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Description of key information

The LD50 by oral route in rats was determined to be 160 mg/kg (males) and 210 mg/kg (females).
The LD50 by dermal route in rabbits was determined to be 371 mg/kg on male, 418 mg/kg on female and 400 mg/kg male/female.

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:
Report date: 2002-04-19
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study performed according to OECD Guideline and EU Method and according to GLP.
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, L'Arbresle, France
- Age / weight at study initiation: On the day of treatment, the animals were approximately 6 weeks old, and had a mean body weight ± standard deviation of 182 ± 5 g for the males and 150 ± 9 g for the females. Females were nulliparous and non pregnant.
- Fasting period before study: The animals were fasted for an overnight period of approximately 18 hours before dosing, but had free access to water. Food was given back approximately 4 hours after administration of the test item.
- Housing: The animals were housed in polycarbonate cages with stainless steel lid (48 cm x 27 cm x 20 cm). Each cage contained one to seven animals of the same sex during the acclimation period and three rats of the same sex and group during the treatment period.
Each cage contained autoclaved sawdust (SICSA, Alfortville, France).
- Diet (e.g. ad libitum): All the animals had free access to A04 C pelleted diet (UAR, Villemoisson, Epinay-sur-Orge, France).
- Water (e.g. ad libitum): Drinking water filtered by a FG Millipore membrane (0.22 micron) was provided ad libitum.
- Acclimation period: At least 5 days before the beginning of the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 30 to 70%
- Air changes (per hr): Approximately 12 cycles/hour of filtered, non-recycled air.
- Photoperiod (hrs dark / hrs light): 12 h/12 h
The temperature and relative humidity were under continuous control and recording. The records were checked daily and filed. In addition to these daily checks, the housing conditions and corresponding instrumentation and equipment are verified and calibrated at regular intervals.

IN-LIFE DATES: From: 6 December 2001 To: 17 january 2002
Route of administration:
oral: gavage
Vehicle:
other: purified water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 20 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: no data available

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

DOSAGE PREPARATION: On the day of treatment, the test item, at the chosen concentration, was incorporated in the vehicle. Each test item preparation was made freshly on the morning of administration by the CIT Pharmacy and any unused material was discarded that same day.

CLASS METHOD
- Rationale for the selection of the starting dose: Three animals of one sex were used for each step. Males were used in the initial step.
The dose-level used as the starting dose was selected from one of three fixed levels, 25, 200 or 2000 mg/kg body weight.
As no information on the toxic potential of the test item was available, for animal welfare reasons, the starting dose-level of 200 mg/kg was chosen.
After the first assay, as 2/3 males died, another assay was carried out on three males at the next lower dose-level (25 mg/kg).
After the second assay, as no mortality occurred, the results were confirmed in three females at the dose-level 25 mg/kg.
At the request of the Sponsor, another assay was performed at the dose-level of 200 mg/kg in three females.


Doses:
25 and 200 mg/kg bw
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: Mortality of each animal were observed frequently during the hours following administration of the test item, for detection of possible treatment-related clinical signs. Thereafter, observation of the animals was made at least once a day. Time of death was recorded individually, in terms of the number of hours or days after dosing. The animals were weighed individually just before administration of the test item on day 1 and then on days 8 and 15.
- Necropsy of survivors performed: Yes
- Other examinations performed: Clinical signs (Type, time of onset and duration of clinical signs were recorded for each animal individually.), Macroscopic post-mortem examination (All study animals were subjected to a macroscopic examination as soon as possible after death. After opening the thoracic and abdominal cavities, a macroscopic examination of the main organs (digestive tract, heart, kidneys, liver, lungs, pancreas, spleen and any other organs with obvious abnormalities) was performed.).
Statistics:
Not applicable
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 200 mg/kg bw
Mortality:
At the 25 mg/kg dose-level, no deaths occurred.
At the 200 mg/kg dose-level, mortality was 2/6 animals (two males 4h15 after treatment).
Clinical signs:
other: At the 25 mg/kg dose-level: Dyspnea and piloerection were noted in all males one hour after treatment. No other clinical signs were observed during the observation period. At the 200 mg/kg dose-level: - On day 1, hypoactivity then sedation, dyspnea, tonic
Gross pathology:
Macroscopic examination of the main organs of the animals revealed no apparent abnormalities.
Interpretation of results:
toxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under these experimental conditions, the oral LD50 of the test item BIS TRIFLUOROMETHANESULFONIMIDE LITHIUM is higher than 200 mg/kg in rats.
Executive summary:

An acute oral toxicity study was performed with the test item Bis trifluoromethanesulfonimide lithium (TFSILi) in rats, in compliance with OECD Guideline n°423, under GLP conditions. The test item was prepared in purified water and was administered by oral route (gavage), under a volume of 10 mL/kg, to groups of fasted Sprague-Dawley rats.

The study design was as follows:

 

Dose

(mg/kg)

 

Vehicle

 

Volume (mL/kg) 

 

Male

 

Female

200

Purified water

10

3

-

25

Purified water

10

3

-

25

Purified water

10

-

3

200

Purified water

10

-

3

 

Clinical signs, mortality and body weight gain were checked for a period of up to 14 days following the single administration of the test item.

All animals were subjected to necropsy.

At the 25 mg/kg dose-level, no deaths occurred. Dyspnea and piloerection were noted in all males one hour after treatment. No other clinical signs were observed during the observation period.

At the 200 mg/kg dose-level, mortality was 2/6 animals (two males 4h15 after treatment). On day 1, hypoactivity then sedation, dyspnea, tonic-clonic convulsions, hypersalivation and piloerection were the clinical signs observed in all the animals. On day 2, hypoactivity and piloerection were noted in the surviving male; no clinical signs persisted in females. From day 3 until the end of the observation period, no clinical signs were recorded.

The body weight gain of the animals given 25 or 200 mg/kg was not affected by treatment with the test item.

At necropsy, no apparent abnormalities were observed in any animal.

The oral LD50 of the test item Bis trifluoromethanesulfonimide lithium in Sprague-Dawley rats was established to be higher than 200 mg/kg.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
160 mg/kg bw
Quality of whole database:
GLP-compliant OECD guideline study

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study technically not feasible
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
GLP-compliant OECD guideline study

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:
April - August 1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study, OECD 402 compliant.
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
environmental conditions are outside of those recommended by guideline.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hazleton Research Products, Inc., Kalamazoo, MI
- Age at study initiation: young adults
- Weight at study initiation: Three acclimated animals weighing from 2032 to 2486 g were chosen at random for the test.
- Housing: maintained individually in screen-bottom cages in temperature and humidity-controlled quarters.
- Diet: measured amount of High Fiber Rabbit Chow 5326, Purina Mills, Inc., ad libitum
- Water: ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): controlled, 16 to 27°C
- Humidity (%): controlled 31 to 81%

IN-LIFE DATES: From: 01/05/1991 To: 10/07/1991
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
An individual dose of the test material was calculated and weighed out based on each animal's body weight on the day of test material administration. Each dose was thoroughly moistened with 0.9% saline before application.

TEST MATERIAL
The test material was applied to each respective animal's shaved back at dose levels of 200, 350, 500, or 2000 mg/kg of body weight. The area of
application was covered with a 10 cm x 10 cm gauze patch secured with paper tape, and overwrapped with Saran Wrap and Elastoplast tape. Collars were applied to restrain the test animals during the 24-hour exposure period.

REMOVAL OF TEST SUBSTANCE
At the end of the 24-hour exposure period, the bandages were removed and the backs were washed using tap water and disposable paper towels.
Duration of exposure:
Single exposure
Doses:
200, 350, 500 and 2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: observation at approximately 1, 2.5, and 4 hours after test material administration. The animals were observed daily thereafter for 14 days for clinical signs and twice daily (morning and afternoon) for mortality.
Body weights were determined before test material administration (Day 0).
Additional body weights were determined at Day 7 and at termination of the experimental phase (Day 14) or at death when survival exceeded 1 day.

- Pathology: At termination of the experimental phase, surviving animals were euthanatized.
All animals, whether dying during the study or euthanatized, were subjected to a gross necropsy examinationand all abnormalities were recorded. After necropsy, the animals were discarded and no tissues were saved.
Statistics:
The LD50 for males, females, and the sexes combined was determined by a computer program utilizing a modified Behrens-Reed-Muench Cumulant Method
Sex:
male/female
Dose descriptor:
LD50
Effect level:
400 mg/kg bw
Based on:
test mat.
95% CL:
329 - 486
Sex:
male
Dose descriptor:
LD50
Effect level:
371 mg/kg bw
Based on:
test mat.
95% CL:
254 - 542
Sex:
female
Dose descriptor:
LD50
Effect level:
418 mg/kg bw
Based on:
test mat.
95% CL:
329 - 486
Mortality:
200 mg/kg: 0/5 for both sex
350 mg/kg: 2/5 and 0/5 for male and female respectivly
500 and 2000 mg/kg: 5/5 for both sex
Clinical signs:
other: hypoactivity, loss of appetite, staggered gait, subconvulsive jerking, miosis, excessive salivation, aggressive behavior, tremors, prostration, shallow breathing, clonic convulsions, and death.
Other findings:
Dermal irritation consisted of slight to severe erythema and slight edema and desquamation. Subcutaneous hemorrhaging and a possible necrotic were also observed.
Interpretation of results:
toxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
TFSILI tested is toxic by skin contact.
Executive summary:

The acute dermal toxicity of TFSILi was evaluated in male and female rabbits when administered as a single topical application at levels of 200, 350, 500, and 2000 mg/kg of body weight. Based on the observed mortality, the estimated dermal LD50 was determined to be 371, 418 and 400 mg/kg for males, females, and the sexes combined, respectively.

Clinical signs of toxicity included hypoactivity, loss of appetite, staggered gait, subconvulsive jerking, miosis, excessive salivation, aggressive behavior, tremors, prostration, shallow breathing, clonic convulsions, and death.

All animals surviving to the end of the observation period exhibited no meaningful effect on weight gain. The test material produced slight to severe erythema and slight edema and desquamation dermal reactions. Subcutaneous hemorrhaging and a possible necrotic area were also observed. All mortality occurred within 2 days of test material administration.

Based on the results of this study, the test substance is considered toxic by skin contact according to the CLP 1272/2008 criteria.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
371 mg/kg bw
Quality of whole database:
GLP-compliant OECD guideline study

Additional information

Oral

Three reliable acute oral toxicity studies in rats are available for Bis trifluoromethanesulfonimide Lithium. One GLP compliant OECD Guideline study of reliability 1 (Pelcot, 2002a) was considered as the key study for acute oral toxicity. Two screening studies of reliability 2 were selected as supporting studies (Prinsen, 1997; Glaza, 1988).

Based on the results of the key study, it is expected that the oral LD50 in rat would be > 200 and < 2000 mg/kg bw since 2/6 animals were found dead after exposure to 200 mg/kg bw and it is considered unlikely that more than 50% of the animals will survive a dose of 2000 mg/kg bw.

The study performed by TNO (Prinsen, 1997) results in an LD50 of >200 mg/kg bw (females) whereas the study performed by Hazleton (Glaza, 1988) leads to an LD50 of 160 mg/kg bw (males) and 210 mg/kg bw (females).

Based on the experimental results a classification as "Toxic if swallowed" is warrented according to CLP regulation 1272/2008 which is in accordance with the harmonized EU classification of TFSILi according to Annex VI 3.1 and 3.2.

Inhalation

Testing for acute inhalation toxicity is not required since Bis trifluoromethanesulfonimide lithium (TFSILi) has very low vapor pressure and high melting point, so the potential for the generation of inhalable forms is low.

Dermal

For acute dermal toxicity two GLP-compliant OECD 402 studies are available that were considered as key studies. One study was performed in rat (Pelcot, 2002b) and the other study was performed in rabbits (Perkins, 1991). In the study performed by Pelcot in 2002, the test item was applied on rat skin just moistened with water. No cutaneous reactions were observed. No clinical signs and no mortality was observed during the study and for this reason the dermal LD50 of the test item was >2000 mg/kg.

In the other study (Perkins, 1991), the test item was diluted with 0.9% NaCl and applied on rabbit skin. Clinical signs of toxicity included hypoactivity, loss of appetite, staggered gait, subconvulsive jerking, miosis, excessive salivation, aggressive behavior, tremors, prostration, shallow breathing, clonic convulsions, and death. The test item produced slight to severe erythema and slight edema and desquamation dermal reactions. Subcutaneous hemorrhaging and a possible necrotic area were also observed.All mortality occurred within 2 days of test material administration. Based on the observed mortality, the estimated dermal LD50 was determined to be 371, 418 and 400 mg/kg for males, females, and the sexes combined, respectively.

Based on the experimental results a classification as "Toxic in contact with skin" is warrented according to CLP regulation 1272/2008 which is in accordance with the harmonized EU classification of TFSILi according to Annex VI 3.1 and 3.2

Justification for classification or non-classification

Based on the experimental data and in accordance with the harmonized EU classification, Bis trifluoromethanesulfonimide lithium is to be classified:

- "Toxic if swallowed" (Category 3, H301) according to the CLP regulation 1272/2008 criteria, based on the LD50 > 200 mg/kg

- "Toxic in contact with skin" (Category 3, H311) according to the CLP regulation 1272/2008, based on the LD50 of 371 - 418 mg/kg.