Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well documented study according to international accepted guidelines and GLP compliant.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2014
Report Date:
2014

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
Test item: Levodione
CAS number: 21800-83-9
Batch number: 242027N
Physical state: Solid, crystalline powder
Colour: White
Storage: At a temperature of 15 to 30 °C

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
Species and strain: Crl:(WI)Br rats
Source: TOXI COOP ZRT.
Hygienic level at arrival: SPF
Hygienic level during the study: good conventional
Number of animals: 3 animals/group
Sex: Female, nulliparous and non pregnant animals
Age of animals: Young adult rat, 8 weeks old in first and second step
Body weight range at starting (first step): 173 - 177 g
Body weight range at starting (second step): 168 - 170 g
Acclimatization time: 11 days in first step and 12 days in second step
Animal health: Only healthy animals were used for the study. Health status was certified by the study director.

Housing: Group caging (3 animals/cage)
Light: Artificial light, from 6 a.m. to 6 p.m.
Temperature: 22 ± 3 °C
Relative humidity: 30 - 70 %
Ventilation: 10-15 air exchanges/hour by central air-condition system

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: Methylcellulose (0.5 %) aq. solution
Details on oral exposure:
A single oral administration - followed by a fourteen-day observation period - was performed by gavage.
An acute toxic class method was carried out involving a stepwise procedure with the use of 2000 mg/kg bw as the starting dose in three female rats. No animal died in the first step at 2000 mg/kg bw dose level, therefore treatment with 2000 mg/kg bw was repeated on further three female rats. Only one animal died in the second step, so the test was finished.

The dose used was formulated in the vehicle. Concentration of formulation was adjusted to maintain a treatment volume of 10 mL/kg bw. The test item was applied in a concentration of 200 mg/mL. Formulation were prepared just before the administration and stirred continuously during the treatment.

The day before treatment the animals were fasted. The food but not water was withheld overnight. Animals were weighed before the application and the food was given back 3 hours after the treatment.
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
3 female/dose
Control animals:
no
Details on study design:
The observation period was 14 days. Animals were observed individually after dosing at least once during the first 30 minutes, then 1 h, 2 h, 3 h, 4 h, 5 h and 6 h after the treatment and twice each day for 14 days thereafter.
The body weights were recorded on day 0 (just before the treatment), on day 7 and on day 15 with a precision of 1 g.
At the end of the observation period survivor animals were sacrificed and necropsy were performed.

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No death occurred in step 1, 2000 mg/kg bw single oral dose of the test item Levodione (CAS 21800-83-9). All female rats in this group survived until the end of the 14-day observation period.
One rat dosed at 2000 mg/kg bw (step 2) died on the treatment day 4 hours after the treatment. Death seemed to be consequences of systemic toxic effect of the test item. Two animals survived until the end of the 14-day observation period.
Clinical signs:
In group 1 treated with 2000 mg/kg bw dose:
No treatment related symptoms were observed throughout the 14-day post-treatment period.
In group 2 treated with 2000 mg/kg bw dose:
Decreased activity (score -1; -2; -4) was observed in two animals. Prostration (score +4) and dyspnoea (score +3) were detected in one animal. Abnormal gait (score +1) and incoordination (score +1; +2) occurred in one animal. The symptoms were observed on the treatment day between 30 min. and 5 hours after the treatment. The third animal was free of symptoms during the study.
Body weight:
The mean body weight of animals corresponded to their species and age throughout the study.
Gross pathology:
One rat treated with 2000 mg/kg bw dose (group 2) of the test item spontaneously died during the study. The other animals survived until the scheduled necropsy on Day 15.
Moderate hydrometra was observed in two females of the group 1. This alteration is physiological finding and connected to the cycle of the animal. No pathological changes were found related to the effect of the test item during the macroscopic examination of animals.

Any other information on results incl. tables

Groups

Treatment

Lethality

Test item

Dose (mg/kg bw)

Females

1

“Levodione
Step1

2000

0/3

2

“Levodione
Step2

2000

1/3

 

Applicant's summary and conclusion

Interpretation of results:
Category 5 based on GHS criteria
Remarks:
Migrated information
Conclusions:
The method used was not intended for the calculation of a precise LD50 value.
The test item was ranked into classes of Globally Harmonized Classification System (GHS) described in the OECD Guideline No. 423.
Hazard Category: Acute Tox. 5.
Executive summary:

 Dose (mg/kg bw) Mortality (dead/treated)   LD50 (mg/kg bw)  GHS Category
2000   1/6  above 2000  5