α-(2,4-dichlorophenyl)-1H-imidazole-1-ethanol

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From February 25th to March 22nd, 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 420 (Acute Oral Toxicity - Fixed Dose Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

α-(2,4-dichlorophenyl)-1H-imidazole-1-ethanol

EC Number:

246-042-5

EC Name:

α-(2,4-dichlorophenyl)-1H-imidazole-1-ethanol

Cas Number:

24155-42-8

Molecular formula:

C11H10Cl2N2O

IUPAC Name:

1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethan-1-ol

Test material form:

solid: particulate/powder

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Husbandry of laboratory animals of the Experimental Medicine Centre at the Medical University in Białystok.
- Females nulliparous and non-pregnant: yes
- Age and weight at study initiation: Two 11-week-old animal weighing 205.0 and 219.0 g (dose of 300 and 2000 mg/kg bw respectively) were used in the preliminary experiment, and four 12-week-old animals, whose average body weight was 213.0 g (dose of 2000 mg/kg b.w.) were used in the main experiment.
- Fasting period before study: 19 hours
- Housing: The animals were kept in plastic cages covered with wire bar lids. The dimensions of the cages were 58 x 37 x 21 cm. In the preliminary experiment, the animals were caged individually. In the main experiment, there were four animals in one cage. UV-sterilized wood shavings were used as bedding. The environment of the animals was enriched by placing wooden blocks and nesting materials for laboratory animals in the cages.
- Diet (e.g. ad libitum): Murigran standard granulated laboratory fodder ad libitum.
- Water (e.g. ad libitum): Tap water ad libitum.
- Acclimation period: 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-23ºC
- Humidity (%): 28-55%
- Air changes (per hr): 16 times/hour
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 60mg/mL (300 mg/kg bw) and 400 mg/mL (2000 mg/kg bw)
- Amount of vehicle (if gavage): 1 mL
- Justification for choice of vehicle: Low water solubility.
- Other: The suspensions were prepared on the administration day (shortly before the administration).

MAXIMUM DOSE VOLUME APPLIED: 0.5 mL/100 g bw

Doses:

Preliminary test: 300 mg/kg bw and 2000 mg/kg bw.
Main test: 2000 mg/kg bw.

No. of animals per sex per dose:

One female was used for the preliminary experiment at 300 mg/kg bw. One female was then used at 2000 mg/kg bw.
Based on the results, four additional females were used at 2000 mg/kg bw in the main experiment.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: General condition of the animals at least once a day, clinical detailed observations on day 0: 10, 30 and 60 minutes after the administration and then at hourly intervals up to 5th hour after the administration of the test item. Thereafter once a day from the day 1 to the day 14. Weight was determined on day 0 (directly before administration), 7 and 14 before euthanasia.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross examinations.

Results and discussion

Preliminary study:

Since no data were available, the preliminary experiment started with the administration of the test item at a dose of 300 mg/kg b.w. to one animal.
Since no evident toxicity was observed in dose 300 mg/kg bw, the test item at a single dose of 2000 mg/k g b.w. was administered to the second animal.
On the grounds of the preliminary experiment results, the dose of 2000 mg/kg bw was selected to be used in the main experiment and it was applied to four further rats.

Effect levels

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

One animal (1/5) died on the third day after administration of the test item at a dose of 2000 mg/kg bw.

Clinical signs:

other: Following administration of the test item at a single dose of 2000 mg/kg bw, the following changes were observed on the day of administration of the test item: rounded back, slightly decreased locomotor activity, bristled coat. In two animals distinct dec

Gross pathology:

In the preliminary experiments gross examinations did not reveal any pathological changes in the examined animals (one animal received 300 mg/kg bw and other 2000 mg/kg bw). In the main experiment (four animals 2000 mg/kg bw) the female no. 4, died during the experiment. The macroscopic examination showed porphyrin deposition around the eyes. No pathological changes were noticed in the remaining animals

Any other information on results incl. tables

Table 1. Acute oral toxicity results in rats.

	Preliminary experiment		Main experiment
Test item (mg/kg bw)	300	2000	2000
Mortality	0/1	0/1	1/4
Clinical signs	No	Rounded back; slight, and then distinct decreases of locomotor activity, bristled coat.	In all animals: Rounded back, slight decreases of locomotor activity, bristled coat.
			In two animals (no. 4, 5): distinct decreases of locomotor activity.
			In one animal (no.4): wavering gait, animal lying on one side, animal could be easy to catch, no reaction to sound stimuli, porphyrin deposition around the eyes.

 

Table 2. Body weights of the animals, overall list

Dose (mg/kg b.w.)	Animal number	Day of the experiment			Body weight gain (g) 0 to14
		0	7	14
300	1*	205	223	237	32
2000	1*	219	238	248	29
	2	212	229	237	25
	3	210	234	235	25
	4	218	195**	-	-
	5	212	227	247	35

* Females from the preliminary experiment

** Animal body weight after death       

Table 3. Clinical signs, overall list.

Dose (mg/kg bw)	Day after Administration	No. of living Animals	Animal number
			1*	2	3	4	5
300	0	1	NC
	1	1	NC
	2	1	NC
	3	1	NC
	4	1	NC
	5	1	NC
	6	1	NC
	7	1	NC
	8	1	NC
	9	1	NC
	10	1	NC
	11	1	NC
	12	1	NC
	13	1	NC
	14	1	NC
2000	0	5	SIGNS	SIGNS	SIGNS	SIGNS	SIGNS
	1	5	SIGNS	NC	NC	SIGNS	NC
	2	5	SIGNS	NC	NC	SIGNS	NC
	3	4	SIGNS	NC	NC	D	NC
	4	4	SIGNS	NC	NC	-	NC
	5	4	SIGNS	NC	NC	-	NC
	6	4	NC	NC	NC	-	NC
	7	4	NC	NC	NC	-	NC
	8	4	NC	NC	NC	-	NC
	9	4	NC	NC	NC	-	NC
	10	4	NC	NC	NC	-	NC
	11	4	NC	NC	NC	-	NC
	12	4	NC	NC	NC	-	NC
	13	4	NC	NC	NC	-	NC
	14	4	NC	NC	NC	-	NC

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Remarks:

EU criteria

Conclusions:

The oral LD50 for the test substance in female rats was superior to 2000 mg/kg bw.

Executive summary:

The potential acute toxicity of the test item was studied on female Wistar rats, according to OECD TG 420, under GLP conditions. Since no data on acute toxicity was available, the first dose used in the preliminary test was 300 mg/kg bw test item in corn oil. As no evident toxicity was observed at this dose, a second animal was administered 2000 mg/kg bw test item. Based on the preliminary test results, the main experiment was performed by administering a single dose of 2000 mg/kg bw test item to four animals. Following administration, changes in body posture, locomotor activity, and bristled coat were observed in all animals. One animal died on the third day after the administration of the test item, the remaining animals survived the experiment and showed no pathological changes upon necrosis. Based on the results, the oral LD50 was found to be > 2000 mg/kg bw.