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Description of key information

Reliable acute toxicity studies via the oral and dermal routes of exposure are available conducted in accordance with OECD guidelines and GLP.

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:
From 5 December 2003 to 10 February 2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP compliance
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
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
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
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.
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.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
500 mg/kg bw
Quality of whole database:
Reliable study conducted in accordance with GLP and OECD guidance.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
Reliable study conducted in accordance with GLP and OECD guidance.

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:
From 21 September 2007 to 25 February 2008
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP compliance
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes
Remarks:
(21 July 2004)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: HsdRccHan : WIST rats
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Winkelmann GmbH, D-33178 Borchen.
- Females nulliparous and non-pregnant: no data
- Age at study initiation: Approximately 8 weeks for the male and 10 - 11 weeks for female animals
- Weight at study initiation: males: 215 - 233 g and females: 201 - 218 g
- Housing: The animals were kept in Macrolon cages on Altromin saw fiber bedding.
- Diet: Ad libitum, Altromin 1324 maintenance diet for rats and mice, totally-pathogen-free (TPF)
- Water: Free access to tap water (drinking water, municipal residue control, microbiol. controlled periodically)
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 55 ± 10%
- Air changes (per hr): 10 x I hour
- Photoperiod: Artificial light, sequence being 12 hours light, 12 hours dark

IN-LIFE DATES: From: 7 January 2008 To: 29 January 2008
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: dorsal area
- % coverage: Approximately 10% of the total body surface
- Type of wrap if used: The occlusive dressing consisted of a gauze dressing and non-irritating tape and was fixed with an additional dressing in a suitable manner.

REMOVAL OF TEST SUBSTANCE
At the end of the exposure, the residual test item was removed by using tap water.

TEST MATERIAL
The test item was applied uniformly over an area of approx. 10% of the total body surface at a single dose (2000 mg/kg bw).
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5 males and 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed for 14 days after dosing. A careful clinical examination was made at least twice on the day of dosing and once a day thereafter.
The animals were weighed prior to application and once a week thereafter.
- Necropsy of survivors performed: Yes
- Other examinations performed:
*Clinical signs: Cageside observations included changes in the skin and fur, eyes and mucous membranes. Also respiratory, circulatory, autonomic and central nervous systems and somatomotor activity and behaviour pattern were examined. Particular attention was directed to observations of tremor, convulsions, salivation, diarrhoea, lethargy, sleep and coma.
*Pathology: All gross pathological changes were recorded.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
At 2000 mg/kg, 1 male wad found dead on day 2 post-dose.
Clinical signs:
Small wounds, unevenly spread on the application site (8 - 10 days post-dose); eschar formation, partial eschar ablation (11 days post-dose); eschar formation, eschar ablation (12 - 13 days post-dose); wounds on the application site partially healed, eschar formation (14 days post-dose) were observed for all female animals and for 3 male animals.

Slightly to moderately reduced spontaneous activity, piloerection, apathy, half eyelid-closure, bent back (1 - 2 days) were observed for 1 male animal. During 3 to 7 days post-dose, no treatment-related symptoms were observed. After, small wounds, unevenly spread on the application site (8 - 10 days post-dose); eschar formation, partial eschar ablation (11 days post-dose); eschar formation, eschar ablation (12 - 13 days post-dose); wounds on the application site partially healed, eschar formation (14 days post-dose) were observed for this animal.

Slightly to moderately reduced spontaneous activity, piloerection, apathy, half eyelid-closure, bent back (24 - 26 hours) were observed for 1 male animal. After, this animal was found dead in abdominal position; piloerection (2 days post-dose).

Body weight:
Weight gain of all animals was within the expected range (see Table 1 in "Any other information on result incl. tables"), although female animal no. 2 and male animal no. 1 lost weight during the first 7 days.
Gross pathology:
Beside acute injection of blood vessels in the abdominal region of the sacrificed animals, which is due to the euthanasia injection, no specific gross pathological changes were found in any animal of any step.
Other findings:
After removing the dressing, the skin of the dorsal area of the test animals showed an orange discoloration.

Table 1: Weight gain in g (Dose: 2000 mg/kg)

Animal No.

Sex

Day 0

Day 7

Day 14

1 - male

215

185

236

2 - male

232

251

284

3 – male

224

--

--

4 - male

233

247

289

5 - male

221

245

286

1 - female

212

220

231

2 - female

205

179

210

3 – female

201

205

211

4 – female

218

224

236

5 - female

208

208

220

-- : Dead animal

Interpretation of results:
Category 5 based on GHS criteria
Conclusions:
Considering the reported data of this dermal toxicity test it can be stated that the test item Monofluoroethylene carbonate has acute dermal toxic potential and may be harmful in contact with skin.
The dermal LD50 was determined to be > 2000 mg/kg bw ≤ 5000 mg/kg bw.
Executive summary:

The acute dermal toxicity of Monofluoroethylene carbonate was evaluated in male and female rats when administered as a single topical application at level of 2000 mg/kg bw. The test item was held in contact with the skin by a semi-occlusive dressing throughout a 24 -hour period. Mortality, clinical signs and bodyweight changes were monitored throughout the study.

At the end of the observation period, all animals were sacrificed and were subjected to gross necropsy.

One male was found dead on Day 2 post-dose in abdominal position.

Two males showed reduced spontaneous activity, piloerection, half eyelid closure and bent back immediately after the termination the exposure.

The formation of small wounds on the application site were observed in all animals (except the dead animal) as from day 8 post-dose. Eschar formation was observed on days 11 - 13 post dose. At the end of the observation period the wounds were partially healed, although eschar formation was still observed.

After removing the dressing, the skin of the dorsal area of the test animals showed an orange discoloration.

Weight gain of all animals was within the excepted range.

Beside acute injection of blood vessels in the abdominal region of the sacrificed animals, which is due to the euthanasia injection, no specific gross pathological changes were found in any animal of any step.

Considering the reported data of this dermal toxicity test it can be stated that the test item Monofluoroethylene carbonate has acute dermal toxic potential and may be harmful in contact with skin.

The dermal LD50 was determined to be > 2000 mg/kg bw ≤ 5000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
Reliable study conducted in accordance with GLP and OECD guidance.

Additional information

Justification for classification or non-classification

The LD50 cut of value in accordance with the OECD 423 guideline for the acute oral toxicity study provides a value of 500 mg/kg based on the mortality observed. This equates to a classification of 'Harmful if swallowed' (H302) in accordance with the CLP Regulation (EC No. 1272/2008, as amended).

For the acute dermal study, only 1 death was observed at the limit dose of 2000 mg/kg. As such, the LD50 cut-off value was deemed to be greater than 2000 mg/kg based on the observed mortality. As such, no classification is warranted for acute dermal effects in accordance with the CLP Regulation (EC No. 1272/2008, as amended).