2-fluoro-6-trifluoromethylpyridine

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1999

Report date:

1999

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

428-100-3

EC Name:

-

Cas Number:

94239-04-0

Molecular formula:

C6H3NF4

IUPAC Name:

2-fluoro-6-(trifluoromethyl)pyridine

Details on test material:

- Purity: 99.5%

Specific details on test material used for the study:

Substance ID: F6TF
Lot #: R646899
Purity: 99.5%

Test animals

Species:

rat

Strain:

other: Alpk:APfSD

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 8-12 weeks
- Weight at study initiation: Males 388-524 g; females 249-310g
- Housing: The rats were housed 5 per cage, sexes separately, in multiple rat racks suitable for animals of this strain and weight range expected during the course of the study
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3°C
- Humidity (%): 30-70%
- Air changes (per hr): At least 15 changes/hour
- Photoperiod (hrs dark / hrs light): Artificial giving 12 hours light, 12 hours dark

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
- Exposure apparatus: PERSPEX exposure chamber
- Method of holding animals in test chamber: The restraining tubes consisted of a polycarbonate tube, one end of which was tapered and fitted into the exposure chamber.
- Source and rate of air: clean air, 10 L/m
- System of generating particulates/aerosols: The highest concentration required was generated beneath the chamber at a total flow rate of about 10 L/minute. This passed through the lowest exposure chamber and out via the dilution stage. A known proportion of this flow was extracted and replaced with clean air again to a total flow of about 10 L/minute. It was important that the sample port and any spare exposure ports were sealed on each required level or the system would not work properly
- Temperature, humidity, pressure in air chamber: 18.8-20.6°C; 15-62%; pressure not reported

TEST ATMOSPHERE
- Brief description of analytical method used: Test atmospheres were sampled from a front-facing port of the relevant exposure chamber, using a I mL gas-tight syringe and thermal desorption tube containing Carbotrap (Supelco). Samples were taken at typical intervals of 30 minutes, for each group, and analysed immediately after sampling, by placing the tube containing absorbed sample into the heated injection port of the gas chromatograph with a flame ionisation detector (FID).
- Samples taken from breathing zone: yes

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

Nominal: 500, 2000 and 5000 ppm
Measured: 451, 1914 and 4939 ppm

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were also subjected to detailed clinical observations, including the finding of no abnormalities detected, daily during the 14 day observation period. The body weight of each rat was recorded on day -1 (to ensure animals of one sex were within a similar weight range), 1, 8 and prior to termination on day 15.
- Necropsy of survivors performed: yes

Statistics:

For the male mortality data, linear log-dose interpolation was used to estimate the median lethal concentration. Approximate confidence limits, where appropriate, are given by the highest dose with no mortalities and the lowest dose with 100% mortalities. For the female mortality data, the median lethal concentration was estimated by logistic regression. Confidence limits were calculated using a likelihood ratio interval.

Results and discussion

Effect levels

Effect levels 1

Key result

Sex:

male

Dose descriptor:

LC50

Effect level:

3 075 ppm

Based on:

test mat.

95% CL:

>= 1 914 - <= 4 939

Exp. duration:

4 h

Effect levels 2

Key result

Sex:

female

Dose descriptor:

LC50

Effect level:

1 984 ppm

Based on:

test mat.

95% CL:

>= 1 226 - <= 3 212

Exp. duration:

4 h

Mortality:

Mortality (died or killed in extremis):
Male: 5 of 5 at 4939 ppm
Female: 5 of 5 at 4939 ppm, 2 of 5 at 1914 ppm

Clinical signs:

other: decreased activity and reduced reflexes, hypothermia, breathing problems, lacrymation and salivation

Body weight:

In animals exposed to 451 ppm, all males had gained weight by day 8 and continued to gain weight to the end of the study. In females, most animals showed a bodyweight loss on day 8, but all animals had gained weight by the end of the study. In the surviving animals exposed to 1914 ppm, the majority of animals from both sexes showed a bodyweight loss, but all animals had gained weight by the end of the study (with the exception of one female).

Gross pathology:

Macroscopic findings:
Treatment-related changes were seen in the majority of intercurrent animals. Pale lungs were seen in 3/5 males at 4939 ppm, 1 of which also had dark areas. Dark lungs were seen in 3/5 females at 4939 ppm. Also, mottled lungs were seen in a single terminal female at 1914 ppm. Stained nares seen in 5/5 males at 4939 ppm and in 2/2 intercurrent females at 1914 ppm may be associated with the clinical condition of these animals prior to death. Stomach discolouration was seen in a single intercurrent male at 4939 ppm, and the discoloured fluid contents of the jejunum in a single intercurrent female at 4939 ppm. These observations are considered to be related to the moribund condition of these individuals. The speckled thymus in a terminal male at 1914 ppm and in an intercurrent female at 4939 ppm may be incidental as this is a common agonal change.

Applicant's summary and conclusion

Conclusions:

LC50 male = 3075 ppm (equivalent to 21 mg/L respectively)
LC50 female = 1984 ppm (equivalent to 13.7mg/l respectively)

Executive summary:

Groups of 5 male and 5 female rats were exposed nose-only for a single 4 hour period to the test substance vapour at 500, 2000 and 5000 ppm. The measured concentrations were 451, 1914 and 4939, ppm respectively. Following exposure, the animals were retained without treatment for a 14-day observation period. Clinical observations were recorded and animals were subject to a post mortem examination.

All animals exposed to 4939 ppm either died during observation immediately after exposure, or were killed in extremis shortly after the first post exposure clinical observation. Two females exposed to 1914 ppm were also killed in extremis a number of hours after cessation of exposure. Severe clinical symptoms were seen in surviving animals. These included signs of general toxicity (decreased activity and reduced reflexes), hypothermia, breathing problems, lacrymation and salivation, as well as those symptoms usually associated with restraint. Most clinical symptoms had resolved by day 4 in both lower test concentration groups. It is concluded that the median lethal concentration of the test substance was 3075 ppm for males and 1984 ppm for females.