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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
8 Aug. 2017 to 8 Sept. 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2017
Report date:
2017

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
17 Dec. 2001
Qualifier:
according to guideline
Guideline:
other: "Regulation on Test Methods for Chemical Substances" Notification No. 2017-4, National Institute of Environmnetal Research, Republic of Korea
Version / remarks:
14 Mar. 2017
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2,4-dihydro-2,5-dimethyl-3H-pyrazol-3-one
EC Number:
220-389-2
EC Name:
2,4-dihydro-2,5-dimethyl-3H-pyrazol-3-one
Cas Number:
2749-59-9
Molecular formula:
C5H8N2O
IUPAC Name:
1,3-dimethyl-4,5-dihydro-1H-pyrazol-5-one
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Supplier: Japan Finechem Company, Inc. Japan
- Lot No.of test material: 7E18
- Expiration date of the lot/batch: 14 Sept. 2017 (3 months after receipt)
- Purity: 99.98%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature (27 Jun. 2017 - 3 Jul. 2017), Refrigerator (3 Jul 2017 - 18 Aug. 2017)

OTHER SPECIFICS:
- Appearance: White powder

Test animals

Species:
rat
Strain:
Sprague-Dawley
Remarks:
Crl:CD(SD), SPF
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Orientbio Inc., Republic of Korea
- Age at study initiation: 8-9 weeks
- Weight at study initiation: 175.4 - 210.4 g
- Fasting period before study: Overnight for 16 h
- Housing: Individually, in stainless wire mesh cage, 260Wx350Dx210H (mm)
- Diet: ad libitum, pelleted rodent chow (Teklad Ceritified Irradiated Global 10% Protein Rodent Diet 2918C), Envigo RMS, Inc. U.S.A.
- Water: ad libitum, public tap water in Cheongju-si was filtered and irradiated
- Acclimation period: All animals were quarantined for 3 days. Then, they were moved and acclimated for 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.4 - 23.3 (permissible value: 19.0 - 25.0)
- Humidity (%): 46.4 - 58.4 (permissible value: 30.0 - 70.0%)
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Name: Water for injection
- Storage condition: Room temperature
- Concentration in vehicle: 30 and 200 mg/mL
- Amount of vehicle (if gavage): 3 mL
- Manufacturer: JW Pharmaceutical Co., Ltd., Republic of Korea

CLASS METHOD
- Rationale for the selection of the starting dose: The starting dose level for this study was selected as 300 mg/kg because there is no available toxicity information on the test substance.
Doses:
- Group 1 and 2: 300 mg/kg bw
- Group 3 and 4: 2000 mg/kg bw
No. of animals per sex per dose:
3 animals per group
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- All animals were observed for mortality general condition and clinical signs at 30 min after dosing at at 1, 2, 4 and 6 hours after dosing oond day 0 and once daily thereafter for 14 days.
- Body weight was recorded prior to dosing, on day 0, 1, 3, 7 and on the day of necropsy (day 14).
- Necropsy of survivors performed: yes
Statistics:
No statistical analysis performed.
Mean scores and values were determined.

Results and discussion

Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 300 - < 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths at the dose of 300 mg/kg while 3 animals died at the dose of 2000 mg/kg (one animal in group 3 and 2 animals in group 4).
Clinical signs:
- Lacrimation was observed at the dose of 300 mg/kg in 3 animals at 0.5, 1, and/or 2 h after dosing. Lacrimation and salivation were observed at the dose of 300 mg/kg in one animal at 0.5 h after dosing. Chromaturia (orange) was observed in all animals on Day 1. However, these changes disappeared in Day 2.
- In surviving animals tested at the dose of 2000 mg/kg, lacrimation, salivation and chromaturia (orange) were observed in 1 – 3 animals at 0.5, 1, 2, 4 and 6 hours after dosing and chromaturia(orange) and/or no stool were observed in 2 – 3 animals on Day 1 and/or Day 2. These changes all disappeared on Day 3.
- In dead animals at 2000 mg/kg, clinical signs of lacrimation, salivation and/or chromaturia (orange) were observed at 0.5, 1, 2, 4 and 6 hours after dosing. Then, these animals were found dead in a state of chromaturia (orange), staining around mouth, soiled perineal region and/or lying on a side, on Day 1.
Body weight:
Normal body weight gain was observed in all animals at 300 mg/kg throughout the study
A decrease in body weight was observed in 3 animals at 2000 mg/kg on Day 1. Then, normal body weight gain was observed in these animals on Day 3.
Gross pathology:
No grossly visible abnormalities were observed in any animal at 300 and 2000 mg/kg.

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The LD50 was determined to be > 300 - < 2000 mg/kg bw.
Executive summary:

In this GLP compliant study, performed according to OECD guideline 423, the potential toxicity of the test substance was determined. 4 groups of 3 female 8 -9 week old Sprague-Dawley rats were exposed to the test substance via oral gavage. The animals received the test substance via a single administration of either 300 or 2000 mg/kg bw. A dose of 300 mg/kg bw was administrated to group 1. As no mortality was observed in this group, another group received the dose of 300 mg/kg bw. No mortality was observed in this group. Thus, as dose of 2000 mg/kg bw was administered to the third group. Of this group 1 animal died. A dose of 2000 mg/kg bw was administered to the fourth group. 2 animals of this group died. All animals were monitored for clinical signs and body weight changes during the 14-day observation period after administration. They were subjected to a gross necropsy at the end of the observation period. There were no deaths of animals at 300 mg/kg bw. Lacrimation and/or salivation were overserved in animals of the day of dosing and chromaturia (orange) was observed in Day 1. These changes disappeared in Day 2. No test substance-related effects were observed in body weight data or necropsy findings in any animal at 3000 mg/kg bw. 3 animals were found dead at 2000 mg/kg bw on Day 1. In surviving animals at 2000 mg/kg bw, lacrimation, salivation and/or chromaturia (orange) were observed on the day of dosing, and chromaturia (orange) and/or no stool were observed in Day 1 and/or Day 2. These changes all disappeared on Day 3. In dead animals at 2000 mg/kg, clinical signs of lacrimation, salivation, and/or chromaturia (orange) were observed before death. A decrease in body weight was observed in these animals on Day 3. No test substance-related effects were observed in necropsy findings in any animal at 2000 mg/kg bw. Based on the results of the acute oral toxicity study the LD50 was determined to be >300 - <2000 mg/kg bw.

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