Isobutylisopropyldimethoxysilane

Endpoint summary

Description of key information

The test substance is classified as Acute Toxicity Category 4 by the inhalation route. It is not classified for acute toxicity by the oral route or by the dermal route.

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:

14 December 1987

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study conducted in accordance with EC Guidelines.

Qualifier:

equivalent or similar to guideline

Guideline:

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

Deviations:

yes

Remarks:

Only 3M/3F per dose group.

Principles of method if other than guideline:

The study was performed according to EC-test guidelines, which provided an animal number of 5F/5M per dose group. Divergent from that, only 3M/3F animals per dose group were employed in the study, since this procedure leads to equivalent results.

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: Wistar-Han-Schering

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Schering
- Age at study initiation: No data
- Weight at study initiation: (I): 79 to 98 g, (IIa): 76 to 91 g, (IIb): 95 to 117 g
- Fasting period before study: 18.5 to 19.5 hours
- Housing: Conventional
- Diet (e.g. ad libitum): pell. Altromin R ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-22°C
- Humidity (%): 52-66%
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data

Route of administration:

oral: gavage

Vehicle:

other: Isotonic sodium chloride solution

Details on oral exposure:

VEHICLE
- Concentration in vehicle: No data
- Amount of vehicle (if gavage): Control groups: 1.25 mL vehicle/kg or 2.5 mL vehicle/kg
- Justification for choice of vehicle: No information
- Lot/batch no. (if required): Batch no. KL 150 A2
- Purity: 1L contains 9.0 g sodium chloride

MAXIMUM DOSE VOLUME APPLIED: No data

Doses:

Two doses: 1.09 mg/kg bw/day (female only) and 2.18 mg/kg bw/day ( male and female)

No. of animals per sex per dose:

1.09 mg/kg bw/day: 3 female
Control (1.25 mL vehicle/kg): 3 female
2.18 mg/kg bw/day: 3 female + 3 male
Control (2.5 mL vehicle/kg): 3 female + 3 male

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Weighings on day 1, day 8 and day 14. Clinical observations performed on day 1, 30 mins, 1.5 hr and 3hr after exposure and then daily.
- Necropsy of survivors performed: yes
- Other examinations performed: None

Statistics:

None

Preliminary study:

Not applicable

Sex:

male

Dose descriptor:

LD50

Effect level:

> 2 180 mg/kg bw

Based on:

test mat.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 1 090 mg/kg bw

Based on:

test mat.

Mortality:

One female animal treated with 2.18 g ZK 119.649/kg died on day 3 of the test.

Clinical signs:

other: other: The main findings after application of ZK 119.649/kg in male and female animals were apathy, disturbances in gait and breathing, eyelid closure (incomplete), ruffled fur and wet fur sticking together. Male animals revealed, additionally, lateral po

Gross pathology:

In animals which died before the end of the observation period: In animal no. 11F which died on day 3 of the study a yellowish mucous content within the small intestine as well as a reddening of mucosa of the urinary bladder were observed.
In animals sacrificed at the end of the observation period: none

Other findings:

None

Application schedule of ZK 119.649 and rate of mortality:

Dose (g/kg)	No. of animals, sex	Observation period after administration (time of administration)	D/U
1.25 mL vehicle /kg (control)	3 F	25 Aug to 7 Sept 1987 (9:55 to 10:10)	0/3
1.09	3F		0/3
2.5 mL vehicle /kg (control)	3M	11 Aug to 24 Aug 1987 (9:55 to 10:05)	0/3
2.18	3M		0/3
2.5 mL vehicle /kg (control)	3F	13 Aug to 26 Aug 1987 (11:00 to 11:15)	0/3
2.18	3F		1/3

 

D: No. of dead animals

U: No. of animals used

Clinical findings after application of 2.18 g ZK 119.649/kg in male rats

Dose (g/kg)	Findings	Number of animals with findings/number of surviving animals
		Day 1 + 30 min	Day 1 + 1.5 hr	Day 1 + 3 hr	Day 2	Day 3	Days 4 - 14
2.5 mL/kg vehicle (control)	without findings	3/3	3/3	3/3	3/3	3/3	3/3
2.18	apathy, slight apathy, severe lateral position conscious gait, atactic gait, severely atactic tremor, total, spontaneous respiration, irregular incomplete eyelid closure fur, ruffled fur, wet, sticking together without findings	3/3             3/3	3/3           0/3	3/3               1/3   0/3	1/3 1/3 1/3   1/3 1/3 1/3 1/3 2/3 0/3	2/3 1/3	3/3

Clinical findings after application of 2.18 g resp. 1.09 g ZK 119.649/kg in female rats

Dose (g/kg)	Findings	Number of animals with findings/number of surviving animals
		Day 1 + 30 min	Day 1 + 1.5 to 2 hr	Day 1 + 3 to 3.5 hr	Day 2	Day 3	Days 4 - 14
1.25 mL/kg vehicle (control)	without findings	3/3	3/3	3/3	3/3	3/3	3/3
1.09	gait, atactic without findings	3/3	3/3	3/3 0/3	3/3	3/3	3/3
2.5 mL/kg vehicle (control)	without findings	3/3	3/3	3/3	3/3	3/3	3/3
2.18 g	apathy, severe prone, lateral or supine position in state of unconsciousness gait, atactic gait, severely atactic disturbances in breathing incomplete eyelid closure dacryorrhea, slight fur, wet, sticking together fur, ruffled without findings	3/3	3/3           2/3 0/3	1/3 2/3         2/3 0/3	1/3 1/3       1/3 1/3 1/3 1/3   0/3	2/2	2/2

Body weight in g at the start (day 1), day 8 and day 14 of the test in male rats

Dose (g/kg)	No. of animals, sex	Animal nos.	Day 1 X/SD	Day 8 X/SD	Day 14 X/SD
2.5 mL/kg vehicle (control	3 M	1 M 2 M 3 M	91/4	149/2	183/10
2.18	3 M	4 M 5 M 6 M	89/10	144/11	180/13

Body weight in g at the start (day 1), day 8 and day 14 of the test in female rats

Dose (g/kg)	No. of animals, sex	Animal nos.	Day 1 X/SD	Day 8 X/SD	Xi	Day 14 X/SD	Xi
1.25 mL/kg vehicle (control	3 F	1 F 2 F 3 F	107/11	150/4			161/7
1.09	3 F	4 F 5 F 6 F	111/5	152/5			166/6
2.5 ml vehicle/kg (control)	3 F	7 F 8 F 9 F	85/8	137/11		150/12
2.18	3 F	10 F 11 F 12 F	88/3		136   124		149   144

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The LD50 determination after a single i.g. application of ZK 119.649 yielded in male rats a dose > 2.18 g ZK 119.649/kg and in female rats a dose > 1.09 g/kg, presumably close to 2.18 g ZK 119.649/kg. No clear cut differences between surviving male and female animals of dose group 2.18 g/kg were observed in respect of clinical observations, body weight gain and autopsy findings.
Derived from the findings of the present study it is concluded that the LD50 in the rat is > 2 g/kg. Therefore, ZK 119.649 is not classified as "harmful'.

Executive summary:

For the toxicological characterization of ZK 119.649 an acute toxicity study with approximate LD50 determination in rats (M+F) was

to be performed after a single intragastric (i.g.) application.

The LD50 determination after a single i.g. application of ZK 119.649 yielded in male rats a dose > 2.18 g ZK 119.649/kg and in female rats a dose > 1.09 g/kg, presumably close to 2.18 g ZK 119.649/kg. No clear cut differences between surviving male and female animals of dose group 2.18 g/kg were observed in respect of clinical observations, body weight gain and autopsy findings.

Derived from the findings of the present study it is concluded that the LD50 in the rat is > 2 g/kg. Therefore, ZK 119.649 is not classified as "harmful'.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 180 mg/kg bw

Quality of whole database:

GLP study conducted in accordance with EC guidelines therefore rated as a Klimisch 1 study.

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:

12 January to 26 January 1988

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study conducted in accordance with OECD Guideline.

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: Wistar-Han-Schering

Sex:

male/female

Details on test animals or test system and environmental conditions:

animal strain: Wistar-Han-Schering rat
animal quality: barrier sustained
animal number: 20 M, 20 F
breeder: Schering AG
body weight: 124-147g (M), 109-131g (F)
identification: ear slits
randomization: by lot
acclimatization: 7 days
caging conditions: conventional
cage type: Makrolon, typ<=> II with wiremesh bottom
feed type: pelleted Altromin R
type of drinking water: tap water
feeding time, watering time: ad libitum, except during exposure period
room temperature, minimum: 22°C
romm temperature, maximum: 22°C
relative humidity, minimum: 48 %
relative humidity, maximum: 74 %
light period: artificial lighting (12-hours day/night-rhythm)

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Details on inhalation exposure:

Inhalation equipment
The dynamically operated inhalation system consisted of a generator unit to enrich air with vapour of ZK 119.649 and an exposure unit for nose-only exposure of the rats.

Generation of ZK 119.649 vapour-air mixtures
Dried compressed air was passed through a fine-particle filter, a pressure-stabilizer, a regulator and a ROTA flow meter. Then it was led through two special gas-washing bottles (70 mm diameter) with D1 sintered frits (d = 48 mm), connected in series. The bottles were filled with ZK 119.649 at a height of about 50 mm and kept at 20°C (+ 0.2°C) in a thermostated water-bath. For generation of graduated, defined mixtures of ZK 119.649 with
air, a second flow of air, processed and regulated as above, could be admixed in the requisite proportions, so that total volume flows of 1000 1 x h-1 (at 20°C, 1013 mbar) per chamber were accomplished. Before mixing with fresh air, aerosol particles were eliminated by an "on line" fiber glass filter (MILLIPORE, pore size less than or equal to 0.3 uM) from the generator line.

Exposure unit
The cylindric inhalation chambers of the Kimmerle type (60 L volume) were composed of an upper aerosol dispersion part and a lower exposure part with acrylic animal restraint tubes. The tubes were radially mounted to the chambers and designed such that only the noses of the animals were in contact with the aerosol flow in the chamber (nose-only exposure system). The exhaust air from the chamber was drawn under slight vacuum through a gas washing bottle with granulated charcoal (about 200 g) at a flow rate of 1000 1/h (+/- 5% at 20°C, 1013 mbar) which was controlled by a flow-meter.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

0.66 g x m-3
2.7 g x m-3
3.3 g x m-3
4.0 g x m-3

Higher concentrations were not tested, because exposure at a practically saturated vapour concentration of 4.4 g x m ZK 119.649 had already produced mortality after 125 min in a previous inhalation hazard test.

No. of animals per sex per dose:

5 male + 5 female per dose

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The test animals were observed repeatedly during exposure and three times after exposure on day 1 (day 1 = day of exposure). During the following observation period until day 14, a careful clinical examination and an additional check for dead and moribund animals were performed once daily. Body weights were recorded on day 1 (prior to treatment), 8 and 14 .
- Necropsy of survivors performed: yes. All animals were sacrificed at the end of the observation period (day 14) and autopsied. All gross pathological changes were recorded.
- Other examinations performed: clinical signs, body weight.

The actual chamber concentrations of the product were determined by gas chromatography.

Statistics:

None

Preliminary study:

Not applicable.

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 4 000 mg/m³ air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

There were no deaths during the exposure or in the 14 day observation period.

Clinical signs:

other: Prominent clinical findings during exposure were irregular respiration in all groups and respiratory distress and drawn in flanks at the two high concentrations. Additionally in one animal each at the highest concentration marked sialorrhea and spontaneou

Body weight:

No definite effects of exposure on weight gain were observed.

Gross pathology:

At necropsy, no exposure related macroscopic alterations were found.

Other findings:

None

In summary, the following prominent clinical signs were regarded as effects of exposure to ZK 119.649:

During exposure:

in all groups: irregular respiration

in group 4 and 5: respiratory distress, drawn in flanks

in group 5: in one animal each: marked sialorrhea, spontaneous total spasmodic twitches

After exposure:

in all groups: ruffled and wet, sticky fur

in group 3: slight apathy

in group 4 and 5: slight to severe apathy, atactic gait

additionally in

group 5: spontaneous total tremor, prone position conscious (in 1 M)

Interpretation of results:

harmful

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

An acute inhalation toxicity study was conducted with the test substance in agreement with the test guidelines of the OECD (no. 403, adopted May 12, 1981). The LC50 of the test substance (as aerosol) for male and female rats may be given as follows: LC50 (4 h) > 4.0 g/m3.

Executive summary:

An acute inhalation toxicity study was conducted with the test substance in agreement with the test guidelines of the OECD (no. 403, adopted May 12, 1981). The LC50 of the test substance (as aerosol) for male and female rats may be given as follows: LC50 (4 h) > 4.0 g/m3.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

4 000 mg/m³ air

Quality of whole database:

GLP study conducted in accordance with OECD guideline therefore rated as a Klimisch 1 study.

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:

5 August to 18 August 1987

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study conducted according to EU Guideline.

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: Wistar-Han-Schering

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Schering
- Age at study initiation: No data
- Weight at study initiation: 92-118 g males, 98-119 g females
- Fasting period before study: 18.5 hours
- Housing: No data
- Diet (e.g. ad libitum): pell. Altromin R
- Water (e.g. ad libitum): No data
- Acclimation period: 6 days (F) or 7 days (M)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23°
- Humidity (%): 60-68%
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data

IN-LIFE DATES: From: 5 August 1987 To: 18 August 1987

Type of coverage:

not specified

Vehicle:

other: isotonic sodium chloride solution

Details on dermal exposure:

Single dermal application of 2.18 g ZK 119.649/kg body weight

Vehicle:
Isotonic sodium chloride solution
Dose: 2.5 mL/kg
1L contains 9.0 g sodium chloride
Batch no. KL 150 A2
Stable till June 30, 1990
Manufacturer: Fresenius, Bad Homburg, FRG

Duration of exposure:

24 hours

Doses:

2.18 g/kg body weight

No. of animals per sex per dose:

3 males + 3 females per dose

Control animals:

yes, concurrent vehicle

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
- Necropsy of survivors performed: yes. On day 14 of the test all surviving animals were sacrificed.
- Other examinations performed: clinical signs, body weight

Statistics:

None

Preliminary study:

Not applicable

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 180 mg/kg bw

Based on:

test mat.

Mortality:

None

Clinical signs:

other: other: None

Gross pathology:

No substance-related findings on autopsy.

Other findings:

No local findings.

Body weight in g at the start (day 1), day 8 and at the end (day 14) of the test:

Dose (g/kg)	No. of animals, sex	Animal no.	Day 1 (X/SD)	Day 8 (X/SD)	Day 14 (X/SD)
2.5 ml/kg vehicle (control)	3M/3F	1M	110/111	144/111	185/17
		2M
		3M
		1F	111/7	135/9	152/12
		2F
		3F
2.18	3M/3F	4M	98/6	132/7	167/9
		5M
		6M
		4F	99/1	126/1	140/1
		5F
		6F

 

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The LD50 of ZK 119.649 after a single dermal application in rats (M+F) is > 2.18 g/kg body weight.

Executive summary:

The acute dermal toxicity of the test substance was determined in accordance with EU Guidance.

The LD50 of ZK 119.649 after a single dermal application in rats (M+F) is > 2.18 g/kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 180 mg/kg bw

Quality of whole database:

GLP study conducted in accordance with EC guidelines therefore rated as a Klimisch 1 study.

Additional information

The LD50 determination after a single i.g. application of ZK 119.649 yielded in male rats a dose > 2.18 g ZK 119.649/kg and in female rats a dose > 1.09 g/kg, presumably close to 2.18 g ZK 119.649/kg. No clear cut differences between surviving male and female animals of dose group 2.18 g/kg were observed in respect of clinical observations, body weight gain and autopsy findings.Derived from the findings of the present study it is concluded that the LD50 in the rat is > 2 g/kg. Therefore, ZK 119.649 is not classified as "harmful'.

An acute inhalation toxicity study was conducted with the test substance in agreement with the test guidelines of the OECD (no. 403, adopted May 12, 1981). The LC50 of the test substance (as aerosol) for male and female rats may be given as follows: LC50 (4 h) > 4.0 g/m³(4 mg/L). The test substance is therefore classified as Acute Toxicity Category 4 by the inhalation route.

The acute dermal toxicity of the test substance was determined in accordance with EU Guidance. The LD50 of the test substance after a single dermal application in rats is > 2.18 g/kg body weight. Therefore, the substance is not classified for acute toxicity by the dermal route.

Justification for selection of acute toxicity – oral endpoint

Only one study is available.

Justification for selection of acute toxicity – inhalation endpoint

Only one study is available.

Justification for selection of acute toxicity – dermal endpoint

Only one study is available.

Justification for classification or non-classification

The above studies have all been ranked reliability 1 according to the Klimisch et al system. This ranking was deemed appropriate because the studies were GLP studies conducted according to recognised test methods. Sufficient dose ranges and numbers are detailed; hence it is appropriate for use based on reliability and animal welfare grounds.

According to the CLP Regulation, the substance is classified as Acute Toxicity Category 4 by the inhalation route.