1,3-bis(trimethylsilyl)urea

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

01 Apr - 12 May 2020

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2020

Report date:

2020

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 433 (Acute Inhalation Toxicity: Fixed Concentration Procedure)

Version / remarks:

adopted in 2018

Deviations:

no

GLP compliance:

yes

Test type:

fixed concentration procedure

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

1,3-bis(trimethylsilyl)urea

EC Number:

242-177-9

EC Name:

1,3-bis(trimethylsilyl)urea

Cas Number:

18297-63-7

Molecular formula:

C7H20N2OSi2

IUPAC Name:

1,3-bis(trimethylsilyl)urea

Test animals

Species:

rat

Strain:

Wistar

Remarks:

RccHan®:WIST

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Envigo RMS Ltd. (UK)
- Age at study initiation: 8 - 12 weeks
- Weight at study initiation: 242 - 295 g (males) and 185 - 191 g (females)
- Fasting period before study: no
- Housing: Individually during the sighting study and in groups of 5 during the main study. The cages were made of a polycarbonate body with a stainless steel mesh lid. Autoclaved softwood bark-free fiber was used as bedding.
- Diet: Teklad 2014C Diet, ad libitum
- Water: potable water from the public water supply, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 40 - 70
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

2 - 2.2 µm

Geometric standard deviation (GSD):

2.25 - 2.64

Remark on MMAD/GSD:

The Mass Median Aerodynamic Diameter (MMAD) ± Geometric Standard Deviation (GSD) was 2.1 ± 2.25 µm at 1 mg/L (sighting study) and 2.0 ± 2.34 µm (sighting study) and 2.2 ± 2.64 µm (main study) at 5 mg/L air, respectively.

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The exposure apparatus was a Flow through nose-only chamber (ADG Developments Ltd, Hitchin, Hertfordshire, England) with an aluminum alloy construction comprising a base unit, one animal exposure section with 20 exposure ports, and a top section.
- Exposure chamber volume: approximately 30 L
- Method of holding animals in test chamber: plastic nose-only restraint tube
- Source and rate of air (airflow): The aerosol was generated by Wright Dust Feed Mechanism, which produces and maintains test atmospheres containing dust by suspending material scraped from the surface of compressed powder in a stream of dry air. The inlet airflow was 44 L/min.
- Method of particle size determination: The particle size distribution was characterized twice during each exposure period. The aerosol samples were drawn with a flow of 2 L/min. Particle size distribution was determined by cascade impaction using a Marple 290 Series Personal Cascade Impactor (Andersen Instruments, Smyrna, Georgia, USA). Amounts of test item collected were measured gravimetrically. Subsequently the Mass Median Aerodynamic Diameter (MMAD) and the Geometric Standard Deviation (GSD) were derived.
- Treatment of exhaust air: Extract airflow was drawn by in-house vacuum system and filtered locally. The flow was 45 - 46 L/min.
- Mean temperature in air chamber: 19.8 ± 0.65 °C (1 mg/L, sighting study), 19.4 ± 0.22 °C (5 mg/L, sighting study) and 19.7 ± 0.21 °C (5 mg/L, main study).
- Humidity in air chamber: 9.4 ± 0.88% (1 mg/L, sighting study), 14.8 ± 2.42% (5 mg/L, sighting study) and 16.8 ± 1.23% (5 mg/L, main study).

TEST ATMOSPHERE
- Brief description of analytical method and equipment used: Aerosol samples were collected by using a glass microfiber filter held in an open face filter holder. Five samples were collected during each exposure.
- Samples taken from breathing zone: yes

Analytical verification of test atmosphere concentrations:

yes

Remarks:

gravimetric

Duration of exposure:

4 h

Concentrations:

Sighting study:
1.02 ± 0.020 and 5.04 ± 0.283 mg/L air (analytical concentrations)
1.34 and 6.58 mg/L air (nominal concentrations)

Main study:
5.30 ± 0.225 mg/L air (analytical concentration)
6.34 mg/L air (nominal concentration)

No. of animals per sex per dose:

Sighting study: 1 male and 1 female per step (2 steps)
Main study: 5 males

Control animals:

no

Details on study design:

- Duration of observation period following administration: 8 - 10 days (sighting study) and 15 days (main study).
- Frequency of observations: Throughout the study all cages were checked at least twice daily, once in the morning and again towards the end of the normal working day, for dead or moribund animals. The animals were observed for clinical signs prior to dosing, at hourly intervals during exposure, 1 and 2 hours after exposure and as late as possible in the working day of exposure. Thereafter, the animals were inspected visually at least twice daily for evidence of ill-health or reaction to treatment. Any deviation from normal was recorded at the time in respect of nature and severity, date and time of onset, duration and progress of the observed condition, as appropriate. Detailed physical examinations were performed weekly.
- Frequency of weighing: In the sighting study, rats were weighed at least once during the week prior to exposure, on Day 1 (prior to dosing) and on Days 2, 4 and 10. In the main study, rats were weighed at least once during the week prior to exposure, on Day 1 (prior to dosing) and on Days 2, 4, 8 and 15.
- Necropsy of survivors performed: Yes, all main study animals were subjected to a macroscopic examination which consisted of opening the cranial, thoracic and abdominal cavities. The macroscopic appearance of all examined organs was recorded. Tissues were discarded following necropsy. Special attention was paid to the lungs and respiratory tract for signs of irritancy and local toxicity during necropsy observation.

Statistics:

No statistical analysis was performed.

Results and discussion

Preliminary study:

In the sighting study, each one male and one females were dosed at 1 mg/L air, corresponding to an analytical concentration of 1.02 ± 0.020 mg/L air. Evident toxicity was not observed therefore a further one male and one female received a single 4-hour nose only exposure of the test item at the target concentration of 5 mg/L, corresponding to an analytical concentration of 5.04 ± 0.283 mg/L air, and observed for seven days. The results of this exposure determined the starting exposure level for the main exposure.

Effect levels

Key result

Sex:

male

Dose descriptor:

LC50

Effect level:

> 5.3 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No mortality occurred during the study period.

Clinical signs:

other: Please refer to "Any other information on results incl. tables".

Body weight:

A slight loss in mean body weight was noted in the animals one day following exposure, which was considered to be a consequence of food and water removal during exposure. The finding was considered as normal body weight variation and therefore not attributed to treatment. For details please refer to Table 2 under "Any other information on results incl tables".

Gross pathology:

Necropsy revealed no substance-related findings. 1/5 males was observed to have small testes and epididymides bilaterally. The findings were reported to be occasionally observed in inhalation studies due to the method of restraint and duration of exposure and therefore not attributed to treatment.

Any other information on results incl. tables

Clinical signs:

After dosing, powder in the nose was observed in 4/5 males and an unsteady gait was noted in 5/5 males one hour after exposure. The findings had resolved in 2/5 males within 2 hours after exposure and by study Day 5 in the remaining animals. Decreased activity was seen in 4/5 males, with a flattened posture seen in 3/5 males in Day 1. Both signs resolved in all animals by study Day 2.

Piloerection and hunched posture were noted in 2/5 males 1 and 2 hours after exposure. Salivation was noted in 1/5 animals, which further showed closed bilateral eyes 1 hour after exposure and slow breathing 2 hours after exposure. All signs had resolved by study Day 2.

Clinical signs associated with the dosing procedure included wet fur (1/5) and staining of the nose (1/5) for some animals, these were considered to be a consequence of tube restraint during exposure.

Body weight development:

Table 2: Mean body weights

	Day P19	Day 1	Day 2	Day 4	Day 8	Day 15
Mean	275.2	282	278.8	281.2	288.4	297.8
SD	9.44	10.54	10.28	11.54	14.33	14.18
% control	100.00	102.47	101.31	102.18	104.80	108.21

Applicant's summary and conclusion

Interpretation of results:

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

Conclusions:

CLP: not classified