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Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From September 25th, 1997 to January, 20th, 1998
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1998
Report date:
1998

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
24th February 1987
Deviations:
yes
Remarks:
The relative humidity recorded in animals room was outside of the target ranges specified in the protocol. The minor deviation was not considered to compromise the validity or integrity of the study.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
3-methyl-1-phenyl-5-pyrazolone
EC Number:
201-891-0
EC Name:
3-methyl-1-phenyl-5-pyrazolone
Cas Number:
89-25-8
Molecular formula:
C10H10N2O
IUPAC Name:
5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one
Test material form:
solid: particulate/powder
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 91N058
- Expiration date of the lot/batch: no data
- Purity test date: mesured on 4th June 1997, certificated on 18th September 1997

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: glass flask at room temperature
- Stability under test conditions:no data
- Solubility and stability of the test substance in the solvent/vehicle: no data
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: no data

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Final preparation of a solid: suspension in the vehicle

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Iffa Crédo 69210 L'Arbresle, France
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: approximately 6 weeks old
- Weight at study initiation: males 163±5g and female 138±5g
- Fasting period before study: fasted for an overnight period
- Housing: animals were housed in polycarbonate cages (48 cm x 27 cm x 20cm). Each cage contained four to seven animals of the same sex during the acclimation period and five rats of the same sex during the treatment period. Each cage contained dust free sawdust (SICSA, 94142 Alfortville, France). Bacteriological analysis of the sawdust and detection of possible contaminants (pesticides, heavy metals) are performed periodically.
- Diet (e.g. ad libitum): free access to A04C pelleted diet. Each batch of food was analysed (composition and contaminants) by the supplier.
- Water (e.g. ad libitum): free access to water filtered by F.G. Millipore membrane (0.22 micron) Bacteriological and chemical analysis of the water and diet and detection of possible contaminants (pesticides, heavy metals and nitrosamines) are performed periodically.
- Acclimation period:5 days before the beginning of the study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21±2°C
- Relative humidity : 30 to 70%
- Air changes (per hr): 12 cycles per hours of filtered air and non recycled air
- Photoperiod (hrs dark / hrs light): 12h/12h

IN-LIFE DATES: From 3rd October 1997 to 22th October 2017

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: Vehicle 1 : 0.5% methylcellulose Vehicle 2 : 0.5% CMC (carboxymethylcellulose) Vehicle 3 : propylene glycol
Details on oral exposure:
VEHICLE
- Amount of vehicle (if gavage): 10ml/kg
- Justification for choice of vehicle: no data

MAXIMUM DOSE VOLUME APPLIED: 10ml/kg

DOSAGE PREPARATION (if unusual): The test substance was ground using a mortar and pestle, then prepared in each vehicle

Doses:
2000 mg/kg bodyweight
No. of animals per sex per dose:
5 rats per sex per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:observations frequently during the hours following administration, thereafter observations were made once a day. Weighing just before administration, at day 1, 8 and 15.
- Necropsy of survivors performed: yes ; A macroscopic examination of the main organs (digestive tract, heart, kidneys, liver, lungs, pancreas, spleen and any other organs with obvious abnormalities) was performed.
- Other examinations performed: clinical signs, body weight
Statistics:
not applicable

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other:
Remarks:
Limit dose doesn't reach 50% of mortality in the study
Mortality:
Mortality was 20% in group 1 ion day 1 and 2, 30% in group 2 on 4 and 6 hours after administration, and 0% of mortality in group 3.
Clinical signs:
In treated group 1 (vehicle: 0.5% methylcellulose), hypoactivity or sedation, piloerection, ptosis of the eyelids, reddish colouration of the extremites, dyspnoe and rhinorrhea were observed in all animals on day 1. Lateral recumbence was noted in one female prior to death. Tremors were also observed in one male, which was found dead on day 2. Recovery was mentioned to be complete in the other animals.
In treated group 2 (vehicle: 0.5% carboxymethylcellulose), hypoactivity or sedation, piloerection, ptosis of the eyelids, reddish colouration of the extremities, dyspnoea and rhinorrhea were observed in all animals on day 1. One male died 4 hours after treatment,and 2 females died 4 hours or 6 hours after treatment, respectively. Recovery was mentioned to be complete in the other animals.
In the treated group 3 (vehicle: propylene glycol) hypoactivity or sedation, piloerection, ptosis of the eyelids, reddish colouration of the extremities and dyspnoea were observed in all animals on day 1. No death occurred. Recovery was complete in all animals 6 hours after dosing.
Body weight:
Body weight gain of the surviving animals of all groups was not affected by treatment with
the test substance.
Gross pathology:
At necropsy, no apparent macroscopic abnormalities were observed in the animals which died during the study or in the animals killed at the end of the observation period.

Any other information on results incl. tables

Clinical signs and mortality

Dosage mg/kg

Clinical Signs

Number of animals after treatment

Level %

Hours

Days

1/2

1

2

4

6

2am

2pm

3

4

5

6 to 15

2000

Group 1

(MALE)

Death

 

 

 

 

 

1

 

 

 

 

 

20

Surviving

5

5

5

5

5

4

4

4

4

4

4

80

No abnormality

 

 

 

 

 

4

4

4

4

4

4

 

Hypoactivity

 

1

1

2

 

 

 

 

 

 

 

 

Sedation

5

4

4

3

5

 

 

 

 

 

 

 

Tremors

 

 

 

 

1

 

 

 

 

 

 

 

Piloerection

5

5

5

5

 

 

 

 

 

 

 

 

Dyspnea

 

 

5

5

5

 

 

 

 

 

 

 

Rhinorrhoea

 

 

 

2

 

 

 

 

 

 

 

 

Ptosis of the eyelids

5

5

5

 

 

 

 

 

 

 

 

 

Redish colouration of extremities

 

 

5

 

 

 

 

 

 

 

 

 

 

 

Dosage mg/kg

Clinical Signs

Number of animals after treatment

Level %

Hours

Days

1/2

1

2

4

6

2

3

4

5

6

7 to 15

2000

Group 2

(MALE)

Death

 

 

 

1

 

 

 

 

 

 

 

20

Surviving

5

5

5

4

4

4

4

4

4

4

4

80

No abnormality

1

 

 

4

4

4

4

4

4

4

4

 

Sedation

4

5

5

 

 

 

 

 

 

 

 

 

Piloerection

 

5

5

 

 

 

 

 

 

 

 

 

Dyspnea

 

 

5

 

 

 

 

 

 

 

 

 

Ptosis of the eyelids

4

5

5

 

 

 

 

 

 

 

 

 

Redish colouratio nof extremities

 

 

5

 

 

 

 

 

 

 

 

 

 

Dosage mg/kg

Clinical Signs

Number of animals after treatment

Level %

Hours

Days

1/2

1

2

4

6

2

3

4

5

6

7 to 15

2000

Group 3

(MALE)

Death

 

 

 

 

 

 

 

 

 

 

 

0

Surviving

5

5

5

5

5

5

5

5

5

5

5

100

No abnormality

 

 

 

 

5

5

5

5

5

5

5

 

Hypoactivity

 

 

 

2

 

 

 

 

 

 

 

 

Sedation

5

5

5

3

 

 

 

 

 

 

 

 

Piloerection

5

5

5

 

 

 

 

 

 

 

 

 

Dyspnea

 

 

5

3

 

 

 

 

 

 

 

 

Ptosis of the eyelids

5

5

5

 

 

 

 

 

 

 

 

 

Redish colouration of extremities

 

 

5

5

 

 

 

 

 

 

 

 

 

Dosage mg/kg

Clinical Signs

Number of animals after treatment

Level %

Hours

Days

1/2

1

2

4

6

2

3

4

5

6

7 to 15

2000

Group 1

(FEMALE)

Death

 

 

 

 

1

 

 

 

 

 

 

20

Surviving

5

5

5

5

4

4

4

4

4

4

4

80

No abnormality

 

 

 

 

 

 

 

 

 

 

 

 

Hypoactivity

 

1

1

 

 

 

 

 

 

 

 

 

Sedation

5

4

4

5

4

 

 

 

 

 

 

 

Lateral decubitus

 

 

 

1

 

 

 

 

 

 

 

 

Piloerection

5

5

5

4

 

 

 

 

 

 

 

 

Dyspnea

 

 

5

5

4

 

 

 

 

 

 

 

Rhinorrhoea

 

 

 

5

 

 

 

 

 

 

 

 

Ptosis of the eyelids

5

5

5

 

 

 

 

 

 

 

 

 

Redish colouration of extremities

 

 

5

4

 

 

 

 

 

 

 

 

 

Dosage mg/kg

Clinical Signs

Number of animals after treatment

Level %

Hours

Days

1/2

1

2

4

6

2

3

4

5

6

7 to 15

2000

Group 2

(FEMALE)

Death

 

 

 

1

1

 

 

 

 

 

 

40

Surviving

5

5

5

4

3

3

3

3

3

3

3

60

No abnormality

1

 

 

2

3

3

3

3

3

3

3

 

Sedation

4

5

5

2

 

 

 

 

 

 

 

 

Piloerection

 

5

5

2

 

 

 

 

 

 

 

 

Dyspnea

 

 

5

2

 

 

 

 

 

 

 

 

Ptosis of the eyelids

4

5

5

 

 

 

 

 

 

 

 

 

Redish colouration of extremities

 

 

5

 

 

 

 

 

 

 

 

 

 

Dosage mg/kg

Clinical Signs

Number of animals after treatment

Level %

Hours

Days

1/2

1

2

4

6

2

3

4

5

6

7 to 15

2000

Group 3 (FEMALE)

Death

 

 

 

 

 

 

 

 

 

 

 

 

Surviving

5

5

5

5

5

5

5

5

5

5

5

100

No abnormality

 

 

 

 

5

5

5

5

5

5

5

 

Hypoactivity

 

 

 

5

 

 

 

 

 

 

 

 

Sedation

5

5

5

 

 

 

 

 

 

 

 

 

Piloerection

5

5

5

 

 

 

 

 

 

 

 

 

Dyspnea

 

 

5

 

 

 

 

 

 

 

 

 

Ptosis of the eyelids

5

5

5

 

 

 

 

 

 

 

 

 

Redish colouration of extremities

 

 

5

5

 

 

 

 

 

 

 

 

 

Mean body weight change of treated rats (g)

Group

Dose

Volume

Sex

Days

mg/kg

ml/kg

 

1 to 8

8 to 15

1

2000

10

Male

M

69

50

SD

3

7

2

2000

10

M

74

55

SD

6

15

3

2000

10

M

70

60

SD

6

12

1

2000

10

Female

M

47

23

SD

10

9

2

2000

10

M

43

20

SD

8

2

3

2000

10

M

40

17

SD

6

5

 M = Mean

SD = Standart Deviation

Applicant's summary and conclusion

Interpretation of results:
Category 5 based on GHS criteria
Conclusions:
Under the experimental conditions of this study, the oral LD50 of the test substance PHENYL METHYL PYRALOZONE is higher than 2000mg/kg in rats, whatever the vehicle used. Thus, the test material is not classified as hazardous for acute oral toxicity according to the Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) criteria. Nevertheless, this substance is classified in Category 5 of GHS, as some mortality occured at the limit dose (2000 mg/kg bw).
Executive summary:

This GLP-compliant study was performed to assess the acute oral toxicity of Phenyl Methyl Pyrazolone, according to fixed dose OECD Guideline 401 method (dated 24th February 1987).

Material and Method

The test material diluted in 0.5% of methylcellulose (vehicle 1) 0.5 % carboxymethylcellulose (vehicle 2) and propylen glycol (vehicle 3) was administered by oral route (gavage) to a group of 5 females and 5 males Sprague Dawley rats per vehicle at a single dose of 2000 mg/kg body weight. Animals were observed for mortality, clinical signs and body weight for 14 days and were then subjected to necropsy at day 15.

Results

In treated group 1 (vehicle: 0.5% methylcellulose), hypoactivity or sedation, piloerection, ptosis of the eyelids, reddish colouration of the extremites, dyspnoe and rhinorrhea were observed in all animals on day 1. Lateral recumbence was noted in one female prior to death. Tremors were also observed in one male, which was found dead on day 2. Recovery was mentioned to be complete in the other animals.

In treated group 2 (vehicle: 0.5% carboxymethylcellulose), hypoactivity or sedation, piloerection, ptosis of the eyelids, reddish colouration of the extremities, dyspnoea and rhinorrhea were observed in all animals on day 1. One male died 4 hours after treatment,and 2 females died 4 hours or 6 hours after treatment, respectively. Recovery was mentioned to be complete in the other animals.

In the treated group 3 (vehicle: propylene glycol) hypoactivity or sedation, piloerection, ptosis of the eyelids, reddish colouration of the extremities, dyspnoea and rhinorrhea were observed in all animals on day 1. No death occurred. Recovery was complete in all animals 6 hours after dosing.

Conclusion

Under the experimental conditions of this study, the oral LD50 of the test substance PHENYL METHYL PYRALOZONE is higher than 2000mg/kg in rats, whatever the vehicle used. Thus, the test material is not classified as hazardous for acute oral toxicity according to the Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) criteria. Nevertheless, this substance is classified in Category 5 of GHS. As some mortality occured at the limit dose (2000 mg/kg bw).