2-fluoro-6-trifluoromethylpyridine

Endpoint summary

Description of key information

Oral: OECD 425. discriminating dose, rat. The overall discriminating dose level was 50 mg/kg. Reliability = 1 
Dermal: OECD 402. LD50, rat. The LD50 was >2500 mg/kg. Reliability = 1
Inhalation: OECD 403. 4-hr LC50, rat. The LC50 was 1984 ppm (13396 mg/m3) in females and 3075 ppm (20762 mg/m3) in males. Reliability =1.  

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)

Deviations:

no

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

no

Specific details on test material used for the study:

Substance ID: F6TF
Lot #: 8922/16
Purity: 99.7%

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 weighed 291-430 g and the females weighed 238-248 g
- Fasting period before study: Fasted overnight immediately prior to dosing
- Housing: A maximum of 5 rats was housed per cage, sexes separately
- 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): A minimum of 15 changes per hour
- Photoperiod (hrs dark / hrs light): Artificial, giving 12 hours light, 12 hours dark

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

DOSAGE PREPARATION: Dose levels were altered by adjusting the concentration of the dosing preparations. The volume of the dose was calculated for each animal according to its weight at the time of dosing. A standard volume of l0 mL/kg of the dosing preparation was administered by oral gavage using a stomach tube.

Doses:

Sighting phase: 500 and 2000 mg/kg
Main Study: 50 and 500 mg/kg

No. of animals per sex per dose:

Sighting phase: 1 female per dose
Main study: 5 per sex at 500 mg/kg; 5 males at 50 mg/kg

Control animals:

no

Details on study design:

- Duration of observation period following administration: Main study up to day 15; Sighting phase up to day 7
- Frequency of observations and weighing: The animals were observed for signs of systemic toxicity twice following dosing on day 1. Subsequent observations were made daily. The animals were weighed prior to fasting on the day before dosing (day -1), immediately before dosing (day 1) and on days 8 and 15.
- Necropsy of survivors performed: yes

Key result

Sex:

male

Dose descriptor:

discriminating dose

Effect level:

50 mg/kg bw

Based on:

test mat.

Mortality:

Sighting Phase: Following a dose of 500 mg/kg, the animal survived and showed signs of slight, but evident, toxicity. Following a dose of 2000 mg/kg, the animal was killed in extremis on day 2. At examination post mortem this animal had a dark liver.

Main Study: Following a dose of 500 mg/kg to male and female rats, three males were killed in extremis on day 2. Surviving animals showed signs of evident toxicity, with complete recovery by day 5. No animals died following a dose of 50 mg/kg.

Clinical signs:

other: There were signs of evident toxicity in the surviving animals, with complete recovery by day 5.

Body weight:

other body weight observations

Remarks:

With the exception of one female, which showed a slight weight loss, all surviving animals showed an overall bodyweight gain during the study.

Gross pathology:

Distension of the stomach was seen in the three males dosed with 500 mg/kg which were killed in extremis. This finding is considered to be treatment-related. In the males dosed with 50 mg/kg, one animal had only one testis (congenitally absent) and two males had speckling of the thymus. These are spontaneous or non-specific findings and are considered to be unrelated to treatment.

Conclusions:

The highest fixed dose of the test substance administered in this test without causing any lethality (i.e., the overall discriminating dose-level) was 50 mg/kg.

Executive summary:

A group of 5 male and 5 female rats was dosed with 500 mg/kg of the test substance and assessed daily for 14 days for any signs of systemic toxicity. A further group of 5 male rats was similarly treated, but dosed with 50 mg/kg. Bodyweights were recorded at intervals throughout the study. Animals in extremis and those surviving to the end of the study were killed and subjected to a macroscopic examination post mortem.

 

Following a dose of 500 mg/kg to 5 male and 5 female rats, 3 males were killed in extremis on day 2. Surviving animals showed signs of evident toxicity, with complete recovery by day 5. Distension of the stomach was seen in the 3 males killed in extremis. This finding is considered to be treatment-related. No mortality was observed following a dose of 50 mg/kg to 5 male rats, and there were no signs of toxicity. The highest fixed dose of the test substance administered in this test without causing any lethality (i.e., the overall discriminating dose-level) was 50 mg/kg.

Endpoint conclusion

Dose descriptor:

discriminating dose

Value:

50 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

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

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

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

Specific details on test material used for the study:

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

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

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.

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

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.

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.

Endpoint conclusion

Dose descriptor:

LC50

Value:

13 396 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

Substance ID: F6TF
Purity: 99.56%

Species:

rat

Strain:

other: Sprague Dawley(SD), Grade SPF

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 8 weeks
- Weight at study initiation: male rats 202-216 g, female rats 186-192 g
- Housing: housed one rat per cage in suspended stainless steel wire mesh cages
- Diet (e.g. ad libitum): amount not reported
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-22ºC
- Humidity (%): 50-52%

Type of coverage:

semiocclusive

Vehicle:

other: Soybean oil

Details on dermal exposure:

TEST SITE
- Area of exposure: test substance was applied uniformly over an area which was approximately 10% of the total body surface area
- Type of wrap if used: held in contact with the skin with a porous gauze dressing and non-irritating tape

REMOVAL OF TEST SUBSTANCE
- Washing: yes, warm water
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2500 mg/kg body weight

Duration of exposure:

24 hours

Doses:

2500 mg/kg

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: daily after test substance administration and at sacrifice
- Frequency of weighing: shortly before test substance administration, weekly thereafter, and at sacrifice
- Necropsy of survivors performed: yes

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 500 mg/kg bw

Based on:

test mat.

Mortality:

No mortality was observed.

Clinical signs:

other: No clinical signs were observed.

Gross pathology:

No abnormalities were found during necropsy.

Interpretation of results:

GHS criteria not met

Conclusions:

Rat Dermal LD50: >2500 mg/kg

Executive summary:

Male and female Sprague Dawley rats were dosed with the test substance in a dermal limit test according to the State Environmental Protection Administration's Guidelines for Testing of Chemicals (402) at a dose of 2500 mg/kg.  There were no obvious signs of toxicity and no mortality occurred during the study. No abnormalities were found during necropsy.  According to these results, an approximate acute dermal LD₅₀ for the test substance in rats is >2500 mg/kg for male and female rats.

Endpoint conclusion

Dose descriptor:

LD50

Value:

2 500 mg/kg bw

Additional information

The substance was evaluated for acute toxicity (lethality) via the acute oral, dermal and inhalation routes of exposure. The highest fixed dose in the oral study that did not cause lethality (i.e., the overall discriminating dose-level) was 50 mg/kg. In the rat acute oral toxicity study, no clinical signs of toxicity were observed at 50 mg/kg, but at higher doses, piloerection, sides pinched in, urine stains (wet and dry), stains around the nose and mouth, lacrymation, signs of salivation, tip toe gait, decreased activity, splayed gait, reduced stability, hunched posture, pale, and/or upward curvature of the spine were observed. In a rat acute dermal toxicity study, male and female rats were exposed to the test substance for 24 hours. No deaths occurred. The rats exhibited no clinical signs of systemic toxicity or body weight loss. No gross lesions were present in the rats at necropsy. The male and female rat dermal LD₅₀ was greater than 2500 mg/kg. In a rat 4-hour acute inhalation study, the LC₅₀ was 3075 ppm (20762 mg/m³) for male rats and 1984 ppm (13396 mg/m³) for female rats. Clinical signs of toxicity observed in all groups during exposure included wet fur, salivation, reduced response to sound, chromodacryorrhea, reduced breathing rate, lacrymation, and/or increased breathing depth. Observations observed after exposure included reduced reflexes, hypothermia, breathing problems, dehydration, lacrymation, wet fur, stains around the snout, piloerection, and/or salivation. Signs of toxicity had resolved by day 5 post exposure. No gross pathological findings were observed in rats that survived the 14-day post-exposure period.

Justification for classification or non-classification:

In an acute oral toxicity study, severe toxicity was observed at 500 mg/kg, as well as moribundity preceding sacrifice in extremis (3/5 rats) at this dose. The discriminating dose (no mortality) for this study was 50 mg/kg. In an acute inhalation study, the 4-hour LC₅₀ in rats was 13396 mg/m³ (1984 ppm). Based on the findings in the acute oral and inhalation studies, the test substance is classified as Xn, R20/22/ (harmful by inhalation and if swallowed) for acute toxicity according to EU Directive 67/548/EEC. The test substance is also classified as Cat 4 (harmful if swallowed) for acute oral and Cat 4 (harmful if inhaled) for acute inhalation, according to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) regulation (EC) No. 1272/2008. 

Based on the dermal LD₅₀ in rats of >2500 mg/kg, no classification is required for the acute dermal endpoint, according to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) regulation (EC) No. 1272/2008.