Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 5 December 2003 to 10 February 2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP compliance

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2004
Report date:
2004

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
483-360-5
EC Name:
-
Cas Number:
114435-02-8
Molecular formula:
C3H3FO3
IUPAC Name:
4-fluoro-1,3-dioxolan-2-one
Test material form:
other: Solid with a low melting point (i.e. liquefied solid)
Details on test material:
Name of the test susbtance: Monofluoroethylene carbonate

Test animals

Species:
rat
Strain:
Sprague-Dawley
Remarks:
(CrjBgi:CD®(SD)IGS rats)
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Orient Co. Ltd., Korea
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 7 weeks old
- Weight at study initiation: 176.6 to 197.1 g
- Fasting period before study: Animais were overnight fasted prior to dosing.
- Housing: The animais were individually housed in stainless steel cages with wire mesh floors (W260 x D380 x H180 mm, Dae Jong Instrument, Korea) in Barrier Room No. 1PB59.
- Diet (e.g. ad libitum): A certified rodent diet (2014C, Lot. 100903MA, Teklad Global Certified 14% Protein Rodent Diet, Harlan Teklad, USA) was provided ad libitum.
- Water (e.g. ad libitum): Filtered/UV-treated tap water was provided ad libitum.
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.0 to 24.6°C
- Humidity (%): 27.5 to 77.2%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 hours of artificial light (08:00 - 20:00 hours, 150 - 300 Lux) in each 24 hours period

IN-LIFE DATES: From: 16 December 2003 To: 12 January 2004

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 30 or 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: no data available
- Lot/batch no.: CS146 and 147, Lot. 122K0131, Sigma-Aldrich)

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

DOSAGE PREPARATION: The test article was weighed, mixed in an appropriate volume (approximately 80% of the intended final volume) of vehicle. The solution was then diluted with vehicle to the required volume and subsequently mixed using a vortex mixer (2-3 minutes) until visibly homogeneous. lmmediately before dosing, the dose formulation was mixed using a vortex mixer for homogeneity.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: According to the test guideline, three fasted female rats were used for each step. The starting dose of 300 mg/kg bodyweight as the 1st step, for animal welfare reasons, was selected because there is no information on the test article. Although one rat was found dead, the 2nd step started to confirm at this dosage. And the 3rd step was dosed as results at the starting dose indicated mortality was not observed except one rat. All rats were found dead immediately after dosing, therfore the study ended.
Doses:
30 and 200 mg/mL
No. of animals per sex per dose:
3 per group
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Cages of rats were checked at least once daily for any mortality and morbidity. Animals were individually observed 0.5-1, 2 and 3-4 hours after dosing with special attention, and daily for a total of 14 days.
The bodyweight of each rat was recorded on Day 1 (prior to dosing), Day 8 and Day 15 (prior to necropsy).
- Necropsy of survivors performed: Yes
- Other examinations performed:
*Clinical signs: The nature and severity of the clinical signs and time were recorded at each observation. Changes in skin and fur, eyes and mucous membrane, and also respiratory, circulatory, autonomic and central nervous systems, and somatomotor activity and behavior pattern were also additionally observed with special attention.
*Body weight: Group mean bodyweights and individual bodyweight changes were calculated.
*Gross pathology: All surviving animals were subjected to a macroscopic examination which consisted of opening the thoracic and abdominal cavities. The macroscopic appearance of all examined organs was recorded. Microscopic examination of found dead was not conducted because the animals were acutely dead within 24 hours after dosing.
Statistics:
Not applicable

Results and discussion

Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
ca. 500 mg/kg bw
Based on:
test mat.
Mortality:
During the study, one rat (F2) on Day 2 at the starting dose (1st and 2nd step; 300 mg/kg) and three rats immediately after dosing at the next higher dose (3rd step; 2,000 mg/kg) were found dead.
Clinical signs:
Piloerection, diarrhea/soft stool, hypoactivity, staining and/or wet of the hair coat around the anogenital region, reddish staining of the head area, incomplete eye opening, or blackish stool/decrease in quantity were observed during the 1st and 2nd step. These signs were observed until on Day 3 or Day 4, the severity of signs slightly decreased except found dead rat and recovered to normal on Day 4 or Day 5. At the 3rd step, all rats showed severe signs such as convulsion, lateral/prone position and immobile, labored breathing and blackish color in foot paw immediately after dosing and then were found dead within 4 hours after dosing at the 3rd step.
Body weight:
No adverse effect on bodyweight development was detected during the study except found dead animal at the 1st and 2nd step.
Gross pathology:
No macroscopic abnormalities were detected at study termination except found dead animal.
Found dead animals showed treatment-related gross findings such as perioral discharge, residue of dosing materials within stomach, dark and red discoloration of liver, hemorrhage and reddish discoloration of intestine. One rat (F8) additionally showed dark and brown discoloration of kidney.

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
Treatment-related clinical signs were observed at the 1st and 2nd step and the rats recovered to normal except one rats. However, at the 3rd step, all rats were found dead immediately after dosing. Considering the nature and severity of the clinical signs and time to death, deaths were considered to be related to treatment. Based on the mortality, clinical signs, bodyweight changes and gross pathology findings, the acute lethal oral dose (LD50 cut-off values) to rats of the test article was considered to be around 500 mg/kg bodyweight under the conditions of this study.