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

Endpoint summary

Description of key information

The substance was tested in a reliable OECD 422 study using dose levels of 0.75, 1.5 and 3 mg/kg/day. The main study demonstrated no adverse effects at any dose level and no target organ was identified. The NOEL is 3 mg/kg/day.

The dose selection for the main study was based on a 14 day range finding study. In the study dose levels of 0, 3, 5 and 10 mg/kg/day were used which resulted in a reduction in overall mean body weight gain in all treated dose groups. Based on these results, dose levels of 10 or 5 mg/kg bw/day were considered to be too high for repeat dosing in an OECD 422 study. A dose level of 3 mg/kg bw/day was considered to be suitable as the high dose level for the main OECD 422 study.

The requirement for the 90 day subchronic study is waived in accordance with REACH Annex XI, 3.2.(b). The substance is not incorporated in an article and for all relevant scenarios throughout the life cycle is used under strictly controlled conditions.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

repeated dose toxicity: oral

Remarks:

other: 14 day dose ranging study

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study is a dose ranging study only. It was not conducted to a specific guideline however was conducted to GLP.

Principles of method if other than guideline:

3 males and 3 females were dosed for 14 days

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

arachis oil

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

14 days

Frequency of treatment:

Once daily

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

3 mg/kg bw/day (nominal)

Dose / conc.:

5 mg/kg bw/day (nominal)

Dose / conc.:

10 mg/kg bw/day (nominal)

No. of animals per sex per dose:

3 males and 3 females

Control animals:

yes, concurrent vehicle

Positive control:

None

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION: Yes

FOOD EFFICIENCY: Yes

WATER CONSUMPTION: Yes

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY:No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

ORGAN WEIGHTS: No
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: No

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

effects observed, treatment-related

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Details on results:

BODY WEIGHT AND WEIGHT GAIN: At all dose levels, overall mean body weight gains for males were lower than controls but without any dose-relationship. At 10 mg/kg/day, this was mainly due to lower body weight gain during the first week of the treatment period with subsequent improvement evident during the second week. At 3 and 5 mg/kg/day, lower overall body weight gains were also mainly due to reduced body weight gains or body weight losses during the first week of the dosing period; individual males from these dose groups also showed body weight losses during the second week which further contributed to the lower overall body weight gains for these dose groups. For treated females, overall mean body weight gains were lower than controls with 10 mg/kg/day females showing an actual body weight loss over the treatment period. At 10 mg/kg/day, reduced body weight gains or actual body weight losses were apparent throughout the dosing period whilst for females from 3 or 5 mg/kg bw/day, it was mainly due to the initial effect over Days 1 to 4 of dosing.

Critical effects observed:

not specified

Conclusions:

The oral administration of 3, 5 and 10 mg/kg bw/day resulted in a reduction in body weight gains in animals of either sex. Based on these results, dose levels of 10 or 5 mg/kg bw/day were considered to be too high for repeat dosing in an OECD 422 study. A dose level of 3 mg/kg bw/day was considered to be suitable as a high dose level for the OECD 422 study.

Reference 2

Endpoint:

short-term repeated dose toxicity: oral

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

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

Species:

rat

Strain:

Wistar

Sex:

male/female

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

Dose / conc.:

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

Dose / conc.:

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

Dose / conc.:

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

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

Observations and examinations performed and frequency:

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

Sacrifice and pathology:

ORGAN WEIGHTS: Yes
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: 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.

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

Food efficiency:

no effects observed

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Key result

Dose descriptor:

NOEL

Effect level:

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

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: No specific target organ or systemic toxicity was seen.

Key result

Critical effects observed:

no

Conclusions:

No changes were observed in male and female rats following dosing with the substance, when administered by oral gavage for 54 consecutive days at dosages of 0.75, 1.5 and 3 mg/kg bw/day. A 'No Observed Effect Level’ (NOEL) for systemic 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 mortality, clinical signs, body weight, food and water consumption, haematology, clinical chemistry, behaviour, organ weights, or gross and histologic pathology.  The NOEL is considered to be 3 mg/kg bw/day (highest dose employed).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

3 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Sufficient to meet data requirements. The study is Klimisch 1.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the data from a 14 day range finding study and an OECD 422 screening study, the substance has the potential to produce severe toxicity following repeated exposure. Given the range of dose levels giving rise to adverse effects, the substance is classified as a Specific Target Organ Toxicant, Category 1 (H372).