Lithium bis(fluorosulfonyl)imide

Repeated dose toxicity: oral

Administrative data

Endpoint:

repeated dose toxicity: oral, other

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2018.01.16~2018.11.16

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2018

Report date:

2018

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Version / remarks:

adapted 29 July 2016

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Lithium bis(fluorosulfonyl)imide

EC Number:

686-526-7

Cas Number:

171611-11-3

Molecular formula:

F2 H N O4 S2 . Li

IUPAC Name:

Lithium bis(fluorosulfonyl)imide

Test material form:

solid: bulk

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Details on species / strain selection:

Crl:CD(SD), Rat, SPF

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Male : 64 / Female : 64
- weight : 9w (M - 300.8g~354.5g) 7W(F-165.8g~199.4g)
- Injection : 58(Male), 58(Female)
- Injection : 10W(M : 337.8~405.2g) , 10W(F : 207.06~276.0g)

Administration / exposure

Route of administration:

oral: gavage

Details on route of administration:

The route of administration is oral. prepared test substance was continuously stirred using a magnetic stirrer before and after the administration,
and was directly administered into the stomach using a sonde-attached syringe.

Vehicle:

other:

Remarks:

Distilled water

Analytical verification of doses or concentrations:

yes

Remarks:

KTR Study No. TBK-001907-2017

Details on analytical verification of doses or concentrations:

Analysis was performed before treatment (1st dosing) based on the analytical method
validation (KTR Study No. TBK-001907-2017), Analytical method validation of the LiFSI
in dosing formulation by using ICP-OES. The results were as follows and were met
the acceptance criteria as follows (precision: less than 10 %, accuracy: 80 – 120 %);
Homogeneity – 1.71 %, 2.10 %, 0.88 %, Concentration – 101.92 %, 104.35 %, 104.35 %)

Duration of treatment / exposure:

7 days/week

Frequency of treatment:

The substance was administrated once/day

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

45 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

90 mg/kg bw/day (nominal)

Doses / concentrations 4

Dose / conc.:

180 mg/kg bw/day (nominal)

No. of animals per sex per dose:

1) 0 mg/kg bw/day "Control animal"
- Male(17), Female(17)

2) 45mg/kg bw/day
- Male (12)/ Female(12)

3) 90mg/kg bw/day
- Male(12)/Female(12)

4) 180mg/kg bw/day
- Male(17) / Female(17)

Control animals:

yes

Details on study design:

Group1) Dose : 0(mg/kg. bw/day) , Volume = 10(mg/kg.bw/day)
Group2) Dose : 45(mg/kg. bw/day) , Volume = 10(mg/kg.bw/day)
Group3) Dose : 90(mg/kg. bw/day) , Volume = 10(mg/kg.bw/day)
Group4) Dose : 180(mg/kg. bw/day) , Volume = 10(mg/kg.bw/day)

Positive control:

Vehicle control group : Group1) Dose : 0(mg/kg. bw/day) , Volume = 10(mg/kg.bw/day)

Examinations

Observations and examinations performed and frequency:

Clinical sign : Signs of clinical mortality and prolonged parturition( once a day)
Detailed clinical observation : Onec a week

Statistics:

liver discoloration (median, left lateral lobe –Animal No. 1203) at male 45 mg/kgㆍbw/day group,
small seminal vesicle, right –Animal No. 1402) at male 180 mg/kgㆍbw/day group, liver notch and discoloration
(whole lobe – Animal No. 2102) at female control group, kidney notch (both sides –Animal No. 2304) at female 90 mg/kgㆍbw/day.
Also, gross abnormalities were not observed in recovery group at any dose group

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

The treatment-related moribund (or dead) animals were not observed during the study
period.

Mortality:

no mortality observed

Description (incidence):

No evidence of death or death due to the administration of the test substance was observed in all test substance-treated groups.
In the case of general symptoms, salivation was observed in the main symptom observed during the administration period in the group treated with cancer 90 and 180 mg / kg · bw / day.

In male, the symptom was temporarily observed (3 days, 17 days; 1 day) in 3 of 90 mg / kg ㆍ bw / day administration group and 13 of 180 mg / kg bw / Were observed intermittently or continuously according to the duration of administration (17-49 days after administration, Animal No. 1406, 1411, 1414, 1416 exclusion animals).

In females, symptom was temporarily observed (from 36 to 49 days) in 4 of 90 mg / kg ' bw / day administration group, and in 9 of 180 mg / kg' bw / Intermittent
Or continuously observed.

In addition, in the 180 mg / kg bw / day administration group, the soiled perineal region; 2 female-Animal No. 2401 (15-17 days of administration), 2406 (15-19 days of administration)], tremor; 6 males - Animal No. 1401, 1407, 1409, 1411, 1415, 1416 (administration 40-47 days), female 3 animals - Animal No. 2413, 2414, 2417 (administration 40-49 days)], aggression [aggression; 1 male, Animal No. 1415 (43 to 49 days of administration)], staining around mouth; 1 female - Animal No. 2417 (41 days of administration)] were observed temporarily or intermittently.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

As a result of body weight measurement, no significant change was observed in males during the administration period and recovery period of the test substance administration group as compared with the control group.
In the case of females, the amount of body weight gain during the fermentation period was significantly decreased (89.6%, p <0.05) in the 180 mg / kg ㆍ bw / day group compared to the control group.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

In food consumption of parents, significantly increase was observed at male on
post-mating period (180 mg/kgㆍbw/day group; 3rd week; 18.3 %, recovery group; 2nd
week; 31.5%), pre-mating period (recovery group, pre-mating 2nd week; 0.5 %) (p <0.05).
In female of 180 mg/kgㆍbw/day group, significantly decreased (PND 0 – 1 day: 37.5 %,
PND 6 – 7 day: 40.6 %, PND 12 – 13 day: 46.6 %, p <0.05). And these observations were
similar to decrease body weight gain of an individual.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Haematological findings:

no effects observed

Description (incidence and severity):

There were no significant differences in treatment group of both sexes.
In recovery group, HGB was significantly increased in female at 180 mg/kgㆍbw/day. Also,
Lymph was significantly decreased in female at 180 mg/kgㆍbw/day (p <0.05).

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

In treatment group, T-BIL was significantly decreased in male at 180 mg/kgㆍbw/day
(p <0.05). Na was significantly decreased in male at 45, 180 mg/kgㆍbw/day and
female at 180 mg/kgㆍbw/day (p <0.05). CK was significantly decreased at female in
treatment group (p <0.05). In recovery group, BUN was significantly increased in female
at 180 mg/kgㆍbw/day (p <0.05).

Urinalysis findings:

no effects observed

Description (incidence and severity):

There were no significant difference compared control group to treatment group.

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

In absolute weight, there were significantly increased in Cowper's gland (right side;
male 45 mg/kgㆍbw/day), heart and thymus (female 180 mg/kgㆍbw/day) (p <0.05).
In relative weight, there were significantly increased in liver (male – 45, 180 mg/kgㆍ
bw/day), spleen (male – 180 mg/kgㆍbw/day), heart and thymus (female – 180 mg/kg
ㆍbw/day) (p <0.05). Besides, kidneys (left, both sides) were significantly decreased in
female at 180 mg/kgㆍbw/day. In recovery group, there were significantly decreased
(p <0.05) in testes (absolute – left, right, both sides) and epididymitis (absolute – left,
right, both sides, relative – right, both sides).
In thyroid gland, The thyroid gland was significantly decreased in absolute weight
(male; low dose – right, both sides, high dose – both sides, female; low dose and middle dose
– left, right, both sides, high dose – both sides) and relative weight
(male; low dose – left, right, both sides, middle dose – left, female; low dose - left,
right, both sides, middle and high dose – both sides). In recovery group, there was
significantly increased in female (180 mg/kgㆍbw/day) (p <0.05).

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

In reproductive organ, there were no treatment-related effects in both sexes of
treatment group.
In 180 mg/kgㆍbw/day group, lesions were observed in kidney (tubular basophilia; 1
male – Animal No. 1405, medullary mineralization; 2 females – Animal No. 2403, 2409),
adrenal gland (cortical vacuolation; 3 males – Animal No. 1401, 1403, 1409), heart
(myocardial inflammatory cell infiltration; 1 male – Animal No. 1405), prostate gland
(interstitial inflammatory cell infiltration; 1 male – Animal No. 1407).
In the case of necropsy findings, there was no abnormal lesions in the small seminal
vesicle (right, Animal No. 1402) and liver discoloration (Animal No. 2102). Besides, lesions
were observed as follows; parenchymal necrosis (liver, Animal No. 1203), cyst (kidney,
Animal No. 2304).
Also, there was no treatment-related effect in thyroid of pups (all treatment group).

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 180 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical biochemistry

clinical signs

food consumption and compound intake

haematology

organ weights and organ / body weight ratios

Target system / organ toxicity

Key result

Critical effects observed:

no

System:

female reproductive system

Applicant's summary and conclusion

Conclusions:

no repeated-dose toxicity of LiFSI was observed on 0, 45, 90 and 180
mg/kgㆍbw/day until pre-mating, mating, post-natal day 13. However, toxicological
effects of reproductive/developmental toxicity were observed in live birth index (PND
0), viability index (PND 4), number of pup (PND 4) on 180 mg/kgㆍbw/day group (high
dose). In conclusion, the NOAEL (No Observed Adverse Effect Level) for repeated-dose
toxicity was 180 mg/kgㆍbw/day and the NOAEL for reproductive/developmental toxicity
was 90 mg/kgㆍbw/day.