Scheduling medicines and poisons
The delegates of the Secretary to the Department of Health hereby give notice of delegates' final decisions for amending the Poisons Standard (commonly referred to as the Standard for the Uniform Scheduling of Medicines and Poisons - SUSMP) under subsections 42ZCZS/42ZCZX of the Therapeutic Goods Regulations 1990 (the Regulations). This notice also provides the reasons for each decision and the date of effect (implementation date) of the decision.
The delegates' final decisions and reasons relate to:
On 4 August 2016 and 22 September 2016, under subsection 42ZCZK of the Therapeutic Goods Regulations 1990 (the Regulations), the delegate published a pre-meeting public notice on the TGA website which specified the proposed amendments to the current Poisons Standard and invited public comment.
The pre-meeting consultation periods were each open for public comment for 20 business days and closed on 1 September 2016 and 20 October 2016.
In accordance with subsection 42ZCZL of the Regulations redacted versions of public submissions received in response this invitation were published on 2 February 2017 on the TGA website.
November 2016 ACCS#18, ACMS#19 and Joint ACCS-ACMS#14.
On 2 February 2017, in accordance with subsection 42ZCZN of the Regulations, the delegate made an interim decision on an application and under subsection 42ZCZP of the Regulations, the interim decision and the reasons for the decision was published on TGA website. Further submissions were also invited from the applicants and parties who made valid pre-meeting submissions. The inivitation to make submissions was open for 10 business days and closed on 16 February 2017.
Redacted versions of public submissions will be published at Public submissions on scheduling matters on or after the date of this notice.
In accordance with subsection 42ZCZR of the Regulations, if a delegate makes an interim decision on an application, the delegate may make a final decision either, confirming, varying or setting aside the interim decision, but only after considering any valid submissions received in response to the interim decisions.
According to subsections 42ZCZT/42ZCZU of the Regulations a delegate may decide not to refer a scheduling proposal to an expert advisory committee for advice and instead may make a delegate-only decision. When deciding not to refer a matter to a committee, the delegate considers the scheduling guidelines as set out in the Scheduling Policy Framework for Chemicals and Medicines (SPF, 2015), available at SPF, February 2015.
The amendments to the Schedules, Appendices or other parts of the Poisons Standard are published electronically on the Federal Register of Legislation (FRL) as amendments to the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) prior to the date of effect (implementation date) of the final decisions. Further information, including links to the Poisons Standard on FRL, is available at SUSMP.
Scheduling medicines and poisons
The following final decisions have an implementation date of 1 February 2018 unless otherwise specified.
Substance | Final decision |
---|---|
Pegbovigrastim |
Appendix B - New Entry PEGBOVIGRASTIM Part 1 - Reasons for entry Part 2 - Area of use Implementation date: 1 June 2017. |
3-nitro-p-hydroxyethylaminophenol Also known as: 4-[(2-Hydroxyethyl)amino]-3-nitrophenol |
Schedule 6 - New Entry 3-NITRO-p-HYDROXYETHYLAMINOPHENOL except:
Appendix E, Part 2 - New Entry 3-NITRO-p-HYDROXYETHYLAMINOPHENOL Standard statement: E1 (if in eyes wash out immediately with water). Appendix F, Part 3 - New Entry 3-NITRO-p-HYDROXYETHYLAMINOPHENOL Warning statements: 28 ((over) (repeated) exposure may cause sensitisation). Index - New Entry 3-NITRO-p-HYDROXYETHYLAMINOPHENOL Schedule 6 |
Hydroxyethyl-3,4-methylenedioxyaniline |
Schedule 6 - New Entry HYDROXYETHYL-3,4-METHYLENEDIOXYANILINE (including its salts) except in oxidative hair dye preparations containing 1.5 per cent or less of hydroxyethyl-3,4-methylenedioxyaniline after mixing under oxidative conditions when the immediate container and primary pack are labelled with the following statements: KEEP OUT OF REACH OF CHILDREN, and WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use. This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye, and Written in letters not less than 1.5 mm in height. Appendix E, Part 2 - New Entry HYDROXYETHYL-3,4-METHYLENEDIOXYANILINE Standard statements: 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 - New Entry HYDROXYETHYL-3,4-METHYLENEDIOXYANILINE Warning statements: 28 ((over) (repeated) exposure may cause sensitisation). |
1,3-Bis(2,4-diaminophenoxy)propane tetrahydrochloride |
Schedule 6 - New entry 1,3-BIS(2,4-DIAMINOPHENOXY)PROPANE (including its salts) except when in hair dye preparations containing 1.2 per cent or less of 1,3-bis(2,4-diaminophenoxy)propane after mixing when the immediate container and primary pack are labelled with the following statements: KEEP OUT OF REACH OF CHILDREN, and WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use. This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye, and Written in letters not less than 1.5 mm in height. Appendix E, Part 2 - New Entry 1,3-BIS(2,4-DIAMINOPHENOXY)PROPANE Standard statements: 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 - New Entry 1,3-BIS(2,4-DIAMINOPHENOXY)PROPANE Warning statements: 28 ((over) (repeated) exposure may cause sensitisation), 79 (Will irritate eyes). Index - New entry 1,3-BIS(2,4-DIAMINOPHENOXY)PROPANE Schedule 6 |
2,2'-[(4-Amino-3-nitrophenyl)imino]bisethanol and its monohydrochloride |
Schedule 6 - New Entry 2,2'-[(4-AMINO-3-NITROPHENYL)IMINO]BISETHANOL (including its salts) except:
Appendix E, Part 2 - New Entry 2,2'-[(4-AMINO-3-NITROPHENYL)IMINO]BISETHANOL Standard statements: E1 (if in eyes wash out immediately with water). Appendix F, Part 3 - New Entry 2,2'-[(4-AMINO-3-NITROPHENYL)IMINO]BISETHANOL Warning statements: 28 ((over) (repeated) exposure may cause sensitisation). Index - New Entry 2,2'-[(4-AMINO-3-NITROPHENYL)IMINO]BISETHANOL Schedule 6 HC RED 13 |
2-[(4-Amino-2-methyl-5-nitrophenyl)amino]-ethanol Also known as: HC Violet 1 |
Schedule 6 - New Entry HC VIOLET 1 (2-[(4-amino-2-methyl-5-nitrophenyl)amino]-ethanol except:
Appendix E, Part 2 - New Entry HC VIOLET 1 Standard statements: E1 (if in eyes wash out immediately with water). Appendix F, Part 3 - New Entry HC VIOLET 1 Warning statements: 28 ((over) (repeated) exposure may cause sensitisation). Index - New Entry HC VIOLET 1 Schedule 6 |
Abamectin |
Schedule 5 - Amend Entry ABAMECTIN:
Implementation date: 1 June 2017. |
1-Deoxy-1-(methylamino)-D-glucitol-N-coco acyl derivatives |
Schedule 6 - New Entry 1-DEOXY-1-(METHYLAMINO)-D-GLUCITOL N-COCO ACYL DERIVATIVES except:
Appendix E, Part 2 - New Entry 1-DEOXY-1-(METHYLAMINO)-D-GLUCITOL N-COCO ACYL DERIVATIVES Standard statement: E1 (if in eyes wash out immediately with water). Appendix F, Part 3 - New Entry 1-DEOXY-1-(METHYLAMINO)-D-GLUCITOL N-COCO ACYL DERIVATIVES Warning statement: 79 (Will irritate eyes). Index - New Entry 1-DEOXY-1-(METHYLAMINO)-D-GLUCITOL N-COCO ACYL DERIVATIVES Schedule 6 |
o-Toluidine and o-Anisidine |
Schedule 10 - New Entries o-TOLUIDINE (excluding derivatives) in preparations for skin colouration (including tattooing) and dyeing of hair, eyelashes or eyebrows except in preparations containing 0.001 per cent or less of o‑toluidine. o-ANISIDINE (excluding derivatives) in preparations for skin colouration (including tattooing) and dyeing of hair, eyelashes or eyebrows except in preparations containing 0.001 per cent or less of o‑anisidine. |
Scheduling medicines and poisons
An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to consider whether pegbovigrastim requires scheduling.
This was a general application. The applicant's proposed amendments to the Poisons Standard are as follows:
Appendix B - New Entry
PEGBOVIGRASTIM.
The applicant's reasons for the request are:
Pegbovigrastim is not currently scheduled and has not been previously considered for scheduling; therefore a scheduling history is not available.
Three related substances (filgrastim, pegfilgrastim and lenograstim) have been considered for scheduling, and are currently in Schedule 4 for human therapeutic use.
Products containing pegbovigrastim are registered in New Zealand, USA, Canada, the European Union (EU), Mexico and Brazil. Pegbovigrastim is subject to the following labelling requirements internationally:
The pegylated bovine granulocyte colony stimulating factor (bG-CSF) (Figure 1) is almost identical to the endogenously produced bovine protein. The points of differences are:
The proposed product will contain 15 mg pegbovigrastim/syringe for subcutaneous injection as an aid in the prevention of mastitis in dairy cows, through restoration of immune function in the periparturient period.
Figure 1.1: Amino acid sequence of pegbovigrastim
Note the two di-sulfide bridges at positions 36 to 42 and 64 to 74. At position 133 (F*), threonine in the endogenously produced bG-CSF has been replaced with a novel amino acid, p-acetylphenylalanine glycol.
Property | Pegbovigrastim |
---|---|
Amino acid sequence | MTPLGPARSLP QSFLLKCLEQ VRKIQADGAE LQERLCAAHK LCHPEELMLLRHSLGIPQAP LSSCSSQSLQ LTSCLNQLHG GLFLYQGLLQ ALAGISPELAPTLDTLQLDV TDFATNIWLQ MEDLGAAPAV QPFQGAMPTF TSAFQRRAGGVLVASQLHRF LELAYRGLRY LAEP |
Molecular weight | 40 600 Da |
Empirical formula | C859H1370N236O248S9[C2H4O]n where n = 454 |
CAS number | 1363409-60-2 |
IUPAC and/or common and/or other names | Pegylated bovine Granulocyte Colony Stimulating Factor (PEG bG-CSF) |
SUSMP name | To be advised. 'Pegbovigrastim' or 'Pegylated bovine Granulocyte Colony Stimulating Factor' suggested. |
Product name | Elanco Imrestor |
The following information was extracted from the APVMA Human Health Risk Assessment Technical Report for pegbovigrastim (product name: Elanco Imrestor).
Toxicity | Species | Pegbovigrastim | SPF (2015) Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | No data | No data | No data |
Acute dermal toxicity LD50 (mg/kg bw) | No data | No data | No data |
Acute inhalational toxicity LC50 (mg/m3/4h) | No data | No data | No data |
Skin irritation | Rabbit | Non-irritant | Non-irritant |
Eye irritation | Rabbit | Non-irritant | Non-irritant |
Skin sensitisation | No data | No data | No data |
No pre-meeting submissions were received for pegbovigrastim.
The committee advised that a new Appendix B entry for pegbovigrastim be created in the Poisons Standard as follows:
Appendix B - New Entry
PEGBOVIGRASTIM
Part 1 - Reasons for entry
a (low toxicity)
Part 2 - Area of use
2.1 (For animal use)
The committee also advised an implementation date of 1 June 2017.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the advice comprised the following:
The delegate considered the following in regards to this proposal:
The delegate's interim decision is to create a new Appendix B entry for pegbovigrastim for use in animals due to its low toxicity.
The proposed wording for the schedule entry is as follows:
Appendix B - New Entry
PEGBOVIGRASTIM
Part 1 - Reasons for entry
a (low toxicity)
Part 2 - Area of use
2.1 (For animal use)
The proposed implementation date is 1 June 2017.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.
The reasons for the interim decision are the following:
No submissions were received for pegbovigrastim.
The delegate has confirmed the interim decision and reasons for the decision as no evidence has been received to alter the interim decision. The delegate's final decision is to create a new Appendix B entry for pegbovigrastim for use in animals due to its low toxicity to be implemented on 1 June 2017.
Scheduling medicines and poisons
An application was submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) to create a new Schedule 6 entry for 4-[(2-hydroxyethyl)amino]-3-nitrophenol in hair dye and eyelash/eyebrow colouring products and to determine whether an appropriate exemption cut-off is required.
This was a general application. The applicant's proposed amendments to the Poisons Standard are as follows:
Schedule 6 - New Entry
4-[(2-HYDROXYETHYL)AMINO]-3-NITROPHENOL except when used in hair dye colouring preparations containing 3 per cent or less of 4-[(2-hydroxyethyl)amino]-3-nitrophenol under oxidising conditions (after mixing with hydrogen peroxide), or containing 1.85 per cent or less of 4-[(2-hydroxyethyl)amino]-3-nitrophenol under non-oxidising conditions, and in ready to use preparations when the immediate container and primary pack are labelled with the following statements:
KEEP OUT OF REACH OF CHILDREN; and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use.
written in letters not less than 1.5 mm in height.
Appendix E, Part 2 - New Entry
4-[(2-HYDROXYETHYL)AMINO]-3-NITROPHENOL
Standard statements: E1 (if in eyes wash out immediately with water).
Appendix F, Part 3 - New Entry
4-[(2-HYDROXYETHYL)AMINO]-3-NITROPHENOL
Warning statements: 28 ((over) (repeated) exposure may cause sensitisation).
The applicant's reasons for the request are:
4-[(2-Hydroxyethyl)amino]-3-nitrophenol is not currently scheduled and has not been previously considered for scheduling; therefore, scheduling history is not available.
The chemical is listed on the following:
Property | 4-[(2-Hydroxyethyl)amino]-3-nitrophenol |
---|---|
CAS No. | 65235-31-6 |
Alternative names | Phenol, 4-[(2-Hydroxyethyl)amino]-3-nitro- (CAS); 3-nitro-p-hydroxyethylaminophenol (INCI); 1-hydroxy-3-nitro-4-(ß-hydroxyethyl)-aminobenzene; 3-nitro-4-n-(beta-hydroxyethyl)aminophenol; 4-((2-hydroxyethyl)amino)-3-nitrophenol |
Chemical structure | ![]() |
Molecular formula | C8H10N2O4 |
Molecular weight | 198.2 g/mol |
The following information has been extracted from the NICNAS IMAP Human Health Tier II assessment report for Phenol, 4-[(2-hydroxyethyl)amino]-3-nitro-.1
Toxicity | Species | 4-((2-hydroxyethyl)amino)-3-nitrophenol | SPF (2015) Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Sprague Dawley (SD) rats | >2000 | Schedule 5 |
Acute dermal toxicity LD50 (mg/kg bw) No dermal absorption data is available |
N/A | No data | N/A |
Acute inhalational toxicity LC50 (mg/m3/4h) | N/A | No data | N/A |
Skin irritation | New Zealand White Rabbits | Non-irritant at 4 and 6% | N/A |
Eye irritation | New Zealand White Rabbits | Slight irritant at 4 and 6% | N/A |
Skin sensitisation | CBA/J Mice | Strong sensitiser | Schedule 6 |
4-((2-Hydroxyethyl)amino)-3-nitrophenol is considered to have low acute oral toxicity. The available LD50 of >2000 mg/kg bw supports this conclusion. No data are available for dermal or inhalation toxicity.
Based on the limited data available, 4-((2-hydroxyethyl)amino)-3-nitrophenol is not considered to be a skin irritant. However, it is considered to be a slight eye irritant:
Based on the available data, the chemical is considered to be an extreme skin sensitiser:
Apart from developmental effects, 4-((2-hydroxyethyl)amino)-3-nitrophenol is not considered to cause to adverse health effects following repeated oral exposure (NOAEL 200 mg/kg). No data are available for repeated dermal and inhalation toxicity.
Based on the weight of evidence from the available in vitro and in vivo genotoxicity studies, the chemical is not considered to be genotoxic. All in vivo genotoxicity test were negative.
No animal toxicity data are available on the carcinogenicity of 4-((2-hydroxyethyl)amino)-3-nitrophenol. Based on the available genotoxicity data, it is not considered to be genotoxic carcinogenic.
Limited data are available. The available data indicate that 4-((2-hydroxyethyl)amino)-3-nitrophenol may have potential for developmental toxicity following oral exposure:
4-((2-Hydroxyethyl)amino)-3-nitrophenol is reported to be used in permanent and semi-permanent hair dye preparations in Australia.
One (1) pre-meeting submission was received in support. The main points were that the new schedule entry would be in alignment with international regulators in the EU, ASEAN and NZ.
The committee advised that 4-((2-hydroxyethyl)amino)-3-nitrophenol be entered in Schedule 6 as the INCI name, 3-nitro-p-hydroxyethylaminophenol, in the Poisons Standard as follows:
Schedule 6 - New Entry
3-NITRO-p-HYDROXYETHYLAMINOPHENOL except:
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use. This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye, and
Written in letters not less than 1.5 mm in height; or
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use. This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye, and
Written in letters not less than 1.5 mm in height.
The committee also recommended appendix and index entries be created as follows:
Appendix F, Part 3 - New Entry
3-NITRO-p-HYDROXYETHYLAMINOPHENOL
Warning statements: 28 ((over) (repeated) exposure may cause sensitisation).
Index - New Entry
3-NITRO-p-HYDROXYETHYLAMINOPHENOL
cross reference: 4-[(2-hydroxyethyl)amino]-3-nitrophenol
Schedule 6
Appendix F, Part 3
The committee also advised an implementation date of 1 June 2017.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.
The reasons for the advice comprised the following:
The delegate considered the following in regards to this proposal:
The delegate's interim decision is to create a new Schedule 6 entry for 4-((2-hydroxyethyl)amino)-3-nitrophenol under the INCI name, 3-nitro-p-hydroxyethylaminophenol.
The wording for the schedule, appendix and index entries are as follows:
Schedule 6 - New Entry
3-NITRO-p-HYDROXYETHYLAMINOPHENOL except:
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use. This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye, and
Written in letters not less than 1.5 mm in height; or
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use. This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye, and
Written in letters not less than 1.5 mm in height.
Appendix F, Part 3 - New Entry
3-NITRO-p-HYDROXYETHYLAMINOPHENOL
Warning statements: 28 ((over) (repeated) exposure may cause sensitisation).
Index - New Entry
3-NITRO-p-HYDROXYETHYLAMINOPHENOL
cross reference: 4-[(2-hydroxyethyl)amino]-3-nitrophenol
Schedule 6
Appendix F, Part 3
The proposed implementation date is 1 June 2017.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.
The reasons for the interim decision are the following:
One (1) submission was received which supported the delegate's interim decision with amendments. The main point in support was that the proposed schedule entry would be in alignment with international regulations in the EU. The main points were:
The delegate's final decision is to create new Schedule 6, Appendices E & F and Index entries for 4-((2-hydroxyethyl)amino)-3-nitrophenol under the INCI name, 3-nitro-p-hydroxyethylaminophenol as follows:
Schedule 6 - New Entry
3-NITRO-p-HYDROXYETHYLAMINOPHENOL except:
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use. This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye, and
Written in letters not less than 1.5 mm in height; or
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use. This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye, and
Written in letters not less than 1.5 mm in height.
Appendix E, Part 2 - New Entry
3-NITRO-p-HYDROXYETHYLAMINOPHENOL
Standard statement: E1 (if in eyes wash out immediately with water).
Appendix F, Part 3 - New Entry
3-NITRO-p-HYDROXYETHYLAMINOPHENOL
Warning statements: 28 ((over) (repeated) exposure may cause sensitisation).
Index - New Entry
3-NITRO-p-HYDROXYETHYLAMINOPHENOL
cross reference: 4-[(2-hydroxyethyl)amino]-3-nitrophenol
Schedule 6
Appendix E, Part 2
Appendix F, Part 3
The implementation date has been extended to 1 February 2018.
The delegate confirms that the reasons for the final decision are the same as those provided from the interim decision. Additional reasons for the final decision include:
1 Publicly available on the NICNAS website at: https://www.nicnas.gov.au/chemical-information/imap-assessments/imap-assessment-details?assessment_id=1799
Scheduling medicines and poisons
An application was submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) to create a new Schedule 6 entry for hydroxyethyl-3,4-methylenedioxyaniline and its hydrochloride salt in hair dyes and eyebrow/eyelash colouring products and to determine whether appropriate exemption cut-off and labelling is required.
This was a general application. The applicant's proposed amendments to the Poisons Standard are as follows:
Schedule 6 - New Entry
HYDROXYETHYL-3,4-METHYLENEDIOXYANILINE AND ITS HYDROCHLORIDE except in hair dye preparations containing 1.5 per cent or less of hydroxyethyl-3,4-methylenedioxyaniline or its hydrochloride under oxidising conditions (after mixing with hydrogen peroxide), and when the immediate container and primary pack are labelled with the following statement:
KEEP OUT OF REACH OF CHILDREN; and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals, and when used for eyelash or eyebrow tinting may cause injury to the eye. A preliminary test according to the accompanying directions should be made before use.
written in letters not less than 1.5mm in height.
Appendix E, Part 2 - New Entry
HYDROXYETHYL-3,4-METHYLENEDIOXYANILINE AND ITS HYDROCHLORIDE
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).], E1 (if in eyes wash out immediately with water).
Appendix F, Part 3 - New Entry
HYDROXYETHYL-3,4-METHYLENEDIOXYANILINE AND ITS HYDROCHLORIDE
Warning statements: 28 ((over) (repeated) exposure may cause sensitisation).
The applicant's reasons for the request are:
Hydroxyethyl-3,4-methylenedioxyaniline and its hydrochloride salt are not currently scheduled and have not been previously considered for scheduling; therefore, a scheduling history is not available.
The following restrictions are reported for the chemical. Similar restrictions to those in the European Union (EU) Cosmetics Directive apply to all jurisdictions:
Property | Hydroxyethyl-3,4-methylenedioxyaniline | Hydroxyethyl-3,4-methylenedioxyaniline hydrochloride |
---|---|---|
CAS names | Ethanol, 2-(1,3-benzodioxol-5-ylamino)- | Ethanol, 2-(1,3-benzodioxol-5-ylamino)-, hydrochloride |
CAS numbers | 81329-90-0 | 94158-14-2 |
IUPAC and/or common and/or other names | Hydroxyethyl-3,4-methylenedioxyaniline | Hydroxyethyl-3,4-methylenedioxyaniline HCl (INCI) |
Chemical structure | ![]() |
![]() |
Molecular formula | C9H12ClNO3 | C9H12ClNO3 |
Molecular weight | 217.649 g/mol | 217.6 g/mol |
The following toxicology information was extracted from the NICNAS IMAP Human Health Tier II assessment for Ethanol, 2-(1,3-benzodioxol-5-ylamino)-, hydrochloride2. Further information can also be found in the European Commission Scientific Committee on Consumer Safety (SCCS) report for hydroxyethyl-3,4-methylenedioxyaniline hydrochloride3.
Toxicity | Species | Hydroxyethyl-3,4-methylenedioxyaniline HCl | SPF (2015) Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | 1550 (male); 1650 (female) | Schedule 6 |
Mouse | 850 (female) | ||
Acute dermal toxicity LD50 (mg/kg bw) | N/A | No data | N/A |
Acute inhalational toxicity LC50 (mg/m3/4h) | N/A | No data | N/A |
Skin irritation | Guinea pig | Not irritating at 5% concentration | N/A |
Eye irritation | Guinea pig | Transiently irritating at 2% concentration | N/A |
Skin sensitisation (LLNA) | Mouse | Skin sensitiser (calculated EC3<0.5%) | Schedule 6 |
A short summary of the toxicity, exposure, use, international risk management control of hydroxyethyl-3,4-methylenedioxyaniline HCl are included below. For further information, please see assessment report.
The hydrochloride salt of hydroxyethyl-3,4-methylenedioxyaniline has moderate acute oral toxicity in male and female rats and in female mice. There are no data on acute dermal and inhalation toxicity.
Limited data are available in guinea pigs. Hydroxyethyl-3,4-methylenedioxyaniline HCl at a 5% concentration is not irritating to the skin. Hydroxyethyl-3,4-methylenedioxyaniline HCl at a 2% concentration is transiently irritating to the eyes.
In a local lymph node assay (LLNA) conducted according to the OECD TG 429. Hydroxyethyl-3,4-methylenedioxyaniline HCl, at dilutions of 0.5, 1.5, 5 or 10%, was applied to the ears of female CBA/J mice (5/group) for three consecutive days. Two separate vehicles were used, dimethyl sulfoxide (DMSO) or in a mixture (3:3:1) of water/acetone/olive oil (equal to the maximum solubility). For the DMSO vehicle, the mean stimulation indices (SIs) were dose-dependent at 6.4, 5.0, 8.0 and 12.4 for the 0.5, 1.5, 5 and 10% dilutions, respectively. For the other vehicle (water/acetone/olive oil), the SIs were 4.3, 3.6, 3.3 and 4.4 for the 0.5, 1.5, 5 and 10% dilutions, respectively. The estimated concentration (EC) needed to produce a three-fold increase in lymphocyte proliferation (EC3) was calculated to be <0.5%, indicating strong sensitising potential (SCCS, 2009).
Based on a 90-day study in rats, hydroxyethyl-3,4-methylenedioxyaniline HCl is not expected to cause serious damage to health from repeated oral exposure.
Based on the available data from in vitro and in vivo genotoxicity studies, hydroxyethyl-3,4-methylenedioxyaniline HCl is not considered to be genotoxic.
No data were available for carcinogenicity.
Based on the available data, hydroxyethyl-3,4-methylenedioxyaniline HCl is not expected to have reproductive or developmental toxicity. Foetal effects observed in the animals at high doses are considered secondary to maternal toxicity
One (1) pre-meeting submission was received in support. The main points were that the new schedule entry would be in alignment with international regulators in the EU, ASEAN and NZ.
The committee advised that hydroxyethyl-3,4-methylenedioxyaniline be entered in Schedule 6 in the Poisons Standard, with an exemption cut-off of 1.5% as follows:
Schedule 6-New Entry
HYDROXYETHYL-3,4-METHYLENEDIOXYANILINE (including its salts) except in oxidative hair dye preparations containing 1.5 per cent or less of hydroxyethyl-3,4-methylenedioxyaniline after mixing under oxidative conditions when the immediate container and primary pack are labelled with the following statements:
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use. This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye, and
Written in letters not less than 1.5 mm in height.
The committee also advised that appendix entries be created as follows:
Appendix E, Part 2 - New Entry
HYDROXYETHYL-3,4-METHYLENEDIOXYANILINE
Standard statements: 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 - New Entry
HYDROXYETHYL-3,4-METHYLENEDIOXYANILINE
Warning statements: 28 ((over) (repeated) exposure may cause sensitisation).
The committee recommended an implementation date of 1 June 2017.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance (b) the purpose for which a substance is to be used and the and extent of use; and (c) the toxicity of a substance.
The reasons for the advice comprised the following:
The delegate considered the following in regards to this proposal:
The delegate's interim decision is to create a new Schedule 6 entry for hydroxyethyl-3,4-methylenedioxyaniline, with an exemption cut-off of 1.5 per cent.
The proposed wording for the schedule and appendix entries is as follows:
Schedule 6 - New Entry
HYDROXYETHYL-3,4-METHYLENEDIOXYANILINE (including its salts) except in oxidative hair dye preparations containing 1.5 per cent or less of hydroxyethyl-3,4-methylenedioxyaniline after mixing under oxidative conditions when the immediate container and primary pack are labelled with the following statements:
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use. This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye, and
Written in letters not less than 1.5 mm in height.
Appendix E, Part 2 - New Entry
HYDROXYETHYL-3,4-METHYLENEDIOXYANILINE
Standard statements: 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 - New Entry
HYDROXYETHYL-3,4-METHYLENEDIOXYANILINE
Warning statements: 28 ((over) (repeated) exposure may cause sensitisation).
The proposed implementation date is 1 June 2017.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; and (c) the toxicity of a substance.
The reasons for the interim decision are the following:
One (1) submission was received which supported the delegate's interim decision with amendments. The main point in support was that the proposed schedule entry would be in alignment with international regulations in the EU. The main points were:
The delegate's final decision is to create new Schedule 6 and Appendices E & F entries for hydroxyethyl-3,4-methylenedioxyaniline as follows:
Schedule 6 - New Entry
HYDROXYETHYL-3,4-METHYLENEDIOXYANILINE (including its salts) except in oxidative hair dye preparations containing 1.5 per cent or less of hydroxyethyl-3,4-methylenedioxyaniline after mixing under oxidative conditions when the immediate container and primary pack are labelled with the following statements:
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use. This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye, and
Written in letters not less than 1.5 mm in height.
Appendix E, Part 2 - New Entry
HYDROXYETHYL-3,4-METHYLENEDIOXYANILINE
Standard statements: 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 - New Entry
HYDROXYETHYL-3,4-METHYLENEDIOXYANILINE
Warning statements: 28 ((over) (repeated) exposure may cause sensitisation).
The implementation date has been extended to 1 February 2018.
The delegate confirms that the reasons for the final decision are the same as those provided from the interim decision. Additional reasons for the final decision include:
2 Publicly available on the NICNAS website at: https://www.nicnas.gov.au/chemical-information/imap-assessments/imap-assessment-details?assessment_id=1797
3 Publicly available at: http://ec.europa.eu/health//sites/health/files/scientific_committees/consumer_safety/docs/sccs_o_006.pdf
Scheduling medicines and poisons
An application was submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) to create a new Schedule 6 entry for 1,3-bis(2,4-diaminophenoxy)propane tetrahydrochloride in hair dyes and eyebrow/eyelash colouring products and to determine whether an appropriate exemption cut-off is required.
This was a general application. The applicant's proposed amendments to the Poisons Standard are as follows:
Schedule 6 - New entry
1,3-BIS(2,4-DIAMINOPHENOXY)PROPANE TETRAHYDROCHLORIDE except when used in hair dye colouring products at a concentration of 1.8 per cent or less of 1,3-bis(2,4-diaminophenoxy)propane tetrahydrochloride, or 1.2 per cent or less of 1,3-bis(2,4-diaminophenoxy)propane (the free base), and when the immediate container and primary pack are labelled with the following statements:
KEEP OUT OF REACH OF CHILDREN; and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use.
written in letters not less than 1.5mm in height.
Appendix E, Part 2 - New Entry
1,3-BIS(2,4-DIAMINOPHENOXY)PROPANE TETRAHYDROCHLORIDE
Standard statements: E1 (if in eyes wash out immediately with water).
Appendix F, Part 3 - New Entry
1,3-BIS(2,4-DIAMINOPHENOXY)PROPANE TETRAHYDROCHLORIDE
Warning statements: 28 ((over) (repeated) exposure may cause sensitisation).
The applicant's reasons for the request are:
1,3-Bis(2,4-diaminophenoxy)propane tetrahydrochloride is not currently scheduled and has not been previously considered for scheduling; therefore, scheduling history is not available. There is however, a derivative of 1,3-bis(2,4-diaminophenoxy)propane tetrahydrochloride, 1,3-benzenediamine that is currently listed in the SUSMP in Schedule 10 as follows:
Schedule 10
1,3-BENZENEDIAMINE in preparations for cosmetic use and skin colouration (including tattooing).
The chemical is reported to be used in permanent hair dye preparations in Australia. Currently, there are no restrictions in Australia on using this chemical in cosmetics/hair dyes or eyelash colouring products. In the absence of any regulatory controls, the characterised critical health effects (skin sensitisation) have the potential to pose an unreasonable risk to the public under the uses identified.
The chemical is listed on the following:
Property | 1,3-bis(2,4-diaminophenoxy)propane tetrahydrochloride |
---|---|
CAS No. | 74918-21-1 |
Chemical structure | ![]() |
Molecular formula | C15H24Cl4N4O2 |
Molecular weight | 434.2 g/mol |
Alternative names | 1,3-Bis-(2,4-Daiminophenoxy)propane HCL (INCI); 1,3-Bis(2,4-diaminophenoxy)propane tetrahydrochloride (CAS); 1,3-Benzenediamine, 4,4'-[1,3-propanediylbis(oxy)]bis-, tetrahydrochloride |
The following toxicology information was extracted from the NICNAS IMAP Human Health Tier II assessment4. Further information can also be found in the European Commission Scientific Committee on Consumer Products (SCCP) report5.
Toxicity | Species | 1,3-bis(2,4-diaminophenoxy)propane tetra hydrochloride | SPF (2015) Classification |
---|---|---|---|
Acute oral toxicity median lethal dose (LD50) (mg/kg bodyweight (bw)) | Wistar rat | 3570 | Schedule 5 |
Acute dermal toxicity LD50 (mg/kg bw) | N/A | No data | N/A |
Acute inhalational toxicity LC50 (mg/m3/4h) | N/A | No data | N/A |
Skin irritation | New Zealand White rabbits | Mild skin irritant | Schedule 5 |
Eye irritation | New Zealand White rabbits | Moderate eye irritation | Schedule 5 |
Skin sensitisation (LLNA) | CBA/J mice | The chemical is a moderate skin sensitiser (EC3 value of 14.7%) | Schedule 6 |
1,3-Bis(2,4-diaminophenoxy)propane tetrahydrochloride has low acute toxicity based on results from animal tests following oral exposure. The LD50 in rats is 3570 mg/kg bw.
1,3-Bis(2,4-diaminophenoxy)propane tetrahydrochloride was assessed in a non-guideline acute oral toxicity study in male Wistar rats (10 animals/group). The animals were dosed by oral gavage at 2510, 3160, 3570, 3980 or 5010 mg/kg bw. Animals were observed for 14 days. Mortalities occurred in the groups as follows: 0/10 (2510 mg/kg bw), 2/10 (3160 mg/kg bw), 5/10 (3570 mg/kg bw), 8/10 (3980 mg/kg bw), and 9/10 (5010 mg/kg bw). An LD50 of 3570 mg/kg bw was determined from this study.
1,3-Bis(2,4-diaminophenoxy)propane tetrahydrochloride was reported in a study to cause mild, transient skin irritation in New Zealand White rabbits:
1,3-Bis(2,4-diaminophenoxy)propane tetrahydrochloride was reported to irritate the eyes when tested according to OECD TG 405 (acute eye irritation/corrosion). The average corneal, iridial, conjunctival redness and conjunctival chemosis scores were given as (1/1/3/4). The effects were reversible within 14 days of application.
In a study conducted according to OECD TG 405, 1,3-bis(2,4-diaminophenoxy)propane tetrahydrochloride (approximately 45.2 mg as an undiluted solution) was instilled into the conjunctival sac of one eye each of three New Zealand White rabbits and left for 24 hours. The chemical caused corneal injury including opacity (maximum grade 1 in all animals up to 72 hours after instillation) and epithelial damage (maximum 65% of the corneal surface, 24 hours after instillation). Corneal injury resolved within 72 hours. Iridial irritation (grade 1) was observed in all animals but resolved during the observation period. Conjunctival irritation consisted of redness (up to grade 3), chemosis (up to grade 4) and discharge (up to grade 2) and had completely resolved in one animal within seven days and in the other animals within 14 days. No mortalities or evidence of systemic toxicity were observed. Under the conditions of the study, the test substance was irritating to rabbit eyes.
1,3-Bis(2,4-diaminophenoxy)propane tetrahydrochloride is considered to be a moderate skin sensitiser based on the positive results seen in a single LLNA. The EC3 (estimated concentration required to produce a three-fold increase in lymphocyte proliferation) was 14.7%.
The potential for 1,3-bis(2,4-diaminophenoxy)propane tetrahydrochloride to promote sensitisation was investigated in a study conducted according to OECD TG 429 (skin sensitisation: local lymph node assay). Female CBA/J mice (five animals/group) were topically administered the chemical in solution on the dorsal surface of each ear lobe once daily, for three consecutive days at 5, 25 and 50% (in ethanol/water mixture (7/3, volume/volume)). The rate of radio-labelled thymidine incorporation in the lymph nodes was used to calculate stimulation indices. Even at the highest concentration, no local effects were observed on the skin of the ears. The SI for the different dose groups were 1.2 ± 1.0 (5%), 4.9 ± 1.1 (25%) and 4.3 ± 1.0 (50%), respectively. An EC3 value of 14.7% was calculated. On the basis of this finding, the test chemical is considered to be a skin sensitiser.
In a 90-day oral gavage study in rats, a no observed adverse effect level (NOAEL) of 40 mg/kg bw/day was reported.
Based on the weight of evidence from the available in vitro and in vivo genotoxicity studies, 1,3-bis(2,4-diaminophenoxy)propane tetrahydrochloride is not considered to be genotoxic. All in vivo genotoxicity tests were negative.
Based on the results, a reported NOAEL of 180 mg/kg bw/day was determined for maternal and foetal toxicity.
One (1) pre-meeting submission was received in support. The main points were that the new schedule entry would be in alignment with international regulators in the EU, ASEAN and NZ.
The committee advised that a new Schedule 6 entry for 1,3-bis(2,4-diaminophenoxy)propane tetrahydrochloride be created under the common name, HC Blue 166, with an exemption cut-off of 1.2% in the Poisons Standard as follows:
Schedule 6 - New entry
HC BLUE 16 (including its salts) except when in hair dye preparations containing 1.2 per cent or less of HC Blue 16 when the immediate container and primary pack are labelled with the following statements:
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use. This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye, and
Written in letters not less than 1.5 mm in height.
The committee also advised that appendix and index entries be created as follows:
Appendix E, Part 2 - New Entry
HC BLUE 16
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)), 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 - New Entry
HC BLUE 16
Warning statements: 28 ((over) (repeated) exposure may cause sensitisation), 79 (Will irritate eyes).
Safety directions: 1 (Avoid contact with eyes).
Index - New entry
HC BLUE 16
cross reference: 1,3-bis(2,4-diaminophenoxy)propane tetrahydrochloride
Schedule 6
Appendix E, Part 2
Appendix F, Part 3
The committee recommended an implementation date of 1 June 2017.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the advice comprised the following:
The delegate considered the following in regards to this proposal:
The delegate's interim decision is to create a new Schedule 6 entry for 1,3-bis(2,4-diaminophenoxy)propane tetrahydrochloride under the common name, HC Blue 167, with an exemption cut-off of 1.2 per cent.
The wording for the schedule, appendix and index entries are as follows:
Schedule 6 - New entry
HC BLUE 16 (including its salts) except when in hair dye preparations containing 1.2 per cent or less of HC Blue 16 when the immediate container and primary pack are labelled with the following statements:
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use. This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye, and
Written in letters not less than 1.5 mm in height.
Appendix E, Part 2 - New Entry
HC BLUE 16
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)), 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 - New Entry
HC BLUE 16
Warning statements: 28 ((over) (repeated) exposure may cause sensitisation), 79 (Will irritate eyes).
Safety directions: 1 (Avoid contact with eyes).
Index - New entry
HC BLUE 16
cross reference: 1,3-bis(2,4-diaminophenoxy)propane tetrahydrochloride
Schedule 6
Appendix E, Part 2
Appendix F, Part 3
The proposed implementation date is 1 June 2017.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the interim decision were the following:
One (1) submission was received which supported the delegate's interim decision with amendments. The main point in support was that the proposed schedule entry would be in alignment with international regulations in the EU. The main points were:
The delegate's final decision is to create new Schedule 6, Appendices E & F and Index entries for 1,3-bis(2,4-diaminophenoxy)propane tetrahydrochloride as follows:
Schedule 6 - New entry
1,3-BIS(2,4-DIAMINOPHENOXY)PROPANE (including its salts) except when in hair dye preparations containing 1.2 per cent or less of 1,3-bis(2,4-diaminophenoxy)propane after mixing when the immediate container and primary pack are labelled with the following statements:
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use. This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye, and
Written in letters not less than 1.5 mm in height.
Appendix E, Part 2 - New Entry
1,3-BIS(2,4-DIAMINOPHENOXY)PROPANE
Standard statements: 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 - New Entry
1,3-BIS(2,4-DIAMINOPHENOXY)PROPANE
Warning statements: 28 ((over) (repeated) exposure may cause sensitisation), 79 (Will irritate eyes).
Safety directions: 1 (Avoid contact with eyes).
Index - New entry
1,3-BIS(2,4-DIAMINOPHENOXY)PROPANE
Schedule 6
Appendix E, Part 2
Appendix F, Part 3
The implementation date has been extended to 1 February 2018.
The delegate confirms that the reasons for the final decision are the same as those provided from the interim decision. Additional reasons for the final decision include:
4 Publicly available on the NICNAS website at" https://www.nicnas.gov.au/chemical-information/imap-assessments/imap-assessment-details?assessment_id=1794
5 Publicly available at http://ec.europa.eu/health/ph_risk/committees/04_sccp/docs/sccp_o_105.pdf. This report incorrectly identifies a synonym of 1,3-bis(2,4-diaminophenoxy)propane tetra hydrochloride to be HC Blue 16.
6 The committee recommended that the name of the schedule entry should be the common name, HC BLUE 16 (identified as a synonym of 1,3-bis(2,4-diaminophenoxy)propane tetra hydrochloride in the Scientific Committee on Consumer Products report (2007)). However, a public submission in response to the interim decision has indicated that HC Blue 16 does not refer to 1,3-bis(2,4-diaminophenoxy)propane tetrahydrochloride (CAS No. 74918-21-1) but refers to a different chemical, N,N-dimethyl-3-{[4-(methylamino)-9,10-dioxo-9,10-dihydro-1-anthracenyl] amino}-N-propyl-1-propanaminium bromide (CAS No. 502453-61-4).
7 A public submission in response to the interim decision has indicated that HC Blue 16 does not refer to 1,3-bis(2,4-diaminophenoxy)propane tetrahydrochloride (CAS No. 74918-21-1) but refers to a different chemical, N,N-dimethyl-3-{[4-(methylamino)-9,10-dioxo-9,10-dihydro-1-anthracenyl] amino}-N-propyl-1-propanaminium bromide (CAS No. 502453-61-4).
Scheduling medicines and poisons
An application was submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) to create a new Schedule 6 entry for 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol and its monohydrochloride in hair dyes and eyebrow/eyelash colouring products and to determine whether an appropriate exemption cut-off is required.
This was a general application. The applicant's proposed amendments to the Poisons Standard are as follows:
Schedule 6 - New Entry
2,2'-[(4-AMINO-3-NITROPHENYL)IMINO]BISETHANOL except when used in hair dye preparations containing 1.25 per cent or less of 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol or its monohydrate under oxidative conditions (after mixing with hydrogen peroxide), or 2.5 per cent of 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol or its monohydrate under non-oxidative conditions, and when the immediate container and primary pack are labelled with the following statements:
KEEP OUT OF REACH OF CHILDREN; and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use.
written in letters not less than 1.5mm in height.
Appendix E, Part 2 - New Entry
2,2'-[(4-AMINO-3-NITROPHENYL)IMINO]BISETHANOL AND ITS MONOHYDROCHLORIDE
Standard statements: E1 (if in eyes wash out immediately with water).
Appendix F, Part 3 - New Entry
2,2'-[(4-AMINO-3-NITROPHENYL)IMINO]BISETHANOL AND ITS MONOHYDROCHLORIDE
Warning statements: 28 ((over) (repeated) exposure may cause sensitisation).
The applicant's reasons for the request are:
2,2'-[(4-Amino-3-nitrophenyl)imino]bisethanol and its monohydrochloride (HC Red 13) are not currently scheduled and have not been previously considered for scheduling; therefore, scheduling history is not available.
The salt of 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol is reported to be used in semi-permanent hair dye preparations in Australia. Currently, there are no restrictions in Australia for using these chemicals in cosmetic products.
The use of 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol and its salt as cosmetics in the European Union (EU) is subject to the restrictions described in the EU Cosmetics Regulation 344/2013 (as an amendment to the listing under Annex III of Regulation 1223/2009). 2,2'-[(4-Amino-3-nitrophenyl)imino]bisethanol and its salt may be used as a hair dye substance in ready-for-use preparations of non-oxidising hair dye products at a maximum concentration of 2.5 % (as hydrochloride salt). Additionally, after mixing under oxidative conditions (i.e. with hydrogen peroxide), the maximum concentration applied to hair must not exceed 1.25 % (as hydrochloride salt). The Cosmetics Regulation also mandates label warning statements relating to the sensitisation potential of 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol.
2,2'-[(4-Amino-3-nitrophenyl)imino]bisethanol and its salt are also listed, with the same use restrictions as described above for the EU, as follows:
Property | 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol | 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol monohydrochloride |
---|---|---|
CAS No. | 29705-39-3 | 94158-13-1 |
Alternative names | Ethanol, 2,2'-[(4-amino-3-nitrophenyl)imino]bis- (CAS) | 2,2'-((4-amino-3-nitrophenyl)imino)bisethanol hydrochloride; Ethanol, 2,2'-[(4-amino-3-nitrophenyl)imino]bis-, monohydrochloride (CAS); HC Red 13 (INCI) |
Chemical structure | ![]() |
![]() |
Molecular formula | C10H15N3O4 | C10H16ClN3O4 |
Molecular weight | 241.2 g/mol | 277.7 g/mol |
The following information was extracted from the NICNAS IMAP Human Health Tier II group assessment report for Ethanol, 2,2'-[(4-amino-3-nitrophenyl)imino]bis- and its monohydrochloride8.
The hazards of 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol and its monohydrochloride were assessed together using the toxicological data available. Where data was unavailable for the parent base, the data available for the salt is considered relevant for the hazard assessment due to the structural similarity of the two chemicals. However, the monohydrochloride salt could have different properties from the parent base with respect to local effects.
Toxicity | Species | 2,2'-((4-amino-3-nitrophenyl)imino)bisethanol hydrochloride | SPF (2015) Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | 2120 | Schedule 5 |
Acute dermal toxicity LD50 (mg/kg bw) | N/A | No data | - |
Acute inhalational toxicity LC50 (mg/m3/4h) | N/A | No data | - |
Skin irritation | Rabbit | Limited reliability. Not irritating at low concentrations | - |
Eye irritation | Rabbit | Limited reliability. Not irritating at low concentrations | - |
Skin sensitisation (Local lymph node assay, LLNA) | Mice | Moderate sensitiser | Schedule 6 |
2,2'-((4-Amino-3-nitrophenyl)imino)bisethanol hydrochloride is expected to have low acute toxicity based on results from animal tests following oral exposure. No acute dermal or inhalation toxicity data are available.
The limited available data from experimental animal studies, suggest that 2,2'-((4-amino-3-nitrophenyl)imino)bisethanol hydrochloride, at 2.5%, is not irritating to the skin or eyes. However, it is noted that a concentration of 2.5% is too low for hazard evaluation.
Based on the available data, the chemicals are considered to be moderate skin sensitisers.
The available data suggest that the chemicals have low to moderate repeated dose toxicity based on results from animal tests following repeated oral exposure. Based on the limited data available from animal studies, the chemicals are not expected to have systemic toxicity following repeated dermal exposure. No repeated inhalation toxicity data are available.
Based on the weight of evidence from the available in vitro and in vivo genotoxicity studies, the chemicals are not considered to be genotoxic. Positive results were seen in some in vitro genotoxicity tests, but all in vivo tests were negative.
No carcinogenicity studies are available for the chemicals, except for a dermal study conducted using the salt at low concentrations. The data available do not provide sufficient information to make a conclusion on the carcinogenicity of the chemicals. Based on the available genotoxicity data, the chemicals are not considered to be genotoxic carcinogenic.
Based on the available data, the chemicals are not expected to have reproductive or developmental toxicity.
One (1) pre-meeting submission was received in support. The main points were that the new schedule entry would be in alignment with international regulators in the EU, ASEAN and NZ.
The committee advised that 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol be entered in Schedule 6 under the INCI name, HC Red 139 with exemption cut-off concentrations as follows:
Schedule 6 - New Entry
HC RED 13 (including its salts) except:
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use, and
Written in letters not less than 1.5 mm in height; or
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use. This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye, and
Written in letters not less than 1.5 mm in height.
The committee also that advised that appendix and index entries are created as follow:
Appendix E, Part 2 - New Entry
HC RED 13
Standard statements: E1 (if in eyes wash out immediately with water).
Appendix F, Part 3 - New Entry
HC RED 13
Warning statements: 28 ((over) (repeated) exposure may cause sensitisation).
Index - New Entry
HC RED 13
cross reference: 2,2'-[(4-AMINO-3-NITROPHENYL)IMINO]BISETHANOL
Schedule 6
Appendix E, Part 2
Appendix F, Part 3
The committee recommended an implementation date of 1 June 2017.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (b) the purpose for which a substance is to be used and the and extent of use; and (c) the toxicity of a substance.
The reasons for the advice comprised the following:
Delegate's considerations
The delegate considered the following in regards to this proposal:
The delegate's interim decision is to create a new Schedule 6 entry for 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol under the INCI name, HC Red 1310 with exemption cut-off concentrations for oxidative and non-oxidative hair dye preparations.
The proposed wording for the schedule, appendix and index entries are as follows:
Schedule 6 - New Entry
HC RED 13 (including its salts) except:
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use, and
Written in letters not less than 1.5 mm in height; or
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use. This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye, and
Written in letters not less than 1.5 mm in height.
Appendix E, Part 2 - New Entry
HC RED 13
Standard statements: E1 (if in eyes wash out immediately with water).
Appendix F, Part 3 - New Entry
HC RED 13
Warning statements: 28 ((over) (repeated) exposure may cause sensitisation).
Index - New Entry
HC RED 13
cross reference: 2,2'-[(4-AMINO-3-NITROPHENYL)IMINO]BISETHANOL
Schedule 6
Appendix E, Part 2
Appendix F, Part 3
The proposed implementation date is 1 June 2017.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (b) the purposes for which a substance is to be used and the extent of use of a substance; and (c) the toxicity of a substance.
The reasons for the interim decision are the following:
One (1) submission was received which supported the delegate's interim decision with amendments. The main point in support was that the proposed schedule entry concentration cut-offs would be in alignment with international regulations in the EU. The main points were:
The delegate's final decision is to create a new Schedule 6 entry for 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol with exemption cut-off concentrations for oxidative and non-oxidative hair dye preparations and new Appendices E & F and Index entries as follows:
Schedule 6 - New Entry
2,2'-[(4-AMINO-3-NITROPHENYL)IMINO]BISETHANOL (including its salts) except:
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use, and
Written in letters not less than 1.5 mm in height; or
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use. This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye, and
Written in letters not less than 1.5 mm in height.
Appendix E, Part 2 - New Entry
2,2'-[(4-AMINO-3-NITROPHENYL)IMINO]BISETHANOL
Standard statements: E1 (if in eyes wash out immediately with water).
Appendix F, Part 3 - New Entry
2,2'-[(4-AMINO-3-NITROPHENYL)IMINO]BISETHANOL
Warning statements: 28 ((over) (repeated) exposure may cause sensitisation).
Index - New Entry
2,2'-[(4-AMINO-3-NITROPHENYL)IMINO]BISETHANOL
cross reference: HC RED 13
Schedule 6
Appendix E, Part 2
Appendix F, Part 3
HC RED 13
cross reference: 2,2'-[(4-AMINO-3-NITROPHENYL)IMINO]BISETHANOL
The implementation date has been extended to 1 February 2018.
The delegate confirms that the reasons for the final decision are the same as those provided from the interim decision. Additional reasons for the final decision include:
8 Publicly available from the NICNAS website at: https://www.nicnas.gov.au/chemical-information/imap-assessments/imap-group-assessment-report?assessment_id=1796
9 A public submission received in response to the interim decision indicated that HC Red 13 is the INCI name for the hydrochloride salt of 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol specifically. The phrase 'including its salts' in the schedule entry is therefore redundant.
10 A public submission received in response to the interim decision indicated that HC Red 13 is the INCI name for the hydrochloride salt of 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol specifically. The phrase 'including its salts' in the schedule entry is therefore redundant.
Scheduling medicines and poisons
An application was submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) to create a new Schedule 6 entry for 2-[(4-amino-2-methyl-5-nitrophenyl)amino]-ethanol in hair dyes and eyebrow/eyelash colouring products and to determine whether an appropriate exemption cut-off is required.
This was a general application. The applicant's proposed amendments to the Poisons Standard are as follows:
Schedule 6 - New Entry
2-[(4-AMINO-2-METHYL-5-NITROPHENYL)AMINO]ETHANOL except when used in hair dye preparations containing 0.25 per cent or less of 2-[(4-amino-2-methyl-5-nitrophenyl)amino]ethanol under oxidative conditions (after mixing with hydrogen peroxide), or 0.28 per cent or less of 2-[(4-amino-2-methyl-5-nitrophenyl)amino]ethanol under non-oxidative conditions, and when the immediate container and primary pack are labelled with the following statements:
KEEP OUT OF REACH OF CHILDREN; and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use.
written in letters not less than 1.5mm in height
Appendix E, Part 2 - New Entry
2-[(4-AMINO-2-METHYL-5-NITROPHENYL)AMINO]ETHANOL
Standard statements: E1 (if in eyes wash out immediately with water).
Appendix F, Part 3 - New Entry
2-[(4-AMINO-2-METHYL-5-NITROPHENYL)AMINO]ETHANOL
Warning statements: 28 ((over) (repeated) exposure may cause sensitisation).
The applicant's reasons for the request are:
2-[(4-Amino-2-methyl-5-nitrophenyl) amino]-ethanol (HC Violet 1) is not currently scheduled and has not been previously considered for scheduling; therefore, a scheduling history is not available.
2-[(4-Amino-2-methyl-5-nitrophenyl) amino]-ethanol is reported to be used in semi-permanent hair dye preparations in Australia (NICNAS, 2007). Currently, there are no restrictions in Australia on using this chemical in cosmetic products. In the absence of any regulatory controls, the characterised critical health effects (skin sensitisation) have the potential to pose an unreasonable risk to public under the uses identified.
The European Union (EU), New Zealand and the Association of South East Asian Nations (ASEAN) have restricted the use of the chemical in cosmetics: '(a) the maximum authorised concentration in the finished cosmetic products as hair dye substances in non-oxidative hair dye products is 0.28 %; and (b) after mixing with hydrogen peroxide under oxidative conditions the maximum concentration applied to hair must not exceed 0.25 %'. The EU Cosmetics Regulation No. 344/2013 Annex III, Part 1 also mandates label warning statements relating to the sensitisation potential of the chemical at lower concentrations.
Property | 2-[(4-amino-2-methyl-5-nitrophenyl)amino]-ethanol |
---|---|
CAS No. | 82576-75-8 |
Alternative names | HC Violet 1(INCI); Imexine FAA; 1-amino-3-methyl-4-(2-hydroxyethyl)amino-6-nitrobenzene; ethanol, 2-[(4-amino-2-methyl-5-nitrophenyl)amino]- (CAS) |
Chemical structure | ![]() |
Molecular formula | C9H13N3O3 |
Molecular weight | 211.2 g/mol |
The following information was extracted from the NICNAS IMAP Human Health Tier II assessment report for Ethanol, 2-[(4-amino-2-methyl-5-nitrophenyl)amino]-.11
Toxicity | Species | HC Violet 1 | SPF (2015) Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | >2000 | Schedule 5 |
Acute dermal toxicity LD50 (mg/kg bw) | N/A | No data | N/A |
Acute inhalational toxicity LC50 (mg/m3/4h) | N/A | No data | N/A |
Skin irritation | Rabbit | Slight irritant | N/A |
Eye irritation | Rabbit | Slight irritant | N/A |
Skin sensitisation (local lymph node assay, LLNA) | Mouse | Strong sensitiser | Schedule 6 |
Based on the available data, the chemical is considered to be a strong skin sensitiser:
Based on the available data, 2-[(4-amino-2-methyl-5-nitrophenyl) amino]-ethanol is not expected to cause serious damage to health from repeated oral exposure. No information was available for repeated dose toxicity by dermal and inhalation routes.
Based on the negative results observed in several in vitro and in vivo genotoxicity studies, 2-[(4-amino-2-methyl-5-nitrophenyl) amino]-ethanol is not expected to be genotoxic.
No data are available for carcinogenicity. However, the lack of genotoxicity in vivo and negative bacterial reverse mutation assay results indicates that the likelihood of carcinogenic effects is low.
Based on the limited available data, 2-[(4-amino-2-methyl-5-nitrophenyl) amino]-ethanol is not expected to have reproductive and developmental toxicity.
One (1) pre-meeting submission was received in support. The main points were that the new schedule entry would be in alignment with international regulators in the EU, ASEAN and NZ.
The committee advised that a new Schedule 6 entry for 2-[(4-amino-2-methyl-5-nitrophenyl)amino]-ethanol be created under the INCI name of HC Violet 1 with exemption cut-off concentrations as follows:
Schedule 6 - New Entry
HC VIOLET 1 except:
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use, and
Written in letters not less than 1.5 mm in height; or
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use. This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye, and
Written in letters not less than 1.5 mm in height.
The committee also advised that appendix and index entries be created as follows:
Appendix E, Part 2 - New Entry
HC VIOLET 1
Standard statements: E1 (if in eyes wash out immediately with water).
Appendix F, Part 3 - New Entry
HC VIOLET 1
Warning statements: 28 ((over) (repeated) exposure may cause sensitisation).
Index - New Entry
HC VIOLET 1
cross reference: 2-[(4-AMINO-2-METHYL-5-NITROPHENYL)AMINO]-ETHANOL
Schedule 6
Appendix E, Part 2
Appendix F, Part 3
The committee recommended an implementation date of 1 June 2017.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (b) the purpose for which a substance is to be used and the and extent of use; and (c) the toxicity of a substance.
The reasons for the advice comprised the following:
Delegate's considerations
The delegate considered the following in regards to this proposal:
The delegate's interim decision is to create a new Schedule 6 entry for 2-[(4-amino-2-methyl-5-nitrophenyl)amino]-ethanol under the INCI name of HC Violet 1 with exemption cut-off concentrations.
The proposed wording for the schedule, appendix and index entries are as follows:
Schedule 6 - New Entry
HC VIOLET 1 except:
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use, and
Written in letters not less than 1.5 mm in height; or
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use. This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye, and
Written in letters not less than 1.5 mm in height.
Appendix E, Part 2 - New Entry
HC VIOLET 1
Standard statements: E1 (if in eyes wash out immediately with water).
Appendix F, Part 3 - New Entry
HC VIOLET 1
Warning statements: 28 ((over) (repeated) exposure may cause sensitisation).
Index - New Entry
HC VIOLET 1
cross reference: 2-[(4-AMINO-2-METHYL-5-NITROPHENYL)AMINO]-ETHANOL
Schedule 6
Appendix E, Part 2
Appendix F, Part 3
The proposed implementation date is 1 June 2017.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (b) the purposes for which a substance is to be used and the extent of use of a substance; and (c) the toxicity of a substance.
The reasons for the interim decision are the following:
One (1) submission was received which supported the delegate's interim decision with amendments. The main point in support was that the proposed schedule entry concentration cut-offs would be in alignment with international regulations in the EU. The main points were:
The delegate's final decision is to create a new Schedule 6 entry for 2-[(4-amino-2-methyl-5-nitrophenyl)amino]-ethanol under the INCI name of HC Violet 1 with exemption cut-off concentrations; and to create new Appendices E & F and Index entries as follows:
Schedule 6 - New Entry
HC VIOLET 1 (2-[(4-amino-2-methyl-5-nitrophenyl)amino]-ethanol except:
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use, and
Written in letters not less than 1.5 mm in height; or
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use. This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye, and
Written in letters not less than 1.5 mm in height.
Appendix E, Part 2 - New Entry
HC VIOLET 1
Standard statements: E1 (if in eyes wash out immediately with water).
Appendix F, Part 3 - New Entry
HC VIOLET 1
Warning statements: 28 ((over) (repeated) exposure may cause sensitisation).
Index - New Entry
HC VIOLET 1
cross reference: 2-[(4-AMINO-2-METHYL-5-NITROPHENYL)AMINO]-ETHANOL
Schedule 6
Appendix E, Part 2
Appendix F, Part 3
The implementation date has been extended to 1 February 2018.
The delegate confirms that the reasons for the final decision are the same as those provided from the interim decision. Additional reasons for the final decision include:
11 Publicly available on the NICNAS website at: https://www.nicnas.gov.au/chemical-information/imap-assessments/imap-assessment-details?assessment_id=1795#cas-A_82576-75-8
Scheduling medicines and poisons
An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to amend the Schedule 5 entry for abamectin to accommodate preparations containing 0.05 per cent or less of abamectin in a gel formulation.
This was a general application. The applicant's proposed amendments to the Poisons Standard are as follows:
Schedule 5 - Amend Entry
ABAMECTIN:
The applicant's reasons for the request are:
Abamectin is currently listed in Schedules 7, 6 and 5 and is also included in Appendix J, Part 2 as follows:
Schedule 7
ABAMECTIN except when included in Schedule 5 or 6.
Schedule 6
ABAMECTIN:
Schedule 5
ABAMECTIN in preparations, for internal use for the treatment of animals, containing 1 per cent or less of abamectin.
Appendix J, Part 2 - ABAMECTIN
Condition: 1 (not to be available except to authorised or licensed persons).
Abamectin has been considered several times by the committee, both on its own, and in combination with other substances.
Abamectin was first considered in November 1984 as avermectin. In November 1984, the Poisons Schedule (Standing) Committee (PSC) considered scheduling of a 1 per cent avermectin B1 (a synonym for abamectin) injection to be used as an antiparasitic agent in animals. Based on toxicity, PSC decided to include this substance in Schedule 7. However, the PSC also noted the intent to only market a sealed container product for use with automated injection equipment and agreed to a Schedule 6 cut-off for such preparations when included in 10 mL or less injections.
In May 1992, the Drugs and Poisons Schedule Standing Committee (NDPSC) agreed to a request to change the name of avermectin B1 in the schedule entries to abamectin, noting that this was the name approved by the Standards Association of Australia (now called Standards Australia).
In August 1994, the NDPSC decided to include emulsifiable concentrate formulations containing abamectin at 18 g/L or less in Schedule 6.
In August 1995, NDPSC agreed to include ≤ 1 per cent abamectin for animal internal use in Schedule 5.
In June 2008, the NDPSC decided also to include slow-release plastic matrix ear tags for livestock use containing 1 g or less of abamectin in Schedule 6.
In October 2009, the NDPSC considered whether preparations for pesticidal use containing 0.0015 per cent or less of abamectin were consistent with the Schedule 5 criteria. It was agreed that although low concentration of abamectin were likely to be less hazardous, because insufficient data had been provided to allay the concern regarding the high acute oral, dermal and inhalation toxicity of abamectin, it was decided that the existing scheduling was appropriate.
Following recommendation of the March 2013 Advisory Committee on Chemicals Scheduling (ACCS), Schedule 6 cut-off for abamectin in preparations for pesticidal use has been increased from 2 per cent to 4 per cent or less of abamectin, except when included in Schedule 5, or in slow-release plastic matrix ear tags for livestock use containing 1 g or less of abamectin.
As an AgVet chemical, abamectin is subject to labelling requirements according to the First Aid Instruction and Safety Directions (FAISD) Handbook.
Property | Abamectin | |
---|---|---|
CAS No. | Abamectin: 71751-41-2 containing 65195-55-3 (abamectin B1a) and 65195-56-4 (abamectin B1b). |
|
Chemical structure | ![]() Abamectin B1a R = CH2CH3 Abamectin B1b R = CH3 |
|
Alternative names | Abamectin: mixture of ≥80% abamectin B1a & <20% abamectin B1b Abamectin B1a: (10E,14E,16E)-(1R,4S,5'S,6S,6'R,8R,12S,13S,20R,21R,24S)-6'-[(S)-sec-butyl]-21,24-dihydroxy-5',11,13,22-tetramethyl-2-oxo-(3,7,19-trioxatetracyclo[15.6.1.14,8.020,24]pentacosa-10,14,16,22-tetraene)-6-spiro-2'-(5',6'-dihydro-2'H-pyran)-12-yl 2,6-dideoxy-4-O-(2,6-dideoxy-3-O-methyl-α-L-arabino-hexopyranosyl)-3-O-methyl-α-L-arabino-hexopyranoside Abamectin B1b: (10E,14E,16E)-(1R,4S,5'S,6S,6'R,8R,12S,13S,20R,21R,24S)-21,22-dihydroxy-6'-isopropyl-5',11,13,22-tetramethyl-2-oxo-(3,7,19-trioxatetracyclo[15.6.1.14,8.020,24]pentacosa-10,14,16,22-tetraene)-6-spiro-2'-(5',6'-dihydro-2'H-pyran)-12-yl 2,6-dideoxy-4-O-(2,6-dideoxy-3-O-methyl-α-L-arabino-hexopyranosyl)-3-O-methyl-α-L-arabino-hexopyranoside. |
The following toxicology information was extracted from the Office of Chemical Safety (OCS) human health risk assessment technical report for Abamectin, Pyriproxyfen (product name PestXPert DIY Pest Control Like the Professionals Cockroach Bait).
Toxicity | Species | Product containing abamectin (0.05%) |
SPF (2015) Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | >5000 | N/A |
Acute dermal toxicity LD50 (mg/kg bw) | Rat | >5000 | N/A |
Acute inhalational toxicity LC50 (mg/m3/4h) | No data | No data | N/A |
Skin irritation | Rabbit | Non-irritant | N/A |
Eye irritation | Rabbit | Slight irritant | Schedule 5 |
Skin sensitisation (Buehler Method) | Guinea pigs | Sensitiser | - |
No pre-meeting submissions were received for abamectin.
The committee advised that Schedule 5 entry for abamectin in the Poisons Standard be amended to include gel formulations containing 0.05 per cent or less of abamectin as follows:
Schedule 5 - Amend Entry
ABAMECTIN:
The committee also recommended an implementation date of 1 June 2017.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.
The reasons for the advice comprised the following:
The delegate considered the following in regards to this proposal:
The delegate's interim decision is to amend the Schedule 5 entry for abamectin to include gel formulations containing 0.05 per cent or less of abamectin.
The proposed wording for the schedule entry is as follows:
Schedule 5 - Amend Entry
ABAMECTIN:
The proposed implementation date is 1 June 2017.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.
The reasons for the interim decision are the following:
No submissions were received for abamectin.
The delegate has confirmed the interim decision and reasons for the decision as no evidence has been received to alter the interim decision. The delegate's final decision is to amend the Schedule 5 entry for abamectin to include gel formulations containing 0.05 per cent or less of abamectin. The implementation date is 1 June 2017.
Scheduling medicines and poisons
An application was submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) to create a new Schedule 6 entry for 1-deoxy-1-(methylamino)-d-glucitol N-coco acyl derivatives; to consider if an exemption cut-off for rinse-off cosmetics and household cleaning products is appropriate; and to determine whether an Appendix E listing for 1-deoxy-1-(methylamino)-d-Glucitol N-coco acyl derivatives is required.
This is a general application. The applicant's proposed amendments to the Poisons Standard are as follows:
Schedule 6 - New Entry
1-DEOXY-1-(METHYLAMINO)-d-GLUCITOL N-COCO ACYL DERIVATIVES in cosmetic and household cleaning preparations except:
IF IN EYES WASH OUT IMMEDIATELY WITH WATER; and
Appendix E, Part 2 - New Entry
1-DEOXY-1-(METHYLAMINO)-d-GLUCITOL N-COCO ACYL DERIVATIVES
Standard statement: E1 (if in eyes wash out immediately with water).
The applicant's reasons for the request are:
1-Deoxy-1-(methylamino)-d-Glucitol N-coco acyl derivatives are not currently scheduled and have not been previously considered for scheduling; therefore, a scheduling history is not available.
The public exposure to the substance is widespread and repeated. The principal route of exposure is dermal, while ocular exposure is highly possible. Based on current use proposals, the exposure to the substance is up to 8% concentration in rinse-off cosmetics for skin and hair cleansing and at up to 10% concentration in household cleaning products. Without warnings and appropriate directions, use of above consumer products could result in severe eye irritations to users. Setting a concentration cut-off for the substance used in cosmetics and household products, and providing users with labelling and first aid information could protect consumers.
Property | 1-Deoxy-1-(methylamino)-d-glucitol N-coco acyl derivatives |
---|---|
CAS No. | 1591783-13-9 |
Alternative names | Cocoyl Methyl Glucamaide (INCI Name); d-Glucitol, 1-deoxy-1-(methylamino)-, N-coco acyl derivatives (CAS) |
Chemical structure | ![]() Where R = C7-C17 alkyl group or C17 alkenyl group |
The following toxicology information was extracted from the NICNAS New Chemical assessment report for D-Glucitol, 1-deoxy-1-(methylamino)-, N-coco acyl derivs12.
Toxicity |
Species |
1-Deoxy-1-(methylamino)-d-glucitol N-coco acyl derivatives |
SPF (2015) Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | ˃2,000 | Schedule 5 |
Acute dermal toxicity LD50 (mg/kg bw) | Rat | ˃2,000 | None |
Acute inhalational toxicity LC50 (mg/m3/4h) | Not provided | Not provided | N/A |
Skin irritation | In vitro | Non-irritating | None |
Eye irritation | Rabbit | Severely irritating | Schedule 6 |
Skin sensitisation (LLNA / Buehler etc) | Guinea pig | No evidence of sensitisation | None |
Based on studies provided, 1-deoxy-1-(methylamino)-D-Glucitol N-coco acyl derivatives are of low acute oral and dermal toxicity. However, 1 of 3 test animals died of the treatment at 2000 mg/kg bw in the acute oral toxicity study.
An in vitro study on eye irritation using bovine corneal opacity and permeability test method indicated that the substance may have potential for eye irritation. Subsequent eye irritation study in rabbits demonstrated that 1-deoxy-1-(methylamino)-D-Glucitol N-coco acyl derivatives are severely irritating to the eyes. A single ocular application of the substance produced severe irritation effects. These effects included corneal opacity, conjunctiva redness, chemosis and discharge that were not reversible within 21 days after the application in 2 of 3 test animals. The results warranted following classification of the substance under GHS:
Hazard classification | Hazard statement |
---|---|
Serious eye damage/eye irritation (Category 1) | H318 - Causes serious eye damage |
Guinea pig maximisation test on the substance at up to 5% concentration did not reveal evidence of skin sensitisation.
In a 28 day repeated dose oral toxicity study on 1-deoxy-1-(methylamino)-D-Glucitol N-coco acyl derivatives, no treatment-related adverse effects were observed in the test animals at any dose tested.
1-Deoxy-1-(methylamino)-D-Glucitol N-coco acyl derivatives tested negative in bacterial reverse mutation assay and in vitro mammalian cell gene mutation tests.
1-Deoxy-1-(methylamino)-D-Glucitol N-coco acyl derivatives tested negative in an in vivo mouse bone marrow micronucleus test via the oral route.
1-Deoxy-1-(methylamino)-D-Glucitol N-coco acyl derivatives are used as a surfactant-cleaning agent in consumer products with widespread and repeated public exposure. The finished products include cleansing products for skin/hair, laundry, dishwashing and hard surface cleaning.
One (1) pre-meeting submission was received which opposed the scheduling proposal. The main points are in relation to the toxicity and risks of 1-deoxy-1-(methylamino)-d-glucitol N-coco-acyl derivatives; and the scheduling inconsistencies and international regulations of similar surfactants.
The committee advised that a new Schedule 6 entry be created for 1-deoxy-1-(methylamino)-d-glucitol N-coco acyl derivatives with exemptions and cut-offs as follows:
Schedule 6 - New Entry
1-DEOXY-1-(METHYLAMINO)-d-GLUCITOL N-COCO ACYL DERIVATIVES except:
IF IN EYES WASH OUT IMMEDIATELY WITH WATER, or
IF IN EYES WASH OUT IMMEDIATELY WITH WATER.
The committee also advised appendix and index entries as follows:
Appendix E, Part 2 - New Entry
1-DEOXY-1-(METHYLAMINO)-d-GLUCITOL N-COCO ACYL DERIVATIVES
Standard statement: E1 (if in eyes wash out immediately with water).
Appendix F, Part 3 - New Entry
1-DEOXY-1-(METHYLAMINO)-d-GLUCITOL N-COCO ACYL DERIVATIVES
Warning statement: 79 (Will irritate eyes).
Safety direction: 1 (Avoid contact with eyes)
Index - New Entry
1-DEOXY-1-(METHYLAMINO)-d-GLUCITOL N-COCO ACYL DERIVATIVES
cross reference: cocoyl methyl glucamaide
Schedule 6
Appendix E, Part 2
Appendix F, Part 3
The committee recommended an implementation date of 1 June 2017.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; and(d) the dosage, formulation, labelling, packaging and presentation of a substance.
The reasons for the advice comprised the following:
The delegate considered the following in regards to this proposal:
The delegate's interim decision is to create a new Schedule 6 entry for 1-deoxy-1-(methylamino)-d-glucitol N-coco acyl derivatives with exemptions and cut-offs in cosmetic rinse-off preparations and household cleaning preparations.
The proposed wording for the schedule, appendix and index entries is as follows:
Schedule 6 - New Entry
1-DEOXY-1-(METHYLAMINO)-D-GLUCITOL N-COCO ACYL DERIVATIVES except:
IF IN EYES WASH OUT IMMEDIATELY WITH WATER, or
IF IN EYES WASH OUT IMMEDIATELY WITH WATER.
Appendix E, Part 2 - New Entry
1-DEOXY-1-(METHYLAMINO)-D-GLUCITOL N-COCO ACYL DERIVATIVES
Standard statement: E1 (if in eyes wash out immediately with water).
Appendix F, Part 3 - New Entry
1-DEOXY-1-(METHYLAMINO)-D-GLUCITOL N-COCO ACYL DERIVATIVES
Warning statement: 79 (Will irritate eyes).
Safety direction: 1 (Avoid contact with eyes)
Index - New Entry
1-DEOXY-1-(METHYLAMINO)-D-GLUCITOL N-COCO ACYL DERIVATIVES
cross reference: cocoyl methyl glucamaide
Schedule 6
Appendix E, Part 2
Appendix F, Part 3
The proposed implementation date is 1 June 2017.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.
The reasons for the interim decision are the following:
One (1) public submission was received which opposed the interim decision. The main points were:
The delegate's final decision is to create a new Schedule 6 entry for 1-deoxy-1-(methylamino)-D-glucitol N-coco acyl derivatives with exemptions and cut-offs in cosmetic rinse-off preparations and household cleaning preparations. The implementation date has been extended to 1 February 2018.
The delegate confirms that the reasons for the final decision are the same as those provided from the interim decision. Additional reasons for the final decision include:
12 Publicly available on the NICNAS website
Scheduling medicines and poisons
An application was submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) to create new Schedule 10 entries for o-toluidine and o-anisidine for use in preparations for skin colouration (including tattooing) and dyeing of hair, eyelashes or eyebrows.
This was a general application. The applicant's proposed amendments to the Poisons Standard are as follows:
Schedule 10 - New Entries
o-TOLUIDINE in preparations for skin colouration (including tattooing) and dyeing of hair, eyelashes or eyebrows.
o-ANISIDINE in preparations for skin colouration (including tattooing) and dyeing of hair, eyelashes or eyebrows.
The applicant's reasons for the request are:
Neither o-anisidine nor o-toluidine are specifically scheduled. The chemicals are named as part of Schedule 7 entry for azo dyes as follows:
Schedule 7
AZO DYES that are derivatives by diazotisation of any of the following substances:
p-aminoazobenzene (CAS No. 60-09-3)
o-aminoazotoluene (CAS No. 97-56-3)
o-anisidine (CAS No. 90-04-0)
p-chloroaniline (CAS No. 106-47-8)
4-chloro-o-toluidine (CAS No. 95-69-2)
6-methoxy-m-toluidine (p-cresidine) (CAS No. 120-71-8)
2-naphthylamine (CAS No. 91-59-8)
5-nitro-o-toluidine (CAS No. 99-55-8)
2,4-toluenediamine (CAS No. 95-80-7)
o-toluidine (CAS No. 95-53-4)
2,4,5-trimethylaniline (CAS No. 137-17-7)
o-Toluidine and o-anisidine were first included in Schedule 7 in February 2016 as part of the azo dyes entry due to their carcinogenicity and genotoxicity (see section Current scheduling status above). The toxicological data for both o-toluidine and o-anisidine were provided by NICNAS to support the application for the scheduling of azo dyes at the August 2015 Advisory Committee for Chemicals Scheduling (ACCS) meeting. The reports provided at the August 2015 meeting were the same as those provided with this application.
o-Toluidine and o-anisidine are not otherwise specifically scheduled.
The chemicals have been detected in tattoo inks in Australia. It was not possible to identify all popular tattoo inks used in Australia. Of the 49 tattoo inks analysed:
The limit of detection for the assay was 5 ppm.
The data analysis conducted by NICNAS suggests that for the majority of amine-containing tattoo inks, the amines are introduced at some point during manufacture rather than as a result of the reduction of the azo colourants. The pigments used in tattoos are not produced specifically for such application and purity is on average around 70-90 % (European Commission, 2015; European Commission, 2016).
The popularity of tattoos is reported to have increased in the last decade. Based on a survey completed by a representative sample of 8656 men and women ages 16-64 years in Australia, the prevalence of tattoos was reported to be 14.5 % in men and 13.6 % in women. Tattoo prevalence in young adults may represent more than double (European Commission, 2015).
The chemicals have also been detected in tattoo inks (overseas) (European Commission, 2015, p180). The brands in which the chemicals were detected are reported to be available in Australia. Two thirds of the RAPEX notifications in Europe are reported to pertain to imported products, with the highest percentages from the United States (European Commission, 2015). Therefore it is considered likely that these tattoo inks could be imported into Australia.
The chemicals have also been detected in permanent hair dyes and commercial henna samples (colours not specified) overseas. In the absence of specific Australian data, this is considered to be representative of Australian use.
o-Toluidine and o-anisidine are restricted under Annex XVII to REACH Regulations. 'The chemical cannot be used in substances and preparations placed on the market for sale to the general public in individual concentrations ≥0.1 %' (European Parliament and Council 1999; European Parliament and Council 2006; European Parliament and Council 2008). o-Toluidine and o-anisidine are also included as part of 22 aromatic amines listed in Appendix 8 which places restrictions on their presence in leather or textile articles.
o-Toluidine and o-anisidine are on the candidate list of substances of very high concern (SVHC) for eventual inclusion in Annex XIV (ECHA, 2013). In the EU, companies could have legal obligations if the chemical that they produce, supply or use is included on the candidate list whether on its own, in mixtures, or present in articles.
ResAP (2008)1 specifies requirements for the composition, labelling, uses and risk evaluation of tattoo inks in the European Union. ResAP (2008)1 lists 27 aromatic amines (including o-toluidine and o-anisidine) that should not be present in tattoo inks or released from azo-colourants in concentrations that are technically avoidable. The non-binding ResAP are the reference for the national legislation in several European countries and New Zealand (NZ EPA, 2012).
o-Toluidine and o-anisidine are listed on the following (Galleria Chemica):
In addition o-toluidine is listed in the Health Canada List of prohibited and restricted cosmetic ingredients (The Cosmetic Ingredient "Hotlist") under the entry 'Toluidines, their isomers, salts and halogenated and sulfonated derivatives'.
Property | o-Toluidine | o-Anisidine |
---|---|---|
CAS No. | 95-53-4 | 90-04-0 |
CAS name | benzenamine, 2-methyl- | benzenamine, 2-methoxy- |
IUPAC and/or common and/or other names | o-toluidine | o-anisidine |
Chemical structure | ![]() |
![]() |
Molecular formula | C7H9N | C7H9NO |
Molecular weight | 107.16 g/mol | 123.15 g/mol |
The following toxicology information was extracted from the NICNAS assessment report for o-toluidine13 and o-anisidine14.
Toxicity | Species | Outcome | SPF (2015) Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rats | 750* | Schedule 6 |
Acute dermal toxicity LD50 (mg/kg bw) | rabbit | 3250 | Schedule 5 |
Acute inhalational toxicity LC50 (mg/m3/4h) | rats | 3800* | Schedule 5/6 |
Skin irritation | Rabbit | Slight irritant | Schedule 5 |
Eye irritation | Rabbit | irritant | Schedule 6 |
Skin sensitisation | Limited data | N/A |
* Methaemoglobinaemia has been observed in cats and humans at relatively low doses
Toxicity | Species | Outcome | SPF (2015) Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rats | 1505-1890* | Schedule 6 |
Acute dermal toxicity LD50 (mg/kg bw) | Rats | >2000 | Schedule 5 |
Acute inhalational toxicity LC50 (mg/m3/4h) | Rats | >3870 | Schedule 5 |
Skin irritation | Rabbits | Slight irritant | Schedule 5 |
Eye irritation | Rabbits | Slight irritant | Schedule 5 |
Skin sensitisation | local lymph node assay (LLNA) and guinea pig maximisation test (GPMT) | Equivocal | N/A |
* Methaemoglobinaemia has been observed in cats and other species at relatively low doses
Refer to tables 1.9B and 1.9C.
The toxic effects of the o-toluidine have been investigated in several sub-chronic and chronic repeated dose oral toxicity studies. The results demonstrated not only chemically-induced development of tumours (see carcinogenicity section), but also non-cancer effects. The sub-chronic studies, whilst limited by poor documentation or a single dose test concentration, demonstrated consistent effects with the targets for toxicity being the blood, liver, kidney, spleen and urinary bladder. A no observed adverse effect level (NOAEL) value could not be established with a lowest observed adverse effect level (LOAEL) for effects on the blood of 24 mg/kg bw/day in a 14-day study.
The toxic effects of o-anisidine from repeated oral exposure were investigated in a number of well-conducted studies (OECD TG 407) in Fischer 344, Wistar rats, and B6C3F1 mice. The results demonstrated not only chemically-induced development of tumours (see Carcinogenicity section), but also non-cancerous effects. The lowest observed adverse effect level (LOAEL) available from the 28-day study in rats was 80 mg/kg bw/day. The targets for toxicity are the bone marrow and spleen.
o-Toluidine is considered mutagenic based on the weight of evidence from available, well-documented in vitro and in vivo studies. The chemical was recommended for classification as a category 2 (1B for GHS) mutagenic substance). The chemical has been reported to cause mutations, DNA and chromosomal damage and cell transformation. o-Toluidine was reported to induce DNA lesions in different organs of exposed rats (liver, bladder) and mice (liver, bladder and brain. Furthermore, inhibited testicular DNA synthesis was reported in male mice following oral intubation. Renal DNA synthesis was also inhibited after a single intraperitoneal injection of the lethal doses of the chemical in the suckling mice.
o-Anisidine classified or as hazardous (Category 3 mutagenic substance) with the risk phrase 'Possible risk of irreversible effects' (Xn; R68) The genotoxic and mutagenic potentials of the chemicals were evaluated in several well-conducted in vitro and in vivo studies. DNA adducts derived from the N-hydroxylated metabolite have been detected in both in vitro and in vivo (i.p. route of administration) studies.
o-Toluidine
o-Toluidine is currently classified as hazardous (Category 2 carcinogen) with the risk phrase 'May cause cancer' (T; R45) in HSIS (Safe Work Australia). The available epidemiological data support an amendment to this classification to a Category 1 carcinogen.
The carcinogenicity of the hydrochloride salt (not listed on the AICS) was investigated in a number of well-conducted OECD TG 452-compliant oral studies (feeding) in male and female F344 and CD-1 rats and mice (B6C3F1 and CD-1). In addition to reduced bodyweight and survival, significant increases in the incidence of multi-organ benign and/or malignant tumours were reported in mice and rats exposed to 3000-16000 ppm of the chemical over three months to two years. The equivalent intake doses were calculated at 130-800 mg/kg bw/day. In rats, tumours were found in the spleen, scrotum, urinary bladder, mammary glands, liver, skin, abdominal cavity and blood vessels of the chemically-exposed animals. In mice, hepatocellular carcinomas, adenomas, haemangiosarcomas, abdominal haemangiosarcomas and haemangiomas were observed.
In humans, findings derived from several cohort studies of workers provide strong evidence for an increased risk of urinary bladder cancer associated with long-term occupational exposure to o-toluidine. The chemical is listed in the National Toxicology Program (NTP) Report on Carcinogens (Twelfth Edition) as 'reasonably anticipated to be a human carcinogen' (NTP, 2011). The International Agency for Research on Cancer (IARC) has reviewed epidemiological data and subsequently concluded that it is 'carcinogenic to humans' (Group 1) (IARC, 2010; IARC, 2012).
The mechanism of action underlying the carcinogenicity of o-toluidine is not fully understood, although it is considered to involve metabolic activation, DNA adduct formation and induction of DNA-damaging effects. A mechanism which includes genotoxicity is suspected.
o-Anisidine
o-Anisidine is currently classified as hazardous (Category 2 carcinogen) with the risk phrase 'May cause cancer' (T; R45) in HSIS (Safe Work Australia). The available data support this classification.
Data from long-term carcinogenicity studies indicated that chronic exposure to o-anisidine in its hydrochloride form, CAS No.134-29-2 (not listed on the Australian Inventory of Chemical Substances) produced malignant and benign tumours, particularly in the urinary bladder of rats and mice.
Chronic oral exposure of F344 rats and B6C3F1 mice to o-anisidine and its hydrochloride salt for two years resulted in transitional-cell papillomas and carcinomas of the urinary bladder in both species. The doses tested were 5000 or 10000 ppm (average of 333 or 666 mg/kg bw/day) for rats and 2500 or 5000 ppm for mice (average of 214 or 428 mg/kg bw/day). A very rare form of tumour in the rat, leiomyosarcoma, was also observed in the urinary bladder of high dose animals. Kidney and thyroid gland cancer, including transitional cell carcinoma of the renal pelvis, follicular-cell adenoma and carcinoma, papillary cystadenoma, and cystadenocarcinoma, were also identified in rats. Cancer-related deaths occurred within 83-88 weeks in animals treated with 5000 or 10000 ppm of the chemical. Another study has indicated the tumour-promoting activity of the chemical.
No human case reports or epidemiological studies are available. The International Agency for Research on Cancer (IARC) overall evaluation is that o-anisidine is 'possibly carcinogenic to humans' (Group 2B).
The mechanism of action for carcinogenicity of the animal is not completely understood; although, both genotoxic and non-genotoxic modes of action are considered plausible. The formation of reactive species that are capable of binding to DNA has been observed. Results from a two-year carcinogenicity study suggested that the observed increased incidence of follicular-cell tumours in male Fischer 344 rats is a potential consequence of the inhibition of thyroid hormone formation, which is catalysed by the thyroid peroxidase.
Limited data are available.
o-Toluidine
o-Toluidine is highly toxic to humans and can be absorbed via inhalation and through dermal contact. Exposed individuals have been reported to exhibit clinical signs of toxicity including methaemoglobinaemia, haematuria, renal and bladder irritation, physiological and psychological deficits. Severe intoxication was also observed in individuals exposed to 40 ppm of the chemical for 60 minutes.
Results from a patch test study in 40 dermatitis patients, known to be hypersensitive to p-phenylenediamine, indicated positive reactions in 25% of participants following exposure to o-toluidine in yellow paraffin.
Workers with chronic exposure to the o-toluidine have been reported to display anaemia, weight loss, anorexia, cyanosis, methaemoglobinaemia, skin lesions, and disturbance in the central nervous system such as headache, dizziness and confusion. Additionally, haemoglobin adducts were found in the urine of workers exposed to the chemical, where higher levels were identified in those with existing impaired skin condition. These adducts were also present in the blood of children with exposure to the chemical and in hairdressers with chronic exposure to hair dyes containing the chemical.
o-Anisidine
Complaints of headache and vertigo, increased sulfhaemoglobin and methaemoglobin, and frequent occurrence of Heinz bodies were reported in workers exposed to o-anisidine (0.4 ppm (2 mg/m³)).
One (1) pre-meeting submission was received in support. The main points were that the new schedule entry would be in alignment with international regulators in the EU, ASEAN and NZ.
The committee advised that new Schedule 10 entries be created for o-toluidine and o-anisidine for use in preparations for skin colouration (including tattooing) and dyeing of hair, eyelashes or eyebrows as follows:
Schedule 10 - New Entries
o-TOLUIDINE in preparations for skin colouration (including tattooing) and dyeing of hair, eyelashes or eyebrows.
o-ANISIDINE in preparations for skin colouration (including tattooing) and dyeing of hair, eyelashes or eyebrows.
The committee also recommended an implementation date of 1 June 2017.
Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989included: (b) the purpose for which a substance is to be used and the and extent of use; and (c) the toxicity of a substance.
The reasons for the advice comprised the following:
The delegate considered the following in regards to this proposal:
The delegate's interim decision is to create new Schedule 10 entries for o-toluidine and o-anisidine for use in preparations for skin colouration (including tattooing) and dyeing of hair, eyelashes or eyebrows.
The proposed wording for the schedule entries is as follows:
Schedule 10 - New Entries
o-TOLUIDINE in preparations for skin colouration (including tattooing) and dyeing of hair, eyelashes or eyebrows.
o-ANISIDINE in preparations for skin colouration (including tattooing) and dyeing of hair, eyelashes or eyebrows.
The proposed implementation date of 1 June 2017.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (b) the purposes for which a substance is to be used and the extent of use of a substance; and (c) the toxicity of a substance.
The reasons for the interim decision are the following:
One (1) public submission was received that generally supported the interim decision, but proposed amendments. The main points of concern were:
The delegate's final decision is to create new Schedule 10 entries for o-toluidine and o-anisidine (excluding derivatives) for use in preparations for skin colouration with a concentration cut-off of 0.001 per cent or less as follows:
Schedule 10 - New Entries
o-TOLUIDINE (excluding derivatives) in preparations for skin colouration (including tattooing) and dyeing of hair, eyelashes or eyebrows except in preparations containing 0.001 per cent or less of o toluidine.
o-ANISIDINE (excluding derivatives) in preparations for skin colouration (including tattooing) and dyeing of hair, eyelashes or eyebrows except in preparations containing 0.001 per cent or less of o anisidine.
The implementation date has been extended to 1 February 2018.
The delegate confirms that the reasons for the final decision are the same as those provided from the interim decision. Additional reasons for the final decision include:
13 Publicly available on the NICNAS website at: https://www.nicnas.gov.au/chemical-information/imap-assessments/imap-assessment-details?assessment_id=1158
14 Publicly available on the NICNAS website at: https://www.nicnas.gov.au/chemical-information/imap-assessments/imap-assessment-details?assessment_id=1161
15 Basic Violet 2 COLIPA n° B115 available at https://ec.europa.eu/health/scientific_committees/consumer_safety/sccs_09-13/opinions_en
16 Basic Violet 2 COLIPA n° B115 available at httphttps://ec.europa.eu/health/scientific_committees/consumer_safety/sccs_09-13/opinions_en
Substance | Interim decision |
---|---|
Nicotine | The delegates' final decision is that the current scheduling of nicotine remains appropriate. |
Pentobarbital (pentobarbitone) | The delegates' final decision is that the current scheduling of pentobarbital remains appropriate. |
Cannabis, tetrahydrocannabinols and cannabidiol | The delegate has deferred making a final decision at this time regarding the possible rescheduling of cannabis. The deferral of a final decision will allow sufficient time for the delegate to thoroughly consider all public submissions on the interim decision, including two late submissions. Further information on the final decision regarding the possible rescheduling of cannabis is likely to be provided by late May 2017. Should the final decision be released at this time and require an implementation date, it will be announced at the time of publication. |
Epidermal Growth Factor | The delegates' final decision is that the current scheduling of epidermal growth factor remains appropriate. |
Fennel Oil | Schedule 5 - New Entry FENNEL OIL except:
Appendix E, Part 2 - New Entry FENNEL OIL 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) Part 2, Section 2.4 Child-resistant closures - New Entry Column 1, Name of the poison: Fennel oil when included in Schedule 5. Column 2, Nominal capacity: 200 millilitres or less Implementation date of 1 June 2017. |
An applicant has proposed to exempt nicotine from Schedule 7 at concentrations of 3.6 per cent or less of nicotine for self-administration with an electronic nicotine delivery system ('personal vaporiser' or 'electronic cigarette') for the purpose of tobacco harm reduction.
This was a general application. The applicant's proposed amendments to the Poisons Standard are as follows:
Schedule 7 - Proposed amendment
NICOTINE except:
The applicant's reasons for the request are as follows:
Nicotine is currently listed in the Poisons Standard in Schedules 7, 6 and 4, Appendix F (Part 3), and Appendix J (Part 2) as follows:
Schedule 7
NICOTINE except:
Schedule 6
NICOTINE in preparations containing 3 per cent or less of nicotine when labelled and packed for the treatment of animals.
Schedule 4
NICOTINE in preparations for human therapeutic use except for use as an aid in withdrawal from tobacco smoking in preparations for oromucosal or transdermal use.
Appendix F, Part 3 − NICOTINE except when in tobacco
Safety directions: 1 (Avoid contact with eyes), 4 (Avoid contact with skin).
Appendix J, Part 2 - NICOTINE
Condition: 1 (Not to be available except to authorised or licensed persons).
In June 1991, the Drugs and Poisons Schedule Standing committee (DPSSC) amended the Schedule 4 entry for nicotine to include all preparations (except Schedule 3 chewing tablets) which could be used as an aid in smoking cessation, containing between 2 and 4 mg of nicotine or roll-on devices with 0.65 per cent or less of nicotine e.g. transdermal patches.
In August 1993, the National Drugs and Poisons Schedule committee (NDPSC) rejected a proposal to have 2 mg sublingual tablets rescheduled from Schedule 3 to Schedule 2 and 4 mg sublingual tablets rescheduled from Schedule 4 to Schedule 3.
In November 1993, the NDPSC agreed that Schedule 4 remained appropriate for patch formulations. Subsequently, in November 1997, transdermal patches were included in Schedule 3.
In February 1997, the NDPSC rescheduled nicotine 2 mg chewable tablets to Schedule 2. However, committee decided that the higher dosage (4 mg) should only be rescheduled to Schedule 3 to facilitate the counselling of heavy smokers by a pharmacist.
In August 1998, the NDPSC agreed to the inclusion of nicotine gum and transdermal patches in Appendix H.
In November 1998, the NDPSC considered down-scheduling nicotine for inhalation, when packed in cartridges for use as an aid in withdrawal from tobacco smoking, from Schedule 4 to Schedule 3 and decided that Schedule 3 was appropriate. The NDPSC noted that this form of oral inhalation was similar in many respects to the chewing gum, being absorbed mainly in the mouth and throat. The data provided indicated that nicotine plasma levels obtained via the inhaler were similar to those obtained with the 2 mg chewing gum.
In February 1999, the NDPSC amended this Schedule 3 nicotine entry to 'Nicotine as an aid in withdrawal from tobacco smoking in preparations for inhalation or sublingual use'. In August 2001, the NDPSC agreed that nicotine lozenges would have a comparable safety profile to that of sublingual tablets, and so it was appropriate to also include lozenges in Schedule 3. Subsequently, lozenge-preparations were down scheduled to Schedule 2 in June 2003. In February 2002, nicotine inhalers were rescheduled from Schedule 3 to Schedule 2.
In February 2010, the NDPSC considered an application to broaden the exemptions for specified NRT buccal dosage formats i.e. chewing gum and lozenges, to buccal preparations in general. The NDPSC decided to only down-schedule oromucosal sprays and did not support an exemption for oromucosal preparations in general, noting that this could potentially include preparations such as mouthwashes. The NDPSC was of the opinion that there was insufficient data for such a broad exemption.
In June 2010, the NDPSC considered a post-meeting submission regarding the February 2010 decision to exempt nicotine preparations for oral mucosal spray use from scheduling. The committee confirmed the February 2010 resolution (2010/58-20) to amend the scheduling of nicotine to exempt oromucosal spray use as an aid in withdrawal from tobacco smoking. The committee agreed that this decision should be referred to a delegate under the new scheduling arrangements commencing 1 July 2010 for consideration of inclusion into the first instrument under these new arrangements with an implementation date of 1 September 2010.
In June 2011, the ACMS considered a proposal to amend the Schedule 4 entry to exempt from scheduling when used for human therapeutic use as an aid in withdrawal from tobacco smoking: (i) nicotine oromucosal film; and (ii) nicotine inhalation cartridges for oromucosal use. These proposed exemptions were similar to the exemptions for nicotine in chewing gums, lozenges, and preparations for sublingual, transdermal or oromucosal spray use when used as an aid in withdrawal from tobacco smoking.
ACMS advised that the Schedule 4 exemption for nicotine in preparations for human therapeutic use be extended to include all oromucosal use and include a definition for oromucosal in the Poisons Standard Part 1, Interpretation. The committee advised and the delegate agreed with the deletion of the Schedule 2 nicotine entry (i.e. all nicotine inhalation cartridge preparations for oromucosal use as aids in withdrawal from tobacco smoking would become exempt with any other inhalation preparations for human therapeutic use being captured by Schedule 4). Further, the delegate extended the scheduling exemption for nicotine in preparations for human therapeutic use to include all oromucosal use (to harmonise with the New Zealand scheduling of nicotine for human therapeutic use). The decisions were implemented on 1 January 2012.
Electronic Nicotine Delivery Systems (ENDS) are also known as e-cigarettes, personal vaporisers and vape pens. Nicotine for human consumption is listed in Schedule 4 in the Poisons Standard, except when used as an aid in the withdrawal from tobacco smoking in preparations intended for oromucosal or transdermal use (e.g. nicotine patches, gum or mouth sprays). Nicotine is in Schedule 7, except in preparations for human therapeutic use or in tobacco prepared and packed for smoking. There are no restrictions on importation, but individuals may commit an offence under state and territory laws when they take possession of, use or import nicotine.
In the states and territories, it is an offence to manufacture, sell or supply nicotine as Schedule 7 poison without a licence or specific authorisation. This means e-cigarettes containing nicotine cannot be sold in any Australian state or territory. Nicotine can be imported by an individual for use as an unapproved therapeutic good (e.g. a smoking cessation aid), but the importer must hold a prescription from an Australian registered medical practitioner and only import not more than 3 months' supply at any one time. The total quantity imported in a 12-month period cannot exceed 15 months' supply of the product at the maximum dose recommended by the manufacturer. The purchase and possession of nicotine by individuals are not regulated by Commonwealth legislation, except for importation as allowed under Commonwealth law.
Non-nicotine e-cigarettes are currently not regulated as a therapeutic good under the Commonwealth Therapeutic Goods Act. To date, none have been approved by the TGA for registration as a medical device.
In April 2015, the Commonwealth Department of Health engaged the University of Sydney (in partnership with the Cancer Council New South Wales) to explore options to minimise the risks associated with the marketing and use of ENDS in Australia. The project was initiated under the auspices of the Intergovernmental committee on Drugs (IGCD) which reports to the Australian Health Ministers Advisory Council Mental Health, Drug and Alcohol Principal committee. The IGCD nominated that the Department of Health act as the lead agency to oversee the project.
The outcomes of the project are to inform policy options for ENDS (with or without nicotine) that may be considered separately or in coordination by the Commonwealth, state and territory governments. The project is due to report in mid-2016. The Tobacco Control Policy Section has indicated that the report is imminent. However, the broader dissemination of the report will be a matter for the IGCD. At this time it is unknown when the IGCD will be meeting to discuss this report.
UK: The 2016 UK guidance policy on regulation of e-cigarettes is available through the following link https://www.gov.uk/guidance/e-cigarettes-regulations-for-consumer-products.
NZ: In August 2016, the NZ Ministry of Health released a consultation document, considering policy options for the regulation of electronic cigarettes and agreeing in principle to allowing the sale of nicotine e-cigarettes as a consumer product. This consultation is attached and is in TRIM at R16/613417.
USA: The USA National Institute on Drug Abuse includes information on e-cigarettes at https://www.drugabuse.gov/publications/drugfacts/electronic-cigarettes-e-cigarettes.
Information on the US FDA ruling on e-cigarettes is available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm499234.htm and US FDA labelling information on vaporisers, e-cigarettes and ENDS is at http://www.fda.gov/tobaccoproducts/labeling/productsingredientscomponents/ucm456610.htm
Nicotine is a liquid alkaloid obtained from the dried leaves of the tobacco plant, Nicotiana tabacum and related species (Solanaceae). Tobacco leaves contain 0.5 to 8% of nicotine combined as malate or citrate. Nicotine is a colourless or brownish, volatile, hygroscopic, viscous liquid. Soluble in water and; miscible with dehydrated alcohol.
Table 2.1: Chemical information
Property | Nicotine |
---|---|
CAS No. | 54-11-5 |
Chemical name | 3-[(2S)-1-Methylpyrrolidin-2-yl]pyridine; (−)-1-Methyl-2-(3-pyridyl)pyrrolidine; (S)-3-(1-Methyl-2-pyrrolidinyl)pyridine |
Chemical structure | ![]() |
Molecular formula | C10H14N2 |
Molecular weight | 162.2 g/mol |
When smoked, nicotine is distilled from burning tobacco and carried on tar droplets (particulate matter), which are inhaled. Nicotine has a plasma half-life of approximately 2 hours. It is metabolised in the liver primarily by the CYP2A6 enzyme into cotinine which is excreted by the kidneys. Nicotine used in nicotine solutions for e-cigarettes is extracted from tobacco leaves.
The toxicity of other ingredients inhaled in solutions used in e-cigarettes was not addressed in this application. The Applicant states that other chemicals in e-cigarette vapour include volatile organic compounds, carbonyls, aldehydes, tobacco-specific nitrosamines (TSNAs) and metal particles.
Of the 71 public submissions received, 54 supported and 17 opposed the proposal.
The 54 submissions in support of the proposal were from consumers (35), business owners or manufactures (6), peak bodies (2), advocacy groups (3), medical professionals (7) and a consultant (1).
The main points supporting the proposal were as follows:
The 17 submissions that do not support the proposal were from academia (1), Government Health Departments (7), non-government organisations (4) and peak bodies (5).
The main points opposing the proposal were as follows:
The committee advised that the current scheduling of nicotine remains appropriate.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; (f) any other matters that the Secretary considers necessary to protect the public health
The reasons for the advice comprised the following:
The delegates considered the following in regards to this application:
The delegates' interim decision is that the current scheduling of nicotine remains appropriate.
The delegates considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; (f) any other matters that the Secretary considers necessary to protect the public health.
The reasons for the interim decision are the following:
Twenty-one (21) submissions were received. Five supported and 16 opposed the delegate's interim decision.
The main points in support of the proposal were as follows:
The main points in opposition to the proposal were as follows:
The delegates have confirmed the interim decision and reasons for the decision as no evidence has been received to alter the interim decision. The delegates' final decision is that the scheduling for nicotine remains appropriate.
Reasons for the final decision additional to those provided from the interim decision include:
17 Bernd Mayer. How much nicotine kills a human? Tracing back the generally accepted lethal dose to dubious self-experiments in the nineteenth century. Arch Toxicol. 2014; 88(1): 5-7: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3880486/
18 Grana et al. 'E-cigarettes: A Scientific review' Circulation. 2014, 129(19), 1972-1986 (Attachment G)
19 McRobbie et al. 'Electronic cigarettes for smoking cessation (Review)' Cochrane Database of Systematic Reviews, 2016, 9, CD010216 (Attachment G)
20 Personal importation scheme (https://www.tga.gov.au/personal-importation-scheme)
21 http://www.localgov.co.uk/Retailers-flout-laws-on-selling-e-cigarettes-to-children/41409
22 https://www.cdc.gov/tobacco/data_statistics/sgr/e-cigarettes/pdfs/2016_sgr_entire_report_508.pdf
The delegate is considering up-scheduling pentobarbital (pentobarbitone) when packed and labelled for injection from Schedule 4 (Prescription Only Medicine or Prescription Animal Remedy) to Schedule 8 (Controlled Drug). This is due to the reported misuse of injectable pentobarbital and its involvement in suicides and whether the greater access control of Schedule 8 is more appropriate.
This was a delegate-initiated application. The delegate's proposed amendments to the Poisons Standard are as follows:
Schedule 8 - Amend entry
PENTOBARBITAL except when included in Schedule 4.
Schedule 4 - Delete entry
PENTOBARBITAL when packed and labelled for injection.
The delegate-initiated rescheduling proposal is due to the reported misuse of injectable pentobarbital and its involvement in suicides and whether the greater access control of Schedule 8 is more appropriate.
Pentobarbital is currently listed in Schedule 4, Schedule 8 and Appendix K, as follows:
Schedule 8
PENTOBARBITAL except when included in Schedule 4.
Schedule 4
PENTOBARBITAL when packed and labelled for injection.
Appendix K
PENTOBARBITAL
Index
PENTOBARBITAL
Schedule 8
Schedule 4
Appendix K
PENTOBARBITONE
cross reference: PENTOBARBITAL
Other barbiturates are currently listed in the Poisons Standard as follows:
In January 1955, at the first meeting of the Poisons Schedule committee, barbituric acid was placed in Schedule 4, with concentrations of barbituric acid below 1% placed in Schedule 2.
In July 1968, the Poisons Schedule Sub-Committee (PSC) suggested that barbiturate tablets should be strip packed, following an article in the Medical Journal of Australia raising concern that some attempts at suicide could be avoided if barbiturate drugs were individually wrapped in tin foil, rather than packed in bottles.
In June 1980, the committee considered barbiturate scheduling, following media reports of proposed changes in NSW relating to availability and the Capital Territory Health Commission Deputy Chair's concerns around danger and abuse of barbiturates. The committee sought views of the Pharmaceutical Benefits Advisory committee (PBAC), the Department of Veterans' Affairs (DVA), Australian Drug Evaluation committee (ADEC) and the Medicines Advisory committee on the use of barbiturates in medical practice.
In November 1980, the committee considered a minute from the Secretary of the Dental Health committee listing pentobarbitone and other barbiturates as necessary for anaesthesia and conscious sedation in dental practice. Other views of the MAC were presented and included use in the treatment of cholestasis of pregnancy, management of jaundice and infantile colic. A direction from the Public Health Advisory committee (October 1980) meeting to PSC required examination of barbiturate use and advice on appropriate methods of control. It was agreed that ramifications of placing barbiturates in Schedule 8 would be considered at the next meeting.
In March 1981, the November 1980 meeting's proposal to retain barbiturate group of drugs in Schedule 4 for use to treat epilepsy and for anaesthesia and reclassify all other as Schedule 8 was considered. A consensus was not reached and the matter referred to the May 1981 meeting. Members were to raise the matter with their own Poisons Advisory committees.
In May 1981, the committee received correspondence from the WA Commissioner for Public Health indicating that the WA Poisons Advisory committee favoured tightening supplies of barbiturates rather than reclassification into Schedule 8. There was general agreement that barbiturates should be included in Appendix D. A final decision on barbiturates was deferred to the next meeting.
In August 1985, the committee was advised that Queensland intended to allocate many barbiturates to Schedule 8, with other states initiating legislation for Schedule 8 as well. In August 1985, the committee recommended that barbiturates be included in Schedule 8, with the original Schedule 4 remaining for parenterals [i.e. delivery by injection] during a phasing-in period [i.e. implementation date] of 6-12 months.
Schedule 4 - PENTOBARBITONE when packed and labelled for injection.
Schedule 8 - PENTOBARBITONE except when included in Schedule 4.
In November 1986, the committee noted ADEC's view that barbiturates were used as anticonvulsants and parenteral barbiturate formulations should be excluded from any Schedule 8 proposals. Members were informed of the Ministerial Council on Drug Strategy adopting the scheduling proposal (excluding barbiturate anticonvulsants from Schedule 8).
In February 1987, the TAS member reported changing the wording of the barbiturate entries so that they are similar to the Poisons Standard. WA reported that barbiturates have been S8 for some months now and barbiturate prescriptions were reported.
In the United States of America, pentobarbital (as a derivative of barbituric acid) is a Schedule III Controlled Substance, along with narcotics such as amphetamine and other substances such as nalorphine, glutethimide and anabolic steroids (https://www.law.cornell.edu/uscode/text/21/812), from 27 October 1970. Anabolic steroids and other chemicals including barbital and phenobarbital were added to Schedule III in 1990.
While it is a Class III psychotropic substance of the United Nations Convention on Psychotropic Substances 1971, no country that is a signatory to the convention has prohibited its import (as of the 2016 edition of the Green List of the International Narcotics Control Board).
It is a Class B Controlled Drug in the United Kingdom, from 1 January 1985. It is a Schedule IV Controlled Drug under the Controlled Drugs and Substances Act in Canada.
Barbiturates are substituted pyrimidine derivatives in which the common structure, barbituric acid, has no CNS activity. CNS activity is conferred by substituting alkyl, alkenyl or aryl groups on the pyrimidine ring. Barbiturates are primarily used as sedative hypnotics and also anticonvulsants in sub-hypnotic doses.
Short-acting barbiturates are well absorbed (primarily from the small intestine), with the onset of action being more rapid than with long- or intermediate-acting barbiturates.
The relative lipophilicity of each barbiturate determines the extent that they partition into fat. At steady state, the highest concentration of barbiturate in non-adipose tissue occurs in the liver and the kidney. The bio-transformation of most short-acting barbiturates occurs in the liver, where side-chains are oxidised to more polar and inactive compounds (e.g. alcohols, ketones, phenols or carboxylic acid) (Ellenhorn, 1988).
Pentobarbital is a short-acting barbiturate that is effective as an anaesthetic and euthanasia treatment for animals due to the nonselective central nervous system (CNS) depressant action. The sodium salt occurs as a white, slightly bitter powder which is freely soluble in water and alcohol but practically insoluble in benzene and ether (FDA, 2012).
Table 2.2: Chemical informatio
Property | Pentobarbital | Pentobarbital sodium |
---|---|---|
CAS Number | 76-74-4 | 57-33-0 |
EC Number | 200-983-8 | 200-323-9 |
IUPAC name | 5-ethyl-5-(1-methylbutyl)-2,4,6(1H,3H,5H)-Pyrimidinetrione | 5-ethyl-5-(1-methylbutyl)-2,4,6(1H,3H,5H)-Pyrimidinetrione sodium salt |
Chemical structures | ![]() |
![]() |
Molecular formula | C11H18N2O3 | C11H18N2NaO3 |
Molecular Weight | 226.27 g/mol | 249.26 g/mol |
Other names | Pentobarbitone; 5-ethyl-5-(1-methylbutyl) barbituric acid; 5-ethyl-5-(sec-pentyl)barbituric acid; pentobarbituric acid; ethaminal; mebubarbital; NSC 28708; nembutal; neodorm | Sodium 5-ethyl-5-(1-methylbutyl) barbiturate; sodium 5-ethyl-4,6-dioxo-5-(pentan-2-yl)-1,4,5,6-tetrahydropyrimidin-2-olate; auropan; barpental; biosedan; butylone; diabutal; embutal; entobar; etaminal sodium; ethaminal sodium; euthanyl; euthatal; isobar; mebubarbital sodium; mebumal sodium; mebunat; NSC 10816; napental; narcoren; nembutal sodium; pacifan; pental; pentobarbital sodium; pentobarbitone sodium; pentonal; pentone; praecicalm; RS-pentobarbital sodium; sagatal; sodium 5-ethyl-5-(1-methylbutyl)barbiturate; sodium ethaminal; sodium Nembutal; sodium pental; sodium pentobarbital; sodium pentobarbitone; sodium pentobarbiturate; sodium-pent; soluble pentobarbital; somnopentyl; somnotol; sopental; sotyl; V-pento; vetbutal |
Human Therapeutic names: Carbrital; Nembutal; Pentalgin (with codeine and paracetamol); and Pentobarbitone
Veterinary names: Valabarb Euthanasia Solution; Lethabarb Euthanasia Injection; Lethapharm Euthanasia Injection; Illium Pentobarbitone Sodium Anaesthetic Injection; and Euthanimal 40% Euthanasia Injection.
Of the 32 pre-meeting submissions received, 7 supported and 25 opposed the proposal.
The main points supporting the proposal were as follows:
The main points opposing the proposal were as follows:
The committee advised that the current scheduling of pentobarbital remains appropriate.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; (f) any other matters that the Secretary considers necessary to protect the public health.
The reasons for the advice comprised the following:
The delegates considered the following in regards to this application:
The delegates' interim decision is that the current scheduling of pentobarbital remains appropriate and the delegates' recommend that that state and territory governments consider standardisation of the controls under their legislation.
The delegates considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; (f) any other matters that the Secretary considers necessary to protect the public health.
The reasons for the interim decision are the following:
One (1) submission was received in response to the interim decision. It was unclear whether the submission supported or opposed the interim decision. The submission included a transcript of a presentation by Hon Nick Goiran and Ms Elizabeth Storer and noted the following statement from the interim decision, 'Impact on intentional suicide is unclear, but was thought to be low when considering the available data of suicides, and the people that were misusing pentobarbital for suicidal purposes'.
The delegates have confirmed the interim decision and reasons for the decision as no evidence has been received to alter the interim decision. The delegates' final decision is that the current scheduling for pentobarbital remains appropriate and that state and territory governments consider standardisation of the controls under their legislation.
Reasons for the final decision additional to those provided from the interim decision include:
The medicines scheduling delegate in view of the upcoming rescheduling of cannabis and tetrahydrocannabinols (THCs) proposes to consider:
The final decision for cannabis provides for hemp seed oil to be exempt from Schedules 8 and 9 when the levels of total cannabinoids are 50 mg/kg or less.
Due to further information provided after the publication of the final decision, the scheduling delegate is undertaking further consideration. This proposal seeks to determine whether this cut-off for total cannabinoids is appropriate for hemp seed oil, and the delegate is requesting additional information on the levels of cannabinoids (including tetrahydrocannabinols) in hemp seed oil. The delegate is also proposing to add to the cannabis entries regarding the hemp seed oil exception the following:
"when labelled with either of the following warning statements:
This was a delegate-initiated application. The delegate's proposed amendments to the Poisons Standard are as follows:
Schedule 9 - Amend entry
CANNABIS (including seeds, extracts, resins, and the plant and any part of the plant when packed or prepared), except:
Schedule 8 - Amend entry
CANNABIS (including seeds, extracts, resins and the plant, and any part of the plant) when prepared or packed for human therapeutic use, when:
Appendix D, Item 1
CANNABIS for human use.
Appendix K
CANNABIS
The delegate's reasons for the proposal is:
Cannabis and cannabinoids are currently listed in Schedules 4, 8 and 9, and in Appendix D and Appendix K.
Hemp seed oil is defined in the Interpretation of the Poisons Standard as follows:
PART 1 - INTERPRETATION
"Hemp seed oil" means the oil obtained by cold expression from the ripened fruits (seeds) of Cannabis sativa.
Following the 31 August 2016 final scheduling decision for cannabis and tetrahydrocannabinols to be implemented on 1 November 2016, the entries for cannabis, tetrahydrocannabinols and nabiximols will be listed in Schedules 8 and 9, and Appendix D and Appendix K as follows:
Schedule 9
CANNABIS (including seeds, extracts, resins, and the plant and any part of the plant when packed or prepared), except:
TETRAHYDROCANNABINOLS and their alkyl homologues, except:
Schedule 8
CANNABIS (including seeds, extracts, resins and the plant, and any part of the plant) when prepared or packed for human therapeutic use, when:
TETRAHYDROCANNABINOLS when extracted from cannabis for human therapeutic use, when:
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.
Schedule 4
CANNABIDIOL in preparations for therapeutic use containing 2 per cent or less of other cannabinoids found in cannabis.
Appendix D, Item 1
CANNABIS for human use.
TETRAHYDROCANNABINOLS for human use.
Appendix K
CANNABIS
TETRAHYDROCANNABINOLS
Index
CANNABICHROMENE
cross reference: NABIXIMOLS, CANNABIS
CANNABIDIOL
cross reference: NABIXIMOLS, CANNABIS
CANNABIDIOLIC ACID
cross reference: NABIXIMOLS, CANNABIS
CANNABIDIVAROL
cross reference: NABIXIMOLS, CANNABIS
CANNABIGEROL
cross reference: NABIXIMOLS, CANNABIS
CANNABINOIDS
cross reference: NABIXIMOLS, CANNABIS, TETRAHYDROCANNABINOLS
CANNABINOL
cross reference: NABIXIMOLS, CANNABIS
CANNABIS
cross reference: CANNABIS SATIVA, HEMP, HEMP SEED OIL, TETRAHYDROCANNABINOLS
TETRAHYDROCANNABINOLIC ACID
cross reference: NABIXIMOLS, TETRAHYDROCANNABINOLS
TETRAHYDROCANNABINOLS
cross reference: CANNABIS, HEMP SEED OIL, NABIXIMOLS
TETRAHYDROCANNABIDIVAROL
cross reference: NABIXIMOLS, TETRAHYDROCANNABINOLS
In August 1999, the committee reviewed the status of its foreshadowed proposal to amend the Schedule 9 entry for cannabis to exempt from scheduling cannabis when grown commercially for fibre production and manufactured goods containing hemp fibre. It was seen that such a proposal would provide uniformity in controls exerted by state and territory governments. A general exemption for hemp fibre and hemp fibre products could be made. The committee considered a general exemption for hemp fibre and hemp fibre products could be made. The exemption would allow sale of such hemp fibre and manufactured products in all jurisdictions.
In May 1998, the committee considered additional technical and regulatory information relating to a request to exempt from Schedule 9 tetrahydrocannabinols when in hemp seed oil and products for external use when containing 50 mg/kg or less of tetrahydrocannabinols (THC). The committee supported the proposal that hemp seed oil and products containing hemp seed oil should be exempt from the Schedule 9 entry for tetrahydrocannabinols when containing 50 mg/kg of THC and when for external use.
In October 2009, the committee considered an entry specific for Cannabis sativa extract, nabiximols, after the issue was raised at the June 2009 meeting that certain jurisdictions were unable to allow SAS access to the substance as it was captured under Schedule 9. As discussed in June, the committee members agreed on the Schedule 8 listing. The committee also agreed that the Schedule 8 entry should limit the allowed presentation to buccal sprays as this would further reinforce the very restricted scope of this entry and would require any new presentation to be brought to the attention of the committee.
In May 2010, nabiximols were included in Schedule 8 and Appendices D and K. The committee advised that nabiximols needed to be added to Appendix D, Item 3 to limit access through SAS Category A. This addition would allow restricted access to nabiximols only, not to cannabis extracts, but would not prohibit use for clinical trials provided by an authorised prescriber only. The committee agreed to not restrict the Schedule 8 nabiximols entry by indication (for Multiple Sclerosis). Members additionally agreed that it would be appropriate to include nabiximols in Appendix K due to sedating effects.
In March 2013, the committee considered a proposal to reschedule nabiximols from Item 3 of Appendix D to Item 1 of Appendix D of the SUSMP and amended Appendix D to include the entry of nabiximols.
In August 2016, the delegate amended the nabiximols entry in line with the August 2016 decision for cannabis and tetrahydrocannabinols to use the plural 's' for tetrahydrocannabinols and their acids.
In March 2016, the committee considered a proposal to amend the Schedule 9 entries and create new Schedule 8 entries for cannabis and tetrahydrocannabinols with Appendix D, Part 1 and Appendix K warnings. The committee supported the proposal and in August 2016, the Medicines Scheduling Delegate decided to amend the scheduling entries for cannabis, tetrahydrocannabinols and nabiximols, with an implementation date of 1 November 2016.
Minutes of these meetings are available on Govdex (Dashboard/Advisory committee on Medicines Scheduling/Meeting/Minutes).
Under the Narcotic Drugs Act 1967 (the ND Act) a 'drug' includes all extracts of cannabis (including hemp) from cannabis plants.
The manufacture of a drug that includes (or is from) a cannabis plant, can only be authorised under a manufacture licence in limited circumstances under the ND Act. As outlined under Section 11K, the Secretary must refuse to grant a manufacture licence if not satisfied on reasonable grounds with one of the following (these are set out in paragraphs 11K(2)(b) and (c), respectively):
Therefore extracts of cannabis (or hemp), or the manufacture of drugs from cannabis plants, may only be for the purposes of the aforementioned activities.
Extracts for food, cosmetics, veterinary use (including pet food) are not permitted.
Cannabis, cannabinoids, cannabis resins, tetrahydrocannabinols, cannabis seeds, cannabis plants and parts of cannabis plants are prohibited imports under the Customs (Prohibited Imports) Regulations 1956. Cannabis and THCs that are in Schedule 9 will not be granted an import permit, unless a State or Territory Health Department agency also authorises/grants the applicant a permission to possess, hold or supply cannabis or THC listed under Schedule 9 of the current Poisons Standard.
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 that 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 tetrahydrocannabinols 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 (Sativex®) as an adjunctive treatment for the symptomatic relief of neuropathic pain in 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 articles26 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, ad 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 be naturally occurring.
Three (3) public submissions were received for cannabis. Of these, 2 were opposed to the proposed amendments, and one proposed an additional amendment. The main points were:
The committee advised that the Schedule 9 and Schedule 8 entries for cannabis and Schedule 9 entry for tetrahydrocannabinols be amended as follows:
Schedule 9 - Proposed Amended Entry
CANNABIS (including seeds, extracts, resins, and the plant and any part of the plant when packed or prepared), except:
Schedule 8 - Proposed Amended Entry
# CANNABIS (including seeds, extracts, resins and the plant, and any part of the plant) when prepared or packed for human therapeutic use, when:
Schedule 9 - Proposed Amended Entry
TETRAHYDROCANNABINOLS and their alkyl homologues, except:
Schedule 8 - Proposed Amended Entry
# TETRAHYDROCANNABINOLS when extracted from cannabis for human therapeutic use, when:
The committee recommended that the schedule entry for cannabidiol be amended in Schedule 4 of the Poisons Standard to include a consistent hemp seed oil exemption:
Schedule 4 - Proposed Amended Entry
CANNABIDIOL in preparations for therapeutic use containing 2 per cent or less of other cannabinoids found in cannabis, except when:
The committee recommended an implementation date of 1 June 2017.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; (f) any other matters that the Secretary considers necessary to protect the public health.
The reasons for the advice comprised the following:
The delegates considered the following in regards to this application:
The delegates' interim decision is that:
The amended wording for the Schedule 8 and Schedule 9 entries for cannabis and tetrahydrocannabinols and the Schedule 4 entry for cannabidiol are as follows:
Schedule 9 - Amend Entry
# CANNABIS (including seeds, extracts, resins, and the plant and any part of the plant when packed or prepared), except:
Schedule 8 - Amend Entry
# CANNABIS (including seeds, extracts, resins and the plant, and any part of the plant) when prepared or packed for human therapeutic use, when:
Schedule 9 - Amend Entry
# TETRAHYDROCANNABINOLS and their alkyl homologues, except:
Schedule 8 - Amend Entry
# TETRAHYDROCANNABINOLS when extracted from cannabis for human therapeutic use, when:
Schedule 4 - Amend Entry
CANNABIDIOL in preparations for therapeutic use containing 2 per cent or less of total other cannabinoids found in cannabis.
Appendix D, item 1 - Current entries
CANNABIS for human use.
TETRAHYDROCANNABINOLS for human use.
Appendix K - Current entries
CANNABIS
TETRAHYDROCANNABINOLS
The proposed implementation date is 1 June 2017.
The delegates considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; (f) any other matters that the Secretary considers necessary to protect the public health.
The reasons for the interim decision are the following:
One (1) submission was received and this opposed the interim decision. The main points of the submission were:
The delegate has deferred making a final decision at this time regarding the possible rescheduling of cannabis. The deferral of a final decision will allow sufficient time for the delegate to thoroughly consider all public submissions on the interim decision, including two late submissions. Further information on the final decision regarding the possible rescheduling of cannabis is likely to be provided by late May 2017. Should the final decision be released at this time and require an implementation date, it will be announced at the time of publication.
23 "Cultivation", "production" and "manufacture" have the same meaning as in the Narcotic Drugs Act 1967
24 The November 2016 Poisons Standard contains an error, referring to 'cannabinols' instead of 'cannabinoids' under the Schedule 9 cannabis entry at item c. This will be corrected in the February 2017 update to be consistent with the August 2016 decision, pending the outcome of the advice of the committees.
25 "Cultivation", "production" and "manufacture" have the same meaning as in the Narcotic Drugs Act 1967
26 http://www.foodstandards.gov.au/code/proposals/Pages/P1042LowTHChemp.aspx and Leizer, C. et al., The Composition of Hemp Seed Oil and Its Potential as an Important Source of Nutrition, J. Nutraceuticals, Functional & Medical Foods 2000 2(4) 35 - 53, http://www.extsoilcrop.colostate.edu/CropVar/documents/oilseeds/alternative_oil/potential_of_hemp_seed_oil.pdf
27 "Cultivation", "production" and "manufacture" have the same meaning as in the Narcotic Drugs Act 1967
An applicant has proposed to amend the wording of the Schedule 7 entry for Epidermal Growth Factor (EGF), to exempt topical cosmetic preparations containing low concentrations of transgenic plant-made epidermal growth factor from the scope of the Schedule 7 entry.
This was a general application. The applicant's proposed amendments to the Poisons Standard are as follows:
Schedule 7 - Proposed amended Entry
EPIDERMAL GROWTH FACTOR except:
The applicant's reasons for the proposal are:
Epidermal growth factor is in Schedule 7 and Appendix J of the Poisons Standard as follows:
Schedule 7
EPIDERMAL GROWTH FACTOR except in preparations for human therapeutic use.
Appendix J
EPIDERMAL GROWTH FACTOR, Condition 1 (Not to be available except to authorised or licensed persons).
In November 1996, the NDPSC considered an application for a recombinant epidermal growth factor for use in sheep. It was listed in the SUSMP in Schedule 7 and Appendix J, Condition 1.
In June 2008, the NDPSC considered a minor editorial amendment to the Schedule 7 entry of epidermal growth factor, changing the entry from "other than for" to "except for" in reference to "preparations for human therapeutic use".
No information was found on the clinical use of EGF in Australia, the USA or EU. It has been used experimentally to treat diabetic foot ulcers (https://www.ncbi.nlm.nih.gov/pubmed/23396236) and mucositis in patients undergoing radiotherapy (https://www.ncbi.nlm.nih.gov/pubmed/19514089). A collation of published papers (through PubMed and Bioline International) related to the clinical use of EGF was published in 2009 (http://onlinelibrary.wiley.com/doi/10.1111/j.1742-481X.2009.00622.x/full).
Human epidermal growth factor (EGF) is a short 53 amino acid polypeptide. It is secreted by cells and acts as a mitogen, stimulating cellular proliferation, differentiation and survival primarily through the epidermal growth factor receptor (EGFR).
Figure 2.4: Signal transduction activity resulting from EGF binding to its receptor28.
The applicant summarises the plant-made EGF as follows:
One (1) pre-meeting submission was received which supported the proposal on the basis that it will align Australian regulatory controls with comparable overseas jurisdictions.
The committee advised that the current scheduling of epidermal growth factor remains appropriate.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; (f) any other matters that the Secretary considers necessary to protect the public health
The reasons for the advice comprised the following:
The delegates considered the following in regards to this application:
The delegates' interim decision is that the current scheduling of epidermal growth factor remains appropriate.
The delegates considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; (f) any other matters that the Secretary considers necessary to protect the public health.
The reasons for the interim decision are the following:
Two submissions were received and both opposed the delegate's interim decision. The main points were:
The delegates note the submissions and have confirmed the interim decision and reasons for the decision as no evidence has been received to alter the interim decision. The delegates' final decision is that the current scheduling for epidermal growth factor remains appropriate.
28 Sourced from: http://www.abcam.com/index.html?pageconfig=resource&rid=10723
29 Magnusdottir A, Vidarsson H, Björnsson JM, and Örvar BL (2013), 'Barley grains for the production of endotoxin-free growth factors', Trends in Biotechnology, 31 (10), 572-580.
The TGA has proposed that a new Schedule 5 entry be created for fennel oil (active component of fennel oil - methyl chavicol), with consideration of the appropriateness of low volume containers with a restricted flow insert, Medicines Advisory Statements, such as 'keep out of reach of children'; or exemption cut-off of 5 per cent or less of methyl chavicol.
This was a general application. The applicant's proposed amendments to the Poisons Standard are as follows:
Schedule 5 - New Entry
FENNEL OIL except:
KEEP OUT OF REACH OF CHILDREN; or
The applicant's reasons for the request are:
Fennel oil is not specifically scheduled in the Poisons Standard however basil oil (which also may contain methyl chavicol) is included in Schedule 5 and Appendix E as follows:
Schedule 5
BASIL OIL - except:
KEEP OUT OF REACH OF CHILDREN; or
Appendix E, Part 2 - BASIL OIL
Warning 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).
Basil Oil is also included in Part 2.4 with a container nominal capacity limit of 200 mL or less for CRCs.
The ARTG contains multiple entries for listed medicines containing fennel oil. It is currently used as an excipient in 17 listed medicines and as an active in eleven listed medicines.
Fennel oil is listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 1 of 2017 as an active, excipient and homoeopathic preparation ingredient. There are no specific requirements applying to the ingredient.
Fennel oil is unclassified in New Zealand and the USA with brief searches for drug products or medicines containing fennel oil, methyl chavicol, chavicol, or estragole on the FDA or Medsafe databases returning no information.
Fennel oil is extracted from the seeds of Foeniculum vulgare Mill. (Apiaceae; International Plant Names Index: kew-2813604).
Property | Fennel oil |
---|---|
CAS No. | 8006-84-6. |
Australian Approved Name (AAN) | Fennel oil (53603) |
Structure of major volatile components of fennel oil | ![]() |
There are two varieties of fennel in use - sweet fennel (Foeniculum vulgare Mill. subsp. vulgare var. dulce (Mill.) Batt.) and bitter fennel (Foeniculum vulgare Mill. subsp. vulgare var. vulgare). The oils extracted from the two varieties differ slightly in their chemical composition. Sweet and bitter fennel oils contain several components of which trans-anethole (50-80%) and estragole (methyl chavicol, 5-20%) are of concern due to their toxic effects.
The safety report concluded that on the basis of the unequivocal evidence of carcinogenicity for estragole, in combination with the current Schedule 5 entry for basil oil (containing a similar content of estragole), suggests that fennel oil should also be scheduled with the similar restrictions.
One (1) public submission was received. The submission did not indicate whether or not it supported the proposal. The main points were:
The committee advised that a new Schedule 5 entry be created for fennel oil as follows:
Schedule 5 - New entry
FENNEL OIL except:
KEEP OUT OF REACH OF CHILDREN; or
Appendix E, Part 2 - New Entry
FENNEL OIL
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)
2.4 Child resistant closures - New Entry
Column 1
Name of the poison: Fennel oil when included in Schedule 5
Column 2
Nominal capacity: 200 millilitres or less
The ACCS/ACMS advised an implementation date of 1 June 2017
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (f) any other matters that the Secretary considers necessary to protect the public health.
The reasons for the advice comprised the following:
The delegate considered the following in regards to this application:
The delegates' interim decision is that a new Schedule 5 entry be created for fennel oil.
The proposed wording for the schedule and appendix entries is as follows:
Schedule 5 - New Entry
FENNEL OIL except:
KEEP OUT OF REACH OF CHILDREN; or
Appendix E, Part 2 - New Entry
FENNEL OIL
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)
Part 2, Section 2.4 Child-resistant closures - New Entry
Column 1, Name of the poison: Fennel oil when included in Schedule 5.
Column 2, Nominal capacity: 200 millilitres or less.
The proposed implementation date is 1 June 2017.
The delegates considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (f) any other matters that the Secretary considers necessary to protect the public health.
The reasons for the interim decision are the following:
One (1) submission was received, which opposed the delegate's interim decision. The main points were:
The delegates note the submission and have confirmed the interim decision and reasons for the decision as no evidence has been received to alter the interim decision. The delegates' final decision is that a new Schedule 5 entry be created for fennel oil with an implementation date of 1 June 2017.
Scheduling medicines and poisons
The final decisions listed below all have an implementation date of 1 June 2017 unless separately specified.
Substance | Final decision |
---|---|
Vitamin D | Appendix H - New Entry VITAMIN D |
Melatonin | The current scheduling for melatonin remains appropriate. |
Paracetamol/caffeine | Schedule 2 – Amend Entry PARACETAMOL for therapeutic use:
|
Vardenafil | The current scheduling of vardenafil remains appropriate. |
Cetirizine hydrochloride | Schedule 4 –Amend Entry CETIRIZINE HYDROCHLORIDE except:
Schedule 2 –Amend Entry CETIRIZINE HYDROCHLORIDE in preparations for oral use except in preparations for the treatment of seasonal allergic rhinitis in adults and children 12 years of age an over when:
|
Tianeptine | Schedule 4 – New Entry TIANEPTINE. Appendix D Item 5 – New Entry TIANEPTINE. |
Olaparib | Schedule 4 – New Entry OLAPARIB. |
Ceritinib | Schedule 4 – New Entry CERITINIB. |
Panobinostat lactate | Schedule 4 – New Entry PANOBINOSTAT. |
Brivaracetam | Schedule 4 – New Entry BRIVARACETAM. Appendix K – New Entry BRIVARACETAM. |
Guanfacine hydrochloride | Schedule 4 – New Entry GUANFACINE. Appendix K – New Entry BRIVARACETAM. |
Follitropin delta | Schedule 4 – New Entry #FOLLITROPIN DELTA. Appendix D, Item 1 – New Entry FOLLITROPIN DELTA (recombinant human follicle-stimulating hormone) for human use. Index – New Entry FOLLITROPIN DELTA cross reference: FOLLICLE-STIMULATING HORMONE, RECOMBINANT HUMAN Schedule 4 Appendix D, Item 1 |
Scheduling medicines and poisons
An application was submitted to include Vitamin D in Appendix H in the Poisons Standard.
This is a general application. The applicant's proposed amendments to the Poisons Standard are as follows:
Appendix H – New Entry
VITAMIN D.
The applicant's reasons for the request are:
Vitamin D is currently listed in Schedule 3 and Schedule 4 of the SUSMP as follows:
Schedule 4
VITAMIN D for human internal therapeutic use except:
Schedule 3
VITAMIN D for human therapeutic use in preparations containing 175 micrograms or less of vitamin D per recommended single weekly dose except in preparations containing 25 micrograms or less of vitamin D per recommended daily dose.
Vitamin D is cross-referenced with cholecalciferol and ergocalciferol in the Index.
In October 2012, the ACMS considered a proposal by the same applicant to create a new Schedule 3 entry for vitamin D to allow a weekly dose up to 175 micrograms per recommended dose and to include vitamin D in Appendix H. The ACMS supported the proposal to allow the higher weekly dose, but advised against an Appendix H entry. Some members supported the Appendix H entry, stating that it would promote awareness of the weekly dosage regime. Other members did not support the Appendix H entry as public health activities were considered sufficient to promote appropriate use of vitamin D. There were also concerns about off label use and no limits on pack sizes. The committee also noted that other vitamin D products, as different formulations, were unscheduled and could be advertised. The delegate made a final decision (8 February 2013) to include vitamin D, as a single weekly dose of up to 175 micrograms (7000 IU), in Schedule 3 and not to include vitamin D in Appendix H.
Vitamin D is available primarily as cholecalciferol (vitamin D3), and ergocalciferol (vitamin D2). The major natural source of vitamin D in humans comes from the action of ultraviolet light on 7-dehydrocholesterol in the skin to form provitamin D3 which is then converted to cholecalciferol.
Table 3.1: Chemical information
Property | Cholecalciferol (vitamin D3) | Ergocalciferol (vitamin D2) |
---|---|---|
CAS No. | 67-97-0 | 50-14-6 |
Chemical structure | ![]() |
![]() |
Molecular formula | C27H44O | C28H44O |
Molecular weight | 384.6 | 396.7 |
Units | 25 micrograms = 1000 IU 175 micrograms = 7000 IU |
- |
AAN | cholecalciferol | ergocalciferol |
Chemical name | (5Z,7E)-9,10-secocholesta-5,7,10(19)-trien-3β-ol | (5Z,7E,22E)-9,10-secoergosta-5,7,10(19),22-tetraen-3β-ol |
Four (4) public submissions were received and all supported the proposal. The main points were:
The Committee recommended that Vitamin D be entered in Appendix H of the Poisons Standard.
The Committee also recommended an implementation date of 1 June 2017.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; (f) any other matters that the Secretary considers necessary to protect the public health.
The reasons for the advice comprised the following:
The delegate considered the following in regards to this application:
The delegate's interim decision is that a new Appendix H entry for Vitamin D is appropriate.
The proposed wording for the appendix entry is as follows:
Appendix H - New Entry
VITAMIN D
The proposed implementation date is 1 June 2017.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (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 the public health.
The reasons for the interim decision are the following:
No public submissions were received in response to the interim decision for vitamin D.
The delegate has confirmed the interim decision and reasons for the decision as no evidence has been received to alter the interim decision. The delegate's final decision is to create a new Appendix H entry for Vitamin D with an implementation date of 1 June 2017.
Scheduling medicines and poisons
An application was submitted to exempt melatonin for human use in preparations containing 1 mg or less of melatonin.
This was a general application. The Applicant’s proposed amendment to the Poisons Standard is as follows:
Schedule 4 – Proposed Amended Entry
MELATONIN for human use except when in preparations containing 1 mg or less of melatonin.
The applicant’s reasons for the request are:
Melatonin for human use is currently in Schedule 4 of the Poisons Standard.
In February 1987, the DPSC considered melatonin in a veterinary medicine to synchronise oestrous in ewes. Members agreed to include melatonin in Appendix B.
In February 1997, the NDPSC was advised of the compounding of melatonin capsules by a pharmacist, although the product had not been evaluated or registered by the TGA.
In May 1997, the NDPSC considered responses and information provided following the pre-meeting gazette notice advising it was its intent to consider the scheduling of melatonin at the May 1997 meeting. The NDPSC noted some of melatonin's current popularity related to its benefits in alleviating the symptoms of 'jet lag' and also to claims that it had anti-oxidant, anticancer and anti-aging effects. It was noted that New Zealand had scheduled melatonin as a prescription only medicine, in the absence of adequate data on safety and efficacy being provided to the regulators. The NDPSC considered that insufficient information was available on the safety of melatonin to allow it to remain exempt from scheduling for human therapeutic use and that it should not be available without prescription.
In November 2001, the NDPSC decided that where an entry existed in the Schedules for a particular use/s, no entry should be made in Appendix B; subsequently melatonin was deleted from the Appendix B listing.
Melatonin is a naturally occurring hormone, which is normally produced by the brain’s pineal gland. It is involved in co-ordinating the body’s sleep cycle by acting on cells in specific areas of the brain and helping to bring about sleep. Blood levels normally increase after the onset of darkness and peak in the middle of the night.
Property | Melatonin |
---|---|
CAS No. | 73-31-4 |
Chemical structure | ![]() |
Molecular formula | C13H16N2O2 |
Molecular weight | 232.3 |
IUPAC name | N-[2-(5-methoxy-1H-indol-3-yl)ethyl]; N-[2-(5-methoxyindol-3-yl)ethyl]acetamide |
Other chemical name/s | N-acetyl-5-methoxy tryptamine |
AAN | Melatonin |
Seven (7) public submissions were received. Two (2) submissions supported the proposal and five (5) submissions did not support the proposal.
The main points in support were:
The main points in opposition were:
The Committee recommended that the scheduling of melatonin remains appropriate.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; (f) any other matters that the Secretary considers necessary to protect the public health.
The reasons for the advice comprised the following:
The delegate considered the following in regards to this application:
The delegate’s interim decision is that the current scheduling for melatonin remains appropriate.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; (f) any other matters that the Secretary considers necessary to protect the public health.
The reasons for the interim decision are the following:
One (1) public submission was received which opposed the interim decision for melatonin. The submission proposes that the decision not to down-schedule melatonin when used in preparations containing 1 mg or less of melatonin should be re-considered with the following conditions:
The delegate has confirmed the interim decision and reasons for the decision as no evidence has been received to alter the interim decision. The delegate’s final decision is that the current scheduling for melatonin remains appropriate.
Additional reasons for the final decision are the following:
Scheduling medicines and poisons
An application was submitted to amend the scheduling of paracetamol when compounded with caffeine (paracetamol/caffeine), such that it will be exempt from Schedule 2 when supplied in primary packs of not more than 10 tablets/caplets or 5 sachets of powders/granules.
This is a general application. The Applicant’s proposed amendment to the Poisons Standard (which is not from the current October 2016 Poisons Standard) is as follows:
Schedule 2 – Proposed amendment
PARACETAMOL for therapeutic use except:
The applicant’s reasons for the request are:
The reasons cited were:
There has been little change in the core data sets supporting the favourable clinical efficacy and safety profile of paracetamol/caffeine since the 2014 submission. The current submission therefore focuses primarily on addressing the reasons previously cited by the ACMS to justify retaining paracetamol/caffeine in Schedule 2.
Paracetamol is currently listed in Schedule 2, Schedule 3, Schedule 4 and Appendix F in the Poisons Standard. It is also cross-referenced to aspirin, ibuprofen, metoclopramide, salicylamide. The recently implemented scheduling of paracetamol is 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:
Appendix F, Part 3 – PARACETAMOL
Standard 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. |
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. |
In June 2007, the NDPSC considered the scheduling of paracetamol and caffeine when combined in a compound analgesic as the only active agents. The NDPSC agreed to down schedule paracetamol when combined with caffeine from Schedule 4 as the indications for use, safety profile and potential for misuse met the criteria for a Schedule 2 medicine.
The scheduling of paracetamol combined with caffeine was reviewed in October 2009 by the NDPSC on the grounds of potential toxicity if used in excess. The NDPSC agreed that single active caffeine should remain unscheduled given that the evidence for long-term detrimental or toxic effects from abuse was generally lacking and that the Australian Guidelines for Registration of over-the-counter (OTC) Medicines (ARGOM) required all OTC medicines using caffeine as a stimulant or alerting agent to have an adult dose compliant with “100 mg/dose maximum, which may be repeated at 3 hourly intervals. Do not exceed 600 mg in 24 hours”.
NDPSC noted the concern of the addictive nature of caffeine and could lead to dependence and potential overuse or abuse of paracetamol with caffeine preparations possibly resulting in an increase in the likelihood of hepatotoxicity due to the paracetamol. NDPSC noted, however, that they had undertaken extensive deliberations in June 2007 on the scheduling of paracetamol with caffeine. It was asserted that the concerns raised were reviewed comprehensively at that time and the NDPSC had agreed to down-schedule paracetamol with caffeine from Schedule 4 to Schedule 2. NDPSC agreed that applicant had not provided any information about the safety of paracetamol with caffeine that had not been previously considered in June 2007. The Committee decided that Schedule 2 remained appropriate.
In November 2014, the ACMS considered a proposal to amend Schedule 2 entry to exempt paracetamol when compounded with caffeine by the same applicant, in a powder or granule product containing 1000mg or less of paracetamol and in tablets or capsules containing 500mg or less of paracetamol when paracetamol is the only therapeutic active constituent and when supplied in primary packs of not more than 20 tablets/caplets or 10 sachets of powders/granules.
The applicant provided the following reasons to support their 2014 proposal:
The ACMS advised that the current scheduling of paracetamol when compounded with caffeine remained appropriate.
In March 2016, the ACMS considered and supported a proposal by OTC Medicines Evaluation to amend the Schedule 2 entry for paracetamol to (a) restrict the pack size requirements to no more than 100 tablets or capsules per pack and no more than 50 wrapped powders or sachets of granules per pack for domestic supply, and (b) specifically limit bulk pack sizes of paracetamol for supply only to hospital, nursing homes and pharmacies for dispensing purposes. The delegate published a final decision on 23 June 2016 with an implementation date of 1 October 2016.
Paracetamol is a synthetic, non-opiate derivative of p-aminophenol that produces analgesia and antipyresis. It is a white crystalline powder with a slightly bitter taste. Paracetamol is soluble in boiling water and freely soluble in ethanol. A saturated aqueous solution has a pH of 5.1 - 6.5 and is stable if stored in an airtight container and is protected from light. The stability of paracetamol decreases in alkaline conditions, where it is slowly broken down into acetic acid and p-aminophenol. The pKa of paracetamol is 9.5.
Caffeine is a methylxanthine that acts on the higher centres of the central nervous system. Its stimulant properties can increase mental alertness and reduce fatigue. Caffeine is not an analgesic, but has been used as an analgesic adjuvant for many years. It is partially soluble in water and ethanol. Caffeine is stable under normal conditions and weakly light sensitive in solution. Caffeine is a white powder or crystals. The pKa of caffeine is 14.
Property | paracetamol | caffeine |
---|---|---|
CAS No. | 103-90-2 | 50-08-2 |
Chemical name | N-(4-hydroxyphenyl)acetamide | 1,3,7-trimethylpurine-2,6-dione |
AAN | paracetamol | caffeine |
Chemical structure | ![]() |
![]() |
Molecular formula | C8H9NO2 | C8H10N4O2 |
Molecular weight | 151.2 g/mol | 194.2 g/mol |
Form | white crystalline powder | white powder or crystals |
Six (6) public submissions were received. Two (2) submissions supported the proposal and four (4) submissions did not support the proposal.
The main points in support were:
The main points opposed were:
The Committee recommended that the existing Schedule 2 entry be amended for paracetamol when compounded with caffeine as follows:
Schedule 2 – Amend Entry
PARACETAMOL for therapeutic use:
The ACMS advised an implementation date of 1 June 2017.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance.
The reasons for the advice comprised the following:
The delegate considered the following in regards to this application:
The delegate’s interim decision is that the existing Schedule 2 entry for paracetamol be amended to include combinations with caffeine.
The proposed schedule wording is as follows:
Schedule 2 – Amend Entry
PARACETAMOL for therapeutic use:
The proposed implementation date is 1 June 2017.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (e) the potential for abuse of a substance.
The reasons for the interim decision are the following:
One (1) public submission was received which supported the interim decision and the reasons for the decision.
The delegate has confirmed the interim decision and reasons for the decision as no evidence has been received to alter the interim decision. The delegate’s final decision is that the existing Schedule 2 entry for paracetamol be amended to include combinations with caffeine. The implementation date is 1 June 2017.
Scheduling medicines and poisons
An application was submitted to reschedule vardenafil in oral preparations containing up to 10 mg in Schedule 3.
This was a general application. The Applicant’s proposed amendment to the Poisons Standard is as follows:
Schedule 4 – Proposed Amended Entry
VARDENAFIL except when included in Schedule 3.
Schedule 3 – Proposed New Entry
VARDENAFIL in oral preparations containing 10 mg or less of vardenafil per dosage unit in packs containing not more than 8 dosage units.
The applicant’s reasons for the request are:
Vardenafil is currently listed in Schedule 4 of the Poisons Standard as follows:
Schedule 4
VARDENAFIL.
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 Australia, vardenafil 5, 10, and 20 mg tablets and vardenafil 10 mg dispersible tablets were registered as Prescription Only Medicines on the ARTG in April 2003.
Internationally (Canada and USA), vardenafil appears to be classified as prescription medicine.
Vardenafil is present in oral dosage forms as vardenafil hydrochloride trihydrate, which is nearly colourless, very slightly soluble in water, soluble in dilute hydrochloric acid and soluble in ethanol.
Vardenafil inhibits the most prominent phosphodiesterase (PDE) in the corpus cavernosum, the enzyme phosphodiesterase type 5 (PDE5), which specifically hydrolyses cGMP. By preventing the breakdown of cGMP, vardenafil allows the male to reach and maintain an erection when sexually stimulated to produce nitric oxide.
The maximum recommended dose is one orodispersible tablet daily (10 mg vardenafil) - Australian Public Assessment Report for Vardenafil.
Property | Vardenafil |
---|---|
CAS No. | 330808-88-3 (hydrochloride trihydrate), 224785-91-5 (anhydrous) |
Chemical structure | ![]() |
Chemical name | 2-[2-Ethoxy-5-[(4-ethylpiperazin-1-yl)sulfonyl]phenyl]-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(3H)-one hydrochloride. |
AAN | Vardenafil hydrochloride trihydrate (INNM) and vardenafil (INN) |
Molecular formula | C23H32N6O4S·HCl·3H2O (hydrochloride trihydrate) |
Molecular weight | 579.1 g/mol (hydrochloride trihydrate) |
Seven (7) public submissions were received. Six (6) submissions supported the proposal and one (1) opposed the proposal.
The main points in support were:
The main points opposed was:
The Committee advised that the current scheduling of vardenafil remains appropriate.
The Committee recommended adding this issue to the SPF review – Schedule 3/Schedule 4 boundary for ‘switch’ products. The Committee also recommended providing feedback to the applicant.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (e) the potential for abuse of a substance; (f) any other matters that the Secretary considers necessary to protect the public health.
The reasons for the advice comprised the following:
The delegate considered the following in regards to this application:
The delegate’s interim decision is that the current scheduling of vardenafil remains appropriate.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (e) the potential for abuse of a substance; (f) any other matters that the Secretary considers necessary to protect the public health.
The reasons for the interim decision are the following:
Two (2) public submissions were received that opposed the interim decision. The main points were:
The delegate has confirmed the interim decision and reasons for the decision as no evidence has been received to alter the interim decision. The delegate’s final decision is that the current scheduling of vardenafil remains appropriate.
Reasons for the final decision additional to those provided from the interim decision include:
Scheduling medicines and poisons
An application was submitted to reschedule cetirizine hydrochloride from Schedule 2 to unscheduled when in preparations for the treatment of seasonal allergic rhinitis in adults and children 12 years of age and over, when in a maximum pack size of 10 days’ supply labelled with a recommended daily dose not exceeding 10 mg of cetirizine hydrochloride.
This was a general application. The applicant’s proposed amendment to the Poisons Standard is as follows:
Schedule 4 – Proposed Amended Entry
CETIRIZINE HYDROCHLORIDE except:
Schedule 2 – Proposed Amended Entry
CETIRIZINE HYDROCHLORIDE in preparations for oral use except in preparations for the treatment of seasonal allergic rhinitis in adults and children 12 years of age an over when:
The applicant’s reasons for the request are:
Cetirizine hydrochloride is currently in Schedules 4 and 2 of the Poisons Standard as follows:
Schedule 4
CETIRIZINE HYDROCHLORIDE except:
Schedule 2
CETIRIZINE HYDROCHLORIDE in preparations for oral use except in preparations for the treatment of seasonal allergic rhinitis in adults and children 12 years of age an over when:
The scheduling of other histamine H1-receptor antagonists, loratadine and fexofenadine are as follows:
Loratadine
Schedule 4
LORATADINE except:
Schedule 2
LORATADINE in preparations for oral use except in divided preparations for the treatment of seasonal allergic rhinitis in adults and children 12 years of age and over when:
Fexofenadine
Schedule 4
FEXOFENADINE except:
FEXOFENADINE in preparations for oral use except in divided preparations for the treatment of seasonal allergic rhinitis in adults and children 12 years of age and over when:
Cetirizine
In May 1993, the DPSSC decided to include cetirizine hydrochloride in Schedule 4 and Appendix K.
In May 1997, the NDPSC decided to include cetirizine hydrochloride in Schedule 3 as the only therapeutically active substance in divided preparations for oral use containing 10 mg or less of cetirizine hydrochloride. A limit on pack size was not considered necessary. Cetirizine hydrochloride remained in Schedule 4 except when included in Schedule 3.
In February 1998, the NDPSC decided to amend the Schedule 3 entry for cetirizine hydrochloride to include all oral formulations of cetirizine hydrochloride, when it was the only active substance in the preparation (the Schedule 3 entry was no longer to be restricted to divided preparations and the maximum dosage unit size was deleted).
At the February 1999 Meeting, the NDPSC supported a recommendation from the Trans-Tasman Harmonisation Working Party (TTHWP) that, on grounds of harmonisation, cetirizine hydrochloride in preparations for oral use be rescheduled from Schedule 3 to Schedule 2. A consequence of the deletion from Schedule 3 was the deletion of the Appendix H entry.
In November 1999, the NDPSC decided to reschedule cetirizine in all preparations for oral use to Schedule 2. The Appendix H entry for cetirizine was deleted.
In October 2005, the NDPSC considered an application to amend the working of Appendix F Part 1 for cetirizine and to remove cetirizine from oral use from Appendix K. The evidence at the time indicated that cetirizine was no more sedating than loratadine and the NDPSC agreed to alter the wording of Appendix F Part 3 and remove cetirizine for oral use from Appendix K of the SUSDP.
In June 2012, the ACMS advised that cetirizine should be exempt from scheduling, when in divided forms for oral use containing 10 mg or less of cetirizine per dose, in packs containing not more than 5 days' supply for the treatment of seasonal allergic rhinitis.
Loratadine
In July 2013, the ACMS considered a proposal to reschedule loratadine from Schedule 2 to unscheduled in oral preparations containing 10 mg or less in packs containing not more than 5 daily doses for the treatment of seasonal allergic rhinitis in adults and children 6 years of age and over, with a warning label recommending a daily dose not exceeding 10 mg loratadine for adults and children with body weight over 30 kg, or recommended daily dose not exceeding 5 mg loratadine for children with body weight 30 kg and under. The ACMS recommended that the current scheduling of loratadine remained appropriate, due to the risk of inappropriate use and delay in correct diagnosis, the lack of data on adverse effects/experiences/poisoning in Australia, no substantial public health benefit in exempting from schedules and a complicated dosage regimen with risk of inappropriate dosing.
In March 2016, the ACMS considered a proposal to increase the pack size of unscheduled loratadine (10 mg or less) divided oral preparations from 5 dosage units to 10 dosage units when used in adults and children 12 years of age and over for the treatment of seasonal allergic rhinitis. The delegate made a final decision (23 June 2016) that the Schedule 2 and Schedule 4 entries for loratadine be amended to increase the unscheduled loratadine dosage from 5 dosage units to 10 dosage units in divided oral preparations when used in adults and children 12 years of age and over for the treatment of seasonal allergic rhinitis with an implementation date of 1 October 2016.
Cetirizine hydrochloride is an orally active H1-receptor antagonist and is indicated for relief of symptoms of seasonal allergic rhinitis.
Property | cetirizine hydrochloride |
---|---|
CAS No. | 83881-52-1 |
Chemical structure | ![]() |
Chemical name | (RS)-2-[2-[4-[(4-chlorophenyl)phenylmethyl]piperazin-1-yl]ethoxy]acetic acid dihydrochloride |
Australian Approved Name (AAN) | cetirizine hydrochloride |
Molecular Formula | C21H27Cl3N2O3 |
Molecular Weight | 461.8 g/mol |
Form | white, crystalline powder |
Solubility | water-soluble (160 g/100 mL) |
Formulation | It is formulated as white, film-coated, scored 10 mg tablets, oral liquid 1 mg/mL and oral drops 10 mg/mL |
The main point in support was:
The main points opposed were:
The Committee advised that the Schedule 2 and Schedule 4 listing for cetirizine hydrochloride should be amended to include 10 days’ supply.
The recommended wordings for the entries are as follows:
Schedule 4 – Amend Entry
CETIRIZINE HYDROCHLORIDE except:
Schedule 2 – Amend Entry
CETIRIZINE HYDROCHLORIDE in preparations for oral use except in preparations for the treatment of seasonal allergic rhinitis in adults and children 12 years of age an over when:
The ACMS advised an implementation date of 1 June 2017.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance.
The reasons for the advice comprised the following:
The delegate considered the following in regards to this application:
The delegate’s interim decision is that the Schedule 2 and Schedule 4 entries for cetirizine hydrochloride be amended from 5 days’ supply to 10 days’ supply.
The wording for the proposed schedule entries are as follows:
Schedule 4 - Amend Entry
CETIRIZINE HYDROCHLORIDE except:
Schedule 2 - Amend Entry
CETIRIZINE HYDROCHLORIDE in preparations for oral use except in preparations for the treatment of seasonal allergic rhinitis in adults and children 12 years of age an over when:
The proposed implementation date is 1 June 2017.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance.
The reasons for the interim decision are the following:
Two (2) public submissions were received that supported the interim decision and the delegate’s reasons for the decision. The main points were:
The delegate has confirmed the interim decision and reasons for the decision as no evidence has been received to alter the interim decision. The delegate’s final decision is that the Schedule 2 and Schedule 4 entries for cetirizine hydrochloride be amended from 5 days’ supply to 10 days’ supply with an implementation date of 1 June 2017.
Scheduling medicines and poisons
An application was submitted to include a new entry for tianeptine in Schedule 4.
This was a delegate-initiated application. The delegate’s proposed amendments to the Poisons Standard are as follows:
Schedule 4 – Proposed New Entry
TIANEPTINE.
The reason for the request is that tianeptine is currently being sold as a product name Stablon on at least one Australian website in powder form. Safety concerns have been raised that tianeptine is being abused, and poses a public health risk, requiring restrictions on its use.
Tianeptine is not currently scheduled and has not been previously considered for scheduling; a scheduling history is not available.
There have been several requests for special access of tianeptine in the past 10 years in Australia through the Special Access Scheme for Category B patients. Administration is usually by tablet, 37.5 mg – 75 mg daily, orally for twelve months.
Tianeptine is not an active in any products listed on the ARTG.
Tianeptine is marketed as Stablon in 15 European Union countries (France, Luxembourg, Portugal, Bulgaria, Romania, Slovakia, Poland, Malta, Hungary, Lithuania, Slovenia, Czech Republic, Austria, Latvia, and Estonia) and in 66 countries throughout the world.
France: Authorised for marketing in February 1987. Tianeptine is included in List I, for prescription duration restricted to 28 days with overlap prescription prohibited except on the express instruction of the prescriber written on the prescription. Further conditions apply on pharmacist where a copy of the prescription is to be held for 3 years. It is also included on the list of medicines refundable by National Health Insurance.
Singapore: Stablon (tablet 12.5 mg tianeptine sodium) is a prescription-only drug under Licence No. SIN11182P. It is included in the First Schedule (special restrictions under Rule 10 apply) and the Third Schedule (substances required by Rule 15 (Additional Restrictions on sale of certain poisons) to be sold upon a prescription given by a medical practitioner, dentist or veterinary surgeons) of the Poisons Act.
Bahrain: The Drug Control Directorate has classified tianeptine sodium under the 'special-drugs under-controlled prescriptions' category due to increasing reports of misuse and abuse by patients.
No information could be located for US, Canada or New Zealand regulation for tianeptine.
Tianeptine is a tricyclic compound with psycho-stimulant, anti-ulcer and anti-emetic properties. Tianeptine is considered as an anti-depressive agent and is used for treatment of major depressive disorder. Unlike other traditional anti-depressants that are selective serotonin reuptake inhibitors (SSRIs), tianeptine acts by increasing the presynaptic reuptake of serotonin and has indirect effects on alteration of glutamatergic receptors (AMDA and NMDA) activity. Reviews on the neurobiological activities of tianeptine, are attached.
Martindale states that tianeptine is given in oral doses of 12.5 mg, three times daily in treatment of depression. Doses should be reduced to a total of 25 mg daily in elderly patients. Isolated cases of hepatitis have been reported during treatment with tianeptine. Martindale also states that tianeptine has been reported to improve symptoms in patients with asthma. Martindale refers to reported misuse of tianeptine.
Tianeptine has one chiral centre and is present at the racemate. The stereocentre is at the C-11 position in the central thiazepinyl ring. Tianeptine differs chemically to other antidepressants by the presence of a sulphonamide function in the central nucleus and a lateral amino acid chain (see Table 3.6 for additional chemical information).
Property | Tianeptine (free acid) | Tianeptine sodium |
---|---|---|
CAS No. | 66981-73-5 (online websites and Martindale) 72797-41-2 (Merck Index and SciFinder) |
30123-17-2 (BP monograph and SciFinder) |
Chemical structure | ![]() |
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Molecular formula | C21H25ClN2O4S | C21H24ClN2NaO4S |
Molecular Weight | 436.9 g/mol | 458.9 g/mol |
Form | White solid | White or yellowish powder |
Melting point | 129 – 131°C | 180°C |
Chemical names | 7-[(3-chloro-6,11-dihydro-6-methyl-5,5-dioxidodibenzo[c,f][1,2]thiazepin-11-yl)amino]-heptanoic acid | 7-[(3-chloro-6,11-dihydro-6-methyl-5,5-dioxidodibenzo[c,f][1,2]thiazepin-11-yl)amino]-heptanoic acid monosodium salt (9CI) |
British Approved Name (BAN) | N/A | Sodium 7-[[(11RS)-3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-yl]amino]heptanoate S,S-dioxide |
International trade names | Stablon; Coaxil; Tatiniol; Tianeurax; and Zinosal. | As for Tianeptine (free acid) |
WHO ATC Classification | N: Central nervous system N06: Psychoanaleptics N06A: Anti-depressants N06AX: Other Anti-depressants N06AX14: Tianeptine |
As for Tianeptine (free acid) |
Tianeptine is hygroscopic, and freely soluble in water. Tianeptine is amphoteric with two pKa values, 4.4 (acidic) and 6.86 (basic), and is weakly lipophilic (log P at pH 7.4 = 1.06).
Literature30 reports that absorption of tianeptine from tablet form is rapid and complete following oral administration to fasting healthy subjects. The mean Cmax of tianeptine is 334 +/- 79 ng/mL. Tmax is 0.94 +/- 0.47 h following oral administration. Absolute bioavailability is 99 +/- 29%. Tianeptine is rapidly and completely absorbed in the tablet form and is not subject to first-pass effect. Distribution of tianeptine in the body is characterized by the following: its rapidity, the mean distribution half-life being about 0.7 h; its limited extent, the apparent volume of distribution being about 0.8 L/kg (0.77 +/- 0.31 L/kg); and protein binding, which averages 93.8 +/- 2.4%. Elimination of tianeptine is characterized by a short mean half-life of 2 h 30 min (2.5 +/- 1.1 h) and by renal excretion of 0.4 ml/min (0.4 +/- 0.4 mL/min). Tianeptine is extensively metabolized. Major metabolites are analogues of tianeptine with a C5 and C3 lateral chain and an N-demethylated derivative. Studies have shown negligible influence on pharmacokinetic parameters of chronic alcoholism even in case of hepatic cirrhosis.
There is a BP/EP 2016 harmonised monograph for tianeptine sodium. There are no current USP monographs for Tianeptine or the Tianeptine Sodium. Online websites refer to both a sulfate and a sodium salt. The BP monograph for tianeptine sodium is transparent in relation to 4 impurities.
No pre-meeting submissions were received for tianeptine.
The Committee advised that tianeptine should be added to Schedule 4 and Appendix D Item 5.
The recommended wording for the entry is as follows:
Schedule 4 – New Entry
TIANEPTINE.
Appendix D item 5 – New Entry
TIANEPTINE.
The ACMS advised an implementation date of 1 June 2017.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance.
The reasons for the advice comprised the following:
The delegate considered the following in regards to this application:
The delegate’s interim decision is that a new Schedule 4 entry for tianeptine with an Appendix D item 5 entry is appropriate.
The proposed wording for the schedule and appendix entries is as follows:
Schedule 4 – New Entry
TIANEPTINE.
Appendix D item 5 – New Entry
TIANEPTINE.
The proposed implementation date is 1 June 2017.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance.
The reasons for the interim decision are the following:
No public submissions were received in response to the interim decision for tianeptine.
The delegate has confirmed the interim decision and reasons for the decision as no evidence has been received to alter the interim decision. The delegate’s final decision is to create new Schedule 4 and Appendix D Item 5 entries for tianeptine with an implementation date of 1 June 2017.
30Royer, R.J. et al., Pharmacokinetics and metabolic parameters of tianeptine in healthy volunteers and in populations with risk factors. Clin Neuropharmacol 1988, 11 Suppl 2:S90-6 http://www.ncbi.nlm.nih.gov/pubmed/3180120
Scheduling medicines and poisons
A New Chemical Entity (NCE) delegate from the Therapeutic Goods Administration has referred the substance olaparib, proposing that it be listed in Appendix L with warning statement 62 – Do not use if pregnant.
The proposed amendment to the Poisons Standard is as follows:
Schedule 4 – Proposed New Entry
OLAPARIB.
Appendix L – Proposed New Entry
OLAPARIB.
62 - Do not use if pregnant.
The reasons provided by the clinical delegate are based on its mechanism of action (PARP inhibition), LYNPARZA (olaparib) could cause foetal harm when administered to pregnant woman. Studies in rats have shown that olaparib causes embryofoetal lethality and induces major foetal malformations (major eye and vertebral/rib malformations) at exposures below those expected at the recommended human dose of 400 mg twice daily.
While this is currently approved for women who have had ovarian cancer (and will have had hysterectomy, salpingo-oophorectomy), there are proposed extensions of indications and the scheduling may not be reviewed again. This is a sensitive issue, as obviously such women cannot become pregnant.
Olaparib is not currently scheduled and has not been previously considered for scheduling; a scheduling history is therefore not available.
Olaparib is the active ingredient in one ARTG entry (product name Lynparza, AUST R 234008), formulated as a 50 mg capsule bottle by AstraZeneca Pty Ltd and registered on 13 October 2016.
Olaparib is not classified in New Zealand. In the USA and Canada, olaparib is a Prescription Only medicine.
Olaparib is an inhibitor of human poly (ADP-ribose) polymerase enzymes (PARP-1, PARP-2, and PARP-3) and is indicated as monotherapy for the maintenance treatment of patients with platinum-sensitive relapsed BRCA-mutated (germline or somatic) high grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer who have responded (complete response or partial response) after platinum-based chemotherapy. Prior treatment must have included at least 2 courses of platinum-based regimens.
Chemical information for olaparib is shown in Table 3.7. Several polymorphs of olaparib are reported. Olaparib is a non-hygroscopic crystalline powder, stable in the A form (non-solvated polymorph). There are no potential olaparib isomers except for tautomers of the phthalazinone which are likely to strongly favouring one form in solution. The pKa has been calculated to be -1.16 (basic) and 12.07 (acidic) on the phthalazinone moiety. Given this, olaparib would be unionised across the physiological pH range. Solubility is independent of pH.
The structure is not closely related to registered kinase inhibitors, nor to veliparib (an experimental PARP inhibitor). There are no official monographs for olaparib.
Property | Olaparib |
---|---|
CAS No. | 763113-22-0 |
Chemical structure | ![]() |
Chemical name | 4-[(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorophenyl)methyl]phthalazin-1(2H)-one |
Molecular formula | C24H23FN4O3 |
Molecular weight | 434.5 g/mol |
Melting point | 206°C |
Chirality | achiral |
Origin | synthetic |
Solubility | Low |
BCS* | Class IV (low solubility, low permeability) |
*Biopharmaceutical Classification System
One public submission was received and supported the proposal. No additional reasons for the support were provided.
The Committee advised that a new Schedule 4 entry for olaparib without an Appendix L entry is appropriate.
The recommended wording for the entry is as follows:
Schedule 4 – New Entry
OLAPARIB.
The ACMS advised an implementation date of 1 June 2017.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (f) any other matters that the Secretary considers necessary to protect the public health.
The reasons for the advice comprised the following:
The delegate considered the following in regards to this application:
The delegate’s interim decision is that a new Schedule 4 entry for olaparib without an Appendix L entry is appropriate.
The proposed wording for the schedule entry is as follows:
Schedule 4 - New Entry
OLAPARIB.
The proposed implementation date is 1 June 2017.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (f) any other matters that the Secretary considers necessary to protect the public health.
The reasons for the interim decision are the following:
No public submissions were received in response to the interim decision for olaparib.
The delegate has confirmed the interim decision and reasons for the decision as no evidence has been received to alter the interim decision. The delegate’s final decision is to create a new Schedule 4 entry for olaparib without an Appendix L entry with an implementation date of 1 June 2017.
Scheduling medicines and poisons
A New Chemical Entity (NCE) delegate from the Therapeutic Goods Administration has referred the substance ceritinib, proposing that the substance be listed in Appendix L with warning statement 62 – Do not use if pregnant.
The proposed amendment to the Poisons Standard is as follows:
Schedule 4 – Proposed New Entry
CERITINIB.
Appendix L – Proposed New Entry
CERITINIB.
62 - Do not use if pregnant
The reason provided by the clinical delegate is on the basis that there are no human data, but in animals, embryofoetal toxicity occurred at very low exposures (as low as 0.2-fold exposure intended in humans).
Ceritinib is not currently scheduled in Australia and has not been previously considered for scheduling; a scheduling history is therefore not available.
One registered product containing ceritinib (150 mg) was entered onto the ARTG on 16 September 2016. It is available for use as an active ingredient in prescription medicines but not available as an excipient or equivalent ingredient in any application.
Ceritinib lactate is not classified in New Zealand. In the USA and Canada, ceritinib is a Prescription Only Medicine.
Ceritinib is an inhibitor of anaplastic lymphoma kinase (ALK). The ALK inhibitor works against the ALK translocation involved in the development of certain cancers.
Property | Ceritinib |
---|---|
CAS No. | 1032900-25-6 |
Chemical structure | ![]() |
Chemical name | 5-chloro-2-N-{5-methyl-4-(piperidin-4-yl)-2-[(propan-2-yl)oxy]phenyl}-4-N-[2-(propane-2-sulfonyl) phenyl]pyrimidine-2,4-diamine |
Molecular formula | C28H36ClN5O3S |
Molecular weight | 558.1 g/mol |
Origin | Synthetic |
Form | White to almost white or light yellow or light brown powder |
Solubility | Good solubility in very acidic aqueous medium. The solubility decreases significantly with increasing pH. Good solubility is achieved in methanol. |
pH | 6.86 (in 1% water) |
Melting point | 174°C |
pKa | 4.1 and 9.7 |
Biopharmaceutical Classification System (BCS) status | Class IV (Low Permeability, Low Solubility) |
Isomerism | Ceritinib shows no isomerism with two known polymorphs. |
Ceritinib is indicated as monotherapy for the treatment of adult patients with anaplastic lymphoma kinase (ALK) positive locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on or who are intolerant of crizotinib. This indication is approved based on tumour response rates and duration of response. An improvement in survival or disease-related symptoms has not been established.
Two public submissions were received, one submission supported the Appendix L entry, with warning statement 62 – ‘Do not use if pregnant’, and one submission did not support the proposal.
The main points in opposition were:
The Committee advised that ceritinib be entered in Schedule 4 without an Appendix L entry.
The recommended wording for the entry is as follows:
Schedule 4 –New Entry
CERITINIB.
The ACMS recommended an implementation date of 1 June 2017.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (f) any other matters that the Secretary considers necessary to protect the public health.
The reasons for the advice comprised the following:
The delegate considered the following in regards to this application:
The delegate’s interim decision is that a new Schedule 4 entry for ceritinib without an Appendix L entry is appropriate.
The proposed wording for the schedule entry is as follows:
Schedule 4 - New Entry
CERITINIB.
The proposed implementation date is 1 June 2017.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (f) any other matters that the Secretary considers necessary to protect the public health.
The reasons for the interim decision are the following:
No public submissions were received in response to the interim decision for ceritinib.
The delegate has confirmed the interim decision and reasons for the decision as no evidence has been received to alter the interim decision. The delegate’s final decision is to create a new Schedule 4 entry for ceritinib without an Appendix L entry to be implemented on 1 June 2017.
Scheduling medicines and poisons
A delegate from the Therapeutic Goods Administration has referred the substance panobinostat lactate, a new chemical entity (NCE), proposing that it be listed in Appendix L with warning statement 62 – Do not use if pregnant.
The proposed amendment to the Poisons Standard is as follows:
Schedule 4 – Proposed New Entry
PANOBINOSTAT.
Appendix L – Proposed New Entry
PANOBINOSTAT.
62 - Do not use if pregnant.
The reason provided by the clinical delegate is on the basis that the effects of panobinostat are unknown in humans, but there is evidence of maternal toxicities, embryo-foetal lethality and malformations in two species, including at 0.5 times the proposed clinical exposure in rabbits in the nonclinical studies.
Other consideration: There is a boxed warning to alert prescribers and consumers to the potentially multiple and severe toxicities that may occur with this medicine. The indication was restricted to those with very limited remaining treatment options and includes the following statement: Treatment should be initiated and monitored by a specialist with experience in treating haematological malignancies.
Panobinostat lactate is not currently scheduled and has not been previously considered for scheduling; a scheduling history is therefore not available.
Panobinostat lactate is as an active ingredient in Farydak (Novartis Pharmaceuticals Australia Pty Ltd) as 10 mg, 15 mg and 20 mg capsules (AUST R. 229941, 230844 and 230845 respectively), registered on 31 March 2016.
Panobinostat lactate is not classified in New Zealand or Canada. In the USA, panobinostat lactate is a Prescription Only medicine.
Panobinostat lactate, in combination with bortezomib and dexamethasone, is indicated for the treatment of adult patients with relapsed and/or refractory multiple myeloma, who have received at least 2 prior regimens including bortezomib and an immunomodulatory agent. Treatment should be initiated and monitored by a specialist with experience in treating haematological malignancies.
Panobinostat lactate is a pan-inhibitor of Class I, II, and IV histone (and non-histone) deacetylases (HDACs/DACs).
While the free base of panobinostat has no chiral centres, the lactic acid is chiral and the racemate of lactic acid is used to prepare panobinostat lactate. The panobinostat double bond has controlled E (trans) stereochemistry. Panobinostat has a hydroxamic acid group ( CONHOH). See Table 3.9 for additional chemical information on panobinostat and panobinostat lactate.
Property | Panobinostat (free base) | Panobinostat lactate |
---|---|---|
CAS No. | 404950-80-7 | 960055-68-9 |
Chemical structure | ![]() |
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Molecular Formula | C21H23N3O2 | C21H23N3O2.C3H6O3 |
Molecular weight | 349.4 g/mol | 439.5 g/mol |
Chemical name | 3-[4-[2-(2-methyl-1H-indol-3-yl)ethylaminomethyl]phenyl]-2(E)-propenohydroxamic acid | (2E)-N-hydroxy-3-[4-({[2-(2-methyl-1H-indol-3-yl)ethyl]amino}methyl)phenyl]-2-propenamide 2-hydroxypropanoate (1:1) |
IUPAC name | (E)-N-hydroxy-3-[4-[[2-(2-methyl-1H-indol-3-yl)ethylamino]methyl]phenyl]prop-2-enamide | (E)-N-hydroxy-3-[4-[[2-(2-methyl-1H-indol-3-yl)ethylamino]methyl]phenyl]prop-2-enamide;2-hydroxypropanoic acid |
Origin and form | Synthetic; yellow solid | Synthetic; stable; crystalline (one known polymorph) |
Melting point | - | 175°C |
pKa | 8.4 and 9.0 (alkaline) | - |
Solubility | - | The aqueous solubility of panobinostat lactate is pH dependent, with maximum solubility at pH 2 or 3 (~ 5 mg/mL) and low solubility at neutral pH (0.3 mg/mL at pH 6.8); low solubility at pH 7.6 (0.07 mg/mL) |
Biopharmaceutics Classification System (BCS) | - | Class II (low solubility, high permeability).* |
* The solubility classification is borderline high.
Two public submissions were received. One submission supported the Appendix L entry, with warning statement 62 – ‘Do not use if pregnant’; and one submission did not support the proposal. The main points in opposition of the proposal were:
The Committee advised that panobinostat should be entered in Schedule 4 without an Appendix L entry.
The recommended wording for the entry is as follows:
Schedule 4 – New Entry
PANOBINOSTAT.
The ACMS advised an implementation date of 1 June 2017.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (f) any other matters that the Secretary considers necessary to protect the public health.
The reasons for the advice comprised the following:
The delegate considered the following in regards to this application:
The delegate’s interim decision is that a new Schedule 4 entry for panobinostat without an Appendix L entry is appropriate.
The proposed wording for the schedule entry is as follows:
Schedule 4 - New Entry
PANOBINOSTAT.
The proposed implementation date is 1 June 2017.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (f) any other matters that the Secretary considers necessary to protect the public health.
The reasons for the interim decision are the following:
No public submissions were received in response to the interim decision for panobinostat lactate.
The delegate has confirmed the interim decision and reasons for the decision as no evidence has been received to alter the interim decision. The delegate’s final decision is to create a new Schedule 4 entry for panobinostat without an Appendix L entry to be implemented on 1 June 2017.
Scheduling medicines and poisons
A New Chemical Entity (NCE) delegate from the Therapeutic Goods Administration has referred the substance brivaracetam, proposing that the substance be listed in Appendix K.
The proposed amendment to the Poisons Standard is as follows:
Schedule 4 – Proposed New Entry
BRIVARACETAM.
Appendix K – Proposed New Entry
BRIVARACETAM.
The reason provided by the clinical delegate is that brivaracetam is an antiepileptic medicine causing sedation.
Brivaracetam is not currently scheduled in Australia and has not been previously considered for scheduling; a scheduling history is therefore not available.
Brivaracetam is registered (product name Briviact) on the ARTG (as of 4 August 2016) for use as add-on therapy in the treatment of partial-onset seizures with or without secondary generalisation in patients from 16 years of age with epilepsy. Briviact (UCB Australia Pty Ltd T/A UCB Pharma Division of UCB Australia) is available as:
Brivaracetam is not classified in New Zealand. In the USA and Canada, brivaracetam is classified as a Prescription Only medicine.
Brivaracetam is indicated as adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalisation in patients from 16 years of age with epilepsy.
As a 4-n-propyl analogue of levetiracetam, brivaracetam is also a Synaptic Vesicle Glycoprotein 2A (SV2A) anti-seizure/anti-epileptic drug, displaying a high and selective affinity for synaptic vesicle protein 2A (SV2A) in the brain. Binding to SV2A is considered to be the primary mechanism for brivaracetam anticonvulsant activity, however, the precise mechanism by which brivaracetam exerts is anticonvulsant activity has not been fully elucidated. Brivaracetam did not act via Na+ channels in normal adult neurons and may act, in part, by inhibiting N-methyl-D-aspartate (NMDA) excitatory pathways and disinhibiting gamma-amino butyric acid (GABA) and glycine inhibitory pathways.
Brivaracetam has 2 chiral centres associated with C2 of the butanamide group and C4 of the 2-oxo-4-(1-propyl)pyrrolidine ring. Two polymorphs of brivaracetam are reported. Brivaracetam is highly soluble and is Class I according to the Biopharmaceutical Classification System (BCS) (Table 3.10).
The pharmacokinetic profile of brivaracetam is favourable and linear, and it undergoes extensive metabolism into inactive compounds, mainly through the hydrolysis of its acetamide group. Furthermore, it does not significantly interact with other antiepileptic drugs and more than 95% is excreted through the urine, with an unchanged fraction of 8%–11%.
Property | Brivaracetam |
---|---|
CAS No. | 357336-20-0 |
Chemical structure | ![]() |
Chemical name | (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl]butanamide |
Molecular Formula | C11H20N2O2 |
Molecular weight | 212.3 g/mol |
pKa | Brivaracetam has no ionisable centres, so pKa cannot be measured. |
Origin | Synthetic |
Form | White to off-white crystalline powder |
Solubility | It is very soluble in water, buffer (pH 1.2, 4.5 and 7.4), ethanol, methanol, and glacial acetic acid. Brivaracetam is freely soluble in acetonitrile and acetone and soluble in toluene. It is very slightly soluble in n-hexane. |
BCS status | Class 1 |
One public submission was received and supported the proposal. No reasons were given.
The Committee advised that brivaracetam should be entered in Schedule 4 with an Appendix K entry.
The recommended wording for brivaracetam is as follows:
Schedule 4 – New Entry
BRIVARACETAM.
Appendix K – New Entry
BRIVARACETAM.
The Committee recommended an implementation date of 1 June 2017.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance.
The reasons for the advice comprised the following:
The delegate considered the following in regards to this application:
The delegate’s interim decision is that a new Schedule 4 entry for brivaracetam with an Appendix K entry is appropriate.
The proposed wording for the schedule and appendix entries is as follows:
Schedule 4 –New Entry
BRIVARACETAM.
Appendix K –New Entry
BRIVARACETAM
The proposed implementation date is 1 June 2017.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance.
The reasons for the interim decision are the following:
No public submissions were received in response to the interim decision for brivaracetam.
The delegate has confirmed the interim decision and reasons for the decision as no evidence has been received to alter the interim decision. The delegate’s final decision is to create new Schedule 4 and Appendix K entries for brivaracetam with an implementation date of 1 June 2017.
Scheduling medicines and poisons
The New Chemical Entity (NCE) delegate from the Therapeutic Goods Administration has referred the substance guanfacine hydrochloride, proposing that the substance be listed in Appendix K.
The proposed amendment to the Poisons Standard is as follows:
Schedule 4 – Proposed New Entry
GUANFACINE HYDROCHLORIDE.
Appendix K – Proposed New Entry
GUANFACINE HYDROCHLORIDE
The reason provided by the clinical delegate is on the basis that guanfacine hydrochloride causes sedation.
Guanfacine hydrochloride is not currently scheduled in Australia and has not been previously considered for scheduling; a scheduling history is therefore not available.
Guanfacine hydrochloride is not classified in New Zealand. In the USA and Canada, Guanfacine hydrochloride is classified as a Prescription Only medicine.
Guanfacine hydrochloride is a central alpha2A-adrenergic receptor agonist and is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in paediatric patients (children and adolescents 6-17 years old inclusive).
Guanfacine hydrochloride is not a central nervous system (CNS) stimulant, a monoamine transporter inhibitor or releaser of presynaptic dopamine or norepinephrine. The mode of action of guanfacine hydrochloride in ADHD is not fully established. Preclinical research suggests guanfacine hydrochloride modulates signalling in the prefrontal cortex and basal ganglia through direct modification of synaptic norepinephrine transmission at the alpha 2-adrenergic receptors. The INN is guanfacine31.
There is a USP 36 monograph for guanfacine hydrochloride, but no BP 2016 monograph.
Property | Guanfacine hydrochloride |
---|---|
CAS No. | 29110-48-3 |
Chemical structure | ![]() |
Chemical name | N-amidino-2-(2,6-dichlorophenyl)acetamide monohydrochloride |
Australian Approved Name (AAN) | guanfacine hydrochloride (reference USP, USAN) |
Molecular formula | C9H9Cl2N3O.HCl |
Molecular weight | 282.6 g/mol (for the hydrochloride salt) |
Form | White to off-white powder (single polymorphic form) |
Solubility | sparingly soluble in water and alcohol and slightly soluble in acetone |
partition coefficient (logP) | 2-octanol/water: 0.10 |
Dissociation constant | 7.69 |
pH | ~4 when dissolved in water |
No pre-meeting submissions were received for guanfacine.
The Committee advised that guanfacine should be entered in Schedule 4 with an Appendix K listing.
The recommended wording for the guanfacine entry is as follows:
Schedule 4 –New Entry
GUANFACINE.
Appendix K –New Entry
GUANFACINE.
The Committee also recommended an implementation date of 1 June 2017.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (a) the risks and benefits of the use of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (f) any other matters that the Secretary considers necessary to protect the public health.
The reasons for the advice comprised the following:
The delegate considered the following in regards to this application:
The delegate’s interim decision is that a new Schedule 4 entry for guanfacine with an Appendix K listing is appropriate.
The proposed wording for the schedule and appendix entries is as follows:
Schedule 4 – New Entry
GUANFACINE.
Appendix K – New Entry
GUANFACINE
The proposed implementation date is 1 June 2017.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; (f) any other matters that the Secretary considers necessary to protect the public health.
The reasons for the interim decision are the following:
No public submissions were received in response to the interim decision for guanfacine hydrochloride.
The delegate has confirmed the interim decision and reasons for the decision as no evidence has been received to alter the interim decision. The delegate’s final decision is to create new Schedule 4 and Appendix K entries for guanfacine with an implementation date of 1 June 2017.
31 http://www.who.int/substance_abuse/publications/opioid_dependence_guidelines.pdf?ua=1 and http://apps.who.int/iris/bitstream/10665/68742/1/WHO_EDM_QSM_2004.5.pdf?ua=1
Scheduling medicines and poisons
A New Chemical Entity (NCE) delegate from the Therapeutic Goods Administration has referred the substance follitropin delta, proposing that the substance be listed in Appendix D, Item 1 – Poisons available only from or on the prescription or order of an authorised medical practitioner.
The proposed amendment to the Poisons Standard is as follows:
Schedule 4 – Proposed New Entry
FOLLITROPIN DELTA.
Appendix D – Proposed New Entry
FOLLITROPIN DELTA for human use.
Item 1 – Poisons available only from or on the prescription or order of an authorised medical practitioner.
The reason provided by the clinical delegate is that follitropin delta should only be prescribed by specialist medical practitioners (e.g., FRANZCOG, FRCOG) in respect of particular patients, following endocrine function tests carried out at an endocrine laboratory - as for other follitropins (alpha and beta).
Follitropin delta is not currently scheduled in Australia; however, the analogues follitropin alpha and follitropin beta are currently in the Poisons Standard as follows:
Schedule 4
# FOLLITROPIN ALPHA.
# FOLLITROPIN BETA.
Appendix D, Item 1 – Poisons available only from or on the prescription or order of an authorised medical practitioner.
FOLLITROPIN ALPHA (recombinant human follicle-stimulating hormone) for human use.
FOLLITROPIN BETA (recombinant human follicle-stimulating hormone) for human use.
Index
FOLLITROPIN ALPHA
cross reference: FOLLICLE-STIMULATING HORMONE, RECOMBINANT HUMAN
FOLLITROPIN BETA
cross reference: FOLLICLE-STIMULATING HORMONE, RECOMBINANT HUMAN
No products containing follitropin delta are on the Australian Register of Therapeutic Goods (ARTG). Currently registered products containing follitropin alpha or follitropin beta on the ARTG are tabulated below.
Active ingredient/s | Drug name | Additional actives | Relevant ARTG IDs | Formulation | Sponsor |
---|---|---|---|---|---|
Follitropin alpha | AFOLIA | N/A | 262649, 262648, 262647, 262646, 262645. | 5.5, 11, 16.5, 22 and 33 mg; solution for injection cartridge in a pre-filled pen. | Finox Biotech Australia Pty Ltd |
Follitropin alpha | BEMFOLA | N/A | 231053, 231052, 231051, 231046, 231039. | 5.5, 11, 16.5, 22 and 33 mg; solution for injection cartridge in a pre-filled pen | Finox Biotech Australia Pty Ltd |
Follitropin alpha | GONAL-F | N/A | 96237, 96236, 96230, 96114, 93043, 91564, 91563, 91562, 81623. | 37.5 IU (2.73 mg), 75 IU (5.46 mg), 150 IU (10.92 mg), 300IU /0.5mL (21.84 mg), 450IU /0.75mL (32.76 mg), 900IU /1.5mL (65.52 mg); and 45 and 1050 IU (retrievable dose); solution for injection cartridge, pre-assembled in a pen; powder for injection vial with diluent vial/syringe; and/or multidose powder for injection vial with diluent pre-filled syringe. | Merck Serono Australia Pty Ltd |
Follitropin alpha | PERGOVERIS | Lutropin alpha | 152797. | 150 IU / 75 IU; powder for injection vial with diluent vial. | Merck Serono Australia Pty Ltd |
Follitropin beta | PUREGON | N/A | 76437, 76436, 70858, 70857, 70856, 116843, 116842. | 50 IU/0.5mL, 100 IU/0.5mL, 150 IU/0.5mL, 300 IU, 600 IU, 900 IU; solution for injection cartridge, solution for injection vial. | Merck Sharp & Dohme Australia Pty Ltd |
Follitropin delta is not classified in New Zealand and does not appear to be an approved drug product in the USA or Canada. However, follitropin alpha and follitropin beta are approved as follows:
The US FDA:
Drug name | Active ingredient/s |
---|---|
Bravelle | Urofollitropin |
Fertinex | Urofollitropin |
Follistim | Urofollitropin alfa/beta |
Follistim AQ | Urofollitropin alfa/beta |
Gonal-F | Urofollitropin alfa/beta |
Gonal-F RFF | Urofollitropin alfa/beta |
Gonal-F RFF REDI-JECT | Urofollitropin alfa/beta |
Metrodin | Urofollitropin |
Canada: In Canada there are three prescription products for human use containing follitropin alfa as the active ingredient (Gonal-F, Gonal-F Pen and Pergoveris, multiple presentations); and one prescription product for human use containing follitropin beta as the active ingredient (Puregon, multiple presentations).
Follitropin delta is a novel human recombinant follicle-stimulating hormone indicated for controlled ovarian stimulation for the development of multiple follicles in women undergoing assisted reproductive technology (ART) therapy such as in vitro fertilisation (IVF) or intra-cytoplasmic sperm injection (ICSI). The most important effect resulting from parenteral administration of FSH is the development of multiple mature follicles.
Follitropin delta is a recombinant human follicle-stimulating hormone (FSH) produced in a human cell line (PER.C6®) by recombinant DNA technology. Follitropin delta is a heterodimer composed of one α and one β subunit (Table 3.12B).
Property | Follitropin delta | |
---|---|---|
CAS No. | 146479-72-3 | |
Form | Clear and colourless in solution (pH 6.0–7.5) | |
Subunit | FSH subunit α | FSH subunit β |
Amino acid sequence (N – indicates glycosylation sites of the mature α and β subunits) |
1 APDVQDCPEC TLQENPFFSQ PGAPILQCMG CCFSRAYPTP LRSKKTMLVQ KNVTSESTCC 61 VAKSYNRVTV MGGFKVENHT ACHCSTCYYH KS |
1 NSCELTNITI AIEKEECRFC ISINTTWCAG YCYTRDLVYK DPARPKIQKT CTFKELVYET 61 VRVPGCAHHA DSLYTYPVAT QCHCGKCDSD STDCTVRGLG PSYCSFGEMK |
Molecular weight (Da) (Approximately 40% of the total molecular weight of the molecule is due to glycosylation) |
15,200 | 18,500 |
The amino acid sequences of the two FSH subunits are identical to the endogenous human FSH sequences. The expressing cell line can influence the characteristics of the recombinant FSH. Differences in glycosylation profile, salic acid pattern and isoform profile have been documented between follitropin delta and recombinant FSH products, such as follitropin alpha and follitropin beta which are produced in Chinese hamster ovary (CHO) cell lines.
Compared to unglycosylated FSH, the glycosylated FSH contains:
Two public submissions were received and both supported the proposal. The main points were that the entry in Appendix D for UROFOLLITROPIN (human follicle stimulating hormone) for human use covers its recombinant forms as well. However, for clarity it would be desirable to add follitropin delta to Appendix D.
The Committee advised that follitropin delta should be entered in Schedule 4 with an Appendix D, Item 1 listing.
The recommended wording for the follitropin delta entry is as follows:
Schedule 4 –New Entry
#FOLLITROPIN DELTA.
Appendix D –New Entry
Item 1. Poisons available only from or on the prescription or order of an authorised medical practitioner.
FOLLITROPIN DELTA (recombinant human follicle-stimulating hormone) for human use.
The Committee recommended an implementation date of 1 June 2017.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance.
The reasons for the advice comprised the following:
The delegate considered the following in regards to this application:
The delegate’s interim decision is that a new Schedule 4 entry for follitropin delta with an Appendix D Item 1 listing is appropriate.
The proposed wording for the schedule and appendix entries is as follows:
Schedule 4 – New Entry
#FOLLITROPIN DELTA.
Appendix D, Item 1 – New Entry
FOLLITROPIN DELTA (recombinant human follicle-stimulating hormone) for human use.
Index
FOLLITROPIN DELTA
cross reference: FOLLICLE-STIMULATING HORMONE, RECOMBINANT HUMAN
Schedule 4
Appendix D, Item 1
The proposed implementation date is 1 June 2017.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance.
The reasons for the interim decision are the following:
No public submissions were received in response to the interim decision for follitropin delta.
The delegate has confirmed the interim decision and reasons for the decision as no evidence has been received to alter the interim decision. The delegate’s final decision is to create new Schedule 4 and Appendix D entries for follitropin delta with an implementation date of 1 June 2017.
The implementation date of the below final decisions is 1 June 2017 unless separately specified.
Substance | Final Decision |
---|---|
Albutrepenonacog alfa | Albutrepenonacog alfa is exempt from scheduling as it falls under the Appendix A entry for human blood products. |
Sebelipase alfa | Schedule 4 - New Entry SEBELIPASE ALFA. |
Meningococcal Group B Vaccine | Schedule 4 - New Entry MENINGOCOCCAL GROUP B VACCINE. Index - New Entry MENINGOCOCCAL GROUP B VACCINE Schedule 4 |
Sodium Phenylbutyrate | Schedule 4 - New Entry SODIUM PHENYLBUTYRATE. |
Silodosin | Schedule 4 - New Entry SILODOSIN. |
Dengue Vaccine Also known as: Live attenuated chimeric dengue virus (serotypes 1, 2, 3 & 4) |
Schedule 4 - New Entry DENGUE VACCINE. Index - New Entry DENGUE VACCINE Schedule 4 |
The delegate considered an application from the Therapeutic Goods Administration (TGA) for the scheduling of albutrepenonacog alfa, a new chemical entity (NCE) for a human therapeutic medicine.
Albutrepenonacog alfa is a recombinant form of coagulation factor IX (FIX) genetically fused to human albumin to prolong clotting activity and is indicated for IV use in adults and children with haemophilia B to control and prevent bleeding episodes.
Nomenclature: Albutrepenonacog alfa (ABN and INN).
Albutrepenonacog alfa is currently exempt from scheduling because it is captured under the Appendix A entry for HUMAN BLOOD PRODUCTS under item (c)(iv) clotting factors in the current Poisons Standard:
Appendix A - General exemptions
HUMAN BLOOD PRODUCTS including:
Albutrepenonacog alfa is classified as a Schedule D (biological) drug in Canada and is a prescription only medicine in the EU and the USA. Albutrepenonacog alfa is not classified in New Zealand.
The delegate decided to make a delegate-only decision. The Advisory Committee on Medicines Scheduling was not consulted.
The delegate considered the following in regards to this application for scheduling:
The delegate noted that currently there are no issues of concern that require additional control other than by inclusion in Appendix A.
The delegate has made a final decision that albutrepenonacog alfa is exempt from scheduling as it falls under the Appendix A entry for human blood products in the Poisons Standard.
The delegate decided that the relevant matters under subsection 52E(1) of the Therapeutic Goods Act 1989 are: (a) the risks and benefits of the use of a substance; (b) the purpose and the extent of use of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.
The reasons for the final decision comprise the following:
The delegate considered an application from the Therapeutic Goods Administration (TGA) for the scheduling of sebelipase alfa, a new chemical entity (NCE) for a human therapeutic medicine.
Sebelipase alfa is an enzyme replacement therapy that addresses the underlying cause of lysosomal acid lipase deficiency (LAL-D) by reducing substrate accumulation in the lysosomes of cells throughout the body.
Sebelipase alfa is indicated for long-term enzyme replacement therapy (ERT) in patients of all ages with lysosomal acid lipase deficiency (LAL-D).
Australian Approved Name (AAN) and International Non-Proprietary Name (INN): Sebelipase alfa
Sebelipase alfa is not specifically scheduled and is not captured by any entry in the current Poisons Standard.
Sebelipase alfa is not classified in New Zealand and Canada.
Sebelipase alfa is approved for use in the USA and the EU.
The delegate decided to make a delegate-only decision. The Advisory Committee on Medicines Scheduling (ACMS) was not consulted.
The delegate considered the following in regards to this application for scheduling:
The delegate noted that currently there are no issues of concern that require additional control other than by inclusion in Schedule 4.
The delegate has made a final decision to amend the Poisons Standard to include Sebelipase alfa in Schedule 4, with an implementation date of 1 June 2017.
The delegate has decided that the wording for the schedule entry will be as follows:
Schedule 4 - New Entry
SEBELIPASE ALFA.
The delegate decided that the relevant matters under subsection 52E(1) of the Therapeutic Goods Act 1989 are: (a) the risks and benefits of the use of a substance; (b) the purpose and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (e) the potential for abuse.
The delegate decided that the reasons for the final decision comprise the following:
The delegate considered an application from the Therapeutic Goods Administration (TGA) for the scheduling of Neisseria Meningitidis Serogroup B Recombinant LP2086 (MnB rLP2086) Subfamily A Protein and Subfamily B Protein (Meningococcal Group B Vaccine), a new chemical entity (NCE) for a human therapeutic medicine.
Meningococcal Group B Vaccine consists of two recombinant lipidated factor H binding protein (fHBP) variants from N. meningitidis serogroup B. fHBP.
Meningococcal Group B Vaccine is indicated for individuals 10 years and older for active immunisation to prevent invasive meningococcal disease caused by Neisseria meningitidis serogroup B.
ABN - Neisseria Meningitidis Serogroup B Recombinant LP2086 (MnB rLP2086) Subfamily A Protein and Subfamily B Protein (Meningococcal Group B Vaccine)
Meningococcal Group B Vaccine is not specifically scheduled in the current Poisons Standard but is captured under the following group entry:
Schedule 4
MENINGOCOCCAL VACCINE.
Meningococcal Group B Vaccine is not specifically classified in New Zealand. However, it would be classified under the group entry, MENINGOCOCCAL VACCINE, as a prescription medicine except when administered to a person 16 years of age or over by a registered pharmacist who has successfully completed a vaccinator training course approved by the Ministry of Health and who is complying with the immunisation standards of the Ministry of Health.
The delegate decided to make a delegate-only decision. The Advisory Committee on Medicines Scheduling was not consulted.
The delegate considered the following in regards to this application for scheduling:
The delegate noted that currently there are no issues of concern that require additional control other than by inclusion in Schedule 4.
The delegate has made a final decision to amend the Poisons Standard to include Meningococcal Group B Vaccine in Schedule 4, with an implementation date of 1 June 2017.
The delegate has decided that the wording for the schedule and index entries will be as follows:
Schedule 4 - New Entry
MENINGOCOCCAL GROUP B VACCINE.
Index - New Entry
MENINGOCOCCAL GROUP B VACCINE
cross reference: Neisseria Meningitidis Serogroup B Recombinant LP2086 (MnB rLP2086) Subfamily A Protein and Subfamily B Protein
Schedule 4
The delegate decided that the relevant matters under subsection 52E(1) of the Therapeutic Goods Act 1989 is: (a) the risks and benefits of the use of a substance.
The delegate decided that the reasons for the final decision comprise the following:
The delegate considered an application from the Therapeutic Goods Administration (TGA) for the scheduling of sodium phenylbutyrate, a new chemical entity (NCE) for a human therapeutic medicine.
Sodium phenylbutyrate is a pro-drug and is rapidly metabolised to phenylacetate. Phenylacetate is a metabolically active compound that conjugates with glutamine via acetylation to form phenylacetylglutamine which is then excreted by the kidneys.
Sodium phenylbutyrate is indicated as adjunctive therapy in the chronic management of urea cycle disorders and should be used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, and protein-free calorie supplements). Sodium phenylbutyrate is indicated in all patients with neonatal-onset presentation (complete enzyme deficiencies, presenting within the first 28 days of life). It is also indicated in patients with late-onset disease (partial enzyme deficiencies, presenting after the first month of life) who have a history of hyperammonaemic encephalopathy. Sodium phenylbutyrate has not been studied in the geriatric (> 65 years of age) population.
Australian Approved Name (AAN) and International Non-Proprietary Name (INN): Sodium phenylbutyrate.
Sodium phenylbutyrate is not specifically scheduled and is not captured by any entry in the current Poisons Standard.
Sodium phenylbutyrate is classified as a prescription medicine in New Zealand, Canada and USA.
The delegate decided to make a delegate-only decision. The Advisory Committee on Medicines Scheduling was not consulted.
The delegate considered the following in regards to this application for scheduling:
The delegate noted that currently there are no issues of concern that require additional control other than by inclusion in Schedule 4.
The delegate has made a final decision to amend the Poisons Standard to include Sodium phenylbutyrate in Schedule 4, with an implementation date of 1 June 2017.
The delegate has decided that the wording for the schedule entry will be as follows:
Schedule 4 - New Entry
SODIUM PHENYLBUTYRATE.
The delegate decided that the relevant matters under subsection 52E(1) of the Therapeutic Goods Act 1989 are: (a) the risks and benefits of the use of a substance; (b) the purpose and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (e) the potential for abuse.
The delegate decided that the reasons for the final decision comprise the following:
The delegate considered an application from the Therapeutic Goods Administration (TGA) for the scheduling of silodosin, a new chemical entity (NCE) for a human therapeutic medicine.
Silodosin is an alpha-adrenergic blocker that blocks alpha1A adrenoreceptors in the prostate gland, bladder, urethra and blood vessels. When these receptors are activated, they cause the muscles controlling the flow of urine to contract. By blocking these receptors, silodosin allows these muscles to relax, making it easier to pass urine and relieving the symptoms of benign prostatic hyperplasia (BPH).
Silodosin is indicated for the relief of lower urinary tract (LUTS) associated with BPH in adult men.
Australian Approved Name (AAN) and International Non-Proprietary Name (INN): Silodosin
Silodosin is not specifically scheduled and is not captured by any entry in the current Poisons Standard.
Silodosin is not classified in New Zealand.
Silodosin is a prescription only medicine in Canada, the USA and EU.
The delegate decided to make a delegate-only decision. The Advisory Committee on Medicines Scheduling was not consulted.
The delegate considered the following in regards to this application for scheduling:
The delegate noted that currently there are no issues of concern that require additional control other than by inclusion in Schedule 4.
The delegate has made a final decision to amend the Poisons Standard to include silodosin in Schedule 4, with an implementation date of 1 June 2017.
The delegate has decided that the wording for the schedule entry will be as follows:
Schedule 4 - New Entry
SILODOSIN.
The delegate decided that the relevant matters under subsection 52E(1) of the Therapeutic Goods Act 1989 are: (a) the risks and benefits of the use of a substance; (b) the purpose and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (e) the potential for abuse.
The delegate decided that the reasons for the final decision comprise the following:
The delegate considered an application from the Therapeutic Goods Administration (TGA) for the scheduling of live attenuated chimeric dengue virus (serotypes 1, 2, 3 & 4) (Dengue Vaccine), a new chemical entity (NCE) for a human therapeutic medicine.
Live attenuated chimeric dengue virus (serotypes 1, 2, 3 & 4) is a live attenuated tetravalent vaccine, composed of four live recombinant, attenuated vaccines (CYD-1-4) based on a well-characterized Yellow Fever virus strain 17D (YFV 17D) genomic backbone modified to express the pre-membrane and envelope genes of one of the four Dengue virus serotypes.
Live attenuated chimeric dengue virus (serotypes 1, 2, 3 & 4) is indicated for the prevention of dengue disease caused by dengue virus serotypes 1, 2, 3 and 4 in individuals 9 through 60 years of age living in endemic areas.
The Dengue vaccine (live attenuated chimeric dengue virus (serotypes 1, 2, 3 & 4) is not specifically scheduled and is not captured by any entry in the current Poisons Standard.
Live attenuated chimeric dengue virus (serotypes 1, 2, 3 & 4) (Dengue vaccine) is not classified in New Zealand.
The delegate decided to make a delegate-only decision. The Advisory Committee on Medicines Scheduling was not consulted.
The delegate considered the following in regards to this application for scheduling:
The delegate noted that currently there are no issues of concern that require additional control other than by inclusion in Schedule 4.
The delegate has made a final decision to amend the Poisons Standard to include live attenuated chimeric dengue virus (serotypes 1, 2, 3 & 4) (Dengue Vaccine) in Schedule 4, with an implementation date of 1 June 2017.
The delegate has decided that the wording for the schedule entry will be as follows:
Schedule 4 - New Entry
DENGUE VACCINE.
Index - New Entry
DENGUE VACCINE
crosses reference: LIVE ATTENUATED CHIMERIC DENGUE VIRUS (SEROTYPES 1, 2, 3 & 4)
Schedule 4
The delegate decided that the relevant matters under subsection 52E(1) of the Therapeutic Goods Act 1989 are: (a) the risks and benefits of the use of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.
The delegate decided that the reasons for the final decision comprise the following: