1,2-dimethyl-3-propyl imidazolium bis((trifluoromethyl)sulfonyl)amide

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

06 SEP 2016 - 04 OCT 2016

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2016

Report date:

2016

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes (incl. QA statement)

Remarks:

GROUPE INTERMINISTERIEL DES PRODUITS CHIMIQUES, France

Test type:

acute toxic class method

Test material

Test material information

Constituent 1

Reference substance name:

1,2-dimethyl-3-propyl imidazolium bis((trifluoromethyl)sulfonyl)amide

EC Number:

805-807-9

Cas Number:

169051-76-7

Molecular formula:

C10H15F6N3O4S2

IUPAC Name:

1,2-dimethyl-3-propyl imidazolium bis((trifluoromethyl)sulfonyl)amide

Test material form:

liquid

Details on test material:

Appearance : colorless oil
Composition: a base stock containing (C, 28.64; H, 3.61; F, 27.18; N, 10.02; O, 15.26; S, 15.29)
Molecular formula : C10H15F6N3O4S2
Molecular Weight : 419.12 g/mol
Purity >99% (purity determined by MNR)
Homogeneity : homogeneous

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Sponsor's batch N° L16-0587
- Expiration date of the lot/batch: 02 Jan 2030

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- a part of the test item was diluted in dimethyl sulfoxide. the preparations were stirred by vortex to obtained colorless solutions just before administration.
- an other part of the test item is used as supplied.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Elevage JANVIER LABS (F-53941 Le Genest St Isle)
- Females nulliparous and non-pregnant: Yes
- Age at study initiation: 8 weeks
- Weight at study initiation: mean 197.7 mg SD 1.5 (animals Rf0263-Rf0265; step 1) , mean 204.7 mg SD 7.5 (animals Rf0323-Rf0325 and Rf0383-Rf0385 ; steps 3 and 4)
- Fasting period before study: no
- Housing: by group of three in solid-bottomed clear polycarbonate cages with a stainless steel mesh lid. Each cage contains sawdust bedding wich was changed at least 2 times a week.
- Diet: 2016 Teklad global 16% protein rodent diets (ENVIGO) ad libitum
- Water: drinking water (tap-water from public distribution) ad libitum
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25 °C
- Humidity (%): 30-70%
- Air changes (per hr): at least ten
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: In the first step of the study : unchanged. In the third and fourth step of the study : DMSO

Details on oral exposure:

In the first step of the study, the test item was administrated by gavage under a volume of 1.34 mL/kg body weight (corresponding to 2 g/kg, according to the calculated density) using a suitable graduated syringe fitted with an oesophageal metal canula.

In the third and fourth step of the study, 0.42 mL and 0.21 mL of the test item (corresponding to 600 mg and 300 mg)were added to 2.40 mL and 1.20 mL of dimetyl sulfoxide, respectively.The preparation were stirred by vortex to obtain colorless solutions just before the administration. Each preparation was administrated under a volume of 1.41 ml/kg (corresponding to 300 mg/kg) body weight using a suitable graduated syringe fitted with an oesophageal metal canula.

Doses:

Step 1: 2000 mg/kg bw
Steps 3 and 4: 300 mg/kg bw

No. of animals per sex per dose:

3 per step

Control animals:

yes

Remarks:

three animals, received the control item Diethyl sulfoxide, administrated by gavage under a volume of 10 ml/kg body weight. study dates: 20 SEP 2016 to 04 OCT 2016

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: animals were observed 0.5, 1, 3 and 4 h after substance administration and daily thereafter; individual body weights were determined on Day 0 (prior to substance administration), 2, 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: systematic examinations to identify any behavioural or toxic effects, macroscopical examination of oesophagus, stomach, duodenum, jejunum, ileon, caecum, colon, rectum, spleen, liver, thymus, trachea, lungs, heart, kidneys, urinary bladder, ovaries, uterus, adrenals and pancreas.

Results and discussion

Effect levels

Effect levels 1

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 300 - < 2 000 mg/kg bw

Based on:

test mat.

Effect levels 2

Sex:

female

Dose descriptor:

LD50 cut-off

Effect level:

500 mg/kg bw

Based on:

test mat.

Mortality:

Step 1 (2000 mg/kg bw): 3 females died at T0+1h
Step 3 (300 mg/kg): 1 females died at T0+3h
Step 4 (300 mg/kg): 1 femal died at T0+24h

Clinical signs:

other: Step 1: the mortalities were preceded by an absence or decrease in spontaneous activity (3/3), muscle tones (3/3), righting reflex (3/3), associated with clonic convulsions (3/3), eyes partly closed (3/3), polypnea (3/3), decrease of body temperature (3/3

Gross pathology:

Step 1: The macroscopic exmination of the animals did not reveal treatment related changes except a red coloration of the lungs and the liver.
Step 3 and 4: The macroscopic exmination of the animals dead during the test revealed in one of them (1/2) a thinning of the forestomach and red foci on the corpus. the macroscopic examination of the surviving animals at the end of the study did not reveal treatment related changes.

Any other information on results incl. tables

TOXICITY LEXICON
Spontaneous activity	Normal (N)	decreased (D)	Increased (A)	None(0)
Preyer's reflex (noise)	Normal (N)	None(0)	decreased (D)
Respiratory Rate	Normal (N)	Dyspnea (D)	Bradypnea (B)	polypnea (P)
Convulsions	None(0)	Tonic (T)	Clonic (C )
tremors	None(0)	Tremors (tr)
Body Temperature	Normal (N)	Hypothermia (D)	Hyperthermia (A)
Muscle tone	Normal (N)	decreased (D)	Increased (A)	None(0)
Palpebral Opening	Normal (N)	Eye partly closed (Pc)	Eye completely closed (Cc)
Pulpil Appearance	Normal (N)	Mydriasis (Md)	Myosis (Ms)
Salivation	Normal (N)	Increased (A)
Lachrymation	Normal (N)	Increased (A)
Rightening Reflex	Normal (N)	Limited(D)	None(0)
Back Hair Appearance	Normal (N)	Piloerection (Pi)

OBSERVATION DATA

Dose 200 mg/kg body weight

D0: 06 September 2016 (step 1)

OBSERVATIONS :	FEMALES
T0 + 30 minutes	Rf 0263	Rf 0264	Rf 0265
Spontaneous activity	0	0	v
Preyer's reflex (noise)	N	N	N
Respiratory Rate	P	P	P
Convulsions	C	C	C
tremors	N	N	N
Body Temperature	D	D	D
Muscle tone	0	0	0
Palpebral Opening	Pc	Pc	Pc
Pulpil Appearance	Md	Md	Md
Salivation	N	N	N
Lachrymation	N	N	N
Rightening Reflex	D	D	D
Back Hair Appearance	N	N	N
MORTALITY	0	0	0
remarks	None

Dose 200 mg/kg body weight

D0: 06 September 2016 (step 1)

OBSERVATIONS :	FEMALES
T0 + 1 hour	Rf 0263	Rf 0264	Rf 0265
Spontaneous activity
Preyer's reflex (noise)
Respiratory Rate
Convulsions
tremors
Body Temperature
Muscle tone
Palpebral Opening
Pulpil Appearance
Salivation
Lachrymation
Rightening Reflex
Back Hair Appearance
MORTALITY	1	1	1
remarks	All animals found dead at  T0 + 1 hour

Dose 300 mg/kg body weight

D0: 13 September 2016 (step 3) &  20 September 2016 (step 4)

OBSERVATIONS :	FEMALES			FEMALES
T0 + 30 minutes	Rf 0323	Rf 0324	Rf 0325	Rf 0383	Rf 0384	Rf 0385
Spontaneous activity	N	D	N	N	N	N
Preyer's reflex (noise)	N	N	N	N	N	N
Respiratory Rate	N	N	N	N	N	N
Convulsions	N	T	N	N	N	N
tremors	N	N	N	N	N	N
Body Temperature	N	N	N	N	N	N
Muscle tone	N	N	N	N	N	N
Palpebral Opening	N	N	N	N	N	N
Pulpil Appearance	Ms	N	Ms	N	N	N
Salivation	N	N	N	N	N	N
Lachrymation	N	N	N	N	N	N
Rightening Reflex	N	N	N	N	N	N
Back Hair Appearance	N	N	N	N	N	N
MORTALITY	0	0	0	0	0	0
remarks	None			None

Dose 300 mg/kg body weight

D0: 13 September 2016 (step 3) &  20 September 2016 (step 4)

OBSERVATIONS :	FEMALES			FEMALES
T0 + 1 hour	Rf 0323	Rf 0324	Rf 0325	Rf 0383	Rf 0384	Rf 0385
Spontaneous activity	D	D	D	D	N	N
Preyer's reflex (noise)	N	N	N	N	N	N
Respiratory Rate	N	N	N	N	N	N
Convulsions	N	T	N	N	N	N
tremors	N	N	N	N	N	N
Body Temperature	N	N	N	N	N	N
Muscle tone	N	D	N	N	N	N
Palpebral Opening	N	N	N	N	N	N
Pulpil Appearance	Ms	Md	Ms	N	N	N
Salivation	N	A	N	N	N	N
Lachrymation	N	N	N	N	N	N
Rightening Reflex	N	N	N	N	N	N
Back Hair Appearance	N	N	N	N	N	N
MORTALITY	0	0	0	0	0	0
remarks	None			None

Dose 300 mg/kg body weight

D0: 13 September 2016 (step 3) &  20 September 2016 (step 4)

OBSERVATIONS :	FEMALES			FEMALES
T0 + 3 hours	Rf 0323	Rf 0324	Rf 0325	Rf 0383	Rf 0384	Rf 0385
Spontaneous activity	D		D	D	D	D
Preyer's reflex (noise)	N		N	N	N	N
Respiratory Rate	N		N	N	N	N
Convulsions	N		T	N	T	N
tremors	N		N	N	N	N
Body Temperature	N		N	N	N	N
Muscle tone	D		D	D	0	D
Palpebral Opening	N		N	N	Pc	N
Pulpil Appearance	Ms		Ms	Md	Md	Md
Salivation	N		N	N	N	N
Lachrymation	N		N	N	N	N
Rightening Reflex	N		N	D	0	D
Back Hair Appearance	N		N	N	N	N
MORTALITY	0	1	0	0	0	0
remarks	Rf0324: found dead at  T0 + 3 hours			None

Dose 300 mg/kg body weight

D0: 13 September 2016 (step 3) &  20 September 2016 (step 4)

OBSERVATIONS :	FEMALES			FEMALES
T0 + 4 hours	Rf 0323	Rf 0324	Rf 0325	Rf 0383	Rf 0384	Rf 0385
Spontaneous activity	D		D	D	D	D
Preyer's reflex (noise)	N		N	N	N	N
Respiratory Rate	N		N	N	N	N
Convulsions	N		N	T	T	N
tremors	N		N	N	N	N
Body Temperature	N		N	N	N	N
Muscle tone	D		D	D	D	D
Palpebral Opening	N		N	Pc	Pc	Pc
Pulpil Appearance	Ms		Ms	Ms	Ms	Ms
Salivation	N		N	N	A	N
Lachrymation	N		N	N	N	N
Rightening Reflex	N		N	D	D	D
Back Hair Appearance	Pi		Pi	Pi	Pi	Pi
MORTALITY	0		0	0	0	0
remarks	None			None

Dose 300 mg/kg body weight

D0: 13 September 2016 (step 3) &  20 September 2016 (step 4)

OBSERVATIONS :	FEMALES			FEMALES
D1 to D14	Rf 0323	Rf 0324	Rf 0325	Rf 0383	Rf 0384	Rf 0385
Spontaneous activity	N		N	N		N
Preyer's reflex (noise)	N		N	N		N
Respiratory Rate	N		N	N		N
Convulsions	N		N	N		N
tremors	N		N	N		N
Body Temperature	N		N	N		N
Muscle tone	N		N	N		N
Palpebral Opening	N		N	N		N
Pulpil Appearance	N		N	N		N
Salivation	N		N	N		N
Lachrymation	N		N	N		N
Rightening Reflex	N		N	N		N
Back Hair Appearance	N		N	N		N
MORTALITY	0		0	0	1	0
remarks	None			Rf0384 found dead at  T0 + 23 hours and 33 minutes

BODY WEIGHT EVOLUTION

Dose 200 mg/kg body weight

D0: 06 September 2016 (step 1)

FEMALES	D0	D2	D2-D0	d7	D7-D0	D14	D14-D0
Rf 0263	199	†
Rf 0264	196	†
Rf 0265	198	†
MEAN	197.7
Standard deviation	1.5

Dose 300 mg/kg body weight

D0: 13 September 2016 (step 3) &  20 September 2016 (step 4)

FEMALES	D0	D2	D2-D0	d7	D7-D0	D14	D14-D0
Rf 0323	211	227	16	250	39	268	57
Rf 0324	198	†
Rf 0325	214	227	13	249	35	272	58
Rf 0383	195	207	12	235	40	256	61
Rf 0384	202	†
Rf 0385	208	227	19	251	43	275	67
MEAN	204.7	222.0	15.0	246.3	39.3	267.8	60.8
Standard deviation	7.5	10.0	3.2	7.5	3.3	8.3	4.5

NECROPSY DATA

3 females Rf0263 to Rf0265; 2000mg/kg; found dead

	Observed  Organs	Observations
Oesophagus	x	Nothing to report
stomach	x	Nothing to report
Duodenum	x	Nothing to report
jejunum	x	Nothing to report
ileon	x	Nothing to report
caecum	x	Nothing to report
colon	x	Nothing to report
rectum	x	Nothing to report
spleen	x	Nothing to report
liver	x	Red colored
thymus	x	dark
trachea	x	Nothing to report
lungs	x	Red colored
heart	x	Nothing to report
kidneys	x	Nothing to report
urinary bladder	x	Nothing to report
ovaries	x	Nothing to report
uterus	x	Nothing to report
treatment area	-	-
adrenals	x	Nothing to report
pancreas	x	Nothing to report
Particulars: None

1 female Rf0324; 300mg/kg; found dead

	Observed  Organs	Observations
Oesophagus	x	Nothing to report
stomach	x	Thinning of the forestomach, red spots on the corpus
Duodenum	x	Nothing to report
jejunum	x	Nothing to report
ileon	x	Nothing to report
caecum	x	Nothing to report
colon	x	Nothing to report
rectum	x	Nothing to report
spleen	x	Nothing to report
liver	x	Nothing to report
thymus	x	Nothing to report
trachea	x	Nothing to report
lungs	x	Nothing to report
heart	x	Nothing to report
kidneys	x	Nothing to report
urinary bladder	x	Nothing to report
ovaries	x	Nothing to report
uterus	x	Nothing to report
treatment area	-	-
adrenals	x	Nothing to report
pancreas	x	Nothing to report
Particulars: None

1 female Rf0384; 300mg/kg; found dead

	Observed  Organs	Observations
Oesophagus	x	Nothing to report
stomach	x	Nothing to report
Duodenum	x	Nothing to report
jejunum	x	Nothing to report
ileon	x	Nothing to report
caecum	x	Nothing to report
colon	x	Nothing to report
rectum	x	Nothing to report
spleen	x	Nothing to report
liver	x	Nothing to report
thymus	x	Nothing to report
trachea	x	Nothing to report
lungs	x	dark
heart	x	Nothing to report
kidneys	x	Nothing to report
urinary bladder	x	Nothing to report
ovaries	x	Nothing to report
uterus	x	Nothing to report
treatment area	-	-
adrenals	x	Nothing to report
pancreas	x	Nothing to report
Particulars: None

4 females Rf0323, Rf0325, Rf0383, Rf0385 ; 300mg/kg; surviving animals

	Observed  Organs	Observations
Oesophagus	x	Nothing to report
stomach	x	Nothing to report
Duodenum	x	Nothing to report
jejunum	x	Nothing to report
ileon	x	Nothing to report
caecum	x	Nothing to report
colon	x	Nothing to report
rectum	x	Nothing to report
spleen	x	Nothing to report
liver	x	Nothing to report
thymus	x	Nothing to report
trachea	x	Nothing to report
lungs	x	Nothing to report
heart	x	Nothing to report
kidneys	x	Nothing to report
urinary bladder	x	Nothing to report
ovaries	x	Nothing to report
uterus	x	Nothing to report
treatment area	-	-
adrenals	x	Nothing to report
pancreas	x	Nothing to report
Particulars: None

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The LD50 of the test item 1-propyl-2,3-dimethylimidazolium bis(trifluoromethanesulfonyl)imide is higher than 300 mg/kg body weight and lower than 2000 mg/kg by oral route in rat. In accordance with O.E.C.D Test Guideline No. 423, the LD50 cut-off of the test item may be considered as 500 mg/kg body weight by oral route in rat.
According to CLP, 1-propyl-2,3-dimethylimidazolium bis(trifluoromethanesulfonyl)imide has to be classified Acute oral 4. The signal word "warning" and hazard statement H302 "harmful if swallowed" are required.

Executive summary:

The test item 1-propyl-2,3-dimethylimidazolium bis(trifluoromethanesulfonyl)imide was administrated to a group of 3 female sprague Dawley rats at the dose of 2000 mg/kg body weight and then to a group of 6 female sprague Dawley rats at the dose of 300 mg/kg body weight. The experimental protocol was established according to the official method as defined in the O.E.C.D. Test Guidline No. 423 dated december 17th, 2001 and the test method B. a tris of the Council regulation No. 440/2008.

Three mortalities were noted in animals treated at the dose of 200 mg/kg body weight, at one post dose.
The mortalities were preceded by an absence or decreased in spontaneous activity (3/3), muscle tones (3/3), righting reflex (3/3), associated with clonic convulsions (3/3), eyes partly closed (3/3), polypnea (3/3), decrease of body temperature (3/3), and mydriasis (3/3). Rigor mortis were noted before the necroscopy (3/3).
The macroscopic examination of the animals did not reveal treatment related changes except a red coloration of the lungs and the liver.

Two mortalities were noted in animals treated at the dose of 300 mg/kg body weight, one at the three hours post dose during the 3rd step and another one at 24 hours post dose during the 4th step. The mortalities were preceded by an absence or decrease in spontaneous activity (2/2), muscle tones (2/2), associated with clonic convulsions (2/2), eyes partly closed (2/2), salivation (2/2), mydriasis (1/2), myosis (1/2), and piloerection(1/2). Rigor mortis were noted before the necroscopy (2/2).

The macroscopic examination of the animals (4/6) revealed in one of them (1/2) a thinning of the forestomach and red foci of the corpus.

In the surviving animals (4/6), a decrease in in spontaneous activity (4/4) and in muscle tones (4/4), tonic convulsions (2/4) associated with piloerection (4/4), myosis and/or mydriasis (4/4), eye partially closed (2/4) were noted during the first hours of the test. The animals recovered a normal activity at 24 hours post dose.

The macroscopic examination of the animals at the end of the study did not reveal treatment related changes.

In conclusion, the LD50 of the test item 1 -propyl-2,3-dimethylimidazolium bis(trifluoromethanesulfonyl)imide is higher than 300 mg/kg body weight and lower than 2000 mg/kg by oral route in rat. In accordance with O.E.C.D Test Guideline No. 423, the LD50 cut-off of the test item may be considered as 500 mg/kg body weight by oral route in rat.

According to the criteria for classification, packaging and labelling of dangerous substances and preparations in accordance with the Regulation EC No. 1272/2008, the test item 1-propyl-2,3-dimethylimidazolium bis(trifluoromethanesulfonyl)imide has to be classified in category 4. The signal word "warning" and hazard statement H302 "harmful if swallowed" are required.