N,N-Disilylsilanamine

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2013

Report date:

2013

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

yes

Remarks:

Deviations did not negatively impact the quality or integrity of the data nor the outcome of the study.

GLP compliance:

yes (incl. QA statement)

Test type:

fixed concentration procedure

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

trisilylamine

EC Number:

680-408-9

Cas Number:

13862-16-3

Molecular formula:

H9NSi3

IUPAC Name:

trisilylamine

Test material form:

liquid

Specific details on test material used for the study:

Name of test material: Trisilylamine
Description: Clear, colourless liquid
Purity: 99.62%

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

ANIMAL RECEIPT AND ACCLIMATION

Crl:CD(SD) from Charles River Laboratories, Raleigh, NC
Rats were acclimated in the laboratory for a minimum of 5 days. During the acclimation period, the rats were observed twice daily for mortality and moribundity.

ANIMAL HOUSING

All animals were housed in individual suspended wire-mesh cages. The animals were maintained by the WIL Research Animal Husbandry staff in accordance with SOPs. On the day of exposure, the animals were placed in a wire mesh battery containing separate cages, transported to the exposure room, exposed for the requisite duration then returned to their home cages.

DIET, DRINKING WATER, AND MAINTENANCE

The basal diet used in this study, PMI Nutrition International, LLC, Certified Rodent LabDiet® 5002, is a certified feed with appropriate analyses performed by the manufacturer and provided to WIL Research. Municipal water supplying the facility is
analyzed for contaminants according to SOPs. The results of the diet and water analyses are maintained at WIL Research. No contaminants were present in animal feed or water at concentrations sufficient to interfere with the objectives of this study. The basal diet and municipal water, delivered by an automatic watering system, were provided ad libitum, except during the exposure periods.

ENVIRONMENTAL CONDITIONS

The animal room was maintained with controlled temperature, humidity, and light (12 hours light/12 hours dark). The room temperature and humidity controls were set to maintain daily averages of 71°F ± 5°F (22°C ± 3°C) and 50% ± 20% relative humidity. Room temperature and relative humidity were monitored using the Metasys DDC Electronic Environmental control system and were scheduled for data collection on an hourly basis. These data are summarized in Appendix C. Actual mean daily temperature ranged from 70.4°F to 73.3°F (21.3°C to 22.9°C) and mean daily relative humidity ranged from 38.6% to 60.6% during the study.

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: nitrogen

Details on inhalation exposure:

Exposure:

Exposures were conducted using a 130-L stainless steel and glass whole-body exposure chamber. Chamber temperature, relative humidity, ventilation rate, and negative pressure within the chamber were recorded at approximately 30-minute intervals during the exposure.

Omega model no. HX94C temperature and humidity transmitter probe (Omega Engineering, Inc.,Stamford, CT) provided monitoring of temperature and percent relative humidity. The chamber was operated with at least 10 air changes per hour. Test substance atmosphere was passively exhausted into a walk-in fume hood in Exposure Room 5.

Oxygen content was measured during the pre-exposure method development phase for the 49, 250, 519, and 1996 ppm groups and during animal exposure for the 121 ppm group using a Dräger PAC III equipped with a calibrated oxygen sensor (Dräger Safety, Inc., Pittsburgh, PA). The oxygen content was 20.1%, 20.1%, 20.0%, 19.6%, and 19.4% for the 49, 121, 250, 519, and 1996 ppm groups, respectively.

The calculated t99 equilibrium time was 13, 13, 13, 13, and 17 minutes for the 49, 121, 250, 519, and 1996 ppm groups. For each exposure, the animals were placed in the chamber and the test substance generation was initiated. One estimated t99 interval was added to the 4-hour exposure period. For the 49, 121, 250, and 519 ppm groups, the total exposure/generation period was 260, 253, 254, and 260 minutes, respectively. The 1996 ppm group was 166 minutes due to all animals dying during exposure. The exposure period was terminated when the test substance generation was stopped. The animals were removed from the chamber after at least 1 estimated t99 clearance time.

Test Atmosphere Generation:

Vapors of the test substance were generated using a Sponsor-provided bubbler-type vaporization system containing liquid test substance. Using a regulator (model no. 1L-350, Matheson, Montgomeryville, PA for the 49, 519, and 1996 ppm groups and model no. 8802K, Coilhose Pneumatics Inc., East Brunswick, NJ for the 121 and 250 ppm groups) and rotameter-type flowmeter (model no. 10, Omega Engineering, Inc., Stamford, CT for the 49, 121, and 250 ppm groups and model no. PMR1-010334, Cole-Parmer, Vernon Hills, IL for the 519 and 1996 ppm groups), nitrogen was metered into the inlet stem (“diptube out”) of the bubbler.

The test substance vapors were piped to the chamber inlet and diluted to the desired concentration by mixing with additional nitrogen, dilution air, and oxygen. Dilution nitrogen was added to a tee that was placed in-line after the bubbler using the previously mentioned nitrogen regulator and a rotameter-type flowmeter (model no. 150MM, Barnant Co./Gilmont Instruments, Barrington, IL). Using a Coilhose Pneumatics regulator (model no. 8802K) and Gilmont rotameter-type flowmeter (model no. 150MM), compressed air was added to a second tee in-line with the test atmosphere delivery system to provide dilution air. To maintain the protocol-specified oxygen requirements and to further dilute the atmosphere, compressed oxygen was added prior to the chamber using a Matheson regulator (model no. 3121-590) and a Cole-Parmer rotameter-type flowmeter (model no. PMR1-012020).

The approximate airflows used for each exposure are summarized in the following table:

Group
(ppm)
Generation
Nitrogen
(mL/minute)
Dilution
Nitrogen
(L/minute)
Dilution
Airflow
(L/minute)
Oxygen
(L/minute)
Total
Airflow Rate
(L/minute)
49 4-6 11 31 2.8 45
121 10-12 13 31 2.4 47
250 18-21 11 31 2.1 44
519 73-83 13 26-31 2.8 42-47
1996 143-221 11-13 22 2.8 36-37

Due to the hazardous nature of the test substance, one-way check valves were placed inline to prevent backflow of the test substance vapors at the following locations in the generation system: prior to the bubbler (519 and 1996 ppm only), exiting the bubbler, after the dilution nitrogen, and after the oxygen flowmeter.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

Acute single exposure: 49, 121, 250, 519 and 1996 ppm (nominal)

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

The acute inhalation toxicity of trisilylamine was evaluated in this 4-hour, single-exposure study in rats. The test substance was administered to 5 groups of 5 male and 5 female Crl:CD(SD) albino rats via whole-body inhalation exposure as a vapor at nominal concentrations of 49, 121, 250, 519, and 1996 ppm.

Mortality, clinical observations, body weights, and body weight changes were evaluated over a 14-day post-exposure observation period. Necropsies were conducted on all animals.

Statistics:

LC50 value with 95% confidence limits will be calculated by the method of Litchfield and Wilcoxon (1949).

Results and discussion

Preliminary study:

No

Effect levels

Sex:

male/female

Dose descriptor:

LC50

Effect level:

99 ppm

Based on:

test mat.

95% CL:

>= 64 - <= 153

Exp. duration:

4 h

Mortality:

All animals in the 1996 ppm group died during the exposure. All animals in the 519 and 250 ppm groups were found dead by study day 1 and 2, respectively. All deaths were noted within 4 days of exposure. Total mortality was 0/10, 9/10, 10/10, 10/10, and 10/10 animals for the 49, 121, 250, 519, and 1996 ppm groups, respectively.
The LC50 value, in ppm, and slope (with 95% confidence limits) were estimated using the method of Litchfield and Wilcoxon (Litchfield and Wilcoxon, 1949). Based on the data obtained, the LC50 value and slope for combined sexes were 99 (64-153) and 1.17 (1.05-1.31), respectively.

Clinical signs:

other: Clinical observations immediately following exposure consisted of rapid respiration, clear material around the eye(s), protruding right eye, dilated pupil right eye, and red material around the nose for the 519 ppm group; and rales and red vaginal dischar

Body weight:

The surviving female in the 121 ppm group lost 44 and 24 grams during the study day 0 to 7 interval and the study day 7 to 14 interval, respectively. Body weight gain during the study day 7 to 14 interval appeared to be higher than during the study day 0 to 7 interval for animals in the 49 ppm group. Therefore, test substance exposure appeared to produce lower body weight gain during the period following exposure. All animals in the 49 ppm group surpassed their initial (study day 0) body weight by study day 14 and were considered normal

Gross pathology:

The following table summarizes the internal macroscopic findings (number of animals with finding) noted for animals that died:

Group (ppm)
121 250 519 1996
Macroscopic Finding M F M F M F M F
Number of Animals Examined 5 4 5 5 5 5 5 5
Dark Red Discoloration of the Lungs 5 3 5 5 2 1 5 5
Lungs Not Fully Collapsed 2 1 0 1 4 2 5 5
Clear Fluid Contents in the Thoracic Cavity 0 0 0 0 5 5 2 0
Thick White Contents in the Thoracic Cavity 0 0 0 0 1 0 0 0
Dark Red Area(s) on the Lungs 0 0 0 0 3 4 0 0
Dilated Renal Pelvis 0 0 0 0 1 0 0 0
Dark Red Discoloration of the Thymus 0 0 0 0 1 1 0 0
Foamy Contents in the Trachea 0 0 0 0 1 1 0 0
Accessory Spleen 0 0 0 0 0 1 0 0
Dark Red Discoloration of the Liver 4 3 0 0 0 0 0 0
Swollen Liver 0 1 0 0 0 0 0 0
M = Male F = Female

The following table summarizes the macroscopic findings (number of animals with finding) noted for animals at the scheduled necropsy:

Group (ppm)
49 121
Macroscopic Finding M F M F
Number of Animals Examined 5 5 0 1
Lungs Not Fully Collapsed 2 0 0 1
Pale Lungs 0 0 0 1
Dark Red Area(s) on the Lungs 1 0 0 0
Clear Fluid Contents in the Uterus 0 1 0 0
M = Male F = Female

Applicant's summary and conclusion

Interpretation of results:

Category 1 based on GHS criteria

Conclusions:

Based on the results of this study, the LC50 of trisilylamine was 99 ppm (with a 95% confidence interval of 64 to 153 ppm) when male and female albino rats were exposed to a vapor of the test substance as a single, 4-hour, whole-body exposure.

Executive summary:

The objective of this study was to determine the acute inhalation toxicity of trisilylamine to rats when administered as a vapor for a single, 4-hour, whole-body inhalation exposure.

The protocol was designed to be in general compliance with the Environmental Protection Agency (EPA) Office of Prevention, Pesticides and Toxic Substances (OPPTS) Guideline 870.1300, August 1998 and the Organisation for Economic Cooperation and Development (OECD) Guidelines for Testing of Chemicals, Section 403.

Based on the results of this study, the LC50 of trisilylamine was 99 ppm (with a 95% confidence interval of 64 to 153 ppm) when male and female albino rats were exposed to a vapor of the test substance as a single, 4-hour, whole-body exposure.