lithium bis(fluorosulfonyl)imide

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

The study was conducted between 22 December 2010 and 9 February 2011

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2011

Report date:

2011

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

lithium(1+) bis(fluorosulfonyl)azanide

EC Number:

924-516-9

Cas Number:

171611-11-3

Molecular formula:

(FSO2)2NLi

IUPAC Name:

lithium(1+) bis(fluorosulfonyl)azanide

Specific details on test material used for the study:

Name (abbr. name): LiFSI
Chemical name: Lithium bis(fluorosulfonil)imide
Rational formula: (FS02)2NLi
Molecular formula: F2LiN04S2
Molecular weight: 187.07
CAS No.: 171611·11·3
Lot No.: 100527475
Purity: 99.5%
Expiration date: May 27, 2011

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

Eight female Sprague-Dawley [Crj:CD(SD)IGS] rats at 7.0 weeks of age (body weight range: 165 to 179g) were purchased from Charles River Japan Inc. (Hino Breeding Center, 735 Shimokomazuki, Hino·cho, Gamou·gun, Shiga, Japan).
The animals were quarantined for 5 days after arrival, observed for general conditions once daily, and their body weights were measured with an electric balance (LC2200S, Sartorius Co., Ltd.) on the first day and last day of the quarantine period. The animals were evaluated for health conditions on the last day of the quarantine period, confirming the absence of abnormality. Animals were acclimatized to housing conditions until the day before administration including the quarantine period. Each animals was identified with a color label attached to the cage (study No, name of the test substance, temporary animal no., date of arrival etc. were entered).
Animals were weighed on the day before administration. One animal with the highest body weight was selected for the sighting study, and 4 healthy animals with body weight within the body weight of the animal used in the sighting study on the day before administration ± 20%. Animals were 8·9 weeks old on the day of administration, and the body weight range was 233·253g. Animals excluded from the study were euthanized at the time of necropsy in the main study. After grouping animals were identified with brevity codes of animal numbers marked with an oil marker on the root of the tail, and cages were identified with attached color labels showing the study No., route of administration, animal species, dose level, animal no. etc.
Housing and environmental conditions

Environmental conditions
Animals were individually housed m stainless-steel bracket cages for rats (260W x 380D x 180H mm) in a conventional system animal room No.2, where the environmental conditions were maintained as follows. Temperature: 22±3°C (actual values: 18.2 to 23.2°C; humidity: 50±20% (actual values: 19.9 to 60.6%); ventilation frequency: 10 times/hr or more (all·fresh·air system); and lighting: 12 hr/day (TOO a.m. to 7:00 p.m., 150·300 lux).
Cages, feeders, trays and watering bottles were sterilized with 500-fold aqueous dilution of sodium hypochlorite prior to use, and trays and wateringbottles were changed for new ones 2 times per week. Cages and feeders were not changed. The animal room was cleaned after work every day, and the floor was sterilized by wiping with 200-fold aqueous dilution of benzethonium chloride (Hyamine solution; Daiichi Sankyo Co., Ltd.).

Feed
Pellet diet for experimental animals CE-2 (Lot Nos. E2090 and E2100, Clea Japan Inc., 1·2·7 Higashiyama, Meguro·ku, Tokyo, Japan) was provided ad libitum via feeders.
Feed analysis for impurities and contaminants in the lot used in the study was entrusted by the maker to Tokyo Kenbikyo·in foundation (44· 1 Nihonbashi Hakozaki-cho, Chuo-ku, Tokyo, Japan). Based on the results (obtained as a copy), the conformity to the standards specified by Nippon Experimental Medical Research Institute Co., Ltd. was confirmed before feeding.

Drinking water
Shibukawa·city tap water was provided ad libitum via polycarbonate watering bottles (500mL). Water analysis in the samples periodically collected at sites specified by this facility was entrusted to Environmental Technical Co., Ltd. (1709· l Kaneko·cho, Takasaki·shi, Gunma, Japan) based on the "Ministerial Ordinance Concerning Water Quality Standards (MHLW Ordinance No. 101, 2003)", "Partial Amendment of Ministerial Ordinance Concerning Water Quality Standards (MHLW Ordinance No. 174, 2008)", and "Partial Amendment of the Ordinance for Enforcement of the Water Law (MHLW Ordinance No.175, 2008)". Based on the results [common bacteria (once per month), chloric acid, chloride ion, organic matters, pH, taste, odor, chromaticity, turbidity (4 times per year) and the test of 50 items (once per 3 years)], the conformity to the above-mentioned water quality standards was confirmed.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

Water for injection was preliminarily examined as solvent. As a result, the test substance was readily resolved to prepare 400mg/mL solution without bubble release, heat generation or coloration. Therefore we selected water for injection

As possible human exposure, oral route was selected. The dose volume (5mL/kg) was calculated based on the body weight just before administration. Single dose of the prepared test solution suctioned in a 2.5mL disposable syringe attached with a gastric sonde for rats was orally administered to rats. Animals were fasted from approximately 18hr before administration, and feeding was restarted approximately 3hr after administration.

Preparation of the test substance solution
In the primary sighting study, 0.300g of the test substance weighed with an electric balance (E 1200S, Sartorius Co., Ltd.) was placed in a 5mL measuring cylinder, to which water for injection was added bit by bit and measured up to a total volume of 5mL, and mixed by turning upside down to prepare the test substance solution at a concentration of 60mg/mL. In the second sighting study, 0.050g of the test substance was weighed, and the test substance solution at a concentration of 10mg/mL was prepared in a similar way. In the main study, 0.1g of the test substance was weighed, and measured up to 10mL to prepare the test substance solution at a concentration of 10mg/mL.
The test substance solution was prepared at the time of use. Adjustment to the purity of the test substance was not taken into account. Test substance solution at each concentration was visually confirmed to have no bubble release, heat
generation or coloration. Concentration analysis of the test substance in the solvent was not performed.

Doses:

300 mg/kg and 50 mg/kg

Due to a lack of information available on acute toxicity of the test item, 300 mg/kg was selected as the dose level in the sighting study, based on recommendation of the OECD Guideline.
In the primary sighting study, the test substance was administered at a dose level of 300mg/kg to one animal. As a result, toxic signs were observed at 15min
after administration, and death was noted at 30min after administration. Therefore, in the second sighting study, the test substance was administered at a
dose level of 50mg/kg to one animal. As a result, no toxic sign was observed. Based on these results, we supposed that the test substance at the dose level
having caused death in the sighting study should cause at least 2 deaths in the main study; therefore, in the main study, excepting the said dose level, the test
substance was administered at a dose level of 50mg/kg to 4 animals.

No. of animals per sex per dose:

300 mg/kg - 1 animal
50 mg/kg - 5 animals

Control animals:

no

Details on study design:

Observation and measurement
The day of administration was designated as Day 1, and the following observations and measurements were performed on all animals.
(1) Mortality and general conditions
The observation period was 14 days (Day 1 to Day 15). Animals were observed for changes in general conditions including mortality, just before treatment and at 15 and 30min, 1, 3 and 6hr after treatment on Day 1, and once daily thereafter.
(2) Body weights
Body weights of animals were measured with an electric balance (LC2200S, Sartorius Co., Ltd.) on Days 1 Gust before treatment), 2, 3, 4, 8 and 15.
(3) Necropsy
The animal found dead was immediately necropsied. After observation on Day 15, surviving animals were exsanguinated by cutting the abdominal aorta under ether anesthesia, and the body surface and organs/tissues in the cranial, thoracic
and abdominal cavities were macroscopically examined.

Statistics:

The mean values and standard deviations were calculated for the body weight measurements obtained in the study; however, statistical analyses were not performed.

Results and discussion

Preliminary study:

Initially, a sighting study was performed at the dose level of 300mg/kg using 1 animal. As a result, toxic signs were observed from 15min after administration, and death was observed at 30min after administration. Then, a. sighting study was performed at the dose level of 50mg/kg using 1 animal. As a result, no toxic sign was observed.

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

> 50 - <= 300 mg/kg bw

Based on:

test mat.

Mortality:

300mg/kg group: Death was observed at 30min after administration.
50mg/kg group : No death was observed in any animals throughout the observation period in the sighting study or main study.

Clinical signs:

other: 300mg/kg group: Ataxic gate, hypersensitivity, twitch and tonic convulsion were observed at 15min after administration. Hypersensitivity, twitch, tonic convulsion, side position and irregular respiration were observed at 30min after administration and res

Gross pathology:

300mg/kg group: Light red speck, dark red macula and erosion were observed in the thymus, lung and glandular stomach, respectively.
50mg/kg group: No abnormal finding was observed in any animals.

Applicant's summary and conclusion

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

Based on the above-mentioned results, the approximate LD50 value of LiFSI was estimated to be more than 50mg/kg and equal to or less than 300mg/kg under the conditions of this study.

Executive summary:

In accordance with the OECD Guideline, a single dose of LiFSI was orally administered to female 8-9 weeks old SD [Crl:CD(SD)] rats to investigate the acute oral toxicity and approximate LD50.

Initially, a sighting study was performed at the dose level of 300mg/kg using 1 animal. As a result, toxic signs were observed from 15min after administration, and death was observed at 30min after administration. Then, a sighting study was performed at the dose level of 50mg/kg using 1 animal. As a result, no toxic sign was observed.

Accordingly, the main study was performed at the dose level of 50mg/kg using 4 animals. As a result, no toxic sign was observed, and satisfactory body weight growth were noted throughout the observation period.

In necropsy, light red speck, dark red macula and erosion were observed in the thymus, lung and glandular stomach, respectively, in the dead animal receiving 300mg/kg of the test substance. No abnormal finding was observed in the animal receiving 50mg/kg of the test substance.

Based on the above-mentioned results, the approximate LD50 value of LiFSI was estimated to be more than 50mg/kg and equal to or less than 300mg/kg under the conditions of this study.