5 guinea pigs had died either at a concentration of 48.4 mg/L and 51.4 mg/L at the end of the observation period.

Clinical signs:

other: Clinical signs were observed in all animals irrespective of species at the high concentrations, i.e. 48.4 and 51.4 mg/L.

Test 3 (Toxicity of vapour)
Vapourisation temperature (°C)	Aktivator MO vapour concentration (mg/L)	Exposure duration	Toxicological findings in 14 days
60-70	12.18	4	rabbit: 0/0/1
			cat: 0/0/1
60-70	12.35	4	male mice: 0/0/20
			male rats: 0/0/10
			male guinea pig: 0/0/5
60-70	48.4	4	male mice: 12/20/20
			male rats: 1/10/10
			male guinea pig: 2/5/5
90-100	51.4	4	male mice: 14/20/20
			male rats: 7/10/10
			male guinea pig: 2/5/5
*/*/*	deaths/clinical signs/total number of animals

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The LC50 for inhalation of the test substance vapour in male rats was determined to be > 48.4 mg/L < 51.4 mg/L. In male mice the LC50 is supposed to be > 12.35 mg/L < 41.4 mg/L. For male guinea pigs, cats and rabbits no LC50 could be established under the used test conditions. For precautionaery reasons, although rats are the recommended species according to OECD test guideline under the present test conditions mice are the more sensitive species with a supposed LC50-value > 12.35 mg/L < 48.4 mg/L.

Executive summary:

In an acute inhalation toxicity study, male Wistar II rats were exposed by inhalation route to the test substance vapour for 4 hours to the whole body at concentrations of 12.35 – 51.4 mg/L. Animals then were observed for 14 days.

LC₅₀ male rats > 48.4 < 51.4 mg/L

LC₅₀ male mice > 12.35 < 48.4 mg/L

Based on the results obtained under the present test conditions for male mice 2,2,4-trimethyl-1-oxa-4-aza-2-silacyclohexane should be classified and labelled according to regulation (EC) 1272/2008 (CLP) Category 4 "Harmful if inhaled".

The test was also performed with cats, rabbits and guinea pigs but under the present test conditions no LC₅₀ could be determined.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

12 350 mg/m³

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Additional information

Regarding the investigation of acute toxicity via inhalation route the present study report is only in parts considered to be reliable and sufficiently documented. The dynamic and static spray method is considered to be not appropriate to determine a valid LC50 value. Furthermore, there are significant deficiencies in documentation of the performed tests, thus, this part of the study was not used for classification.

The second part of the acute toxicity inhalation test, exhibited a sufficient detailed documentation of a generally accepted method used, i.e. exposure to the test substance vapour. The results obtained from the second part of the study were used for classification and labelling.

Justification for classification or non-classification

The substance is classified as corrosive. Based on available data, the test substance should be classified and labelled according to the CLP Regulation (EC) No 1272/2008 with respect to acute toxicity by oral and inhalation route in Category 4 "Harmful if swallowed/inhaled". In the study for acute dermal toxicity the LD50 is > 1000 µl/kg bw = 900 mg/kg bw (highest applied dose) and is not exactly determined. According to CLP classification criteria (Regulation (EC) No 1272/2008) the study cannot be used for classification.