4-[fluoro(dimethyl)silyl]butanenitrile

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Remarks:

The study report is not finalized yet. However, the findings in the draft report are relevant for classification and labelling and risk assessment purposes. A dossier update will be submitted after the study report is finalized.

Adequacy of study:

key study

Study period:

March 22, 2017 - ongoing

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2017

Report date:

2017

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)

Version / remarks:

adopted 7 September 2009

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

4-[fluoro(dimethyl)silyl]butanenitrile

EC Number:

812-925-4

Cas Number:

1639345-42-8

Molecular formula:

C6H12FNSi

IUPAC Name:

4-[fluoro(dimethyl)silyl]butanenitrile

Test material form:

liquid

Details on test material:

- Purity: >= 99.9% (including < 3% isomer)
- Lot/batch No.: SO659
- Expiration date of the lot/batch: 7 March 2018

Test animals

Species:

rat

Strain:

Wistar

Remarks:

Wistar outbred (Crl:WI(Han)) rats

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: rats were obtained from a colony maintained under specific pathogen free (SPF) conditions by Charles River Laboratories.
- Age at study initiation: At the time of exposure, the rats were about 8 (group 1) or 10 (group 2) weeks old
- Weight at study initiation: Mean body weight just before exposure on day 0 was 241 g for males and 165 g for females of group 1; and 261 g for males and 188 g for females of group 2.
- Housing: Except during exposure, the animals were housed in groups of three, separated by sex, in macrolon cages (type IV) with a bedding of wood shavings (Lignocel, Rettenmaier, Rosenberg,
Germany) and a piece of gnaw wood (from ABEDD, Austria) and shreds of paper (Enviro-dri, Shepherd Specialty Papers, Michigan, USA) as environmental enrichment. The cages and
bedding were changed at least weekly. During exposure, the animals were housed individually in the exposure unit (see section 4.8). Immediately after exposure, they were returned to their home cages.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 15 (group 1) or 22 (group 2) days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C; Temperature was slightly below the target range on 1-2 June 2017 for a total period of about 8 hours (minimum value recorded: 19.4°C).
- Humidity (%): 45-65%; Occasionally, the relative humidity briefly exceeded 65% after wet cleaning activities. In addition, relative humidity was shortly below the target range on two occasions on
10 May 2017 (minimum value of about 31%).
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

nose only

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
The animals were exposed to the test atmosphere in a nose-only inhalation chamber, a modification of the design of the chamber manufactured by ADG Developments Ltd., Codicote,
Hitchin, Herts, SG4 8UB, United Kingdom. The inhalation chamber consisted of a cylindrical stainless steel column, surrounded by a transparent cylinder. The column had a volume of 35.6
liters and consisted of a top assembly with the entrance of the unit, a mixing section, a rodent tube section and at the bottom the base assembly with the exhaust port. The rodent tube section
had 20 ports for animal exposure. Several empty ports were used for test atmosphere sampling (for analysis of the actual concentration) and measurement of oxygen, carbon dioxide,
temperature and relative humidity. The animals were secured in plastic animal holders (Battelle), positioned radially through the outer cylinder around the central column. Male and
female rats were placed in alternating order. The remaining ports were closed. Only the nose of the rats protruded into the interior of the column.
The unit was illuminated externally by normal laboratory fluorescent tube lighting. The total airflow through the unit was at least 1 liter/min for each rat. The air entering the unit was
maintained between 22 ± 3˚C and the relative humidity between 30% and 70%.
The inhalation equipment was designed to expose the rats to a continuous supply of fresh test atmosphere. A schematic diagram of the generation and exposure system is presented in Figure
1. To generate the test atmosphere, a liquid flow of test material, controlled by a motor-driven syringe pump (WPI Type SPLG110, World Precision Instruments, Sarasota FL, USA) was allowed
to evaporate in a mass flow controlled (Bronkhorst Hi Tec, Ruurlo, The Netherlands) stream humified compressed air, by directing it through a glass evaporator which was kept at a
temperature of 40°C by circulating heated water. The resulting test atmosphere was led through a glass condenser kept at 20°C and was subsequently introduced at the top of the exposure
chamber. From there, the test atmosphere was directed downward towards the noses of the animals, and exhausted at the bottom of the inhalation chamber.

TEST ATMOSPHERE
- Brief description of analytical method used: group 1 GC/MS analysis; group 2 total carbon analysis
- Samples taken from breathing zone: yes

CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration: Prior to the start of the acute inhalation study, technical feasibility trials were conducted to
ensure the accurate generation of a vapor test atmosphere at a concentration of 20 g/m3, the initial target concentration for exposure of group 1. These experiments revealed that the target
vapor concentration of 20 g/m3 cannot be reached, because the saturated vapor concentration proved to be considerably lower than was expected based on the available vapor pressure. Therefore, it was decided – in consultation with the sponsor – to expose the animals of group 1 at the highest attainable vapor concentration.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

0.51 mg/L, 1.42 mg/L (= highest attainable vapor concentration)

No. of animals per sex per dose:

3

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: On the exposure day, the animals were observed for clinical signs just before exposure, four times during exposure (about once per hour), and twice after exposure. During the observation period, each animal was observed daily in the morning hours by cage-side observations and, if necessary, handled to detect signs of toxicity. All animals were checked again in the afternoon.
The body weight of each animal was recorded once during the acclimatization period (on day -1), and just before exposure on day 0. Surviving animals were also weighed on days 1, 3, 7 and on
day 14 prior to necropsy. Body weights were also recorded at the time of discovery after intercurrent death.
- Necropsy of survivors performed: yes

Statistics:

not applicable

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 0.51 - < 1.42 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other:

Remarks:

It was established that the highest attainable vapor concentration under the present experimental conditions was 1.4 g/m3, as determined by GC/MS analysis of test atmosphere samples.

Mortality:

group 1 (1.42 mg/L): Two male and a female animal were found dead during the second half of the 4-hour exposure. The three remaining animals survived, but since their weakened condition kept declining and it was expected that they would not survive the night, these animals were humanely sacrificed at the end of the exposure day.

group 2 (0.51 mg/L): All animals survived until the end of the 14-day observation period.

Clinical signs:

other: group 1 (1.42 mg/L): Within the first half hour after the start of exposure, animals showed moderate to severe breathing changes including dyspnoea, shallow breathing, and a decreased breathing rate, and restlessness. Shortly after exposure, the surviving

Body weight:

Animals of group 1 showed a slight loss of body weight on day 0, in the period between preexposure weighing and necropsy. Animals of group 2 displayed an initial body weight loss of about 5% on the day after exposure, from which they fully recovered during the first week of the observation period; normal growth was observed thereafter.

Gross pathology:

Necropsy of animals of group 1 revealed red discolored and incompletely collapsed lungs due to pulmonary hemorrhages in all animals that were found dead or were sacrificed in moribund condition. In addition, all animals had large amounts of air in the stomach, likely the result of gasping in response to the respiratory distress.
Exposure-related macroscopic lesions in animals of group 2 were limited to few red spots – indicating hemorrhages – found on one or more lung lobes (2 males, 3 females) and on the thymus (2 males, 1 female).

Applicant's summary and conclusion

Interpretation of results:

Category 2 based on GHS criteria

Conclusions:

Based on the results of this study, it was concluded that the 4-hour LC50 of test material vapor in rats is between 0.51 g/m3 and the highest attainable vapor concentration of 1.42 g/m3.