Scheduling medicines and poisons
This consultation closed on 11 October 2018
Publication of interim decisions made pursuant to regulations 42ZCZN of the Therapeutic Goods Regulations 1990
In accordance with regulation 42ZCZP of the Therapeutic Goods Regulations 1990 (the Regulations), this notice gives effect to the Secretary's obligation to publish interim decisions, the reasons for those decisions and the proposed date of effect of decisions made pursuant to regulation 42ZCZN.
The interim decisions to which this notice relates include decisions made in respect to:
In accordance with regulation 42ZCZP of the Regulations, this notice invites interested persons to make submissions to the Secretary in relation to the interim decisions on or before the close of business on 11 October 2018 (second closing date).
See How to respond below.
Your submission should:
Submissions might also include:
Pursuant to regulation 42ZCZQ(4) and (5), the Secretary will publish all public submissions received on or before the second closing date on the TGA's web page titled: Public submissions on scheduling matters.
The Secretary will not, however, publish any information that the Secretary considers to be confidential information.
Accordingly, in order to assist the Secretary to make this assessment, please:
Further information about how TGA considers information which might be personal or sensitive in nature is set out below in the section titled Privacy and your personal information.
After considering all relevant submissions received on or before the second closing date (and or obtaining any further advice), the Secretary may make final decisions confirming, varying or setting aside the interim decisions. Final decisions will be published on the TGA's web page titled Scheduling delegates' final decisions on 29 November 2018.
The Therapeutic Goods Administration (TGA) collects your personal information in this submission in order to:
The TGA will disclose your name and (if applicable) your designation/work title on the TGA Internet site (i.e. make this information publicly available) if, when making your submission, you consent to the publication of your name on the TGA Internet site. If at any point in time, you change your mind and wish for your personal information to be redacted then please contact the Scheduling Secretariat at medicines.scheduling@health.gov.au so that the pubic submissions can be updated accordingly.
The TGA will not publish information it considers confidential, including yours/other individuals' personal information (unless you/they have consented to publication or it is required by law) or commercially sensitive information. Also, the TGA will not publish information that could be considered advertising or marketing (e.g. logos or slogans associated with products), information about any alleged unlawful activity or that may be defamatory or offensive.
Please do not include personal information about other individuals in the body of your submission. Personal information in this context means information or an opinion about an individual whose identity is apparent, or can reasonably be ascertained, from the information or opinion.
For general privacy information, please go to the TGA's webpage on Privacy. The TGA is part of the Department of Health and the link includes a link to the Department's privacy policy and contact information if you have a query or concerns about a privacy matter.
Any questions relating to submissions should be directed by email to medicines.scheduling@health.gov.au (for substances referred to the ACMS or Joint ACCS-ACMS) or chemicals.scheduling@health.gov.au (for substances referred to the ACCS).
Scheduling medicines and poisons
1. Advisory Committee on Medicines Scheduling (ACMS #24)
The delegate's interim decision under regulation 42ZCZN of the Therapeutic Goods Regulations 1990 (the Regulations) is not to amend the current Poisons Standard in relation to sildenafil.
The reasons for the interim decision are as follows:
The delegate considered the following in regards to this interim decision:
The pre-meeting scheduling proposal was published on the TGA website on 12 April 2018 at Consultation: Proposed amendments to the Poisons Standard being referred to the June 2018 meetings of the ACCS, ACMS and Joint ACCS/ACMS.
An application was submitted to amend the Poisons Standard with respect to sildenafil. The application proposed to create new Schedule 3, Appendix H and Appendix M entries for sildenafil and to amend the Schedule 4 entry.
The applicant's proposed amendments to the Poisons Standard were:
Note
New text is shown as green, larger font, with a horizontal line above it.
Schedule 3 - New Entry
SILDENAFIL in divided preparations for oral use containing 50 mg of sildenafil per dosage unit in packs of not more than 8 dosage units when compliant with the requirements of Appendix M.
Schedule 4 - Amend Entry
SILDENAFIL except when included in Schedule 3.
Appendix H - New Entry
SILDENAFIL.
Appendix M - New Entry
SILDENAFIL.
Supply of Schedule 3 sildenafil will be contingent on:
The applicant's reasons for the proposal were:
Sildenafil is in Schedule 4 of the Poisons Standard as follows:
Schedule 4
SILDENAFIL.
The chemically and pharmacologically similar vardenafil and tadalafil are also in Schedule 4 of the Poisons Standard.
In August 1998, the National Drugs and Poisons Schedule Committee (NDPSC) noted that sildenafil was widely publicised in the media following its release in the United States of America. The committee members agreed that a Schedule 4 classification should apply from the time sildenafil was marketed in Australia. The committee considered that the contraindications, precautions and drug interactions were such that medical advice was required.
In July 2017, the ACMS considered an application to down-schedule sildenafil to a Schedule 3 Pharmacist Only Medicine. Based on the potential for incorrect assessment of ED by pharmacists, CVD risk, AEs, drug interactions, possible misuse/abuse, risk of worsened outcomes and no upper age limit, the committee recommended, and the delegate agreed, that the current scheduling of sildenafil remains appropriate.
In June 2003, the NDPSC considered a proposal to schedule vardenafil as a new medicine. The committee decided to list vardenafil in Schedule 4 on the grounds that the condition being treated necessitated appropriate medical diagnosis and the use of this medicine required patient management and monitoring by a medical professional.
In November 2016, the ACMS considered a proposal to down-schedule vardenafil in oral preparations containing up to 10 mg to Schedule 3. The committee advised that the current scheduling of vardenafil remains appropriate on the basis that erectile dysfunction can be a marker of an underlying cardiovascular disease, diabetes or endocrine disorder and men should be assessed by a medical practitioner prior to (or at the very least concurrent with) initiation of phosphodiesterase type 5 (PDE5) inhibitor treatment. Furthermore, although vardenafil shows good toxicological profile and is well-tolerated, the cause/aetiology of the medical condition is of greater concern and should first be assessed by a medical practitioner. The committee also noted that PDE5 inhibitors are commonly misused, often in combination with other drugs such as MDMA (ecstasy/methamphetamines). The delegate agreed with the committee's advice, stating that as there are currently no risk management plans for Schedule 3 medicines, it is premature to down schedule vardenafil when there are no mandated requirements to minimise the risk relating to underlying medical conditions. The delegate also noted that no other PDE5 inhibitors have been down-scheduled.
In July 2017, the ACMS again considered an application to down-schedule vardenafil to a Schedule 3 medicine. The committee recommended that the current scheduling of vardenafil remains appropriate based on the potential for incorrect assessment for ED by pharmacists, CVD risk, AEs, drug interactions, possible misuse/abuse, and lack of risk management plans for Schedule 3 medicines. The delegate agreed with the committee's advice and the scheduling of vardenafil remained unchanged.
The Australian Register of Therapeutic Goods (ARTG) has 101 products that contain sildenafil citrate.
In the last 30 years there have been 1104 reported cases of adverse events related to sildenafil in the Database of Adverse Events Notification (DAEN) - Medicines: 974 cases with a single suspected medicine and 42 cases where death was the reported outcome.
According to the TGA Ingredient Database, sildenafil citrate is:
Health Canada regulates sildenafil as a Prescription Only Medicine. Tablet strengths available include 25 mg, 50 mg and 100 mg, and there is also a 0.8 mg/mL solution of sildenafil registered (as a 10 mg/12.5 mL product) for intravenous use.
Medsafe NZ regulate sildenafil as a prescription medicine with the exception of sildenafil for oral use containing 100 mg or less per dose unit sold in the manufacturer's original pack containing not more than 12 dosage units. This is indicated for the treatment of ED in males aged between 35 and 70 years and is provided by a registered pharmacist who has successfully completed a training programme endorsed by the Pharmaceutical Society of NZ.
The USA Food and Drug Administration regulate sildenafil as a Prescription Only Medicine.
In November 2017, the UK Medicines and Healthcare products Regulatory Agency (MHRA) formally classified sildenafil 50 mg from a prescription only medicine (POM) to a pharmacy medicine (P). Sildenafil 50 mg could be available without prescription for use by men over 18 who have ED. This decision was made following an assessment of the safety of [REDACTED] advice from the Commission on Human Medicines and a public consultation with positive outcome. Sildenafil 50 mg will be sold in pharmacies following a discussion with the pharmacist. Pharmacists will be able to determine whether treatment is appropriate for the patient and can give advice on ED, usage of the medicine, potential side effects and if further consultation with a general practitioner is required.
[REDACTED] will not be sold to those with severe CVD; at high cardiovascular risk; liver failure; severe kidney failure; or taking certain interacting medicines. Use of [REDACTED] in these groups of men must continue to be under the supervision of a doctor.
An application to switch sildenafil from prescription to OTC in the EU in 2008 was withdrawn by the sponsor after the European Medicines Agency (EMA) noted some concerns. The EMA committee expressed concerns that there would be no medical supervision, which could delay diagnosis of possible CVD. The EMA's Committee for Medicinal Products for Human Use (CHMP) was also concerned that availability of sildenafil through pharmacies could lead to an increase in its recreational use, particularly among younger people.
Sildenafil facilitates penile erection by enhancing the relaxant effect of nitric oxide (NO) released in response to sexual stimulation. Sildenafil citrate, a sildenafil salt, is an orally active selective inhibitor of cyclic guanosine monophosphate (cGMP) specificPDE5. Cyclic-GMP PDE5 is the predominant isoenzyme in the human corpora cavernosa responsible for the degradation of cGMP. By inhibiting PDE5, sildenafil causes NO-induced cGMP concentrations to remain elevated in the corpus cavernosum smooth muscle. Elevated cGMP levels signal smooth muscle relaxation, resulting in an inflow of more blood in the corpus cavernosum and subsequent penile erection.[9],[10] To be effective, sexual stimulation is required.
Property | Sildenafil (as citrate) |
---|---|
CAS number | 171599-83-0 (as citrate) |
IUPAC and/or common and/or other names | 5-[2-ethoxy-5-[(4-methylpiperazin-1-yl)sulfonyl]phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d-]pyrimidin-7-one dihydrogen 2-hydroxypropane-1,2,3- tricarboxylic acid. |
Chemical structure | ![]() |
Molecular formula | C22H30N6O4S.C6H8O7 (as citrate) |
Molecular weight | 666.7 g/mol (as citrate) |
Eleven (11) public submissions were received before the first closing date in response to an invitation published on 12 April 2018 under regulation 42ZCZK of the Regulations. Seven (7) submissions supported the proposed amendment (one did not support the proposed Appendix H entry), and four (4) opposed the proposed amendment.
The main points provided in support of the amendment were:
The main points provided in opposition of the amendment were:
The committee recommended that the current scheduling of sildenafil 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 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:
Scheduling medicines and poisons
1. Advisory Committee on Medicines Scheduling (ACMS #24)
The delegate's interim decision under regulation 42ZCZN of the Therapeutic Goods Regulations 1990 (the Regulations) is to amend the current Poisons Standard in relation to budesonide as follows:
Note
New text is shown as green, larger font, with a horizontal line above it.
Deleted text is shown as red, smaller font, with a strikethrough.
Schedule 2 - Amend Entry
BUDESONIDE in aqueous nasal sprays delivering 5064 micrograms or less of budesonide per actuation when the maximum recommended daily dose is no greater than 400 micrograms and when packed in a primary pack containing 200 actuations or less, for the prophylaxis or treatment of allergic rhinitis for up to 6 months in adults and children 12 years of age and over.
Proposed implementation date: 1 February 2019
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate for the decision include:
The delegate considered the following in regards to this interim decision:
The pre-meeting scheduling proposal was published on the TGA website on 12 April 2018 at Consultation: Proposed amendments to the Poisons Standard being referred to the June 2018 meetings of the ACCS, ACMS and Joint ACCS/ACMS.
An application was submitted to amend the Poisons Standard with respect to budesonide. The application proposed to amend the Schedule 2 entry of budesonide.
The applicant's proposed amendments to the Poisons Standard were:
Note
New text is shown as green, larger font, with a horizontal line above it.
Deleted text is shown as red, smaller font, with a strikethrough.
Schedule 2 - Amend Entry
BUDESONIDE in aqueous nasal sprays delivering 5064 micrograms or less of budesonide per actuation when the maximum recommended daily dose is no greater than 400 micrograms and when packed in a primary pack containing 200 actuations or less, for the prophylaxis or treatment of allergic rhinitis for up to 6 months in adults and children 12 years of age and over.
The applicant's reasons for the proposal were:
Budesonide is listed in Schedules 2 and 4 of the Poisons Standard as follows:
Schedule 2
BUDESONIDE in aqueous nasal sprays delivering 50 micrograms or less of budesonide per actuation when the maximum recommended daily dose is no greater than 400 micrograms and when packed in a primary pack containing 200 actuations or less, for the prophylaxis or treatment of allergic rhinitis for up to 6 months in adults and children 12 years of age and over.
Schedule 4
BUDESONIDE except when included in Schedule 2.
The scheduling history for budesonide for intra-nasal use is outlined below.
In November 1990, the Drugs and Poisons Schedule Committee (DPSC) included budesonide in Schedule 4 after receiving an application for use in bronchial asthma and AR.
In November 1998, the NDPSC agreed to include budesonide in Schedule 3 in aqueous nasal sprays delivering 50 micrograms per actuation when the maximum recommended daily dose is no greater than 400 micrograms, for the treatment of seasonal and AR. The Schedule 4 entry was also amended to include 'except when included in Schedule 3'.
In February 1999, the NDPSC agreed to amend the Schedule 3 entry for budesonide to 'budesonide in a dose of 50 microgram or less' to allow the supply of lower dose preparations.
In August 1999, the NDPSC agreed to amend the typographical error in Schedule 3 of 'seasonal and allergic rhinitis' to read 'seasonal allergic rhinitis'. The Schedule 3 entry was also amended to include 'and when packed in a primary pack containing 200 actuations or less' and 'in adults and children 12 years and over'.
In August 2000, the NDPSC agreed to amend the Schedule 3 entry for budesonide to include 'for the short-term prophylaxis'. The committee also agreed to include budesonide in Appendix H based on its similarity of other nasal corticosteroids which are permitted to be advertised.
In October 2002, the NDPSC agreed to amend the Schedule 3 entry for budesonide to include perennial allergic rhinitis (PAR) based on post-marketing safety data and no expected safety issues to arise from the short-term use of intranasal budesonide for the prophylaxis or treatment of allergic rhinitis.
In June 2003, the NDPSC agreed reschedule budesonide in aqueous nasal spray to Schedule 2 for the prophylaxis or treatment of allergic rhinitis for up to 6 months in adult and children 12 years and over based on extensive local and overseas experience, AR not requiring medical diagnosis and is easily diagnosed by the consumer and supporting information that budesonide is substantially safe in adults and children 12 years and over.
In October 2005, the NDPSC agreed to consider removing the pack size restriction 'when packed in a primary pack containing 200 actuations or less' from the Schedule 2 entry at the February 2006 meeting to harmonise with New Zealand (NZ).
In February 2006, the NDPSC agreed to amend the Schedule 2 entry for budesonide by removing the limit of actuations, thereby harmonising with NZ.
In February 2007, the NDPSC amended the Schedule 2 entry for budesonide for clarity and consistency by adding 'of age' after '12 years'.
The Australian Register of Therapeutic Goods (ARTG) has 43 products that contain budesonide. The products marketed include nasal sprays, metered dose inhalers, inhalation ampoules, dry power inhalers, enteric capsules and nebuliser suspension.
Budesonide does not appear in the current Therapeutic Goods (Permissible Indications) Determination No. 2 of 2018 as it is a scheduled substance and is not eligible for use in ARTG listed medicines.
In the last 30 years there have been 521 reported cases of adverse events related to budesonide in the Database of Adverse Events Notification (DAEN) - Medicines: 319 cases with a single suspected medicine and 7 cases where death was the reported outcome.
According to the TGA Ingredient Database, budesonide is:
In Canada, 64 µg budesonide nasal sprays are regulated as a prescription medicine.
In the UK, 64 µg budesonide nasal sprays are regulated as an over-the-counter (OTC) medicine.
Medsafe NZ regulate budesonide as a Pharmacy Only medicine for the treatment or prophylaxis of allergic rhinitis in adults and children over 12 years of age in aqueous nasal sprays delivering up to 50 micrograms per actuation and when the maximum recommended daily dose is no greater than 400 micrograms (200 micrograms per nostril) in a pack containing 200 actuations or less.
In the USA, 32 µg budesonide nasal sprays are regulated as an over-the-counter (OTC) medicine.
Property | Budesonide |
---|---|
CAS name | 51333-22-3 |
IUPAC and/or common and/or other names | (11-beta,16-alpha)-16,17-(Butylidenebis(oxy))-11,21-dihydroxypregna-1,4-diene-3,20-dione |
Chemical structure | ![]() |
Molecular formula | C25H34O6 |
Molecular weight | 430.5 g/mol |
Budesonide is a potent synthetic glucocorticosteroid with special kinetic properties. It has a high affinity for the glucocorticosteroid (aka 'corticosteroid' or simply 'steroid') receptor, and in non-clinical pharmacological studies demonstrates a wide variety of anti-allergic and anti-inflammatory effects.[13] Budesonide inhibits the production and release of a variety of mediators and cytokines from inflammatory cells. Moreover, budesonide inhibits the immediate and late phase allergic reactions, bronchial hyperreactivity and cellular infiltration after provocation.
INCs currently marketed in Australia to treat AR are broadly characterised according to their absorption characteristics, with first-generation including beclomethasone, triamcinolone and budesonide considered hydrophilic molecules, and second-generation molecules mometasone, ciclesonide and fluticasone considered lipophilic.[14],[15] While higher lipophilicity is one pharmacological characteristic that may lead to varied local and systemic absorption, safety and efficacy of INCs is influenced by mucosal solubility (higher hydrophilicity reduces mucociliary clearance) and nasal metabolic pathways inhaler device delivery efficiency.[16],[17] Budesonide's unique reversible fatty acids esterification pathway is believed to contribute to its long duration of action within the airways/lung.[18]
High hepatic metabolism of any swallowed INC dose also contributes to minimise systemic exposure. Budesonide undergoes extensive biotransformation (approximately 90%) on first-passage through the liver to metabolites of 100-fold lower activity than the parent compound.[19],[20]
Four (4) public submissions were received before the first closing date in response to an invitation published on 12 April 2018 under regulation 42ZCZK of the Regulations. All four (4) submissions were in support of the proposed amendments.
The main points provided in support of the amendment were:
The committee recommended that the Schedule 2 entry be amended as follows:
Note
New text is shown as green, larger font, with a horizontal line above it.
Schedule 2 - Amend Entry
BUDESONIDE in aqueous nasal sprays delivering 64 micrograms or less of budesonide per actuation when the maximum recommended daily dose is no greater than 400 micrograms, for the prophylaxis or treatment of allergic rhinitis for up to 6 months in adults and children 12 years of age and over.
The committee also recommended an implementation date of 1 February 2019.
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 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:
Scheduling medicines and poisons
1. Advisory Committee on Medicines Scheduling (ACMS #24)
The delegate's interim decision under regulation 42ZCZN of the Therapeutic Goods Regulations 1990 (the Regulations) is to amend the current Poisons Standard in relation to alkyl nitrites and lubricants as follows:
Note
New text is shown as green, larger font, with a horizontal line above it.
Deleted text is shown as red, smaller font, with a strikethrough.
Schedule 4 - Delete Entries
AMYL NITRITE.
BUTYL NITRITE.
ISOAMYL NITRITE.
ISOBUTYL NITRITE.
OCTYL NITRITE.
Schedule 9 - New Entries
ALKYL NITRITES except those specifically listed elsewhere in these Schedules.
ISOPROPYL NITRITE.
PROPYL NITRITE.
CYCLOHEXANE NITRITE.
Schedule 9 - Entries moved from Schedule 4
AMYL NITRITE.
BUTYL NITRITE.
ISOAMYL NITRITE.
ISOBUTYL NITRITE.
OCTYL NITRITE.
Appendix A - Amend Entry
LUBRICANTS in preparations that provide a lubricating action between machinery parts, except soluble oils and solvent-deposited lubricating agents.
Proposed implementation date: 1 February 2019
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate for the decision include:
The delegate considered the following in regards to this interim decision:
The pre-meeting scheduling proposal was published on the TGA website on 12 April 2018 at Consultation: Proposed amendments to the Poisons Standard being referred to the June 2018 meetings of the ACCS, ACMS and Joint ACCS/ACMS.
An application was submitted to amend the Poisons Standard with respect to alkyl nitrites. The application proposed to amend the Appendix A listing for lubricants and to create a new Schedule 4 group entry for alkyl nitrites.
The applicant's proposed amendments to the Poisons Standard were:
Note
New text is shown as green, larger font, with a horizontal line above it.
Schedule 4 - New Entry
ALKYL NITRITES except those specifically listed elsewhere in these Schedules.
Appendix A - Amend Entry
LUBRICANTS in preparations that provide a lubricating action between machinery parts, except soluble oils and solvent-deposited lubricating agents.
The applicant's reasons for the proposal were:
Five (5) alkyl nitrites are listed in Schedule 4 of the Poisons Standard as follows:
Schedule 4
AMYL NITRITE.
BUTYL NITRITE.
ISOAMYL NITRITE.
ISOBUTYL NITRITE.
OCTYL NITRITE.
In January 1955, the Committee of Poisons Schedules placed amyl nitrite in Schedule 3 of the newly created Poisons Standard. In February 1989, following reports of recreational abuse of amyl nitrite and other nitrites a change to Schedule 4 was foreshadowed. Members considered that the substance had no use in contemporary medicine, although anecdotally it was being used by the mining industry as a cyanide antidote. The Schedule 3 entry was deleted and a new Schedule 4 entry created in February 1990.
In November 1993 (deferred from August 1993), the National Drugs and Poisons Committee (NDPSC) considered a proposal to create new Appendix D (Possession of this drug without authority should be illegal) entries for amyl and butyl nitrites owing to their reported use by paedophiles, who administer it to children for anal dilation. The committee decided that due to the lack of precise information about widespread misuse by paedophiles, this proposal was not warranted at this time and that more attention should be paid to policing the illegal supply of a Schedule 4 substance.
In August 1995, the National Drugs and Poisons Committee (NDPSC) considered the use of amyl nitrite as a first-aid treatment for cyanide poisoning. The Committee considered that the use of amyl nitrite as a first aid treatment for cyanide poisoning could not be supported in view of concerns with its safety and efficacy. Consequently, it would not support any change to its current Schedule 4 status. The committee agreed that if amyl nitrite were to be used as an antidote, existing mechanisms were available in each of the States and Territories to permit such use.
In May 1999, the National Drugs and Poisons Committee (NDPSC) considered harmonisation between Australia and New Zealand for amyl nitrite. At the time the committee noted that amyl nitrite is scheduled in NZ as Part III, but is exempted from scheduling in NZ when sold as an antidote for cyanide poisoning associated with the use of sodium cyanide for vertebrate control. The committee was advised that the Working Party while considering Schedule 4 was appropriate for amyl nitrite recognised the need for an exemption in the NZ entry to allow its availability as an antidote.
In November 1978 a new Schedule 3 entry was created for butyl nitrite, owing to concerns that there were no controls over the substance, which was anecdotally being used as a sex stimulant. In February 1989 an amendment to Schedule 4 was foreshadowed for butyl nitrite and other nitrites. The Schedule 3 entry was deleted and a new Schedule 4 entry created in February 1990.
In November 1993 (deferred from August 1993), the National Drugs and Poisons Committee (NDPSC) considered a proposal to create new Appendix D (Possession of this drug without authority should be illegal) entries for amyl and butyl nitrites owing to their reported use by paedophiles, who administer it to children for anal dilation. The committee decided that due to the lack of precise information about widespread misuse by paedophiles, this proposal was not warranted at this time and that more attention should be paid to policing the illegal supply of a Schedule 4 substance.
In May 1999, the National Drugs and Poisons Committee (NDPSC) considered harmonisation between Australia and New Zealand for butyl nitrite, octyl nitrite, isoamyl nitrite and isobutyl nitrite. The committee noted that the Working Party did not support adoption of the NZ scheduling for two reasons. In Australia, this group of drugs has been abused with severe adverse effects, and the NDPSC decision to shift the group in Schedule 4 in 1993 was related to reports of administration of nitrites to assist anal penetration in children by paedophiles.
In May 1999, the National Drugs and Poisons Committee (NDPSC) considered harmonisation between Australia and New Zealand for butyl nitrite, octyl nitrite, isoamyl nitrite and isobutyl nitrite. The committee noted that the Working Party did not support adoption of the NZ scheduling for two reasons. In Australia, this group of drugs has been abused with severe adverse effects, and the NDPSC decision to shift the group in Schedule 4 in 1993 was related to reports of administration of nitrites to assist anal penetration in children by paedophiles.
In February 1989, isobutyl nitrite was among a number of alkyl nitrites being considered for inclusion in Schedule 4 following reports of recreational abuse. A Schedule 4 entry for isobutyl nitrite was created in February 1990.
In May 1999, the National Drugs and Poisons Committee (NDPSC) considered harmonisation between Australia and New Zealand for butyl nitrite, octyl nitrite, isoamyl nitrite and isobutyl nitrite. The committee noted that the Working Party did not support adoption of the NZ scheduling for two reasons. In Australia, this group of drugs has been abused with severe adverse effects, and the NDPSC decision to shift the group in Schedule 4 in 1993 was related to reports of administration of nitrites to assist anal penetration in children by paedophiles.
In May 1956 the PSC created a new Schedule 3 entry for octyl nitrite. This scheduling was confirmed for all jurisdictions in February 1985. In February 1989, following reports of recreational abuse of amyl nitrite and other nitrites an amendment to a Schedule 4 entry was foreshadowed. The Schedule 3 entry was deleted and a new Schedule 4 entry created in February 1990. In May 1999, the National Drugs and Poisons Committee (NDPSC) considered harmonisation between Australia and New Zealand for butyl nitrite, octyl nitrite, isoamyl nitrite and isobutyl nitrite. The committee noted that the Working Party did not support adoption of the NZ scheduling for two reasons. In Australia, this group of drugs has been abused with severe adverse effects, and the NDPSC decision to shift the group in Schedule 4 in 1993 was related to reports of administration of nitrites to assist anal penetration in children by paedophiles.
When considering a proposal to delete Schedule 3 entries for amyl, butyl and octyl nitrite and to create new Schedule 4 entries for these substances and also for isobutyl nitrite, the committee decided against making a generic entry for 'ALIPHATIC DERIVATIVES OF NITROUS ACID' as there was a trend away from generic scheduling entries, with specific entries being preferred.
Isopropyl nitrite, Isopentyl nitrite, propyl nitrite and cyclohexyl nitrite are not currently scheduled and has not been previously considered for scheduling. Therefore a scheduling history is not available.
Exemptions from scheduling were first proposed at the December 1965 Poisons Schedule Sub-Committee (PSSC) meeting. The original listing was for purposes that in some substances a poison is not likely to be released to cause poisoning. 'Motor fuels and lubricants unless specified in Schedule 5' was first among the first list of exemptions. It was not until the January 1969 PSSC meeting that the recommendation was made to include the list of exemptions, which included 'motor fuels and lubricants'.
The Australian Register of Therapeutic Goods (ARTG) has no products that contain the alkyl nitrites isopentyl nitrite, 2-pentyl and N-propyl nitrite or cyclohexyl nitrite.
Alkyl nitrites do not appear in the current Therapeutic Goods (Permissible Indications) Determination No. 2 of 2018.
According to the TGA Ingredient Database, amyl nitrite, octyl nitrite and nitrite are:
There are no agricultural and veterinary chemicals containing any nitrite listed on the APVMA's PubCRIS.
The international legal status of alkyl nitrites is unclear. In the European Union (EU), isobutyl nitrite was classified as a class 2 carcinogen under the EU Directive 76/769/EEC, making it illegal for shops to sell this variety of poppers.
In January 2016, the United Kingdom (UK) government included alkyl nitrites in a list of banned psychoactive substances, but this decision was set to be reviewed, and it is unclear whether this decision remains.
In New Zealand (NZ), amyl nitrite is a prescription medicine except when sold to a person who holds a controlled substances licence (issued under section 95B of the Hazardous Substances and New Organisms Act 1996) authorising the person to possess cyanide and except when sold to an exempt laboratory covered by a Hazardous Substances and New Organisms Act 1996 approved code of practice. Octyl nitrite, isobutyl nitrite, butyl nitrite and isoamyl nitrite are classified as prescription medicines.
Poppers' is the street term for various alkyl nitrites taken for recreational purposes through direct inhalation. In the past these included amyl nitrite, butyl nitrite and isobutyl nitrite, with more recent variations including isopropyl and cyclohexyl nitrite. Alkyl nitrites have a smooth muscle relaxant effect, and were first used therapeutically (amyl nitrite) to treat angina. They have been used as recreational drug for the reported sensations of head rush, euphoria, uncontrollable laughter or giggling, and other sensations that result from the hypotensive effect and increase sexual arousal and desire. In addition, the smooth muscles of the anus and vagina are relaxed. Adverse effects of short term use include severe headache, throat irritation, nose bleeds, nausea, erectile problems, sensations of spinning or falling and dyspnoea. According to St George's Hospital, University of London, there have been 14 deaths in the UK related to inhaling alkyl nitrites since 1971, three of which were in 2006.[30]
In Australia, the drugs are sold under the guise of room deodorisers and cleaning solvents, and are readily available in adult shops and online. National Drug and Alcohol Research Centre's (NDARC) Ecstasy and Related Drugs Reporting System (EDRS) shows use of amyl nitrite (and may include other alkyl nitrites) running at 27% of those who participated in the survey in 2016 (up from 21% in 2015).[31] The demographics of the survey group suggest popper use has expanded to the community more generally - it was once associated more with the lesbian, gay, bisexual, trans, and/or intersex (LGBTI) community.
Ophthalmologists in Australia are seeing an increase in cases of temporary and permanent macula damage caused by recreational drug use of alkyl nitrite compounds. Ophthalmologists believe that chronic use could lead to irreversible damage. Alkyl nitrite 'popper' maculopathy causes gradual vision loss and clinically is the equivalent of having a hole burned in the macula from gazing at the sun.
Chemical | CAS number | IUPAC and/or common and/or other names | Molecular formula and weight | Chemical structure |
---|---|---|---|---|
General information for volatile alkyl nitrites | N/A | N/A | R-NO2 | ![]() |
Amyl nitrite | 110-46-3 | 3-Methylbutanol nitrite; isoamyl nitrite; nitrous acid, 3-methylbutyl ester; nitrous acid, isopentyl ester |
C5H11NO2 117.1 g/mol |
![]() |
Isopropyl nitrite | 541-42-4 | 2-Propanol nitrite; isopropylester kyseliny dusite; nitrous acid, 1-methylethyl ester |
C3H7NO2 89.1 g/mol |
![]() |
N-Propyl nitrite | 543-67-9 | Nitrous acid, n-propyl ester; propanol nitrite; propyl nitrite |
C3H7NO2 89.1 g/mol |
![]() |
Cyclohexyl nitrite | 5156-40-1 | Nitrous acid, cyclohexyl ester; N-cyclohexyl nitrite; cyclohexyl alcohol nitrite; C-hexyl nitrite; O-nitrosocyclohexanol |
C6H11NO2 129.2 g/mol |
![]() |
Three (3) public submissions were received before the first closing date in response to an invitation published on 12 April 2018 under regulation 42ZCZK of the Regulations. Two (2) submissions were in support of the proposed amendments, and one (1) was in conditional support.
The main points provided in support of the amendment were:
The main points provided in conditional support of the amendment were:
The committee made the following recommendations:
Note
New text is shown as green, larger font, with a horizontal line above it.
Appendix A - Amend Entry
LUBRICANTS in preparations that provide a lubricating action between machinery parts, except soluble oils and solvent-deposited lubricating agents.
Schedule 9 - New Entries
ALKYL NITRITES except those specifically listed elsewhere in these Schedules.
ISOPROPYL NITRITE.
PROPYL NITRITE.
CYCLOHEXANE NITRITE.
Schedule 9 - New Entries moved from Schedule 4
AMYL NITRITE.
BUTYL NITRITE.
ISOAMYL NITRITE.
ISOBUTYL NITRITE.
OCTYL NITRITE.
The committee also recommended an implementation date of 1 February 2019.
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 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 advice included:
*Large file warning: Attempting to open large files over the Internet within the browser window may cause problems. It is strongly recommended you download this document to your own computer and open it from there.
Scheduling medicines and poisons
1. Advisory Committee on Medicines Scheduling (ACMS #24)
The delegate's interim decision under regulation 42ZCZN of the Therapeutic Goods Regulations 1990 (the Regulations) is not to amend the current Poisons Standard in relation to codeine.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate for the decision include:
The delegate considered the following in regards to this interim decision:
The pre-meeting scheduling proposal was published on the TGA website on 12 April 2018 at Consultation: Proposed amendments to the Poisons Standard being referred to the June 2018 meetings of the ACCS, ACMS and Joint ACCS/ACMS.
An application was submitted to amend the Poisons Standard with respect to codeine. The application proposed to amend the Schedule 4 and Schedule 8 entries for codeine.
Note
New text is shown as green, larger font, with a horizontal line above it.
Deleted text is shown as red, smaller font, with a strikethrough.
The applicant's proposed amendments to the Poisons Standard were:
Schedule 4 - Amend Entry
CODEINE when compounded with one or more other therapeutically active substances:
Schedule 8 - Amend Entry
CODEINE alone or when compounded with one or more other therapeutically active substances:
except when included in Schedule 4.
The applicant's reasons for the proposal were:
Codeine is listed in Schedules 4 and 8 and Appendix K of the Poisons Standard as follows:
Schedule 4
CODEINE when compounded with one or more other therapeutically active substances:
Schedule 8
CODEINE except when included in Schedule 4.
Appendix K
CODEINE.
The NDPSC agreed to form a Codeine Working Party to review the availability of all over the counter (OTC) combination analgesics containing codeine. This followed concerns raised at previous NDPSC meetings (June 2005, October 2005 and June 2007) of abuse of codeine from a codeine-ibuprofen combination analgesic product (by cutting a bi-layer tablet in half to access the codeine, or separating codeine from the product by simple dissolution in water).
The NDPSC considered a report from the Codeine Working Party, together with findings from an evaluation of OTC codeine-containing analgesics, and agreed to foreshadow a proposal to re-schedule all OTC codeine to Schedule 3 (with suggestions to limit the maximum daily dose to 100 mg codeine, limit the maximum pack size to 5 days' supply, restrict divided preparations to 12 mg of codeine per dosage unit and restrict undivided preparations to 0.25% codeine). In addition, a member proposed to maintain a Schedule 2 entry for codeine with phenylephrine, if all other OTC codeine was included in Schedule 3. The NDPSC foreshadowed a proposal to include all OTC codeine (and not just analgesics) to encourage public comment.
The NDPSC agreed that the current scheduling of OTC codeine combinations for coughs and colds remained appropriate (but with a pack size limit of 5 days' supply), and that all OTC combination analgesics containing codeine should be re-scheduled from Schedule 2 to Schedule 3 (with the maximum daily dose limited to 100 mg, the duration of treatment limited to 5 days, divided preparations restricted to 12 mg of codeine per dosage unit and undivided preparations restricted to 0.25% codeine) and that Schedule 3 codeine should not be included in Appendix H. The implementation date was to be 1 May 2010.
Following consideration of June 2009 post-meeting submissions and further discussion, the NDPSC agreed to amend the pack size limit for Schedule 2 cough and cold preparations to a maximum of 6 days' supply. The NDPSC also confirmed the June 2009 resolution regarding the Schedule 3 entry for all OTC combination analgesics containing codeine. The implementation date remained as 1 May 2010. An editorial amendment was made to the Schedule 3 entry at the February 2010 NDPSC meeting.
The scheduling of codeine was considered as a part of the cold and cough preparation review, which looked at the use of these preparations for the treatment of children aged 2 to 12 years. Taking into consideration the advice from the ACMS, the delegate decided that there should be no change to the scheduling of codeine in cold and cough preparations.
The ACMS considered a proposal to re-schedule codeine with assistance from an independent external evaluation, public submissions and the original application. Consideration was given as to whether all current Schedule 3 preparations should be rescheduled to Schedule 4, or whether any rescheduling to Schedule 4 should only apply to combination analgesic products containing codeine. Consideration was also given to whether the Schedule 2 entry for codeine should be amended. The committee recommended that the Schedule 2 and Schedule 3 entries for codeine be deleted and that the Schedule 4 and Schedule 8 entries be amended to reflect this.
The delegate announced that a decision on the re-scheduling of codeine would be delayed to allow a more thorough consideration of the numerous submissions received from the pre-meeting and interim decision consultation periods and the broader implications to the then current products in the market.
A notice was published on the TGA website calling for further submissions from interested parties on the proposed re-scheduling options for codeine. This call for further submissions was based on feedback received during the consultation periods.
The ASCOM provided advice on products containing low dose codeine (8-15 mg codeine or codeine phosphate) that were available as a Schedule 2 and Schedule 3 medicine. The committee noted that the OTC availability of codeine-containing medicines supported a general misconception in the community that codeine is safe. It was also noted that there would need to be additional measures, such as education and possible up-scheduling, to achieve the desired outcome to reduce the risks associated with codeine.
The ACMS again considered the proposal to re-schedule codeine. The ACMS advised that their recommendation to up-schedule codeine from Schedule 2 and 3 to Schedule 4 from the August 2015 remains the same. The delegate agreed and made a final decision to up-schedule all medicines containing codeine to be Schedule 4 Prescription Only Medicines. This was published on the TGA website, along with the KPMG report and the RIS. As part of the final decision, an implementation date of 1 February 2018 was announced by the delegate, which provided more than a year for implementation. This balanced the needs of affected stakeholders while addressing the harms associated with these products.
The Australian Register of Therapeutic Goods (ARTG) has 207 products that contain codeine, codeine phosphate hemihydrate or codeine phosphate sesquihydrate.
In the last 30 years there have been 1670 reported cases of adverse events related to codeine in the Database of Adverse Events Notification (DAEN) - Medicines: 634 cases with a single suspected medicine and 103 cases where death was the reported outcome.
According to the TGA Ingredient Database, codeine is:
According to the TGA Ingredient Database, codeine phosphate hemihydrate is:
According to the https://www.ebs.tga.gov.au/ TGA Ingredient Database, codeine phosphate sesquihydrate is:
Countries in Europe including Austria, Belgium, Germany and Italy, as well as the United States, Japan, Russia and the United Arab Emirates all require prescriptions for medicines containing codeine. In some other countries, including Hong Kong, Hungary and the Netherlands, OTC sale of cough linctus (containing codeine) is allowed, with all other medicines containing codeine requiring a prescription.
In July 2017, the new French Government announced that all medicines containing codeine would only be available via prescription.
In November 2017, Canada completed a public consultation on making codeine products Prescription Only.
In November 2017, Medsafe New Zealand made their recommendation that, from 31 January 2020, all codeine in combination medicines, both analgesics and those used for cough and colds, should be reclassified to prescription medicines with a proposed exception applying to medicines containing not more than 15 mg of codeine per unit, with a maximum daily dose not exceeding 90 mg of codeine for use as an analgesic and when sold in a pack of not more than three day's supply. Medsafe is also advocating for a national monitoring of all codeine-containing medicines, including restricted and prescription, subsidised and unsubsidised medicines.
In January 2018, the Kenya Pharmacy and Poisons Board (KPPB) announced that all medicines that contain codeine have been rescheduled from Pharmacy Only Medicines to Prescription Only Medicines in an effort to minimise the risk of overuse and addiction. In addition, the KPPB have given all marketing authorisation holders six months to change packages to include clear and prominently positioned warnings on the label.
Codeine and its salts, especially codeine phosphate, are given orally in the form of linctuses for the relief of cough, and as tablets for the relief of mild to moderate pain, often with a non-opioid analgesic such as aspirin, ibuprofen, or paracetamol. Codeine phosphate is also given by intramuscular injection for the relief of pain, in doses similar to those used orally; the intravenous, subcutaneous, and rectal routes have also been used.
For the relief of pain, codeine phosphate may be given in doses of 30 to 60 mg every 4 hours to a usual maximum of 240 mg daily.
To allay non-productive cough, codeine phosphate may be given in doses of 15 to 30 mg three or four times daily.
Codeine phosphate is also used as tablets or in mixtures for the symptomatic relief of acute diarrhoea in doses of 15 to 60 mg given three to four times daily.
Other codeine salts used include the hydrochloride, sulfate, camsilate, and hydrobromide. Codeine polistirex (a codeine and sulfonate diethenylbenzene-ethenylbenzene copolymer complex) is used in modified-release preparation.
Property | Codeine |
---|---|
CAS number | 76-57-3 |
IUPAC and/or common and/or other names | Morphinan-6-ol, 7,8-didehydro-4,5-epoxy-3-methoxy-17-methyl-, (5-alpha,6-alpha)- (9CI); methylmorphine; codeine phosphate; codeine anhydrous; morphine monomethyl ether. |
Chemical structure | ![]() |
Molecular formula | C18H21NO3 |
Molecular weight | 299.4 g/mol |
Nine (9) public submissions were received before the first closing date in response to an invitation published on 12 April 2018 under regulation 42ZCZK of the Regulations. Two (2) submissions were in support and seven (7) opposed to the proposed amendments.
The main points provided in support of the amendment were:
The main points provided in opposition of the amendment were:
The committee recommended that the current scheduling of codeine 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 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:
Scheduling medicines and poisons
1. Advisory Committee on Medicines Scheduling (ACMS #24)
The delegate's interim decision under regulation 42ZCZN of the Therapeutic Goods Regulations 1990 (the Regulations) is not to amend the current Poisons Standard in relation to cannabidiol and tetrahydrocannabinols (THCs).
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate for the decision include:
The delegate considered the following in regards to this interim decision:
The pre-meeting scheduling proposal was published on the TGA website on 12 April 2018 at Consultation: Proposed amendments to the Poisons Standard being referred to the June 2018 meetings of the ACCS, ACMS and Joint ACCS/ACMS.
An application was submitted to amend the Poisons Standard with respect to cannabidiol and tetrahydrocannabinols (THCs). The application proposed to amend the Schedule 4 entry for cannabidiol.
The applicant's proposed amendments to the Poisons Standard were:
Note
New text is shown as green, larger font, with a horizontal line above it.
Deleted text is shown as red, smaller font, with a strikethrough.
Schedule 4 - Amend Entry
CANNABIDIOL in preparations for therapeutic use containing 2 per cent or less of where other cannabinoids found in cannabis comprise no more than 1% w/v of the product.
The applicant's reasons for the proposal were:
'...are taken to be active ingredients for the purposes of this order (whether or not those ingredients are specified, disclosed, purported or notified to the Secretary to be active ingredients):
(a) any tetrahydrocannabinol present in a medicinal cannabis product, the quantity or proportion of which (together with any corresponding acid) is greater than or equal to 1.0% w/w or w/v of the product'
Cannabidiol is specifically listed in Schedules 4 and 8 of the Poisons Standard as follows:
Schedule 4
CANNABIDIOL in preparations for therapeutic use containing 2 per cent or less of total other cannabinoids found in cannabis.
Schedule 8
# NABIXIMOLS (botanical extract of Cannabis sativa which includes the following cannabinoids: tetrahydrocannabinols, cannabidiol, cannabinol, cannabigerol, cannabichromene, cannabidiolic acid, tetrahydrocannabinolic acids, tetrahydrocannabivarol, and cannabidivarol, where tetrahydrocannabinols and cannabidiol (in approximately equal proportions) comprise not less than 90 per cent of the total cannabinoid content) in a buccal spray for human therapeutic use.
Index
CANNABIDIOL
cross reference: CANNABIS, NABIXIMOLS
Schedule 4
THC is specifically listed in Schedules 8 and 9 and Appendices D and K of the Poisons Standard as follows:
Schedule 8
# TETRAHYDROCANNABINOLS when extracted from cannabis for human therapeutic use, when:
except when:
Schedule 9
TETRAHYDROCANNABINOLS and their alkyl homologues, except:
Appendix D, Item 1
TETRAHYDROCANNABINOLS for human use.
Appendix K
TETRAHYDROCANNABINOLS
In February 2009, cannabidiol (CBD) was discussed by the National Drug and Poisons Scheduling Committee (NDPSC) as a part of a consideration of THC and the product nabiximols, which lead to the creation of the nabiximols entry (June and October 2009).
While the focus of the February 2009 meeting item was on the classification of THC, a number of public submissions received were regarding the availability of the nabiximols product which contains both THC and CBD. It was noted that it was difficult to give approval to special access scheme applications for medications containing CBD as it was considered a Schedule 9 substance. However, access would be granted if CBD was placed in Schedule 8 for therapeutic use. This scheduling consideration was to be discussed at the June 2009 meeting.
In June 2009, following further research regarding the nabiximols product, the NDPSC decided that a Schedule 8 entry needed to exempt only the formulation from Schedule 9 rather than the 'substance' and therefore created the Schedule 8 entry for Cannabis sativa extract, listing the individual cannabidiols and restricting its presentation to buccal sprays for therapeutic use.
In October 2009, the NDPSC considered the scheduling of nabiximols after it was established that the United States of America Adopted Names Council had designated 'nabiximols' as the approved non-proprietary name for an extract of Cannabis sativa. This extract contained THC and CBD as major components and related cannabinoids and non-cannabinoid components alpha- and trans-caryophyllenes as minor components (i.e. the specific THC and CBD formulation considered appropriate for inclusion in Schedule 8 by the June 2009 meeting). The Cannabis sativa extract Schedule 8 entry was amended to nabiximols.
In November 2014, the ACMS considered the scheduling of cannabidiol. The committee recommended to the scheduling delegate that cannabidiol, including extracts of Cannabis sativa, and including preparations of up to 2% of cannabinoids, including cannabidivarin (CBDV) for therapeutic use, be included in Schedule 4. The reasons for the recommendation included:
In May 2016, after extensive consultation, the scheduling delegate agreed with the committee recommendations and provided further reasons and clarification of the decision that included:
As a result, a Schedule 4 entry for cannabidiol was created, and the Schedule 9 entry for THC and their alkyl homologues was amended to exempt the new Schedule 4 entry for cannabidiol.
In November 2016, the Joint Advisory Committee on Chemicals Scheduling-ACMS further considered cannabidiol to improve the clarity of the entry with regards to the component cannabinoids found in cannabis. A final decision was made to improve the clarity of the cannabidiol entry on 31 May 2017, by including the word 'total' in relation to the other cannabinoids found in cannabis.
In March 2018, the ACMS provided advice to the delegate on a proposal to amend the Schedule 4 entry of cannabidiol, Schedule 8 entry of THCs and the Appendix K entries of cannabis and THCs to clarify the meaning of the cannabidiol Schedule 4 entry. The decision on this proposal is still pending.
On the Australian Register of Therapeutic Goods (ARTG), there is one product containing cannabidiol for export only, and no products THC.
According to the TGA Ingredient Database, cannabidiol is available for use as an Active Ingredient in Export Only and Prescription Medicines, and there is no reference to THC.
In the last 30 years, in the Database of Adverse Events Notification (DAEN) - Medicines there have been no reported cases of adverse events related to cannabidiol or THC.
Cannabis is a term used to describe a range of varieties of the Cannabis genus. The Cannabis plant produces a resin containing compounds called cannabinoids. Some cannabinoids possess psychoactive properties.
Cannabis contains about 60 cannabinoids, of which the main active constituent is delta-9-tetrahydrocannabinol. Delta-9-tetrahydrocannabinol reportedly has anti-emetic properties, and has been associated with claims relating to use for the control of nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional anti-emetics. Another active cannabinoid present in Cannabis is cannabidiol, which is associated with claims relating to use as an analgesic, anticonvulsant, muscle relaxant, anxiolytic, neuroprotective, anti-oxidant and anti-psychotic.
Nabiximols is a specific extract of Cannabis sativa which contains a range of cannabinoids, of which THC and cannabidiol, in approximately equal proportions, comprise not less than 90% of the total cannabinoid content. Nabiximols are registered for use in Australia as a buccal spray preparation as an adjunctive treatment for the symptomatic relief of neuropathic pain associated with multiple sclerosis in adults.
Nabilone is a synthetic cannabinoid used as an anti-emetic in the treatment of nausea and vomiting caused by chemotherapy and also for patients who are not responsive to conventional anti-emetic treatments.
Hemp seed oil as defined in Part 1 Interpretation, Paragraph (1) of the Poisons Standard is the oil obtained by cold expression from the ripened fruits (seeds) of Cannabis sativa. Hemp oil is distinct from hemp seed oil and includes extracts from the flowering tops or leaves or any other part of the Cannabis plant other than the ripened fruit (seeds).
Information in the public domain, including websites and literature articles[39] report cannabinoids are not synthesised within the hemp seed. However, traces of delta-9-tetrahydrocannabinol and cannabidiol contamination of the seed may occur due to residual contamination of the outside of the seed coat, even under good agricultural/manufacturing practice. Rigorous cleaning methods, including washing, sieving and shelling, may help reduce or remove any cannabinoid contamination of seeds.
Reported gas chromatography (GC) analytical composition data of hemp seed oil (variety Fedora-19) from Leizer, et al., (2000) includes significant portions of polyunsaturated fatty acids such as linoleic acid, oleic acid, stearic acid eichosanoic acids and palmitic acid, with more than 80% of the content being unsaturated fatty acids. Other trace compounds reported include Vitamin E (tocopherols), β-sitosterol, and terpenes (e.g. myrcene and caryophyllene) and salicylates.
Given this information, hemp seed oil products should not contain significant amounts of cannabinoids. The presence of cannabinoids in hemp seed oil is considered to arise from either a contamination or adulteration, rather than to be naturally occurring.
Cannabidiol is a cannabinoid compound which occurs naturally in Cannabis sativa plants. The pharmacology of cannabidiol is complex and has been well characterised in in vitro environments.
Some cannabinoid compounds work by binding to the cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2) receptors in the brain. Cannabidiol does not activate CB1 and CB2 receptors directly. However, it has effects on many other 'signalling' systems and can be considered a 'multi-target' drug. Some of the effects of cannabidiol may be attributed to inhibition of the inactivation of endocannabinoids, such as anandamide. Other effects may be related to the chemical properties of the compound as opposed to pharmacodynamic effects. For example, it is thought that the presence of two hydroxyl groups enables cannabidiol to have an anti-oxidant action.
There is evidence that cannabidiol affects serotonin receptors (5HT1A), adenosine uptake, nuclear receptors of the peroxisome proliferator-activated receptors (PPAR) family and other pharmacological targets. The pharmacological targets of cannabidiol include receptors, ion channels, enzymes and cellular uptake processes.
There are reports that cannabidiol possesses anti-proliferative, pro-apoptotic effects and inhibits cancer cell migration, adhesion and invasion. Evidence is also accumulating that there are positive effects of cannabidiol in the vasculature, where cannabidiol may induce vasorelaxation. Information about the pharmacokinetics of the substance in humans is also accumulating. Oral absorption is slow and unpredictable relative to other routes of administration, possibly due to the chemical's poor water solubility. There is significant first pass metabolism where the concentration of ingested cannabidiol is greatly reduced before it is absorbed into systemic circulation, and the overall oral bioavailability may be as low as 6%. Other sources suggest an oral bioavailability of between 12 and 19%. Oromucosal and sublingual delivery, through sprays and lozenges, results in less variability with similar overall bioavailability.
The distribution of cannabidiol is governed by its high lipophilicity and there is rapid distribution to the brain, adipose tissue and other organs. It is also highly protein bound.
Like most cannabinoids, cannabidiol is extensively metabolised in the liver by cytochrome P450 enzymes, predominantly the CYP3A and CYP2C series. The terminal half-life is estimated to be 18-32 hours, although earlier work suggested a much shorter half-life of only 9 hours.
Property | Cannabidiol |
---|---|
CAS number | 13956-29-1 |
IUPAC and/or common and/or other names | 2-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol (IUPAC) |
Chemical structure | ![]() |
Molecular formula | C21H30O2 |
Molecular weight | 314.5 g/mol |
THC is one of at least 113 cannabinoids identified in cannabis and is principal psychoactive constituent of cannabis.
The THC effects result from its partial agonist activity at the cannabinoid receptor CB1 located mainly in the central nervous system, and the CB2 receptor mainly expressed in cells of the immune system. The psychoactive effects of THC are primarily mediated by the activation of cannabinoid receptors, which result in a decrease in the concentration of the second messenger molecule cAMP through inhibition of adenylate cyclase.
Eight (8) public submissions were received before the first closing date in response to an invitation published on 12 April 2018 under regulation 42ZCZK of the Regulations. Two (2) of the submissions were in support of the proposed amendments to the Poisons Standard, one (1) in conditional support with amendments to the proposal, and two (2) that opposed the proposal. Three (3) of the submissions stated their opposition to the proposed amendments to the Poisons Standard but appeared to have misunderstood the applicant's proposal.
The main points provided in support of the amendment were:
The main points provided in opposition of the amendment were:
Point a) with the proposed addition adequately addresses the levels of all other cannabinoids present in a cannabidiol preparation. It would assist clarity to explicitly state that tetrahydrocannabinol may be included in the 'total cannabinoid content' within the levels stipulated under the CANNABIDIOL entry and further, by cross referencing tetrahydrocannabinol to cannabidiol in the Index of the Poisons Standard.
In relation to point b) we suggest deleting 'dealing with unavoidable impurities'.
The main points provided in opposition but appear to have misunderstood the amendment were:
The committee recommends that the current scheduling of cannabidiol 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; (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 included:
Scheduling medicines and poisons
1. Advisory Committee on Medicines Scheduling (ACMS #24)
The delegate's interim decision under regulation 42ZCZN of the Therapeutic Goods Regulations 1990 (the Regulations) is not to amend the Poisons Standard in relation to paracetamol combined with ibuprofen.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate for the decision include:
The delegate considered the following in regards to this interim decision:
The pre-meeting scheduling proposal was published on the TGA website on 12 April 2018 at Consultation: Proposed amendments to the Poisons Standard being referred to the June 2018 meetings of the ACCS, ACMS and Joint ACCS/ACMS.
An application was submitted to amend the Poisons Standard with respect to paracetamol. The application proposed to amend the Schedule 3 and Schedule 4 entries for paracetamol.
The applicant's proposed amendments to the /node/5340 Poisons Standard were:
Note
New text is shown as green, larger font, with a horizontal line above it.
Deleted text is shown as red, smaller font, with a strikethrough.
Schedule 3 - Amend Entry
PARACETAMOL when combined with ibuprofen in a primary pack containing 3050 dosage units or less except when included in Schedule 2.
Schedule 4 - Amend Entry
PARACETAMOL:
The applicant's reasons for the proposal were:
"The combination of two non-opioid analgesics (ibuprofen plus paracetamol) appears to be more effective than the codeine-containing analgesics (CCAs), with a number needed to treat (NNT) of 1.5. This combination would fill any gap left by the unavailability of CCAs over the counter, giving consumers access to a more effective analgesic without requiring a prescription and without the risks of the marked variability in pharmacokinetics or abuse potential that are associated with codeine".
Paracetamol is listed in Schedules 2, 3 and 4 of the Poisons Standard as follows:
Schedule 4
PARACETAMOL:
Schedule 3
PARACETAMOL when combined with ibuprofen in a primary pack containing 30 dosage units or less except when included in Schedule 2.
Schedule 2
PARACETAMOL for therapeutic use:
It is also included under the entry PARACETAMOL in Appendix F with the following statements:
Appendix F, Part 3
PARACETAMOL
Warning Statements: 97 (Adults: Keep to the recommended dose. Don't take this medicine for longer than a few days at a time unless advised to by a doctor) AND/OR 98 (Children and adolescents: Keep to the recommended dose. Do not give this medicine for longer than 48 hours at a time unless advised to by a doctor), 99 (If an overdose is taken or suspected, ring the Poisons Information Centre (Australia 13 11 26; New Zealand 0800 764 766) or go to a hospital straight away even if you feel well because of the risk of delayed, serious liver damage), 100 (Do not take with other products containing paracetamol, unless advised to do so by a doctor or pharmacist).
Ibuprofen is listed in Schedules 2, 3 and 4 of the Poisons Standard as follows:
Schedule 4
IBUPROFEN except:
Schedule 3
IBUPROFEN in divided preparations, each containing 400 mg or less of ibuprofen in a primary pack containing not more than 50 dosage units when labelled:
except when included in or expressly excluded from Schedule 2.
Schedule 2
IBUPROFEN in preparations for oral use when labelled with a recommended daily dose of 1200 mg or less of ibuprofen:
It is also included under the entry IBUPROFEN in Appendix F with the following statements:
Appendix F, Part 3
IBUPROFEN
Warning Statements:
101: Don't use [this product/name of the product]:
If you have a stomach ulcer.
In the last 3 months of pregnancy. [This statement may be omitted in preparations used exclusively for the treatment of dysmenorrhoea.]
If you are allergic to (name of substance) or anti-inflammatory medicines
104: Unless a doctor has told you to, don't use [this product/name of the product]:
For more than a few days at a time.
With other medicines containing (name of substance) or other anti-inflammatory medicines.
If you have asthma.
If you are pregnant. [This statement may be omitted in preparations used exclusively for the treatment of dysmenorrhoea.]
In June 2010, the National Drugs and Poisons Scheduling Committee (NDPSC) considered the scheduling of a combination of ibuprofen and paracetamol and agreed that the current scheduling remained appropriate - Schedule 2 for combinations of up to 200 mg ibuprofen and 500 mg paracetamol in packs of up to 100 dosage units.
In February 2011, the Advisory Committee on Medicines Scheduling (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 and in September 2011, the Poisons Standard was amended to move paracetamol combined with ibuprofen to Schedule 3 in pack sizes of 30 units or less and Schedule 4 (all other products).
In October 2012, 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 March 2015 the ACMS considered a proposal to create a new entry for paracetamol/ibuprofen in Appendix H. The ACMS recommended that the current scheduling of paracetamol when combined with ibuprofen remains appropriate. The ACMS considered that the public health risk from advertising is that it would be seen as first line therapy and that there was little evidence to support the applicant claim that an Appendix H entry would transfer demand from codeine combination analgesics to non-codeine combination analgesics. The delegate agreed with the committee's advice.
In November 2015 the ACMS considered a proposal 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 supported the proposal on the basis of the well-established safety profile, low risk of diversion/abuse/addiction and that the medicine provides an effective option for short term use for moderate pain. Following an interim decision in alignment with committee advice and subsequent consideration of the submissions on the interim decision, the delegate decided to vary the interim decision. In view of the dosage levels of paracetamol and ibuprofen the delegate considered it is more appropriate to limit the Schedule 2 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. The implementation date was 1 June 2016.
In July 2017, the ACMS considered a proposal to amend the Schedule 2 entry of ibuprofen combined with paracetamol to increase the pack size from 12 to 24 dosage units or less. The ACMS recommended that the current scheduling of paracetamol when combined with ibuprofen remains appropriate. The ACMS considered the risk of overdosing on ibuprofen combined with paracetamol, the risk of potential adverse effects if the Schedule 2 pack size increase, the reduction in pharmacist advice and the potential for increased delay in consumers seeking advice. The delegate agreed to the committee's advice and the scheduling remained unchanged.
The Australian Register of Therapeutic Goods (ARTG) has 21 products that contain ibuprofen combined with paracetamol.
In the last 30 years there have been 3 reported cases of adverse events related to ibuprofen combined with paracetamol in the Database of Adverse Events Notification (DAEN) - Medicines: 3 cases with a single suspected medicine and no cases where death was the reported outcome.
The ARTG has 776 products that contain paracetamol.
In the last 30 years there have been 3400 reported cases of adverse events related to paracetamol in the DAEN: 1337 cases with a single suspected medicine and 148 cases where death was the reported outcome.
According to the TGA Ingredient Database, paracetamol is:
The ARTG has 217 products that contain ibuprofen.
In the last 30 years there have been 1335 reported cases of adverse events related to ibuprofen in the DAEN: 889 cases with a single suspected medicine and 42 cases where death was the reported outcome.
According to the TGA Ingredient Database, ibuprofen is:
The paracetamol 500 mg with ibuprofen 200 mg product has been approved as an over-the-counter medicine in many countries including the United Kingdom, Poland, New Zealand, Ukraine, Russia, Saudi Arabia, United Arab Emirates, Kuwait, Bahrain, Oman, Qatar and Yemen. It is Pharmacy Only in the United Kingdom and Poland and it is a 'general sale' medicine in New Zealand in pack sizes up to 20 dose units and 'pharmacy medicine' in pack sizes of up to 100 dose units. In the United Kingdom, the paracetamol 500 mg with ibuprofen 200 mg product is available as a 'pharmacy' medicine in packs of up to 32 tablets.
Paracetamol 500 mg with ibuprofen 150 mg tablets were approved in New Zealand in March 2009.
Paracetamol is a p-aminophenol derivative that has analgesic and antipyretic effects and has weak anti-inflammatory activity. It has been available in Australia since the 1970s and is marketed in many OTC medicine brands. Like ibuprofen it is indicated for the management of mild to moderate pain in conditions such as period pain, headache, muscular pain, dental pain, cold and flu symptoms, back pain, rheumatic pain and sinus pain and to reduce fever.
Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) used as an OTC medicine in the management of mild to moderate pain and inflammation in conditions such as period pain, headache, muscular pain, dental pain, cold and flu symptoms, back pain, arthritic pain and sinus pain. It is also used to reduce fever.
Property | Ibuprofen | Paracetamol |
---|---|---|
CAS name | 15687-27-1 | 103-90-2 |
IUPAC and/or common and/or other names | (RS)-2-(4-(2-Methylpropyl)phenyl)propanoic acid (IUPAC); α-Methyl-4-(isobutyl)phenylacetic acid, (±)-2-(4-Isobutylphenyl)propanoic acid; isobutylphenylpropionic acid. | N-(4-hydroxyphenyl)acetamide (IUPAC); 4'-Hydroxyacetanilide; 4-Acetamidophenol, N-Acetyl-4-aminophenol; N-acetyl-p-aminophenol (APAP); Acetaminophen. |
Chemical structure | ![]() |
![]() |
Molecular formula | C13H18O2 | C8H9NO2 |
Molecular weight | 206.3 g/mol | 151.2 g/mol |
Five (5) public submissions were received before the first closing date in response to an invitation published on 12 April 2018 under regulation 42ZCZK of the Regulations. Three (3) submissions supported and two (2) opposed the proposed amendments.
The main points provided in support of the amendment were:
The main points provided in opposition of the amendment were:
The committee recommends that the current scheduling of paracetamol 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 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:
Scheduling medicines and poisons
2. Joint Advisory Committee on Medicines and Chemicals Scheduling (Joint ACMS-ACCS #19)
The delegate's interim decision under regulation 42ZCZN of the Therapeutic Goods Regulations 1990 (the Regulations) is to amend the current Poisons Standard in relation to 2-butoxyethanol as follows:
Note
New text is shown as green, larger font, with a horizontal line above it.
Schedule 6 - Amend Entry
2-BUTOXYETHANOL and its ACETATES except:
Proposed implementation date: 1 February 2019
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate for the decision include:
The delegate considered the following in regards to this interim decision:
The pre-meeting scheduling proposal was published on the TGA website on 12 April 2018 at Consultation: Proposed amendments to the Poisons Standard being referred to the June 2018 meetings of the ACCS, ACMS and Joint ACCS/ACMS.
An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to amend the Poisons Standard with respect to 2-butoxyethanol. The application proposes to amend the Schedule 6 entry for 2-butoxyethanol in the Poisons Standard to increase the exemption concentration from 10 per cent to 20 per cent.
The application proposed the following amendments to the Poisons Standard:
Note
New text is shown as green, larger font, with a horizontal line above it.
Deleted text is shown as red, smaller font, with a strikethrough.
Schedule 6 - Amend Entry
2-BUTOXYETHANOL and its ACETATES except in preparations containing 1020 per cent or less of such substances.
The applicant's reasons for the proposal were:
2-Butoxyethanol is in Schedule 6, Appendix E and Appendix F of the Poisons Standard as follows:
Schedule 6
2-BUTOXYETHANOL and its ACETATES except in preparations containing 10 per cent or less of such substances.
Appendix E, Part 2
2-BUTOXYETHANOL and its acetates
General 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)), E2 (If in eyes, hold eyelids apart and flush the eye continuously with running water. Continue flushing until advised to stop by a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor, or for at least 15 minutes), S1 (If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water).
Appendix F, Part 3
2-BUTOXYETHANOL and its acetates
Safety Directions: 1 (Avoid contact with eyes), 4 (Avoid contact with skin), 8 (Avoid breathing dust (or) vapour (or) spray mist).
In August 1995, the NDPSC considered a proposal to either exempt 2-butoxyethanol from scheduling or create a separate entry for 2-butoxyethanol in Schedule 5. At this time, 2-butoxyethanol was captured by the generic entry in Schedule 6 for ethylene glycol monoalkyl ethers and their acetates except those containing 10% or less. The committee considered that the acute toxicological profile, particularly in regard to eye and skin irritancy and the ready absorption by the dermal route, indicated that Schedule 6 remained appropriate for this compound and did not support the proposal for rescheduling.
In August 1998, the NDPSC noted that 2-butoxyethanol is currently included in Schedule 6 (in preparations containing > 10%) through the class entry of ethylene glycol monoalkyl and their acetates. However, the committee agreed to create a new separate entry in Schedule 6 for 2-butoxyethanol and its acetates with an exception for preparations containing 10 per cent or less. It was agreed that Schedule 6 was appropriate due to the formulation, handling and use of cleaning products containing 2-butoxyethanol which may give rise to a risk of adverse health effects and that 2-butoxyethanol is considered acutely more toxic that most glycol ethers. The Schedule 6 entry for ethylene glycol monoalkyl ethers and their acetates was also amended at this time to add the exception 'when separately specified in these Schedules'.
In November 2014, the ACCS considered a proposal to create separate entries for a number of ethylene glycol monoalkyl ethers and their acetates, including 2-butoxyethanol. The National Industrial Chemicals Notification and Assessment Scheme (NICNAS) Inventory Multi-tiered Assessment and Prioritisation (IMAP) programme had reviewed a number of chemicals in this class and recommended that separate entries be created for selected chemicals (see Human health tier II assessment for Ethanol, 2-butoxy acetate). The advice from the ACCS was that the toxicity profile of 2-butoxyethanol is consistent with Schedule 6 criteria and that it was adequately captured by the current generic entry for ethylene glycol monoalkyl ethers and their acetates, and the specific 2-butoxyethanol and its acetates Schedule 6 entry. Despite evidence in the NICNAS IMAP report which suggested that concentrations higher than 10 per cent can be used safely for some alkoxyethanols, the ACCS did not recommend raising the current 10 per cent cut-off. The delegate accepted the ACCS advice that the current scheduling of 2-butoxyethanol remained appropriate.
In November 1984, the Poisons Schedule (Standing) Committee (PSC) considered the scheduling of ethylene glycol monoalkyl ethers and their acetates. The PSC noted that ethylene glycol monomethyl- and monoethyl ethers were the most toxic of the series, which demonstrated significant testicular effects, reproductive toxicity, haematological effects and were toxic at inhalation levels at the threshold limit value (TLV). The PSC also noted that other alkyl ethers of demonstrated haematological effects which increased with chain lengths. The PSC therefore decided to include preparations containing 5 per cent or more ethylene glycol monoalkyl ethers and their acetates in Schedule 6.
In February 1985, the PSC reconsidered the November 1984 decision and decided to raise the Schedule 6 ethylene glycol monoalkyl ethers and their acetates exemption cut-off from 5 per cent to 10 per cent.
In November 2013, based on the ACCS advice, the delegate created a separate schedule entry for hexyloxyethanol with a cut-off level to exempt from scheduling for preparations containing 10 per cent of less of hexyloxyethanol. The delegate also decided to create new Appendices E, F and I entries specifically for hexyloxyethanol. The delegate's decision was based on the fact that hexyloxyethanol's toxicity profile was different from the chemical class ethylene glycol monoalkyl ethers.
2-Butoxyethanol is listed on the Australian Inventory of Chemical Substances (AICS). An assessment of its uses in cleaning products was completed in 1996. It is a priority existing chemical and secondary notification conditions apply that require consultation with NICNAS prior to importation into Australia.
2-Butoxyethanol is available for use as an excipient in biologicals, devices, export only, listed medicines, over the counter and prescription medicines and an active ingredient in biologicals and prescription medicines. Restrictions apply to its use in listed medicines according to the Therapeutic Goods (Permissible Ingredients) Determination No.2 of 2018:
Column 1 |
Column 2 Ingredient Name |
Column 3 Purpose of the ingredient in the medicine |
Column 4 Specific requirement(s) applying to the ingredient in Column 2 |
---|---|---|---|
968 | BUTOXYETHANOL | 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 0.1%. |
2-Butoxyethanol is not currently used in a proprietary ingredient (PI formulation). Butoxyethanol is an excipient ingredient in 5 products on the Australian Register of Therapeutic Goods (ARTG). Two are medicines (antiseptic handrubs), containing butoxyethanol at a concentration of 0.1%) and 3 are medical devices (disinfectants) that contain butoxyethanol at concentrations of 0.25-9 % w/w.
Canada completed its assessment of 2-butoxyethanol in 2002 and as a result developed regulations to limit its concentration in a variety of consumer products intended for indoor use: 2-Butoxyethanol Regulations (SOR/2006-347).
2-Butoxyethanol appears in the Appendix A to section 1926.55-1970 American Conference of Governmental Industrial Hygienist's threshold limit values of airborne contaminants of the Electronic Code of Federal Regulations as follows:
Substance | CAS No. | ppm | mg/m3 | Skin Designation |
---|---|---|---|---|
2-Butoxyethanol | 111-76-2 | 50 | 240 | X |
Butoxyethanol in is Annex III to Regulation (EC) No 1223/2009 and is permitted for use as a solvent in oxidative hair dye products at 4% and in non-oxidative hair dye products at 2%. Butoxyethanol is not permitted for use in aerosol dispenser (sprays).
2-Butoxyethanol is very widely used in industrial, trade and domestic cleaning applications. Common formulations which include 2-butoxyethanol are surface cleaners, floor strippers, paints, laundry detergents, rust removers, oven and carpet cleaners. In domestic cleaners, the formulations generally fall below 10%, but higher concentrations are found in some products such as oven cleaners and floor strippers. Some industrial cleaners contain greater than 90% 2-butoxyethanol. 2-Butoxyethanol is also used in medicines and medical devices currently registered on the ARTG.
The source of the below information on the toxicological profile for 2-butoxyethanol is from the Concise International Chemical Assessment (CICAD), Document 10 (pdf,164kb).
Property | 2-Butoxyethanol |
---|---|
CAS number | 111-76-2 |
IUPAC and/or common and/or other names | Ethylene glycol mono-n-butyl ether; butyl cellosolve; 2-butoxy-1-ethanol; 2-n-butoxyethanol; butyl glycol; butyl monoether glycol |
Chemical structure | ![]() |
Molecular formula | C6H14O2 |
Molecular weight | 118.2 g/mol |
Toxicity | Species | 2-butoxyethanol | SPF (2018) Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg) | Rat | 2500 mg/kg | 5 |
Mouse | 1400 mg/kg | 6 | |
Guinea pig | 1200 mg/kg | 6 | |
Rabbit | 320 mg/kg | 6 | |
Acute dermal toxicity LD50 (mg/kg) | Guinea pig | 2000 mg/kg | 5/6 |
Rabbit | 404-502 mg/kg | 6 | |
Acute inhalational toxicity LC50 (mg/m3/4h) | Rat (male, 4h) | 2347 mg/m3 | 6 |
Rat (female, 4h) | 2174 mg/m3 | 6 | |
Mouse (7h) | 3381 mg/m3 | 5 | |
Guinea pig (1h) | 3140 mg/m3 | 5 | |
Skin irritation | Rabbit | Severe irritant | 6 |
Eye irritation | Rabbit | Severe irritant | 6 |
Skin sensitisation | Guinea pig | Non-sensitiser | - |
2-Butoxyethanol is moderately toxic via the oral and dermal routes of exposure and it is of low toxicity via the inhalation route of exposure.
When tested undiluted, 2-butoxyethanol is a severe skin irritant.
When tested undiluted, 2-butoxyethanol is a severe eye irritant (CICAD 1998). A study conducted in 1989 tested a series of 2-butoxyethanol concentrations (10, 20, 30, 70 and 100%) for eye irritation. The results showed that 100% was severely irritating, at 30 and 70%, 2-butoxyethanol was moderately irritating, and at 10 and 20%, 2-butoxyethanol was reported in the study as mildly irritating. However, the Draize scores indicate that at those concentrations, it is practically non-irritating (scores of 1/110 and 2/110 at 10% and 20%, respectively) (Kennah et al., 1989).
2-butoxyethanol is not considered to be a skin sensitiser.
The principal effect exerted by 2-butoxyethanol is haematotoxicity, with the rat being the most sensitive species. The results of in vitro studies indicate that human red blood cells are not as sensitive as rat red blood cells to the haemolytic effects of 2-butoxyethanol and 2-butoxyacetic acid and also that red blood cells are more sensitive to haemolysis by 2-butoxyacetic acid than to haemolysis by 2-butoxyethanol. In rats, adverse effects on the central nervous system, kidneys, and liver occur at higher exposure concentrations than do haemolytic effects.
2-Butoxyethanol is not considered to be genotoxic.
2-Butoxyethanol is not classified with respect to carcinogenicity. No studies are available.
In animals, adverse effects on reproduction and fetal development have not been observed below maternally toxic doses.
Based on limited data from case reports and one laboratory study, similar acute effects, including haemolytic and CNS effects are observed in humans and rats exposed to 2-butoxyethanol, although the effects are observed at much higher exposure concentrations in humans than in rats.
No public submissions were received before the first closing date in response to an invitation published on 12 April 2018 under regulation 42ZCZK of the Regulations.
The committee recommended that the Schedule 6 entry for 2-butoxyethanol in the Poisons Standard be amended as follows:
Note
New text is shown as green, larger font, with a horizontal line above it.
Schedule 6 - Amend Entry
2-BUTOXYETHANOL and its ACETATES except:
The committee also recommended an implementation date of 1 February 2019.
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 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 advice included:
Scheduling medicines and poisons
2. Joint Advisory Committee on Medicines and Chemicals Scheduling (Joint ACMS-ACCS #19)
The delegate's interim decision under regulation 42ZCZN of the Therapeutic Goods Regulations 1990 (the Regulations) is to amend the current Poisons Standard in relation to dimethyl sulfoxide as follows:
Note
New text is shown as green, larger font, with a horizontal line above it.
Schedule 6 - Amend Entry
DIMETHYL SULFOXIDE (excluding dimethyl sulfone):
Schedule 4 - Amend Entry
DIMETHYL SULFOXIDE (excluding dimethyl sulfone) in preparations for therapeutic use except:
Proposed implementation date: 1 February 2019
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate for the decision include:
The delegate considered the following in regards to this interim decision:
The pre-meeting scheduling proposal was published on the TGA website on 12 April 2018 at Consultation: Proposed amendments to the Poisons Standard being referred to the June 2018 meetings of the ACCS, ACMS and Joint ACCS/ACMS.
An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to amend the Poisons Standard with respect to dimethyl sulfoxide (DMSO). The application proposed to amend the Schedule 6 entry for in the Poisons Standard by introducing a new exemption concentration cut-off.
The application proposed the following amendments to the Poisons Standard:
Note
New text is shown as green, larger font, with a horizontal line above it.
Deleted text is shown as red, smaller font, with a strikethrough.
Schedule 6 - Amend Entry
DIMETHYL SULFOXIDE (excluding dimethyl sulfone):
The applicant's reasons for the proposal were:
DMSO is listed in Schedules 4 and 6, and Appendices E and F of the Poisons Standard as follows:
Schedule 4
DIMETHYL SULFOXIDE (excluding dimethyl sulfone) for therapeutic use except:
Schedule 6
DIMETHYL SULFOXIDE (excluding dimethyl sulfone):
Appendix E, Part 2
DIMETHYL SULFOXIDE
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)), G3 (If swallowed, do NOT induce vomiting), E1 (If in eyes wash out immediately with water), S1 (If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water)
Appendix F, Part 3
DIMETHYL SULFOXIDE | Warning Statement | Safety Direction |
---|---|---|
|
27 (Not for therapeutic use) | 1 (Avoid contact with eyes), 4 (Avoid contact with skin), 5 (Wear protective gloves when mixing or using), 8 (Avoid breathing dust (or) vapour (or) spray mist) |
|
49 (WARNING - Do not mix with other medication except on veterinarian's advice) | 1 (Avoid contact with eyes), 4 (Avoid contact with skin), 5 (Wear protective gloves when mixing or using), 8 (Avoid breathing dust (or) vapour (or) spray mist) |
Index
DIMETHYL SULFOXIDE
cross reference: COPPER SALICYLATE, METHYL SALICYLATE
Schedule 6
Schedule 4
Appendix E, Part 2
Appendix F, Part 3
DMSO has a long and thorough scheduling history dating back to 1965, whereby all uses have been considered. DMSO was first listed in Schedule 6 (Poison) of the Poisons Standard in 1965 based on toxicological concerns including potentially causing eye lens opacities. This entry included the warning statement in the label 'avoid contact with the skin and avoid breathing its vapour'. It was subsequently listed in Schedule 4 (Prescription Only Medicine) for therapeutic use based on concerns to regulate high-dose human therapeutic use (including clinical trials) for a variety of arthritic conditions. However, DMSO was only to be used with approval of the Commonwealth Director-General of Health.
During the 1980s - 1990s, the Schedule 6 entry was amended to enable some dermally applied veterinary products to escape Schedule 4 controls. The principal concern of DMSO and the reasons for scheduling was to alert those applying the medications to the known propensity for DMSO to markedly enhance the skin penetration of other substances and its capacity to render other organs permeable to drugs and chemicals. This could lead to an enhanced therapeutic response via more extensive absorption of any active therapeutic substances in the preparations. Due to this property, any DMSO-containing formulation should be treated as a new drug. It was also for this reason that the Schedule 6 amendments specified that it only applies when there no other therapeutically active substance in the formulation, or it is a specific formulation that has been assessed as suitable for a Schedule 6 listing. There were also reports of DMSO being abused or prescribed illegally. The Schedule 6 listing also provides for an Appendix F Warning Statement relating to the potential for enhanced skin absorption of other active substances.
DMSO is permitted for use as an excipient in biologicals, devices, listed medicines and prescription medicines; and as an active ingredient in biologicals and prescription medicines. Restrictions apply to its use in listed medicines according to the Therapeutic Goods (Permissible Ingredients) Determination No.2 of 2018 as follows:
Column 1 |
Column 2 Ingredient Name |
Column 3 Purpose of the ingredient in the medicine |
Column 4 Specific requirement(s) applying to the ingredient in Column 2 |
---|---|---|---|
1829 | DIMETHYL SULFOXIDE | E |
Permitted for use only in combination with other permitted ingredients as a flavour. If used in a flavour the total flavour concentration in a medicine must be no more than 5%. |
There are 33 products (31 biologicals and 2 medical devices) on the Australian Register of Therapeutic Goods (ARTG) that contain DMSO at concentrations up to 27%.
DMSO (methane, sulfinylbis-) is listed on the Australian Inventory of Chemical Substances (AICS) and a Human Health Tier II Assessment for Methane, sulfinylbis- has been completed by NICNAS.
Agricultural and veterinary chemicals containing DMSO are listed on the APVMA's PubCRIS. Currently, DMSO is present in some agricultural chemicals at concentrations of up to 515 g/L, and in veterinary chemical preparations of up to 900 mg/g.
DMSO has been considered by the European Chemicals Agency (ECHA) as part of the REACH program.
One orphan designation has been granted by the European Commission for DMSO for the treatment of severe closed traumatic brain injury.
DMSO is a prescription medicine in the US and can be used in concentrations up to 50% in medicines for human use. In animals, DMSO is approved for use only in horses and dogs.
There are 9 prescription medicines that contain DMSO as an active ingredient in Canada, only 3 of which (1 human medicine and 2 veterinary medicines) are currently marketed. Concentrations of DMSO used in the medicines range from 50% (human medicines) to 90% (veterinary medicines).
Property | Dimethyl sulfoxide |
---|---|
CAS number | 67-68-5 |
IUPAC and/or common and/or other names | Dimethyl sulfoxide (IUPAC); sulfinylbismethane (CAS) |
Chemical structure | ![]() |
Molecular formula | C2H6OS |
Molecular weight | 78.1 g/mol |
Toxicity | Species | Dimethyl sulfoxide | SPF (2018) Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg) | Rat | 28300 mg/kg | - |
Acute dermal toxicity LD50 (mg/kg) | Rat | 40000 mg/kg | - |
Acute inhalational toxicity LC50 (mg/m3/4h) | Rat (4h) | >5330 mg/m3 | - |
Skin irritation | Rabbit | Slight skin irritant when applied undiluted | 6 |
Eye irritation | Rabbit | Slight eye irritant when instilled undiluted | 6 |
Skin sensitisation | Mouse (LLNA) | Non-sensitiser | - |
DMSO has low acute oral, dermal and inhalational toxicity.
When applied undiluted (>66%), DMSO is a skin irritant.
When applied in diluted form (<66%), DMSO is a slight skin irritant.
Dermal exposure to DMSO causes skin reactions, erythema and pruritus, which are seen immediately after contact with the undiluted substance. Solutions of 70% are generally well tolerated in humans without symptoms. The skin reaction to the undiluted substance is considered to be the result of the exothermic reaction (heat releasing) process of DMSO when mixed with water. DMSO, being very hygroscopic readily draws water from the atmosphere (and surrounding dermal or ocular tissues).
In a controlled study, 1 g of gel containing 80% DMSO was applied to the skin of 78 human subjects daily for 2 weeks. In addition to the skin reactions noted above, sedation developed in 52%, headaches in 42%, sleepiness in 18% and nausea in 32% of subjects. Moreover, there were no changes noted in the eyes of the subjects.
When instilled undiluted (>66%), DMSO is an eye irritant.
When instilled in diluted form (<66%), DMSO is a slight eye irritant.
DMSO is not considered to be a skin sensitiser.
The main effects of very high doses of DMSO administered to experimental animals by intravenous injection are morphological and functional changes in the liver and kidney. Long-term oral or dermal administration produces only slight toxicity. Hepatotoxicity and nephrotoxicity have not been described in humans (MAK, 1992).
DMSO is not considered to be genotoxic.
Based on the limited data available, DMSO is not expected to be carcinogenic.
Based on the available data, DMSO is not considered to have reproductive or developmental toxicity.
Observations in humans after repeated dermal exposure indicate that DMSO can cause skin dryness or cracking due to its defatting (dissolving dermal lipids) and drying characteristics. Exposure to undiluted (>66%) preparations of DMSO are associated with eye and skin irritation. There are no other critical health effects expected from exposure to diluted preparations of the chemical.
No public submissions were received before the first closing date in response to an invitation published on 12 April 2018 under regulation 42ZCZK of the Regulations.
The committee recommended that the current Schedule 6 entry for dimethyl sulfoxide be amended as follows:
Note
New text is shown as green, larger font, with a horizontal line above it.
Schedule 6 - Amend Entry
DIMETHYL SULFOXIDE (excluding dimethyl sulfone):
The committee also recommended that the current Schedule 4 entry for dimethyl sulfoxide be amended to align this entry with the requirements of the Therapeutic Goods (Permissible Ingredients) Determination No. 1 of 2018, which specifies that in listed medicines, dimethyl sulfoxide is permitted for use only in combination with other permitted ingredients as a flavour and if used in a flavour, the total flavour concentration in a medicine must be no more than 5%. The amendments suggested for the Schedule 4 dimethyl sulfoxide entry are as follows:
Schedule 4 - Current Entry
DIMETHYL SULFOXIDE (excluding dimethyl sulfone) in preparations for therapeutic use except:
The committee also recommended an implementation date of 1 February 2019.
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 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:
Scheduling medicines and poisons
2. Joint Advisory Committee on Medicines and Chemicals Scheduling (Joint ACMS-ACCS #19)
The delegate's interim decision under regulation 42ZCZN of the Therapeutic Goods Regulations 1990 (the Regulations) is to amend the current Poisons Standard in relation to aliphatic allyl esters as follows:
Note
New text is shown as green, larger font, with a horizontal line above it.
Schedule 7 - Amend Entry
ALLYL ALCOHOL except
Schedule 6 - New Entry
ALLYL ESTERS in preparations containing 0.1 per cent or less of free allyl alcohol by weight of allyl ester except in preparations containing 5 per cent or less of allyl esters with 0.1 per cent or less of free allyl alcohol by weight of allyl esters.
Proposed implementation date: 1 February 2019
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate for the decision include:
The delegate considered the following in regards to this interim decision:
The pre-meeting scheduling proposal was published on the TGA website on 12 April 2018 at Consultation: Proposed amendments to the Poisons Standard being referred to the June 2018 meetings of the ACCS, ACMS and Joint ACCS/ACMS.
An application was submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS), under its Inventory Multi-tiered Assessment and Prioritisation (IMAP) program to amend the Poisons Standard with respect to aliphatic allyl esters. The application proposed to amend the Schedule 7 entry for allyl alcohol and create a new Schedule 6 entry for allyl esters.
The application proposed the following amendments to the Poisons Standard:
Note
New text is shown as green, larger font, with a horizontal line above it.
Schedule 7 - Amend Entry
ALLYL ALCOHOL (including its derivatives) except
Schedule 6 - New Entry
ALLYL ESTERS containing less than 0.1 per cent allyl alcohol by weight of allyl ester except in preparations containing 5 per cent or less of allyl esters and containing less than 0.1 per cent allyl alcohol by weight of allyl esters.
The applicant's reasons for the proposal were:
Aliphatic allyl esters are not specifically scheduled in the Poisons Standard but are captured by the Schedule 7 and Appendix J entries for allyl alcohol as derivatives, as follows:
Schedule 7
ALLYL ALCOHOL.
Appendix J, Part 2
ALLYL ALCOHOL
Conditions for availability and use: 1 (Not to be available except to authorised or licensed persons).
Aliphatic allyl esters are not currently specifically scheduled and have not been previously considered for scheduling. Therefore a scheduling history is not available.
Allyl alcohol was placed in Schedule 7 between 1972 and 1980. In February 1989, the Drugs and Poisons Schedule Committee (DPSC) considered the toxicology of allyl alcohol as part of the review of Schedule 7 substances. The committee noted the toxicological profile of allyl alcohol as a severely toxic substance with an LD50 (oral, rat) of 64 mg/kg, LD50 (oral mice) 85 mg/kg, and LC50 (inhalation rat) of 391 mg/m3. Allyl alcohol was assessed as a severe dermal irritant in rabbits as well as a severe eye irritant sometimes leading to opacity. In sub-chronic studies in rats, rabbits, guinea pigs and dogs the liver and kidneys were seen as the target organs, but the effects seen were considered mild and reversible. Furthermore, allyl alcohol was considered to be mutagenic. In view of the severe acute toxic potential in humans, the good penetration by all routes of exposure and the lack of animal data, the committee recommended that allyl alcohol should remain in Schedule 7. Appendix J would be reviewed (no agricultural uses permitted) following information from industry if allyl alcohol has an industrial use.
In November 1989, the DPSC noted that no reply had been received from industry regarding industrial uses of allyl alcohol. Nevertheless, the committee decided that the Appendix J entry for allyl alcohol should be amended to include restrictions 3 (Should be available to authorised or licensed persons), 5 (Should be available for approved research purposes) and 7(Should be available for industrial and manufacturing purposes).
Aliphatic allyl esters CAS 1797-74-6, 2835-39-4, 4728-82-9, 68132-80-9 and 7493-72-3 are not included in the Therapeutic Goods (Permissible Ingredients) Determination No.2 of 2018 and do not appear to be included in any products on the Australian Register of Therapeutic Goods (ARTG).
Aliphatic allyl ester CAS 2705-87-5 (under the name 'ALLYL CYCLOHEXANEPROPIONATE') is included in the Therapeutic Goods (Permissible Ingredients) Determination No.2 of 2018 as follows:
Column 1 |
Column 2 Ingredient Name |
Column 3 Purpose of the ingredient in the medicine |
Column 4 Specific requirements(s) applying to the ingredient in Column 2 |
---|---|---|---|
441 | ALLYL CYCLOHEXANEPROPIONATE | E |
Permitted for use only in combination with other permitted ingredients as a flavour or a fragrance. If used in a flavour the total flavour concentration in a medicine must be no more than 5%. If used in a fragrance the total fragrance concentration in a medicine must be no more 1%. |
Allyl cyclohexanepropionate is permitted for use as an excipient in biologicals, listed medicine and prescription medicines; and as an active ingredient in biologicals and prescription medicines.
Allyl cyclohexanepropionate is in 158 products (Medicine and Other Therapeutic Good) on the ARTG.
Allyl cyclohexanepropionate is used in 10 proprietary ingredient (PI) formulations.
Aliphatic allyl ester CAS 123-68-2 (under the name 'ALLYL HEXANOATE') is included in the Therapeutic Goods (Permissible Ingredients) Determination No.2 of 2018 as follows:
Column 1 |
Column 2 Ingredient Name |
Column 3 Purpose of the ingredient in the medicine |
Column 4 Specific requirements(s) applying to the ingredient in Column 2 |
---|---|---|---|
445 | ALLYL HEXANOATE | E |
Permitted for use only in combination with other permitted ingredients as a flavour or a fragrance. If used in a flavour the total flavour concentration in a medicine must be no more than 5%. If used in a fragrance the total fragrance concentration in a medicine must be no more 1%. |
Allyl hexanoate is permitted for use as an excipient in biologicals, devices, listed medicine and prescription medicines; and as an active ingredient in biologicals and prescription medicines.
Allyl hexanoate is in 420 products (Medicine and Other Therapeutic Good) on the ARTG.
Allyl hexanoate is used in 10 PI formulations.
Aliphatic allyl ester CAS 142-19-8 (under the names 'ALLYL HEPTANOATE' and 'ALLYL HEPTYLATE') is included in the Therapeutic Goods (Permissible Ingredients) Determination No.2 of 2018 as follows:
Column 1 |
Column 2 Ingredient Name |
Column 3 Purpose of the ingredient in the medicine |
Column 4 Specific requirements(s) applying to the ingredient in Column 2 |
---|---|---|---|
443 | ALLYL HEPTANOATE | E |
Permitted for use only in combination with other permitted ingredients as a flavour or a fragrance. If used in a flavour the total flavour concentration in a medicine must be no more than 5%. If used in a fragrance the total fragrance concentration in a medicine must be no more 1%. |
444 | ALLYL HEPTYLATE | E |
Permitted for use only in combination with other permitted ingredients as a flavour. If used in a flavour the total flavour concentration in a medicine must be no more than 5%. |
Allyl heptanoate is permitted for use as an excipient in biologicals, devices, listed and prescription medicines, and as an active ingredient in biologicals and prescription medicines. Allyl heptylate is permitted for use as an excipient in listed medicines.
Allyl heptanoate is in 100 products (Medicine and Other Therapeutic Good) on the ARTG; and allyl heptylate is not in any products on the ARTG.
Allyl heptanoate is used in 10 PI formulations; and allyl heptylate is used in 2 PI formulations.
Aliphatic allyl ester CAS 4230-97-1 (under the name 'ALLYL CAPRYLATE') is included in the Therapeutic Goods (Permissible Ingredients) Determination No.2 of 2018 as follows:
Column 1 |
Column 2 Ingredient Name |
Column 3 Purpose of the ingredient in the medicine |
Column 4 Specific requirements(s) applying to the ingredient in Column 2 |
---|---|---|---|
440 | ALLYL CAPRYLATE | E |
Permitted for use only in combination with other permitted ingredients as a flavour. If used in a flavour the total flavour concentration in a medicine must be no more than 5%. |
Allyl caprylate is permitted for use as an excipient in biologicals, devices, listed medicine and prescription medicines; and as an active ingredient in biologicals and prescription medicines.
Allyl caprylate is not in any products on the Australian Register of Therapeutic Goods (ARTG).
Allyl caprylate is used in 2 PI formulations.
Aliphatic allyl esters are listed on the following:
![]() 1797-74-6 allyl phenylacetate; benzeneacetic acid, 2-propenyl ester (CAS); 2-propenyl benzeneacetate |
![]() 2835-39-4 allyl isovalerate; butanoic acid, 3-methyl-, 2-propenyl ester (CAS); 2-propenyl isovalerate |
![]() 4728-82-9 allyl cyclohexaneacetate; cyclohexaneacetic acid, 2-propenyl ester (CAS); acetic acid, cyclohexyl-, allyl ester |
![]() 2705-87-5 allyl cyclohexanepropionate; cyclohexanepropanoic acid, 2-propenyl ester (CAS) |
![]() 123-68-2 allyl hexanoate; hexanoic acid, 2-propenyl ester (CAS); allyl caproate |
![]() 142-19-8 allyl heptanoate; heptanoic acid, 2-propenyl ester (CAS) |
![]() 4230-97-1 allyl octanoate; octanoic acid, 2-propenyl ester (CAS); allyl caprylate |
![]() 68132-80-9 allyl trimethylhexanoate; hexanoic acid, trimethyl-, 2-propenyl ester (CAS) |
![]() 7493-72-3 allyl nonanoate; nonanoic acid, 2-propenyl ester (CAS) |
Toxicity | Species | Allyl Esters | SPF (2015) Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg) | Rat | 218-1400 mg/kg (for suitable analogues) | Schedule 6 |
Mouse | ≥500 mg/kg (for suitable analogues) | ||
Guinea pig | 280-444 mg/kg (for suitable analogues) | ||
Acute dermal toxicity LD50 (mg/kg) | Rabbit | 300-1600 mg/kg (for suitable analogues) | Schedule 6 |
Acute inhalational toxicity LC50 (mg/m3/4h) | N/A | No data available. | N/A |
Skin irritation | Rabbit | Suitable analogue chemicals slightly to moderately irritating to the skin when applied undiluted. | Schedule 5 |
Human | Skin irritation in humans assessed by patch testing. | ||
Eye irritation | Rabbit | Slightly irritating (allyl hexanoate and allyl cyclohexanepropionate). | Schedule 5 |
Skin sensitisation (Guinea pig maximisation test and human case reports) |
Guinea pig | Not sensitising (allyl heptanoate) and moderately sensitising (allyl cyclohexanepropionate). | Schedule 5 |
Human | Suitable analogue chemicals were not skin sensitisers. |
Toxicity | Species | Allyl Esters | SPF (2018) Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg) | Rat | 64-105 mg/kg | Schedule 6 |
Mouse | 85-96 mg/kg | ||
Rabbit | 52-72 mg/kg | ||
Acute dermal toxicity LD50 (mg/kg) | Rabbit | 45 and 89 mg/kg | Schedule 7 |
Acute inhalational toxicity LC50 (mg/m3/4h) | Rat | >240 mg/m3 and >530 mg/m3 | Schedule 7 |
Skin irritation | Rabbit | Slightly irritating to the skin when applied undiluted. | Schedule 7 (human) |
Human | Intensely irritating to the skin. | ||
Eye irritation | Rabbit | Irritating undiluted. | Schedule 7 |
Human | Irritating at 5 ppm (11.9 mg/m3) as vapour and corneal necrosis and temporary blindness at 25 ppm (59.4 mg/m3). | ||
Skin sensitisation (Guinea pig maximisation test and human case reports) |
Guinea pig | Not sensitising. | N/A |
Human |
Allyl esters are considered to have moderate to high acute oral and dermal toxicity in animals. No data are available for acute inhalation toxicity.
Allyl alcohol is reported to have very high acute oral, dermal and inhalation toxicity in animals. The chemical is extremely toxic to humans.
Allyl cyclohexanepropionate was not an irritant in a patch test on 129 human volunteers at concentrations up to 2 %. The chemical (0.3 mL) was applied (occlusively) to the back of the volunteers for 24 hours and responses were assessed up to 5 days following exposure. The chemical caused less irritation compared with the other allyl esters tested (allyl hexanoate, allyl cyclohexyloxyacetate, allyl phenoxyacetate). In another 24-hour patch test, allyl cyclohexanepropionate (20 µg) was positive in 8 out of 10 volunteers, and allyl heptanoate was positive in 9 out of 10 volunteers. The concentrations were not reported. Although these chemicals were reported to be acute irritants, the data were not considered to be relevant for classification.
Allyl phenylacetate showed mixed results in two 48-hour closed patch tests on human subjects, when tested up to 12 % in petrolatum. No irritation reactions were reported initially, but were observed when retested. When tested at 6 %, it was a significant irritant in a majority of human subjects.
Contact with the liquid causes delayed-onset skin irritation and burns. Additionally, skin absorption leads to deep pain which may be due to muscle spasm.
The chemicals overall are not expected to have skin sensitisation potential. However, allyl cyclohexanepropionate was reported as a moderate skin sensitiser in guinea pigs.
Limited human data have shown that the chemicals are not skin sensitisers in human volunteers.
Allyl alcohol is not expected to have skin sensitisation potential based on data in a guinea pig maximisation study. No allergic responses were reported in humans.
The effects observed in the repeated dose studies suggest that the liver, stomach and hematopoietic system in rats and mice are the primary sites affected following treatment with allyl esters. The mechanism of hepatotoxicity of allyl esters is linked to its rapid hydrolysis in the liver to the metabolites allyl alcohol and acrolein. Many studies on allyl alcohol and acrolein have showed liver damage, often localised to the periportal region. Short chain allyl esters which are not fragrance ingredients (e.g. allyl acetate) have reported effects at doses above 12 mg/kg/day in rats. Other longer chain allyl esters in the group have effect levels above 84 mg/kg/day. No data are available for repeated dermal and repeated inhalation exposure.
Allyl alcohol is considered to cause serious damage to health from repeated oral exposure. The effects observed in the repeat dose oral studies indicate that the liver and forestomach in rats and mice are the primary target sites, with mice being less sensitive to toxicity than rats. Forestomach effects may be due to primary irritation. Hepatotoxicity was evident at ≥25 mg/kg/day in rats and is stated to be due to biotransformation to acrolein. A sex difference in hepatotoxicity in rats was reported to be correlated with the greater alcohol dehydrogenase activity in female rats than in male rats. In a sub-chronic toxicity study, the no observed adverse effect level (NOAEL) in rats was 3 mg/kg based on histopathological effects seen at 6 mg/kg/day. The NOAEL in mice was 6 mg/kg/day based on forestomach squamous epithelial hyperplasia seen at 12 mg/kg/day.
Allyl esters and allyl alcohol are not considered to be genotoxic.
Results from a two-year carcinogenicity study suggested that allyl isovalerate caused increased incidence of haematopoietic system neoplasms (mononuclear cell leukaemia in male rats and malignant lymphomas in female mice). However, in the absence of more comprehensive information and based on the results for allyl alcohol, allyl esters cannot be considered possible human carcinogens.
Based on the available data for the chemical and its metabolite acrolein, the chemical does not have carcinogenic potential.
Based on the data available, allyl esters and allyl alcohol are not likely to be reproductive or developmental toxicants.
Two of these chemicals (CAS Nos. 123-68-2 and 2705-87-5) have reported domestic uses in Australia. The chemicals in this group are also reported to be used in cosmetics and domestic products, particularly perfumery, overseas. The general public could be exposed through the skin when using cosmetic and domestic products containing the chemicals.
At present, as derivatives, the chemicals fall within the scope of the listing of 'ALLYL ALCOHOL' in Schedule 7 of the SUSMP, and it is probable that perfumery imported from the EU or elsewhere is not compliant with this scheduling entry. Therefore, it is recommended that allyl esters are exempted from the Schedule 7 entry, considering the acute toxicity values are consistent with inclusion in Schedule 6. A concentration cut-off (5 %) for allyl esters is recommended. At this concentration, the product LD50 based on allyl ester content would be close to or greater than 5000 mg/kg. This proposed cut-off is also consistent with the maximum concentration reported in fragrance products (not intended for direct human contact, such as air fresheners) as stated in the NICNAS IMAP report. In addition, to maintain alignment with EU restrictions, it is also recommended that a concentration cut-off for allyl alcohol in allyl esters be included.
This requires consequential changes to scheduling of allyl alcohol to exclude the derivatives, allyl esters, meeting a purity criterion consistent with the EU.
While creation of a general exception for allyl esters could impact on the shorter chain allyl esters which have greater local effects, they do not have any reported cosmetic or domestic uses.
One (1) public submission was received before the first closing date in response to an invitation published on 12 April 2018 under regulation 42ZCZK of the Regulations. The submission supported the proposal with amendments.
The main points in provided in conditional support of the amendment were:
The public submission will be made available on the TGA website at Public submissions on scheduling matters.
The committee recommended that the current Schedule 7 entry for allyl alcohol be amended as follows:
Note
New text is shown as green, larger font, with a horizontal line above it.
Schedule 7 – Amend Entry
ALLYL ALCOHOL except
The committee also recommended that a new Schedule 6 entry for allyl esters be created as follows:
Schedule 6 – New Entry
ALLYL ESTERS in preparations containing 0.1 per cent or less of free allyl alcohol by weight of allyl ester except in preparations containing 5 per cent or less of allyl esters with 0.1 per cent or less of free allyl alcohol by weight of allyl esters.
The committee also recommended an implementation date of 1 February 2019.
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 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 advice included
Scheduling medicines and poisons
2. Joint Advisory Committee on Medicines and Chemicals Scheduling (Joint ACMS-ACCS #19)
The delegate's interim decision under regulation 42ZCZN of the Therapeutic Goods Regulations 1990 (the Regulations) is to amend the current Poisons Standard in relation to astodrimer sodium as follows:
Note
New text is shown as green, larger font, with a horizontal line above it.
Schedule 3 – New Entry
ASTODRIMER SODIUM except in a condom lubricant.
Appendix F, Part 1 – New Entries
109 | See your healthcare provider if you consider that you may be at risk of a Sexually Transmitted Infection (STI). |
110 | See your healthcare provider if your symptoms persist or recur, or your condition worsens, as these symptoms may be indicative another infection, including a Sexually Transmitted Infection (STI). |
111 | See your healthcare provider if you are pregnant or plan to become pregnant, or you are breastfeeding or plan to breastfeed; you should seek advice of your healthcare provider before using this product. |
Appendix F, Part 3 – New Entry
ASTODRIMER SODIUM
Warning statements: 63 (See a doctor if you are pregnant or diabetic), 64 (See a doctor if not better after 7 days), 69 (If symptoms recur within two weeks of completing the course, consult a doctor), 75 (Do not use for more than 7 days unless a doctor has told you to), 109, 110, 111.
Appendix H – New Entry
ASTODRIMER SODIUM for the treatment and relief of bacterial vaginosis (BV)
Proposed date of effect of the proposed amendment: 1 February 2019
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate for the interim decision include:
The delegate considered the following in regards to this interim decision:
The pre-meeting scheduling proposal was published on the TGA website on 12 April 2018 at Consultation: Proposed amendments to the Poisons Standard being referred to the June 2018 meetings of the ACCS, ACMS and Joint ACCS/ACMS.
A delegate of the Secretary of the Department of Health proposed an amendment to the Poisons Standard by creating a new Schedule 4 entry for astodrimer sodium.
The proposed amendments to the Poisons Standard that were referred to the Joint ACMS-ACCS #19 for advice are reflected below:
Note
New text is shown as green, larger font, with a horizontal line above it.
Schedule 4 – New Entry
ASTODRIMER SODIUM except when used as a condom lubricant.
The reasons for the proposal were:
Astodrimer sodium is not scheduled in the Poisons Standard and has not been previously considered for scheduling. Therefore, a scheduling history is not available.
The Australian Register of Therapeutic Goods (ARTG) has two products that contain astodrimer sodium (one condom lubricant and one vaginal gel). The sponsor successfully argued, based on the mechanism of action, that the vaginal gel is a medical device. The vaginal gel was approved on 24 October 2017, and is a Class IIA medical device.
Astodrimer sodium is not in the Therapeutic Goods (Permissible Ingredients) Determination No.2 of 2018.
In the last 2 years there have been no reported cases of adverse events related to condoms containing astodrimer sodium in the Database of Adverse Events Notification (DAEN) - Devices.
According to the TGA Ingredient Database, astodrimer sodium is:
The product in a gel formulation indicated for management of BV and sexually transmitted disease prevention, was not available for sale in any countries at the end of 2017. According to information on the sponsor's website, the vaginal gel product has been granted regulatory approval in the European Union for the treatment and symptomatic relief of BV. It is being considered for regulatory approval in the United States of America and other jurisdictions. The condom product, coated in a lubricant containing 0.5% astodrimer sodium, is currently available for purchase in Australia and Canada.
Property | Astodrimer sodium |
---|---|
CAS number | 676271-69-5 |
IUPAC and/or common and/or other names |
Astodrimer sodium (INN, USAN); 2, 6-Bis-{(1-napthalenyl-3,6-disulfonic acid)-oxyacetamido}-2,6-bis-2,6-bis-2,6-bis-(2,6-diamino-hexanoylamino)-2,6-diamino-hexanoic acid (diphenylmethyl)-amide, polysodium salt; Tetrahexacontasodium N2,N6-bis{N2,N6-bis[N2,N6-bis(N2,N6-bis{N2,N6-bis[(3,6-disulfonatonaphthalen-1-yloxy)acetyl]-l-lysyl}-l-lysyl)-l-lysyl]-l-lysyl}-N1-(diphenylmethyl)-l-lysinamide; SPL7013 |
Chemical structure | ![]() |
Molecular formula | C583H577N63Na64O287S64 |
Molecular weight | 16581.57 Da |
Astodrimer sodium is being investigated for its potential to prevent sexual transmission of genital herpes (HSV-2), human immunodeficiency virus (HIV) and other sexually transmitted infections (STIs) including human papillomavirus (HPV), the causative agent of cervical cancer.
Astodrimer sodium is a polyanionic, polysulfonate compound that blocks the formation and disrupts pre-formed bacterial biofilms, which are important in the pathogenesis of BV.
The polyanionic surface of the highly-branched dendrimer molecule attaches to targets on viruses, thus blocking viral attachment and/or adsorption to cells to prevent infection. In standard in vitro assays, astodrimer sodium had antiviral activity against HIV-1, HSV-2 and HPV strains. Reduced efficacy was evident in the presence of biological fluids. Astodrimer sodium may have some antiviral activity in the cervicovaginal region but it is expected to have minimal antiviral activity in semen during use, and resistance may develop with prolonged use. In mouse and guinea pig models of genital herpes and in a macaque HIV model, astodrimer sodium prevented vaginal viral transmission in some animals at doses/concentrations exceeding those expected with the condom lubricant formulation. Astodrimer sodium gel had no impact on the vaginal or rectal flora of the southern pig-tailed monkey.
The dermal bioavailability of drug-related material in rats was 1.5% following vaginal dosing with the astodrimer sodium gel.
The no-observed-adverse-effect-level (NOAEL) and maximum non-lethal dose was 25 mg/kg intravenous (IV) in rats and rabbits. Following IV dosing, similar effects were seen in rats and rabbits with deaths, clinical signs of decreased activity and evidence of haemorrhages seen at necropsy (red discolouration of the kidneys, stomach and heart). All of these effects may be attributed to thromboembolic events. No adverse effects were seen in rats given high oral doses (≤1600 mg/kg). No adverse effects were seen in single dose toxicity studies in rats or rabbits following vaginal dosing of 5% astodrimer sodium gel.
Repeat-dose toxicity studies of up to 3 months duration were performed in mice, 6 months in rats, 2 weeks in rabbits and 39 weeks in dogs using the vaginal route. Toxicity via the rectal, oral and IV routes was also examined in rats. Only limited observations were included in the IV and oral studies.
Findings in the vaginal and rectal studies were largely restricted to local reactions at the site of application. Findings associated with a gel formulation of astodrimer sodium included anal and vaginal inflammatory reactions and reductions in anal and vaginal pH (to ˜4.5). Astodrimer sodium-associated findings included ovarian abscesses in mice (a no observable effect level (NOEL) was not established) and vaginal irritation, oedema, erosion/ulcer and/or haemorrhage in rabbits and dogs. A NOEL was not established in rabbits, while there was no evidence of vaginal irritation in dogs at concentrations ≤3% gel. Species differences noted in local effects of vaginal dosing with the gel was attributed to differences in vaginal structure.
Systemic effects following repeated vaginal dosing were only seen in rabbits – thrombosis in the vagina with thrombi evident in multiple organs of animals that died prematurely. These systemic effects are likely a result of severe local (vaginal) irritation and damage. Rabbits are generally more sensitive to vaginal irritants than human subjects. The NOEL for systemic effects in rabbits was 1% astodrimer sodium gel (2.9 mg/kg/day) suggesting thrombosis may not be seen in human subjects.
Astodrimer sodium is considered to have a low genotoxic potential. No treatment-related increase in tumour incidence was observed in mice or rats in 2-year vaginal carcinogenicity studies at very high doses.
No adverse effects on female fertility, embryofetal development or pre/postnatal development were evident in rats following vaginal dosing. In the rabbit embryofetal development study there was an increased incidence of abortions and early delivery with the 1% astodrimer sodium gel. These effects were considered to be secondary to maternotoxicity (vaginal irritation and thrombosis) rather than a direct drug-related effect.
There was no evidence of delayed contact hypersensitivity in a standard assay in guinea-pigs using 4% astodrimer sodium in the induction phase (3 × oh occluded dermal applications) and challenging with 2% astodrimer sodium 14 days after induction. No gross indications of penile irritation were seen in male dogs following exposure to 3% astodrimer sodium gel.
One (1) public submission was received before the first closing date in response to an invitation published on 12 April 2018 under regulation 42ZCZK of the Regulations. The submission opposed the proposal.
The main points provided in opposition of the amendment were:
The committee recommended that new Schedule 3 and Appendix F entries be created for astodrimer sodium as follows:
Note
New text is shown as green, larger font, with a horizontal line above it.
Schedule 3 – New Entry
ASTODRIMER SODIUM except in a condom lubricant.
Appendix F – New Entry
ASTODRIMER SODIUM
Warning statements: 63 (See a doctor if you are pregnant or diabetic), 64 (See a doctor if not better after 7 days), 69 (If symptoms recur within two weeks of completing the course, consult a doctor), 75 (Do not use for more than 7 days unless a doctor has told you to).
The committee also recommended an implementation date of 1 February 2019.
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 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: