Scheduling medicines and poisons
This consultation closed on 5 March 2018
Subdivision 3D.2 of the Therapeutic Goods Regulations 1990 (the Regulations) sets out the procedure to be followed where the Secretary receives an application under section 52EAA of the Therapeutic Goods Act 1989 (the Act) to amend the current Poisons Standard and decides to refer the proposed amendment to an expert advisory committee. These include, under regulation 42ZCZK, that the Secretary publish (in a manner the Secretary considers appropriate) the proposed amendment to be referred to an expert advisory committee, the committee to which the proposed amendment will be referred, and the date of the committee meeting. The Secretary must also invite public submissions to be made to the expert advisory committee by a date mentioned in the notice as the closing date, allowing at least 20 business days after publication of the notice. Such a notice relating to the interim decisions herein was made available on the TGA website on 6 September 2017 and closed on 6 October 2017. Public submissions received on or before this closing date will be published on the TGA website in accordance with regulation 42ZCZL.
Under regulation 42ZCZN of the Regulations, the Secretary, after considering the advice or recommendation of the expert advisory committee, must (subject to regulation 42ZCZO) make an interim decision in relation to the proposed amendment. If the interim decision is to amend the current Poisons Standard, the Secretary must, in doing so, take into account the matters mentioned in subsection 52E(1) of the Act (including, for example, the risks and benefits of the use of a substance, and the potential for abuse of a substance) and the scheduling guidelines as set out in the Scheduling Policy Framework for Chemicals and Medicines (SPF, 2015), available on the TGA website.
Under regulation 42ZCZP of the Regulations, the Secretary must, among other things, publish (in a manner the Secretary considers appropriate) the scheduling interim decision, the reasons for that decision and the proposed date of effect (for decisions to amend the current Poisons Standard, this will be the date when it is expected that the current Poisons Standard will be amended to give effect to the decision). These Secretary's interim decisions and reasons related to:
Also in accordance with regulation 42ZCZP of the Regulations, this notice invites the applicants and persons who made a submission in response to the original invitation under paragraph 42ZCZK(1)(d), to make further submissions to the Secretary in relation to the interim decisions within 10 business days after publication of this notice. Further submissions must be relevant to the proposed amendment, must address matters mentioned in section 52E of the Act, and be received by the closing date, 5 March 2018.
Submissions, preferably in electronic format (word or unsecured PDF), must be received by 5 March 2018 and should be sent to:
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Scheduling medicines and poisons
Abbreviation | Name |
---|---|
AAN | Australian Approved Name |
AC | Active constituent |
ACCC | Australian Competition and Consumer Commission |
ACCM | Advisory Committee on Complementary Medicines (formerly Complementary Medicine Evaluation Committee [CMEC]) |
ACNM | Advisory Committee on Non-prescription Medicines (formerly Medicines Evaluation Committee [MEC]) |
ACPM | Advisory Committee on Prescription Medicines (formerly Australian Drug Evaluation Committee [ADEC]) |
ACSOM | Advisory Committee on the Safety of Medicines (formerly Adverse Drug Reactions Advisory Committee [ADRAC]) |
ADEC | Australian Drug Evaluation Committee (now Advisory Committee on Prescription Medicines [ACPM]) |
ADI | Acceptable daily intake |
ADRAC | Adverse Drug Reactions Advisory Committee (now Advisory Committee on the Safety of Medicines [ACSOM]) |
AHMAC | Australian Health Ministers' Advisory Council |
APVMA | Australian Pesticides and Veterinary Medicines Authority |
AQIS | Australian Quarantine and Inspection Service |
ARfD | Acute reference dose |
ASCC | Australian Safety and Compensation Council |
ASMI | Australian Self-Medication Industry |
ARTG | Australian Register of Therapeutic Goods |
CAS | Chemical Abstract Service |
CHC | Complementary Healthcare Council of Australia |
CMEC | Complementary Medicine Evaluation Committee (now Advisory Committee on Complementary Medicines [ACCM]) |
CMI | Consumer Medicine Information |
COAG | Councils of Australian Governments |
CRC | Child-resistant closure |
CTFAA | Cosmetic, Toiletry & Fragrance Association of Australia |
CWP | Codeine Working Party |
DAP | Drafting Advisory Panel |
ECRP | Existing Chemicals Review Program |
EPA | Environmental Protection Authority |
ERMA | Environmental Risk Management Authority (New Zealand) |
EU | European Union |
FAISD | First Aid Instructions and Safety Directions |
FDA | Food and Drug Administration (United States) |
FOI | Freedom of Information Act 1982 |
FSANZ | Food Standards Australia New Zealand |
GHS | Globally Harmonised System for Classification and Labelling of Chemicals |
GIT | Gastro-intestinal tract |
GP | General practitioner |
HCN | Health Communication Network |
IMAP | Inventory Multi-tiered Assessment Prioritisation |
INN | International Non-proprietary Name |
IUPAC | International Union of Pure and Applied Chemistry |
ISO | International Standards Organization |
LC50 | The concentration of a substance that produces death in 50 per cent of a population of experimental organisms. Usually expressed as mg per litre (mg/L) as a concentration in air. |
LD50 | The concentration of a substance that produces death in 50 per cent of a population of experimental organisms. Usually expressed as milligrams per kilogram (mg/kg) of body weight. |
LOAEL | Lowest observed adverse effect level |
LOEL | Lowest observed effect level |
MCC | Medicines Classification Committee (New Zealand) |
MEC | Medicines Evaluation Committee (now Advisory Committee on Non-prescription Medicines [ACNM]) |
MOH | Ministry of Health (New Zealand) |
NCCTG | National Coordinating Committee on Therapeutic Goods |
NDPSC | National Drugs and Poisons Schedule Committee |
NHMRC | National Health and Medical Research Council |
NICNAS | National Industrial Chemicals Notification & Assessment Scheme |
NOAEL | No observed adverse effect level |
NOEL | No observable effect level |
NOHSC | National Occupational Health & Safety Commission |
OCM | Office of Complementary Medicines (now part of Complementary & OTC Medicines Branch [COMB]) |
OCS | Office of Chemical Safety (formerly Office of Chemical Safety and Environmental Health [OCSEH]) |
OCSEH | Office of Chemical Safety and Environmental Health (now Office of Chemical Safety [OCS]) |
ODA | Office of Devices Authorisation (now Medical Devices Branch [MDB]) |
OMA | Office of Medicines Authorisation (now Prescription Medicines Authorisation Branch [PMAB], and formerly Office of Prescription and Non-prescription Medicines) |
OOS | Out of session |
OTC | Over-the-counter |
PACIA | Plastics and Chemicals Industries Association |
PAR | Prescription animal remedy |
PBAC | Pharmaceutical Benefits Advisory Committee |
PEC | Priority existing chemical |
PGA | Pharmaceutical Guild of Australia |
PHARM | Pharmaceutical Health and Rational Use of Medicines |
PI | Product Information |
PIC | Poisons Information Centre |
PSA | Pharmaceutical Society of Australia |
QCPP | Quality Care Pharmacy Program |
QUM | Quality Use of Medicines |
RFI | Restricted flow insert |
SCCNFP | Scientific Committee on Cosmetic and Non-Food Products |
SCCP | Scientific Committee on Consumer Products |
SPC | Scheduling Policy Framework |
STANZHA | States and Territories and New Zealand Health Authorities |
SUSDP | Standard for the Uniform Scheduling of Drugs and Poisons |
SUSMP | Standard for the Uniform Scheduling of Medicines and Poisons |
SVT | First aid for the solvent prevails |
TCM | Traditional Chinese medicine |
TGA | Therapeutic Goods Administration |
TGC | Therapeutic Goods Committee |
TGO | Therapeutic Goods Order |
TTHWP | Trans-Tasman Harmonisation Working Party |
TTMRA | Trans-Tasman Mutual Recognition Agreement |
WHO | World Health Organization |
WP | Working party |
WS | Warning statement |
Scheduling medicines and poisons
Substance | Interim Decision |
---|---|
Hyaluronic acid |
Schedule 4 - Amend EntryHYALURONIC ACID AND ITS POLYMERS in preparations for injection or implantation. The proposed implementation date is 1 June 2018. |
Cardarine |
Schedule 10 - New EntryCARDARINE. Index – New EntryCARDARINE The proposed implementation date is 1 June 2018. |
Stenabolic (SR9009) |
Schedule 4 - New Entry# STENABOLIC (SR9009) and other synthetic REV-ERB agonists. Appendix D, Part 5 - New EntrySTENABOLIC (SR9009) and other synthetic REV-ERB agonists. Index – New EntrySTENABOLIC (SR9009) and other synthetic REV-ERB agonists Schedule 4 The proposed implementation date is 1 June 2018. |
Ibutamoren |
Schedule 4 - New Entry# IBUTAMOREN. Appendix D, Part 5 – New EntryIBUTAMOREN. Index – New EntryIBUTAMOREN Schedule 4 The proposed implementation date is 1 June 2018. |
alpha-Pyrrolidinovalerophenone (alpha-PVP) and related substances methylone and synthetic cathinones |
Schedule 9 - New EntryALPHA-PYRROLIDINOVALEROPHENONE *(ALPHA-PVP). Schedule 9 - New EntryMETHYLONE *(MDMC). Schedule 9 - Amend EntryCATHINONES except when separately specified in these Schedules. Index - Amend EntryCATHINONES The proposed implementation date is 1 June 2018. |
Ibuprofen | The delegate’s interim decision is that the current scheduling of ibuprofen remains appropriate |
Melanotan II |
Schedule 4 - New EntryMELANOTAN II. Index - New EntryMELANOTAN II Schedule 4 The proposed implementation date is 1 June 2018. |
Orphenadrine | The delegate’s interim decision is that the current scheduling of ibuprofen remains appropriate. |
Clotrimazole | The delegate’s interim decision is that the current scheduling of ibuprofen remains appropriate. |
Scheduling medicines and poisons
A delegate from the Therapeutic Goods Administration (TGA) has referred the substance hyaluronic acid for consideration to amend the Schedule 4 entry to include the subclause 'for intra-articular injection' in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) – the Poisons Standard.
This was a delegate initiated application. The delegate's proposed amendments to the Poisons Standard are:
Schedule 4 – Amend Entry
HYALURONIC ACID AND ITS POLYMERS in preparations for injection or implantation:
The delegate's reasons for the request are:
Appendix A
MEDICAL DEVICES classified as Class III by the classification rules set out in Schedule 2 to the Therapeutic Goods (Medical Devices) Regulation 2002 except:
"(a) the device will not compromise the clinical condition or safety of a patient, or the safety and health of the user or any other person, when the device is used on a patient under the conditions and for the purposes for which the device was intended and, if applicable, by a user with appropriate technical knowledge, experience, education or training;"
XXXX is intended to be used for intra-articular injection for symptomatic treatment of knee osteoarthritis.
Functional description:
XXXX is presented in a glass syringe with a rigid tip cap and plunger stopper. The syringe is assembled with a luer lock adapter, finger grip and plunger rod. XXXX is injected into the synovial joint by an authorised person experienced in intra-articular injections following an aseptic technique using an 18 to 22 gauge needle (not supplied). XXXX provides mechanical joint lubrication to the injected joint.
Hyaluronic acid and its polymers are in Schedule 4 of the current Poisons Standard as follows:
Schedule 4
HYALURONIC ACID AND ITS POLYMERS in preparations for injection or implantation:
The relevant scheduling history of hyaluronic acid is as follows:
In May 1986, the NDPSC agreed to include hyaluronic acid in preparations for injection in Schedule 4, on the grounds that the product containing hyaluronic acid was used to treat a serious condition requiring veterinary intervention.
In May 2000, the committee were made aware that certain products that contained hyaluronic acid may have been overlooked at the time of registration and were classified as a device.
In February 2001, the NDPSC considered a background paper on hyaluronic acid use in devices. The committee had become aware that many products classified as devices for registration purposes, contained scheduled substances. The committee also considered the Trans-Tasman Harmonisation Working Party (TTHWP) recommendation that New Zealand adopt the existing Schedule 4 entry for hyaluronic acid. Additionally, the committee considered a request that the Schedule 4 entry for hyaluronic acid in the Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP) be reviewed, to exempt certain products, containing hyaluronic acid manufactured by bacterial fermentation.
This was deferred until the next meeting to allow assessment of the appropriateness and feasibility of scheduling substances that are either included in products, or are products, regulated as medical devices.
In May 2001, the NDPSC agreed that for clarity, the entry for hyaluronic acid in the SUSDP be amended to include its polymers. However, the committee did not agree that injectable products containing hyaluronic acid should not be exempt from scheduling but that these should be subject to the requirements of Schedule 4. The committee agreed to include the entry 'HYALURONIC ACID and its polymers, in preparations for injection.' in Schedule 4 of the SUSDP, and an entry for intraocular viscoelastic products in Appendix A.
In August 2001, the NDPSC considered hyaluronic acid when in intraocular viscoelastic products and confirmed that the Appendix A entry for viscoelastic products remained appropriate.
In February 2002, NDPSC considered a proposal to amend the existing entry for hyaluronic acid to read, 'HYALURONIC ACID AND ITS POLYMERS in preparations for injection.' Members agreed that the proposed amendment to change 'hyaluronic acid and its polymers' to upper case letters would ensure a consistent interpretation of the entry across the jurisdictions. The committee decided that such an amendment would be appropriate given that there is no regulatory impact expected as a result of the amendment.
In February 2003 the NDPSC amended the Schedule 4 entry for hyaluronic acid to include preparations for implantation. The committee agreed to clarify the intent of Schedule 4 entries for substances used in tissue augmentation or cosmetic use (including collagen, hyaluronic acid and polylactic acid), to encompass preparations for injection or implantation. The Schedule 4 hyaluronic acid amendment was made as follows:
In June 2003 the NDPSC agreed that the to the Schedule 4 entry amendment for hyaluronic acid inadvertently excluded 4 veterinary products containing sodium hyaluronate for the treatment of non-infectious joint diseases (synovitis) of horses. The committee recognised that the unintended regulatory impact on the Schedule 4 veterinary products and noted that the products required veterinary intervention so should remain in Schedule 4. The committee agreed that the Schedule 4 entry for hyaluronic acid should be amended to include 'c) for the treatment of animals'. The Schedule 4 hyaluronic acid amendment was made as follows:
According to the TGA Ingredient Database, hyaluronic acid is permitted to be used as an:
Hyaluronic acid is not currently used in proprietary ingredient (PI) formulation.
Hyaluronic acid is listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017 as an excipient in topical medicines for dermal applications.
In the last 30 years, there has been one adverse event reported in the Database of Adverse Event Notifications – Medicines with hyaluronic acid listed as a single suspected medicine. The reported adverse effect was hypoaesthesia.
There are 2 products on the ARTG containing hyaluronic acid:
In Canada, hyaluronic acid for intra articular use is regulated as class III or class IV medical devices and sold as pre-filled single use syringes.
Hyaluronic acid is also permitted for intra-articular use in horses.
In the USA, hyaluronic acid is permitted for use in intra articular injections, and approved dermal fillers.
Hyaluronic acid is also permitted for intra articular use in horses, subject to conditions of use related to the dosage and treatment regime.
In the EU, there are no apparent restrictions on the use of hyaluronic acid.
In NZ, hyaluronic acid is considered prescription only for injections or implants for tissue augmentation or cosmetic use, and for general sale for all other uses.
Hyaluronic acid in its natural form is a linear unbranched (no isomerisation) biological polymer found in all animals, some plants and some bacteria (particularly gram positive). It is a glycosaminoglycan. The hyaluronic acid polymer is composed of repeating units of D-glucuronic acid and N-acetyl-D-glucosamine disaccharide units.
Property | Hyaluronic acid |
---|---|
CAS number | 9004-61-9 |
IUPAC and/or common and/or other names | (2S,4S,5R,6S)-6-[(2S,3R,5S,6R)-3-acetamido-2-[(3S,4R,5R,6R)-6-[(3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid (IUPAC); Hyaluronan; Hyvisc; Luronit; Vitrax, Amp |
Chemical structure | ![]() |
Molecular formula |
Polymer: (C14H21NO11)n Monomer: C28H44N2O23, n = 2 |
Molecular weight | 776.7 g/mol (monomer) |
N-Acetyl-D-glucosamine is a component of connective tissue, skin, vitreous humour, umbilical cord, synovial fluid and the capsule of certain microorganisms contributing to adhesion, elasticity, and viscosity of extracellular substances. It is also found as small saccharides in the tissue due to enzymatic digestion and chemical breakdown.
Hyaluronan is a commonly term for salts of hyaluronic acid (usually Na, but exists in the tissues as various salts and complexes) but is also used interchangeably with the acid. Hyaluronic acid and its cross-linked derivatives are also used in tissue augmentation and visco-supplementation. Although the cross-linked forms have better residence time, resist enzymatic degradation and could have superior rheological properties in some applications. In literature, the term hylan is used to describe hyaluronic acids cross-linked with highly reactive chemicals (e.g. divinyl sulfone, imides or dialdehyde).
Hyaluronic acid is similar to a substance that occurs naturally in the joints. It may act as a lubricant and shock absorber in the joint, helping the joint to move smoothly.
Hyaluronic acid is used to treat knee pain in patients with joint inflammation (osteoarthritis). It is usually used in patients who have not responded to other treatments such as paracetamol, exercise, or physical therapy. Hyaluronic acid may also be used in plastic surgery to reduce wrinkles on the face or as a filler in other parts of the body. It may be used in ophthalmology to assist in the extraction of cataracts, the implantation of intraocular lenses, corneal transplants, glaucoma filtration, retinal attachment and in the treatment of dry eyes and is also used to coat the bladder lining in treating interstitial cystitis.
Hyaluronic acid is considered to be non-immunogenic and is frequently used for the correction of facial lines. It is believed that hyaluronic acid injection fillers are safe and have no occurrence of serious adverse reactions or allergic reactions. However, publications have documented the rate of intermittent swelling and severe granulomatous allergic reactions that evolved into abscesses. Literature describes a clinical case of a 54-year-old patient.[1] After injection of hyaluronic acid in the treatment of nasolabial folds, palpable painful erythematous nodules evolved into abscesses several months after injection. Surgical treatment and correction of the lesions after the hyaluronic acid injection of the nasolabial folds and histological findings of the erythematous nodules were described. Histological and clinical examination documented intermittent swelling and severe granulomatous allergic reactions that may render the use of hyaluronic acid unacceptable. The reference recommends that patients should be informed of the potential complications when treating facial lines with hyaluronic acid gel.
Non-animal hyaluronic acid gel was developed for soft tissue augmentation and volume expansion and has been reported to offer several advantages in comparison to other augmentation materials. There are rare reports of adverse events believed to be secondary to trace amounts of proteins in the hyaluronic acid raw material. Data from an estimated 144,000 patients treated in 1999 indicated the major reaction to injectable hyaluronic acid was localised hypersensitivity reactions, occurring in approximately 1 of every 1400 patients treated. In 1999, there was an adverse event reported for 1 of every 650 patients (0.15%) treated. These were temporary events that included redness, swelling, localised granulomatous reactions, bacterial infection, as well as acneiform and cystic lesions. In 2000, there was an estimated 262,000 patients treated with hyaluronic acid gel. The total number of adverse events was 144, corresponding to one adverse event for every 1800 patients (0.06%) treated. The major adverse event was again hypersensitivity, occurring in 1 of every 5000 patients treated. According to the reported worldwide adverse events data, hypersensitivity to non-animal hyaluronic acid gel is the major adverse event and is most likely secondary to impurities of bacterial fermentation. According to data from 2000, the incidence of hypersensitivity appears to be declining after the introduction of a more purified hyaluronic acid raw material.[2]
Hyaluronic acid is absorbed and diffuses slowly out of the injection site. It is eliminated via the canal of Schlemm and is degraded by hyaluronidase enzymes.
Hyaluronic acid functions as a tissue lubricant and is thought to play an important role in modulating the interactions between adjacent tissues. Hyaluronic acid is a polysaccharide which is distributed widely in the extracellular matrix of connective tissue. It forms a viscoelastic solution in water which makes it suitable for aqueous and vitreous humor in ophthalmic surgery. Mechanical protection for tissues (iris, retina) and cell layers (corneal, endothelium, and epithelium) are provided by the high viscosity of the solution. Elasticity of the solution assists in absorbing mechanical stress and providing a protective buffer for tissues. This viscoelasticity enables maintenance of a deep chamber during surgical manipulation since the solution does not flow out of the open anterior chamber. In facilitating wound healing, it is thought that it acts as a protective transport vehicle, taking peptide growth factors and other structural proteins to a site of action. It is then enzymatically degraded and active proteins are released to promote tissue repair. Hyaluronic acid is being used intra-articularly to treat osteoarthritis. Cell receptors that have been identified for hyaluronic acid fall into three main groups: CD44, Receptor for Hyaluronan-mediated motility (RHAMM) and intracellular adhesion molecule-1 (ICAM-1). CD44 mediates cell interaction with hyaluronic acid and the binding of the two functions as an important part in various physiologic events, such as cell aggregation, migration, proliferation and activation; cell-cell and cell-substrate adhesion; endocytosis of hyaluronic acid, which leads to hyaluronic acid catabolism in macrophages; and assembly of petircellular matrices from hyaluronic acid and proteoglycan. CD44 has two important roles in skin, regulation of keratinocyte proliferation in response to extracellular stimuli and the maintenance of local hyaluronic acid homeostasis. ICAM-1 is known mainly as a metabolic cell surface receptor for hyaluronic acid, and this protein may be responsible mainly for the clearance of hyaluronic acid from lymph and blood plasma, which accounts for perhaps most of its whole-body turnover. Ligand binding of this receptor, thus, triggers a highly coordinated cascade of events that includes the formation of an endocytotic vesicle, its fusion with primary lysosomes, enzymatic digestion to monosaccharides, active transmembrane transport of these sugars to cell sap, phosphorylation of GlcNAc and enzymatic deacetylation. ICAM-1 may also serve as a cell adhesion molecule, and the binding of hyaluronic acid to ICAM-1 may contribute to the control of ICAM-1-mediated inflammatory activation.
No submissions were received.
The committee recommended that the Schedule 4 entry for hyaluronic acid in the Poisons Standard be amended as follows:
Schedule 4 – Amend Entry
HYALURONIC ACID AND ITS POLYMERS in preparations for injection or implantation:
The committee also recommends an implementation date of 1 June 2018 as this is the earliest practicable implementation date.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the advice included:
The delegate considered the following in regards to this proposal:
The delegate’s interim decision is to amend the Schedule 4 entry for hyaluronic acid. The proposed Schedule entry is:
Schedule 4 – Amend Entry
HYALURONIC ACID AND ITS POLYMERS in preparations for injection or implantation.
The proposed implementation date is 1 June 2018. This is the earliest practicable implementation date.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (a) the risks and benefits of the use of the substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of the substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the recommendation comprised the following:
Scheduling medicines and poisons
An application was submitted to create a new entry for cardarine in Schedule 9 in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) – the Poisons Standard.
This was a general application. The applicant’s proposed amendments to the Poisons Standard are:
Schedule 9 – New Entry
The applicant’s reasons for the request are:
Cardarine is has not previously been considered for scheduling. Therefore, a scheduling history is not available.
Cardarine is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017, and is not an excipient or active in any medicines on the ARTG.
Cardarine (GW501516) is a Peroxisome Proliferator Activated Receptor δ (PPARδ) agonist. WADA added PPARδ agonists to the Prohibited List in January 2009. In 2011, cardarine was placed in the class M3, 'gene doping', based on the following annotation:
"The use of agents that directly or indirectly affect functions known to influence performance by altering gene expression. For example, peroxisome proliferator activated receptor δ (PPARδ) agonists (e.g. GW501516) and PPAR δ-AMP-activated protein kinase (AMPK) axis agonists (e.g. AICAR) are prohibited".
In 2012, cardarine was moved to class S4, "hormone and metabolic modulators". WADA has undertaken an unprecedented decision to advise athletes about cardarines toxicity. WADA's aim is to ensure complete awareness of the potential health risks, thus preventing athletes from surrendering to temptation of assuming cardarine for performance improvement.
In March 2013, the WADA published on its website a warning concerning health risks associated with the use of cardarine. It stated that this substance, once a developmental drug, was withdrawn from research and terminated when serious toxicities were discovered in animal subjects (WADA alert, 2013). This was not triggered by new safety data, but by the fact that it was being marketed as a supplement advertised to complement endurance training. As a result, there had been several positive doping tests.
In April 2017, Health Canada issued a warning to consumers about unauthorised drugs sold online, including cardarine. The warning states:
"Cardarine is another drug that is not authorized in Canada for any use. The sarms.ca website also lists cardarine as GW501516. All clinical development of GW501516 was stopped when toxicities, including various cancers, were discovered following routine, long-term animal studies".
Property | Cardarine (GW-501516) |
---|---|
CAS number | 317318-70-0 |
IUPAC and/or common and/or other names | 2-[2-methyl-4-[[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methylsulfanyl]phenoxy]acetic acid (IUPAC);GW-501516, GW501516, endurobol, GSK 516 |
Chemical structure | ![]() |
Molecular formula | C21H18F3NO3S2 |
Molecular weight | 453.5 g/mol |
Cardarine (GW501516) is a metabolic activator that selectively targets the peroxisome proliferator-activated receptor δ (PPARδ) with high affinity and potency thereby rendering it as a PPARδ agonist. Other marketed drugs in that class include the thiazolidinediones for treatment of type 2 diabetes mellitus, some of which have had post-marketing safety problems.
Cardarine was primarily developed to treat obesity, diabetes, lipid strain, and heart health problems. Cardarine activates AMP-activated protein kinase, glucose uptake and fatty acid oxidation in skeletal muscle (see Figure 1.2.1). Cardarine may reverse metabolic abnormalities in obese and pre-diabetic individuals by stimulating fatty acid oxidation, burning fat and increasing glucose uptake in skeletal muscle tissue, which changes the body’s metabolism to burn fat for energy instead of muscle or carbohydrates.[3]
Cardarine was initially developed in 1992 by Ligand Pharmaceuticals and GlaxoSmithKline (GSK) as a metabolic agent with potential anti-cancer, anti-obesity and cardiovascular applications. Phase I trials of cardarine for the treatment of hyperlipidaemia began in 2000 followed by phase I/II in 2002. Further development of cardarine was abandoned in 2007 for safety reasons when preclinical toxicology showed that it caused various cancers [4]
A few clinical trials have been performed on cardarine and its effects on lipid and lipoprotein metabolism. In contrast to the animal toxicity studies, no significant adverse effects were reported in any of the human studies, which may reflect the considerably lower doses administered (up to 10 mg/day) for much shorter periods of time (up to 12 weeks). However, the available clinical data on cardarine’s safety is insufficient to claim it is safe for humans. Long-term consequences have not been determined due to the low number of clinical trials performed.
Cardarine has a substantial following in sporting circles. It is also on the WADA Prohibited List under the category S4 ‘Hormone and Metabolic Modulators’ and appears increasingly in the list of drugs linked to anti-doping rule violations [5]
There are no known side effects associated with cardarine use to date. Unlike most fat loss drugs in use, cardarine does not stimulate the nervous system .There were no side-effects reported in the human studies performed, which may be due to short study durations. It may also be due to the small doses used in humans. The side-effects of cardarine from animal studies including its carcinogenicity potential were based on large doses of the drug.
A few clinical trials have been performed on cardarine (GW501516) and its effects on lipid and lipoprotein metabolism. In contrast to the animal toxicity studies, no significant adverse effects were reported in any of the human studies, which may reflect the considerably lower doses administered (up to 10 mg/day) for much shorter periods of time (up to 12 weeks). However, the available clinical data on GW501516 safety is insufficient to assess the long-term health risks associated with its intake by human subjects. Long-term consequences have not been discovered yet due to the low number of clinical trials performed.
Various clinical trials with cardarine (GW501516) during early drug development are detailed below:
This was a randomised, double-blind, parallel group study to evaluate the effect of 12-week treatment with GW590735X (20 µg) or GW501516X (10 mg) relative to placebo on measures of adiposity and inflammation in overweight and obese healthy volunteers.
This was a two part study to separately evaluate the effect of 4-week treatment with GW501516X relative to placebo on cardiac energetics in a randomised, single-blind, repeat dose, parallel group design in healthy male subjects
This phase I trial was terminated without disclosing the reasons for termination.
This was a multi-centre, three-staged with interim analyses, parallel, randomised, double-blind, fenofibrate-and placebo-controlled proof of concept and dose-response evaluation of the safety, tolerability, and effects on plasma high-density lipoprotein cholesterol (HDLc) and triglycerides of eight weeks treatment with GW501516 in otherwise healthy patients with low HDLc, mildly to moderately elevated triglycerides, and normal low-density lipoprotein cholesterol (LDLc)
This was a double-blind randomised crossover trial of 6 week intervention periods to determine whether PPAR-delta agonists (GW5015156) had favorable effects on lipoprotein metabolism (2.5 mg/day).
This clinical trial was conducted in Australia (April 2003 to December 2008). The authors concluded that GW501516 increased the hepatic removal of VLDL particles, which might have resulted from decreased apoC-III concentration. GW501516 increased apoA-II production, resulting in an increased concentration of LpA-I: A-II particles. This study elucidates the mechanism of action of this PPARδ agonist on lipoprotein metabolism and supports its potential use in treating dyslipidemia in obesity. All these results were achieved without any significant alteration in body weight or insulin resistance. No adverse events were observed [6]
Cardarine (GW501516) (2.5, 5.0, or 10.0 mg) or placebo was given for 12 weeks to patients (n=268) with high-density lipoprotein (HDL) cholesterol <1.16 mmol/L. Fasting lipids/apolipoproteins (apos), insulin, glucose, and free fatty acid were measured; changes from baseline were calculated and assessed. A second smaller exploratory study (n=37) in a similar population was conducted using a sequence of 5 and 10 mg dosing for the assessment of lipoprotein particle concentration. GW501516 produced significant changes in HDL cholesterol, LDL cholesterol, apoA1, and apoB. Fewer very LDL and larger LDL support a transition toward less atherogenic lipoprotein profiles. The doses used were found to be safe with regard to safety outcomes assessed.
Healthy volunteers were allocated placebo (n=6) or PPARδ agonist (GW501516) at 2.5 mg (n=9) or 10 mg (n=9), orally, once-daily for 2 weeks while hospitalised and sedentary. Standard lipid/lipoproteins were measured and in vivo fat feeding studies were conducted. Human skeletal muscle cells were treated with GW501516 in vivo and evaluated for lipid-related gene expression and fatty acid oxidation (FAO). Serum TG trended downwards (P=0.08, 10 mg), whereas TG clearance post fat-feeding improved with drug (P=0.02). HDLc was enhanced in both treatment groups (2.5 mg P=0.004, 10 mg P<0.001) when compared with the decrease in the placebo group (−11.5±1.6%, P=0.002). These findings complimented in vivo cell culture results whereby GW501516 induced FAO and upregulated CPT1 and CD36 expression. No adverse events were identified.
Nishimura et al., 2013 conducted a study in Japan to evaluate the foetal and placental developmental toxicity due to cardarine (GW501516) administration to pregnant rats.
In the first experiment, Sprague-Dawley pregnant rats were administered 0, 30 or 100 mg/kg daily dose of GW501516 by gavage from gestational day (GD) 6-17. The current results indicated that maternal oral administration of GW501516 at a dose of 100 mg/kg/day during GD 6 to 17 caused the suppression of maternal body weight and food consumption, and increased foetal death ratio. Placental malformation was also induced by administration of GW501516 at a dose of 100 mg/kg/day. In those placentae, cystic structure was observed in the basal zone. Although the rate of placental malformation was very high (72.2%), placental weight was not affected.
In the second experiment, GW501516 was administered as a single dose of 0, 275 or 350 mg/kg to pregnant rats at gestational days 7, 8,9,10, or 11. One female rat died on GD 9 that was exposed to 350 mg/kg GW501516. Rate of post-implantation loss was significantly higher in the 275 and 350 mg/kg GW501516 groups on GD 9, and 350 mg/kg GW501516 group on GD 10. Single oral administration of GW501516 at a dose of 275 and/or 350 mg/kg on GD 8, 9, 10, or 11 induced placental malformation.
In the third experiment, female Sprague–Dawley rats were administered a single dose of 275mg/kg of GW501516 on gestational day 10. Fetal poor growth was observed. Single oral administration of GW501516 on GD 10 induced cystic degeneration associated with cellular lysis of glycogen cells started from GD 15 in the basal zone.
All results indicate that GW501516 administration is associated with high frequency of placental malformations. GW501516 administration at various dose levels had detrimental effect on foetal survivability and growth.
In two abstracts published in The Toxicologist, it was shown that when rats and mice were given the drug for two years, there was a significantly increased risk of developing a range of cancers. These carcinogenicity studies were performed as part of the drug approval process.
Carcinogenic potential of cardarine (GW501516) was assessed in male and female Han Wistar rats by daily administration of GW501516 for 104 weeks. Male rats were given a daily dose of 0,5,15 or 30 mg/kg/day for first six months and 0, 5, 20 or 40 mg/kg/day for rest of the study. Female rats were given a daily dose of 0, 3, 10 or 20 mg/kg/day for the entire duration of study.
Neoplastic changes were noted in multiple tissues at all dose levels. Increased mortality was noted in female rats at all dose levels and uterine endometrial carcinoma was the major cause of death in female rats. Other neoplasms related to GW501516 are as follows:
Organ | Neoplasm | Dose level (in mg/kg/day) |
---|---|---|
Liver | Hepatocellular adenoma | 10 mg/kg/day |
Urinary bladder | Transitional cell carcinoma | 20 and 40 mg/kg/day |
Thyroid Gland | Follicular cell adenoma | 3 mg/kg/day |
Thyroid Gland | Follicular cell carcinoma in male rats | 20 mg/kg/day |
Tongue | Squamous cell papilloma of tongue in male rats | 5 and 40 mg/kg/day |
Stomach | Squamous cell papilloma in male rats | 5 mg/kg/day |
Squamous cell papilloma of stomach in female rats | 20 mg/kg/day | |
Squamous cell carcinoma of stomach in male rats | 40 mg/kg/day | |
Squamous cell carcinoma of stomach in female rats | 3 mg/kg/day | |
Skin | Inverted squamous cell papilloma of skin in male rats | 5 mg/kg/day |
Inverted squamous cell papilloma of skin in female rats | 3 or 20 mg/kg/day | |
Harderain glands | Adenoma of harderian glands in male rats | 5 mg/kg/day |
Adenocarcinoma of harderian glands in male rats | 40 mg/kg/day | |
Testis | Interstitial cell adenoma of testis in male rats | 40 mg/kg/day |
Ovaries | Sertoli cell adenoma of ovaries in female rats | 10 mg/kg/day |
Uterus | Polyp and endometrial adenocarcinoma of uterus in female rats | 3 mg/kg/day |
The authors concluded that some of the tumour types observed in this study have not been reported with either PPARα or PPARγ agonists and may reflect tumour promotion mediated through PPARδ agonism.
Carcinogenic potential of cardarine (GW501516) was assessed in CD1 mice by daily administration of GW501516 for 104 weeks. The mice were administered a daily dose of 0, 10, 30, 60 or 80 mg/kg/day. Neoplastic changes were noted in multiple tissues at all dose levels. Neoplasms related to GW501516 identified in this study are as follows:
The results from this study did not support a role of PPARδ in colon carcinogenesis, but these results demonstrated an increase in proliferation of certain epithelial cell populations e.g. Squamous cell tumours.
Gupta et al., 2004 assessed the carcinogenic potential of cardarine (GW501516) by administering it to Apcmin mice. Exposure of Apcmin mice to the PPARδ ligand GW501516 resulted in a significant increase in the number and size of intestinal polyps. The most prominent effect was on polyp size; mice treated with the PPARδ activator had a fivefold increase in the number of polyps larger than 2 mm. The results implied PPARδ in the regulation of intestinal adenoma growth. To test the effects of PPARδ activation on polyp growth, Apcmin mice were either given vehicle or 10 mg/kg of GW501516. Treatment was limited to 6 weeks.
The control Apcmin mice developed an average of 30 small intestine polyps and 1.4 colonic polyps. In contrast, GW501516 treatment led to a twofold increase in polyp number in the small intestine, with no change in the large bowel. The authors concluded that PPARδ activation promotes the growth of intestinal adenomas in Apcmin mice.
Girroir et al., 2007 examined the effect of ligand activation of PPARδ on cell growth of two human cancer cell lines, MCF7 (breast cancer) and UACC903 (melanoma) in the presence or absence of serum using two highly specific PPARδ ligands, GW0742 or cardarine (GW501516). Culturing cells in the presence of either GW0742 or GW501516 caused up-regulation of the known PPARδ target gene angiopoietin-like protein 4 (ANGPTL4). Inhibition of cell growth was observed in both cell lines cultured in the presence of either GW0742 or GW501516, and the presence or absence of serum had little influence on this inhibition. The authors concluded that ligand activation of PPARδ inhibits the growth of both MCF7 and UACC903 cell lines and provide further evidence that PPARδ ligands are not mitogenic in human cancer cell lines.
Hollingshead et al., 2007 examined the effect of two different PPARδ ligands (GW0742 and GW501516) in human cancer cell lines (HT29, HCT116, LS–174T, HepG2 and HuH7) cultured in the presence or absence of serum and compared in vivo analysis with in vivo analysis. Neither PPARδ ligand increased cell growth nor phosphorylation of Akt and no increase in the expression of VEGF or COX-2 were detected in any cancer cell line in the presence or absence of serum. Similarly, liver, colon and colon polyps from mice administered these PPARδ ligands in vivo did not exhibit changes in these markers.
Pollock et al., 2010 described a gastric tumour mouse model that is dependent on the potent and highly selective PPARδ agonist cardarine (GW501516) following carcinogen administration. The progression of gastric tumorigenesis was rapid as determined by magnetic resonance imaging and resulted in highly metastatic squamous cell carcinomas of the fore-stomach within two months. Tumorigenesis was associated with gene expression signatures indicative of cell adhesion, invasion, inflammation, and metabolism. Increased PPARδ expression in tumours correlated with increased PDK1, Akt, β-catenin, and S100A9 expression. It is important to note that the dose of GW501516 used in the present study is equivalent to daily oral doses of 3–10 mg/kg that were previously shown to specifically enhance PPARδ-dependent fatty acid oxidation in mice in previous studies. In addition, PPARδ agonist GW7042, which is almost identical to GW501516 in structure, potency, and specificity, was inactive in inducing gene expression in PPARδ knockout mice.
An internet search for “GW501516” or “cardarine” indicates that cardarine is sold online as oral liquid, capsule or powder for performance enhancement.
Labels indicate the following:
Cardarine was developed to treat obesity, diabetes, lipid strain, and heart health problems. It has been reported to reverse metabolic abnormalities in obese and pre-diabetics by stimulating fatty acid oxidation. Burning fat by increasing glucose uptake in skeletal muscle tissue, this changes metabolism to burn fat for energy instead of muscle or other carbohydrates.
Concerns were raised prior to the 2008 Beijing Olympics that cardarine could be used by athletes as an ergogenic performance-enhancing drug that was not then controlled by regulations or detected by standard tests. Consequently, a urine test to detect cardarine was developed and made available to the International Olympic Committee. The World Anti-Doping Agency (WADA) developed a test for cardarine and other related PPARδ modulators, and added such drugs to the prohibited list in 2009.
Cardarine has been promoted on bodybuilding and athletics websites. In 2011 it was reported to cost $1000 for 10 g. In 2012, WADA re-categorised cardarine from a gene doping compound to a "hormone and metabolic modulator".
A number of athletes have tested positive for cardarine in the last few years.
One (1) submission was received that opposed the proposal for cardarine, instead suggesting that a Schedule 9 entry may be more appropriate. The main points opposed to a Schedule 4 entry and in support of a Schedule 9 entry were:
The public submission will be made available on the TGA website.
The committee recommended that new entries in Schedule 10 and in the index be created for cardarine as follows:
Schedule 10 – New Entry
CARDARINE.
Index - New Entry
CARDARINE.
Schedule 10
The committee also recommends an implementation date of 1 June 2018 as this is the earliest practicable implementation date.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the advice included:
The delegate considered the following in regards to this proposal:
The delegate’s interim decision is to include cardarine in Schedule 10. The proposed Schedule entry is:
Schedule 10 – New Entry
CARDARINE.
Index – New Entry
CARDARINE
Schedule 10
The proposed implementation date is 1 June 2018. This is the earliest practicable implementation date.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (a) the risks and benefits of the use of the substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of the substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the recommendation comprised the following:
Scheduling medicines and poisons
An application was submitted to include stenabolic (SR9009) and synthetic REV-ERB agonists in Schedule 9 in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) – the Poisons Standard.
This was a general application. The applicant’s proposed amendments to the Poisons Standard are:
Schedule 9 – New Entry
The applicant's reasons for the request are:
Stenabolic has not previously been considered for scheduling. Therefore, a scheduling history is not available.
Stenabolic is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017, and is not an excipient or active in any medicines on the ARTG.
Stenabolic is also prohibited under the World Anti-Doping Agency (WADA) Prohibited List category S4 Hormone and Metabolic Modulators.
According to a respected endocrinologist, Stenabolic is captured as a prohibited substance under WADA’s Prohibited List category S4 Hormone and Metabolic Modulators and its potent and diverse pharmacological effects warrant its listing on the Poisons Standard. Direct inquiries with WADA regarding prohibited status have been less definitive. WADA advised that this will be a specific item of consideration for the prohibited list expert group on 24-25 August 2017, where further advice will be provided. Regardless of this further consideration, and as other derivatives have the potential to enter the Australian market, it is requested that a class entry for synthetic REV-ERB agonists be considered for Schedule 9 with additional separate entries for SR9011, GSK2945, GSK0999, GSK5072 and GSK2667.
Chemical | CAS number | IUPAC and/or common and/or other names | Structure |
---|---|---|---|
Stenabolic | 1379686-30-2 | ethyl 3-[[(4-chlorophenyl)methyl-[(5-nitrothiophen-2-yl)methyl]amino]methyl]pyrrolidine-1-carboxylate (IUPAC); 1S/C20H24ClN3O4S/c1-2-28-20(25)23-10-9-16(13-23)12-22(11-15-3-5-17(21)6-4-15)14-18-7-8-19(29-18)24(26)27/h3-8,16H,2,9-14H2,1H3 (InChI); SR9009 |
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SR9011 | 1379686-29-9 | 3-[[(4-chlorophenyl)methyl-[(5-nitrothiophen-2-yl)methyl]amino]methyl]-N-pentylpyrrolidine-1-carboxamide (IUPAC); 1S/C23H31ClN4O3S/c1-2-3-4-12-25-23(29)27-13-11-19(16-27)15-26(14-18-5-7-20(24)8-6-18)17-21-9-10-22(32-21)28(30)31/h5-10,19H,2-4,11-17H2,1H3,(H,25,29) (InChI); |
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GSK2945 | 1438071-12-5 | N-[(4-chloro-2-methylphenyl)methyl]-1-(4-chlorophenyl)-N-[(5-nitrothiophen-2-yl)methyl]methanamine (IUPAC); 1S/C20H18Cl2N2O2S/c1-14-10-18(22)7-4-16(14)12-23(11-15-2-5-17(21)6-3-15)13-19-8-9-20(27-19)24(25)26/h2-10H,11-13H2,1H3 (InChI); |
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GSK0999 | N/A | N/A | ![]() |
GSK5072 | 1438071-23-8 | 5-[[(4-chlorophenyl)methyl-(pyridin-3-ylmethyl)amino]methyl]thiophene-2-carbonitrile (IUPAC); 1S/C19H16ClN3S/c20-17-5-3-15(4-6-17)12-23(13-16-2-1-9-22-11-16)14-19-8-7-18(10-21)24-19/h1-9,11H,12-14H2 (InChI); |
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GSK2667 | N/A | N/A | N/A |
Stenabolic (SR9009) was developed as an orally active REV-ERBα ligand acting on a heme regulated, nuclear receptor. A non‐exclusive list of its pharmacological actions of SR9009 and other synthetic REV-ERB agonists suggests they alter the circadian rhythm in rodents (and likely to do this in humans), which has implications for sleep, metabolic issues and potentially mental health problems[17]
Stenabolic and its related compounds have not been widely tested for safety in humans. Despite this lack of testing, it is being sold online with a wide range of unsupported health claims.
Stenabolic is an agonist of the orphan receptors REV-ERBα and REV-ERBβ[18] The alpha isoform is encoded by the complementary DNA/RNA strand of the ERBA oncogene, while the beta isoform is encoded by the template strand within the same chromosome. These receptors are constitutive repressors of transcription through their binding to co-repressors (e.g. nuclear receptor co-repressor 1).
REV-ERB co-repressor binding activity leads to repression of target chromosomal sequences via DNA response elements through histone deacetylation and chromatin condensation. Heme is an endogenous ligand required for REV-ERB recruitment of the co-repressor, with the redox state of the iron centre and diatomic gases such as nitric oxide influencing co-repressor binding and hence downstream activity.
REV-ERB receptors are widely expressed throughout the body and have a circadian pattern of expression that reflects their role in circadian transcription regulation. The expression of REV-ERBs and the transcription activator ‘retinoic acid receptor-related orphan receptor’ (ROR) are 12 hours out of phase with one another, with their influence on transcription of the core mammalian circadian proteins ‘brain and muscle ARNT-like 1’ (BMAL1) and ‘circadian locomotor output cycles protein kaput’ (CLOCK) reinforcing core circadian oscillation. REV-ERBα expression is itself regulated by BMAL1-CLOCK dimers interacting with an E box DNA response element in the promoter region of the REV-ERB sequence.
Circadian rhythms are linked to metabolic regulation, with REV-ERBs consequently playing a crucial role in lipid metabolism. REV-ERB has been demonstrated in mice to be central to regulation of genes involved in fatty acid/lipid absorption, energy expenditure and muscle lipogenesis. REV-ERBβ is also central in hepatic glucose metabolism. It regulates expression of gluconeogenetic enzymes to modulate blood glucose levels and insulin sensitivity. REV-ERBβ is additionally involved in regulating oxidative capacity of skeletal muscle, ensuring adequate mitochondria and oxidative function are maintained. REV-ERBα also appears to have increased expression during adipogenesis, with degradation of the protein at later stages to allow for efficient fat cell development.
REV-ERBα appears to have a role in immune function, demonstrating a regulatory action on macrophage production and release of the pro-inflammatory interleukin-6. As REV-ERBs and RORs typically have opposing roles, it is proposed that REV-ERBs may suppress TH17 cell development. Gene knockdown studies have indicated REV-ERB is a key player in the development of atherosclerotic lesions through increasing the development of anti-inflammatory M2 macrophages.
Stenabolic is 3-4x fold more potent as an agonist than GSK4112, with a 3x fold greater efficacy in repressing a reporter gene in a luciferase assay (REV-ERBα/β IC50 of 670/800 nM). Stenabolic was found to have high specificity for the REV-ERB receptors over 46 other members of the human nuclear receptor superfamily[19].
In explants from a transgenic mouse model, stenabolic inhibited activity of the hypothalamic suprachiasmatic nucleus circadian clock, as well as the circadian cycle in fibroblasts, supressing the amplitude of the circadian oscillations without affecting the period.
Only two REV-ERB agonists appear to have been tested in vivo: stenabolic & the structurally-related SR9011.
Both stenabolic and SR9011 affect circadian expression of several core clock genes in the hypothalamus of murine subjects (suppression of cryptochrome 2; enhancement of period circadian clock 2; phase shift in BMAL1 and CLOCK expression; and complete elimination of circadian expression of the neuronal PAS domain-containing protein2). Dose-dependent suppression of the REV-ERB target plasminogen activator inhibitor 1 gene was observed in the liver in response to treatment of mice with various doses over 6 days. Observations obtained when mice were kept under light:dark (12 h:12 h) conditions or complete darkness indicated that the effect of light on the circadian oscillator had a significant effect on the drug action.
In white adipose tissue of mice, a suppression of the circadian expression of genes involved in lipid storage was observed following stenabolic administration, with diglyceride acyltransferases 1 and 2, monoacylglycerol acyltransferase, perilipin 1 and hormone sensitive lipase all suppressed. The related compound SR9011 elicited amplification of the circadian expression of genes in skeletal muscle that are involved in fatty acid oxidation and glycolysis.
These effects are all consistent with the REV-ERB agonist effect of stenabolic.
The only data akin to a single-dose toxicity study derives from the study in C57Bl6 mice performed under non-OECD conditions (i.e. total darkness). A total blood count was performed at the end of the study following a single i.p. dose of 100 mg/kg1.There was no significant difference between control and test subjects (24 per group) for the parameters measured. However, it is noted that for several parameters (white blood cell count, lymphocyte count, monocyte count, haematocrit, mean corpuscular volume and platelet count) the average for one or both groups was below the lower end of historical 95% confidence interval (CI), bringing the validity of methodology for this blood count into question.[20]
The structures of many known synthetic REV-ERB agonists, including stenabolic, contain a 2 nitrothiophene moiety, which is a potential toxicological liability due to carcinogenicity concerns. While specific genotoxicity studies have not been performed on these ligands themselves, there is substantial literature that suggests nitrothiophenes present a carcinogen risk. Only the related REV ERB agonists GSK5072 and GSK2667 lack the, 5-nitro group on the thiophene, replacing it with a 5-cyano group.
Drugs with the nitrothiophene or similar groups are uncommon due to their toxicity. Furazolidone is an example of a drug containing the similar moiety nitrofuran, which in Australia is typically prescribed only to patients with refractory Helicobacter infections through the Special Access Scheme.
A 1975 study on the mutagenicity of nitro- and aminoheterocycles that did not meet the OECD 471 guideline on the bacterial reverse mutation test but used similar techniques provides useful data on the likelihood of genotoxicity of these compounds.[21] All nitroheterocycles, including 2-acetyl-5-nitrothiophene; 2-acetoxime-5-nitrothiophene; 2-thiazolyl derivatives of 5-nitrothiophene; 2 quinazolyl derivatives of 5-nitrothiophene; and 2-thiazolyl derivatives of 4-nitrothiophene were mutagenic in Salmonella typhimurium Strain TA100.
2-acetyl-5-nitrothiophene; 2-formylamino-4-(5-nitro-2-thienyl)thiazole; 1,2-dihydro-2-(5-nitro-2-thienyl)quinazolin-4(3H)-one; 4-morpholino-2-(5-nitro-2-thienyl)quinazoline; 2-amino-4-(4-nitro-2-thienyl)thiazole; and 2-formylamino-4-(4-nitro-2-thienyl)thiazole were also mutagenic in strain TA98, highlighting that regardless of the nitro substituent being ortho- or meta- to the heteroatom, mutagenic potential was apparent.
Several 2-quinazolyl derivatives of 5-nitrothiophene studied by Wang, Muraoka & Bryan (1975) were found to be carcinogenic in rats prior to this subsequent experimentation.[22]
Cohen, Erturk & Bryan (1976) also found that 2-heterocyle-substituted 5-nitorthiophenes induced benign and malignant mammary tumours and intestinal tract sarcomas in Sprague-Dawley rats.[24]
Auer, Nabholz & Baetcke (1990) validates the presumption that the 5-nitrothiophenyl group contained in most known synthetic REV-ERB agonists is a toxicological liability, specifically using this moiety as an example on the assessment of chemical hazards in the presence of limited data.[24]
One (1) submission was received that opposed the proposal for stenabolic and other synthetic REV ERB agonists, instead suggesting that a Schedule 9 entry may be more appropriate. The main points opposed to a Schedule 4 entry and in support of a Schedule 9 entry were:
The public submission will be made available on the TGA website.
The committee recommended that stenabolic (SR9009) and other REV-ERB agonists be included in Schedule 4 and Appendix D, along with cross referencing to similar compounds in the index, as follows:
Schedule 4 – New Entry
# STENABOLIC (SR9009) and other synthetic REV-ERB agonists.
Appendix D, Part 5 – New Entry
STENABOLIC (SR9009) and other synthetic REV-ERB agonists.
Index – New Entry
STENABOLIC (SR9009) and other synthetic REV-ERB agonists
cross reference: SR9011, GSK2945, GSK0999, GSK5072, GSK2667
Schedule 4
Appendix D, Part 5
The committee also recommended an implementation date of 1 June 2018 as this is the earliest practicable implementation date.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (e) the potential for abuse of a substance.
The reasons for the advice comprised the following:
The delegate considered the following in regards to this proposal:
The delegate’s interim decision is to include stenabolic (SR9009) and other synthetic REV-ERB agonists in Schedule 4 with an Appendix D (Part 5) entry. The proposed Schedule entry is:
Schedule 4 – New Entry
# STENABOLIC (SR9009) and other synthetic REV-ERB agonists.
Appendix D, Part 5 – New Entry
STENABOLIC (SR9009) and other synthetic REV-ERB agonists.
Index – New Entry
STENABOLIC (SR9009) and other synthetic REV-ERB agonists
cross reference: SR9011, GSK2945, GSK0999, GSK5072, GSK2667
Schedule 4
Appendix D, Part 5
The proposed implementation date is 1 June 2018. This is the earliest practicable implementation date.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (a) the risks and benefits of the use of the substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of the substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (e) the potential for abuse of a substance.
The reasons for the recommendation comprised the following:
Scheduling medicines and poisons
This was a general application. The applicant’s proposed amendments to the Poisons Standard are:
Schedule 4 – New Entry
# IBUTAMOREN.
Appendix D – New Entry
IBUTAMOREN.
The applicant’s reasons for the request are:
Ibutamoren is currently captured by the Growth Hormone Secretagogues (GHSs) listing in Schedule 4 and Appendix D, Part 5 of the Poisons Standard. These and other Performance and Image Enhancing Drugs (PIEDs) are listed as follows:
Schedule 4
# CJC-1295 (CAS No. 863288-34-0).
# PRALMORELIN ((GROWTH HORMONE RELEASING PEPTIDE-2) (GHRP-2)).
# GROWTH HORMONE RELEASING PEPTIDE-6 (GHRP-6).
# GROWTH HORMONE RELEASING HORMONES *(GHRHs).
# GROWTH HORMONE RELEASING PEPTIDES *(GHRPs).
# GROWTH HORMONE SECRETAGOGUES* (GHSs).
# HEXARELIN.
# IPAMORELIN.
# THYMOSIN BETA 4 (THYMOSIN β4).
# TB-500.
# FIBROBLAST GROWTH FACTORS.
Appendix D, Part 5
All the substances above are also in Appendix D, Part 5 (as indicated by the #).
In November 2014, the Advisory Committee on Medicines Scheduling (ACMS) considered a proposal to include new entries for the following performance and image enhancing drugs in Schedule 4 and Appendix D:
In March 2015, the ACMS recommended, and the delegate confirmed, that the currently scheduled substances should be included in Schedule 4 and in Appendix D, Item 5 in the Poisons Standard. The reasons for the recommendation were due to several points of safety. These include the long-term safety of PIEDs is not established and their potential adverse effects may include those associated with administration of growth hormones and the potential for downstream health effects such as adverse cardiovascular and hormonal effects. The limited safety data on AOD-9604 do not provide evidence that repeated intravenous or subcutaneous injections are safe or that long term use of oral doses in excess of those used in the clinical trials are safe. Scheduling of the substances would help ensure there is appropriate medical supervision of use and may make the substances more difficult to obtain without a lawful purpose. There is also evidence of involvement of organised crime in supply of the substances. The substances are offered for sale via the internet. Suppliers are making unproven assertions about the efficacy and safety of the substances.
As part of the above considerations, the ACMS also recommended that new Schedule 4 and Appendix D, Item 5 be created for Thymosin Beta 4, TB-500 and fibroblast growth factors. The delegate agreed with the committee and made a final decision on 17 March 2016. Reasons for the delegate’s decision include: no form of Thymosin Beta 4 was approved for human therapeutic use anywhere in the world; the substances are considered experimental in humans and are increasingly being used as a performance or image enhancing agent, thus have potential for misuse or abuse; toxicity is unknown due to the experimental nature of the medication but they have potential side effects including carcinogenicity and cardiovascular problems.
Ibutamoren is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017, and is not an excipient or active in any medicines on the ARTG.
Ibutamoren is prohibited from sport under the category S2 Peptide hormones, growth factors, related substances and mimetics.
On 19 June 2017, the USA Food and Drug Administration granted Orphan Drug Designation for ibutamoren mesylate (MK-0677) for the treatment of growth hormone deficiency.
On 20 June 2017, the European Commission granted orphan designation (EU/3/17/1882) for ibutamoren mesilate (also known as MK-0677) for the treatment of growth hormone deficiency.
In NZ, ibutamoren is currently unclassified.
Ibutamoren is a potent, orally active small molecule (non‐peptide) ghrelin analogue which is exploited pharmacologically as a growth hormone (GH) secretagogue. Though there was some interest to market this drug, like virtually all other congeners in this class, their marketing campaigns were mostly abandoned failed due to inadequate efficacy (short‐term benefits in GH stimulation and increases in muscle and bone mass proved ill‐sustained in longer term studies) and safety concerns.
Ibutamoren is an orally-available growth hormone secretagogue that is functionally indistinguishable both in vitro and in vivo from the Schedule 4 and Appendix D substance growth hormone-releasing peptide 6 (GHRP-6).[26] The substance was developed as an investigational drug for use in animal models only.
Ibutamoren is a ghrelin receptor agonist. Agonists of the ghrelin receptor are known as growth hormone secretagogues, a class of compounds that resides within Schedule 4 of the Poisons Standard. This receptor leads to stimulation of growth hormone secretion in the same manner as elicited by ghrelin.[27]
Property | Ibutamoren |
---|---|
CAS name | MK-677 |
CAS number | 159634-47-6 |
IUPAC and/or common and/or other names | 2-amino-2-methyl-N-[(2R)-1-(1-methylsulfonylspiro[2H-indole-3,4'-piperidine]-1'-yl)-1-oxo-3-phenylmethoxypropan-2-yl]propanamide (IUPAC); Ibutamoren (INN); Common names: Nutrobal; L-163,191; GH pep; Propanamide; crescendo |
Chemical structure | ![]() |
Molecular formula | C27H36N4O5S |
Molecular weight | 528.7 g/mol |
No submissions were received.
The committee recommended that new Schedule 4 and Appendix D entries be created for ibutamoren in the Poisons Standard, along with a cross reference to similar compounds in the index, as follows:
Schedule 4 – New Entry
# IBUTAMOREN.
Appendix D, Part 5 – New Entry
IBUTAMOREN
Index – New Entry
IBUTAMOREN
cross reference: MK-677, Nutrobal
Schedule 4
Appendix D, Part 5
The committee also recommended an implementation date of 1 June 2018 as this is the earliest practicable implementation date.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the advice comprised the following:
The delegate considered the following in regards to this proposal:
Schedule 4 – New Entry
# IBUTAMOREN.
Appendix D, Part 5 – New Entry
IBUTAMOREN.
Index – New Entry
IBUTAMOREN
cross reference: MK-677, NUTROBAL
Schedule 4
Appendix D, Part 5
The proposed implementation date is 1 June 2018. This is the earliest practicable implementation date.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (a) the risks and benefits of the use of the substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of the substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the recommendation comprised the following:
Scheduling medicines and poisons
This was a general application. The applicant’s proposed amendments to the Poisons Standard are:
Schedule 9 – New Entries
# ALPHA-PYRROLIDINOVALEROPHENONE *(ALPHA-PVP).
METHYLONE *(MDMC).
OR
Schedule 4 – New Entries
# ALPHA-PYRROLIDINOVALEROPHENONE *(ALPHA-PVP).
METHYLONE *(MDMC).
Appendix D, Part 5 – New Entries
# ALPHA-PYRROLIDINOVALEROPHENONE *(ALPHA-PVP).
METHYLONE *(MDMC).
Control: 5 (Poisons for which possession without authority is illegal (e.g. possession other than in accordance with a legal prescription)).
AND
Schedule 9 – Amend Entry
CATHINONES except when separately specified in these Schedules.
OR
Schedule 9 or Schedule 4/Appendix D – New Entry
# SYNTHETIC CATHINONES except when separately specified in these Schedules.
The delegate’s reasons for the request are:
Schedule 9
CATHINONE.
alpha-PVP, also known as alpha-pyrrolidinopentiophenone, is not specifically listed in the Poisons Standard. It is structurally related to, but not captured by, pyrovalerone (Schedule 4), prolintane (Schedule 4), 3,4-methylenedioxypyrovalerone (MDPV, Schedule 9) and cathinone (Schedule 9).
Methylone is not specifically listed in the Poisons Standard. Methylone is structurally related to, but not captured by, the Schedule 9 entry for MDMA (differing only by a single beta-ketone). Methylone is also chemically related to several other cathinones and amphetamines already included in Schedules 9 and 8.
Schedule 9
N-ETHYL-α-METHYL-3,4-(METHYLENEDIOXY)PHENETHYLAMINE *(N-ETHYL MDA).
5-METHOXY-3,4-METHYLENEDIOXYAMFETAMINE *(MMDA).
3,4-METHYLENEDIOXYAMFETAMINE *(MDA).
3,4-METHYLENEDIOXYPYROVALERONE *(MDPV).
N-α-[METHYL-3,4-(METHYLENEDIOXY)PHENETHYL]HYDROXYLAMINE *(N-HYDROXY MDA).
N, α -DIMETHYL-3,4-(METHYLENEDIOXY)PHENYLETHYLAMINE *(MDMA).
N-METHYL-1-(3,4-METHYLENEDIOXYPHENYL)-2-BUTANAMINE *(MBDB).
METHCATHINONE.
4-METHYLMETHCATHINONE.
Schedule 8
AMFETAMINE.
DEXAMFETAMINE.
LEVAMFETAMINE.
LEVOMETHAMFETAMINE.
METAMFETAMINE.
Schedule 4
BUPROPION.
PROLINTANE.
PYROVALERONE.
alpha-PVP, also known as alpha-pyrrolidinopentiophenone, has not been previously considered for scheduling. Therefore, a scheduling history is not available.
In August 1986, the Drugs and Poisons Schedule Committee (DPSC) considered a Schedule 9 entry for cathinone in the Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP) under Psychotropic Substances. It was discussed after a notification from the Secretary-General from the United Nations.
In November 1986, after review of the States and Territories, the DPSC agreed to add cathinone into Schedule 9 of the SUSDP.
In November 1998, the National Drugs and Poisons Schedule Committee (NDPSC) agreed to the inclusion of methcathinone in Schedule 9 due to its potential as a problem drug.
Methylone has not been previously considered for scheduling. Therefore, a scheduling history is not available.
In June 2010, the NDPSC decided to create a new entry in Schedule 9 for 4-methylmethcathinone (mephedrone). The committee agreed that 4-methylmethcathinone, as a derivative of methcathinone, is captured by the Schedule 9 entry for methcathinone. The committee further agreed that it would be appropriate to create a new entry for 4-methylmethcathinone in Schedule 9 to clarify that this substance is indeed a prohibited substance.
In October 2011, the Advisory Committee on Medicines Scheduling (ACMS) considered an application to include MDPV in Schedule 9 of the Poisons Standard due to it being structurally related to cathinone and MDMA. The ACMS recommended that MDPV be included in Schedule 9, with a cross-reference to 3,4-methylenedioxypyrovalerone, due to its potency and its associated dangers with heavy and repetitive use.
Alpha-PVP, methylone and cathinone are not an excipient or active in any medicines on the ARTG.
According to the TGA Ingredient Database, prolintane is available for use as an:
There are no recorded adverse event reports for any related substances on the Database of Adverse Events Notification (DAEN) - Medicines.
Cathinone and methcathinone are listed in Schedule I of the UN 1971 Convention on Psychotropic Substances. Amfepramone and pyrovalerone are in Schedule IV of that Convention, but other derivatives are not under international control. A few synthetic cathinones are controlled in some Member States under drug control or equivalent legislation, for example:
Mephedrone is controlled under medicines legislation in Finland and the Netherlands. By Council Decision of 2 December 2010, 4-methylmethcathinone (mephedrone) was submitted to control measures in EU Member States (2010/759/EU).[33]
Generic control in the UK covers a wide group of cathinone derivatives. In the UK, the 31 March 2010 report of the UK Advisory Council on the Misuse of Drugs – Consideration of the cathinones indicated that the harms associated with mephedrone and related cathinones were commensurate with the amphetamines and the substances in Class B. This UK report, defines cathinone derivatives generically as follows:
Any compound (not being bupropion or a substance for the time being specified in paragraph 2.2) structurally derived from 2-amino-1-phenyl-1- propanone by modification in any of the following ways, that is to say,
Present UK controls include:
In the USA, alpha-PVP (also known as alpha-pyrrolidinopentophenone) is reported by the US DEA to be a synthetic cathinone and was temporarily placed in the US Schedule 1 of controlled drug substances in March 2017. After consideration of the relevant matter presented as a result of public comment, the scientific and medical evaluations and accompanying recommendations of the Department of Health and Human Services (HHS), and the DEA's consideration of its own eight-factor analysis, the DEA finds that these facts and all other relevant data constitute substantial evidence of potential for abuse of 4-MEC, 4-MePPP, alpha-PVP, butylone, pentedrone, pentylone, 4-FMC, 3-FMC, naphyrone, and alpha-PBP. As such, the DEA is permanently scheduling them as controlled substances under the Controlled Substances Act.
See also the DEA warning in relation to synthetic cathinones.
Schedule I of the Controlled Drugs and Substances Act:
Property | Punishment |
---|---|
Possession | Maximum 7 years imprisonment |
Trafficking/possession for the purpose of | Maximum life imprisonment (mandatory minimum 1-year jail sentence for trafficking a Schedule I drug under 1 kg, 2 years if amount exceeds 2 kg) |
Exportation/possession for the purpose of | Maximum life imprisonment |
Production | Maximum life imprisonment |
Schedule III of the Controlled Drugs and Substances Act:
Property | Punishment |
---|---|
Possession (requires a prescription to legally possess) | Maximum 10 years imprisonment |
Trafficking/possession for the purpose of | Maximum 10 years imprisonment |
Exportation/possession for the purpose of | Maximum 10 years imprisonment |
Production | Maximum 10 years imprisonment |
Ingredient | Classification |
---|---|
Cathinone | Class B2 Controlled Drug |
Methcathinone | Class B2 Controlled Drug |
Monomethylpropion (synonym for methcathinone) | Class B2 Controlled Drug |
Synthetic cathinones are chemically similar to cathinone, which comes from the khat plant (Catha edulis). Khat is a shrub grown in East Africa and southern Arabia, and people sometimes chew its leaves for their mild stimulant effects.
Synthetic cathinones are included in a group of drugs that concern public health officials called "new psychoactive substances" (NPS). NPS are unregulated psychoactive (mind-altering) substances that have become newly available on the market and are intended to copy the effects of illegal drugs. Some of these substances may have been around for years but have re-entered the market in altered chemical forms or due to renewed popularity.
The most well-known synthetic cathinone is mephedrone (4-MMC or meow meow), although there are several others, including methylone, alpha-PVP, methedrone, naphyrone, butylone and MDPV. These substances reportedly produce similar effects to methamphetamine and MDMA (ecstasy).[34] Synthetic cathinones have only been used as street drugs since the 2000s.[35]
Until recently, these drugs were available under the guise of 'research chemicals' or 'plant food', either online or in shops which sell legal highs.
Chemical | CAS number | IUPAC and/or common and/or other names | Molecular structure and weight | Structure |
---|---|---|---|---|
Cathinone | 42542-10-9 | 1-(1,3-benzodioxol-5-yl)-N-methylpropan-2-amine (IUPAC); Mandy, MDMA, Molly, ecstasy; |
C11H15NO2 193.2 g/mol |
![]() |
Mephedrone (4-methylmethcathinone) | 1189805-46-6 | 2-(methylamino)-1-(4-methylphenyl)propan-1-one (IUPAC); M-CAT, HSB 7979, Meow Meow, Bounce, Bubbles; |
C11H15NO
177.2 g/mol |
![]() |
Methylone | 186028-79-5 | 1-(1,3-benzodioxol-5-yl)-2-(methylamino)propan-1-one (IUPAC); BK-MDMA, HSB 7997, M1; |
C11H21NO | ![]() |
Pyrovalerone | 3563-49-3 | 1-(4-methylphenyl)-2-pyrrolidin-1-ylpentan-1-one (IUPAC); | C16H23NO
245.4 |
![]() |
Prolintane | 493-92-5 | 1-(1-phenylpentan-2-yl)pyrrolidine (IUPAC); Catovit; |
C15H23N
217.4 g/mol |
![]() |
3,4-methylenedioxypyrovalerone (MDPV) | 687603-66-3 | 1-(1,3-benzodioxol-5-yl)-2-pyrrolidin-1-ylpentan-1-one (IUPAC);
MDPV, MDPK; |
C16H21NO3 275.3 g/mol |
![]() |
General chemical structure of a cathinone derivative showing substitution patterns | ![]() |
Cathinones act as central nervous system stimulants, although the potencies of the cathinones are generally lower than their amphetamine congeners. This may be due to the increased polarity conferred on a cathinone by the presence of a β-keto group reducing their ability to cross the blood-brain barrier.
Cathinone derivatives are the β-keto (βk) analogues of a corresponding phenethylamine. Synthetic variants of cathinone can be much stronger than the natural product and, in some cases, very dangerous.[36]
Cathinone is structurally very similar to amphetamine (1-phenylpropan-2-amine), differing only in the functionality present at the β-carbon. Cathinone possesses a ketone oxygen at the β-carbon; cathinone can therefore be considered as the 'beta;-keto analogue' of amphetamine. The molecular architecture of 2-amino-1-phenyl propanone (cathinone) can be altered to produce a series of different compounds which are closely structurally related to cathinone. Together these are known as the 'cathinones', 'synthetic cathinones' or 'cathinone derivatives'.
The basic cathinone structure can be altered in a number of predictable ways, such as the inclusion of additional functionality to the aromatic ring (ring substitution, R1), N-alkylation (or inclusion of the nitrogen atom in a ring structure, R3 and R4), and variation of the (typically alkyl) α-carbon substituent (R2). Multiple modifications may be present in a single derivative. Cathinones are all usually N-alkylated (or the nitrogen is incorporated into a ring structure, typically pyrrolidine) and many also bear ring substituents.
Three (3) public submissions were received that opposed the proposal for for alpha-PVP and related substances (cathinones and methylone), instead suggesting that a Schedule 9 entry may be more appropriate. The main points opposed to a Schedule 4 entry and in support of a Schedule 9 entry were:
The public submissions will be made available on the TGA website.
The committee recommended that new Schedule 9 entries be created for alpha-PVP and methylone in the Poisons Standard, and the current Schedule 9 cathinone entry be amended as follows:
Schedule 9 – New Entry
ALPHA-PYRROLIDINOVALEROPHENONE *(ALPHA-PVP).
Schedule 9 – New Entry
METHYLONE *(MDMC).
Schedule 9 – Amend Entry
CATHINONES except when separately specified in these Schedules.
Index – Amend Entry
CATHINONES
cross reference: SYNTHETIC CATHINONES
The committee also recommended an implementation date of 1 June 2018 as this is the earliest practicable implementation date.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the advice comprised the following:
The delegate considered the following in regards to this proposal:
The delegate’s interim decision is create a new Schedule 9 entries for alpha-pyrrolidinovalerophenone and methylone, as well as amend the Schedule 9 entry for cathinone. The proposed Schedule entries are:
Schedule 9 – New Entry
ALPHA-PYRROLIDINOVALEROPHENONE *(ALPHA-PVP).
Schedule 9 – New Entry
METHYLONE *(MDMC).
Schedule 9 – Amend Entry
CATHINONES except when separately specified in these Schedules.
Index – Amend Entry
CATHINONES
cross reference: SYNTHETIC CATHINONES
The proposed implementation date is 1 June 2018. This is the earliest practicable implementation date.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (a) the risks and benefits of the use of the substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of the substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the advice comprised the following:
Scheduling medicines and poisons
An application was submitted to amend the Schedule 2 to and Schedule 3 entries in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) – the Poisons Standard.
This was a general application. The applicant’s proposed amendments to the Poisons Standard are:
Schedule 2 – Amend Entry
IBUPROFEN in preparations for oral use when labelled with a recommended daily dose of 1200 mg or less of ibuprofen:
Schedule 3 – Amend Entry
IBUPROFEN for oral use when labelled with a recommended daily dose of 1200 mg or less of ibuprofen and not labelled for the treatment of children under 12 years of age:
except when included in or expressly excluded from Schedule 2.
On 29 June 2017, the delegate decided to amend the Schedule 3 entry to include a modified release dosage form of ibuprofen. As a result, the secretariat has amended the proposed entry for consistency with the delegate's decision, which came into effect on 1 October 2017:
Schedule 3 – Amend Entry
IBUPROFEN:
except when included in or expressly excluded from Schedule 2.
The applicant's reasons for the request are:
'NSAIDs are among the most commonly used pharmacological agents worldwide due to their efficacy as non-addictive analgesics and their anti-inflammatory properties. Hence, even a small absolute risk of serious cardiovascular effects associated with these drugs could produce a significant health burden in a given population.'
Ibuprofen is currently listed in Schedules 2, 3 and 4 and Appendix F, Part 3 and Appendix H of the Poisons Standard as follows:
Schedule 2
IBUPROFEN in preparations for oral use when labelled with a recommended daily dose of 1200 mg or less of ibuprofen:
Schedule 3
IBUPROFEN:
except when included in or expressly excluded from Schedule 2.
Schedule 4
IBUPROFEN except:
Appendix F, Part 3
Warning Statements: 101, 104
Appendix H
IBUPROFEN.
In November 1985, the National Health and Medical Research Council (NHMRC) considered a request to amend the scheduling of ibuprofen from Schedule 4 to Schedule 2 as ibuprofen was not scheduled in Victoria. It was agreed there were anaphylactic problems with people sensitive to aspirin. It was decided not to alter the scheduling.
In November 1987 the NHMRC considered a request to move ibuprofen from Schedule 4 to Schedule 2 with pack size restrictions. The committee was of the opinion that there was a place for ibuprofen outside Schedule 4. Recommendation for a new Schedule 3 entry with pack size restrictions of less than 50 tablets or capsules (200 mg).
In May 1995, the NDPSC considered proposal for a new Schedule 2 entry for ibuprofen and agreed to a new entry. Schedule 4 entry amended. New Schedule 2 for ibuprofen in divided preparations for oral use containing 200mg or less with a recommended dose of 1200mg or less.
In November 1998, the NDPSC considered an application for ibuprofen liquid suspension 100 mg/5 mL to be rescheduled from Schedule 4 to Schedule 2. Overall, the committee considered that a Schedule 3 classification was more appropriate for this formulation, and agreed that the Poisons Standard be amended accordingly. The committee agreed that a maximum daily dose should be stipulated, but because the proposed pack size was 200 mL (maximum of 4 g ibuprofen) a restriction on total content was not required for this classification. A new entry for Schedule 3 was agreed in undivided preparations for oral use when labelled with a recommended daily dose of not more than 1200 mg of ibuprofen.
In May 2000, the NDPSC considered a proposal to amend the Schedule 2 entry for ibuprofen to include oral liquid preparations containing more than 20 mg/1 mL. The committee considered the safety profile of ibuprofen and that Schedule 2 is appropriate when used in analgesic dose for minor and temporary ailments for short periods. The committee was seeking consistency with divided dose formulations.
In June 2003, the NDPSC considered a proposal to exempt ibuprofen from scheduling in divided preparations containing 200 mg or less of ibuprofen per dosage unit in packs containing 24 or less dosage units when labelled with a maximum recommended daily dose of 1200 mg of ibuprofen. The NDPSC decided to exempt ibuprofen from scheduling as requested, but with an amended maximum pack size (25 dosage units) and additional restrictions as follows: ibuprofen as the only therapeutically active constituent other than an effervescent agent; and requirements for label warnings (consistent with Appendix F warnings for Schedule 2 ibuprofen). The minutes note that the NDPSC had agreed that the schedule wording should be comparable with that of the current aspirin and paracetamol entries.
In October 2003, following consideration of further public submissions, the NDPSC made some amendments to the label warning statements required for ibuprofen when exempted from scheduling, in particular, by adding warnings not to use the product unless advised by a doctor in children ages 6 years or less, or by people aged 65 years or over.
The NDPSC subsequently made some editorial amendments to the Schedule 2 exemption in June 2004 and February 2005.
In August 2010 the NDPSC considered the scheduling of paracetamol in combination with ibuprofen in June 2010. At that time, divided dose combinations containing up to 200 mg ibuprofen + 500 mg paracetamol were included in Schedule 2 (when labelled with a maximum daily dose of 1200 mg ibuprofen, and in packs of up to 100 dosage units). The NDPSC recommended, and the delegate confirmed, that the scheduling of ibuprofen and paracetamol that was current at that time remained appropriate.
In June 2011 the ACMS considered a proposal from the Advisory Committee on Non-prescription Medicines (ACNM) that the delegate/ACMS consider up-scheduling paracetamol/ibuprofen combinations (containing up to 500 mg paracetamol/200 mg ibuprofen) from Schedule 2 to Schedule 3. The ACNM had also recommended consideration of a maximum pack size for Schedule 3 paracetamol/ibuprofen combinations. The ACNM, in an assessment of an application to register a combination paracetamol/ibuprofen product, had raised concerns that the sponsor had not satisfactorily established the safety of the product, and considered that pharmacist intervention was needed to assist consumers with safe use of the combination.
The ACMS recommended that the combination paracetamol/ibuprofen products that were in Schedule 2 should be rescheduled to Schedule 3, when in packs containing 30 dosage units or less, with larger packs to be included in Schedule 4. The delegate agreed with the ACMS advice.
In February 2013 the ACMS considered proposals to reschedule paracetamol 500 mg when combined with ibuprofen 200 mg from Schedule 3 to Schedule 2 in packs containing 12 dosage units or less, and to also include Schedule 3 paracetamol when combined with ibuprofen in Appendix H. The ACMS recommended that the current scheduling of paracetamol in combination with ibuprofen remained appropriate, and that paracetamol in combination with ibuprofen should not be included in Appendix H. The reasons for opposing rescheduling to Schedule 2 included insufficient data to disprove the safety concerns with the combination, lack of evidence to support rescheduling, lack of long-term evidence of safety of the combination, potential for additive gastrointestinal side effects, potential for inadvertent misuse and no experience with use of paracetamol/ibuprofen combination products in Australia. The ACMS also considered that there were no public health benefits with inclusion of the combination in Appendix H, and that advertising could lead to inappropriate use. The delegate agreed with the ACMS advice.
In June 2012, the ACMS considered a submission to reschedule ibuprofen from Schedule 2 to unscheduled when in divided preparations containing 200 mg or less of ibuprofen in fixed dose combination with 5 mg or less of phenylephrine, in packs containing not more than 25 tablets. ACMS recommended to the delegate that ibuprofen in combination with phenylephrine should be exempt from scheduling, as requested. The delegate decided to also restrict the scheduling exemption to use for the treatment of adults and children aged 12 years of age and over.
In November 2015, the ACMS considered a submission to amend the Schedule 2 entry for paracetamol to include paracetamol when combined with ibuprofen in pack sizes of 12 dosage units or less. The ACMS recommended that paracetamol should be included in Schedule 2 when combined with ibuprofen in preparations for oral use when labelled with a recommended daily dose of 1200 mg or less of ibuprofen in divided doses in a pack of not more than 3 day supply. The delegate agreed with the ACMS and made an interim decision based on the ACMS advice. After deferring their final decision to give consideration to a late submission received during the interim decision consultation period, the delegate decided to vary their decision. In view of the dosage levels of paracetamol and ibuprofen the delegate considers it is more appropriate to limit the Schedule 2 part a) entry to 12 dosage units per pack rather than 3 days' supply packs as this would ensure the total paracetamol available in the pack would not be excessive.
In March 2017, the ACMS considered a proposal to amend the Schedule 3 entry for ibuprofen to include a modified release dosage form of 600 mg of ibuprofen per dosage unit in packs of 32 or less dosage units. ACMS recommended that the Schedule 3 entry should be amended as suggested, allowing consumers greater access to a product for pain relief that is longer-lasting than other products currently available. The delegate's final decision was to amend the Schedule 3 entry for ibuprofen to include the modified release dosage form, with an implementation date of 1 October 2017.
The Australian Register of Therapeutic Goods (ARTG) has 229 entries for products containing ibuprofen. They are approved for treatment of infants, children and adults and come in multiple dosage strengths and forms.
Combination products available include ibuprofen with codeine, ibuprofen with paracetamol and ibuprofen with pseudoephedrine. The ARTG also included entries for ibuprofen lysine 324 mg tablets and capsules and ibuprofen sodium dihydrate 256 mg tablets and capsules.
In the last 30 years there have been 1222 reported cases of adverse events related to ibuprofen in the Database of Adverse Events Notification (DAEN) - Medicines: 813 cases with a single suspected medicine and 35 cases where death was a reported outcome.
According to the TGA Ingredient Database, ibuprofen, ibuprofen lysine and ibuprofen sodium dihydrate are available for use as an:
Health Canada regulates ibuprofen in strengths of 200 mg, 300 mg and 400 mg as over-the-counter medicines.
Medsafe NZ regulates ibuprofen in solid dose forms containing not more than 200 mg in packs of more than 25 and less than 100 tablets as Pharmacy Only.
The USA Food and Drug Administration regulate ibuprofen in varying dose forms as an over-the-counter medicine.
The European Medicines Authority regulates ibuprofen and dexibuprofen (the dextrorotatory enantiomer of ibuprofen) in varying doses and formulations and these are available on prescription as well as over the counter.
Property | Ibuprofen |
---|---|
CAS name | Ibuprofen |
CAS number | 15687-27-1 |
IUPAC and/or common and/or other names | 2-[4-(2-methylpropyl)phenyl]propanoic acid (IUPAC); Ibuprofen (INN); |
Chemical structure | ![]() |
Molecular formula | C13H18O2 |
Molecular weight | 206.3 g/mol |
Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) used as an analgesic, antipyretic, and anti-inflammatory. It decreases synthesis of pain and inflammation, promoting prostaglandins via non-selective inhibition of both cyclo-oxygenase 1 and 2 (COX-1 and COX-2) enzymes.
Ibuprofen is a white or almost white, crystalline powder or colourless crystals. It is practically insoluble in water, freely soluble in acetone, in methanol and in methylene chloride. It dissolves in dilute solutions of alkali hydroxides and carbonates.
Numerous oral non-prescription ibuprofen formulations are available in Australia with various dosage forms, strengths and combinations. These 'immediate release' (IR) non-prescription formulations are indicated for the management of mild to moderate pain and inflammation, including reducing fever, and for the treatment of headache including migraine, period pain, dental pain, musculoskeletal and joint pain and post-operative pain.
Australian therapeutic guidelines recommends that the non-prescription ibuprofen oral dose in people aged more than 12 years of age is 200–400 mg every 4 to 6 hours as needed, with a maximum daily dose of 1200 mg.
Toxic effects are unlikely at doses below 100 mg/kg, but can be severe above 400 mg/kg. Risks noted include increased risk of cardiac arrest, risk of spontaneous abortion, risk of gastrointestinal side effects (including bleeding), as well as renal function changes. Additionally, NSAIDs such as ibuprofen may not be suitable for people with stomach problems such as ulcers or bleeding, people with heart or kidney problems or people with high blood pressure.
Seventeen (17) submissions were received, three (3) in support and fourteen (14) opposed.
The public submissions will be made available on the TGA website.
The committee recommended that the current Schedule 2 and Schedule 3 entries for ibuprofen remain appropriate.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the advice comprised the following:
The delegate considered the following in regards to this proposal:
The delegate's interim decision is that the current Schedule 2 and Schedule 3 entries for ibuprofen remain appropriate.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (a) the risks and benefits of the use of the substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of the substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the recommendation comprised the following:
Based on the current evidence, there are no major changes required to the availability and warnings on labels for over-the-counter (OTC) diclofenac, ibuprofen and naproxen. These drugs provide effective pain relief when used according to the label at recommended doses for short durations.
Scheduling medicines and poisons
An application was submitted to create a new entry in Schedule 10 for melanotan II in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) – the Poisons Standard.
This was a general application. The applicant’s proposed amendments to the Poisons Standard are:
Schedule 10 – New Entry
MELANOTAN II for cosmetic or therapeutic use.
Index – New Entry
MELANOTAN II
cross reference α–MELANOCYTE STIMULATING HORMONE
Schedule 10
The applicant's reasons for the request are:
Melanotan II is not specifically scheduled. Therefore a scheduling history is not available.
Schedule 4
ADRENOCORTICAL HORMONES except when separately specified in these Schedules.
CORTICOTROPHIN.
Afamelanotide
In December 2010, the delegate made a delegate only decision to include afamelanotide (also known as melanotan I) with a cross-reference to melanocyte stimulating hormone (MSH) for inclusion into the current Poisons Standard. It was noted that afamelanotide should not be confused with a similar substance commonly known as Melanotan-II, which is a cyclic lactam synthetic analogue of α-MSH. It was noted that melanotan-II was under investigation for treating sexual dysfunction, although this has been abandoned due to side effects associated with the immune and cardiovascular systems. Its metabolite, bremelanotide, is under investigation for treating haemorrhagic shock.
Adreno-corticotrophic hormone
In January 1955, adreno-corticotrophic hormone (ACTH) was included in the very first Poisons Schedules. It was included in Schedule 4, Part A, which is equivalent to the current Schedule 4 of the Poisons Standard. Provisions for a repeated script must be authorised by an authorised prescriber, including general practitioners, veterinarian or dentist (if required for the purposes of the dental profession or are permitted to be prescribed by a dentist).Corticotrophin
In May 1956, corticotrophin and other pituitary hormones for parenteral use in humans were included in Schedule 4 of the Draft Uniform Poisons Schedules.
Melanotan II is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017, and is not an excipient or active in any medicines on the ARTG.
The European Medicines Agency granted orphan designation to α-melanocyte stimulating hormone for the treatment of erythropoietic porphyria.
Multiple European governing authorities including Danish Medicines Agency, Norwegian Medicines Agency, Swedish Medical Products Agency, United Kingdom Medicines and Healthcare products Regulatory agency have issued warnings on the sale and use of melanotan products.
According to the USA Food and Drugs Administration (FDA) website, melanotan I, melanotan II and bremalanotide are unapproved injectable drugs in the USA.
In September 2007, the FDA issued a public notice advising consumers to stop using melanotan II as it was an unapproved drug with no safety or efficacy data for the advertised indications. Furthermore, the FDA issues a warning notice to a company owner that was illegally selling and marketing the product via a website. This led to subsequent indictment.
The European Medicines Agency granted orphan designation to α-melanocyte stimulating hormone for the treatment of erythropoietic porphyria.
Multiple European governing authorities including Danish Medicines Agency, Norwegian Medicines Agency, Swedish Medical Products Agency, United Kingdom Medicines and Healthcare products Regulatory agency have issued warnings on the sale and use of melanotan products.
In November 2008, the UK Medicines and Healthcare products Regulatory Agency (MHRA) warned the public against melanotan use stating it was an unlicensed medicine that may not be safe. As such, it is illegal to market or supply this product in the UK due to its unlicensed nature. Additionally the MHRA warned 18 companies about selling or advertising the product and closed down 72 websites involving melanotan. By 2013, the MHRA had received 18 reports of 74 separate reactions to the products and reactions have involved stomach and heart problems, as well as blood and eye disorders.
In February 2009, the Irish Medical Board (IMB) indicated that they had detected the presence of microbial contamination in the water vial supplied with melanotan which poses a risk of serious infection. Further the IMB stated that this product is not authorised for use in the EU due to no guarantees as to quality, safety or efficacy.
Property | Melanotan II |
---|---|
CAS name | Melanotan II acetate salt |
CAS number | 121062-08-6 |
IUPAC and/or common and/or other names | (3S,6S,9R,12S,15S,23S)-15-[[(2S)-2-acetamidohexanoyl]amino]-9-benzyl-6-[3-(diaminomethylideneamino)propyl]-12-(1H-imidazol-5-ylmethyl)-3-(1H-indol-3-ylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-23-carboxamide (IUPAC); |
Chemical structure | ![]() |
Molecular formula | C50H69N 15O9 |
Molecular weight | 1024.2 g/mol |
Melanotans include melanotan I (afamelanotide) and melanotan II. Both melanotan I and II are widely abused to obtain a cosmetic tan. The melanotans are potent, non-selective melanocortin receptor agonists affecting MC1, MC3, MC4 and MC5 receptors. These receptors are responsible for many physiological systems including: pigmentation, energy, sexual function, immune system, inflammation and the cardiovascular system.
Melanotan II is a synthetic analogue of the α-melanocyte stimulating hormone (α-MSH). α-MSH is a melanocortin I receptor agonist which has a role in human pigmentation by stimulating production of eumelanin. As melanotan II is a non-specific melanocortin receptor agonist, it has been reported to cause toxicity effects involving the many physiological systems affected by the receptors.
Melanotan II was originally developed as a treatment for sexual dysfunction. However, this was abandoned when the metabolite bremelanotide was developed instead for treatment of haemorrhagic shock. Melanotan II is usually injected subcutaneously for the purposes of sunless tanning, appetite suppression, inducing sexual desire and penile erection and other conditions such as rosacea and fibromyalgia. There are also dose forms available for nasal administration. The therapeutic dose is considered to be 0.01 mg/kg.
Toxicity effects of melanotan II from therapeutic and overdose exposures include renal dysfunction, rhabdomyolysis, sympathomimetic overdrive, change in size and pigmentation of pre-existing moles, rapid increase in the number of new moles, associated with causing melanomas, posterior reversible encephalopathy syndrome, refractory priapism, stretching and yawning syndrome, shortness of breath, chest pain, abdominal cramping and pain, dizziness and lethargy.
XXXXXX experience shows overdose appears to be relatively common, with the most frequent observation being a 10 fold overdose error resulting in toxicity symptoms and some have required hospitalisation.
There are reports that these products have tested positive for microbial contaminants. After reconstitution, these vials are marketed for multiple uses for up to a few weeks, which pose a stability issue and further increase the infection risk issue.
Melanotan II tanning injections have received media attention over the past few years and have been dubbed the "barbie drug" by XXXXXX. The XXXXXX website states that all products are manufactured and compounded in pharmacies in Australia and, pending the satisfactory completion of a short medical assessment, will express post products to a nominated shipping address. The XXXXXX website also states that melanotan II is defined as a 'more potent peptide' when compared to melanotan I, offering a greater density in peptide chain with noticeable results in a shorter timeframe. There are also claims of enhancing male libido, sexual performance, curing erectile dysfunction and as an appetite suppressant.
No submissions were received.
The committee recommended that a new Schedule 4 entry, along with cross referencing to alpha-melanocyte stimulating hormone in the Index, be created for melanotan II.
Schedule 4 – New Entry
MELANOTAN II.
Index – New Entry
MELANOTAN II.
cross reference: α–MELANOCYTE STIMULATING HORMONE
Schedule 4
The committee also recommended an implementation date of 1 June 2018 as this is the earliest practicable implementation date.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the advice comprised the following:
The delegate considered the following in regards to this proposal:
The delegate’s interim decision is to include melanotan II in Schedule 4. The proposed Schedule entry is:
Schedule 4 – New Entry
MELANOTAN II for cosmetic or therapeutic use.
Index – New Entry
MELANOTAN II
cross reference α–MELANOCYTE STIMULATING HORMONE
Schedule 4
The proposed implementation date is 1 June 2018. This is the earliest practicable implementation date.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (a) the risks and benefits of the use of the substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of the substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the recommendation comprised the following:
Scheduling medicines and poisons
An application was submitted to amend the Schedule 4 entry and create a new Schedule 3 entry for orphenadrine in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) – the Poisons Standard.
This was a general application. The applicant’s proposed amendments to the Poisons Standard are:
Schedule 3 – New Entry
ORPHENADRINE in oral preparations containing 35 mg or less of orphenadrine:
Schedule 4 – Amend Entry
ORPHENADRINE except when included in Schedule 3.
The applicant's reasons for the request are:
Orphenadrine is currently listed in Schedule 4 of the Poisons Standard as follows:
Schedule 4
ORPHENADRINE.
Paracetamol is currently listed in Schedules 2, 3 and 4 of the Poisons Standard as follows:
Schedule 2
PARACETAMOL for therapeutic use:
Schedule 3
PARACETAMOL when combined with ibuprofen in a primary pack containing 30 dosage units or less except when included in Schedule 2.
Schedule 4
PARACETAMOL:
It is also included under the entry paracetamol in Appendix F with the following statements:
Appendix F, Part 3
PARACETAMOL
Warning Statements:
In February 1987, orphenadrine was first scheduled. Based on a jurisdiction list of sedating drugs, orphenadrine was included in Appendix K by the Drugs and Poisons Scheduling Committee (DPSC).
In November 1987, the DPSC noted that orphenadrine was included in the list of substances requiring a child-resistant closure in TGO 20. The committee agreed this was appropriate, and that it should not be replicated in the Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP).
In June 2011, the ACMS considered a proposal to reschedule orphenadrine in dosage units containing less than 35 mg from Schedule 4 to Schedule 3 when combined with paracetamol in a pack size of 24 dosage units or less. The application was referred to an external evaluator, who recommended that the application be rejected.
In September 2011, the delegate concluded that the recommendations of the ACMS were clear and appropriately supported. The delegate agreed with the recommendations that the scheduling of orphenadrine and paracetamol in Schedule 4 of the Poisons Standard remained appropriate.
The Australian Register of Therapeutic Goods (ARTG) has two entries for products registered containing both orphenadrine and paracetamol. The products differ in container presentation – blister pack vs. tablet bottle.
In the last 30 years there have been 39 reported cases of adverse events related to orphenadrine, and 3237 related to paracetamol in the Database of Adverse Events Notification (DAEN) - Medicines: 21 cases with the single suspected medicine being orphenadrine, and 1244 cases with paracetamol. Of these, no cases reported death as the outcome associated with orphenadrine, compared to 137 cases reported death as an outcome associated with paracetamol over the same 30 year period.
Tablets containing orphenadrine citrate 100 mg (as the only active ingredient) are marketed as OTC in Canada.
Both Medsafe New Zealand and the United States of America’s Food and Drug Authorisation classify orphenadrine citrate as a prescription medicine.
Orphenadrine is a congener of diphenhydramine. It is a tertiary amine antimuscarinic agent with weak antihistaminic and local anaesthetic properties. It also inhibits noradrenaline transport and blocks NMDA receptors and voltage-gated sodium channels.
Orphenadrine is a skeletal muscle relaxant. Its citrate salt is used to relieve pain due to muscle spasm. However, efficacy for this indication is not well established.
Paracetamol is an analgesic. The combination of a skeletal muscle relaxant and an analgesic is useful in conditions where pain is associated with muscle spasm. The individual substances relieve the two defining symptoms of the targeted indication (pain and muscle spasm) and contribute to the clinical effect via different modes of action.
Property | Orphenadrine | Paracetamol |
---|---|---|
CAS number | 83-98-7 | 103-90-2 |
IUPAC and/or common and/or other names |
N,N-dimethyl-2-[(2-methylphenyl)-phenylmethoxy]ethanamine (IUPAC); 1S/C18H23NO/c1-15-9-7-8-12-17(15)18(20-14-13-19(2)3)16-10-5-4-6-11-16/h4-12,18H,13-14H2,1-3H3 (InChI); Orphenadrine (INN); |
N-(4-hydroxyphenyl)acetamide (IUPAC); 1S/C8H9NO2/c1-6(10)9-7-2-4-8(11)5-3-7/h2-5,11H,1H3,(H,9,10) (InChI); Acetaminophen (USP); |
Chemical structure | ![]() |
![]() |
Molecular formula | C18H23NO | C8H9NO2 |
Molecular weight | 269.4 g/mol | 151.2 g/mol |
Five (5) public submissions were received, four (4) that oppose and one (1) that supports the scheduling proposal for orphenadrine.
The public submissions will be made available on the TGA website.
The committee recommended that the current scheduling of orphenadrine remains appropriate.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the advice comprised the following:
The delegate considered the following in regards to this proposal:
The delegate’s interim decision is that the current scheduling of orphenadrine remains appropriate.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (a) the risks and benefits of the use of the substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of the substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the recommendation comprised the following:
Scheduling medicines and poisons
An application was submitted to amend the Schedule 2 and Schedule 4 entries and to delete the Schedule 3 and Appendix H entries for clotrimazole in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) – the Poisons Standard.
This was a general application. The applicant’s proposed amendments to the Poisons Standard are:
Schedule 2 – Amend Entry
CLOTRIMAZOLE for human use in vaginal preparations, dermal preparations and for application to the nails except in preparations for the treatment of tinea pedis.
Schedule 3 – Delete Entry
CLOTRIMAZOLE in preparations for vaginal use.
Schedule 4 – Amend Entry
CLOTRIMAZOLE except:
Appendix F, Part 3 Warning Statements – Amend Entry
CLOTRIMAZOLE in vaginal preparations when included in Schedule 32.
Appendix H –Delete Entry
CLOTRIMAZOLE.
The applicant's reasons for the request are:
Clotrimazole is currently listed in Schedules 2, 3, 4 and 6 and Appendices F and H of the Poisons Standard as follows:
Schedule 2
CLOTRIMAZOLE for human use in dermal preparations and for application to the nails except in preparations for the treatment of tinea pedis.
Schedule 3
CLOTRIMAZOLE in preparations for vaginal use.
Schedule 4
CLOTRIMAZOLE except:
Schedule 6
CLOTRIMAZOLE for the external treatment of animals.
Clotrimazole is also included in Appendix F and Appendix H as follows:
Appendix F, Part 3
CLOTRIMAZOLE in vaginal preparations when included in Schedule 3.
Warning Statements: 54 (Seek medical advice before first course of treatment); 63 (See a doctor if you are pregnant or diabetic); 64 (See a doctor (or) (dentist) if no better after (Insert number of days as per approved Product Information) days); 66 (See a doctor if problem returns).
Appendix H
CLOTRIMAZOLE.
Clotrimazole was first scheduled in August 1977. Clotrimazole has an extensive scheduling history since 1985. The scheduling history relevant to vaginal preparations have been presented below.
The August 1977, the Drugs and Poisons Schedule Standing committee (DPSSC) included clotrimazole in Schedule 4.
In April 1994, the National Drugs and Poisons Schedule Committee (NDPSC) agreed to down-schedule preparations of clotrimazole for vaginal use to Schedule 3 to give its current entry. Following out-of-session consideration, the committee also agreed to include the current warning statements in Appendix F for clotrimazole when included in Schedule 3.
In November 1996, the NDPSC considered a submission to reschedule clotrimazole for vaginal use to Schedule 2. The committee did not support the rescheduling application.
In February 1997, the NDPSC considered the post-meeting comment concerning the November 1996. The committee agreed that the November 1996 decision remained appropriate and that clotrimazole for vaginal use should remain in Schedule 3.
In August 1998, the NDPSC considered a submission to include miconazole in Appendix H, and decided to allow other antifungals currently included in Schedule 3 to be advertised by including them in Appendix H. These substances were clotrimazole, econazole, miconazole and nystatin.
In February 2006, the NDPSC considered a submission to reschedule clotrimazole for vaginal use to Schedule 2. After consideration of the new data presented, the committee agreed that the current scheduling of clotrimazole remained appropriate. The committee noted that maintaining mandatory pharmacist involvement in the sale of clotrimazole was needed to fully address the committee's concerns, particularly the risk of repeated clotrimazole use masking an underlying serious condition.
In February 2007, the NDPSC considered a submission to reschedule clotrimazole for vaginal use to Schedule 2. The committee agreed that the current scheduling of clotrimazole for vaginal use remained appropriate. Maintaining mandatory pharmacist involvement in the sale of clotrimazole was needed to fully address the committee's concerns, particularly the risk of repeated clotrimazole use masking an underlying serious condition without referral to a pharmacist or doctor or being used incorrectly on non-fungal vaginal infections or conditions.
Clotrimazole is listed in 85 entries on the Australian Register of Therapeutic Goods (ARTG). The products marketed include creams in varying strengths and quantities (including in combination with hydrocortisone), capsules for oral use and pessaries for internal use.
In the last 30 years there have been 141 adverse event reports in the Database of Adverse Events Notification (DAEN) - Medicines: 95 cases with a single suspected medicine and no cases resulting in death.
According to the TGA Ingredient Database, clotrimazole is available for use as an:
Clotrimazole is listed as a prescription medicine in New Zealand, with the exception of preparations for vaginal (restricted) or external use (Pharmacy Only and General Sale).
The USA Food and Drug Administration regulate preparations of clotrimazole as prescription and over-the-counter medicines, based on formulation type and indication. There are a number of lozenges and creams available on prescription, with creams for internal use available over-the-counter.
Clotrimazole vaginal preparations are available over-the-counter in Canada.
Clotrimazole is listed in Annex I in the EU for cutaneous use at 1% w/w.
Clotrimazole is an antimycotic drug with activity against the yeast Candida albicans, and lesser activity against other species of Candida. It was first approved in Australia 50 years ago for topical use, and has continued to be available for treatment of mucocutaneous fungal infections in dermal creams and solutions and vaginal creams and pessaries.
Property | Clotrimazole |
---|---|
CAS name | Clotrimazole |
CAS number | 23593-75-1 |
IUPAC and/or common and/or other names | 1-[(2-chlorophenyl)-diphenylmethyl]imidazole (IUPAC); Clotrimazole (INN); |
Chemical structure | ![]() |
Molecular formula | C22H17ClN2 |
Molecular weight | 344.8 g/mol |
Clotrimazole is an imidazole derivative with a broad spectrum antimycotic activity arising from inhibition of ergosterol synthesis. This leads to structural and functional impairment of the cytoplasmic membranes of dermatophytes, yeasts and moulds.
Clotrimazole is an antimycotic drug with excellent activity against Candida albicans, and lesser activity against other species of Candida. Clotrimazole also acts on Trichomonas vaginalis. The minimum inhibitory concentration (MIC) is approximately 10-1000 times greater than for Candida albicans. With MICs intermediate to that of Candida sp. and Trichomonas vaginalis, clotrimazole also have activity on gram-positive (Streptococci sp. / Staphylococci sp.) and gram-negative bacteria (Bacteroides sp. / Gardnerella vaginalis).
Primarily-resistant fungal variants to clotrimazole are very rare, and secondary fungal resistance has only been observed in very isolated cases.
A maximum of 10% of the dose of vaginally applied clotrimazole is said to be absorbed systemically. Various pharmacokinetic studies with XXXXXX pessaries demonstrated maximum clotrimazole plasma concentrations 10 to 72 hours post administration of only 10 µg/mL. Similar maximum plasma concentrations were detected after application of XXXXXX vaginal cream.
Clotrimazole is metabolised extensively in the liver to inactive compounds. The primary route of excretion is likely to be via the faeces, given urinary excretion of dermally-applied XXXXXX cream.
No carcinogenicity or mutagenicity has been observed in animal studies. Administration of XXXXXX vaginal preparations to a small number of women in the 2nd and 3rd trimesters of pregnancy was not associated with obvious untoward effects on the course of the pregnancy or on the foetus. Clotrimazole is classified as a pregnancy Category A medicine. There are no contraindications, other than hypersensitivity, for XXXXXX vaginal preparations. There are no precautions for use that have urgent/serious clinical consequences with common and/or high-risk coexisting diseases, treatments or conditions.
Medications available in Australia are now limited to formulations for topical treatment and prevention of mucocutaneous fungal infections. Dermal creams and solutions are commonly used for fungal skin infections including tinea pedis, nappy rash, candididal balanoposthitis and facial, flexural or scrotal seborrheic dermatitis. Vaginal clotrimazole creams and pessaries are used to treat vulvovaginal candidiasis which is primarily caused by Candida albicans. Atypical Candida sp. is isolated in only 5% of women with vulvovaginal candidiasis (VVC).
Five (5) public submissions were received, one (1) that supported and four (4) that opposed the scheduling proposal.
The public submissions will be made available on the TGA website.
The committee recommended that the scheduling of clotrimazole remains appropriate.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the advice comprised the following:
The delegate considered the following in regards to this proposal:
The delegate's interim decision is that the current scheduling of clotrimazole remains appropriate.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (a) the risks and benefits of the use of the substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of the substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the recommendation comprised the following:
Scheduling medicines and poisons
Substance | Interim Decision |
---|---|
Helium | Helium does not require scheduling. |
Salts of Boric Acid |
Schedule 5 – Amend EntryBORIC ACID except
Index – Amend EntryBORIC ACID The proposed implementation date is 1 October 2018. |
Polihexanide |
Schedule 6 – Amend EntryPOLIHEXANIDE except
Appendix F, Part 3 – Amend EntryPOLIHEXANIDE Warning Statement: 28 (Repeated exposure may cause sensitisation). Safety Directions: 1 (Avoid contact with eyes); 4 (Avoid contact with skin); 8 (Avoid breathing dust (or) vapour (or) spray mist). Index Entry – Amend EntryPOLIHEXANIDE Schedule 6 The proposed implementation date is 1 June 2018. |
Cimicoxib |
Schedule 4 – New EntryCIMICOXIB. The proposed implementation date is 1 June 2018. |
Scheduling medicines and poisons
An application was submitted by the Australian Competition and Consumer Commission (ACCC) to include helium gas in Schedules 6 and 7, and Appendices E and F in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) – the Poisons Standard. The ACCC proposed that helium gas in pressurised gas canisters or cylinders sold or hired to consumers for household or domestic use must contain an aversive and that the supply of helium gas for commercial and industrial uses would not require an aversive, but its supply would be restricted by scheduling.
This was a general application. The applicant’s proposed amendments to the Poisons Standard are:
Schedule 6 – New Entry
HELIUM GAS in pressurised gas canisters or cylinders sold or hired for household or domestic use and containing XX mg/kg, XX ppm or XX mg/m3 XXXXXXXXXXXXXX of an aversive agent.
Schedule 7 –New Entry
HELIUM GAS, except when included in Schedule 6.
Appendix E, Part 2 – New Entry
Standard Statements A (For advice, contact a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor (at once)), G1 (Urgent hospital treatment is likely to be needed), R1 (If inhaled, remove from contaminated area. Apply artificial respiration if not breathing).
Appendix F, Part 1 – New Entry
Warning Statement: 109: May be fatal if inhaled.
This is a truncated version of statement 13 with the words, 'swallowed or absorbed through skin' omitted.
110: Inhalation may cause brain damage.
Appendix F, Part 3 – New Entry
Warning Statement: 15 (Liquid will cause burns); 109 (May be fatal if inhaled) [new]; 110 (Inhalation may cause brain damage) [new].
The applicant's reasons for the request are:
Helium gas is not currently scheduled and has not been previously considered for scheduling. Therefore a scheduling history is not available.
According to the Globally Harmonised System (GHS) of classification, helium is a non-flammable non-toxic gas 2.2 and requires the following label:
The ACCC is aware of some efforts to address the misuse of helium in NZ and the UK. However, no jurisdictions appear to have been able find an appropriate solution or achieve any regulatory change.
According to Title 21: Food and Drugs:
The hazard classification and labelling of helium is 'Warning' in the EU:
Helium gas is a simple asphyxiant that is insoluble in body tissues.
Property | Helium |
---|---|
CAS number | 7440-59-7 |
Chemical structure | He |
Chemical name | Helium |
Atomic weight | Ar (He) = 4.003 |
Colour | Colourless |
Odour | Odourless |
Taste | Tasteless |
Reactivity | Inert (Noble) gas |
Flammability and explosivity | Not combustible; If heated in a sealed vessel, may expand to rupture container |
Lethal doses or concentrations not established.
Not an eye or skin irritant and non-corrosive.
No sensitisation effects.
N/A
Not mutagenic, carcinogenic or a teratogen.
Not a reproductive toxicant.
Helium gas is non-toxic. It is a colourless, odourless and tasteless gas and is a simple asphyxiant.
The public health policy framework includes a system for safe access to chemicals and safe use of these chemicals through the chemical scheduling arrangements, including any necessary restrictions on supply and requirement of appropriate labelling. Chemical scheduling considerations include:
Schedule 9 is not suitable.
Suitable when the substance is used in a commercial or industrial setting and adequate safety precautions and training are in place.
The ACCC notes that application of Appendix J to Schedule 7 may add further controls for commercial and industrial suppliers and users of helium gas. However, adoption of Appendix J varies between States and Territories and there is currently no reason to expect that supplies of helium without an aversive would be illicitly supplied to consumers.
Suitable when the substance has an added aversive and is supplied for household or domestic use.
The proposal is for the substance to be required to include an aversive when supplied for household or domestic use. The aversive e.g. a mercaptan, will have an aversion effect.
Suitable when the substance has an added aversive and is supplied for household or domestic use.
Not suitable as helium gas meets factors for Schedule 7 (DANGEROUS POISON) for industrial and commercial uses of helium and Schedule 6 (POISON) or Schedule 5 (CAUTION) for domestic and household use when an aversive is included to prevent deliberate inhalation that results in fatalities.
Consideration of the Scheduling Factors indicates that helium (with an aversive) for household or domestic use could be included in either Schedule 6 or Schedule 5 of the Poisons Standard. The ACCC recommends that the substance is included in Schedule 6, given the rapidity of the asphyxiation effect, even if an aversive is included.
Mercaptans (thiols) are organosulfur compounds that contain a carbon-bonded sulfhydryl group:
Mercaptan | Descriptors | Acute Exposure Guideline Levels (AEGL[50]) for 10 minute exposure | Acute Exposure Guideline Levels (AEGL ) for 10 minute exposure Odour intensity or awareness (LOA[51]) detection thresholds and descriptors | 4 hour inhalation LC50 (ppm) (rats/mice) |
---|---|---|---|---|
methyl mercaptan CH4S | Strong odour, garlic-like, rotten cabbage, bad breath | AEGL-1 = no recommendation AEGL-2 = 40 ppm (80 mg/m3) AEGL-3 = 120 ppm (240 mg/m3) |
LOA = 0.0019 ppm Detection threshold = 0.041 ppm Strong intensity = 110 ppm |
675 / 1667 |
ethyl mercaptan C2H6S | Penetrating, persistent odour, garlic/leek-like, skunk-like, decaying cabbage | AEGL-1 = 1 ppm (2.5 mg/m3) AEGL-2 = 150 ppm (380 mg/m3) AEGL-3 = 450 ppm (1100 mg/m3) |
LOA = 1.4 x 10-4 ppm Detection threshold = 2.6-9.7 x 10-4 ppm Strong = 21-97 ppm |
4420 / 2770 |
phenyl mercaptan C2H6S | Disagreeable, penetrating and repulsive odour, garlic-like | AEGL-1 = no recommendation AEGL-2 = 1 ppm (4.5 mg/m3) AEGL-3 = 3 ppm (14 mg/m3) |
Detection threshold = 0.00025 ppm Strong = 38 ppm |
33 / 28 |
tert-mercaptan C2H6S | Disagreeable | AEGL-1 = no recommendation AEGL-2 = 0.77 ppm (4.6 mg/m3) AEGL-3 = 2.3 ppm (14 mg/m3) |
- | 51 / 47 (both males only) |
Many mercaptans have strong odours and are dominant contributors to repulsive smells including garlic, rotten eggs, rotten cabbage, skunk spray and certain chemical faults in wines etc. Mercaptans (generally methyl mercaptan and ethyl mercaptan) and sulfides are added to natural gas supplies and other odourless gases so that consumers can be aware of the gas.
Inhalational toxicity levels and ability of people to detect mercaptans vary. Phenyl mercaptan and tert-octyl mercaptan are both highly toxic than the lower molecular weight mercaptans, methyl mercaptan and ethyl mercaptan. Compared to methyl mercaptan, ethyl mercaptan has lower inhalational toxicity in rats and mice as well as a lower detection threshold.
Ethyl mercaptan appears to be the most suitable mercaptan candidate for inclusion in helium gas as an aversive.
The ACCC requests the Scheduling Delegate commission expert advice about the suitability of the mercaptans (and potentially other aversives) as suitable candidates for inclusion in helium gas for consumer or domestic use.
Eight (8) public submissions were received for helium, one (1) in support and seven (7) opposed.
The public submissions will be made available on the TGA website.
The committee recommended that helium does not require scheduling.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the recommendation comprised the following:
The delegate considered the following in regards to this proposal:
The delegate’s interim decision is not to schedule helium.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the interim decision are the following:
Scheduling medicines and poisons
An application was submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) to amend the current entry for boric acid in Schedule 5, to remove “excluding its salts”, so salts of boric acid are captured by scheduling in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) – the Poisons Standard.
This was a general application. The applicant’s proposed amendments to the Poisons Standard are:
Schedule 5 – Amend Entry
BORIC ACID (excluding its salts) and BORAX except:
The applicant’s reasons for the request are:
The salts of boric acid are captured by the Schedule 4 entry for BORON in the current Poisons Standard as follows:
Schedule 4
BORON, including boric acid and borax, for human therapeutic use except:
Boric acid is included in Schedule 5 and Appendix E, Part 2. However, salts of boric acid are specifically excluded as follows:
Schedule 5
BORIC ACID (excluding its salts) and BORAX except:
Appendix E, Part 2
BORIC ACID
Standard statements: A (For advice, contact a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor (at once)).
Index
BORON
cross reference: BORATES, BORAX, BORIC ACID, BORON COMPOUNDS
Schedule 4
The scheduling history for boron compounds dates back to July 1968. The most recent scheduling considerations are highlighted below.
The May and August 2001 NDPSC Meetings agreed to revise the boron Schedule 4 entry to exempt a daily oral dose of 3 mg and to exempt dermal preparations containing 0.35 per cent or less to harmonise with the New Zealand (NZ) classification for dermal use. However, the committee did not agree to harmonise on other use patterns. This outcome was referred to NZ's Medicines Classification Committee (MCC) for consideration.
The February 2006 NDPSC Meeting:
The June 2007 NDPSC Meeting agreed that consideration of the scheduling of boron should be deferred, pending information from NZ regarding a potential proposal to set a new exemption cut-off, and the reasons for any such recommendation.
At the December 2007 Meeting, the MCC agreed that boron, including boric acid and borax, should be a prescription medicine except when for internal use in medicines containing 6 mg or less per recommended daily dose; for dermal use other than paediatric use in medicines containing 0.35 per cent or less or when present as an excipient.
The February and June 2008 NDPSC Meetings, following reconsideration of the issues (including the reasons for the adoption by New Zealand of a 6 mg cut-off for internal use), agreed to foreshadow the following amendments to the Schedule 4 boron entry (including capture of all paediatric use as Schedule 4) to allow stakeholders a further opportunity to comment, and to help identify any potential unintended consequences:
Boric acid is an ingredient in 80 products on the ARTG including eye drops, antifungal treatments, contact lens solution, detergents and vitamins.
Boric acid is listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017 as follows:
Ingredient Name | Purpose of the ingredient in the medicine | Specific requirements | |
---|---|---|---|
890 | BORIC ACID | A, H | Boron is a mandatory component of Boric acid. The percentage of Boron from Boric acid should be calculated based on the molecular weight of Boric acid
The maximum recommended daily dose must provide no more than 6mg of Boron. In preparations for dermal use, which are not for paediatric or antifungal use, the concentration of boron in the medicine must be no more than 3500 mg/kg or 3500 mg/L or 0.35% The indication 'For mineral (may state the mineral) supplementation' is only permitted for use when the medicine is for oral or sublingual use. |
Some members of this group (CAS Nos. 1330-43-4, 12267-73-1, 13840-56-7) are classified as hazardous for reproductive and developmental toxicity – Category 1B; H360FD (May damage fertility. May damage the unborn child) in the HCIS (Safe Work Australia).
Boric acid (CAS No. 10043-35-3) is classified as a hazardous for reproductive and developmental toxicity – Category 1B; H360FD (May damage fertility. May damage the unborn child) in the HCIS (Safe Work Australia).
Boric acid, disodium salt and boric acid, dipotassium salt are listed on the following:
1330-43-4
Boric acid (H2B4O7), disodium salt; Boron sodium oxide, (B4Na2O7) (CAS); Sodium borate (INCI); disodium tetraborate; sodium borate anhydrous; disodium tetraborate, anhydrous
1332-77-0
Boric acid (H2B4O7), dipotassium salt; Boron potassium oxide (B4K2O7) (CAS); potassium tetraborate; potassium borate; dipotassium tetraborate
26038-87-9
Boric acid (H3BO3), compd. with 2-aminoethanol; monoethanolamine, boric acid salt; Boric acid (H3BO3), compd. with 2-aminoethanol (1:?) (CAS); MEA-borate (INCI)
26038-90-4
Boric acid (H3BO3), compd. with 1-amino-2-propanol (1:?) (CAS); MIPA-borate (INCI); 1-aminopropan-2-ol, compound with orthoboric acid; boric acid, monoisopropanolamine salt; orthoboric acid isopropanolamine salt
68003-13-4
Boric acid (H3BO3), compd. with 1-amino-2-propanol (1:1) (CAS); MIPA-borate (INCI); Isopropanolamine borate; (2 hydroxypropyl)ammonium dihydrogen orthoborate
The following information was extracted from the NICNAS IMAP Human Health Tier II assessment report for salts of boric acid.
Toxicity | Species | Salts of boric acid | SPF (2015) Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | >2000 mg/kg bw (for suitable analogues) | Schedule 5 |
Acute dermal toxicity LD50 (mg/kg bw) | Rat | >2000 mg/kg bw (for suitable analogues) | Schedule 5 |
Acute inhalational toxicity LC50 (mg/m3/4h) | Rat | >2000 mg/m3 (for suitable analogues) | Schedule 5 |
Skin irritation | Rabbit | Suitable analogue chemicals non-irritating. | Schedule 5 |
Eye irritation | Rabbit | Suitable analogue chemicals produced mild irritation in some studies | Schedule 5 |
Skin sensitisation | Guinea pig | Suitable analogue chemicals are non-sensitising | Schedule 5 |
The Scientific Committee on Consumer Safety (SCCS) has recently concluded that substances such as borates, tetraborates, and octaborates as well as other boric acid salts/esters (MEA-borate, MIPA-borate, potassium borate, trioctyldodecyl borate and zinc borate reported in the CosIng database) produce boric acid following contact with water. Therefore, as these compounds have chemical, biological and toxicological properties similar to boric acid, the general restrictions applicable to boric acid for safe use in cosmetic products should apply to the whole group of borates (SCCS, 2013).
Limited data was provided for the chemicals in this group. The information available for sodium borate, anhydrous (CAS No. 1330-43-4) and analogues boric acid (CAS No. 10043-35-3), borax (CAS No. 1303-96-4) and zinc borates suggest that the chemicals in this group are likely to have low acute toxicity in animal tests following oral exposure. The median lethal dose (LD50) in rats for the tested chemicals in the group and the analogue chemicals is >2000 mg/kg bw. The boric acid amine salts are also expected to have low acute oral toxicity (>2000 mg/kg bw).
No data was provided for the chemicals in this group.
Data available for the analogue chemicals, boric acid (CAS No. 10043-35-3), borax (CAS No. 1303-96-4) and zinc borates indicate that the chemicals in this group are likely to have low acute toxicity in animal tests following dermal exposure. The dermal LD50 in rats is >2000 mg/kg bw for each of these analogues. It is also noted that the dermal absorption through intact skin is very low (dermal absorption rate of 0.5% was assumed for borates. [52][53][54]
No data was provided for the chemicals in this group.
Information available on the analogues boric acid (CAS No. 10043-35-3), borax (CAS No. 1303-96-4) and zinc borates indicates that the chemicals in this group are likely to have low acute toxicity in animal tests following inhalational exposure. The highest achievable inhalational dose produced no mortalities in these studies.
There is a large database of accidental or intentional poisoning in humans following exposure to borates. A review of more than 700 cases of acute boric acid exposures in adults and children found 88.3% of cases were without symptoms. Although the report provided only limited information on dose response, dose ranges of 0.1–55 g and 0.01–89 g of boric acid were reported for symptomatic and asymptomatic cases, respectively. There are case reports of lethal oral exposures in humans involving accidental or intentional ingestion of high doses of boric acid. While oral lethal doses for boric acid have been quoted as 2–3 g for infants, 5–6 g for children, and 15–30 g for adults, the data are largely unsubstantiated. Further difficulty in making an appropriate quantitative judgment about a lethal dose was also noted due to medical intervention in most cases. Following ingestion of a formula accidentally prepared with a 2.5% aqueous solution of boric acid, 5 infants became lethargic, developed vomiting and diarrhoea, and died within 3 days of exposure (estimated dose of 4.5–14 g boric acid). Deaths have also occurred in a 77-year-old man following ingestion of 30 g of boric acid and in a 45-year-old man following ingestion of approximately 280 g of boric acid. In both instances, clinical signs were similar: vomiting, diarrhoea, erythema, cyanotic extremities, acute renal failure, cardiopulmonary hypertension and death from heart failure.
Although the data for the chemicals in this group are limited, the available information on the analogues, boric acid (CAS No. 10043-35-3), borax (CAS No. 1303-96-4), and on zinc borates indicate that the chemicals in this group are not likely to be skin irritants.
Limited data was provided on the chemicals in this group. In an eye irritation study, potassium pentaborate (CAS No. 11128-29-3) (0.1 g) was placed in the conjunctival sac of the right eye of each of the three New Zealand White (NZW) rabbits and treated eyes were rinsed with water 24 hours after administration of the test substance. The untreated left eye of each rabbit served as a control. As significant eye irritation scores were not observed in any animal throughout the study, the chemical was classified as non-irritant to the eyes. Slight eye irritant effects were reported in animal studies for the analogues: boric acid (CAS No. 10043-35-3); borax (CAS No. 1303-96-4) and on zinc borates. The reported effects were not sufficient to warrant hazard classification for the chemicals in this group.
The limited data indicate that the chemicals in this group are unlikely to be specific respiratory irritants.
Although no information is available on the skin sensitisation potential of chemicals in this group, based on the available information on the analogue chemicals, the chemicals in this group are not likely to be skin sensitisers.
No evidence of skin or respiratory sensitisation in humans occupationally exposed to borates has been reported.
No data was provided for the chemicals in this group.
The available information on boron-containing compounds indicates that the chemicals in this group are not likely to cause serious damage to health from repeated oral exposure.
No data was provided.
No data was provided.
Although the data for the chemicals in this group are limited, the available information on boric acid (CAS No. 10043-35-3) and zinc borates indicates that the chemicals in this group are not likely to have a mutagenic or genotoxic potential.
Limited data are available on the chemicals in this group. Available information on other inorganic borates and on zinc borates indicates that the chemicals in this group are not likely to have a carcinogenic potential. The chemicals in this group are also not considered to have a mutagenic or genotoxic potential.
No data was provided regarding reproductive or developmental effects of chemicals in this group in animals and humans, although there are studies on the analogues boric acid and borax. While the appropriate data are not available for chemicals in this group, information on boron-containing compounds (boric acid) in animals is sufficient to support classification for all chemicals in this group.
The testes and the developing foetus have been identified as the most sensitive targets of boron toxicity in animal studies, with the rat being the most sensitive species. The reported testicular effects included reduced organ weight and organ:body weight ratio; atrophy and degeneration of the spermatogenic epithelium; impaired spermatogenesis; and reduced fertility. The reported developmental effects included high prenatal mortality; reduced foetal body weight; and malformations and variations of the eyes, central nervous system, cardiovascular system and axial skeleton. The NOAEL for fertility of 100 mg/kg bw/day of boric acid (equivalent to 17.5 mg boron/kg bw/day) has been determined from two-year and three-year generational studies in rats, based on testicular effects. The critical NOAEL for developmental effects has been determined as 55 mg/kg bw/day of boric acid (equivalent to 9.6 mg boron/kg
As the chemicals in this group dissociate in water and give rise to boric acid, these results are applicable to borate salts.
Although specific use in cosmetic products in Australia is not known, the chemicals are reported to be used in cosmetic products overseas as buffering agents and viscosity controlling agents.
Two (2) public submissions were received for salts of boric acid, which opposed the scheduling proposal.
The public submissions will be made available on the TGA website.
The committee recommended that the Schedule 5 and Index entries of boric acid be amended as follows:
Schedule 5 – Amend Entry
BORIC ACID (excluding its salts) and BORAX except:
Index – Amend Entry
BORIC ACID
cross reference: BORAX, BORON
The committee also recommended an implementation date of 1 October 2018 to allow time for industry to accommodate the changes.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.
The reasons for the recommendation comprised the following:
The delegate considered the following in regards to this proposal:
The delegates’ interim decision is to amend the Schedule 5 and index entries for boric acid. The proposed Schedule and index entries are:
Schedule 5 – Amend Entry
BORIC ACID except:
Index – Amend Entry
BORIC ACID
cross reference: BORAX, BORON
The proposed implementation date is 1 October 2018. This is to allow time for industry to accommodate the changes.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989 (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.
The reasons for the interim decision are the following:
Scheduling medicines and poisons
An application was submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) to amend the current entry for polihexanide in Schedule 6 in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) – the Poisons Standard.
This was a general application. The applicant’s proposed amendments to the Poisons Standard are as:
Schedule 6 – Amend Entry
POLIHEXANIDE except:
Appendix F, Part 3 – Amend Entry
POLIHEXANIDE
Warning Statement: 28 (Repeated exposure may cause sensitisation).
Safety Directions: 1 (Avoid contact with eyes); 4 (Avoid contact with skin); 8 (Avoid breathing dust (or) vapour (or) spray mist).
The applicant’s reasons for the request are:
Polihexanide is currently listed in Schedule 6 and in Appendices E and F of the Poisons Standard as follows:
Schedule 6
POLIHEXANIDE except:
Appendix E, Part 2
POLIHEXANIDE
Standard Statement: E1 (If in eyes, wash out immediately with water).
Appendix F, Part 3
POLIHEXANIDE
Safety Directions: 1 (Avoid contact with eyes); 4 (Avoid contact with skin); 8 (Avoid breathing dust (or) vapour (or) spray mist).
Chlorhexidine (polihexanide is a polymer of chlorhexidine) is in Schedules 7, 6 and 5 of the Poisons Standard as follows:
Schedule 7
CHLORHEXIDINE except:
Schedule 6
CHLORHEXIDINE in preparations containing 7 per cent or less of chlorhexidine except:
Schedule 5
CHLORHEXIDINE in preparations containing 3 per cent or less of chlorhexidine except:
In May 1977, the Poisons Schedule (Standing) Committee (PSC) considered the substance (at that time it was called poly(hexamethylene biguanide) hydrochloride) and decided to list it in Schedule 5 and the then Appendix A (now Appendix E). The reason for these entries was its LD50 in the rat was 1 g/kg (toxicity end-point details were not provided).
In November 1982, the PSC considered an application requesting that preparations containing less than 20% of poly(hexamethylene biguanide) be exempted from scheduling. The PSC did not accept the proposal because of concerns over "equivocal" results in developmental studies in rats, low survival rate in sub-acute oral studies in rats, and severe eye irritancy. The PSC, however, agreed to a 5% cut-off as exempt from scheduling, on the basis that poly(hexamethylene biguanide) was not a skin or eye irritant at that concentration.
In November 2000, the NDPSC decided to change the nomenclature of the Schedule 5 entry from poly (hexamethylene biguanide) hydrochloride to polihexanide. This decision was to reflect the World Health Organisation's decision to use the International Non-proprietary Name (INN).
In June 2011, the Australian Pesticides and Veterinary Medicines Authority's (APVMA) released an updated report, 'polihexanide carcinogenicity: analysis of human health risk', based on an OCS evaluation on the carcinogenicity potential of polihexanide. The report indicated that polihexanide has a potential for carcinogenicity in whole-of life studies in rodents via the oral route, but only at high exposure levels that are unlikely to be encountered in occupational or public settings. Negative results were obtained in an 80-week dermal study in mice. There were no carcinogenic effects on skin. The occurrence of haemangiosarcoma in the liver at the high dose in the dermal study was considered not to be treatment related as it was within historical controls. Polihexanide did not appear to be genotoxic. The OCS evaluation report did not regard carcinogenicity findings in rodents as a barrier to continuing registration of products containing polihexanide.
In September 2014, the Office of Chemical Safety (OCS), based on the APVMA's review on polihexanide, submitted a proposal to delete the current Schedule 5 polihexanide entry and create a new Schedule 6 entry for preparations containing more than 5% of polihexanide. This application was considered at the November 2014 Joint Advisory Committee on Medicines and Chemicals Scheduling (Joint ACMS-ACCS#10). The committee recommended that the current Schedule 5 polihexanide entry be deleted and a new Schedule 6 entry be created for preparations containing more than 5% of polihexanide. The committee also recommended that the new entry specifically exempt from scheduling preparations containing polihexanide when packed and labelled for therapeutic use; and that a First Aid Statement 'E1 - If in eyes wash out immediately with water' be applied. The delegate agreed based on the critical toxicological endpoints driving this categorisation (acute toxicity, severe skin/eye irritancy and sensitisation potential) consistent with SPF criteria for listing in Schedule 6, and given the public health risk sufficiently ameliorated for products under 5 per cent. This was implemented on 1 June 2015.
The applicant states that no restrictions in Australia exist for using polihexanide in cosmetic or domestic products.
Polihexanide (as polyhexamethlenebiguanidine) is an ingredient in 8 products on the ARTG including contact lens solution, irrigation fluid for medical/surgical procedures, dental material for root fillings, sanitising wipes and disinfectant spray.
According to the ARTG database, Polyhexamethlenebiguanidine (PHMB) is permitted for use as an excipient in Devices only. It is not currently used in any PI formulations.
There are no recorded adverse events in the Database of Adverse Event Notifications – media devices for polyhexamethlenebiguanidine.
Polihexanide is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017. However, the similar compound polyaminipropyl biguanide (CAS No. 133029-32-0, Figure 1 below) and chlorhexidine (as the acetate and gluconate) are listed as follows:
Ingredient Name | Purpose of the ingredient in the medicine | Specific requirements | |
---|---|---|---|
3908 | POLYAMINOPROPYL BIGUANIDE | E | Only for use in topical medicines for dermal application and not to be included in medicines intended for use in the eye. The concentration in the medicine must be no more than 0.3%. |
1298 | CHLORHEXIDINE ACETATE | E | Only for use in topical medicines for dermal application. |
1299 | CHLORHEXIDINE GLUCONATE | E | Only for use in topical medicines for dermal application. |
The chemicals are permitted as preservatives in cosmetic products in the EU and NZ at a maximum permitted concentration of 0.3%.
The use of polihexanide in cosmetics in the European Union (EU) is subject to the EU Cosmetics Regulation 1223/2009 Annex V—List of preservatives allowed in cosmetic products. Polihexanide may be used as preservatives in cosmetic products at a maximum permitted concentration of 0.3%. According to the 2017 SCCS opinion a reduction in this concentration was recommended, but this has not yet been finalised, nor implemented in legislation.
Polihexanide are also listed, with similar use restrictions described above, in the NZ Cosmetic Products Group Standard—Schedule 7.
Property | Polihexanide |
---|---|
CAS numbers |
32289-58-0 |
Chemical structure | ![]() |
IUPAC, CAS and/or common and/or other names | Poly(iminocarbonimidoyliminocarbonimidoylimino-1,6-hexanediyl); polyhexamethylene biguanide (PHMB); 1-(diaminomethylidene)-2-hexylguanidine (IUPAC); Polyaminopropyl Biguanide (INCI) |
Polihexanide (polyhexamethylene biguanide hydrochloride or PHMB) is a polymer of chlorhexidine and a preservative ingredient/biocide in cosmetics and domestic products and therapeutic goods including disinfectants and sanitisers.
Polihexanide is used as an active ingredient in various preparations such as wet wipes, wound irrigation solutions, sterile dressings as well as disinfectants (e.g. medical equipment, medical procedures, contact lens cleaners, food preparation surfaces, industrial situations, veterinary products and milk handling equipment). Polihexanide is also used an antimicrobial for the control of microorganisms, algae and fungi in swimming pools and spas.
Due to its excellent biocidal properties, the usage of polihexanide has increased in personal care products and pharmaceuticals, for instance in the treatment of chronic wounds and burns. This widely used biocide has been reviewed by the US EPA, which noted that the biocide has very low aggregate risk of adverse health effects to the public or environment, except for occupational users.
Polihexanide binds to the negatively charged phosphate head groups of phospholipids on the bacterial cell wall causing increased rigidity by sinking nonpolar segments into hydrophobic domains, and membrane disruption with subsequent cytoplasmic shedding, culminating in cell death. The antibacterial activity of polihexanide depends on its molecular structure. Minimum requirements for biocidal activity are met by having more than 2 biguanide moieties and 5-7 methylene groups as a spacer. Therefore, polihexanide represents an oligomeric substance with a number-average degree of polymerization of 2-5. It is a cationic biocide marketed worldwide, because of its excellent antimicrobial activity, chemical stability, low toxicity and reasonable cost. Polihexanide is highly soluble in water (20%, w/v) and aliphatic alcohols, but poorly soluble in nonpolar liquids. The biguanide moieties are strong bases and monoprotonated at a pH value of 7 (pKa1=2–3; pKa2=10.5–11.5) resulting in a polycation with a positive charge at each biguanide moiety[55]
The following information was extracted from the NICNAS IMAP Human Health Tier II assessment report for polihexanide.
Toxicity | Species | Polihexanide | SPF (2015) Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | 501-1049 mg/kg bw | Schedule 6 |
Acute dermal toxicity LD50 (mg/kg bw) | Rat, Rabbit | >2000 mg/kg bw | Schedule 5 |
Acute inhalational toxicity LC50 (mg/m3/4h) | Rat | 0.29-0.48 mg/L/4 hours (290-480 mg/m3/4 hours) | Schedule 7 |
Skin irritation | Rabbit | Slightly irritating | Schedule 5 |
Eye irritation | Rabbit | Highly irritating | Schedule 6 |
Skin sensitisation (GPMT, Buehler) | Guinea pig | Moderate | Schedule 6 |
Polihexanide has moderate acute toxicity based on results from animal tests following oral exposure, with median lethal dose (LD50) values ranging from 501-1049 mg/kg bw. Observed sub-lethal effects in these studies included lethargy, ataxia, salivation, laboured breathing, lacrimation, piloerection, and partial drooping of the upper eyelids (ptosis).
Polihexanide has low acute toxicity based on results from animal tests following dermal exposure, with LD50 values > 2000 mg/kg bw.
Polihexanide has high acute toxicity based on results from animal tests following inhalation exposure, with median lethal concentration (LC50) values ranging from 0.29-0.48 mg/L/4 hours. Observed sub-lethal effects in these studies included breathing irregularities, abnormal respiratory noise, partial drooping of the upper eyelids (ptosis), decreased activity and pathological changes in the lungs.
Polihexanide, when applied at neat concentrations, is slightly irritating to rabbit skin.
Polihexanide is highly irritating to rabbit eyes
In a study compliant with the Organisation for Economic Co-operation and Development (OECD) Test Guideline (TG) 405, 0.1 mL of neat polihexanide was instilled into the conjunctival sac of one eye of a male New Zealand White (NZW) rabbit. The other eye was used as a control. The treatment-related effects on the cornea, iris, and conjunctivae were evaluated at the following time points: 1, 24, 48, 72 hours; and 7, 14, 21 days. This single treatment resulted in corneal opacity (opalescent), iridial inflammation and severe conjunctival irritation. Additionally, other treatment-related effects observed include vascularisation and pale appearance of the nictating membrane. These changes were not reversible by 21 days. Considering the severity of the effects, no additional animals were used in the study. Although there were no irritation scores provided, polihexanide was considered corrosive to the rabbit eye following this single application.
Similar results to the study above were reported in another neat application of the chemical to NZW rabbits.
Based on the available information from guideline-compliant studies in animals, polihexanide is considered to be a moderate skin sensitiser.
In an OECD TG 406-compliant guinea pig maximisation study in Alpk:Dunkin Hartley guinea pigs, intradermal induction used 0.06% polihexanide under occlusive conditions for 48 hours. Topical induction was with 20.2% polihexanide solution. The challenge concentrations used were 20.2% and 6% polihexanide under occlusive condition for 24 hours. The ensuing skin reactions were observed and scored 24 or 48 hours following patch removal. In the guinea pigs challenged with 20.2% polihexanide, scattered redness or moderate diffuse redness were observed in 18/20 and 16/20 animals 24 and 48 hours after patch removal, respectively. The average scores for redness were 1.4 at 24 hours and 1.2 at 48 hours. Similar effects were observed in some animals challenged with 6% polihexanide: 5/20 after 24 hours; and 2/20 48 hours after patch removal. The average scores were 0.3 at 24 hours and 0.1 at 48 hours. Under these tests conditions, polihexanide is considered to be a moderate sensitiser. However, the SCCS has noted that, at 20.2%, polihexanide 'should be considered a strong sensitiser according to Regulation (EC) No 1272/2008 (CLP regulation)'.
Results from several other guinea pig maximisation tests and Buehler studies conducted according or comparable to OECD 406 support the observations of the critical study above.
Based on the available information from guideline-compliant studies in animals, polihexanide is not expected to cause serious damage to health following repeated oral or dermal exposure.
Based on the treatment-related effects reported in repeated dose toxicity studies, repeated inhalation exposure to polihexanide is considered to cause serious damage to health.
In a 28-day repeated dose inhalation toxicity study in male and female Wistar-derived [Alpk:APfSD] rats, the no observed adverse effect concentration (NOAEC) for polihexanide was reported to be 0.0239 mg/m3 (nominal concentration). In this OECD TG 412-compliant study, rats were exposed nose-only to 0.025, 0.25, and 2.5 mg/m3 polihexanide for 6 hours a day, 5 days a week for 28 days. Measured concentrations were 0.0239 mg/m3 (particle size range - 0.32-1.30 μm); 0.257 mg/m3 (particle size range - 0.48-5.06 μm); and 2.47 mg/m3 (particle size range - 0.67-1.67 μm). The recovery period following treatment was 13 weeks. Changes in bodyweight and food consumption were observed in males exposed to 0.25 or 2.5 mg/m3 polihexanide. No deaths occurred in any of the treatment groups. Histopathological analysis showed transient changes in the larynx and trachea in animals from the 0.25 and 2.5 mg/m3 groups. In these groups, increased liver, lung and thymus weights (males only) were reported. Irreversible pneumonitis (severity reduced at the end of the recovery period) and bronchitis were seen in the lungs of animals treated with 2.5 mg/m3 polihexanide.
The results from a 21-day repeat dose inhalation study conducted in rats (predates establishment of test guidelines) support the observations of the critical study above.
Based on the limited available in vitro and in vivo genotoxicity studies, polihexanide is not considered to be genotoxic.
Based on several studies conducted in accordance with, or comparable to, United States Environmental Protection Agency, and The Organisation for Economic Cooperation and Development test guidelines, polihexanide induced vascular tumours in rats and mice at high doses only. The doses were above the maximum tolerated dose. As such, the effects may not be relevant under the conditions of human exposure.
Based on the available data from several animal studies, polihexanide is not expected to exhibit reproductive or developmental toxicity.
Polihexanide, at concentrations up to 1.5%, was not irritating to the skin in a skin irritation study in human volunteers. In clinical case reports, 0.02% of aqueous polihexanide solution used in the treatment of Acanthamoeba keratitis was tolerated by human corneal and conjunctival epithelium.
In an unpublished 2016 report, the Australian Government Department of Health conducted a detailed evaluation of the available skin sensitisation studies and concluded that polihexanide is a possible skin sensitiser in humans in product formulations at 0.5%, with a potential for causing sensitisation at 0.2% in sensitive individuals.
The following case studies have been reported:
There are no cosmetic or domestic uses identified for polihexanide in Australia. However, overseas information indicates such uses are likely in Australia.
Three (3) public submissions were received for polihexanide. One (1) submission raised no objections as it outlined that the proposed scheduling amendment would not have any impact on therapeutic goods. One (1) submission was opposed and one (1) submission supported the proposal for cosmetic products, but opposed the proposal for non-cosmetic products.
One submission also requested an amendment to the index entry and a longer implementation date:
The public submissions will be made available on the TGA website.
The committee recommended that the current Schedule 6, Appendix F and Index entries for polihexanide be amended, as follows:
Schedule 6 – Amend Entry
POLIHEXANIDE except:
Appendix F, Part 3 – Amend Entry
POLIHEXANIDE
Warning Statement: 28 (Repeated exposure may cause sensitisation).
Safety Directions: 1 (Avoid contact with eyes); 4 (Avoid contact with skin); 8 (Avoid breathing dust (or) vapour (or) spray mist).
Index Entry – Amend Entry
POLIHEXANIDE
cross reference: 1-(diaminomethylidene)-2-hexylguanidine, poly (iminocarbonimidoyliminocarbonimidoylimino-1,6-hexanediyl), polyhexamethylene biguanide (PHMB)
Schedule 6
Appendix E, Part 2
Appendix F, Part 3
The committee also recommended an implementation date of 1 June 2018 as this is the earliest practicable implementation date.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.
The reasons for the recommendation comprised the following:
The delegate considered the following in regards to this proposal:
Schedule 6 – Amend Entry
POLIHEXANIDE except:
Appendix F, Part 3 – Amend Entry
POLIHEXANIDE
Warning Statement: 28 (Repeated exposure may cause sensitisation).
Safety Directions: 1 (Avoid contact with eyes); 4 (Avoid contact with skin); 8 (Avoid breathing dust (or) vapour (or) spray mist).
Index Entry – Amend Entry
POLIHEXANIDE
cross reference: 1-(diaminomethylidene)-2-hexylguanidine, poly (iminocarbonimidoyliminocarbonimidoylimino-1,6-hexanediyl), polyhexamethylene biguanide (PHMB)
Schedule 6
Appendix E, Part 2
Appendix F, Part 3
The proposed implementation date is 1 June 2018. This is the earliest practicable implementation date.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.
The reasons for the recommendation comprised the following:
Scheduling medicines and poisons
An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to create a new entry for cimicoxib in Schedule 4 with no exemption or cut-off in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) – the Poisons Standard.
This was a general application. The applicant’s proposed amendments to the Poisons Standard are:
Schedule 4 – New Entry
CIMICOXIB
The applicant’s reasons for the request are:
Cimicoxib is not currently scheduled and has not been previously considered for scheduling. Therefore a scheduling history is not available.
Related selective COX-2 inhibitors with similar properties are listed in Schedule 4, such as celecoxib, lumiracoxib, mavacoxib and meloxicam.
Cimicoxib is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017, or PubCRIS, and is not an excipient or active in any medicines on the ARTG.
Due to the withdrawal of rofecoxib from the market in 2004, the COX-2 inhibitors have been reviewed by the TGA to address safety concerns.
Cimicoxib was registered by EMA/CVMP in February 2011 under the trade name Cimalgex. In March 2015, as part of a veterinary pharmacovigilance initiative, it was recommended to add the following warnings to address relatively high number of reports that include renal disorders and renal failure: 'In very rare cases, increases in renal biochemistry parameters were noted. Furthermore, in very rare cases, renal failure has been reported. As for any long term NSAID treatment, renal function should be monitored'.
Cimicoxib is approved for use in the UK for the treatment of pain and inflammation associated with osteoarthritis, and the management of peri-operative pain due to orthopaedic or soft tissue surgery, in dogs.
Cimicoxib could not be found as being available in the USA or Canada or New Zealand.
Property | CIMICOXIB |
---|---|
CAS name | Benzenesulfinamide, 4-[4-Chloro-5-(3-fluoro-4-methoxyphenyl)-1H-imidazol-1-yl] |
CAS numbers | 265114-23-6 |
Chemical structure | ![]() |
Molecular formula | C16H13ClFN3O3S |
Molecular formula | 381.8 g/mol |
IUPAC, CAS and/or common and/or other names | IUPAC: 4-[4-Chloro-5-(3-fluoro-4-methoxyphenyl)-1H-imidazol-1-yl]benzenesulfonamide;
UR-8880 |
The following information was extracted from the Human Health Risk Assessment – Technical Report for cimicoxib.
Toxicity | Species | Cimicoxib | Product | SPF (2015) Classification |
---|---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Mouse Rat |
>2000 (1/6 deaths) >2000 (no deaths) |
>5000 (rat) | Schedule 5 |
Acute dermal toxicity LD50 (mg/kg bw) | Rat | No data | >5000 | Schedule 5 |
Acute inhalational toxicity LC50 (mg/m3/4h) | Rat | No data | - | - |
Skin irritation | Rabbit | No data | Slight | Schedule 5 |
Eye irritation | Rabbit | No data | Moderate | Schedule 5 |
Skin sensitisation (GPMT)n | Guinea pig | No data | Sensitiser | Schedule 6 |
In response to the above tables the applicant stated:
Based on the available oral and dermal data, cimicoxib has low acute toxicity.
In short-term repeat-dose oral (gavage) studies in rats and dogs, the primary target organ was the gastrointestinal tract. In rats, deaths were seen that were associated with inflammation/perforation of the small intestine and gastrointestinal adhesions, with secondary septic peritonitis seen at higher dose levels. Clinical signs such as hunched posture, swollen abdomen that was hard to the touch and decreased motor activity were observed. In dogs, emesis, soft faeces/diarrhoea and hidden blood in the faeces were seen, with adverse decreases also seen in RBC count, haemoglobin, haematocrit, total protein and albumin at higher dose levels.
There was no evidence that cimicoxib was neurotoxic or immunotoxic.
Cimicoxib was tested for genotoxicity in an adequate range of in vitro and in vivo assays and was negative. It was concluded that cimicoxib is unlikely to pose a carcinogenic risk to humans.
No studies investigating the chronic toxicity or carcinogenic potential of cimicoxib are available.
In a one-generation rat study, a decrease in the fertility index at the low dose and greater that lacked a dose response and did not obtain statistical significance was considered incidental, compared to controls. A decrease was also seen in the mean number of corpora lutea. No historical control data were provided, although obtained data on the background incidence of corpora lutea in rats indicated that it was likely to be incidental to treatment. A treatment-related and adverse decrease was seen in uterus weight, the number of implantations and live foetuses, and an increase in the percentage of resorptions and pre- and post-implantation loss in the absence of parental toxicity.
In a study of developmental toxicity in rats, a slight increase was seen in the foetal and litter incidence of haemorrhagic liver, pale liver, malpositioned kidneys and misaligned sternebrae at the top dose level, compared to controls. No historical control data were provided, although data on the background incidence of misaligned sternebrae in rat foetuses indicated it was likely incidental to treatment. No historical control data were identified for haemorrhagic liver, pale liver and malpositioned kidneys in rat foetuses. However, noting that these minor visceral abnormalities were observed in control foetuses and the slight increase seen at the top dose level (that produced deaths and adhesion and perforation in the small intestine of dams) did not obtain statistical significance, it is considered they were likely incidental to treatment.
In a study of developmental toxicity in rabbits, an increased incidence of total external and internal (visceral) macroscopic abnormalities was seen in foetuses at the low dose and greater in the absence of maternal toxicity at the low and mid dose, compared to controls. At the mid and greater doses, a decrease was seen in uterus weight, increase in percentage post-implantation loss and resorptions and decrease in the number of live foetuses. At the top dose compared to controls, an increase was seen in the foetal incidence of cleft palate, gastroschisis, enlarged fontanelle, absence of 1 or 2 sternebrae and fused sternebrae along with an increase in the litter incidence of enlarged fontanelle and fused sternebrae were seen in the presence of maternal toxicity (mortality, decreased bodyweight gain and gastric perforation and gastrointestinal fibrous adherences in dams). It was concluded that cimicoxib is a reproductive toxicant in rats and teratogenic in rabbits but not rats.
In a human clinical trial study in males (aged 18-45 years), cimicoxib was safe and well tolerated following a single oral does up to 600 mg, the highest dose administered.
No public submissions were received for cimicoxib.
Schedule 4 – New Entry
CIMICOXIB.
The committee also recommended an implementation date of 1 June 2018 as this is the earliest practicable implementation date.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; and (c) the toxicity of a substance.
The reasons for the recommendation comprised the following:
The delegate considered the following in regards to this proposal:
The delegate’s interim decision is create a new Schedule 4 entry for cimicoxib. The proposed Schedule entry is:
Schedule 4 – New Entry
CIMICOXIB.
The proposed implementation date is 1 June 2018. This is the earliest practicable implementation date.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; and (c) the toxicity of a substance.
The reasons for the recommendation comprised the following:
Scheduling medicines and poisons
Substance | Interim Decision |
---|---|
Fluralaner |
Schedule 4 - New EntryFLURALANER except when included in Schedule 5. Index – Amend EntryFLURALANER Schedule 4 The proposed implementation date is 1 June 2018. |
Metofluthrin |
Schedule 5 – Amend EntryMETOFLUTHRIN:
The proposed implementation date is 1 June 2018. |
Alpha-cypermethrin |
Schedule 6 – Amend EntryALPHA-CYPERMETHRIN:
except when included in Schedule 5. The proposed implementation date is 1 June 2018. |
Silver oxide |
Appendix B – New EntrySILVER OXIDE Reasons for Entry: b (Use pattern restricts hazard) Areas of Use: 7.14 (Spa/pool sanitiser) The proposed implementation date is 1 June 2018. |
1-Deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives |
Schedule 6 – Amend Entry1-DEOXY-1-(METHYLAMINO)-D-GLUCITOL N- ACYL DERIVATIVES
IF IN EYES WASH OUT IMMEDIATELY WITH WATER, or IF IN EYES WASH OUT IMMEDIATELY WITH WATER. Index – Amend Entry1-DEOXY-1-(METHYLAMINO)-D-GLUCITOL N- ACYL DERIVATIVES The proposed implementation date is 1 June 2018. |
Phenyl methyl pyrazolone | Schedule 6 – New EntryPHENYL METHYL PYRAZOLONE except when used in hair dye and eyebrow/eyelash preparations at a concentration of 0.25 per cent or less after mixing for use when the immediate container and primary pack are labelled with the following statements: KEEP OUT OF REACH OF CHILDREN, and WARNING – This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use. written in letters not less than 1.5 mm in height. Appendix E, Part 2 – New EntryStandard Statements: A (For advice, contact a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor (at once)), S1 (If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water). Appendix F, Part 3 – New EntryWarning Statement: 28 ((Over) (repeated) exposure may cause sensitisation). Safety Direction: 4 (Avoid contact with skin). The proposed implementation date is 1 June 2018. |
Dinotefuran |
Schedule 5 – Amend EntryDINOTEFURAN except in preparations containing 1 per cent or less of dinotefuran. The proposed implementation date is 1 June 2018. |
Afidopyropen | Appendix B – New EntryAFIDOPYROPEN. Reasons for Entry: b (Use pattern restricts hazard) The proposed implementation date is 1 June 2018. |
Scheduling medicines and poisons
An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to amend the current entry for fluralaner in Schedule 5 to broaden the use to include products for external use on cats and dogs in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) – the Poisons Standard.
This was a general application. The applicant’s proposed amendments to the Poisons Standard are:
The applicant's reasons for the request are:
Fluralaner is currently listed in Schedules 5 as follows:
Related ectoparasiticides afoxolaner and sarolaner are in the Poisons Standard as follows:
In August 2014, the Office of Chemical Safety (OCS) [based on an application made to the Australian Pesticides and Veterinary Medicines Authority (APVMA) to register a new active ingredient and the approval of five different tablets containing various concentrations of Fluralaner] submitted a proposal to create a new Schedule 5 listing for oral divided preparations, each containing 1400 mg or less of fluralaner per dosage unit, for the treatment and prevention of flea infestations and control of ticks in dogs. The delegate noted the following in the October 2014 final decision for Fluralaner:
"Fluralaner belongs to a novel class of ectoparasiticides (isoxazoline-substituted benzamide derivatives), two other members of which have been listed in Schedule 5 (isoxaflutole and afoxolaner). The toxicology package indicates that fluralaner also has a sufficiently low acute toxicity profile to be consistent with SPF criteria for listing in Schedule 5. The acute poisoning risk to humans (in particular children) is low, partly associated with the proposed packaging of only four tablets in blister packaging. The delegate considered whether Schedule 4 listing could be more appropriate, providing for oversight of treatment by a veterinarian, noting that this is a condition imposed for registration in the USA, but in the end decided against this, on the basis that the treatment instructions are sufficiently clear that pet owners should be able to manage the required dosage regimen"
In October 2014, the delegate made a decision to create a new Schedule 5 entry for Fluralaner in the Poisons Standard for the treatment and prevention of flea infestations and control of ticks in dogs in oral divided preparations each containing 1400 mg or less of fluralaner per dosage unit. This was implemented on 1 February 2015.
Two other ectoparasiticides afoxolaner and sarolaner, also used for treatment of flea infestations and control of ticks in dogs, were all recently considered for scheduling:
Fluralaner is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017. Fluralaner is neither an excipient nor active in any medicines on the ARTG.
Fluralaner is the active constituent of approved veterinary medicines (oral chews for dogs for the treatment and prevention of flea infestations and control of ticks). Five (5) products are currently registered by the APVMA.
Fluralaner (as a chewable tablet) was approved for use in the EU and US in 2014, with the spot-on being approved in both jurisdictions in 2016. It is available as a spot-on by prescription for use on dogs and cats for the treatment of fleas and ticks for up to 12 weeks. It is available as a 280 mg/mL solution; the largest pipette contains 1400 mg.
Fluralaner is also available as a spot-on and chewable tablet in other countries including Canada and New Zealand.
Property | Fluralaner |
---|---|
CAS number | 864732-61-3 |
Chemical structure | ![]() |
Molecular formula | C22H17C12F6N3O3 |
Molecular weight | 556.3 g/mol |
IUPAC and/or common and/or other names | 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-1,2-oxazol-3-yl]-2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]benzamide (IUPAC) |
Fluralaner is a isoxazoline that has shown potent acaricidal and insecticidal activity through a dual mechanism of binding to neuronal γ-aminobutyric acid (GABA) - and glutamate-gated chloride channels in susceptible invertebrates.
Fluralaner has high selectivity for arthropods and a very favourable safety profile in vertebrates including dogs.[56] It is a potent inhibitor of parts of the arthropod nervous system by acting antagonistically on ligand-gated chloride channels (GABA receptor and glutamate-receptor). In molecular on-target studies on insect GABA receptors of flea and fly, fluralaner is not affected by dieldrin resistance.
Toxicity | Species | Fluralaner | SPF (2015) Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | >2000 | Schedule 5 |
Acute dermal toxicity LD50 (mg/kg bw) | Rat | >2000 | Schedule 5 |
Acute inhalational toxicity LC50 (mg/m3/4h) | No data | - | N/A |
Skin irritation | Rabbit | Nil | N/A |
Eye irritation | Rabbit | Nil | N/A |
Skin sensitisation (Maximisation test) | Guinea pig | Negative | N/A |
The delegate previously considered the acute toxicity of fluralaner and no new information is available.
The delegate previously considered short-term studies by both the oral and dermal route of exposure in rats, the main signs associated with treatment included minor variations in haematological and blood chemistry parameters, and organ weight changes. Of the organ weight changes, the liver was the most affected with increases in liver weights associated with fatty changes (diffuse and mid-zonal). The route of exposure did not markedly change the effects seen in treated animals, with similar haematological, blood chemistry and organ weight changes in both orally and dermally treated rats. Additional treatment-related findings in the oral toxicity study included thymic atrophy, zymogen depletion in the pancreas and diffuse vacuolation/hypertrophy in the adrenal cortices at high doses. In more recent dermal and oral 28 day and 90 day repeat-dose studies in rats the main signs associated with treatment at high doses again included similar effects on the liver, thymus and adrenals, as well as the lungs (inflammatory lesions).
The delegate previously considered the mutagenicity of fluralaner and no new information is available. There was no evidence of a mutagenic and/or genotoxic potential in vitro, with and without metabolic activation, or in vivo.
The delegate previously considered the genotoxicity of fluralaner and no new information is available. Fluralaner was not genotoxic in a standard suite of in vitro and in vivo genotoxicity studies.
No carcinogenicity studies have been submitted in support of fluralaner. The use pattern of the spot-on as a quarterly or half-yearly treatment in a non-food-producing use situation, and noting the relatively minor effects seen in short-term studies and the lack of any positive genotoxicity potential, the long-term toxicity potential associated with the proposed use of the active constituent as a veterinary medicine for companion animals (cats and dogs) is likely to be low.
The delegate previously considered developmental toxicity studies in the rat. Minor effects were seen in treated foetuses, such as a slight decrease in foetal bodyweights, increases in dilated renal pelvis and ureter, and supernumerary ribs. The effects, however, were at dose levels where maternal effects (decreased food consumption and bodyweight gain) were observed, suggesting foetal effects were secondary to maternal toxicity. In a more recent pivotal one-generation oral study in rats, fluralaner had effects on the thymus (reduction in weight and lymphoid atrophy) of foetuses and caused a slight reduction in implantation rates and post-implantation losses at high doses resulting in a slight reduction of living pups at the first litter check. In rabbits, high oral doses of fluralaner had effects on the foetal skeleton (cervical vertebra fusion, and reduced fore- and hind-limb ossification) as well as increases in dilated renal pelvis and ureter.
No information provided.
The APVMA will conduct a risk assessment for users of the product as well for bystanders who may have incidental contact with the treated animal or product. The product hazard and exposure risks will be mitigated through label First Aid Instructions and Safety Directions. Any acute exposure is expected to be limited through the product being applied in small dose volumes (up to 5 mL). Also, the product will be supplied packs containing no more than two pipettes each enclosed in a child-resistant sachet (laminated polyester aluminium foil sachet). Acute exposure in the home is expected to be further limited by administration being no less than every three months for an individual animal.
No submissions were received.
The committee recommended that the Schedule 5 entry for fluralaner remains appropriate. However, a new Schedule 4 entry should be created for fluralaner, along with an amendment to the index entry as follows:
Schedule 4 – New Entry
FLURALANER except when included in Schedule 5.
Index – Amend Entry
FLURALANER
cross-reference: CARBAMOYL BENZAMIDE PHENYL ISOXAZOLINE
Schedule 4
Schedule 5
The committee also recommended an implementation date of 1 June 2018 as this is the earliest practicable implementation date.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the recommendation comprised the following:
The delegate considered the following regarding this proposal:
The delegate’s interim decision is to create a new Schedule 4 entry for fluralaner, along with a cross-reference in the index to carbamoyl benzamide phenyl isoxazoline. The proposed Schedule entry is:
Schedule 4 – New Entry
FLURALANER except when included in Schedule 5.
Index – Amend Entry
FLURALANER
cross-reference: CARBAMOYL BENZAMIDE PHENYL ISOXAZOLINE
Schedule 4
Schedule 5
The proposed implementation date is 1 June 2018. This is the earliest practicable implementation date.
The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (a) the risks and benefits of the use of the substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of the substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the interim decision are the following:
Scheduling medicines and poisons
An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to amend the Schedule 5, subclause b entry for metofluthrin to remove 'for use as a mosquito repellent' in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) – the Poisons Standard.
This was a general application. The applicant’s proposed amendments to the Poisons Standard are:
The applicant's reasons for the request are:
Metofluthrin is in Schedule 5 and 6 of the Poisons Standard as follows:
In February 2011, the Advisory Committee on Chemicals Scheduling (ACCS) considered a proposal to include metofluthrin in Schedule 6. This was based on its toxicity profile of moderate acute inhalation toxicity and neurotoxicity (with clinical signs of neurotoxicity seen at 100 mg/kg bw in a rat acute neurotoxicity study, and at 30 mg/kg bw/d in a 12-month oral study in dogs and in dams in an oral rat developmental study). This was recommended by the ACCS and agreed to by the delegate. The ACCS recommended a new Schedule 6 entry be created for metofluthrin. The delegate decided that the recommendations of the ACCS were clear and appropriately supported and included metofluthrin in Schedule 6. The delegate decided that a 6 month implementation period was appropriate.
In July 2014, the delegate referred a proposal to the ACCS to amend the current Schedule 6 to exclude mosquito repellent preparations containing 312 g/kg or less of metofluthrin from scheduling. The applicant indicated that the toxicity of the product (the substance impregnated onto non-woven polyester fabric, which is incorporated in a device that is designed to release the substance in the atmosphere) is the same as the toxicity of the substance. The committee recommended that, based on the toxicity profile and use pattern/exposure to the product, the current Schedule 6 metofluthrin entry be amended to exempt impregnated fabric mosquito repellent preparations for use in a vaporiser containing 15 mg or less of metofluthrin per disk to Schedule 5. They recommended that the schedule 5 entry should specifically include the preparation and the refill. The delegate accepted the advice provided by the ACCS and decided to include a new entry for metofluthrin in Schedule 5 and to amend the current Schedule 6 entry. The implementation date for this decision was 1 February 2015.
In March 2015, the ACCS considered a proposal to amend the Schedule 5 entry of metofluthrin to allow it to be used in an impregnated woven polyethylene sheet containing 250 mg or less of metofluthrin. While metofluthrin is a moderately toxic pyrethroid insecticide, the packaging and presentation of the product, i.e. the polyethylene slow release matrix and the overall low toxicity, and risk of inhalation toxicity was considered to be low due to the formulation of the product. This was considered to mitigate the overall exposure risk and warranted inclusion in Schedule 5. The committee recommended that the current Schedule 5 listing for metofluthrin be amended to include preparations impregnated into a polyethylene slow release matrix containing 250 mg or less of metofluthrin. The delegate agreed and made a final decision for metofluthrin on 22 July 2017.
Metofluthrin is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017 and is not an excipient or active in any medicines on the ARTG.
There are no reported adverse events or safety issues in the Database of Adverse Events Notifications (DAEN) from 1971 to 2017 for methfluthrin.
Metofluthrin is not listed in the Australian Inventory of Chemical Substances (AICS).
One active constituent and two registered products were found on the PubCRIS database. Both registered products are for household use for mosquito control/repellent.
Metofluthrin is included in Annex I of the Directive 98/8/EC. Biocidal products containing active substances that have been included in Annex I or IA of the Biocides Directive are subject to product authorisation or registration, respectively, as per the requirements of the Biocides Directive.
As of 23 July 2017, metofluthrin is not on the registered substances database.
In New York State, two products containing metofluthrin have been registered with the following condition:
'The registrant is required to provide us with a summary of any adverse effects that have been associated with these products, including any FIFRA 6(a)(2) reports, on a quarterly basis'.
The US Environment Protection Authority (EPA) issued the metofluthrin Pesticide Fact Sheet in September 2006 (EPA Chemical Code 109709).
In April 2015, the New Zealand EPA approved the importation of metofluthrin as strips impregnated with 312 g/kg of metofluthrin. Each strip contains 13 mg of metofluthrin as part of a refill cartridge for a portable vaporiser to be used by the general public during outdoor activities.
In October 2011, another product was registered for use as a personal insect repellent. Within the first year of its registration, the Pest Management Regulatory Agency (PMRA) received six human incident reports associated with this product. A wide range of symptoms such as dizziness, swelling, nausea, lethargy, muscular weakness, pruritus, irregular heart rate, or loss of consciousness was noted. The effects reported were considered to be either possibly or probably related to pesticide exposure. The product currently holds a registration that is conditional upon the submission of additional data on product exposure. The PMRA indicated that:
'Although only a few incidents were reported, this is a new product and the PMRA will continue to monitor incidents reported in the following year'.
In 2016, the Canadian Pest Management Regulatory Agency approved metofluthrin in similar to the NZ clip-on devices. The Canadian evaluation report is publicly available.
Property | Metofluthrin |
---|---|
CAS name | 2,3,5,6-tetrafluoro-4-(methoxymethyl)phenyl]methyl 2,2-dimethyl-3-(1-propenyl)cyclopropanecarboxylate |
CAS number | 240494-70-6 |
Chemical structure | ![]() |
Molecular formula | C18H20F4O3 |
Molecular weight | 360.3 g/mol |
IUPAC and/or common and/or other names | 1-propenyl)cyclopropanecarboxylate;
[2,3,5,6-tetrafluoro-4-(methoxymethyl)phenyl]methyl 2,2-dimethyl-3-[(E)-prop-1-enyl]cyclopropane-1-carboxylate (IUPAC); (2,3,5,6-tetrafluoro-4-methoxymethylphenyl)methyl-2,2-dimethyl-3-(1-propenyl)cyclopropanecarboxylate; Matofluthrin |
Metofluthrin is a synthetic pyrethroid ester insecticide. This class of chemicals act on the nervous system of insects, disturbing the function of neurons by interacting with sodium channels.
Other pyrethroid insecticides include transfluthrin, permethrin, deltamethrin, esfenvalerate and alpha-cypermethrin. While some of these share structural similarity with metofluthrin, this does not appear to be sufficient to class metofluthrin as a derivative (for the purpose of scheduling) of any of these compounds.
The following information was extracted from APVMA assessment report - Human Health Risk Assessment Technical Report – metofluthrin.
Toxicity | Species | Metofluthrin | SPF (2015) Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | >2000 | Schedule 5 |
Acute dermal toxicity LD50 (mg/kg bw) | Rat | >2000 | Schedule 5 |
Acute inhalational toxicity LC50 (mg/m3/4h) | Rat | >1080 and ≤1960 | Schedule 6 |
Skin irritation | Rabbit | Slight irritant | Schedule 5 |
Eye irritation | Rabbit | Non-irritant | Schedule 5 |
SSkin sensitisation (Guinea Pig Maximisation Test) | Guinea pig | Non-sensitiser | Schedule 5 |
Hazard profiles of metofluthrin and of the product containing 250 mg or less of metofluthrin impregnated into a polyethylene slow release matrix have previously been considered at the March 2015 ACCS scheduling meeting.
After conducting an online search for metofluthrin toxicology data, the APVMA concludes that these hazard profiles remain appropriate.
It is noteworthy that although metofluthrin was a slight skin irritant, the proposed product containing 250 mg or less of metofluthrin impregnated into a polyethylene slow release matrix was a non-irritant to rabbit skin.
The previous assessment of the product, supporting the "metofluthrin July 2015 scheduling decision", considered the main concern to be exposure by inhalation, especially in toddlers and young children. The APVMA estimated the theoretically maximum attainable metofluthrin concentration in air, noting that this approach is very conservative, and that the actual metofluthrin concentration in air is always less than the theoretically maximum attainable concentration. Using the theoretically maximum attainable metofluthrin concentration in air, the APVMA estimated the inhalation exposure for 1-2 year old children, and concluded that exposure to the product was unlikely to pose an unacceptable health risk (margins of exposure at 20˚C and 35˚C were 1350 and 204, respectively).
No submissions were received.
The committee recommended that the Schedule 5 entry for metofluthrin be amended as follows:
Schedule 5 – Amend Entry
METOFLUTHRIN:
The committee also recommended an implementation date of 1 June 2018 as this is the earliest practicable implementation date.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.
The reasons for the recommendation comprised the following:
The delegate considered the following regarding this proposal:
The delegate’s interim decision is to amend the Schedule 5 entry for metofluthrin by removing the phrase "for use as a mosquito repellent" from subclause (b). The proposed Schedule entry is:
Schedule 5 – Amend Entry
METOFLUTHRIN:
The proposed implementation date is 1 June 2018. This is the earliest practicable implementation date.
The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (a) the risks and benefits of the use of the substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of the substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.
The reasons for the interim decision are the following:
An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to amend the current entry for alpha-cypermethrin in Schedule 6 to increase the cut-off in aqueous preparations from 25 per cent or less to 30 per cent or less in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) – the Poisons Standard.
This was a general application. The applicant’s proposed amendments to the Poisons Standard are:
The applicant's reasons for the request are:
Alpha-cypermethrin is in Schedule 5,6 and is cross-referenced in the Index to cypermethrin as follows:
Schedule 6
Schedule 5
In November 1994, the National Drugs and Poisons Schedule Committee (NDPSC) created new entries for alpha-cypermethrin in Schedule 6 and 7 of the Poisons Standard, with a general cut-off in Schedule 6 of 10%.
In February 1998, the NDPSC decided to down-schedule alpha-cypermethrin to Schedule 5, with a general cut-off of 1.5%, irrespective of formulation. Although alpha-cypermethrin has greater toxicity when it is formulated in oil rather than aqueous suspensions, the committee considered that the 1.5% cut-off provides a reasonable safety factor.
In May 1999, the NDPSC decided that the Schedule 5 cut-off could be increased from 1.5% to 3% for aqueous formulations. The committee did not support an increase in the cut-off for formulations in oil.
In November 1999, the NDPSC made an amendment to the Schedule 5 entry for alpha-cypermethrin. The entry content was changed from alpha-cypermethrin to alpha-cypermethrin.
In November 2000, the NDPSC decided amend the Schedule 6 entry to its current cut-offs.
In June 2003, the NDPSC made a minor editorial amendment to the Schedule 6 entry, that did not alter its meaning or cut-offs, to its current entry.
Alpha-cypermethrin is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017.
A search of the Database of Adverse Events Notifications (DAEN) database did not reveal any adverse events or safety issues for alpha-cypermethrin from 1 January 1971 to 17 May 2017.
Eighty five (85) registered or approved insecticide, herbicide, vertebrate poison and parasiticide products were found on the APVMA’s PubCRIS database.
Alpha-cypermethrin was registered for use in the USA in January 2013 as an insecticide.
Active substance | Product type (PT) | BPC opinion | Date of opinion |
---|---|---|---|
Alpha-cypermethrin | PT 18 | Opinion | 17/6/2014 |
Property | Alpha-cypermethrin |
---|---|
CAS name | (R)-cyano(3-phenoxyphenyl)methyl (1S,3S)-rel-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate;
Note: Cypermethrin is a racemic mixture of 8 enantiomers. Alpha-cypermethrin consists of two of the cis isomers (i.e. alpha-cypermethrin constitutes 25% of technical cypermethrin, namely the 1-R cis S and 1-S cis R isomers) |
CAS number | 67375-30-8 |
Chemical structure | ![]() |
Molecular formula | C22H19CI2NO3 |
Molecular weight | 416.3 g/mol |
IUPAC and/or common and/or other names | Alphamethrin;
|
The following information was extracted from the AVPMA human health risk assessment (HHRA) technical report for the toxicology of alpha-cypermethrin.
Toxicity | Species | Alpha-cypermethrin and product | SPF (2015) Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | >5000 mg/kg bw for 50% aqueous suspension >2000 mg/kg bw for product |
N/A Schedule 5 |
Acute dermal toxicity LD50 (mg/kg bw) |
Mouse Rat |
>100 mg/kg bw alpha-cypermethrin (concentration unknown) >2000 mg/kg bw for product |
Schedule 7 Schedule 5 |
Acute inhalational toxicity LC50 (mg/m3/4h) |
Not given Rat |
>400 mg/m3 (30% silica powder dust) >1150 mg/m3 (4h) (maximum attainable concentration) for the product |
Schedule 7 Schedule 6 |
Skin irritation | Rabbit |
Slight for active constituent Nil for product |
Schedule 5 N/A |
Eye irritation | Rabbit |
Slight for active constituent Moderate for product |
Schedule 5 Schedule 5 |
Skin sensitisation (Buehler) | Guinea pig | Negative for active constituent Negative for product |
N/A N/A |
The acute toxicity profile of alpha-cypermethrin varies with vehicle and/or species. The acute oral toxicity in rats ranges from low in 50% aqueous suspension (LD50 > 5000 mg/kg bw) to high in 5% corn oil (LD50 = 79 mg/kg bw). The comparable LD50 values for mice are 798 mg/kg bw (50% aqueous suspension) and 35 mg/kg bw (5% corn oil). The major sign of toxicity was clonic convulsions. An acute dermal toxicity study in mice gave an LD50 > 100 mg/kg bw. There is one acute inhalational LC50 value for alpha-cypermethrin of > 400 mg/m3 which is based on a study using a 30% silica powder dust. Based on the acute toxicity studies with the proposed product, which contains 30% alpha-cypermethrin, the product has low acute oral, dermal and inhalation toxicity.
Alpha-cypermethrin is a slight skin irritant in rabbits. Based on an acute dermal irritation study, the proposed product is not a skin irritant.
Alpha-cypermethrin is a slight eye irritant in rabbits. Based on available data, the proposed product is a moderate eye irritant:
Three female rabbits were administered the proposed product by ocular instillation. Ocular irritation was scored according to the Draize scale and compared with the untreated eye for each animal at 1, 24, 48, 72, 96 hours and 5, 6 and 7 days after treatment. All three animals exhibited ocular lesions (conjunctival oedema, redness and corneal opacity) in the treated eye from 1h till day 6 post instillation. These lesions were reversible and comparable to the untreated eye on day 7. Thereafter all animals appeared healthy and gained body weight during the study. No signs of gross toxicity or behavioural changes were observed in any of the animals. Under the study conditions described, with corneal opacity for 6 days that was reversible on day 7, the proposed product is a moderate eye irritant.
Alpha-cypermethrin did not cause skin sensitisation in guinea pigs. Based on a guideline-compliant Buehler study, the proposed product is not a skin sensitiser.
In 4- to 13-week dietary studies in rats and dogs, neurotoxicity was the primary effect. Clinical signs of toxicity included ataxia, body tremors, agitation, and abnormal gait. Histopathological changes were seen in the liver (glycogenic vacuolation of parenchyma), and axonal degeneration of the sciatic nerve. There was decreased bodyweight gain, and increased liver and kidney weights. The NOAEL was 6.4 mg/kg bw/d in rats and 4.7 mg/kg bw/d dogs.
Alpha-cypermethrin was not mutagenic in bacteria or yeast. It did not break DNA or induce chromosome damage in in vivo assays in rat and was not clastogenic in the rat liver cells in vitro.
There are no long term repeat dose, reproduction or developmental studies conducted using alpha-cypermethrin that have been previously evaluated.
Human volunteers participated in two oral dose-excretion studies using alpha-cypermethrin. On two occasions, two volunteers per dose received a single oral dose of 0.25, 0.5 or 0.75 mg alpha-cypermethrin in corn oil (as a gelatine capsule) with 24-h urine collections. Urinary excretion was rapid, with 43% - 49% of the dose excreted within the first 24 h, 1-5% on Day 2 and 1-7% on Day 6.
The product is not intended for home garden use. Dermal absorption of alpha-cypermethrin is low. Public exposure to the product is unlikely to occur.
No submissions were received.
The committee recommended that the Schedule 6 entry for alpha-cypermethrin be amended as follows:
Schedule 6 – Amend Entry
ALPHA-CYPERMETHRIN:
except when included in Schedule 5.
The committee also recommended an implementation date of 1 June 2018 as this is the earliest practicable implementation date.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the recommendation comprised the following:
The delegate considered the following regarding this proposal:
The delegate’s interim decision is to amend the Schedule 6 entry for alpha-cypermethrin by increasing the permitted concentration from 25% to 30% in aqueous preparations. The proposed Schedule entry is:
Schedule 6 – Amend Entry
ALPHA-CYPERMETHRIN:
The proposed implementation date is 1 June 2018. This is the earliest practicable implementation date.
The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (c) the toxicity of the substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the interim decision are the following:
Scheduling medicines and poisons
An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to consider silver oxide for scheduling in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) – the Poisons Standard.
This was a general application. The applicant’s proposed amendments to the Poisons Standard are:
The applicant's reasons for the request are:
The majority of studies used to establish a toxicological profile for silver oxide (soluble silver) were conducted with silver nitrate that is included on the APVMA list of actives not requiring evaluation. Therefore, it is recommended that consideration is given to include silver oxide on this list.
SILVER OXIDE is not specifically scheduled.
Related silver scheduling:
Silver oxide is not currently scheduled and has not been previously considered for scheduling. Therefore a scheduling history is not available.
Silver oxide is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017.
Silver oxide is not an excipient or active ingredient in any medicines on the ARTG.
Silver substances currently approved for use in Europe include silver oxide, silver chloride, metallic silver, silver citrate and silver nitrate. Functions of these silver containing substances vary from deodorising and antimicrobial to preserving and skin conditioning.
Silver oxide is the silver source in cosmetic grade Nolla™ in Europe. Other silver substances such as metallic silver and silver chloride can be used when regulations allow it outside Europe. All approved cosmetic ingredients in Europe can be found on the database maintained by the European Commission.
Code of Federal Regulations, Sec. 310.548 Drug products containing colloidal silver ingredients or silver salts offered over the counter (OTC) for the treatment and/or prevention of disease.
Colloidal silver ingredients and silver salts have been marketed in OTC drug products for the treatment and prevention of numerous disease conditions. There are serious and complicating aspects to many of the diseases these silver ingredients purport to treat or prevent. Further, there is a lack of adequate data to establish general recognition of the safety and effectiveness of colloidal silver ingredients or silver salts for OTC use in the treatment or prevention of any disease. These ingredients and salts include, but are not limited to, silver proteins, mild silver protein, strong silver protein, silver, silver ion, silver chloride, silver cyanide, silver iodide, silver oxide, and silver phosphate.
Natural health products ingredients database – homeopathic substance:
Ingredient | Proper Name(s) | Common Name(s) |
---|---|---|
EHP_Argentum oxydatum (Homeopathic Substance) |
|
|
Property | Silver oxide |
---|---|
CAS name | Silver oxide |
CAS number | 20667-12-3 |
Chemical structure | ![]() |
Molecular formula | Ag2O |
Molecular weight | 231.7 g/mol |
IUPAC and/or common and/or other names | Silver monoxide; Argentous oxide; Silver rust InChI: 1S/2Ag.O IUPAC: Silver (I) oxide |
The following information was extracted from the AVPMA human health risk assessment (HHRA) technical report for the toxicology of silver oxide.
Toxicity | Species | [Silver oxide] | SPF (2015) Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat Mouse |
280 (for ionic silver) 32 (ionic silver) |
Schedule 6 |
Acute dermal toxicity LD50 (mg/kg bw) | - | No data | - |
Acute inhalational toxicity LC50 (mg/m3/4h) | - | No data | - |
Respiratory irritation | - | Respiratory irritant (>20%) | - |
Skin irritation | - | No data | - |
Eye irritation | - | No data | - |
Skin sensitisation (Buehler) | Guinea pig | Non-sensitiser | N/A N/A |
Since no studies were available for silver oxide (the salt source of soluble silver), the toxicological profile for silver oxide was determined using data on soluble silver compounds from published reviews. Many of the studies reported in these reviews were conducted prior to the principles of GLP being established by the OECD in 1978. However, as a toxicological profile was established for registration of the product and not approval of the active constituent, the data that also included information on human exposure to silver compounds were considered to be sufficient for risk assessment purposes.
The majority of studies used to establish a toxicological profile for silver oxide (soluble silver) were conducted with silver nitrate that is included on the APVMA list of actives not requiring evaluation. Therefore, the APVMA recommends that consideration is given to include silver oxide on this list.
Silver oxide is formed in the manufacturing process for the product the proposed product. Silver oxide is present in the proposed product at 1% of which 0.93% is silver. The proposed product is a spa pool product intended for domestic use, whose sanitising effects are due to the gradual release of silver from the silver oxide over time. The product's formulation type, presentation and packaging means that direct user exposure to the product would not be considered to occur under normal conditions of use (i.e. presentation/packaging restricts hazard).
The qualitative determination of exposure and risk undertaken indicates that the acute and repeated risks from swimming in the proposed product treated spa pools are considered to be low to negligible and therefore acceptable (i.e. use pattern restricts hazard).
Silver and silver nitrate that established the toxicology profile are both currently scheduled in the Poisons Standard.
For soluble silver, the oral and dermal absorption in humans was 21% and <1% respectively, and it was of moderate acute oral toxicity in the rat (LD50 280 mg/kg bw). No acute dermal or inhalation studies were available. Skin and ocular "burns" have been reported with occupational exposure to silver nitrate, though such findings are likely due to the corrosive effect of nitrate rather than by silver itself. The most frequent abnormal ocular finding in workers was argyrosis which was also observed in rats. Silver was not considered a skin sensitiser. Human and animal data indicate it was a respiratory irritant. The limited systemic findings in rats do not warrant scheduling.
The product the proposed product was estimated to have low acute oral, dermal and inhalation toxicity, moderate skin irritation, severe eye irritation, and neither a skin sensitiser or respiratory irritant. The estimated skin and eye irritant potential were attributed to product constituents other than silver oxide.
In vitro, silver was not mutagenic in bacteria but was clastogenic in mammalian cells causing chromosome aberrations and DNA strand breaks. No in vivo studies were available. There is no historical evidence of silver having a carcinogenic potential. It was concluded that silver is unlikely to pose a carcinogenic risk to humans. The findings in the one generation study were not considered to provide robust evidence that silver is a reproductive toxicant. Silver was not teratogenic, neurotoxic or immunotoxic in rats.
The only data reported on silver oxide in the published reviews were for occupational exposure, with co-exposure to silver nitrate also reported to occur. In humans, the main reported effect after long-term inhalation or ingestion to high doses of silver was the development of argyria and/or argyrosis, with the evidence suggesting the pigmentation does not interfere with the normal functioning of organs. Respiratory irritation and argyrosis were reported to occur, along with abdominal pain in one study. However, the limited reporting detail for these studies meant they were not reliable for risk assessment purposes.
One (1) submission was received for silver oxide that supported the proposal. The main point was:
The public submission will be made available on the TGA website.
The committee recommended that silver oxide does not require scheduling and should therefore be included in Appendix B, as follows:
Appendix B – New Entry
SILVER OXIDE
Reasons for Entry: b (Use pattern restricts hazard)
Areas of Use: 7.14 (Spa/pool sanitiser)
The committee also recommended an implementation date of 1 June 2018 as this is the earliest practicable implementation date.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the recommendation comprised the following:
The delegate considered the following regarding this proposal:
The delegate’s interim decision is that silver oxide does not require scheduling and to include it in Appendix B of the Poisons Standard. The proposed decision is:
Appendix B – New Entry
SILVER OXIDE
Reasons for Entry: b (Use pattern restricts hazard)
Areas of Use: 7.14 (Spa/pool sanitiser)
The proposed implementation date is 1 June 2018. This is the earliest practicable implementation date.
The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (a) the risks and benefits of the use of the substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of the substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and( f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the interim decision are the following:
Scheduling medicines and poisons
An application was submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) to create a new entry for 1-deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives in Schedule 6 to restrict the use in cosmetic rinse-off and household cleaning preparations in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) – the Poisons Standard.
This was a general application. The applicant’s proposed amendments to the Poisons Standard are:
IF IN EYES WASH OUT IMMEDIATELY WITH WATER, or
IF IN EYES WASH OUT IMMEDIATELY WITH WATER
The applicant's reasons for the request are:
1-Deoxy-1-(methylamino)-d-glucitol N-C10-16 acyl derivatives is not currently specifically scheduled in the Poisons Standard.
1-Deoxy-1-(methylamino)-d-glucitol N-coco acyl derivatives, an analogue of 1-deoxy-1-(methylamino)-d-glucitol N-C10-16 acyl derivatives, was recently considered for scheduling at the November 2016 Advisory Committee on Chemicals Scheduling (ACCS). The delegate's final decision for 1-deoxy-1-(methylamino)-D-glucitol N-coco acyl derivatives, to be implemented on 1 February 2018, was to create a new Schedule 6 entry as follows:
IF IN EYES WASH OUT IMMEDIATELY WITH WATER, or
IF IN EYES WASH OUT IMMEDIATELY WITH WATER.
Due to the similarity in chemical structure, hazard, use and risk profiles 1-deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives is captured by the above Schedule 6 entry for 1-deoxy-1-(methylamino)-D-glucitol N-coco acyl derivatives :
1-deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives
Scheduling under consideration |
1-deoxy-1-(methylamino)-D-glucitol N-coco acyl derivatives
Schedule 6 |
---|---|
![]() Major components: R = C11H23 (lauroyl methyl glucamide) |
![]() Where R = C7-C17 alkyl group or C17 alkenyl group |
1-Deoxy-1-(methylamino)-d-glucitol N-C10-16 acyl derivatives has not been previously considered for scheduling. A scheduling history is therefore not available for 1-deoxy-1-(methylamino)-d-glucitol N-C10-16 acyl derivatives.
An analogue of 1-deoxy-1-(methylamino)-d-glucitol N-C10-16 acyl derivatives, 1-deoxy-1-(methylamino)-d-glucitol N-coco acyl derivatives has been previously considered for scheduling as follows:
At the November 2016 ACCS meeting the committee considered a proposal to schedule 1-deoxy-1-(methylamino)-d-glucitol N-coco acyl derivatives. The committee recommended that based on the use of 1-deoxy-1-(methylamino)-d-glucitol N-coco acyl derivatives as a surfactant, its severe eye irritancy and risk of spray products containing 1-deoxy-1-(methylamino)-d-glucitol N-coco acyl derivatives entering the eye, that 1-deoxy-1-(methylamino)-d-glucitol N-coco acyl derivatives be scheduled with exemptions and cut-off concentrations in cosmetic rinse-off preparations and household cleaning products. The delegate agreed however noting that a longer implementation time of 1 February 2018 would be required to allow for labelling changes and/or reformulation.
1-Deoxy-1-(methylamino)-d-glucitol N-C10-16 acyl derivatives (lauroyl/myristoyl methyl glucamide) does not appear to be in any products on the ARTG.
1-Deoxy-1-(methylamino)-d-glucitol N-C10-16 acyl derivatives (lauroyl/myristoyl methyl glucamide) is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017.
The chemical was registered under REACH as of 6 July 2012. The registration dossier was updated on 17 April 2017, following compliance checks by ECHA.
No known international restrictions or regulations have been identified by the applicant or the Secretariat.
Property | 1-Deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives |
---|---|
CAS number | 173145-38-5 |
Chemical structure | ![]() Major components: R = C11H23 (lauroyl methyl glucamide) |
IUPAC and/or common and/or other names |
D-glucitol, 1-deoxy-1-(methylamino)-, N-C10-16 acyl derivatives (CAS); Lauroyl/myristoyl methyl glucamide (INCI) C12-14 linear glucose amide; Lauryl methyl glucamide. |
The following information was extracted from the NICNAS assessment report for C12-14 Linear Glucose Amide and the NICNAS Existing Chemical secondary notification assessment report for d-glucitol, 1-deoxy-1-(methylamino)-, N-C10-16 acyl derivatives.
Toxicity | Species | 1-Deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives | SPF (2015) Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | >2000 | N/A Schedule 5 |
Acute dermal toxicity LD50 (mg/kg bw) | Rabbit | >2000 | Schedule 5 |
Acute inhalational toxicity LC50 (mg/m3/4h) | No data provided | No data provided | Schedule 5 |
Skin irritation (human three application patch test) |
Rabbit Human |
Slight irritant | Schedule 5 |
Eye irritation | Rabbit | Slight irritating | Schedule 6 |
Skin sensitisation (Buehler) | Guinea pig | Not skin sensitising | Schedule 5 |
Based on the studies provided, 1-deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives has a low acute oral and dermal toxicity (LD50 > 2000 mg/kg bw) in rats.
1-Deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives is slightly irritating to rabbit skin, with Grade 1 erythema (two of three animals) and Grade 1 oedema (one of three animals) persisting for up to 7 days. The results do not warrant classification of the substance under the GHS.
1-Deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives is a severe irritant to rabbit eyes in pure form, with vascularisation of the cornea observed in one out of the three animals tested. The irritation scores in this test could not be directly assessed against the GHS as the quantity instilled in the eyes was less than 10 mg, rather than the 100 mg required by the relevant Organisation for Economic Co-operation and Development (OECD) test guideline. The irritation scores were below the level for classification as an eye irritant, but instillation of larger quantities may have resulted in higher scores. Even at the lower quantity, the irritation was persistent, with effects seen in all animals at 4 days, and persisting up to 35 days in one animal. The results warrant the following classification of the substance under the GHS:
Hazard classification | Hazard statement |
---|---|
Serious eye damage/eye irritation (Category 1) | h518 – Causes serious eye damage |
1-Deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives was not a skin sensitiser in guinea pigs using a modified Buehler test.
Based on the available information from studies in rats, repeated oral exposure to the substance is not considered to cause serious damage to health.
1-Deoxy-1-(methylamino)-d-glucitol N-C10-16 acyl derivatives tested negative in two in vitro mutagenicity tests (Salmonella typhimurium reverse mutation assay and mouse lymphoma forward mutation assay) in the presence and absence of S9 metabolic activation. Positive results were observed in an in vitro study of chromosomal aberrations in Chinese hamster ovary (CHO) cells in the absence of metabolic activation, although the study authors concluded that the results were not biologically significant because of lack of reproducibility in repeat tests and because the values were within historical control ranges. This conclusion was supported by the negative genotoxicity results in an in vivo cytogenicity study in rat bone marrow cells.
No information was provided.
In a one generation study in rats, 1-deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives was not toxic to fertility or development. It caused adverse effects in parental animals on prolonged exposure to 350 mg/kg bw/day (reduction in body weight gains and in feed consumption in females).
In a developmental toxicity study, 1-deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives did not cause developmental toxicity in rats at a dose where maternal toxicity was observed. The NOEL for developmental toxicity was determined to be 363 mg/kg bw/day (the highest dose tested) while the NOAEL for maternal toxicity was found to be 150 mg/kg bw/day based on decreased bodyweight gain at the higher dose.
A three application patch test in human volunteers showed that 1-deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives was a mild skin irritant.
Several skin irritation and sensitisation studies in humans have been performed using the C12 glucose amide component of 1-deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives and formulations containing this component. However, the full details the formulation studies were not available. Consistent with the results of the animal studies for the substance, the C12 component was found to be a slight skin irritant under the conditions of the tests but was not a skin sensitiser.
The public exposure to 1-deoxy-1-(methylamino)-d-glucitol N-C10-16 acyl derivatives is widespread and repeated. The principal route of exposure is dermal, while ocular exposure is highly possible. Based on current use proposals, the exposure to the substance is up to 7% concentration in rinse-off cosmetics for skin and hair cleansing and at up to 12% concentration in household cleaning products. As 1-deoxy-1-(methylamino)-d-glucitol N-C10-16 acyl derivatives is classified as a Category 1 severe eye irritant at concentrations at or above 3%, without label warnings and appropriate directions, use of 1-deoxy-1-(methylamino)-d-glucitol N-C10-16 acyl derivatives in consumer products at or above 3% could result in severe eye irritation to users. Setting a concentration cut-off for 1-deoxy-1-(methylamino)-d-glucitol N-C10-16 acyl derivatives used in cosmetics and household products, and providing users with labelling and first aid information could protect consumers.
Two (2) pre-meeting submission was received, one (1) that opposed the scheduling proposal for 1-deoxy-1-(methylamino)-D-glucitol N-C10-16 acyl derivatives and one (1) that did not state their position.
The public submissions will be made available on the TGA website.
The committee recommended that the schedule 6 and index entries for the 1-deoxy-1-(methylamino)-D-glucitol N-coco acyl derivatives be amended as follows:
Schedule 6 – Amend Entry
1-DEOXY-1-(METHYLAMINO)-D-GLUCITOL N-COCO ACYL DERIVATIVES except:
IF IN EYES WASH OUT IMMEDIATELY WITH WATER, or
IF IN EYES WASH OUT IMMEDIATELY WITH WATER.
Index – Amend Entry
1-DEOXY-1-(METHYLAMINO)-D-GLUCITOL N-COCO ACYL DERIVATIVES
cross-reference: COCOYL METHYL GLUCAMIDE, LAUROYL METHYL GLUCAMIDE, MYRISTOYL METHYL GLUCAMIDE
The committee also recommended an implementation date of 1 June 2018 as this is the earliest practicable implementation date. It should be noted that the new Schedule 6 entry for delegate’s final decision on 1-deoxy-1-(methylamino)-D-glucitol N-coco acyl derivatives is to be implemented on 1 February 2018.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the recommendation comprised the following:
The delegate considered the following regarding this proposal:
The delegate's interim decision is to not specifically list 1-deoxy-1-(methylamino)-d-glucitol N-C10-16 acyl derivatives as it is captured by the Schedule 6 entry for 1-deoxy-1-(methylamino)-d-glucitol N-coco acyl derivatives, which is to be implemented on 1 February 2018, and to amend the 1-deoxy-1-(methylamino)-d-glucitol N-coco acyl derivatives by removing "coco" to capture similar substances. The proposed schedule entry is:
Schedule 6 – Amend Entry
1-DEOXY-1-(METHYLAMINO)-D-GLUCITOL N- ACYL DERIVATIVES except:
IF IN EYES WASH OUT IMMEDIATELY WITH WATER, or
IF IN EYES WASH OUT IMMEDIATELY WITH WATER.
Index – Amend Entry
1-DEOXY-1-(METHYLAMINO)-D-GLUCITOL N-ACYL DERIVATIVES
cross-reference: COCOYL METHYL GLUCAMIDE, LAUROYL METHYL GLUCAMIDE, MYRISTOYL METHYL GLUCAMIDE
The proposed implementation date is 1 June 2018. This is the earliest practicable implementation date.
The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: a) the risks and benefits of the use of the substance; b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance; d) the dosage, formulation, labelling, packaging and presentation of a substance; and f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the interim decision are the following:
Scheduling medicines and poisons
An application was submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) to create a new entry for phenyl methyl pyrazolone in Schedule 6 or 5 with an exemption cut-off of 0.25% in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) – the Poisons Standard.
This was a general application. The applicant’s proposed amendments to the Poisons Standard are:
The applicant's reasons for the request are:
Phenyl methyl pyrazolone is not currently scheduled in the current Poisons Standard. Phenyl methyl pyrazolone has not been previous considered for scheduling. Therefore, a scheduling history is not available for phenyl methyl pyrazolone.
Phenyl methyl pyrazolone shares some structural similarity with aminophenazone (amidopyrine), which is in Schedule 10 for human therapeutic use and Schedule 4 for the treatment of animals as follows:
Schedule 10
AMINOPHENAZONE (amidopyrine) and its derivatives for human therapeutic use.
Schedule 4
AMINOPHENAZONE (amidopyrine) and derivatives for the treatment of animals.
Phenyl methyl pyrazolone does not appear to be in any products listed on the ARTG.
Phenyl methyl pyrazolone is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017.
In New Zealand and the Association of Southeast Asian Nations, phenyl methyl pyrazolone may be used in oxidative hair dyes at a maximum concentration applied to hair of 0.25%, after mixing under oxidative conditions.
In the European Union (EU) (Annex III / Cosmetics Regulation (EC) No. 1223/2009 no. 228), the current restriction for phenyl methyl pyrazolone is as follows:
Property | Alpha-cypermethrin |
---|---|
CAS number | 89-25-8 |
Chemical structure | ![]() |
Molecular formula | C10H10N2O |
Molecular weight | 174.2 g/mol |
IUPAC and/or common and/or other names | Phenyl methyl pyrazolone (INCI);3H-pyrazol-3-one, 2,4-dihydro-5-methyl-2-phenyl- (CAS); 5-methyl-2-phenyl-4H-pyrazol-3-one (IUPAC); 3H-pyrazol-3-one, 2,4-dihydro-5-methyl-2-phenyl- (AICS); 3-methyl-1-phenyl-5-pyrazolone (EINECS); Evaravone; Radicut; norphenazone; norantipyrine; MCI 186 |
The following information was extracted from the NICNAS IMAP Human Health Tier II assessment report for 3H-Pyrazol-3-one, 2,4-dihydro-5-methyl-2-phenyl-.
Toxicity | Species | Phenyl methyl pyrazolone | SPF (2015) Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat (Sprague Dawley) | >2000 mg/kg bw | Schedule 5 |
Acute dermal toxicity LD50 (mg/kg bw) | No data available | N/A | N/A |
Acute inhalational toxicity LC50 (mg/m3/4h) | No data available | N/A | N/A |
Skin irritation | Rabbit (New Zealand White) | Slight irritating | Schedule 5 |
Eye irritation | Rabbit (New Zealand White) | Not irritating | N/A |
Skin sensitisation (Buehler) | Mouse (CBA) Mouse (CBA) |
Strong (EC3=1%) Moderate (EC3 >2.5%) |
Schedule 6 |
Phenyl methyl pyrazolone has low acute oral toxicity:
No data are available for other routes of exposure.
Phenyl methyl pyrazolone has been reported to slightly irritate the skin but to have no effect on the eyes. The limited data available are insufficient to warrant hazard classification for skin or eye irritation.
Norantipyrine (Phenyl methyl pyrazolone), at a concentration of 1 %, showed no signs of irritation (SCCS 2006).
Phenyl methyl pyrazolone is a moderate to strong skin sensitiser based on the results of two local lymph node assays (LLNA) on CBA mice, indicating an estimated concentration required to produce a three-fold increase in lymphocyte proliferation (EC3) of 1% in one test and >2.5% in the other test.
Phenyl methyl pyrazolone is not expected to be harmful to health following repeated oral exposure. A no observed adverse effect level (NOAEL) of 100 mg/kg bw/day for Sprague-Dawley rats was determined in a guideline subchronic toxicity study. No data are available for other routes of exposure.
Based on the weight of evidence from the available in vitro and in vivo studies conducted in accordance with OECD test guidelines, phenyl methyl pyrazolone is not considered to be genotoxic. Two in vitro genotoxicity tests showed positive results, but all in vivo tests were negative.
Phenyl methyl pyrazolone did not induce gene mutations in bacteria. It was also not mutagenic in an in vitro gene mutation test with mammalian cells (hprt locus). A mutagenic response was observed in the Mouse Lymphoma assay (tk locus) but only in the presence of S9. In an in vitro micronucleus assay no genotoxic effect (structural and/or numerical chromosomal aberrations) was observed. An in vivo bone marrow micronucleus assay in mice and an in vivo UDS assay in rats were negative. The results of the tests performed indicate that phenyl methyl pyrazolone itself is not mutagenic in vivo. To reach a definitive conclusion, the SCCS requested appropriate tests with m-aminophenol in combination with hydrogen peroxide have to be provided (SCCS 2006).
Based on the available data, phenyl methyl pyrazolone is not expected to be carcinogenic.
Based on the limited information available, phenyl methyl pyrazolone does not show specific reproductive or developmental toxicity. Developmental effects were only observed secondary to maternal toxicity. A NOAEL of 200 mg/kg bw/day was determined for both maternal and developmental toxicity incidence.
The critical health effect for risk characterisation is skin sensitisation. Phenyl methyl pyrazolone is a slight skin irritant at a concentration of 1%.
Phenyl methyl pyrazolone has cosmetic use identified in Australia in hair dye products. No use concentrations of phenyl methyl pyrazolone in these products are available, although it is known to be used overseas at a maximum concentration of 0.25% on the hair. Based on this use, the general public may be exposed to phenyl methyl pyrazolone via dermal contact.
Two (2) pre-meeting submission were received, neither of which objected to the proposed scheduling for phenyl methyl pyrazolone.
The public submissions will be made available on the TGA website.
The committee recommended that a new Schedule 6 and Appendix E and F entries for phenyl methyl pyrazolone be created as follows:
Schedule 6 – New Entry
PHENYL METHYL PYRAZOLONE except when used in hair dye and eyebrow/eyelash preparations at a concentration of 0.25 per cent or less after mixing for use when the immediate container and primary pack are labelled with the following statements:
KEEP OUT OF REACH OF CHILDREN, and
WARNING – This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use.
written in letters not less than 1.5 mm in height.
Appendix E, Part 2 – New Entry
Standard Statements: A (For advice, contact a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor (at once)), S1 (If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water).
Appendix F, Part 3 – New Entry
Warning Statement: 28 ((Over) (repeated) exposure may cause sensitisation).
Safety Direction: 4 (Avoid contact with skin).
The committee also recommended an implementation date of 1 June 2018 as this is the earliest practicable implementation date.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the recommendation comprised the following:
The delegate considered the following regarding this proposal:
The delegate’s interim decision is to create a new Schedule 6 and Appendix E and F entries for phenyl methyl pryazolone. The proposed Schedule entry is:
Schedule 6 – New Entry
PHENYL METHYL PYRAZOLONE except when used in hair dye and eyebrow/eyelash preparations at a concentration of 0.25 per cent or less after mixing for use when the immediate container and primary pack are labelled with the following statements:
KEEP OUT OF REACH OF CHILDREN, and
WARNING – This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use.
written in letters not less than 1.5 mm in height.
Appendix E, Part 2 – New Entry
Standard Statements: A (For advice, contact a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor (at once)), S1 (If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water).
Appendix F, Part 3 – New Entry
Warning Statement: 28 ((Over) (repeated) exposure may cause sensitisation).
Safety Direction: 4 (Avoid contact with skin).
The proposed implementation date is 1 June 2019 to allow for any labelling changes that may be required.
The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included:(a) the risks and benefits of the use of the substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of the substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the interim decision are the following:
Scheduling medicines and poisons
An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to amend the current Schedule 5 entry to exempt preparations containing 10 per cent or less of dinotefuran in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) – the Poisons Standard.
This was a general application. The applicant’s proposed amendments to the Poisons Standard are:
The applicant's reasons for the request are:
Dinotefuran is currently listed in Schedule 5 as follows:
In July 2015, the ACCS considered a proposal to include dinotefuran in the Poisons Standard. The committee recommended, and the delegate agreed, to include dinotefuran in the Poisons Standard 1 October 2015.
Although other members of the neonicotinoid class are listed in Schedule 6, on 22 July 2015 the delegate made a final decision for dinotefuran to create a new Schedule 5 entry due to its low toxicological profile consistent with the Scheduling Policy Framework (SPF) Schedule 5 criteria. However, evidence of mild/moderate skin/eye irritancy for the formulated product meant that it was inappropriate to provide a schedule exemption for the formulated product considered in the application.
Dinotefuran is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017 and is not an excipient or active in any medicines on the ARTG.
A search of the Database of Adverse Events Notifications (DAEN) database for dinotefuran did not reveal any adverse events or safety issues from 1 January 1971 to 17 May 2017.
Dinotefuran is an APVMA approved active constituent and is contained in one APVMA registered product on the PubCRIS database.
APVMA Public Release Summary on the 'Evaluation of the new active Dinotefuran in the Product Starkle 200 SG Insecticide', August 2015
JMPR have previously evaluated dinotefuran. The report The Joint FAO/WHO Meeting on Pesticide Residues (JMPR) has previously evaluated the toxicology of dinotefuran.
Dinotefuran was approved for use by the Committee for Medicinal Products for Veterinary Use (CVMP)/the European Medicines Agency's (EMA) in October 2013 as part of the registration a product.
Dinotefuran was first registered with the USA Environmental Protection Agency in September 2004 by the applicant.
Dinotefuran is a member of the neonicotinoid class of chemicals that act through binding to nicotinic acetylcholine receptors. There are no new data or changes for the active constituent from the acute and repeat-dose toxicology data that was presented at the July 2015 ACCS meeting.
The following information was extracted from the AVPMA human health risk assessment (HHRA) technical report for the toxicology of dinotefuran.
Property | Dinotefuran |
---|---|
CAS name | N-methyl-N′-nitro-N″-[(tetrahydro-3-furanyl)methyl]guanidine |
CAS number | 165252-70-0 |
Chemical structure | ![]() |
Molecular formula | C7H14N4O3 |
Molecular weight | 202.2 g/mol |
IUPAC and/or common and/or other names | 1-Methyl-2-nitro-3-(tetrahydro-3-furylmethyl)guanidine (IUPAC); |
Toxicity | Species | Dinotefuran | SPF (2015) Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | >2450 | Schedule 5 |
Acute dermal toxicity LD50 (mg/kg bw) | Rat | >2000 (no deaths) | Schedule 5 |
Acute inhalational toxicity LC50 (mg/m3/4h) | Rat | >4090 (no deaths) | Schedule 5 |
Skin irritation | Rabbit | Non-irritant | N/A |
Eye irritation | Rabbit | Moderate | Schedule 5 |
Skin sensitisation (GPMT) | Guinea pig | Not sensitising | N/A |
The submitted acute toxicity data supports a cut-off for dinotefuran from Schedule 5 at 10 per cent. Acute toxicity is summarised below.
Toxicity[59] | Dust (DU) | Pressurised fly bait (AE) | Pressurised insecticide PI (AE) | Gel Bait (BA) | Water-soluble granules (WG) |
---|---|---|---|---|---|
Dinotefuran Concentration (g/kg) | 2.5 | 10 | 5 | 5 | 400 |
Acute oral toxicity LD50 (mg/kg bw) | >5000 | >5000 | >5000 | >5000 | >5000 |
Acute dermal toxicity LD50 (mg/kg bw) | >5000 | >5000 | >5000 | >5000 | >5000 |
Acute inhalational toxicity LC50 (mg/kg bw) | >2080 | >5090 | >2050 | >2070 | >5090 |
Skin irritation | Non-irritant | Non-irritant | Slight | Non-irritant | Non-irritant |
Eye irritation | Moderate – due to abrasive ground rock in formulation, not due to active | Very slight | Slight | Slight | Moderate |
Skin sensitisation (Buehler) | Not sensitising | Not sensitising | Not sensitising | Not sensitising | Not sensitising |
SPF (2015) Classification | Schedule 5/6 | N/A-Schedule 5 | Schedule 5/6 | Schedule 5/6 | Schedule 5 |
The proposed products all have low acute oral, dermal and inhalational toxicity, and none were skin sensitisers. The toxicity endpoints relevant to scheduling are skin and eye irritation. More details from these relevant acute toxicity studies on the products are summarised below in Table 3.
Toxicity[60] | Dust (DU) | Pressurised fly bait (AE) | Pressurised insecticide PI (AE) | Gel Bait (BA) | Water-soluble granules (WG) |
---|---|---|---|---|---|
Dinotefuran Conc (g/kg) | 2.5 | 10 | 5 | 5 | 400 |
Skin irritation NZ White rabbits, n=3 Results: |
0.5 g (1.25 g of the 40% w/w test mixture). Very faint erythema (score of 0.3) at 1 h post-application; Fully resolved by 24 h. |
0.5 g. No observed erythema or oedema |
0.5 g. Erythema (score of 1) in all rabbits at 1 h post-application, remaining in 2/3 animals at 24 hours, and fully resolving by 48 h. |
0.5 mL. Very slight erythema (score of 1) mean in 3/3 rabbits at 1 h post-application. Full recovery at 24 h. |
40% solution. No erythema or oedema was observed. |
Conclusion | Non-irritant | Non-irritant | Slight irritant | Non-irritant | Non-irritant |
Eye irritation NZ White rabbits, n=3 Results: |
0.03 g. Conjunctivitis and iritis in all animals within 1 h post-instillation; resolved by Day 7. One animal exhibited corneal opacity by 24 h, resolved by Day 4 was observed in the experimental period. |
A ‘burst’ (0.3-0.5 g) to the right eye from a distance of approximately 10 cm. Very slight (scores of 1/3) conjunctivae redness, and discharge in 2/3 eyes each at 1 h, fully resolved by 24 h. |
0.1 mL. Conjunctivitis in all animals at 1 h; recovery by 48 h. No corneal opacity or iritis were observed in the experimental period. |
0.1 mL. Conjunctivitis observed in all treated eyes within 1 h post-instillation, remaining in 1/3 eyes at 24 h, and fully resolving at 48 h. |
0.07 g (0.1 mL). Conjunctivitis and corneal opacity observed in all animals at 24 h, partially resolving at 48 h, and fully resolving by 72 h. |
Conclusion | Moderate irritant (due to ground rock in formulation, not due to active ingredient) | Very slight irritant | Slight irritant | Slight irritant | Moderate irritant |
No submissions were received.
The committee recommended that the current Schedule 5 entry for dinotefuran be amended as follows:
Schedule 5 – Amend Entry
DINOTEFURAN except in preparations containing 1 per cent or less of dinotefuran.
The committee also recommended an implementation date of 1 June 2018 as this is the earliest practicable implementation date.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the recommendation comprised the following:
The delegate considered the following regarding this proposal:
The delegate’s interim decision is to amend the current Schedule 5 entry of dinotefuran. The proposed Schedule entry is:
Schedule 5 – Amend Entry
DINOTEFURAN except in preparations containing 1 per cent or less of dinotefuran.
The proposed implementation date is 1 June 2018. This is the earliest practicable implementation date.
The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (a) the risks and benefits of the use of the substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of the substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the interim decision are the following:
Scheduling medicines and poisons
An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to consider afidopyropen for scheduling in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) – the Poisons Standard.
This was a general application. The applicant's proposed amendments to the Poisons Standard are:
The applicant's reasons for the request are:
Afidopyropen is not currently scheduled.
The applicant states that the mode of action of Afidopyropen may be similar to another insecticide, pymetrozine (see Substance summary below), which is in Schedule 5 of the Poisons Standard as follows:
Afidopyropen is not currently scheduled and has not been previously considered for scheduling. Therefore a scheduling history is not available
In February 1997, the National Drugs and Poisons Schedule Committee (NDPSC) considered an application to create a new Schedule 5 entry for pymetrozine. The committee considered toxicological data and considered that Schedule 5 was appropriate for pymetrozine on the basis of moderate eye irritation in the rabbit.
Afidopyropen is not currently registered with the APVMA as an active constituent or product.
Afidopyropen is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017 and is not an excipient or active in any medicines on the ARTG.
Afidopyropen (ISO approved name) is the first member of a new chemical class of insecticides that has not been previously considered by the Chemicals Scheduling Delegate or Advisory Committee on Chemicals Scheduling (ACCS).
A recent published report (May, 2017) suggests that its mode of action may be similar another insecticide pymetrozine, in that it overstimulates and eventually silences vanilloid-type transient receptor potential (TRPV) channels which are expressed exclusively in insect chordotonal stretch receptor neurons.[61] The consequence of this binding is to inhibit plant-sucking insects' ability to feed, resulting in starvation and eventually death. Afidopyropen and pymetrozine have overlapping binding sites, with afidopyropen having higher affinity than pymetrozine. Pymetrozine is in Schedule 5 on the basis of moderate acute eye irritation.
Property | Afidopyropen |
---|---|
CAS number | 915972-17-7 |
Chemical structure | C33H39NO9 ![]() |
IUPAC and/or common and/or other names | [(3S,4R,4aR,6S,6aS,12R,12aS,12bS)-3-(cyclopropylcarbonyloxy)-1,2,3,4,4a,5,6,6a,12a,12b-decahydro-6,12-dihydroxy-4,6a,12b-trimethyl-11-oxo-9-(3-pyridyl)-11H,12H-benzo[f]pyrano[4,3-b]chromen-4-yl]methyl cyclopropanecarboxylate (IUPAC); [(3S,4R,4aR,6S,6aS,12R,12aS,12bS)-3-[(cyclopropylcarbonyl)oxy]-1,3,4,4a,5,6,6a,12,12a,12b-decahydro-6,12-dihydroxy-4,6a,12b-trimethyl-11-oxo-9-(3-pyridinyl)-2H,11H-naphtho[2,1-b]pyrano[3,4-e]pyran-4-yl]methyl cyclopropanecarboxylate (CAS) |
The following information was extracted from APVMA assessment report [Interim Human Health Technical Report – afidopyropen – Versys Insecticide (BAS 440 001)].
Toxicity | Species | Afidopyropen | SPF (2015) Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | >2000 (no deaths) | Schedule 5 |
Acute dermal toxicity LD50 (mg/kg bw) | Rat | >2000 (no deaths) | Schedule 5 |
Acute inhalational toxicity LC50 (mg/m3/4h) | Rat | >5480 (no deaths) | Schedule 5 |
Skin irritation | Rabbit | Non-irritating | N/A |
Eye irritation | Rabbit | Slight (with ground powder) | Schedule 5 |
Skin sensitisation (GPMT) | Guinea pig | Non-sensitising | N/A |
Based on the available data from studies done according to OECD guidelines, afidopyropen has low acute oral, dermal and inhalation toxicity in rats.
Based on available data from an OECD Guideline-compliant study in rabbits, afidopyropen is not a skin irritant:
Based on available data, afidopyropen in a fine powder is a slight eye irritant:
Based on available data using the guinea pig maximisation test method according to OECD guidelines, afidopyropen is not a skin sensitiser.
Repeat-dose toxicity studies indicate:
Afidopyropen gave negative results in an adequate range of assays for genotoxicity in vitro and in vivo.
Having regard to the submitted experimental findings (see assessment report) on afidopyropen and available body of evidence from experimental and clinical studies with bromocriptine and other dopamine agonists, the reviewing toxicologist has concluded that afidopyropen should be regulated as a non-genotoxic, threshold dose, reproductive system carcinogen in female rats, which is of low relevance and risk to humans under the anticipated magnitude and conditions of exposure.
The NOAEL in rats for reproductive toxicity was 1500 ppm (equal to 122 mg/kg bw/d in dams) due to impaired implantation at and above the maternal dose of 3000 ppm. The NOAEL for parental toxicity was 150 ppm (equal to 9.6 mg/kg bw/d in dams) based on depressed seminal vesicle weight, maternal food consumption and gestational bodyweight gain, and increased maternal liver weight at 1500 ppm and above. The NOAEL for offspring toxicity was 150 ppm (equal to 9.6 mg/kg bw/d) based on increased post-natal mortality, depressed bodyweight and decreased spleen weight in pups at and above the maternal dose of 1500 ppm.
In rats, a concentration of 1500 ppm (equal to 122 mg/kg bw/d in dams) afidopyropen in the parental diet did not cause developmental malformations in pups exposed in utero. In another rat study, under the study conditions, afidopyropen did not cause foetal malformations at up to 100 mg/kg bw/d, the highest dose administered. In rabbits, the NOAEL for effects on foetal survival, growth and development was 32 mg/kg bw/d, the highest administered dose. Under the study conditions, afidopyropen did not cause developmental malformations in rabbits.
No submissions were received.
No submissions were received.
The committee recommended that afidopyrofen be included in Schedule 5 as follows:
Schedule 5 – New Entry
AFIDOPYROPEN.
The committee also recommended an implementation date of 1 June 2018 as this is the earliest practicable implementation date.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (c) the toxicity of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the recommendation comprised the following:
The delegate considered the following in regards to this proposal:
The delegate notes the committee's advice. However, the delegate's interim decision is to create a new Appendix B entry for afidopyropen in the Poisons Standard. The proposed Schedule entry is:
Appendix B – New Entry
AFIDOPYROPEN
Reasons for Entry: b (Use pattern restricts hazard)
Areas of Use: 1.2 (Insecticide)
The proposed implementation date is 1 June 2018. This is the earliest practicable implementation date.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (a) the risks and benefits of the use of the substance; (c) the toxicity of the substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the interim decision are the following: