Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
31 May 2012 to 28 June 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report Date:
2012

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
2008
Deviations:
no
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
2001
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Version / remarks:
2002
Deviations:
no
Qualifier:
according to
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries, Test Data for Registration of Agricultural Chemicals, Acute oral toxicity (2-1-1), 12 Nousan No 8147, Agricultural Production Bureau, November 24, 2000.
Version / remarks:
2000
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: flakes
Details on test material:
- Name of test material (as cited in study report): Rikabinol HB
- Substance type: Monomer
- Physical state: White solid
- Analytical purity: 95.6%
- Impurities (identity and concentrations):
- Lot/batch No.: 7095
- Expiration date of the lot/batch: 31 December 2012
- Storage condition of test material: Room temperature in the dark
- Other: Date received 12 December 2011

Test animals

Species:
rat
Strain:
other: CD (Crl:CD ‘SD’)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd
- Age at study initiation: Approximately 8 to 12 weeks.
- Weight at study initiation: 195 to 228 g.
- Fasting period before study: Yes
- Housing: Housed in groups of three rats of the same sex, in solid bottomed polycarbonate cages with a stainless steel mesh lid. Each cage contained a quantity of autoclaved wood flake bedding. Cages, food hoppers, water bottles and bedding were changed at appropriate intervals.
- Diet: The animals were allowed free access to a standard rodent diet (Rat and Mouse No. 1 Maintenance Diet), except for overnight prior to and approximately four hours after dosing.
- Water: Potable water taken from the public supply was freely available via polycarbonate bottles fitted with sipper tubes.
- Acclimation period: At least 6 days

ENVIRONMENTAL CONDITIONS
- Temperature: 19 to 23°C
- Humidity: 40 to 70%
- Air changes: The animal room was kept at positive pressure with respect to the outside by its own supply of filtered fresh air, which was passed to atmosphere and not re-circulated.
- Photoperiod (hrs dark / hrs light): 12 hours continuous light and 12 hours continuous dark per 24 hours.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 30 and 200 mg/mL
- Amount of vehicle: dose volume of 10 mL/kg bodyweight.
- Justification for choice of vehicle: No data

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bodyweight.

CLASS METHOD
- Rationale for the selection of the starting dose: The dose levels for the study were chosen in compliance with the study guidelines. As no previous toxicological information was available the initial dose level was 300 mg/kg.
Doses:
300 and 2000 mg /kg bw
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The weight of each rat was recorded on Days 1 (prior to dosing), 8 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs and macroscopic pathology

Results and discussion

Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths during the study. Cages of rats were checked at least twice daily for any mortalities.
Clinical signs:
Animals were observed soon after dosing and at frequent intervals for the remainder of Day 1. On subsequent days, animals were observed once in the morning and again at the end of the experimental day (with the exception of Day 15 - morning only). The nature and severity, where appropriate, of the clinical signs and the time were recorded at each observation. All animals were observed for 14 days after dosing.
Clinical signs of reaction to treatment in animals dosed at 2000 mg/kg comprised unsteady gait, seen in three animals (A8,A11,A12), reduced body tone in one animal (A8) and fast breathing seen in one animal (A8). These signs were first noted approximately one to two hour after dosing. Recovery of animals, as judged by external appearance and behaviour, was complete by Day 2. No clinical signs were seen in any animal dosed at 300 mg/kg.
Body weight:
The weight of each rat was recorded on Days 1 (prior to dosing), 8 and 15. Individual weekly bodyweight changes and group mean bodyweights were calculated.
Bodyweight stasis was noted for one female (A8) dosed at 2000 mg/kg on Day 15. All other animals were considered to have achieved satisfactory bodyweight gains throughout the study.
Gross pathology:
All animals were subject to a macroscopic examination which consisted of opening the cranial, thoracic and abdominal cavities. The macroscopic appearance of all examined organs was recorded.
Macroscopic examination at study termination on Day 15 revealed a small (atrophy) stomach in one female (A8) dosed at 2000 mg/kg. No abnormalities were revealed in any other animal.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The acute median lethal oral dose (LD50) to rats of Rikabinol HB was demonstrated to be greater than 2000 mg/kg bodyweight.