EXPLANATORY STATEMENT
THERAPEUTIC GOODS (LISTING) NOTICE 2008 (No. 4)
Rhodiola rosea
Section 9A(5), Therapeutic Goods Act 1989
OUTLINE
Therapeutic Goods (Listing) Notice 2008 (No. 4) (the Listing Notice) is a Notice made by the delegate of the Minister for Health and Ageing under subsection 9A(5) of the Therapeutic Goods Act 1989 (the Act).
The Listing Notice permits the use of Rhodiola rosea as an active ingredient in Listed complementary medicines subject to certain conditions. Preparations containing Rhodiola rosea as their therapeutically active ingredient are for oral use only and may only be in the form of either the dried root (powdered), the dried root (powdered) as an aqueous extract or the dried root (powdered) as a hydroethanolic extract with up to 70% ethanol v/v.
The Listing Notice commenced on the day after it was registered on the Federal Register of Legislative Instruments (FRLI).
BACKGROUND
The Act provides for the establishment and maintenance of a national system of controls for the quality, safety, efficacy and timely availability of therapeutic goods that are used in Australia or exported from Australia. The Therapeutic Goods Administration (TGA) is responsible for administering the Act.
Unless specifically exempted or authorised under the Act, therapeutic goods are required to be included in the Australian Register of Therapeutic Goods (ARTG) before being supplied in, imported into, manufactured in, or exported from Australia (sections 19B and 19D of the Act). Medicines are Registered or Listed in the ARTG, depending on the ingredients they contain and the therapeutic claims that are being made.
In Australia, products such as vitamins, minerals, nutritional supplements and herbal, homoeopathic and aromatherapy products are regarded as ‘complementary’ medicines. Most, but not all, complementary medicines are considered to be of relatively low risk compared to other types of medicines, such as prescription and over-the-counter medicines, and are Listed in the ARTG.
Listed medicines may only contain ingredients that have been approved by the TGA as being of low risk and may only make limited therapeutic claims.
In order to facilitate the timely approval of new Listable substances, subsection 9A(5) of the Act allows the Minister for Health and Ageing to publish a Listing Notice that has the effect of permitting the use of particular substances in Listed medicines subject to any specified conditions.
Schedule 4 of the Therapeutic Goods Regulations 1990 (the Regulations) sets out those therapeutic goods that are required to be included in the part of the ARTG for Listed medicines. Part 5 of Schedule 4 is for substances other than vitamins, minerals and plant material that are for use in Listed medicines. Division 1 of Part 5 is for substances not mentioned in Division 2 or 3, that may be ingredients of preparations.
Pursuant to subsection 9A(6) of the Act, when Schedule 4 of the Regulations is amended to include reference to a substance that has been the subject of Listing Notice, the Listing Notice ceases to have effect.
The dried root of the ingredient Rhodiola rosea is believed to have been traditionally used as a decoction (aqueous extract) in Europe and Russia for at least 2000 years and the hydroethanolic extract of the dried root also has a long tradition of use in Europe and Russia. The chemical characteristics of Rhodiola rosea are well known.
Clinical trials from the 1960s and more recently suggest that, when used in appropriate doses, the extracts of the dried root of Rhodiola rosea are not associated with any significant adverse reactions. Animal studies have shown the hydroethanolic (70% ethanol) extract of the dried root of Rhodiola rosea to be non toxic at acute (2000 mg/kg) and subchronic (1000 mg/kg) doses. Aqueous and hydroethanolic extracts are presently sold worldwide and the main therapeutic uses of Rhodiola rosea root extract are as an adaptogen (a therapeutic substance that improves adaptability to stress) and as a general tonic.
The 63rd Complementary Medicines Evaluation Committee (CMEC) meeting was asked to advise whether Rhodiola rosea is suitable as an ingredient in Listed medicines. CMEC is a statutory committee established under subsection 52G(1) of the Act which gives scientific and policy advice to the Minister for Health and Ageing and the Secretary to the Department of Health and Ageing regarding controls on the supply and use of complementary medicines, with particular reference to the safety and quality of products and, where appropriate, efficacy relating to the claims made for products.
CMEC has recommended that Rhodiola rosea is suitable for use as an active ingredient in Listed medicines for oral use, in the following forms, following finalisation of compositional guidelines for Rhodiola rosea:
- the dried root (powdered);
- the dried root (powdered) as an aqueous extract; or
- the dried root (powdered) as a hydroethanolic extract with up to 70% ethanol v/v.
The TGA has prepared two compositional guidelines for Rhodiola rosea:
- “Draft Compositional Guideline for Rhodiola rosea root/dry powder” (see Attachment A) and;
- “Draft Compositional Guideline for Rhodiola rosea powdered root extract” (see Attachment B).
Compositional guidelines written by the TGA are intended to set out the standards and requirements for the specific forms or types of substances for use in Listed medicines where there is no monograph in the British Pharmacopoeia (BP) or other acceptable monograph.
The compositional guidelines for Rhodiola rosea will be available on the TGA’s internet site <www.tga.gov.au> for consultation for six months following the registration on FRLI of the Listing Notice.
CONSULTATION
Although the listing of the ingredient Rhodiola rosea is minor and machinery in nature, the CMEC was consulted during the approval process for this ingredient.
REGULATION IMPACT STATEMENT
No Regulation Impact Statement is necessary in relation to the Listing Notice as the listing of the ingredient Rhodiola rosea is minor and machinery in nature with no or low compliance costs and impact on business, individuals or the economy.
Draft Compositional Guideline for Rhodiola rosea root dry/powder
Name of the ingredient
‘Powdered root (rhizome) of Rhodiola rosea L’
Definition of the ingredient
The ingredient is obtained from the dried or powdered root (rhizome) of Rhodiola rosea L (Crussalaceae) only. Care should be taken not to confuse this root with any of the related species, such as Rhodiola crenula, R. sacra and R. sachalinensis. The ingredient must meet specific requirements, as described in Table 1 below. The ingredient must meet specific requirements, as described below.
Table 1. Ingredient specific requirements
Requirement | Method(s) | Limits |
Macroscopic Description Dried rootstock: Pieces of rootstocks and roots of different shapes. Rootstock pieces are hard and rugate with traces of died-off stalks and remnants of squamiform leaves. From the rootstocks a few roots branch off 2-9 cm long and 0.5-1 cm thick. Rootstock and root surface is glossy and of greyish-brown colour; on peeling off of cork there is a golden-yellow layer. Fracture colour is rosy-brown or light brown. Microscopic Description Dried rootstock: On the rootstock cross cut is seen a schistous periderm. Rootstock structure is of fascicular type. Duct fascicles are open, collateral, fusiform, ring-shaped, rootstock periphery-oriented by phloem and centre-oriented by xylem. There may be available the second ring of smaller duct fascicles, in which phloem is centre-oriented, while xylem is periphery-oriented. Rootstock parenchyma consists of large cells filled by starch. Starch grains are simple, round or oval, 5-20 µm in diameter.
|
Visual
Visual |
Complies
Complies |
Characters Odour Taste Loss on drying |
Pleasant, specific Astringent, specific BP5 (Vol IV, Appendix IX D)
|
Complies Complies NMT 12%
|
Identification1 Chemical ‘fingerprint’ compares with authenticated reference material
|
HPLC |
Complies |
Assay Phenylpropanoids2 Rosavin3 Salidroside4
|
HPLC HPLC HPLC |
NLT 1.8% NLT 1.2% NLT 0.6% |
Residue after ignition Ash |
BP5 (Vol IV, Appendix IX B)
|
NMT 8% |
Table 2. Incidental constituents
Requirement | Method(s) | Limits |
Incidental metals and non-metals Total heavy metals (determined as lead) |
BP5 (Vol IV, Appendix VII, Limit test for heavy metals)
|
NMT 10 ppm |
Microbiology | In accordance with TGAL Guidelines6
| Complies |
Pesticide residues (including agricultural and veterinary substances) |
BP5 (Vol IV, Appendix XI L, Pesticide residues)
|
Complies |
Key to abbreviations:
HPLC = high performance liquid chromatography; NLT = not less than; NMT = not more than; BP = British Pharmacopoeia; TGAL = TGA Laboratories
1 Test must be validated and capable of discriminating between Rhodiola rosea and related species especially Rhodiola crenula, R. sacra and R. sachalinensis. The suggested method is that by Ganzera et al. (2001) Chemical and Pharmaceutical Bulletin 49(4): 465-467. The HPLC profile should be compared against the ‘fingerprint’ of a genuine standard R. rosea extract, to not only confirm identity but also to determine if any additional peaks are those of potential contaminants. If the comparator ‘fingerprint’ is not available, the identity of peaks can not be determined simply based on their retention time. In order to confirm the identity of each peak, peaks should be collected and specific characterisation performed (e.g. GC-MS, NMR or IR spectrum).
2 The term "Phenylpropanoids of Rhodiola rosea" comprises the sum of the compounds rosavin, rosarin and rosin:
Rosin 3-phenyl-2-propeny1-O-β-d-glucopyranoside
Rosavin 3-phenyl-2-propeny1-O-(6'-O-α-l-arabinopyranosyl)-β-d-glucopyranoside
Rosarin 3-phenyl-2-propeny1-O-(6'-O-α-l-arabinofuranosyl)-β-d-glucopyranoside
3 The term "rosavin" refers specifically to 3-phenyl-2-propeny1-O-(6'-O-α-l-arabinopyranosyl)-β-d-glucopyranoside. The test must be capable of discriminating this compound separately from other phenylpropanoids.
4 A salidroside content in excess of the phenylpropanoid content is anomalous and may suggest that a preparation is not pure Rhodiola rosea powder.
5 Currently promulgated edition of the BP.
6 Finished products containing the ingredient must comply with TGAL Guidelines.
Draft Compositional Guideline for Rhodiola rosea powdered root extract
Name of the ingredient
‘Dried aqueous or hydroethanolic (up to 70% ethanol) extract of the root (rhizome) of Rhodiola rosea L’
Definition of the ingredient
The ingredient is obtained by aqueous or hydroethanolic (up to 70% ethanol) extraction of the dried root (rhizome) of Rhodiola rosea L only, and not from the root of any of the related species, such as Rhodiola crenula, R. sacra and R. sachalinensis. The ingredient must meet specific requirements, as described in Table 1 below. Incidental constituents of the ingredient must be controlled as described in Table 2 below. The typical native extract ratio range is 6-10:1 for aqueous extraction and 3-5:1 for hydroethanolic extraction.
Table 1. Ingredient specific requirements
Requirement | Method(s) | Limits |
Description Brown, non-crystalline powder
|
Macroscopic-Visual |
Complies |
Characters Odour Taste Loss on drying
|
Pleasant, specific Astringent, specific BP5 (Vol IV, Appendix IX D) |
Complies Complies NMT 5% |
Identification1 Chemical ‘fingerprint’ compares with authenticated reference material
|
HPLC |
Complies |
Assay Phenylpropanoids2 Rosavin3 Salidroside4
|
HPLC HPLC HPLC |
3.0 - 5% 1.5 - 3.5% 1.0 - 3.0% |
Table 2. Incidental constituents
Requirement | Method(s) | Limits |
Solvent residues Total solvent residues included in BP |
BP5 (Vol IV, Appendix VIII L, Residual solvents)
|
Complies |
Incidental metals and non-metals Total heavy metals (determined as lead) |
BP5 (Vol IV, Appendix VII, Limit test for heavy metals)
|
NMT 10 ppm |
Microbiology | In accordance with TGAL Guidelines6
| Complies |
Pesticide residues (including agricultural and veterinary substances) |
BP5 (Vol IV, Appendix XI L, Pesticide residues)
|
Complies |
Key to abbreviations:
TLC = thin layer chromatography; HPLC = high performance liquid chromatography; NLT = not less than; NMT = not more than; BP = British Pharmacopoeia; TGAL = TGA Laboratories
1 Test must be validated and capable of discriminating between Rhodiola rosea and related species especially Rhodiola crenula, R. sacra and R. sachalinensis. The suggested method is that by Ganzera et al. (2001) Chemical and Pharmaceutical Bulletin 49(4): 465-467. The HPLC profile should be compared against the ‘fingerprint’ of a genuine reference standard of R. rosea extract, to not only confirm identity but also to determine if any additional peaks are those of potential contaminants. If the comparator ‘fingerprint’ is not available, the identity of peaks can not be determined simply based on their retention time. In order to confirm the identity of each peak, peaks should be collected and specific characterisation performed (e.g. GC-MS, NMR or IR spectrum).
2 The term "Phenylpropanoids of Rhodiola rosea" comprises the sum of the compounds rosavin, rosarin and rosin:
Rosin 3-phenyl-2-propeny1-O-β-d-glucopyranoside
Rosavin 3-phenyl-2-propeny1-O-(6'-O-α-l-arabinopyranosyl)-β-d-glucopyranoside
Rosarin 3-phenyl-2-propeny1-O-(6'-O-α-l-arabinofuranosyl)-β-d-glucopyranoside
3 The term "rosavin" refers specifically to 3-phenyl-2-propeny1-O-(6'-O-α-l-arabinopyranosyl)-β-d-glucopyranoside. The test must be capable of discriminating this compound separately from other phenylpropanoids.
4 A salidroside content in excess of the phenylpropanoid content is anomalous and may suggest that a preparation is not pure Rhodiola rosea extract.
5 Currently promulgated edition of the BP.
6 Finished products containing the ingredient must comply with TGAL Guidelines.