Registration Dossier
Registration Dossier
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EC number: 952-948-8 | CAS number: -
Acute Toxicity: oral
Administrative data
- Endpoint:
- acute toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 29 January 2020 to 29 May 2020
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 020
- Report date:
- 2020
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
- Version / remarks:
- October 2008
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.1100 (Acute Oral Toxicity)
- Version / remarks:
- December 2002
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Test type:
- up-and-down procedure
- Limit test:
- yes
Test material
- Reference substance name:
- 3-bromo-1-(3-chloropyrid-2-yl)-5-methyl-1H-pyrazole
- Molecular formula:
- C9H7BrClN3
- IUPAC Name:
- 3-bromo-1-(3-chloropyrid-2-yl)-5-methyl-1H-pyrazole
- Test material form:
- solid: particulate/powder
- Details on test material:
- Batch/Lot Number: 628-044-00
Analysed Concentration: 974.9 ± 3.3 g/kg
Physical State: Beige Solid
Date of Manufacture: 15 October 2019
Date of Expiry: 15 October 2021
Constituent 1
- Specific details on test material used for the study:
- Storage Condition:
Storage Temperature: Room temperature (15 to 30 °C).
Storage Condition: Cool and dry conditions.
Storage Container: In original container as supplied by the Sponsor.
Storage Location: Test Item Control Office, JRF.
Test animals
- Species:
- rat
- Strain:
- other: RccHan: WIST
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- Species: Rat (Rattus norvegicus).
Strain: RccHan: WIST.
Age/Weight at Dosing: 10 to 12 weeks, Weight (g) Minimum: 208.9, Maximum: 231.4.
Source: Animal Breeding Facility, Jai Research Foundation.
Total Number of Animals Used: Six females (nulliparous and non-pregnant).
Acclimatisation: 7 to 18 days.
Animal Identification: Each rat was uniquely numbered on the tail using a tattoo machine on day 1 of acclimatisation. Appropriate labels were attached to the cages indicating the study number, test item code, group number, sex, dose, type of study, cage number and animal number.
Caging: Polypropylene rat cages covered with stainless-steel grid top were used. Autoclaved clean rice husk was used as the bedding material. Wooden blocks were provided as enrichment material.
Water Bottle: Each cage was supplied with a polypropylene water bottle with a stainless-steel nozzle.
Housing: Maximum of three rats per cage, Room No. BMR 28.
Room Sanitation, daily:
1. Rack was cleaned with cloth.
2. Floor of experimental procedure room was swept.
3. All work tops and the floor were mopped with a disinfectant solution (Dettol 2.5%).
Feed and Water
The rats were provided with feed and water, ad libitum. The quality of feed and water is regularly monitored at Jai Research Foundation. There were no known contaminants in the feed and water at levels that would have interfered with the experimental results obtained.
Feed: Teklad certified Global High Fiber Rat/Mice Feed manufactured by Envigo, USA.
Water: UV sterilised water filtered through Reverse Osmosis water filtration system.
Environmental Conditions
Animal Room: BMR 28, Department of Toxicology.
Temperature: 20 to 23°C.
Relative Humidity: 56 to 66%.
Air Changes: Minimum 15 air changes/hour.
Photoperiod: The photoperiod was 12 hours artificial light and 12 hours darkness, light hours being 06:00 h–18:00 h (photoperiod was maintained through automatic timer).
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Details on oral exposure:
- VEHICLE/Control ITEM
- The test item was found to be insoluble in water. The test item was found to be forming a homogenous suspension in 0.5% aqueous carboxymethyl cellulose solution, so the same was used as vehicle in the study.
- Required amount of test item (175, 550, 1750 or 5000 mg) was mixed in corn oil and then adjusted according to the body weight to permit a constant dose volume (10 mL/kg body weight).
- Gavage solutions were prepared freshly prior to dosing on all the occasions.
- Concentration in vehicle: Individual dose volume was adjusted according to body weight and dose level (10 mL/kg body weight):
Dose: 175 mg/kg = Dose Volume administered: 2.09 mL.
Dose: 550 mg/kg = Dose Volume administered: 2.21 mL.
Dose: 1750 mg/kg = Dose Volume administered: 2.11 mL.
Dose: 5000 mg/kg = Dose Volume administered: 2.12-2.31 mL.
- Amount of vehicle: a constant volume of 10 mL/kg body weight.
ORAL GAVAGE
- All rats were dosed by oral gavage (day 0) using a metal cannula attached to a BD 1 mL disposable syringe, which was graduated up to 1 mL.
Rats were fasted overnight, prior to dosing, until three hours post-dosing. - Doses:
- Dose: 175 mg/kg = Dose Volume administered: 1.93 mL.
Dose: 550 mg/kg = Dose Volume administered: 2.21 mL.
Dose 1750 mg/kg = Dose Volume administered: 2.10 mL.
Dose: 5000 mg/kg = Dose Volume administered: 2.25–2.36 mL. - No. of animals per sex per dose:
- one animal/female/Dose: 175 mg/kg.
one animal/female/Dose: 550 mg/kg.
one animal/female/Dose: 1750 mg/kg.
three animals/female/Dose: 5000 mg/kg. - Control animals:
- no
- Details on study design:
- - The rats were observed twice a day for morbidity and mortality for a period of 14 days following oral dosing.
- Frequency of observations and weighing: At 0.5, 1, 2, 3, 4 and 5 h post-administration on the day of dosing.
- Necropsy of survivors performed: Yes.
- Clinical signs including body weight: The clinical signs were recorded at least once a day.
- Individual body weight was recorded prior to dosing on day 0, and on days 7 and 14.
Results and discussion
Effect levels
- Key result
- Sex:
- female
- Dose descriptor:
- LD50
- Effect level:
- > 5 000 mg/kg bw
- Based on:
- test mat.
- 95% CL:
- > 175 - <= 5 000
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Mortality:
- No mortality was observed in rats treated with 3-bromo-1-(3-chloro-2-pyridyl)-5-methyl-1H-pyrazole.
- Clinical signs:
- No clinical signs were observed in rats treated with 175 mg/kg body weight (rat N° 1), 550 mg/kg body weight (rat N° 2) or 1750 mg/kg body weight (rat N° 3). Lethargy, tremors and piloerection were observed on the day of dosing in rats treated with 5000 mg/kg body weight.
- Body weight:
- Normal gain in body weight was observed in rats treated with 175 mg/kg body weight (rat N° 1), 550 mg/kg body weight (rat N° 2), 1750 mg/kg body weight (rat N° 3) and 5000 mg/kg body weight (rat N° 4, 5, and 6).
- Gross pathology:
- External Examination
There were no external abnormalities in any rats which were sacrificed at the scheduled termination.
Internal Examination
There were no internal abnormalities in any rats which were sacrificed at scheduled termination.
In the absence of any pathological lesion in terminally sacrificed animals, it is concluded that the test item did not produce any treatment related effect at the dose levels used in the present study.
Any other information on results incl. tables
Dose, Mortality/Rats treated:
Dose (mg/kg body weight) |
Female rats (mortality/total) |
175 |
0/1 |
550 |
0/1 |
1750 |
0/1 |
5000 |
0/3 |
Test Sequence and Mortalities:
Rat N° |
Dose (mg/kg body weight) |
Mortality after Dosing |
|||||
½ - 5 h |
24 h |
48 h |
72 h |
4 – 7 Day |
8 – 14 Day |
||
1 |
175 |
O |
O |
O |
O |
O |
O |
2 |
550 |
O |
O |
O |
O |
O |
O |
3 |
1750 |
O |
O |
O |
O |
O |
O |
4 |
5000 |
O |
O |
O |
O |
O |
O |
5 |
5000 |
O |
O |
O |
O |
O |
O |
6 |
5000 |
O |
O |
O |
O |
O |
O |
Note: O = Survived
Individual Clinical Observations:
Rat N° |
Dose (mg/kg body weight) |
Clinical Signs Observed after Dosing |
|||||||||||||||||||
At Hour (Day 0) |
On Day |
||||||||||||||||||||
0.5 |
1 |
2 |
3 |
4 |
5 |
1 |
2 |
3 |
4 |
5 |
6 |
7 |
8 |
9 |
10 |
11 |
12 |
13 |
14 |
||
1 |
175 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
2 |
550 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
3 |
1750 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
4 |
5000 |
1 |
1 |
1 |
1 |
16, 49 |
16, 49 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
5 |
5000 |
1 |
1 |
1 |
49 |
16, 49 |
16, 49 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
6 |
5000 |
1 |
1 |
1 |
1 |
11, 49 |
11, 49 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
Note: Day 0 = Day of dosing
Clinical Sign: 1 = Normal; 11 = Lethargy; 16 = Tremors; 49 = Piloerection.
Individual Necropsy Findings:
Rat N° |
Dose (mg/kg body weight) |
Mode of Death |
External |
Internal |
1 |
175 |
Terminal sacrifice |
No abnormality detected |
No abnormality detected |
2 |
550 |
Terminal sacrifice |
No abnormality detected |
No abnormality detected |
3 |
1750 |
Terminal sacrifice |
No abnormality detected |
No abnormality detected |
4 |
5000 |
Terminal sacrifice |
No abnormality detected |
No abnormality detected |
5 |
5000 |
Terminal sacrifice |
No abnormality detected |
No abnormality detected |
6 |
5000 |
Terminal sacrifice |
No abnormality detected |
No abnormality detected |
Interpretation of Results
The LD50 was calculated using the Dixon’s maximum likelihood method using software (AOT 425 StatPgm) and was found to be greater than 5000 mg/kg body weight.
Applicant's summary and conclusion
- Interpretation of results:
- GHS criteria not met
- Conclusions:
- Based on results of this study, the acute oral median lethal dose for 3-bromo-1-(3-chloro-2-pyridyl)-5-methyl-1H-pyrazole in Wistar rats was found to be greater than 5000 mg/kg body weight. In accordance with the provisions of regulation 1272/2008, Annex I, 3.1, it is proposed classification is not required.
- Executive summary:
In an acute oral toxicity study in female Wistar rats (10 to 12 weeks old), the toxicological profile of 3-bromo-1-(3-chloro-2-pyridyl)-5-methyl-1H-pyrazole was assessed and the median lethal dose determined. A single oral dose of the test item was administered orally to fasted rats (formulated using 0.5% aqueous carboxymethylcellulose solution as a vehicle and at a constant dose volume of 10 mL/kg) through gavage. Initially rat N° 1 was tested with a starting dose level of 175 mg 3-bromo-1-(3-chloro-2-pyridyl)-5-methyl-1H-pyrazole/kg body weight. The tested rat survived at this dose level, subsequently five additional female Wistar rats received the dose of 550 mg 3-bromo-1-(3-chloro-2-pyridyl)-5-methyl-1H-pyrazole/kg body weight (rat N° 2), 1750 mg 3-bromo-1-(3-chloro-2-pyridyl)-5-methyl-1H-pyrazole/kg body weight (rat N° 3) and 5000 mg/kg body weight (rat N° 4, 5,and 6), according to the Up and Down Procedure. All rats were observed for 14 days following dose administration.
There was no treatment-related mortality, no changes in body weight, or necropsy finding recorded.
No clinical signs were observed in rats treated with 175 mg/kg body weight (rat N° 1), 550 mg/kg body weight (rat N° 2) or 1750 mg/kg body weight (rat N° 3). Lethargy, tremors and piloerection were observed on the day of dosing in rats treated with 5000 mg/kg body weight.
The number of animals which died or showed evident toxicity is shown below:
Dose
(mg/kg bw)Mortality
(# dead/total)Time range of deaths (h)
Evident toxicity
(#/total)175
0/1
-
0/1
550
0/1
-
0/1
1750
0/1
-
0/1
5000
0/3
-
3/3
In accordance with the provisions of regulation 1272/2008, Annex I, 3.1, it is proposed classification is not required.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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