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

Endpoint summary

Description of key information

In recently conducted, reliable, guideline studies, the substance showed moderate acute toxicity to Wistar rats by the oral dose route (LD50 = 50 - 300 mg/kg) and low acute toxicity by the dermal dose route (LD50 >2000 mg/kg). Testing by the inhalation route was not justified based on the likely use and exposure.

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

Study period:

12/5/15 to 2/6/15

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)

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harla Laboratories UK Ltd., Oxon, UK
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 179.2 g (variation not exceeding ±20%)
- Fasting period before study: Overnight
- Housing: Suspended solid-floor polypropylene cages furnished with woodflakes
- Diet (e.g. ad libitum): Free access to 1014C Teklad Global Rodent diet
- Water (e.g. ad libitum): Free access to main drinking water
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25 °C
- Humidity (%): 30 to 70 %
- Air changes (per hr): Fifteen changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours dark, twleve hours light

Route of administration:

oral: gavage

Vehicle:

arachis oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 5 mg/ml
- Amount of vehicle (if gavage):
- Justification for choice of vehicle: Arachis oil BP used as the test substance did not dissolve/suspend in distilled water

MAXIMUM DOSE VOLUME APPLIED: 50 mg/kg, 5 mg/ml.

Doses:

An initial sighting test was conducted aty 300 mg/kg. However, the test animal was killed for humane reasons due to the occurence of clinical signs of toxicity that exceeded the severity limit set forth in the UK Home Office Project Literature.

A dose of 50 mg/kg was than administeered. No mortality was recorded at this level.

No. of animals per sex per dose:

5 animals

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations were made 30 minutes, 1, 2 and 4 hours after dosing, and then daily. Individual body weights were checked on Day 0, Day 7 and Day 14 or at death.
- Necropsy of survivors performed: Yes

Preliminary study:

An intial dosing of 300 mg/kg was used in one rat, however this animal was killed for humane reasons one day after dosing due to it showing a severe toxicological effect.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

>= 50 - <= 300 mg/kg bw

Based on:

act. ingr.

Mortality:

Outside of one death at the initial 300 mg/kg dose, no mortality was recorded.

Clinical signs:

other: Signs of systemic toxicity noted in the animal treated at a dose level of 300 mg/kg were prostration, pallor of the extremities, pilo-erection, emaciation, decreased respiratory rate, labored respiration and hypothermia. There were no signs of systemic to

Gross pathology:

Pale liver and pale kidneys were noted at necropsy of the animal treated at a dose level of 300 mg/kg. No abnormalities were noted at necropsy of animals treated at a dose level of 50 mg/kg.

Table 1 Individual Clinical Observations and Mortality Data - 300 mg/kg

Dose level	Animal number and sex	Effects noted after dosing (hours)				Effects noted during period after dosing
		0.5	1	2	4	1 day
300 mg/kg	1 -0 Female	0	0	0	0	Prostration,Pallor of the extremities, Pilo-erection, Emaciation, Decreased respiratory rate, Laboured respiration, Hypothermia. Animal killed for humane reasons.

Table 2 Individual Body Weights and Body Weight Changes - 300 mg/kg

Dose level	Animal number and sex	Body weight at day 0				Body weight at death
300 mg/kg	1 -0 Female	168 g				160 6 g

Table 3 Individual Necropsy Findings - 300 mg/kg

Does level	Animal number and sex	Time of death	Macroscopic Observations
300 mg/kg	1 -0 Female	Humanely killed Day 1	Liver: Pale, Kidneys: Pale

                                                                                                                                                                                                                                                                                       

Table 4 Individual Clinical Observations and Mortality Data - 50 mg/kg

Dose level	Animal number and sex	Effects noted after dosing (hours)				Effects noted during period after dosing (days)
		0.5	1	2	4	1	2	3	4	5	6	7	8	9	10	11	12	13	14
50 mg/kg	2 -0 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
50 mg/kg	3 -0 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
50 mg/kg	3 -1 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
50 mg/kg	3 -2 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
50 mg/kg	3 -3 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

Table 5 Individual Body Weights and Body Weight Changes - 50 mg/kg

Dose level	Animal Number and Sex	Body weight at Day			Body Weight Gain During Week
		0	7	14	1	2
50 mg/kg	2 -0 Female	198	218	228	20	10
50 mg/kg	3 -0 Female	172	189	181	17	-8
50 mg/kg	3 -1 Female	170	170	200	0	30
50 mg/kg	3 -2 Female	178	174	181	-4	7
50 mg/kg	3 -3 Female	178	185	193	7	8

                                           

Table 6 Individual Necropsy Findings - 50 mg/kg

Dose level	Animal Number and Sex	Time of Death	Macroscopic Observatrions
50 mg/kg	2 -0 Female	Killed Day 14	No abnormalities detected
50 mg/kg	3 -0 Female	Killed Day 14	No abnormalities detected
50 mg/kg	3 -1 Female	Killed Day 14	No abnormalities detected
50 mg/kg	3 -2 Female	Killed Day 14	No abnormalities detected

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be in the range of 50 - 300 mg/kg.

Executive summary:

Introduction

The study was performed to assess the acute oral toxicity of the test item in the Wistar strain rat.

Methods

Following a sighting test at dose levels of 300 mg/kg and 50 mg/kg, a further group of four fasted females was given a single oral dose of test item, as a solution in arachis oil BP, at a dose level of 50 mg/kg body weight. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy.

Results

Mortality. The animal treated at a dose level of 300 mg/kg was killed for humane reasons, 1 day after dosing, due to the occurrence of clinical signs of toxicity that exceeded the severity limit set forth in the UK Home Office Project Licence. There were no deaths noted at a dose level of 50 mg/kg.

Clinical Observations. Signs of systemic toxicity noted in the animal treated at a dose level of 300 mg/kg were prostration, pallor of the extremities, pilo-erection, emaciation, decreased respiratory rate, labored respiration and hypothermia. There were no signs of systemic toxicity at a dose level of 50 mg/kg.

Body Weight. Two animals showed body weight loss or no gain in body weight during the first week with expected gain in body weight during the second week. One other animal showed expected gain in body weight during the first week but body weight loss during the second week. Two animals showed expected gains in body weight over the study period.

Necropsy. Pale liver and pale kidneys were noted at necropsy of the animal treated at a dose level of 300 mg/kg. No abnormalities were noted at necropsy of animals treated at a dose level of 50 mg/kg.

Conclusion

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be in the range of 50 - 300 mg/kg body weight (Globally Harmonized Classification System - Category 3).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

300 mg/kg bw

Quality of whole database:

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

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

The substance is only used within closed industrial systems. Testing by the inhalation route is not justified given that exposure of humans via inhalation is unlikely.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

18/5/15 to 4/6/15

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Laboratories UK Ltd., Oxon, UK
- Age at study initiation: 8 to 12 weeks
- Weight at study initiation: At least 200 g, weight variation did not exceed ±20% of the mean weight
- Fasting period before study: None
- Housing: uspended solid floor polypropylene cages furnished with woodflakes.
- Diet (e.g. ad libitum): Free access to 2014C Teklad Global Rodent diet
- Water (e.g. ad libitum): Free access to mains drinking water
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25 °C
- Humidity (%): 30 to 70 %
- Air changes (per hr): At least 15 changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: Shorn skin, precise location not specified
- % coverage: 10 % of the total body surface
- Type of wrap if used: surgical gauze, semi-occluded with a piece of self-ashesive bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Washed with cotton wool and arachis oil BP
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg
- Constant volume or concentration used: yes

Duration of exposure:

24 hours

Doses:

Single dose test

No. of animals per sex per dose:

Five

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 30 minutes, 1 hour, 2 hours and 4 hours after dosing and subsequently daily for the observation period
- Necropsy of survivors performed: yes

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

>= 2 000 mg/kg bw

Based on:

act. ingr.

Mortality:

There were no deaths.

Clinical signs:

other: No signs of systemic toxicity were noted during the observation period.

Gross pathology:

No abnormalities were noted at necropsy.

Other findings:

There were no signs of dermal irritation

Table 1 - Individual Clinical Observations and Mortality Data

		Effects Noted After Dosing (Hours)				Effects Noted During Period After Dosing (Days)
Dose Level (mg/kg)	Animal Number and Sex	0.5	1	2	4	1	2	3	4	5	6	7	8	9	10	11	12	13	14
2000	1 -0 Male	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	3 -0 Male	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	3 -1 Male	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	3 -2 Male	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	3 -3 Male	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	2 -0 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	4 -0 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	4 -1 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	4 -2 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	4 -3 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

Table 2 - Individual Dermal Reactions: Males

			Effects Noted After Initiation of Exposure (Days)
Dose Level (mg/kg)	Animal Number and Sex	Observation	1	2	3	4	5	6	7	8	9	10	11	12	13	14
2000	1 -0 Male	Erythema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	1 -0 Male	Edema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	1 -0 Male	Other	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	3 -0 Male	Erythema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	3 -0 Male	Edema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	3 -0 Male	Other	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	3 -1 Male	Erythema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	3 -1 Male	Edema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	3 -1 Male	Other	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	3 -2 Male	Erythema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	3 -2 Male	Edema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	3 -2 Male	Other	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	3 -3 Male	Erythema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	3 -3 Male	Edema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	3 -3 Male	Other	0	0	0	0	0	0	0	0	0	0	0	0	0	0

Table 3 - Individual Dermal Reactions: Females

			Effects Noted After Initiation of Exposure (Days)
Dose Level (mg/kg)	Animal Number and Sex	Observation	1	2	3	4	5	6	7	8	9	10	11	12	13	14
2000	2 -0 Female	Erythema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	2 -0 Female	Edema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	2 -0 Female	Other	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	4 -0 Female	Erythema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	4 -0 Female	Edema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	4 -0 Female	Other	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	4 -1 Female	Erythema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	4 -1 Female	Edema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	4 -1 Female	Other	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	4 -2 Female	Erythema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	4 -2 Female	Edema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	4 -2 Female	Other	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	4 -3 Female	Erythema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	4 -3 Female	Edema	0	0	0	0	0	0	0	0	0	0	0	0	0	0
2000	4 -3 Female	Other	0	0	0	0	0	0	0	0	0	0	0	0	0	0

Table 4 - Individual Body Weights and Body Weight Changes

		Body Weight (g) at Day			Body Weight Change (g) During Week
Dose Level (mg/kg)	Animal Number and Sex	0	7	14	1	2
2000	1 -0 Male	228	240	262	12	22
2000	3 -0 Male	226	241	260	15	19
2000	3 -1 Male	236	246	269	10	23
2000	3 -2 Male	242	261	284	19	23
2000	3 -3 Male	230	243	262	13	19
2000	2 -0 Female	211	214	217	3	3
2000	4 -0 Female	214	214	224	0	10
2000	4 -1 Female	220	219	234	-1	15
2000	4 -2 Female	213	217	223	4	6
2000	4 -3 Female	214	212	221	-2	9

Table 5 - Individual Necropsy Findings

Dose Level (mg/kg)	Animal Number and Sex	Time of Death	Macroscopic Observations
2000	1 -0 Male	Killed Day 14	No abnormalities detected
2000	3 -0 Male	Killed Day 14	No abnormalities detected
2000	3 -1 Male	Killed Day 14	No abnormalities detected
2000	3 -2 Male	Killed Day 14	No abnormalities detected
2000	3 -3 Male	Killed Day 14	No abnormalities detected
2000	2 -0 Female	Killed Day 14	No abnormalities detected
2000	4 -0 Female	Killed Day 14	No abnormalities detected
2000	4 -1 Female	Killed Day 14	No abnormalities detected
2000	4 -2 Female	Killed Day 14	No abnormalities detected
2000	4 -3 Female	Killed Day 14	No abnormalities detected

Interpretation of results:

not classified

Conclusions:

The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg body weight. The substance is not classified according to the CLP Regulation (EU) 1272/2008.

Executive summary:

Introduction

The study was performed to assess the acute dermal toxicity of the test item in the Wistar strain rat.

Methods

Initially, two animals (one male and one female) were given a single, 24 hour, semi-occluded dermal application of the undiluted test item to intact skin at a dose level of 2000 mg/kg body weight. Based on the results of the initial test, a further group of eight animals (four males and four females) was similarly treated. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy.

Results

Mortality. There were no deaths.

Clinical Observations. There were no signs of systemic toxicity.

Dermal Irritation. There were no signs of dermal irritation.

Body Weight. Three females showed body weight loss or no gain in body weight during the first week with expected gain in body weight during the second week. The remaining animals showed expected gains in body weight over the study period.

Necropsy. No abnormalities were noted at necropsy.

Conclusion

The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

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

Justification for classification or non-classification

Based on the results of the available toxicity studies, the substance is classified for acute toxicity by the oral route (Acute Toxicity category 3, H301). Classification for the dermal route is not justified.