2-fluoro-6-trifluoromethylpyridine

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Oral: OECD 408, rat. No effects were observed in reproductive organs at the highest concentration tested 12500 mg/kg diet (corresponding to 947.0 and 1133.2 mg/kg bw/day for males and females, respectively). Reliability = 1.

Additional information

The reproductive requirement is waived as no effects were observed in male or female reproductive organs in a 90-day repeated dose feeding study and a prenatal developmental toxicity study (OECD 414) revealed no teratogenic effects at 200 mg/kg (the highest dose tested).

Short description of key information:
The reproductive requirement is waived as a 90-day repeated dose feeding study and prenatal developmental toxicity study (OECD 414) are available for the test substance.

Effects on developmental toxicity

Description of key information

Oral: NOAEL; OECD 414, rat. NOAEL for teratogenicity was ≥200 mg/kg/day, the highest dose tested. Reliability = 2.  

Link to relevant study records

Reference

Endpoint:

developmental toxicity

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 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Specific details on test material used for the study:

Substance ID: F6TF
Purity: 99.56%

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: approximately 12 weeks
- Weight at study initiation: approximately 200-250 g
- Fasting period before study: No
- Housing: Plastic cages and numbered individually
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: not reported

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25°C
- Humidity (%): 40-70%
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Prescribed amounts of the test substance were mixed with distilled water according to the prescribed doses at the time of administration.

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

Not reported

Duration of treatment / exposure:

Days 6 to 15 of gestation

Frequency of treatment:

Daily

Duration of test:

20 days

Dose / conc.:

50 mg/kg bw/day

Dose / conc.:

100 mg/kg bw/day

Dose / conc.:

200 mg/kg bw/day

No. of animals per sex per dose:

A minimum of 15 pregnant rats/dose were examined

Control animals:

yes, concurrent vehicle

other: A positive control group was included, but the positive control material was not reported.

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: Every 3 days, including the day of dissection

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No data

Statistics:

T-test method was used for body weight growth of pregnant rats, body length, tail length, and body weights of foetuses. Χ2-test method was used for absorptivity, mortality, and teratogenic rate of foetuses.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

Three rats in 100 mg/kg dose group and six rats in 200 mg/kg dose group died during the test period.

Body weight and weight changes:

no effects observed

Pre- and post-implantation loss:

no effects observed

Changes in number of pregnant:

no effects observed

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Three rats died at 100 mg/kg and 6 rats died at 200 mg/kg during the test period.

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Fetal body weight changes:

effects observed, non-treatment-related

Changes in sex ratio:

no effects observed

Skeletal malformations:

effects observed, treatment-related

Description (incidence and severity):

Delayed sternebral ossification was observed at 200 mg/kg.

Visceral malformations:

no effects observed

Details on embryotoxic / teratogenic effects:

Details on embryotoxic / teratogenic effects:
A slight increase in resorptions was observed at 200 mg/kg, without adverse effects on mean litter size. Reduced mean tail length and fetal weight were observed at 100 and 200 mg/kg. Delayed sternebral ossification was observed at 200 mg/kg.

Key result

Basis for effect level:

other:

Developmental effects observed:

not specified

Conclusions:

The test substance has toxic effects on parents and may cause delay of fetus growth at doses above 100 mg/kg but no teratogenic effects.

Executive summary:

Sprague Dawley (SD) rats were used as test animals. Three dose groups (50, 100, and 200 mg/kg body weight/day) were set based on the results of the preliminary test. A negative control and a positive control were used synchronously. Pregnant rats were administered daily by oral gavage on the 6^th to 15^th day of gestation and were sacrificed at the 20^th day of gestation. At necropsy, the uteri were removed and weighed. The number of corpora lutea, live foetuses, early dead foetuses, late dead foetuses, and resorptions were recorded. The sex, body weight, body length, tail length of each live foetus and the weight of the placenta were recorded as well. External, skeletal, and visceral examinations were conducted. All data were processed.

The test substance has toxic effects on parents and delayed foetal growth at 100 and 200 mg/kg by oral administration. At 200 mg/kg, it also delayed the skeletal growth of the foetus. No teratogenic effects were found at 50, 100, or 200 mg/kg. Based on the findings of the study, the test substance would be considered to be a toxicant at dose levels greater than or equal to 100 mg/kg, based on decreased total number of pregnant rats, delayed foetus growth, and delayed skeletal growth. No teratogenic effects were observed at 200 mg/kg (the highest dose tested).

Effect on developmental toxicity: via oral route

Dose descriptor:

NOAEL

200 mg/kg bw/day

Additional information

Female Sprague Dawley rats were exposed to the test substance via gavage once daily from gestation day 6 through 15 at doses of 50, 100, and 200 mg/kg/day. The no-observed-adverse-effect-level for maternal and developmental toxicity was 50 mg/kg, based on maternal mortality and delayed foetal and skeletal growth at ≥100 mg/kg/day. The NOAEL for teratogenicity was ≥200 mg/kg/day, based on no effects observed at the highest dose tested.

Toxicity to reproduction: other studies

Additional information

No effects were observed in reproductive organs in a repeated dose 90-day feeding study in rats at doses of 500, 2200, and 12500 mg/kg, corresponding to mean daily intake values of 44.3, 218.8, and 947.0 mg/kg/day for males and 48.1, 246.9, and 1133.2 mg/kg/day for females.

Justification for classification or non-classification:

Based on the findings of no effects in male and female reproductive organs in a subchronic 90-day feeding study, as well as the fact that the test substance is not uniquely toxic to the developing fetus, the substance does not need to be classified for reproductive or developmental toxicity according to the EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.