1H-Imidazole-4,5-dicarbonitrile, 2-(trifluoromethyl)-, lithium salt (1:1)

Endpoint summary

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:

06 February 2014 -- 12 May 2014

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:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: breeder: Janvier, Le Genest-Saint-Isle, France.
- Age at study initiation: approximately 8 weeks old on the day of treatment
- Mean body weight at study initiation: 188 g (range: 168 g to 202 g)
- Fasting period before study: yes, during the night before treatment
- Housing: polycarbonate cages with stainless steel lids
- Diet: SSNIFF R/M-H pelleted diet (free access)
- Water: tap water filtered with a 0.22 µm filter (free access)
- Acclimation period: at least 5 days before the beginning of the study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 50 ± 20%
- Air changes (per hr): approximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12 h/12 h

IN-LIFE DATES: 18 March 2014 to 16 April 2014

Route of administration:

oral: gavage

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg/mL
- Justification for choice of vehicle: the first choice vehicle was drinking water treated by reverse osmosis.
- Maximum dose-volume applied: 10 mL/kg

DOSAGE PREPARATION (if unusual): the test item was administered as a solution in the vehicle. The test item was mixed with the required quantity of vehicle under magnetic agitation.
Fresh dose formulations were prepared by the CiToxLAB France Pharmacy on the day of each administration and kept at room temperature prior to administration.

CLASS METHOD (if applicable):
- Rationale for the selection of the starting dose: based on the chemical structure, morbidity or mortality was expected to occur at the dose-level of 2000 mg/kg. Therefore, the starting dose-level was 300 mg/kg.

Doses:

50 and 300 mg/kg

No. of animals per sex per dose:

three females per treatment step

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Clinical observations: frequently during the hours following treatment; then, at least once a day.
- Body weight: the day of group allocation, just before treatment on day 1; then on days 8 and 15.
- Necropsy of survivors performed: yes (macroscopic).

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 50 - < 300 mL/kg bw

Based on:

test mat.

Mortality:

At 300 mg/kg, all animals died after treatment on Day 1.
At 50 mg/kg, no death occurred.

Clinical signs:

other: At 300 mg/kg, abnormal vocalization, lateral recumbency and tonic seizures were observed prior to death. At 50 mg/kg, hypoactivity was noted in all animals on Day 1. Piloerection and hunched posture were observed in 3/6 animals and tonic seizures in 1/6 a

Gross pathology:

There were no gross post-mortem findings.

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

Under the experimental conditions of this study, the oral LD50 of the test item, was comprised between 50 and 300 mg/kg in rats.

Executive summary:

The objective of this study was to evaluate the potential acute toxicity of Lithium 4,5-dicyano 2-(trifluomethyl) imidazolate, following a single oral administration (gavage) to rats. This study was conducted in compliance with the OECD Guideline No. 423 and the principles of Good Laboratory Practice. The test item was administered once by oral route (gavage) to three groups of three fasted female Sprague-Dawley rats under a dosage-volume of 10 mL/kg. The test item was prepared in drinking water treated by reverse osmosis. Based on available test item toxicity data, the starting dose-level was 300 mg/kg. In view of mortality observed at 300 mg/kg, the next lower dose-level of 50 mg/kg was tested. Then, as no toxicity was observed at this lower dose-level, the results were confirmed in other females. Each animal was observed at least once a day for mortality and clinical signs for 15 days. Body weight was recorded on Day 1 and then on Days 8 and 15. On completion of the observation period, the animals were sacrificed and then submitted for a macroscopic post-mortem examination. No tissues were preserved.
At 300 mg/kg, all animals died after treatment on Day 1. Abnormal vocalization, lateral recumbency and tonic seizures were observed within 30 minutes after treatment. At 50 mg/kg, no deaths occurred. On Day 1, hypoactivity was noted in all animals. Piloerection, hunched posture and tonic seizure were also observed in a few animals. No clinical signs were noted thereafter. A moderate lower body weight gain was noted in one female treated at 50 mg/kg, when compared to CiToxLAB France historical control data. Under the experimental conditions of this study, the oral LD50 of Lithium 4,5-dicyano 2-(trifluomethyl) imidazolate, was comprised between 50 and 300 mg/kg in rats.

 

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

discriminating dose

Value:

50 mg/kg bw

Quality of whole database:

Key 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:

22 April 2014 -- 27 May 2014

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: breeder: Janvier, Le Genest-Saint-Isle, France
- Age/Mean body weight at study initiation: on the day of treatment, the animals were approximately 8 (groups 1 and 3) or 9 (group 2) weeks. The males had a mean body weight of 370 g (range: 354 g to 380 g) and the females had a mean body weight of 215.4 g (range: 206 g to 230 g).
- Fasting period before study: yes, during the night before treatment
- Housing: polycarbonate cages
- Diet: SSNIFF R/M-H pelleted diet (free access)
- Water: tap water filtered with a 0.22 µm filter (free access)
- Acclimation period: at least 5 days before the beginning of the study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 50 ± 20%
- Air changes (per hr): approximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12 h/12 h

IN-LIFE DATES: 23 April 2014 to 27 May 2014

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: 10% of body surface, dorsal site
- Type of wrap if used: hydrophilic gauze pad + adhesive hypoallergenic aerated semi-occlusive dressing + restraining bandage

REMOVAL OF TEST SUBSTANCE
- Removal of dressing: 24h post-exposure
- Washing: at 24h post-exposure, with a moistened cotton pad with water for injection (only in females)

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg
- Constant volume: no

Doses:

2000 mg/kg

No. of animals per sex per dose:

Ten Sprague-Dawley rats (five males and five nulliparous and non pregnant females)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Clinical observations: frequently during the hours following treatment; then, at least once a day.
- Body weight: just before treatment, on day 1; then on days 8 and 15.
- Necropsy of survivors performed: yes (macroscopic).

Sex:

male/female

Dose descriptor:

LD0

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No unscheduled deaths occurred during the study.

Clinical signs:

other: No clinical signs indicative of systemic toxicity were observed in any animals and no cutaneous reactions were observed in males. An erythema was noted in all females from Day 2 or 3 until Day 7 at the latest or on Day 7 only and was associated with dryne

Gross pathology:

There were no macroscopic findings at necropsy.

Interpretation of results:

GHS criteria not met

Conclusions:

Under the experimental conditions of this study, the dermal LD50 of the test item was higher than 2000 mg/kg in rats. Since there was no mortality in the study, the dermal LD0, was also higher than 2000 mg/kg in rats.

Therefore, the test item should not be classified for the acute dermal toxicity according to the criteria of CLP Regulation.

Executive summary:

The objective of this study was to evaluate the potential toxicity of Lithium 4,5-dicyano 2-(trifluomethyl) imidazolate following a single dermal application to rats. This study was conducted in compliance with OECD Guideline No. 402 and the principles of Good Laboratory Practices. The test item was applied in its original form to the skin of one female in the first instance, after four female then five male Sprague-Dawley rats at the dose-level of 2000 mg/kg. The application site was covered by a semi-occlusive dressing for 24 hours. Each animal was observed at least once a day for mortality and clinical signs for 15 days. From Day 2, any local reactions at the treatment site were also noted. Body weight was recorded on Day 1 and then on Days 8 and 15. On completion of the observation period, the animals were sacrificed and then submitted for a macroscopic post-mortem examination. No tissues were preserved.

No unscheduled deaths occurred during the study. No clinical signs indicative of systemic toxicity were observed in any animals. No cutaneous reactions and no body weight changes were observed in males. An erythema was noted in all females from Day 2 until Day 7 at the latest. This was associated with dryness from Day 3 until Day 15 at the latest. On Day 15, a lower body weight and a lower body weight gain between Day 1 and Day 15 were noted in females. The test item did not induce any macroscopic findings at necropsy.

Under the experimental conditions of this study, the dermal LD50 of Lithium 4,5-dicyano 2-(trifluomethyl) imidazolate was higher than 2000 mg/kg in rats. Since there was no mortality in the study, the dermal LD0, was also higher than 2000 mg/kg in rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

Key study

Additional information

Oral route

The potential acute toxicity of Lithium 4,5-dicyano 2-(trifluomethyl) imidazolate was evaluated following a single oral administration (gavage) to rats. This study was conducted in compliance with the OECD Guideline No. 423 and the principles of Good Laboratory Practice. The test item was administered once by oral route (gavage) to three groups of three fasted female Sprague-Dawley rats under a dosage-volume of 10 mL/kg. The test item was prepared in drinking water treated by reverse osmosis. Based on available test item toxicity data, the starting dose-level was 300 mg/kg. In view of mortality observed at 300 mg/kg, the next lower dose-level of 50 mg/kg was tested. Then, as no toxicity was observed at this lower dose-level, the results were confirmed in other females. Each animal was observed at least once a day for mortality and clinical signs for 15 days. Body weight was recorded on Day 1 and then on Days 8 and 15. On completion of the observation period, the animals were sacrificed and then submitted for a macroscopicpost-mortemexamination. No tissues were preserved.

At 300 mg/kg, all animals died after treatment on Day 1. Abnormal vocalization, lateral recumbency and tonic seizures were observed within 30 minutes after treatment. At 50 mg/kg, no deaths occurred. On Day 1, hypoactivity was noted in all animals. Piloerection, hunched posture and tonic seizure were also observed in a few animals. No clinical signs were noted thereafter. A moderate lower body weight gain was noted in one female treated at 50 mg/kg, when compared to CiToxLAB France historical control data. Under the experimental conditions of this study, the oral LD50 of Lithium 4,5-dicyano 2-(trifluomethyl) imidazolate, was comprised between 50 and 300 mg/kg in rats.

Dermal route

The potential toxicity of Lithium 4,5-dicyano 2-(trifluomethyl) imidazolate was evaluated following a single dermal application to rats. This study was conducted in compliance with OECD Guideline No. 402 and the principles of Good Laboratory Practices. The test item was applied in its original form to the skin of one female in the first instance, after four female then five male Sprague-Dawley rats at the dose-level of 2000 mg/kg. The application site was covered by a semi-occlusive dressing for 24 hours. Each animal was observed at least once a day for mortality and clinical signs for 15 days. From Day 2, any local reactions at the treatment site were also noted. Body weight was recorded on Day 1 and then on Days 8 and 15. On completion of the observation period, the animals were sacrificed and then submitted for a macroscopicpost-mortemexamination. No tissues were preserved.

No unscheduled deaths occurred during the study. No clinical signs indicative of systemic toxicity were observed in any animals. No cutaneous reactions and no body weight changes were observed in males. An erythema was noted in all females from Day 2 until Day 7 at the latest. This was associated with dryness from Day 3 until Day 15 at the latest. On Day 15, a lower body weight and a lower body weight gain between Day 1 and Day 15 were noted in females. The test item did not induce any macroscopic findings at necropsy.

Under the experimental conditions of this study, the dermal LD50 of Lithium 4,5-dicyano 2-(trifluomethyl) imidazolate was higher than 2000 mg/kg in rats. Since there was no mortality in the study, the dermal LD0, was also higher than 2000 mg/kg in rats.

Lithium 4,5-dicyano 2-(trifluomethyl) imidazolate should not be classified for the acute dermal toxicity according to the criteria of CLP Regulation.

Justification for classification or non-classification

According to the criteria of CLP/GHS Regulations, Lithium 4,5-dicyano 2-(trifluomethyl) imidazolate

should be classified category 3 and assigned the signal word "danger" and the hazard statement "H301: Toxic if swallowed". 

Lithium 4,5-dicyano 2-(trifluomethyl) imidazolate should not be classified for the acute dermal toxicity according to the criteria of CLP/GHS Regulations.