2-Propenoic acid, 2-fluoro-, methyl ester

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

22/6/2015 to 6/5/2016

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2015

Report date:

2016

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

methyl 2-fluoroprop-2-enoate

EC Number:

607-233-2

Cas Number:

2343-89-7

Molecular formula:

C4H5FO2

IUPAC Name:

methyl 2-fluoroprop-2-enoate

Test material form:

other: Light brown liquid

Details on test material:

- Name of test material (as cited in study report): 2-Propenoic acid, 2-fluoro, methyl ester, EC Number: 607-233-2
- Physical state: Light brown liquid
- Analytical purity: 98.7%
- Lot/batch No.: 03026-20140801
- Expiration date of the lot/batch: 27 August 2015
- Storage condition of test material: Approximately 4 °C in the dark

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

arachis oil

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The test substance concentration in the dose samples was determined by HPLC with UV detection (HPLC-UV) using an external standard

Duration of treatment / exposure:

Up to 8 weeks (including a 2 week pre-pairing stage, pairing, gestation and early lactation for females)

Frequency of treatment:

Once daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

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

Doses / concentrations 2

Dose / conc.:

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

Doses / concentrations 3

Dose / conc.:

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

Doses / concentrations 4

Dose / conc.:

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

No. of animals per sex per dose:

12 males and 12 females per dose

Control animals:

yes, concurrent vehicle

Details on study design:

The dose selection was based on the outcome of a 14 day range finding study.

Positive control:

None

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:Immediately before dosing, up to 30 minutes post-dosing and one hour after dosing.

BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights will be recorded for males on Day 1 and then weekly until termination. Individual body weights will also be recorded at terminal kill. For females, individual body weights will be recorded on Day 1 and then weekly until pairing. During the pairing phase, females will be weighed daily until mating is confirmed. Mated females will be weighed on Day 0, 7, 14 and 20 post coitum and body weights for females which give birth will be recorded on Days 1 and 4 post partum. Body weights will also be recorded at terminal kill.

FOOD CONSUMPTION: Yes
- Time schedule: Male dietary intake will be recorded weekly prior to and after pairing. Female dietary intake will be recorded weekly prior to pairing. Food consumptions will not be performed during the pairing phase. Dietary intake for mated females will be recorded on Days 0-7, 7-14 and 14-20 post coitum. Food consumptions for females with live litters will be recorded between Days 1-4 post partum.

FOOD EFFICIENCY: Yes
- Time schedule: Weekly food conversion efficiency (body weight gain/food intake) will be calculated retrospectively for males and females prior to pairing, and for males after the pairing phase.

WATER CONSUMPTION: Yes
- Time schedule for examinations: Daily by visual inspection

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Day 42 (males) and Day 4 post partum (females).
- Animals fasted: No
- How many animals: 5 males and 5 females
- Parameters examined: Hemoglobin, Hematocrit, Erythrocyte count, Total leukocyte count, Differential leukocyte count, Erythrocyte indices (mean cell hemoglobin, mean cell volume, mean cell hemoglobin concentration), Prothrombin time, Activated partial thromboplastin time, Platelet count, Reticulocyte count

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Day 42 (males) and Day 4 post partum (females).
- Animals fasted: No
- How many animals: 5 males and 5 females
- Parameters examined: Blood Urea, Total Protein, Albumin, Albumin/Globulin ratio (by calculation), Sodium, Potassium, Chloride, Calcium, Inorganic phosphorus, Creatinine, Alkaline phosphatase, Alanine aminotransferase, Aspartate aminotransferase, Glucose, Total cholesterol, Total bilirubin, Bile acids

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Before the first exposure to the test item and once weekly thereafter.
- Dose groups that were examined: All test and control
- Battery of functions tested: sensory activity / grip strength / motor activity

Oestrous cyclicity (parental animals):

Not examined

Sperm parameters (parental animals):

Parameters examined in male parental generations: testis weight, epididymis weight, gross pathology, detailed qualitative histopathological examination of the testes, taking into account the tubular stages of the spermatogenic cycle.

Postmortem examinations (parental animals):

ORGAN WEIGHTS: Yes
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Postmortem examinations (offspring):

GROSS NECROPSY: Yes

Statistics:

Where considered appropriate, quantitative data was subjected to statistical analysis to detect the significance of intergroup differences from control; statistical significance was achieved at a level of p<0.05. Statistical analysis was performed on the following parameters: Grip Strength, Motor Activity, Body Weight, Body Weight Change, Food Consumption during gestation and lactation, Pre-Coital Interval, Gestation Length, Litter Size, Litter Weight, Sex Ratio, Corpora Lutea, I plantation Sites, Implantation Losses, Viability Indices, Offspring Body Weight, Offspring Body Weight Change, Offspring Surface Righting, Hematology, Blood Chemistry, Absolute Organ Weights, Body Weight-Relative Organ Weights.

Reproductive indices:

Mating performance, fertility and gestation length

Offspring viability indices:

Litter size, sex ratio, viability, growth and development

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Effect levels (P0)

Key result

Dose descriptor:

NOEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

Effect levels (F1)

Key result

Dose descriptor:

NOEL

Generation:

F1

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: reproductive toxicity

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Repeated dose administration of the substance to rats by oral gavage, at dose levels of 0.75, 1.5 and 3 mg/kg bw/day, was well tolerated during the course of a combined repeat dose reproduction study of at least 54 days duration. Based on the available results, whereby no reproductive toxicity was seen in either adults or the litter animals, the ‘No Observed Effect Level’ (NOEL) for reproductive toxicity was considered to be 3 mg/kg bw/day (the highest dose employed).

Executive summary:

In a subacute study the substance was administered to 12 rats/sex/dose by gavage at dose levels of 0, 0.75, 1.5 and 3 mg/kg bw/day for up to 8 weeks (including a 2 week pre-pairing stage, pairing, gestation and early lactation for females). There were no substance related effects in the parental generation in mortality, clinical signs, body weight, food and water consumption, haematology, clinical chemistry, behaviour, organ weights, or gross and histologic pathology, sperm measures and reproductive performance. There were no substance related effects in the F1 generation in mortality, clinical signs, body weight, or gross pathology. The reproductive NOEL is considered to be 3 mg/kg bw/day (highest dose employed).