Registration Dossier

Administrative data

Description of key information

Neither the derrmal nor the oral study indicated any toxicity in these studies.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
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
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
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.
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
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.
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.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
Klimisch 1

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
14 June 2012 to 04 July 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Version / remarks:
2008
Deviations:
no
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
1987
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Version / remarks:
1998
Deviations:
no
Qualifier:
according to
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries, Test Data for Registration of Agricultural Chemicals, Acute dermal toxicity (2-1-2), 12 Nousan No 8147, Agricultural Production Bureau, November 24, 2000.
Version / remarks:
2000
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
fixed dose procedure
Limit test:
no
Species:
rat
Strain:
other: CD (Crl:CD ‘SD’)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd.
- Age at study initiation: approximately eight to twelve weeks
- Weight at study initiation: 333 to 375 g for males and 246 to 281 g for females
- Fasting period before study: no data
- Housing: The cages were solid bottomed polycarbonate cages with a stainless steel mesh lid. Each cage contained a quantity of autoclaved wood flake bedding.
- Diet: The animals were allowed free access to a standard rodent diet (Rat and Mouse No. 1 Maintenance Diet). This diet contained no added antibiotic or other chemotherapeutic or prophylactic agent.
- Water: Potable water taken from the public supply was freely available via polycarbonate bottles fitted with sipper tubes.
- Acclimation period: The animals were allowed to acclimatise to the conditions described below for 5 days before treatment

ENVIRONMENTAL CONDITIONS
- Temperature: 19 to 23°C.
- Humidity: 40 to 70%.
- Air changes (per hr): 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): Artificial lighting was controlled to give a cycle of 12 hours continuous light and 12 hours continuous dark per 24 hours.
Type of coverage:
occlusive
Vehicle:
corn oil
Details on dermal exposure:
TEST SITE
- Area of exposure: 50 mm x 50 mm
- % coverage: approximately 10%
- Type of wrap if used: porous gauze held in place with a non-irritating dressing, and further covered by a waterproof dressing encircled firmly around the trunk of the animal.

REMOVAL OF TEST SUBSTANCE
- Washing: the treated area of skin was washed with warm water (30 - 40°C), to remove any residual test substance. The treated area was blotted dry with absorbent paper.
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bodyweight
- Concentration (if solution): 500 mg/mL
- Constant volume or concentration used: yes
- For solids, paste formed: yes

VEHICLE
- Amount(s) applied (volume or weight with unit): 4 mL/kg bodyweight
Duration of exposure:
24 hours
Doses:
Dose - 2000 mg/kg bw
Concentration - 500 mg/mL
Dose volume - 4 mL/kg
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 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).
- Necropsy of survivors performed: yes
- Other examinations performed: mortality, clinical signs, body weight, macroscopic pathology and dermal reactions
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
Cages of rats were checked at least twice daily for any mortalities. There were no deaths and no systemic response to treatment in any animal.
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.
There were no systemic response to treatment in any animal.
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.
A low bodyweight gain was noted for one female (D10) on Day 15. All other animals were considered to have achieved satisfactory bodyweight gains throughout the study.
Gross pathology:
No abnormalities were noted in any animal at the macroscopic examination at study termination on Day 15.
Other findings:
Dermal reactions: no dermal reactions were observed in any animal during the study.
Interpretation of results:
GHS criteria not met
Conclusions:
The acute median lethal dermal dose (LD50) to rats of Rikabinol HB was demonstrated to be greater than 2000 mg/kg bodyweight.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Additional information

An acute oral toxicity study was conducted (Huntingdon Life Sciences, 2012, Study MOG0013) to assess the toxicity of HBPA following a single oral administration. The study was conducted in accordance with EC Method B1 tris, OECD test guideline 42, EPA test guidelines OPPTS 870.1100 and 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, and in compliance with GLP.

 

Two groups of three fasted female rats received a single oral gavage dose of the test substance, formulated in corn oil, at a dose level of 300 mg/kg bw. As results at this dose level indicated the acute (median) lethal oral dose of the test substance to be greater than 300 mg/kg bw, in compliance with the study guidelines a further two groups of three fasted females were similarly dosed at 2000 mg/kg bw.

 

There were no deaths during the study. Clinical signs of reaction to treatment in animals dosed at 2000 mg/kg comprised unsteady gait, seen in three animals, reduced body tone and fast breathing seen in one animal. These signs were first noted approximately one to two hours 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. Bodyweight stasis was noted for one female dosed at 2000 mg/kg on Day 15. All other animals were considered to have achieved satisfactory bodyweight gains throughout the study. Macroscopic examination at study termination on Day 15 revealed a small (atrophy) stomach in one female dosed at 2000 mg/kg. No abnormalities were revealed in any other animal.

 

It was concluded that the acute median lethal dose in the female Wistar strain rat following single oral administration of HBPA was greater than 2000 mg/kg body weight.

 

 

No acute inhalation study available.

 

 

An acute dermal toxicity study was conducted (Huntingdon Life Sciences, 2012, Study MOG0014) to assess the toxicity of HBPA following a single topical application. The study was conducted in accordance with EC Method B3, OECD test guideline 402, EPA test guidelines OPPTS 870.1200 and Japanese Ministry of Agriculture, Forestry and Fisheries, Test Data for Registration of Agricultural Chemicals, Acute dermal toxicity (2-1-2), 12 Nousan No 8147, and in compliance with GLP.

 

A group of 10 rats (5 males and 5 females) received a single topical application of the test substance, formulated at a maximum practical concentration in corn oil, at a dose level of 2000 mg/kg bodyweight, for a duration of 24 hours.

 

There were no deaths and no systemic response to treatment in any animal. A low bodyweight gain was noted for one female on Day 15. All other animals were considered to have achieved satisfactory body weight gains throughout the study. No abnormalities were noted in any animal at the macroscopic examination at study termination on Day 15.

 

The acute median lethal dermal dose to rats of HBPA was demonstrated to be greater than 2000 mg/kg bodyweight.

Justification for classification or non-classification

The acute oral and dermal LD50 of HBPA were determined to be greater than 2000 mg/kg. According to table 3.1.1 of CLP Regulation (Commission Regulation 1272/2008) HBPA is not classified for acute oral or dermal toxicity.