Sodium bis(trifluoromethylsulfonyl)imide

Endpoint summary

Description of key information

The acute oral LD50 value of the test item sodium bis(trifluoromethane)sulfonimide was found to be between 50 and 300 mg/kg bw in female Crl:WI rats

Base on the read-across with the source substance, LiTFSI, the LD50 by dermal route in rabbits was determined to be 371 mg/kg (males) and 418 mg/kg (females).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

August 2021

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

yes

Remarks:

Due to technical error, temperature values (maximum of 25.9°C) outside the expected range of 19-25°C was recorded occasionally in the animal rooms during the study. These deviations have no effect on the outcome of the study.

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Specific details on test material used for the study:

Purity: 99%

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH (Address: Sandhofer Weg 7, D-97633 Sulzfeld, Germany)
- Females: nulliparous and non-pregnant
- Age at study initiation: Young adult rats, 8 weeks old- Weight at study initiation:
- Fasting period before study: The night before treatment
- Housing: Group caging (3 animals/cage)
- Diet: Animals received ssniff SM R/M "Autoclavable complete diet for rats and mice – breeding and maintenance" produced by ssniff Spezialdiäten GmbH (Address: D-59494 Soest, Germany) ad libitum. The food was considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study. The supplier provided an analytical certificate for the batch used.
- Water: Animals received tap water from the municipal supply, as for human consumption from a 500 mL bottle, ad libitum. Water was considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study.
Water quality control analysis is performed once every three months and microbiological assessment is performed monthly, by Veszprém County Institute of State Public Health and Medical Officer Service (H-8200 Veszprém, József Attila u. 36., Hungary). The quality control results are retained in the Archives of Test Facility.
- Acclimation period: 5 days. During the acclimation period of at least 5 days, the animals were kept under the same controlled environment conditions as during the experimental period. Only animals without any visible signs of illness were used for the study.
- Microbiological status when known : The health status of the animals assigned to study was verified by the clinical Veterinarian.
- Method of randomisation in assigning animals to test and control groups: The animals were selected by hand at time of delivery. It was checked that all animals were within 20% of the overall mean at the start of the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.3 – 25.9°C
- Humidity (%): 32 - 69%
- Air changes (per hr): 15-20 air exchanges/hour
- Photoperiod (hrs dark / hrs light): 12 hours daily, from 6.00 a.m. to 6.00 p.m.

Route of administration:

oral: gavage

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

CLASS METHOD
- Rationale for the selection of the starting dose: Initially, three females (Group 1) were treated at a dose level of 300 mg/kg bw. All animals died on the day of treatment (Day 0). Therefore, one group (Group 2) was treated at the dose level of 50 mg/kg bw. As no mortality was observed, a confirmatory group (Group 3) was treated at the same dose level. No mortality was observed in this group; therefore, no further testing was required according to OECD 423 and Commission Regulation (EC) No 440/2008 of 2008, B.1.tris.

Doses:

300 and 50 mg/kg bw

No. of animals per sex per dose:

3

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: at least on Days -1 (prior to removal of food), 0 (prior to administration), 7 and 14 with a precision of 1 g.
- Necropsy of survivors performed: yes
- Clinical signs including body weight: Any clinical sign noted during dosing or at any other occasions was recorded at the time seen.

Statistics:

No statistical evaluation was performed in this study.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 50 - < 300 mg/kg bw

Based on:

test mat.

Sex:

female

Dose descriptor:

LD0

Effect level:

50 mg/kg bw

Based on:

test mat.

Sex:

female

Dose descriptor:

LD100

Effect level:

300 mg/kg bw

Based on:

test mat.

Mortality:

All animals died at the dose level of 300 mg/kg bw on Day 0.
No mortality occurred in the study during the 14-day observation period at the dose level of 50 mg/kg bw.

Clinical signs:

convulsions

irregular respiration

other: activity, recumbency, hunched back, piloerection, red discharge

Body weight:

other body weight observations

Remarks:

There were no test item related body weight changes. Body weights were within the range commonly recorded for this strain and age.

INDIVIDUAL BODY WEIGHT AND BODY WEIGHT GAIN

Interpretation of results:

Category 3 based on GHS criteria

Remarks:

According to the Globally Harmonised System (GHS) criteria, sodium bis(trifluoromethane)sulfonimide can be ranked as "Category 3" for acute oral exposure. According to the Classification, Labelling and Packaging (CLP) criteria, sodium bis(trifluoromethane)sulfonimide can be ranked as "Category 3" for acute oral exposure.

Conclusions:

Under the conditions of this study, the acute oral LD50 value of the test item sodium bis(trifluoromethane)sulfonimide was found to be between 50 and 300 mg/kg bw in female Crl:WI rats.

Executive summary:

The single-dose oral toxicity study of sodium bis(trifluoromethane)sulfonimide in rats was performed according to the acute toxic class method (OECD 423 and Commission Regulation (EC) No 440/2008 of 30 May 2008, B.1.Tris) in Crl:WI Wistar rats.

Three groups of three female Crl:WI rats were treated with the test item at dose levels of 300 mg/kg body weight (bw) (Group 1) and 50 mg/kg bw (Group 2 and Group 3).

A single oral treatment was carried out by gavage for each animal after an overnight food withdrawal. Food was made available again 3 hours after the treatment. The test item was administered at the dose levels of 300 and 50 mg/kg bw.

Initially, three females (Group 1) were treated at a dose level of 300 mg/kg bw. All animals died on the day of treatment (Day 0). Therefore, one group (Group 2) was treated at the dose level of 50 mg/kg bw. As no mortality was observed, a confirmatory group (Group 3) was treated at the same dose level. No mortality was observed in this group; therefore, no further testing was required according to OECD 423 and Commission Regulation (EC) No 440/2008 of 2008, B.1.tris.

Clinical observations were performed immediately after treatment and/or at 30 minutes, 1, 2, 3, 4 and 6 hours after dosing and daily for 14 days thereafter. Body weight was measured on Days -1, 0, 7 and before necropsy (Day 14). All animals were subjected to a necropsy and a macroscopic examination.

The results of the study were summarized as follows:

Mortality

All animals died at the dose level of 300 mg/kg bw on Day 0. No mortality occurred in the study during the 14-day observation period at the dose level of 50 mg/kg bw.

Clinical Observations

After treatment at 300 mg/kg bw, decreased activity (moderate) (3/3 animals), recumbency (3/3 animals), hunched back (3/3 animals), clonic / tonic convulsion (whole body) (3/3 animals), laboured respiration (3/3 animals), piloerection (3/3 animals) and red discharge (right eye) (1/3 animals) were observed prior to death. All animals at dose level of 300 mg/kg bw died on Day 0.

Animals at dose level of 50 mg/kg bw, slightly decreased activity (6/6 animals), hunched back (6/6 animals) and slight ataxia (1/6 animals) were observed on Day 0. Slightly decreased activity (3/6 animals) was observed on Day 1. All animals were symptom-free from Day 2.

Body Weight and Body Weight Gain

There were no test item related body weight changes. Body weights were within the range commonly recorded for this strain and age.

Under the conditions of this study, the acute oral LD50 value of the test item sodium bis(trifluoromethane)sulfonimide was found to be between 50 and 300 mg/kg bw in female Crl:WI rats.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

May - August 1988

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Oral screening study according to standard OECD guideline but not GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

no

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:

Young adult albino rats of the Sprague-Dawley strain were procured, separated by sex, maintained in group cages in temperature and humidity-controlled quarters, provided continuous access to Rodent Chow 5001, Purina Mills, Inc., and water, and held for an acclimation period of at least 7 days.
Acclimated animals were chosen at random for the study. Test animals were housed by sex in groups of five and identified by animal number and corresponding ear tag. Five male and five female rats weighing from 200 to 280 g were used for each dose level. The study consisted of three dose levels (0.05, 0.50 and 5.0 g/kg).
Food and water were available ad libitum throughout the study, except for an overnight period just before test material administration when food, but not water was withheld.

IN-LIFE DATES: From: 13/06/1988 To: 07/07/1988

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

The test material was mixed with deionized water to form a uniform suspension at specific concentration for each dose level. An individual dose was calculated for each animal based upon its fasted body weight and administered by garage.
The dose volume for each test mixture was 10.0 ml/kg of body weight.

Doses:

50, 500 and 5000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

Observations: The animals were observed for clinical signs and mortality at 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 for mortality.
All animals were weighed just before test material administration, at 7 days and at study termination (or at death).

Pathology: At study termination surviving animals were euthanatized. Animals which died on study or euthanatized at study termination were subjected to a gross necropsy examination and abnormalities recorded. Following necropsy, animals were discarded and no tissues were saved.

Statistics:

Thakur, A. K., and W. L. Fezio, 1981. A Computer Program for estimating LD50 and its Confidence Limits using a Modified Behrens-Reed-Muench
Cumulant Method. Drug and Chemical Toxicology 4 (3) 292-305.

Sex:

female

Dose descriptor:

LD50

Effect level:

210 mg/kg bw

Based on:

test mat.

95% CL:

50 - 870

Sex:

male

Dose descriptor:

LD50

Effect level:

160 mg/kg bw

Based on:

test mat.

95% CL:

40 - 560

Mortality:

Male: 0/5 at 50 mg/kg bw; 5/5 at 500 mg/kg bw; 5/5 at 5000 mg/kg bw.
Female: 0/5 at 50 mg/kg bw; 4/5 at 500 mg/kg bw; 5/5 at 5000 mg/kg bw.

Clinical signs:

other: At 500 mg/kg bw, hypoactivity, hypersensitivity to touch. Male and female animals experienced clonic convulsions during the first 0.5 hour post-dose.

Gross pathology:

At 500 mg/kg bw: stomach - glandular mucosa has multiple red areas; nasal discharge.
At 5000 mg/kg bw: stomach - glandular mucosa has multiple red areas; nasal discharge; Testes - diffusely light.

Other findings:

The most frequently recorded observations were in those animals that died on test. The glandular mucosa of the stomach in some of these animals had changes which ranged from red foci to diffusely red and were possibly treatment related. All other findings were considered related to postmortem
change or incidental findings which were not related to treatment.

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

In this study, TFSILi is toxic by oral route.

Executive summary:

In a screening study for acute oral toxicity according to OECD 401, Bis trifluoromethanesulfonimide lithium was adminstered to five Sprague-Dawley rats of each sex. The animals were exposed to single oral dose levels of 50, 500 and 5000 mg/kg bw. All animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed on the day of death or after terminal sacrifice. At 5000 mg/kg all animals died within 15 minutes of dose administration. At 500 mg/kg 4 female animals and 5 male animals were found dead within 2.5 hours. No mortality occurred at 50 mg/kg.

The oral LD50 value of Bis trifluoromethanesulfonimide lithium was 160 mg/kg bw for males and 210 mg/kg bw for females.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

>= 50 - <= 300 mg/kg bw

Quality of whole database:

GLP-compliant OECD guideline study

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

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

A study on acute toxicity by oral route is avavilable on the target substance, NaTFSI. Since no acute studies by dermal route are available for Sodium bis(trifluoromethylsulfonyl)imide, the results from the structural analogue Lithium bis(trifluoromethylsulfonyl)imide are used instead (for details see Read-across justification as attached in section 13). The studies are summarized below.

 

Oral

One reliable study is available for the target substance on oral toxicity. The single-dose oral toxicity study of sodium bis(trifluoromethane)sulfonimide in rats was performed according to the acute toxic class method (OECD 423 and Commission Regulation (EC) No 440/2008 of 30 May 2008, B.1.Tris) in Crl:WI Wistar rats. Three groups of three female Crl:WI rats were treated with the test item at dose levels of 300 mg/kg body weight (bw) (Group 1) and 50 mg/kg bw (Group 2 and Group 3).

Animals treated at the highest a dose level of 300 mg/kg bw died on the day of treatment (Day 0). Contrarily, no mortality occurred in the study during the 14-day observation period at the dose level of 50 mg/kg bw. Hence, the acute oral LD50 value of the test item sodium bis(trifluoromethane)sulfonimide was found to be between 50 and 300 mg/kg bw in female Crl:WI rats.

This results is in line with the findings with the source substance.

Dermal

On the source substance lithium (bis)trifluoromethanesulfonimide, two reliable GLP-compliant OECD 402 studies with the source substance are available for dermal toxicity and 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 data of source substance, a classification as "Toxic in contact with skin" (Category 3, H311) is warrented according to CLP regulation 1272/2008.

Justification for classification or non-classification

Based on the experimental data of the target and the source substance (Lithium bis(trifluoromethylsulfonyl)imide), Sodium bis(trifluoromethylsulfonyl)imide is considered to be classified:

- "Toxic if swallowed" (Category 3, H301) according to the CLP regulation 1272/2008 criteria, based on the LD50 of 30 - 300 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.