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 and 42ZCZX 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:
A 'pre-meeting' public notice inviting submissions on the scheduling proposals referred to the expert advisory committees was published on 9 October 2015 on the TGA website at Public notice about scheduling.
Edited versions of public submissions received in response to this invitation were published on 8 January 2016 at: Public submissions on scheduling matters. Redacted versions of public submissions received in response to ACMS items will be published on or after the date of this notice.
The delegates' interim decisions on recommendations by the ACCS #15 and ACMS #16 were published on 4 February 2016 at Reasons for Delegate's interim decisions and invitation for further comment. This public notice also invited further comment from the applicant and from those parties who made a valid submission in response to the original invitation for submissions.
Further submissions from parties other than those who made a valid submission in response to the original invitation or the applicant, or those received after the closing date, may not be considered by the delegate.
Edited versions of valid public submissions received in response to the interim decisions will be published at Public submissions on scheduling matters.
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.
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).
The amendments to the Schedules, Appendices or other parts of the Poisons Standard are published electronically on ComLaw 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.
Scheduling medicines and poisons
Abbreviation | Name |
---|---|
AAN | Australian Approved Name |
AC | Active constituent |
ACCC | Australian Competition and Consumer Commission |
ACCM | Advisory Committee on Complementary Medicines (formerly Complementary Medicine Evaluation Committee [CMEC]) |
ACNM | Advisory Committee on Non-prescription Medicines (formerly Medicines Evaluation Committee [MEC]) |
ACPM | Advisory Committee on Prescription Medicines (formerly Australian Drug Evaluation Committee [ADEC]) |
ACSOM | Advisory Committee on the Safety of Medicines (formerly Adverse Drug Reactions Advisory Committee [ADRAC]) |
ADEC | Australian Drug Evaluation Committee (now Advisory Committee on Prescription Medicines [ACPM]) |
ADI | Acceptable daily intake |
ADRAC | Adverse Drug Reactions Advisory Committee (now Advisory Committee on the Safety of Medicines [ACSOM]) |
AHMAC | Australian Health Ministers' Advisory Council |
APVMA | Australian Pesticides and Veterinary Medicines Authority |
AQIS | Australian Quarantine and Inspection Service |
ARfD | Acute reference dose |
ASCC | Australian Safety and Compensation Council |
ASMI | Australian Self-Medication Industry |
ARTG | Australian Register of Therapeutic Goods |
CAS | Chemical Abstract Service |
CHC | Complementary Healthcare Council of Australia |
CMEC | Complementary Medicine Evaluation Committee (now Advisory Committee on Complementary Medicines [ACCM]) |
CMI | Consumer Medicine Information |
COAG | Councils of Australian Governments |
CRC | Child-resistant closure |
CTFAA | Cosmetic, Toiletry & Fragrance Association of Australia |
CWP | Codeine Working Party |
DAP | Drafting Advisory Panel |
ECRP | Existing Chemicals Review Program |
EPA | Environmental Protection Authority |
ERMA | Environmental Risk Management Authority (New Zealand) |
FAISD | First Aid Instructions and Safety Directions |
FDA | Food and Drug Administration (United States) |
FOI | Freedom of Information Act 1982 |
FSANZ | Food Standards Australia New Zealand |
GHS | Globally Harmonised System for Classification and Labelling of Chemicals |
GIT | Gastro-intestinal tract |
GP | General practitioner |
HCN | Health Communication Network |
IMAP | Inventory Multi-tiered Assessment Prioritisation |
INN | International Non-proprietary Name |
ISO | International Standards Organization |
LC50 | The concentration of a substance that produces death in 50 per cent of a population of experimental organisms. Usually expressed as mg per litre (mg/L) as a concentration in air. |
LD50 | The concentration of a substance that produces death in 50 per cent of a population of experimental organisms. Usually expressed as milligrams per kilogram (mg/kg) of body weight. |
LOAEL | Lowest observed adverse effect level |
LOEL | Lowest observed effect level |
MCC | Medicines Classification Committee (New Zealand) |
MEC | Medicines Evaluation Committee (now Advisory Committee on Non-prescription Medicines [ACNM]) |
MOH | Ministry of Health (New Zealand) |
NCCTG | National Coordinating Committee on Therapeutic Goods |
NDPSC | National Drugs and Poisons Schedule Committee |
NHMRC | National Health and Medical Research Council |
NICNAS | National Industrial Chemicals Notification & Assessment Scheme |
NOAEL | No observed adverse effect level |
NOEL | No observable effect level |
NOHSC | National Occupational Health & Safety Commission |
OCM | Office of Complementary Medicines |
OCS | Office of Chemical Safety (formerly Office of Chemical Safety and Environmental Health [OCSEH]) |
OCSEH | Office of Chemical Safety and Environmental Health (now Office of Chemical Safety [OCS]) |
ODA | Office of Devices Authorisation |
OMA | Office of Medicines Authorisation (formerly Office of Prescription and Non-prescription Medicines) |
OOS | Out of session |
OTC | Over-the-counter |
PACIA | Plastics and Chemicals Industries Association |
PAR | Prescription animal remedy |
PBAC | Pharmaceutical Benefits Advisory Committee |
PEC | Priority existing chemical |
PGA | Pharmaceutical Guild of Australia |
PHARM | Pharmaceutical Health and Rational Use of Medicines |
PI | Product Information |
PIC | Poisons Information Centre |
PSA | Pharmaceutical Society of Australia |
QCPP | Quality Care Pharmacy Program |
QUM | Quality Use of Medicines |
RFI | Restricted flow insert |
SCCNFP | Scientific Committee on Cosmetic and Non-Food Products |
SCCP | Scientific Committee on Consumer Products |
STANZHA | States and Territories and New Zealand Health Authorities |
SUSDP | Standard for the Uniform Scheduling of Drugs and Poisons |
SUSMP | Standard for the Uniform Scheduling of Medicines and Poisons |
SVT | First aid for the solvent prevails |
TCM | Traditional Chinese medicine |
TGA | Therapeutic Goods Administration |
TGC | Therapeutic Goods Committee |
TGO | Therapeutic Goods Order |
TTHWP | Trans-Tasman Harmonisation Working Party |
TTMRA | Trans-Tasman Mutual Recognition Agreement |
WHO | World Health Organization |
WP | Working party |
WS | Warning statement |
Scheduling medicines and poisons
Substance | Final decision |
---|---|
1,3-Dichloropropene |
Schedule 7 - Amend Entry1,3-DICHLOROPROPENE except in biocidal preparations containing 0.3 per cent or less of 1,3-dichloropropene. Implementation date: 1 June 2016 |
1,5-Naphthalenediol |
Schedule 6 - New Entry1,5-NAPHTHALENEDIOL except:
Appendix E (Part 2) - New Entry1,5-NAPHTHALENEDIOL Part 1, Standard Statements: A, E1, S1 Appendix F (Part 3) - New Entry1,5-NAPHTHALENEDIOL Part 1, Warning Statement: 28 Part 2, Safety Directions: 1 Implementation date: 1 October 2016 |
1-Naphthol |
Schedule 6 - New Entry1-NAPHTHOL except in hair dye preparations containing 1 per cent or less of 1-naphthol 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. Written in letters not less than 1.5 mm in height. Appendix E (Part 2) - New Entry1-NAPHTHOL Part 1: Standard Statements: A, E1, S1 Appendix F (Part 3) - New Entry1-NAPHTHOL Part 1: Warning Statement: 28 Part 2: Safety Directions: 1 Implementation date: 1 October 2016 |
2,6-Dimethoxy-3, 5-pyridinediamine |
Schedule 6 - New Entry2,6-DIMETHOXY-3,5-PYRIDINEDIAMINE except when used in hair dye and eyebrow/eyelash colouring products at a concentration of 0.25 per cent or less of 2,6-dimethoxy-3,5-pyridinediamine after mixing for use when the immediate container and primary pack are labelled with the following statements: KEEP OUT OF REACH OF CHILDREN, and WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use. Written in letters not less than 1.5 mm in height. Appendix F (Part 3) - New Entry2,6-DIMETHOXY-3, Part 1, Warning Statement: 28 Implementation date: 1 October 2016 |
2,7-Naphthalenediol |
Schedule 6 - New Entry2,7-NAPHTHALENEDIOL except:
Appendix E (Part 2) - New Entry2,7-NAPHTHALENEDIOL Part 1: Standard Statements: A, E1, S1 Appendix F (Part 3) - New Entry2,7-NAPHTHALENEDIOL Part 1: Warning Statement: 28 Part 2: Safety Directions: 1, 3 Implementation date: 1 October 2016 |
4-Amino-3-nitrophenol |
Schedule 6 - New Entry4-AMINO-3-NITROPHENOL except:
Appendix E (Part 2) - New Entry4-AMINO-3-NITROPHENOL Part 1: Standard Statements: A Appendix F (Part 3) - New Entry4-AMINO-3-NITROPHENOL Part 1: Warning Statement: 28 Implementation date: 1 October 2016 |
Amisulbrom |
Schedule 5 - New EntryAMISULBROM Implementation date: 1 June 2016 |
And an editorial of the C.I. Acid Black 29 entry to include CAS number. |
Schedule 7 - Amend EntryBENZIDINE-BASED AZO DYES
Implementation date: 1 June 2016 |
Azo dyes (not listed on AICS) |
Schedule 7 - Amend EntryAZO DYES that are derivatives by diazotisation of any of the following substances:
Implementation date: 1 June 2016 |
Isethionate, as mixed ammonium and ethanolamine salts of 2-hydroxyethanesulfonic acid |
Appendix B - New EntryISETHIONATE, as mixed ammonium and monoethanolamine salts of 2-hydroxyethanesulfonic acid Part 1 - Reasons for Entry
Part 2 - Area of Use 1.11 Adjuvant in agricultural products. Proposed date for addition to SUSMP: 1 June 2016 |
1-(1,1-Dimethylethyl)-2-methoxy-4-methyl-3,5-dinitrobenzene (musk ambrette) |
Schedule 10 - New Entry1-(1,1-DIMETHYLETHYL)-2-METHOXY-4-METHYL-3,5-DINITROBENZENE (musk ambrette) Cross reference entry in Index: Amber Musk Implementation date: 1 June 2016 |
Oxathiapiprolin |
Appendix B - New EntryOXATHIAPIPROLIN Part 1 - Reasons for Entry a) Low toxicity Part 2 – Area of Use 1.3 Fungicide. Proposed date for addition to SUSMP: 1 June 2016 |
p-Methylaminophenol |
Schedule 6 - New Entryp-METHYLAMINOPHENOL except when used in hair dye and eyebrow/eyelash colouring products at a concentration of 1 per cent or less of p-methylaminophenol after mixing for use when the immediate container and primary pack are labelled with the following statements: KEEP OUT OF REACH OF CHILDREN, and WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use. Written in letters not less than 1.5 mm in height. Appendix F (Part 3) - New Entryp-METHYLAMINOPHENOL Part 1, Warning Statement: 28 Implementation date: 1 October 2016 |
Schedule 5 Paint Labelling Amendment | The delegate has decided to defer making a decision on this issue, pending formal consultation with the States/Territories, as required in the new AHMAC Scheduling Policy Framework for amendments to Parts 1-3 of the Poisons Standard. |
Topramezone |
Schedule 5 - New EntryTOPRAMEZONE Implementation date: 1 June 2016 |
Scheduling medicines and poisons
The chemicals scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS):
The reasons for the request were:
The delegate asked the committee the following questions:
Figure 1. Structure of 1,3-dichloropropene
No toxicity profile was on 1,3-dichloropropene nor the active ingredients CTAC and cis-CTAC by the applicant. The following information was extracted from NICNAS and Safe Work Australia websites.
An Environmental Health Criteria report on 1,3-dichloropropene can be found here at IPCS INCHEM.
1,3-Dichloropropene is classified as hazardous, with the following risk phrases for human health in the HSIS:
No information provided by the applicant.
No information provided by the applicant.
No information provided by the applicant.
No information provided by the applicant.
No information provided by the applicant.
1,3-Dichloropropene is listed in IARC Group 2B (possibly carcinogenic to humans) carcinogens.
Safe Work Australia place 1,3-dichloropropene as a Category 3 carcinogen. Substances suspected of having carcinogenic potential are those substances which have possible carcinogenic effects on humans but in respect of which the available information is not adequate for making a satisfactory assessment. There is some evidence from appropriate animal or epidemiological studies, but this is insufficient to place the substance in Category 2.
1.1 Animal studies
Technical-grade dichloropropene (containing 1% epichlorohydrin) was administered to mice and rats. Dose-related increases in the incidences of tumours of the urinary bladder, lung and fore stomach were observed in mice. In male rats, dose-related increases in the incidences of benign and malignant fore stomach tumours and benign liver tumours were reported; in female rats, benign fore stomach tumours were found.
In one study of subcutaneous administration in female mice, the cis isomers produced malignant tumours at the site of injection. However, skin application of the cis isomers to mice has not produced any conclusive results.
The International Agency for Research on Cancer (IARC) has reviewed many animal inhalation studies, but failed to demonstrate a relationship between inhalation exposure and tumour production.
1.2 Human studies
Two case reports of human malignancy were reviewed by the IARC. There are no epidemiological studies of human carcinogenicity known to the Exposure Standards Working Group.
2. Conclusion
Technical-grade dichloropropene (containing 1% epichlorohydrin) is carcinogenic to experimental animals through oral administration. Carcinogenicity of dichloropropene through inhalation has not been demonstrated in animals.
There is inadequate evidence for carcinogenicity of dichloropropene in humans.
3. Recommendation for carcinogen category
After reviewing the relevant data, the Exposure Standards Working Group is of the view that dichloropropene may have carcinogenic potential to humans, based on the limited evidence from animal studies, but the available information is not adequate for making a satisfactory assessment. The Working Group recommends that dichloropropene be classified as Category 3 carcinogen (Substance Suspected of having Carcinogenic Potential). The reader is encouraged to review the section on Carcinogens in the Guidance Note on the Interpretation of Exposure Standards for Atmospheric Contaminants in the Occupational Environment, for guidance on the classification system of carcinogens.
No information provided by the applicant.
No information provided by the applicant.
No information provided by the applicant.
NICNAS IMAP states 1,3-dichloropropene has an exposure standard of 4.5 mg/m3 (1 ppm) time weighted average (TWA) (Galleria Chemica).
The applicant outlined in their proposal that their antimicrobial CTAC and cis-CTAC substances, of which 1,3-dichloropropene is a product of their manufacture, are compliant to international regulations in the EU and USA. The international regulations for 1,3-dichloropropene, the substance in question, were not provided. These are outlined below.
1,3-dichloropropene is listed on the Health Canada List of prohibited and restricted cosmetic ingredients (The Cosmetic Ingredient 'Hotlist').
A TWA of 4–5 mg/m3 (1 ppm) in Canada, Denmark, Iceland, Norway, and the USA, and 0.5 mg/m3 (0.11 ppm) in Germany and Switzerland.
A STEL of 50 mg/m3 (10 ppm) in Ireland and South Africa, and 2 ppm in Canada (Saskatchewan).
1,3-Dichloropropene is currently listed in Schedule 7 and Appendix J.
Poisons | Standard statements |
---|---|
1,3-dichloropropene | Condition 1: Not to be available except to authorised or licensed persons. |
1,3-Dichloropropene was previously marketed in Australia but its withdrawal by the sponsor (Dow Chemical (Australia) Ltd) was notified to the PACC in 1987, due to recommendations by the Committee, that it would cease its sale and distribution in Australia of Telone II, which comprised 91% of 1,3-dichloropropene. Prior to 1994, commercial formulations included up to 1% of the known genotoxic carcinogen, epichlorohydrin, while post-1994 commercial formulations have included epoxidised soybean oil as a stabiliser.
In November 2000, at the #29 NDPSC meeting, Dow Agrosciences Australia Ltd had submitted data in support of the technical grade active constituent 1,3-dichloropropene and the registration of two end-use-products Telone® Soil Fumigant (1140g/L) and Telone® C-35 Soil Fumigant (825g/L + chloropicrin 460g/L). These products were proposed for use by professional and accredited fumigators in the treatment of a range of soil borne diseases, nematodes, wireworms and other plant parasites as a pre-planting soil fumigant. The proposal was to delete the Appendix J entry and reschedule 1,3-dichloropropene to Schedule 6. This proposal was not supported by the Committee who decided that the current Schedule 7 and Appendix J entries for 1,3-dichloropropene were to remain appropriate. This was made in part due to the Committee noting that the proposed use was limited to accredited fumigators and that this could be enforced as a Restricted Chemical Product (NRA registration) in some jurisdictions. However, other jurisdictions had no legislative mechanism apart from Schedule 7/Appendix J to enforce such controls over use. It was in addition, noted that the request for rescheduling had arisen as a consequence of the new toxicology evaluation and had not been requested by the company.
No public submission was received.
The Committee recommended that the Schedule 7 entry for 1,3-dichloropropene be amended as follows:
Schedule 7 - Amend Entry
1,3-DICHLOROPROPENE except when in biocidal formulations at 0.3 per cent or less.
The committee recommended an implementation date 1 June 2016.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (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.
The reasons for the recommendations comprised the following:
The delegate considered the following in regards to this proposal:
The delegate's interim decision is to accept the advice of the Committee and amend the Schedule 7 entry of 1,3-dichloropropene. The earliest practicable implementation date is warranted since the objective is to amend existing controls for biocidal products already on the market.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance.
1,3-DICHLOROPROPENE except in biocidal preparations containing 0.3 per cent or less of 1,3-dichloropropene.
No public submissions were received.
The delegate has confirmed the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.
1,3-DICHLOROPROPENE except in biocidal preparations containing 0.3 per cent or less of 1,3-dichloropropene.
The proposed implementation date is 1 June 2016.
Scheduling medicines and poisons
The chemicals scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS):
The reasons for the request were:
The delegate asked the committee the following questions:
Please refer to the NICNAS IMAP human health Tier II assessment report for 1,5-napthalenediol. This report is publicly available on the NICNAS website.
Figure 2. Chemical structure of 1,5-napthalenediol
The acute toxicity end-points for the chemical are listed in the below table.
Toxicity | Species | 1,5-naphthalenediol | SPF* Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | 660 or >2000 | Schedule 5 or 6 |
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 | Mild irritant | Schedule 5 |
Eye irritation | Rabbit | Irritant | Schedule 5 |
Skin sensitisation (local lymph node assay) | Mice | Moderate to severe skin sensitiser (EC3 = 3.4 %) | Schedule 6 |
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
A local lymph node assay (LLNA) was performed according to the Organisation of Economic Co-operation and Development test guideline (skin sensitisation) using female CBA/J mice. Various concentrations of 1,5-naphthalenediol were assessed across two experiments. The following stimulation index (SI) values were generated for these concentrations (% / SI): 0.25 / 1.4; 1 / 2.5; 2.5 / 2.8; 5 / 18.4; 25 / 16.7; 50 / 6.1. The estimated concentration required to produce a three-fold increase in lymphocyte proliferation (EC3) was calculated to be 3.4 %. Therefore, under these test conditions, 1,5-naphthalenediol was found to be a moderate to severe skin sensitiser.
Based on the data available, the chemical 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 vivo genotoxicity studies, the chemical is not expected to be genotoxic.
No data are available.
Based on the available data, the chemical is not expected to have developmental toxicity. No data are available on reproductive toxicity.
The chemical is reported to be used in oxidative hair dye preparations in Australia. Internationally, the chemical is reported to be used in oxidative and non-oxidative hair dye preparations.
Following a safety evaluation, the Scientific Committee on Consumer Products (SCCP) (2010) concluded that "1,5-naphthalenediol, as an ingredient in oxidative and non-oxidative hair dye formulations; at a maximum on-head concentration of 1 % does not pose a risk to the health of the consumer, apart from its sensitising potential."
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 public under the uses identified.
Many countries, including New Zealand, the European Union (EU) and the Association of Southeast Asian Nations (ASEAN) have restricted the use of this chemical in cosmetics.
The chemical is listed on the following:
In the EU, it is mandated that products containing the chemical at any concentration have warning labels indicating that the product can be allergenic.
N/A
1,5-naphthalenediol has not been previously considered for scheduling; therefore, scheduling history is not available.
One public submission was received.
No objections to aligning with EU were raised. It was noted in the submission that it is important to maintain "in-use" concentrations for hair dye preparations, due to the mode of use being mixing with an oxidising substance prior to use.
The public submission is available at Public submissions on scheduling matters.
The Committee recommended that new Schedule 6, Appendix E and Appendix F entries be created for 1,5-naphthalenediol with exemptions and cut-offs as follows:
Schedule 6 - New Entry
1,5-NAPHTHALENEDIOL 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.
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.
Written in letters not less than 1.5 mm in height.
Appendix E - New Entry
1,5-NAPHTHALENEDIOL
Part 1, Standard Statements: A, E1, S1
Appendix F - New Entry
1,5-NAPHTHALENEDIOL
Part 1, Warning Statement: 28
Part 2, Safety Directions: 1
The committee recommended an implementation date of 1 June 2016.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (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 recommendations comprised the following:
The delegate considered the following in regards to this proposal:
The delegate's interim decision is to create new Schedule 6, with appropriate exemption and cut-off, Appendix E and Appendix F entries for 1,5-naphthalenediol.
Oxidative hair dyes of the aromatic diamine and aminophenolic classes have some common toxicological properties that warrant controls over scheduling. These features are primarily skin-eye irritancy and sensitization potential. These toxicological properties generally align with SPF criteria for listing in Schedule 6. Several of these dyes (e.g. phenylenediamines, toluenediamines; aminophenols) have already been listed in Schedule 6, but previous scheduling policies have allowed for some products to be exempted where there are label statements warning of the potential for skin irritancy and sensitization, and recommending testing for individual susceptibility before use. This approach is commonly called 'reverse scheduling'. Where there is potential mutagenicity, or the need to prevent uses for skin colouration (tattooing) or use to dye eyebrows or eyelashes, some of these substances have been listed in Schedule 10 to prevent such uses.
This is one of six oxidant hair dyes that were referred to the November 2015 meeting of the ACCS for advice to the delegate on scheduling. The key issues were whether their toxicological profiles sufficiently match the SPF criteria for inclusion in Schedule 6 and whether product exemptions based on 'reverse scheduling' could be applied, consistent with labelling provisions applied to other oxidative hair dyes. Given that some products containing oxidative hair dyes require mixing with an oxidant, such as hydrogen peroxide, before application to the hair, consideration was given to appropriate exemption cut-off concentrations that take account of the final concentration applied to the hair.
The delegate notes, and accepts, ACCS advice that 1,5-naphthalenediol should be listed in Schedule 6, with an exemption cut-off at 1%, provided products are labelled with the warning statements about potential skin/eye irritation and sensitisation that have been required for similar oxidative hair dyes. The delegate also notes ACCS advice that the potential for eye irritation requires warning statements relating to use for dyeing eyebrows and eyelashes. The INCI name (1,5-naphthalenediol) is the preferred name for listing in the Schedules.
A later implementation date is proposed to allow for an orderly process of re-labelling of products already on the market.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance; d) the dosage, formulation, labelling, packaging and presentation of a substance.
1,5-NAPHTHALENEDIOL 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.
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.
Written in letters not less than 1.5 mm in height.
1,5-NAPHTHALENEDIOL
Part 1, Standard Statements: A, E1, S1
1,5-NAPHTHALENEDIOL
Part 1, Warning Statement: 28
Part 2, Safety Directions: 1
One submission was received. The submission supported the delegate's interim decision.
Edited versions of public submissions are available at Public submissions on scheduling matters.
The delegate notes the submission received in response to publication of the interim decision and confirms the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.
1,5-NAPHTHALENEDIOL 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.
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.
Written in letters not less than 1.5 mm in height.
1,5-NAPHTHALENEDIOL
Standard Statements: A, E1, S1
1,5-NAPHTHALENEDIOL
Warning Statement: 28
Safety Directions: 1
The proposed implementation date is 1 October 2016.
Scheduling medicines and poisons
The chemicals scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS):
On the 28th August 2015, the National Industrial Chemicals Notification and Assessment Scheme (NICNAS), under its Inventory Multi-tiered Assessment and Prioritisation (IMAP) programme, referred the following proposal to be considered by the delegate for inclusion in the Poisons Standard:
The reasons for the request are:
The delegate asked the committee the following questions:
Please refer to the NICNAS Inventory Multi-tiered Assessment Prioritisation (IMAP) Human Health Tier II Assessment Report 1-naphthalenol and its related compounds. This report is publicly available on the NICNAS website.
The acute toxicity end-points for this chemical are listed in the below table.
Toxicity | Species | 1-naphthol | SPF* Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | 1870 | Schedule 6 |
Acute dermal toxicity LD50 (mg/kg bw) | Rabbit | 880 | Schedule 6 |
Acute inhalational toxicity LC50 (mg/m3/4h) | Rat | >0.097 (limited data) | N/A |
Skin irritation | Rabbit | Irritant | Schedule 5 |
Eye irritation | Rabbit | Severe irritant | Schedule 6 |
Skin sensitisation (LLNA) | Mouse | Skin sensitiser (EC3 = 1.3 %) | Schedule 6 |
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
Based on the available data, the chemical is a strong skin sensitiser.
In a local lymph node assay (LNNA) conducted according to the Organisation for Economic Co-operation and Development Test Guideline (OECD TG) 429, the chemical at 0.1, 0.25, 0.5, 1 or 2.5 % was applied topically to the ventral and dorsal surfaces of the ears of 18 female CBA/J mice. The mean stimulation indices were 1.4, 1.0, 1.2, 1.5 and 8.5, respectively, for the 0.1, 0.25, 0.5, 1 and 2.5 % concentrations. The effective concentration needed to produce a three-fold increase in lymphocyte proliferation (EC3) was calculated to be 1.3 %, indicating a strong sensitisation potential.
In a guinea pig maximisation test, both intradermal and topical induction used 0.1 % aqueous solutions of the chemical. Two weeks after topical induction, the animals were challenged by an occlusive dermal application of 0.05 % or 0.1 % of the chemical for 24 hours. No skin reaction was observed in this study. However, it should be noted that the concentration of the chemical used in this study was considered to be too low to clearly characterise the sensitisation potential of the chemical.
In an open epicutaneous test, a 3 % dilution of the chemical was applied onto the shaved flank skin of Pirbright white guinea pigs for six days/week for three weeks. Two weeks later a single challenge dose was applied to the opposite flank skin. No skin reaction was observed in the animal.
Based on the available data, the chemical is not expected to cause serious damage to health from repeated oral and dermal exposure. No information was available on repeated dose inhalation toxicity.
Based on the available data from in vitro and in vivo genotoxicity studies, the chemical is not considered to be genotoxic.
Limited data are available. The chemical at 0.5 % concentration was not carcinogenic.
Based on the available data, the chemical is not expected to cause reproductive and developmental toxicity.
The chemical is reported to be used in permanent hair dye preparations in Australia. Internationally, the chemical is used in oxidative hair dyes.
The Association of South East Asian Nations (ASEAN), Canada, New Zealand and the European Union (EU) have restricted the use of this chemical in cosmetics. Following a safety evaluation, the Scientific Committee on Consumer Products concluded that 'apart from the risks associated with the use of a strong sensitiser, the use of the chemical itself in oxidative hair dye formulations at a maximum concentration of 2.0 % on the head, does not pose any other risk to the health of the consumer'.
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 (particularly skin sensitisation) have the potential to pose an unreasonable risk to the public given the identified uses.
The chemical is listed on the following:
In the EU, it is mandated that products containing the chemical at any concentration have warning labels indicating that the product can be allergenic.
N/A
1-naphthol has not been previously considered for scheduling; therefore, scheduling history is not available.
One public submission was received. No objections to aligning with the EU requirements were raised. It was noted however that it is important to maintain "in-use" concentrations for hair dye preps, due to the mode of use being mixing with an oxidising substance prior to use.
The public submission is available at Public submissions on scheduling matters.
The Committee recommended that new Schedule 6, Appendix E and Appendix F entries be created for 1-naphthol with appropriate cut-offs and exemptions as follows:
Schedule 6 - New Entry
1-NAPHTHOL except in hair dye containing 1 per cent or less 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.
Written in letters not less than 1.5 mm in height.
Appendix E - New Entry
1-NAPHTHOL
Part 1: Standard Statements: A, E1, S1
Appendix F - New Entry
1-NAPHTHOL
Part 1: Warning Statement: 28
Part 2: Safety Directions: 1
The committee recommended an implementation date of 1 June 2016.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (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 recommendations comprised the following:
The delegate considered the following in regards to this proposal:
The delegate's interim decision is to create new Schedule 6, with appropriate exemption and cut-off, Appendix E and Appendix F entries for 1-naphthol.
Oxidative hair dyes of the aromatic diamine and aminophenolic classes have some common toxicological properties that warrant controls over scheduling. These features are primarily skin-eye irritancy and sensitization potential. These toxicological properties generally align with SPF criteria for listing in Schedule 6. Several of these dyes (e.g. phenylenediamines, toluenediamines; aminophenols) have already been listed in Schedule 6, but previous scheduling policies have allowed for some products to be exempted where there are label statements warning of the potential for skin irritancy and sensitization, and recommending testing for individual susceptibility before use. This approach is commonly called 'reverse scheduling'. Where there is potential mutagenicity, or the need to prevent uses for skin colouration (tattooing) or use to dye eyebrows or eyelashes, some of these substances have been listed in Schedule 10 to prevent such uses.
This is one of six oxidant hair dyes that were referred to the November 2015 meeting of the ACCS for advice to the delegate on scheduling. The key issues were whether their toxicological profiles sufficiently match the SPF criteria for inclusion in Schedule 6 and whether product exemptions based on 'reverse scheduling' could be applied, consistent with labelling provisions applied to other oxidative hair dyes. Given that some products containing oxidative hair dyes require mixing with an oxidant, such as hydrogen peroxide, before application to the hair, consideration was given to appropriate exemption cut-off concentrations that take account of the final concentration applied to the hair.
The delegate notes, and accepts, ACCS advice that 1-napthol should be listed in Schedule 6, with an exemption cut-off at 1%, provided products are labelled with the warning statements about potential skin/eye irritation and sensitisation that have been required for similar oxidative hair dyes. The delegate also notes ACCS advice that the potential for severe eye irritation requires warning statements relating to use for dyeing eyebrows and eyelashes. The INCI name (1-naphthol) is the preferred name for listing in the Schedules.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance; d) the dosage, formulation, labelling, packaging and presentation of a substance.
1-NAPHTHOL except in hair dye preparations containing 1 per cent or less of 1-naphthol 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.
Written in letters not less than 1.5 mm in height.
1-NAPHTHOL
Part 1: Standard Statements: A, E1, S1
1-NAPHTHOL
Part 1: Warning Statement: 28
Part 2: Safety Directions: 1
One submission was received. The submission supported the delegate's interim decision.
Edited versions of public submissions are available at Public submissions on scheduling matters.
The delegate notes the submission received in response to publication of the interim decision and confirms the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.
1-NAPHTHOL except in hair dye preparations containing 1 per cent or less of 1-naphthol 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.
Written in letters not less than 1.5 mm in height.
1-NAPHTHOL
Standard Statements: A, E1, S1
1-NAPHTHOL
Warning Statement: 28
Safety Directions: 1
The proposed implementation date is 1 October 2016.
Scheduling medicines and poisons
The chemicals scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS):
In August 2015, the National Industrial Chemicals Notification and Assessment Scheme (NICNAS), under its Inventory Multi-tiered Assessment and Prioritisation (IMAP) assessment programme, referred the proposal to be considered by the delegate for inclusion in the Poisons Standard.
The reasons for the request were:
The delegate asked the committee the following questions:
This report, containing more detailed information about the substance, is publicly available on the NICNAS website.
Figure 3. Chemical structure of 2,6-dimethoxy-3,5-pyridinediamine
The acute toxicity end-points for this chemical are listed in the below table.
Toxicity | Species | 2,6-dimethoxy-3,5-pyridinediamine | SPF* Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | 187.5 | Schedule 6 |
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 | Not irritating | N/A |
Eye irritation | Guinea pig | Not irritating at 3 % concentration (limited data) | N/A |
Skin sensitisation (LLNA) | Mouse | Skin sensitiser | Schedule 6 |
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
The chemical is a moderate to severe skin sensitiser.
In the local lymph node assay (LLNA), female CBA/J mice (n = 5/group) were topically treated with 0.25 µL of the chemical at 0, 0.5, 1.5, 5.0 and 10.0 % concentrations (w/v) in dimethyl sulfoxide (DMSO) or in water/acetone (1:1) mixed with olive oil (4:1), once a day for three days (Organisation for Economic Co-operation and Development test guideline. The lymphoproliferation response, determined by the incorporation of (3H)-methyl thymidine was greater than the stimulation index (SI) threshold of three for concentrations 31.5 % in DMSO (SI = 3.6, 4.5 and 4.2 for 1.5, 5 and 10 % concentrations, respectively). The effective concentration needed to produce a three-fold increase in lymphocyte proliferation (EC3) was calculated as 1.25 % in DMSO. The SI was greater than three only at the 10 % concentration in a mixture of water/acetone (1:1) mixed with olive oil (4:1), with a calculated EC3 of 6.88 %. Both treatments indicated the chemical was a skin sensitiser.
In a Magnusson–Kligman maximisation study, female Dunkin Hartley guinea pigs (n = 20) were intradermally injected with the chemical (0.1 mL of a 1 % solution) in sterile water. Freund's complete adjuvant was also injected. On day seven after being injected, the animals were topically treated with 10 % sodium lauryl sulfate in petrolatum to induce slight inflammation and enhance potential absorption. On day eight, the animals were topically treated with the chemical (0.5 mL of a 75 % solution) under occlusive conditions for 24 hours. The animals were challenged on days 22 and 29 with 0.2 mL of a 75 % aqueous solution. A slight increase in skin fold thickness, compared with the vehicle control group, was observed during the challenge. Skin reactions were observed in 55 % and 45 % of the animals at 24 and 48 hours after challenge, respectively, indicating that the chemical is a skin sensitiser.
Based on the treatment-related effects reported in the 90-day study in rats, the chemical is considered to cause serious damage to health from repeated oral exposure. A no observed adverse effect level (NOAEL) of 5 mg/kg bw/day was established based on the effects observed at 15 mg/kg bw/day (significantly decreased blood glucose and creatine levels; significantly decreased absolute liver and kidney weights in females; enlarged cervical lymph nodes; and treatment related changes in the liver (necrosis, mononuclear cell foci), lungs (pneumonitis) and oesophagus (epithelial hyperplasia and hyperkeratosis).
Based on the negative results reported for all in vitro and in vivo genotoxicity studies, the chemical is not considered to be genotoxic.
Based on the available genotoxicity data, mechanistic considerations and mitigating factors of the chemical structure, the chemical is not considered to be carcinogenic.
No reproductive toxicity data are available. The chemical is not expected to have developmental toxicity.
The chemical is reported to be used in permanent hair dye preparations in Australia. The chemical has reported international use in oxidative hair dye products.
Currently, there are no restrictions in Australia on using this chemical in cosmetics or hair dyes. In the absence of any regulatory controls, the characterised critical health effects have the potential to pose an unreasonable risk under the identified uses.
Many countries including Canada, New Zealand, and the European Union (EU) have restricted the use of this chemical in cosmetics.
The chemical is listed on the following:
2,6-dimethoxy-3,5-pyridinediamine is not specifically scheduled.
2,6-dimethoxy-3,5-pyridinediamine has not been previously considered for scheduling; therefore, scheduling history is not available.
One public submission was received. No objections to aligning with the EU requirements were raised. It was noted however, that it is important to maintain "in-use" concentrations for hair dye preparations, due to the mode of use being mixing with an oxidising substance prior to use.
The public submission is available at Public submissions on scheduling matters.
The committee recommended that a new Schedule 6 and Appendix F entries be created for 2,6-dimethoxy-3,5-pyridinediamine with appropriate exemptions or cut-offs as follows:
Schedule 6 - New Entry
2,6-DIMETHOXY-3,5-PYRIDINEDIAMINE except when used in hair dye and eyebrow/eyelash colouring products at a concentration of 0.25 per cent or less after mixing for use when the immediate container and primary pack are labelled with the following statements:
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use.
Written in letters not less than 1.5 mm in height.
Appendix F - New Entry
2,6-DIMETHOXY-3,5-PYRIDINEDIAMINE
Part 1, Warning Statement: 28
The committee recommended an implementation date of 1 June 2016.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (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 recommendations comprised the following:
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance.
The delegate considered the following in regards to this proposal:
The delegate's interim decision is to create new Schedule 6, with appropriate exemption and cut-off, and Appendix F entries for 2,6-dimethoxy-3,5-pyridinediamine.
Oxidative hair dyes of the aromatic diamine and aminophenolic classes have some common toxicological properties that warrant controls over scheduling. These features are primarily skin-eye irritancy and sensitization potential. These toxicological properties generally align with SPF criteria for listing in Schedule 6. Several of these dyes (e.g. phenylenediamines, toluenediamines; aminophenols) have already been listed in Schedule 6, but previous scheduling policies have allowed for some products to be exempted where there are label statements warning of the potential for skin irritancy and sensitization, and recommending testing for individual susceptibility before use. This approach is commonly called 'reverse scheduling'. Where there is potential mutagenicity, or the need to prevent uses for skin colouration (tattooing) or use to dye eyebrows or eyelashes, some of these substances have been listed in Schedule 10 to prevent such uses.
This is one of six oxidant hair dyes that were referred to the November 2015 meeting of the ACCS for advice to the delegate on scheduling. The key issues were whether their toxicological profiles sufficiently match the SPF criteria for inclusion in Schedule 6 and whether product exemptions based on 'reverse scheduling' could be applied, consistent with labelling provisions applied to other oxidative hair dyes. Given that some products containing oxidative hair dyes require mixing with an oxidant, such as hydrogen peroxide, before application to the hair, consideration was given to appropriate exemption cut-off concentrations that take account of the final concentration applied to the hair.
The delegate notes, and accepts, ACCS advice that 2,6-dimethoxy-3,5-pyridinediamine should be listed in Schedule 6, with an exemption cut-off at 0.25%, provided products are labelled with the warning statements about potential skin sensitisation that have been required for similar oxidative hair dyes. The delegate also notes ACCS advice that warning statements relating to use for dyeing eyebrows and eyelashes are not needed, because the substance is not a strong eye irritant.
A later implementation date is proposed to allow for an orderly process of re-labelling of products already on the market.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance; d) the dosage, formulation, labelling, packaging and presentation of a substance.
2,6-DIMETHOXY-3,5-PYRIDINEDIAMINE except when used in hair dye and eyebrow/eyelash colouring products at a concentration of 0.25 per cent or less of 2,6-dimethoxy-3,5-pyridinediamine after mixing for use when the immediate container and primary pack are labelled with the following statements:
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use.
Written in letters not less than 1.5 mm in height.
2,6-DIMETHOXY-3,5-PYRIDINEDIAMINE
Part 1, Warning Statement: 28
One submission was received. The submission supported the delegate's interim decision.
Edited versions of public submissions are available at Public submissions on scheduling matters.
The delegate notes the submission received in response to publication of the interim decision and confirms the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.
2,6-DIMETHOXY-3,5-PYRIDINEDIAMINE except when used in hair dye and eyebrow/eyelash colouring products at a concentration of 0.25 per cent or less of 2,6-dimethoxy-3,5-pyridinediamine after mixing for use when the immediate container and primary pack are labelled with the following statements:
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use.
Written in letters not less than 1.5 mm in height.
2,6-DIMETHOXY-3,5-PYRIDINEDIAMINE
Warning Statement: 28
The proposed implementation date is 1 October 2016.
Scheduling medicines and poisons
The chemicals scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS):
In April 2015, the National Industrial Chemicals Notification and Assessment Scheme (NICNAS), under its Inventory Multi-tiered Assessment and Prioritisation (IMAP) programme, referred the proposal to be considered by the delegate for inclusion in the Poisons Standard.
The reasons for the request were:
The critical health effect for risk characterisation is skin sensitisation. Given the potential for induction and elicitation of skin sensitisation even below the allowed overseas concentration cut-off, the risk would be better controlled by inclusion of warning statements on the label of preparations containing the chemical below the concentration cut-off. The chemical has similar use and hazard profiles to a number of chemicals which have been listed in Schedule 6 with reverse scheduling requirements.
The delegate asked the committee the following questions:
Please refer to the NICNAS Inventory Multi-tiered Assessment Prioritisation (IMAP) Human Health Tier II Assessment Report for 2,7-napthalenediol and its related compounds. This report is publically available on the NICNAS website.
Figure 4. Chemical structure of 2,7-naphthalenediol
The acute toxicity end-points for this chemical are listed in the below table.
Toxicity | Species | 2,7-naphthalenediol | SPF* Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | 2160 | 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 | Not an irritant | N/A |
Eye irritation | Rabbit | Severe irritant | Schedule 6 |
Skin sensitisation (LLNA) | Mouse | Skin sensitiser (EC3 = 2.8 %) | Schedule 6 |
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
Based on the available data, the chemical is a moderate to strong skin sensitiser.
In a local lymph node assay (LLNA) conducted according to the Organisation for Economic Co-operation and Development (OECD) Test Guideline, the chemical, in a 4:1 mixture of acetone and olive oil, was applied to the dorsal surface of both ear lobes of female CBA/CaOlaHsd mice (five animals/group) once daily for three consecutive days. The chemical at test concentrations of 0.5, 1, 2.5, 5, 25 or 50 % produced stimulation indices (SIs) of 1.6, 1.8, 1.4, 4.5, 12.4 or 4.2, respectively. The effective concentration needed to produce a three-fold increase in lymphocyte proliferation (EC3) was calculated to be 2.8 %, indicating moderate skin sensitisation potential.
Based on the available data, the chemical 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 available data from in vitro and in vivo genotoxicity studies, the chemical is not considered to be genotoxic.
No animal toxicity data are available on the carcinogenicity of the chemical.
Based on the limited available data, the chemical is not expected to cause reproductive and developmental toxicity.
The chemical is reported to be used in permanent hair dye preparations in Australia. It has use overseas in both oxidative and non-oxidative preparations.
The Association of South East Asian Nations (ASEAN), European Union (EU) and New Zealand have restricted the use of this chemical in cosmetics. Following a safety evaluation, the Scientific Committee on Consumer Safety concluded that the chemical 'as an ingredient in oxidative and non-oxidative hair dye formulations at a maximum on-head concentration of 1% does not pose a risk to the health of the consumer, apart from its sensitising potential'.
Currently, there are no restrictions in Australia for using this chemical in cosmetic products. In the absence of any regulatory controls, the characterised critical health effects, particularly skin sensitisation, have the potential to pose an unreasonable risk to the public given the identified uses.
The chemical is listed on the following:
In the EU, it is mandated that products containing the chemical at any concentration have warning labels indicating that the product can be allergenic.
N/A
2,7-naphthalenediol has not been previously considered for scheduling; therefore, scheduling history is not available.
One public submission was received. No objections to aligning with the EU requirements were raised. It was noted however that it is important to maintain "in-use" concentrations for hair dye preps, due to the mode of use being mixing with an oxidising substance prior to use.
The public submission is available at Public submissions on scheduling matters.
The Committee recommended that new Schedule 6, Appendix E and Appendix F entries be created for 2,7-naphalenediol as follows:
Schedule 6 - New Entry
2,7-NAPHTHALENEDIOL 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.
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.
Written in letters not less than 1.5 mm in height.
Appendix E - New Entry
2,7-NAPHTHALENEDIOL
Part 1: Standard Statements: A, E1, S1
Appendix F - New Entry
2,7-NAPHTHALENEDIOL
Part 1: Warning Statement: 28
Part 2: Safety Directions: 1, 3
The committee recommended an implementation date of 1 June 2016.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance.
The reasons for the recommendation comprised the following:
The delegate considered the following in regards to this proposal:
The delegate's interim decision is accept the advice of the Committee and create new Schedule 6, with appropriate exemption and cut-off, Appendix E and Appendix F entries for 2,7-naphthalenediol.
Oxidative hair dyes of the aromatic diamine and aminophenolic classes have some common toxicological properties that warrant controls over scheduling. These features are primarily skin-eye irritancy and sensitization potential. These toxicological properties generally align with SPF criteria for listing in Schedule 6. Several of these dyes (e.g. phenylenediamines, toluenediamines; aminophenols) have already been listed in Schedule 6, but previous scheduling policies have allowed for some products to be exempted where there are label statements warning of the potential for skin irritancy and sensitization, and recommending testing for individual susceptibility before use. This approach is commonly called 'reverse scheduling'. Where there is potential mutagenicity, or the need to prevent uses for skin colouration (tattooing) or use to dye eyebrows or eyelashes, some of these substances have been listed in Schedule 10 to prevent such uses.
This is one of six oxidant hair dyes that were referred to the November 2015 meeting of the ACCS for advice to the delegate on scheduling. The key issues were whether their toxicological profiles sufficiently match the SPF criteria for inclusion in Schedule 6 and whether product exemptions based on 'reverse scheduling' could be applied, consistent with labelling provisions applied to other oxidative hair dyes. Given that some products containing oxidative hair dyes require mixing with an oxidant, such as hydrogen peroxide, before application to the hair, consideration was given to appropriate exemption cut-off concentrations that take account of the final concentration applied to the hair.
The delegate notes, and accepts, ACCS advice that 2,7-naphalenediol should be listed in Schedule 6, with an exemption cut-off at 1%, provided products are labelled with the warning statements about potential skin/eye irritation and sensitisation that have been required for similar oxidative hair dyes. The delegate also notes ACCS advice that the potential for severe eye irritation requires warning statements relating to use for dyeing eyebrows and eyelashes.
A later implementation date is proposed to allow for an orderly process of re-labelling of products already on the market.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance; d) the dosage, formulation, labelling, packaging and presentation of a substance.
2,7-NAPHTHALENEDIOL 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.
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.
Written in letters not less than 1.5 mm in height.
2,7-NAPHTHALENEDIOL
Part 1: Standard Statements: A, E1, S1
2,7-NAPHTHALENEDIOL
Part 1: Warning Statement: 28
Part 2: Safety Directions: 1, 3
One submission was received. The submission supported the delegate's interim decision.
Edited versions of public submissions are available at Public submissions on scheduling matters.
The delegate notes the submission received in response to publication of the interim decision and confirms the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.
2,7-NAPHTHALENEDIOL 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.
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.
Written in letters not less than 1.5 mm in height.
2,7-NAPHTHALENEDIOL
Standard Statements: A, E1, S1
2,7-NAPHTHALENEDIOL
Warning Statement: 28
Safety Directions: 1, 3
The proposed implementation date is 1 October 2016.
Scheduling medicines and poisons
The chemicals scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS):
In August 2015, the National Industrial Chemicals Notification and Assessment Scheme (NICNAS), under its Inventory Multi-tiered Assessment and Prioritisation (IMAP) programme, referred the following proposal to be considered by the delegate:
The reasons for the request were:
The delegate asked the committee the following questions:
Please refer to the NICNAS Inventory Multi-tiered Assessment Prioritisation (IMAP) Human Health Tier II Assessment Report for 4-amino-3-nitrophenol and its related compounds. This report is publically available on the NICNAS website.
Figure 5. Chemical structure of 4-amino-3-nitrophenol
The acute toxicity end-points for this chemical are listed in the below table.
Toxicity | Species | 4-amino-3-nitrophenol | SPF* Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | 500 - 1000 | Schedule 6 |
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 | Not irritating at 6 % concentration (limited data) | - |
Eye irritation | Rabbit | Irritating | Schedule 5 |
Skin sensitisation (LLNA) | Mouse | Severe skin sensitiser (EC3 = 0.2 %) | Schedule 6 |
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
Based on the data available, the chemical is considered to be a severe skin sensitiser.
In a local lymph node assay (LLNA) test, groups of female CBA/J mice were topically treated with 25 µL of the chemical (in an acetone/olive oil mixture) at 0.05, 0.1, 0.5, 1 or 2.5 % concentrations, once daily for three days. The lympho-proliferation response, determined by the incorporation of (3H)-methyl thymidine exceeded the threshold of three (stimulation index (SI) >3) at concentrations >0.5 %. The estimated concentration needed to produce three-fold increase in lymphocyte proliferation (EC3) was calculated to be 0.2 %, indicating the chemical to be a severe skin sensitiser.
Based on the data available, the chemical is not considered 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 in vivo genotoxicity data, the chemical is not considered to be genotoxic. However, it was reported that the data available are insufficient to exclude potential gene mutation.
Based on the available genotoxicity data, mechanistic considerations and mitigating factors of the chemical structure, the chemical is not considered to be carcinogenic.
Based on the data available, the chemical is not considered to have reproductive or developmental toxicity.
The chemical is reported to be used in permanent hair dye preparations in Australia. Internationally, the chemical is used in oxidative and non-oxidative hair dyes.
Currently, there are no restrictions in Australia on using this chemical in cosmetics or hair dye products. In the absence of any regulatory controls, the characterised critical health effects (skin sensitisation) have the potential to pose an unreasonable risk for the uses identified.
Many countries, including New Zealand and the EU, have restricted the use of this chemical in cosmetics.
The chemical is listed on the following:
In the EU, it is mandated that products containing the chemical at any concentration have warning labels indicating that the product can be allergenic.
4-amino-3-nitrophenol is not specifically scheduled.
4-amino-3-nitrophenol has not been previously considered for scheduling; therefore, scheduling history is not available.
One public submission was received. In that submission it was noted that for this substance the industry has been applying the NITROPHENOLS entry in Schedule 6, which does not allow for exemptions of small quantities of nitrophenols. In general, the submission indicated support in aligning with the EU with up to 1% in ready-to-use preps and 1.5% for preps intended to be diluted prior to application.
The public submission is available at Public submissions on scheduling matters.
The Committee recommended that new Schedule 6, Appendix E and Appendix F entries be created for 4-amino-3-nitrophenol be created as follows:
Schedule 6 - New Entry
PHENOL, 4-AMINO-3-NITRO 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.
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.
Written in letters not less than 1.5 mm in height.
Appendix E - New Entry
PHENOL, 4-AMINO-3-NITRO
Part 1: Standard Statements: A
Appendix F - New Entry
PHENOL, 4-AMINO-3-NITRO
Part 1: Warning Statement: 28
The committee recommended an implementation date of 1 June 2016.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance.
The reasons for the recommendations comprised the following:
The delegate considered the following in regards to this proposal:
The delegate's interim decision is to accept the advice of the Committee and create a new Schedule 6, with appropriate exemption and cut-off, Appendix E and Appendix F entries.
Oxidative hair dyes of the aromatic diamine and aminophenolic classes have some common toxicological properties that warrant controls over scheduling. These features are primarily skin-eye irritancy and sensitization potential. These toxicological properties generally align with SPF criteria for listing in Schedule 6. Several of these dyes (e.g. phenylenediamines, toluenediamines; aminophenols) have already been listed in Schedule 6, but previous scheduling policies have allowed for some products to be exempted where there are label statements warning of the potential for skin irritancy and sensitization, and recommending testing for individual susceptibility before use. This approach is commonly called 'reverse scheduling'. Where there is potential mutagenicity, or the need to prevent uses for skin colouration (tattooing) or use to dye eyebrows or eyelashes, some of these substances have been listed in Schedule 10 to prevent such uses.
This is one of six oxidant hair dyes that were referred to the November 2015 meeting of the ACCS for advice to the delegate on scheduling. The key issues were whether their toxicological profiles sufficiently match the SPF criteria for inclusion in Schedule 6 and whether product exemptions based on 'reverse scheduling' could be applied, consistent with labelling provisions applied to other oxidative hair dyes. Given that some products containing oxidative hair dyes require mixing with an oxidant, such as hydrogen peroxide, before application to the hair; consideration was given to appropriate exemption cut-off concentrations that take account of the final concentration applied to the hair.
The delegate notes, and accepts, ACCS advice that 4-amino-3-nitrophenol should be listed in Schedule 6, with an exemption cut-off at 1%, provided products are labelled with the warning statements about potential skin sensitisation that have been required for similar oxidative hair dyes. The delegate also notes ACCS advice that warning statements relating to use for dyeing eyebrows and eyelashes are not needed, because the substance is not a strong irritant. The delegate also notes ACCS advice that 4-amino-3-nitrophenol is the name used in EU cosmetics regulations, is the preferred name for listing in Schedule 6, and that the existing Schedule 6 entry for NITROPHENOLS would not capture this substance, since it would not be considered to be a 'derivative'.
A later implementation date is proposed to allow for an orderly process of re-labelling of products already on the market.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance; d) the dosage, formulation, labelling, packaging and presentation of a substance.
4-AMINO-3-NITROPHENOL 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.
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.
Written in letters not less than 1.5 mm in height.
4-AMINO-3-NITROPHENOL
Part 1: Standard Statements: A
4-AMINO-3-NITROPHENOL
Part 1: Warning Statement: 28
One submission was received. The submission supported the delegate's interim decision.
Edited versions of public submissions are available at Public submissions on scheduling matters.
The delegate notes the submission received in response to publication of the interim decision and confirms the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.
4-AMINO-3-NITROPHENOL 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.
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.
Written in letters not less than 1.5 mm in height.
4-AMINO-3-NITROPHENOL
Standard Statements: A
4-AMINO-3-NITROPHENOL
Warning Statement: 28
The proposed implementation date is 1 October 2016.
Scheduling medicines and poisons
The chemicals scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS):
The reasons for the request were:
The delegate asked the committee the following questions:
Figure 6. Chemical structure of amisulbrom
The acute toxicity end-points for amisulbrom are listed in the below table.
Toxicity | Species | Amisulbrom | SPF* Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | >5000 (no deaths) |
N/A |
Acute dermal toxicity LD50 (mg/kg bw) | Rat | >5000 (no deaths) |
N/A |
Acute inhalational toxicity LC50 (mg/m3/4h nose-only) | Rat | >2850 (no deaths) |
N/A |
Skin irritation | Rabbit | Not irritating | N/A |
Eye irritation | Rabbit | Moderate | Schedule 6 |
Skin sensitisation (GPMT) | Guinea Pig | Not sensitising | N/A |
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
The acute toxicity end-points for the product are listed in the below table.
Toxicity | Species | Amisulbrom | SPF* Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | LD50 >2000 (no deaths) |
N/A |
Acute dermal toxicity LD50 (mg/kg bw) | Rat | LD50 >2000 | N/A |
Acute inhalational toxicity LC50 (mg/m3/4h nose-only) | Rat | LC50 >2153 (no deaths) |
N/A |
Skin irritation | Rabbit | Not irritating | N/A |
Eye irritation | Rabbit | Slight irritant | N/A |
Skin sensitisation (GPMT) | Guinea Pig | Not sensitising | N/A |
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
The systemic toxicity of amisulbrom in oral studies in rats, mice and dogs, consisted primarily of decreased body weight and body weight gain, food consumption and conversion efficiency and effects on the liver (e.g. serum liver enzyme changes, increased relative weights and hepatocyte hypertrophy), kidney (increased relative weights and cortical tubular pigmentation) and adrenals (increased relative weights and cortical hypertrophy). No treatment related adverse effects were seen in a short-term dermal toxicity study in the rat, except a small decrease in weight gain in males at the highest dose (1000 mg/kg bw/d). No repeat dose inhalational toxicity studies were available for assessment. The toxicity profile for amisulbrom in repeat-dose toxicity studies (excluding carcinogenicity studies) in rats, mice and dogs indicates a low health hazard from repeated exposure and there was no indication of irreversible toxicity in these studies, except at doses above the MTD.
Potential genotoxicity of amisulbrom was assessed in a bacterial reverse mutation assay (Ames test; adequate S. typhimurium and E. coli strains; with and without metabolic activation [S9]), in vitro mutagenicity assay in mammalian cells (tk assay; mouse lymphoma cells; with and without metabolic activation), in vitro clastogenicity assay (human peripheral blood lymphocytes; with and without metabolic activation), in vivo mouse bone marrow micronucleus test (oral and intraperitoneal dosing), in vivo hepatic micronucleus test in rats (oral dosing), in vivo unscheduled DNA synthesis (UDS) assay (rats; oral dosing), in vivo hepatic comet assays in mice and rats and gastric mucosal cell comet assay in rats (oral dosing). The potential genotoxicity of the primary amisulbrom metabolite, IT-4 was assessed in a bacterial mutation assay ((Ames test; adequate S. typhimurium strains; with and without metabolic activation [S9]),) and a mouse micronucleus test. There was no evidence of a genotoxic potential associated with amisulbrom or IT-4.
In long-term toxicity/carcinogenicity studies with rats (104 weeks) and mice (78 weeks), the target organs of toxicity were the liver and kidney. In the 1-year dog study, the target organs were the liver and adrenals.
Neoplastic findings in these studies were confined to rats and mice, as follows:
Tumours of the forestomach were seen only at doses exceeding the MTD and appear to be related to chronic inflammatory changes caused by local irritation of the stomach mucosa. Histopathological lesions consistent with a local irritant effect in the gastrointestinal tract (epithelial hyperplasia, hyperkeratosis, ulceration and submucosal inflammation) were evident in animals at the same doses at which forestomach tumours were observed. Furthermore, consistent with a local inflammatory reaction in the gastrointestinal tract, sinus histiocytosis was seen in the mesenteric lymph nodes of females in the same dose groups. In addition, a rat forestomach gastric mucosa cell comet assay was negative. Given the high doses at which these effects occurred together with species differences in gastric fluid volumes and the fact that the anatomical target organ (the forestomach) is not present in humans, the forestomach tumours seen in rats are considered to have low relevance to humans.
Although liver tumours were only seen at high doses in rats, they were seen below the MTD in mice. The weight of evidence supports a non-genotoxic (epigenenetic) mechanism in rodents with a clear threshold for induction (i.e. no treatment-related induction of liver tumours occurred in male and female rats at 96 and 129 mg/kg bw/d, respectively, and mice at 11.6 mg/kg bw/d). Mechanistic studies, submitted by the applicant to elucidate the mechanism for liver tumours seen in both rats and mice, indicated a possible phenobarbital type mechanism for amisulbrom. However, although amisulbrom elicited similar DNA proliferative effects (RDS) and specific liver enzyme induction (mainly PROD activity) to phenobarbital, induction of CYP2B enzymes was not characterised and CAR/PXR activation was not demonstrated. Overall, the OCS considers the mechanistic data are only suggestive of a possible phenobarbital type MOA for hepatic tumour formation in rodents and not sufficiently comprehensive or robust to eliminate the possibility of other modes of action leading to liver tumour formation. Therefore liver tumours seen in rodents are considered potentially relevant to humans.
Amisulbrom was not a reproductive toxicant (rats) or developmental toxicant (rats and rabbits). However, in a 2-generation dietary reproductive toxicity study in rats, although no effects were seen in F0 females, prolonged or irregular oestrous cycles, impaired fertility and ovarian atrophy were evident in F1 females. No effects on fertility were seen in males. Mechanistic studies (including anti-oestrogenic uterotrophic assay; anti-aromatase assay, reproductive hormone levels together with cross-fostering and food restriction studies) submitted by the applicant, provided evidence that impaired fertility in F1 females was likely a secondary response to reduced food intake and impaired body weight gain, associated with poor palatability of amisulbrom. Therefore impaired fertility seen in rodents is considered to have low relevance to humans.
No neurotoxic effects (clinical signs, anatomical brain measurements, gross pathology, neurohistopathology or functional observation battery (FOB)) were observed in rats (both sexes) in an acute gavage study (single oral administration of amisulbrom up to 2000 mg/kg bw) or in a follow-up sub-chronic 13 week dietary study (doses up to 860 mg/kg bw/d (males) and 1132 mg/kg bw/d (females) in the same rat strain. The NOEL for general toxicity in the sub-chronic study was 23 mg/kg bw/d in males and 29 mg/kg bw/d in females, based on decreased body weight gain.
No information was provided.
No information was provided.
Amisulbrom has recently been considered for registration by the US EPA and EU (EFSA).
Amisulbrom is not specifically scheduled.
Amisulbrom has not been previously considered for scheduling; therefore, scheduling history is not available.
One public submission was received. In general, the submission supported a Schedule 5 entry and would accept a Schedule 6 entry, as an entry in either schedule would not make any difference to end use product. The submission sought an expedient scheduling implementation date.
The public submission is available at Public submissions on scheduling matters.
The Committee recommended that a new Schedule 5 entry be created for amisulbrom as follows:
Schedule 5 - New Entry
AMISULBROM
The committee recommended an implementation date of 1 June 2016.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance.
The reasons for the recommendations comprised the following:
The delegate considered the following in regards to this proposal:
The delegate notes, and accepts, advice from the ACCS that amisulbrom be listed in Schedule 5. The delegate agrees that the overall toxicological profile of amisulbrom is consistent with SPF criteria for listing in Schedule 5 and that the eye irritancy potential is more appropriately categorised as slight, rather than moderate. The delegate notes that the ACCS considers the evidence for the MoA producing liver tumours in rats and mice is sufficient to discount the relevance of these findings for humans.
Despite the apparent low toxicity profile of the product submitted for evaluation, an exemption cut-off for amisulbrom is not proposed at this time. The submitted product would require Schedule 6 controls since it includes copper sulphate at a concentration exceeding the Schedule 5 range of 5 - 15% that would qualify for the exemption from the Schedule 6 entry for copper sulphate.
The earliest practicable implementation of the scheduling decision will facilitate approval of the substance by the APVMA.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: c) the toxicity of the substance.
AMISULBROM
No public submissions were received.
The delegate has confirmed the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.
AMISULBROM
The proposed implementation date is 1 June 2016.
Scheduling medicines and poisons
The chemicals scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS):
The reasons for the request were:
The delegate asked the committee the following questions:
Please refer to the NICNAS Inventory Multi-tiered Assessment Prioritisation (IMAP) human health Tier II assessment report for C.I. Direct Orange 1.
The critical concern for this chemical and the focus of this assessment relates to the potential carcinogenic effects following exposure. Data are available for four benzidine-based dyes; Direct Red 28 (CAS No. 573-58-0), Direct Blue 6 (CAS No. 2602-46-2), Direct Black 38 (CAS No. 1937-37-7) and Direct Brown 95 (CAS No. 16071-86-6). Based on the common metabolite, benzidine, the data are considered representative for C.I. Direct Orange 1. These data can be found on the NICNAS website.
Metabolism of benzidine-based dyes to free benzidine and its metabolites have been observed in both humans and animals.
In vivo, azo reduction of benzidine-based substances, liberating free benzidine, occurs by an enzyme-mediated reaction. The intestinal microflora have been shown to be particularly active in azo dye reduction, but hepatic enzymes can also catalyse the reductive cleavage.
Bacteria on the skin have also been shown to possess azoreductase activity.
No data are available for the chemical. However, a dose-related increase in the number of circulating peripheral lymphocytes displaying chromosomal aberrations was observed in workers exposed to benzidine and benzidine-based dyes (Direct Black 38 and Direct Blue 6). The highest frequencies of aberrant lymphocytes were associated with the highest airborne dust concentrations of benzidine (0.42–0.86 mg/m3) or benzidine-based dyes (7.8–32.3 mg/m3), and with the highest mean levels of benzidine found in the urine (1.8–2.3 µg/L). The frequency of polyploid lymphocytes was also elevated in workers when compared with controls (ATSDR, 2001; IARC 2010 (referenced in C.I. Direct Orange 1 IMAP report)).
No data are available for the chemical. However, the related chemicals Direct Red 28, Direct Black 38, Direct Blue 6 and Direct Brown 95 are currently classified as hazardous as Category 2 carcinogens with the risk phrase 'May cause cancer' (T; R45) in HSIS (Safe Work Australia). Several other benzidine-based dyes are recommended for classification for carcinogenicity (refer to the IMAP report).
Three benzidine-based dyes (Direct Black 38, Direct Blue 6 and Direct Brown 95) have been tested for carcinogenicity in animals. The International Agency for Research on Cancer (IARC) concluded that there was sufficient evidence for the carcinogenicity of all dyes metabolised to benzidine on the basis of these studies. Observed effects included increased incidence of hepatocellular carcinomas and liver neoplastic nodules with all three dyes, and mammary gland cancers with Direct Black 38. A slight increase in transitional cell carcinoma of the urinary bladder was observed in an implantation study with Direct Blue 6. Hepatocellular carcinomas and liver neoplastic nodules were observed for all three dyes, despite a relatively short exposure period of 13 weeks (NTP, 2011; IARC, 2012; Government of Canada, 2013 (referenced in C.I. Direct Orange 1 IMAP report)).
The evidence of bladder cancer for workers exposed to benzidine-based dyes was not consistent across studies. There were limitations in the studies, including coexposure to known carcinogens in humans. Despite this, IARC has classified dyes metabolised to benzidine as carcinogenic to humans (Group 1) and the US National Toxicology Program has also classified dyes metabolised to benzidine as 'known to be human carcinogens'. The classification was based on findings that:
No data are available for the chemical. However, the related chemicals Direct Red 28, Direct Black 38 and Direct Blue 6 are classified as hazardous - Category 3 substances toxic to reproduction - with the risk phrase 'Possible risk of harm to the unborn child' (T; R63) in HSIS (Safe Work Australia). Several other benzidine-based dyes are recommended for classification for developmental toxicity (see the IMAP report).
Whilst the use of benzidine-based dyes is being phased out in some countries, use of the chemical as a dye has been reported internationally. The introduction of this chemical for home use cannot be excluded.
Cosmetics
No known restrictions have been identified for the chemical. However, the related benzidine-based dyes, Direct Red 28 (CAS No. 573-58-0), Direct Black 38 (CAS No. 1937-37-7), Direct Blue 6 (CAS No. 2602-46-2) and Direct Brown 95 (CAS No. 16071-86-6) are listed on the following (Galleria Chemica):
Other
Access to benzidine-based dyes for home use is no longer permitted in the USA (NTP, 2011).
The chemical is restricted by Annex XVII to REACH Regulation as follows:
CI. Direct Orange 1 is not specifically scheduled.
CI. Direct Orange 1 has not been previously considered for scheduling; therefore, scheduling history is not available.
One public submission was received. There was no objection to the proposal.
The public submission is available at Public submissions on scheduling matters.
The Committee recommended that the following amendments (highlighted in red) be made to the Schedule 7 entry for BENZIDINE-BASED AZO DYES to include C.I. Direct Orange 1 (CAS No. 545779-28-1) and insert any missing CAS numbers as follows:
Schedule 7 - Amend Entry
BENZIDINE-BASED AZO DYES
The committee recommended an implementation date of 1 June 2016.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the recommendations comprised the following:
The delegate considered the following in regards to this proposal:
The delegate notes that a number of benzidine-based azo dyes were listed in Schedule 7 as an outcome of advice from the February 2014 meeting of the ACCS. The listed dyes warrant stringent controls because of their carcinogenic potential via conversion to benzidine (a known human carcinogen). The delegate therefore accepts ACCS advice that CI Direct Orange 1 shares the carcinogenic potential of the already listed benzidine-based azo dyes and that it should be added to the list of such dyes in the current Schedule 7 listing.
Only the dye name/number and CAS number are to be included in the listing, without the chemical name as for other listings, since it appears that C.I Direct Orange 1 may be a mixture of three different substances. In addition, as an editorial amendment, the missing CAS number for C.I. Acid Black 29 is to be included.
This is the earliest practicable date on which this schedule can be implemented in the Poisons Standard.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: a) the risks and benefits of the use of the substance; b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance.
BENZIDINE-BASED AZO DYES
One submission was received. The submission supported the delegate's interim decision.
Edited versions of public submissions are available at Public submissions on scheduling matters.
The delegate notes the submission received in response to publication of the interim decision and confirms the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.
BENZIDINE-BASED AZO DYES
The proposed implementation date is 1 June 2016.
Scheduling medicines and poisons
The chemicals scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS):
The reasons for the request were:
The delegate asked the committee the following questions:
Please refer to the NICNAS Inventory Multi-tiered Assessment Prioritisation (IMAP) human health Tier II assessment report for Dyes that could release selected carcinogenic amines (not listed on AICS).
The critical concern for this group of chemicals and the focus of this assessment relates to the potential carcinogenic effects following exposure. The toxicological data for the chemicals in this group are limited. However, these azo compounds could undergo reductive cleavage of their azo bonds, releasing the following aromatic amines that have known carcinogenic potential: 2-naphthylamine; 2,4,5-trimethylaniline; and p-cresidine. These aromatic amines, are classified carcinogens in Australia. In addition, 2-naphthylamine (cleavage product of CAS No. 85186-64-7 and CAS No. 85186-66-9), is identified as a prohibited carcinogen (Table 10.1, Schedule 10) in Workplace Health and Safety legislation (WHS Regulations, 2011). Whilst these aromatic amines are not listed on the AICS, they are reported to be used overseas. Therefore, these chemicals could potentially be present as impurities in products imported into Australia.
This group of dyes represents the fourth such submission arising from IMAP. The previous three, for dyes based on benzidine, dyes based on benzidine congeners, and dyes based on other carcinogenic amines listed on AICS, have resulted in ACCS recommendations and/or Delegate's decisions for Schedule 7 listing. The current group completes the set of dyes based on "EU 22" amines forwarded for scheduling. The critical fact that separates this group from the previously (August 2015) considered group is that, as the amines are not on AICS, there are no IMAP reports on the amines available for reference, and so consideration of the carcinogenicity of the amines is contained within the assessment of the dyes (see IMAP report).
Based on the limited data available, it is not possible to draw a definite conclusion regarding the genotoxicity of the chemicals in this group. Although available data are neither sufficient nor adequately comprehensive for classification, a genotoxic mode of action cannot be ruled out. Studies on the aromatic amines that are potential cleavage products of the chemicals in this group (2-naphthylamine, 2,4,5-trimethylaniline and p-cresidine) demonstrated genotoxicity/mutagenicity in a number of in vitro and in vivo assays (see IMAP report for more details).
Limited data are available for the carcinogenic potential of the chemicals in this group.
Ponceau 3R is reported to produce tumours in rat livers and mouse urinary bladders. Long-term oral exposure (feeding studies) to Ponceau 3R of up to two years with 0.5-5 % doses in the diet) produced liver tumours in rats (Wistar, Osborne–Mendel, Bethesda Black). These include hepatomas, hepatic adenomas, bile duct adenoma, and adenomatous or nodular hyperplasia (Grice et al., 1961; Mannell, 1964; Aiso et al., 1966; IARC, 1975). The authors suggested that the component compounds present in the chemical, such as 2,4,5-trimethylaniline, contributed to the observed carcinogenic activity of Ponceau 3R (Mannell, 1964). In mice, Ponceau 3R produced bladder tumours on implantation in the urinary bladder (IARC, 1975 (referenced in the IMAP report)).
The International Agency for Research on Cancer (IARC) has classified Ponceau 3R as 'Possibly carcinogenic to humans' (Group 2B), based on inadequate evidence for carcinogenicity in humans, but sufficient evidence for carcinogenicity in animal testing (IARC, 1987 (referenced in the IMAP report)).
Although data are not available for the other chemicals in this group, the aromatic amines that could be released following the azo bond reductive cleavage of these chemicals are known carcinogens.
The aromatic amine, 2-naphthylamine, is classified as hazardous - Category 1 carcinogenic substance - with the risk phrase 'May cause cancer by inhalation' (T; R45) in the (HSIS) (Safe Work Australia).
The IARC has classified 2-naphthylamine as 'known to be a human carcinogen based on the sufficient evidence of carcinogenicity from studies in humans'. A number of studies reported a significant increase in human urinary bladder tumours caused by occupational exposure. Experimentally, urinary bladder tumours were also seen in several species of laboratory animals (rat, hamster, dog and monkey) following repeated exposures to 2-napthylamine via a number of routes including oral, dermal, subcutaneous, intraperitoneal, intravesicular implantation and bladder-instillation (IARC, 2010 (referenced in the IMAP report)). Liver and lung tumours were also observed in mice.
The aromatic amines, p-cresidine and 2,4,5-trimethylaniline are classified as Category 2 carcinogenic substances - with the risk phrase 'May cause cancer' (T; R45) in HSIS (Safe Work Australia). These aromatic amines are considered as 'reasonably anticipated to be human carcinogens based on sufficient evidence of carcinogenicity from studies in experimental animals' (IARC, 1982; NTP, 2011 (referenced in the IMAP report)).
Long-term oral exposure to p-cresidine produced malignant and benign tumours in the urinary bladder and liver of rats and mice, and nasal cancer in rats (NTP, 2011). Chronic exposure of rats and mice to 2,4,5-trimethylaniline caused lung and liver tumours (NCI, 1979; NTP; Wiley VCH (referenced in the IMAP report)).
Metabolic activation of aromatic amines to produce nitrenium ion metabolites, which cause DNA adduct formation and induction of DNA damaging effects, has been postulated to be the likely mechanism of action for their carcinogenicity (SCCNFP, 2002 (referenced in the IMAP report)). The IARC concluded that 'there is strong mechanistic evidence that the carcinogenicity of 2-napthylamine operates by a genotoxic mechanism of action' (IARC, 2010 (referenced in the IMAP report)).
Although the commercial production of Ponceau 3R and dyes based on 2-naphthylamine is restricted in some countries, this does not appear to be the case for dyes based on p-cresidine and 2,4,5-trimethylaniline. In addition, commercial production in other countries such as India and China is not known. Therefore the introduction of these dyes for home use cannot be excluded.
Cosmetic
The chemicals are restricted by the EU Annex XVII to EU Regulation as follows:
Appendix 8 is the list of the "EU 22" aromatic amines.
None of the dyes listed above are not specifically scheduled.
None of the dyes listed above have been previously considered for scheduling; therefore, scheduling history is not available.
One public submission was received. No general objections to proposal, however they note that changing labelling may require a period of transition.
The public submission is available at Public submissions on scheduling matters.
The Committee recommended that the group Schedule 7 entry for AZO DYES that are derivatives by diazotisation of any of the following substances be amended to include the additional following highlighted in red:
Schedule 7 - Amend Entry
AZO DYES that are derivatives by diazotisation of any of the following substances:
The committee recommended an implementation date of 1 June 2016.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the recommendations comprised the following:
The delegate considered the following in regards to this proposal:
The NICNAS IMAP program has previously referred for possible listing in Schedule 7, a number of azo dyes based on the known human carcinogen benzidine, as well as some dyes based on benzidine congeners and those that can be reduced by azo reductases to carcinogenic amine components. Following referral to the August 2015 meeting of the ACCS, the delegate agreed to Schedule 7 listing for azo dyes that can be reduced by azoreductases to yield 8 specific carcinogenic aromatic amines: o-anisidine (CAS No. 90-04-0); o-toluidine (CAS No. 95-53-4); p-aminoazobenzene (CAS No. 60-09-3); o-aminoazotoluene (CAS No. 97-56-3); 2,4-toluenediamine (CAS No. 95-80-7); 5-nitro-o-toluidine (CAS No. 99-55-8);p-chloroaniline (CAS No. 106-47-8);and 4-chloro-o-toluidine (CAS No. 95-69-2). The current proposal seeks to extend the list of carcinogenic amines is this generic entry, in order to capture some additional potentially carcinogenic amines, specifically 2-naphthylamine (CAS No. 91-59-8); 2,4,5-trimethylaniline (CAS No. 137-17-7); and 6-methoxy-m-toluidine(p-cresidine) (CAS No. 120-71-8).
The delegate accepts ACCS advice that the dyes referred in the current submission should also be controlled for use in consumer products by listing in Schedule 7, and agrees that adding them to the current generic listing for AZO DYES that are derivatives by diazotisation of any of the following substances: ... would achieve this objective. The delegate notes a point raised in a public submission that some of the listed aromatic amines may be present as manufacturing impurities in the relevant azo dyes. However, since the objective is to control the parent dyes themselves, and the resultant aromatic amines are not specifically listed as individual substances in Schedule 7, this should not be a problem.
The earliest practicable implementation date is warranted since the objective is to remove any such products from the Australian market on safety grounds.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: c) the toxicity of the substance.
AZO DYES that are derivatives by diazotisation of any of the following substances:
One submission was received. The submission did not object to the delegate's interim decision.
Edited versions of public submissions are available at Public submissions on scheduling matters.
The delegate notes the submission received in response to publication of the interim decision and confirms the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.
AZO DYES that are derivatives by diazotisation of any of the following substances:
The proposed implementation date is 1 June 2016.
Scheduling medicines and poisons
The chemicals scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS):
In August 2014, the Applicant, as part of an application to the Australian Pesticides and Veterinary Medicines Authority (APVMA), requested that the delegate consider not including isethionate in a schedule entry. The OCS evaluated the information provided by the applicant and advised the applicant (in the draft human health risk assessment report of August 2015) that a Schedule 5 entry is appropriate for isethionate.
The applicant responded to the August 2015 OCS draft human health risk assessment report indicating that they have no objections to OCS's scheduling proposal.
The delegate asked the committee the following questions:
Figure 7. Chemical structure of isethionate (sodium salt)
The acute toxicity end-points for isethionate are listed in the below table.
Toxicity | Species | Isethionate | SPF* Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | Low (LD50 >2000 mg/kg bw) | Schedule 5 |
Acute dermal toxicity LD50 (mg/kg bw) | Rat | Low (LD50 >2000 g/kg bw) | Schedule 5 |
Acute inhalational toxicity LC50 (mg/m3/4h) | Rat | Low (LC50 >6295 mg/m3) | Schedule 5 |
Skin irritation | Rabbit | Non-irritant | - |
Eye irritation | Rabbit | Slight | Schedule 5 |
Skin sensitisation | Guinea pig | Non-sensitiser | - |
In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test, Wistar Hannover rats (12/sex/dose) were orally administered the test substance via gavage at 0, 250, 500 or 1000 mg/kg bw isethionate. Male rats received the test substance for 28 days and female rats received the test substance for 54 days (including pre-mating, mating and through gestation and lactation). A satellite group of animals (5/sex) were administered 0 and 1000 mg/kg bw/d of the substance to assess reversibility of findings. Deionised water was used as a vehicle.
There were no mortalities, treatment related clinical findings including neurobehavioral changes in any of the treatment groups. Slight changes in body weight and body weight gain were observed. However, these changes in bodyweight and bodyweight gain were small in magnitude and there was no time or dose response relationship, and were not considered to be treatment related. There was no adverse, treatment related effect on food consumption in any of the treatment groups.
Changes in haematology parameters included decreased mean red blood cell count, haemoglobin, haematocrit and platelets in the mid and highest doses, attaining statistical significance in high dose males (red blood cell count, haemoglobin and haematocrit). Moreover, animals exposed to 500 and 1000 mg/kg bw/d showed changes in clinical chemistry parameters, however there was no clear, consistent, and statistically significant, dose related adverse effects observed at any dose and therefore were not considered to be treatment related.
Both male and female rats exposed to 500 mg/kg bw/d showed increased kidney weights. Increased adrenal weights were seen in males exposed to 500 and 1000 mg/kg bw/d. Low incidence microscopic findings were observed in high dose males including pelvis dilatation and mild congestion in the kidney, mild bilateral tubular degeneration of the testis and mild bilateral tubular degeneration of the epididymis.
Low incidence microscopic findings were observed in high dose females including mild diffuse vacuolisation and isolated hepatocellular hyperthrophy of the liver, slight unilateral pelvis dilatation and slight congestion in the kidney, slight unilateral kidney pelvis dilatation and slight bilateral pelvis dilatation of the kidney.
However, a comprehensive histopathological examination of tissues was not conducted as only the high dose and control animals were examined microscopically. Therefore, the toxicological significance of these findings is unknown in the absence of microscopic examination in the mid-dose groups.
The genotoxic potential of the compound was tested in an Ames test using four strains of S. typhimurium and a strain of E. coli which gave negative results with and without metabolic activation.
The applicant did not provide carcinogenicity studies.
A separate reproduction or developmental toxicity study has not been provided by the applicant. The repeat dose toxicity study (discussed under Repeat-Dose Toxicity) provided by the applicant contained a reproductive/developmental toxicity screening test for isethionate.
In the combined repeated dose toxicity study with the reproduction/developmental toxicity screening test, rats (12/sex/dose) were orally administered the test substance via gavage at 0, 250, 500 and 1000 mg/kg bw/d. Male rats received the test substance for 28 days and female rats were received the test substance for 54 days (including pre-mating, mating and through gestation and lactation). A satellite group of animals (5/sex) were administered 0 and 1000 mg/kg bw/d of the substance to assess reversibility of findings.
Changes in a number of reproductive effects, including increased pre-implantation loss (17.9% increase), decreased fertility index (22.3% decrease) and increased gestation index (12.5% increase) were seen in the high dose treatment group compared with controls. These were not statistically significant and there was no clear dose response relationship to the findings.
Evaluation of pups and litter showed that on day zero, one pup out of 69 and on day four, one pup out of 68 from the control group died. One pup out of 90 treated with 250 mg/kg bw/d and six pups out of 75 treated with 500 mg/kg bw/d of the test substance were found dead on day four, however there were no dead pups in the high dose group. Therefore, in the absence of a dose response relationship and the low magnitude of pup deaths, the finding was not considered to be treatment related. The mean body weight of pups on days zero and four postnatal was similar in all groups.
No information was provided.
No information was provided.
No information was provided.
Isethionate is not specifically listed in the SUSMP.
Isethionate has not been considered for scheduling previously.
Two public submissions were received. The first submission questions the wording of the entry: isethionate (2-hydroxyethanesulfonic acid) noting that according to Part 1, Section 2 of the Poisons Standard, all salts and derivatives are included in entries, unless specified. Isethionate and its salts are used in some cosmetic products and scheduling will impact those existing products. The US Cosmetic Ingredient Review (CIR) deemed isethionate as a safe cosmetic ingredient, when formulated to be non-irritating. The submission seeks for isethionate to remain unscheduled or at least to have a lengthy implementation date applied.
The second submission states isethionate salts are used as alternatives to lauryl sulfates in cosmetics. It refers to the US CIR on isethionate salts that concluded these to be safe for use in cosmetics when formulated to be non-irritating. The submission suggests surfactants do not require scheduling as the risks are known to consumers and due to no international restrictions being in place. They note, however, that a precedent has been set, with ammonium cocoyl isethionate appearing in Schedule 6. Therefore they ask if scheduling is decided upon that a low cut-off (currently used at up to 25%) in rinse-off cosmetics be put in place.
The public submission is available at Public submissions on scheduling matters.
The committee recommended that 2-hydroxyethansulfonic acid and its salts does not require a schedule listing but that the Delegate consider listing the substance in Appendix B for reasons of Part 2, Areas of Use.
The reasons for the recommendations comprised the following:
The committee also proposed a new reason in Appendix B, Part 2, Area of Use be created with wording to the effect of adjuvants in agricultural products.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (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 delegate considered the following in regards to this proposal:
The specific application for scheduling under consideration relates to the use of mixed salts of 'isethionate' as an adjuvant in agricultural herbicide tank mixes. The delegate notes, and accepts, ACCS advice that this substance does not require listing in the Schedules because of its low toxicity and use pattern. Listing in Appendix B for this specific agricultural use avoids any scheduling impacts associated with the use of isethionate salts in cosmetics and other domestic products, as flagged in the industry submissions.
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.
ISETHIONATE, as mixed ammonium and ethanolamine salts of 2-hydroxyethanesulfonic acid
Part 1 - Reasons for Entry
a) low toxicity; and
b) use pattern restricts hazard
Part 2 - Area of Use
1.11 Adjuvant in agricultural products
Two submissions were received.
The first submission supported the Delegate's interim decision to list Isethionate in Appendix B with clear wording on area of use as an adjuvant in agricultural products, to ensure there will be no impact on the scheduling of cosmetics and therapeutic goods.
The second submission noted Isethionates are used in cosmetic preparations, and one of the salts, ammonium cocoyl isethionate, is specifically scheduled. They agree isethionates when used as surfactants belong in Appendix B, however they do not agree that entry should be restricted to agricultural uses. They further note their concern about continuing to regulate surfactants that are commonly used in cosmetics and consumer products globally, such as ammonium cocoyl isethionates, using current concentration restrictions and mandatory statements are not in line with international practice. They cite a recent government statement of support for the "Accepting Trusted International Standards" policy and believe the current regulation of surfactants through the Poisons Standard should be reconsidered.
Edited versions of public submissions are available at Public submissions on scheduling matters.
The delegate notes the submissions received in response to publication of the interim decision and confirms the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.
The delegate notes the ongoing concerns expressed about previous actions to schedule surfactant ingredients in cosmetics and consumer products, but declines to review such decisions at this time. The proposed wording limiting the Appendix B entry to use of this specific mixture of isethionate salts as an adjuvant in agricultural products does not require any label changes or other controls associated with use of isethionates (except the currently scheduled ammonium cocoyl isethionate) in any cosmetic or consumer products.
ISETHIONATE, as mixed ammonium and monoethanolamine salts of 2-hydroxyethanesulfonic acid
Part 1 - reasons for entry
a) Low toxicity and
b) use pattern restricts hazard
Part 2 - Area of Use
1.11 Adjuvant in agricultural products.
The proposed implementation date is 1 June 2016.
Scheduling medicines and poisons
The chemicals scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS):
In August 2015, the National Industrial Chemicals Notification and Assessment Scheme (NICNAS), under its Inventory Multi-tiered Assessment and Prioritisation (IMAP) programme, referred the proposal to be considered by the delegate. The reasons for the request are:
Musk ambrette is a strong neurological and testicular toxicant at low exposures and also has a potential for photosensitisation. The chemical is toxic via dermal contact and hence, there is a concern for the use in cosmetic and domestic products. The environmental assessment also concluded that the chemical is expected to be persistent in the environment.
The European (EU) and Association of Southeast Asian Nations (ASEAN) countries as well as New Zealand have prohibited the use of musk ambrette in cosmetic products. While musk ambrette is generally considered to be phased out the chemical was reported to be used in Denmark in 2012.
Based on the scheduling factors the appropriate parent Schedule is 7 or 10. However, considering that the use of the chemical as a fragrance is prohibited overseas, and other uses are not likely to occur in Australia, Schedule 10 is probably appropriate in this case.
The delegate asked the committee the following questions:
Please refer to the NICNAS IMAP Human Health Tier II assessment report for benzene, 1-(1,1-dimethylethyl)-2-methoxy-4-methyl-3,5-dinitro-. This report is publicly available on the NICNAS website.
Figure 8. Chemical structure of musk ambrette
The acute toxicity end-points for this chemical are listed in the below table.
Toxicity | Species | Musk ambrette | SPF* Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | 339 | Schedule 6 |
Acute dermal toxicity LD50 (mg/kg bw) | Rabbit | >2000 | N/A |
Acute inhalational toxicity LC50 (mg/m3/4h) | N/A | No data | N/A |
Skin irritation | Rabbit | Not expected to be an irritant | N/A |
Eye irritation | Rabbit | Not expected to be an irritant | N/A |
Skin sensitisation | N/A | No data | N/A |
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
In a photosensitivity study in guinea pigs with limited data, musk ambrette was positive for photosensitivity after application to abraded skin, or under occlusive conditions.
In a local lymph node assay, musk ambrette did not induce a positive photo-allergic response. No further details were provided.
Human data also indicate photosensitisation potential of musk ambrette.
Based on the data available from the NICNAS IMAP report, the chemical is neurotoxic via oral and dermal exposure.
In a repeated dose oral toxicity study in rats (strain not provided), 0.5-4 mg/kg bw/day of musk ambrette was fed to rats in the diet. Treatment-related clinical signs included growth retardation and progressive paralysis of hind limbs at 1.5 mg/kg bw/day. Observations at 16-40 weeks showed complete hind limb paralysis in the animals at the high dose. Depressed erythrocyte counts and haemoglobin values in female rats were observed at doses of ≥1.5 mg/kg bw/day of the chemical. Jaundice at all dose levels was observed. Neuropathological changes reported were primary demyelination and distal axonal degeneration.
In a 12-week repeated dose oral toxicity study, young Sprague Dawley (SD) male and female rats were orally administered musk ambrette at 1500 ppm (approximately 75 mg/kg bw/day) of the chemical. Clinical and haematological examinations were conducted after six and 12 weeks. Hind limb weakness was observed in 20/40 treated animals.
In a 12-week repeated dose dermal toxicity study, young SD rats of both sexes were treated by dermal application of a patch with musk ambrette solution in phenyl ethyl alcohol (PEA) at concentrations of 10, 40, 80, or 240 mg/kg bw/day. Clinical and haematological examinations were conducted after six and 12 weeks. No adverse skin reactions to the patch were seen in any of the treatment groups. Hind limb weakness was observed in 1/30 animals treated at 40 mg/kg bw/day, 15/30 animals treated at 80 mg/kg bw/day and all animals treated at 240 mg/kg bw/day. All animals treated with 240 mg/kg bw/day showed severe neuropathological changes in the central and peripheral nervous system. The severity of the changes was dose-related.
The limited data available from several equivocal genotoxicity studies are insufficient for the chemical to be considered genotoxic.
No data are available on the chemical. The data for the structurally related chemical, musk xylene suggest that the mode of action for induction of liver tumours in mice is similar to that for phenobarbital. The relevance of this mode of action to humans has been questioned.
The chemical is considered to be a severe reproductive toxicant at low doses.
In a repeated dose oral toxicity study in rats (strain not provided), 0.5-4 mg/kg bw/day of musk ambrette was fed to rats in the diet. Histopathological investigation showed treatment-related testicular atrophy at 2.5 mg/kg bw/day.
In a 12-week repeated dose dermal toxicity study, young SD rats of both sexes were treated by dermal application of a patch with musk ambrette solution in phenyl ethyl alcohol (PEA) at concentrations of 10, 40, 80, or 240 mg/kg bw/day. Clinical and haematological examinations were conducted after six and 12 weeks. Necropsy revealed depressed testicular weight and testicular tubular degeneration in animals receiving 240 mg/kg bw/day.
While no Australian use information is available, the chemical is reported to be used as a fragrance ingredient in cosmetic and domestic products at up to 2 % concentration in consumer end products.
Many countries, including the European Union, New Zealand and Canada, have prohibited the use of this chemical in cosmetic products.
Currently, there are no restrictions in Australia on using this chemical in cosmetic and or domestic products. In the absence of any regulatory controls, the characterised critical health effects (neurotoxicity and reproductive toxicity) have the potential to pose an unreasonable risk to the public in relation to the uses identified.
The chemical is listed on the following:
This chemical is prohibited under the IFRA Standard (47th Amendment).
Musk ambrette is not specifically scheduled.
Musk ambrette has not been previously considered for scheduling; therefore, scheduling history is not available.
One public submission was received. The submission raised no objections to the proposal to include the substance in Schedule 10.
The public submission is available at Public submissions on scheduling matters.
The committee recommended that a new Schedule 10/Appendix C entry be created for benzene, 1-(1,1-dimethylethyl)-2-methoxy-4-methyl-3,5-dinitro- (musk ambrette) as follows:
Schedule 10 - New Entry
BENZENE, 1-(1,1-DIMETHYLETHYL)-2-METHOXY-4-METHYL-3,5-DINITRO-
Cross reference entry: Amber Musk, Musk Ambrette
The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included c) the toxicity of the substance; and f) any other matters that the Secretary considers necessary to protect public health.
The committee recommended an implementation date of 1 June 2016.
The reasons for the recommendations comprised the following:
The delegate considered the following in regards to this proposal:
The delegate notes, and accepts, ACCS advice that musk ambrette be listed in Schedule 10, to control its use as a fragrance ingredient in cosmetics and other products. Fragrance ingredients previously considered by the delegate and the ACCS may have either been listed in Schedules 5 or 6 because of their skin sensitising potential. In some cases, scheduling was not considered to be necessary based on the very low concentrations expected to be used in products. Musk ambrette warrants the more stringent controls available via listing in Schedule 10 because of demonstrated neurotoxicity and testicular toxicity in rat studies at relatively low doses applied dermally. The delegate agrees that the Schedule 10 listing be made under the chemical name 1-(1,1-dimethylethyl)-2-methoxy-4-methyl-3,5-dinitrobenzene, with the common name musk ambrette included in parenthesis and a cross reference to amber musk added to the index of the Poisons Standard.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989 to be (c) the toxicity of a substance.
The proposed implementation date is 1 June 2016.
Because of the potential health risks associated with any continued use of this fragrance ingredient in products in Australia, and the fact that its use is prohibited in some overseas jurisdictions, the earliest possible implementation date is warranted.
1-(1,1-DIMETHYLETHYL)-2-METHOXY-4-METHYL-3,5-DINITROBENZENE- (musk ambrette)
Cross reference entry in Index: Amber Musk
One submission was received. The submission supported the delegate's interim decision.
Edited versions of public submissions are available at Public submissions on scheduling matters.
The delegate notes the submission received in response to publication of the interim decision and confirms the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.
1-(1,1-DIMETHYLETHYL)-2-METHOXY-4-METHYL-3,5-DINITROBENZENE (musk ambrette)
Cross reference entry in Index: Amber Musk
The proposed implementation date is 1 June 2016.
Scheduling medicines and poisons
The chemicals scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS):
The reasons for the request are:
The delegate asked the committee the following questions:
Figure 9. Chemical structure of Oxathiapiprolin (DPX-QGU42)
The acute toxicity end-points for oxathiapiprolin are listed in the below table.
Toxicity | Species | Oxathiapiprolin | SPF* Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | SD Rat | >5000 (no deaths) | Appendix B |
Acute dermal toxicity LD50 (mg/kg bw) | SD Rat | >5000 (no deaths) | Appendix B |
Acute inhalational toxicity LC50 (mg/m3/4h) | SD Rat | >5100 (no deaths) | Appendix B |
Skin irritation | NZW rabbit | Non-irritant | Appendix B |
Eye irritation | NZW rabbit | Non-irritant | Appendix B |
Skin sensitisation (GPMT method) | Hartley Guinea pigs | Not sensitising | Appendix B |
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
For full summaries and discussion of other endpoints, please see the OCS evaluation report for oxathiapiprolin/the product. An abridged overview is included below.
Short-term and subchronic toxicity studies in rats, mice and dogs reported no systemic toxicity effects of oxathiapiprolin. Chronic dietary studies in mice and rats also reported no systemic toxicity. No treatment related adverse effects were seen in a short-term dermal study in the rat at the limit dose.
There was no evidence of a mutagenic/genotoxic potential of oxathiapiprolin or its primary metabolites in vitro with and without metabolic activation, or a genotoxic potential in vivo. While the metabolite IN-E8S72 was positive in vitro for structural chromosome aberrations in human peripheral blood lymphocytes, the follow-up in vivo micronucleus test with IN-E8S72 was negative at up to the limit dose of 2000 mg/kg bw.
There was no evidence of carcinogenic potential in the long-term rodent tests.
In a dietary two generation study in rats, no parental toxicity was seen and no effect was seen on reproductive parameters. However, there was a slight but significant increase in the mean age to achieve preputial separation in these F1 and F2 males at the highest dose of 17000/10000 ppm (equivalent to 1228/1278 mg/kg bw/day). This singular effect of a delay in preputial separation, associated with decreases in pup body weight at 17000/10000 ppm, a dose level exceeding the limit dose of 1000 mg/kg bw/day (as recommended in the OECD TG 416), occurred without other evidence of reproductive/developmental toxicity across the series of Guideline-compliant studies. No evidence of developmental toxicity potential was seen in an oral (gavage) developmental toxicity study in rats or in rabbits, and androgenic potential of oxathiapiprolin was negative in a series of in vivo and in vitro studies). Therefore, while acknowledging the occurrence of the preputial separation finding, the available data suggests that oxathiapiprolin should not being considered a hazard for reproductive or developmental toxicity.
In an acute oral (gavage) neurotoxicity study in rats no evidence of an acute neurotoxic effect was seen in functional observation battery or motor activity assessment. Oxathiapiprolin was also not neurotoxic in rats in the combined subchronic toxicity/neurotoxicity study at up to limit dose concentrations.
Oxathiapiprolin is not considered to pose any immunotoxicity risk.
No information was provided.
At this time, the proposed agricultural use of oxathiapiprolin is not expected to result in general public (i.e. domestic) exposure. Spray drift considerations have not been considered.
Oxathiapiprolin is part of a Global Joint Review (US EPA as lead with Health Canada, Australia and Mexico as partners) and is currently under national assessment for each individual country. The US EPA has notified a proposed registration decision in July 2015.
Oxathiapiprolin is not specifically scheduled.
Oxathiapiprolin has not been previously considered for scheduling; therefore, scheduling history is not available.
No public submissions were received.
The Committee recommended that a new Appendix B listing be created for oxathiapiprolin as follows:
Appendix B - New Entry
OXATHIAPIPROLIN
The committee recommended an implementation date of 1 June 2016.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (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.
The reasons for the recommendations comprised the following:
The delegate considered the following in regards to this proposal:
The delegate notes, and accepts, ACCS advice that oxathiapiprolin has sufficiently low toxicity that it does not meet any of the SPF criteria for scheduling. Accordingly, listing in Appendix B is considered to be appropriate. The delegate notes that the ACCS was unable to resolve the apparent difference in sensitisation potential between the active ingredient and the tested product, but notes that the Safety Directions provide adequate warning for users of the product and that listing in Schedule 5 is not necessary to flag this unresolved potential toxicity.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: c) the toxicity of the substance.
OXATHIAPIPROLIN
Part 1 - Reasons for Entry
a) Low toxicity
Part 2 - Area of Use
1.3 Fungicide.
No public submissions were received.
The delegate has confirmed the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.
OXATHIAPIPROLIN
Part 1 - reasons for entry
a) Low toxicity
Part 2 - Area of Use
1.3 Fungicide.
The proposed implementation date is 1 June 2016.
Scheduling medicines and poisons
The chemicals scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS):
In August 2015, the National Industrial Chemicals Notification and Assessment Scheme (NICNAS), under its Inventory Multi-tiered Assessment and Prioritisation (IMAP) programme, referred the proposal to be considered by the delegate for inclusion in the Poisons Standard.
The reasons for the request are:
The critical health effect for risk characterisation is skin sensitisation. Given the potential for induction and elicitation of sensitisation even below the overseas restriction cut-off, the risk would be better controlled by inclusion of warning statements on the label of preparations containing the chemical below the concentration cut-off. These chemicals have similar use and hazard profiles to a number of chemicals which have been listed in Schedule 6 with reverse scheduling requirements.
The delegate asked the committee the following questions:
This report, containing more detailed information about the substance, is publicly available on the NICNAS website.
Figure 10. Chemical structure of p-methylaminophenol
The acute toxicity end-points for the chemicals are listed in the table below.
Toxicity | Species | p-methylaminophenol and its sulfate salt | SPF* Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Mouse | 380 | Schedule 6 |
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 | Slight irritant at 3 % (limited data) | - |
Eye irritation | Rabbit | Slight irritant at 3 % (limited data) | - |
Skin sensitisation (LLNA) | Mouse | Moderate to severe skin sensitiser (EC3 = 2.2%) | Schedule 6 |
* Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
The chemicals are considered to be moderate to severe skin sensitisers according to the SPF classification.
The skin sensitising potential of p-methylaminophenol sulfate was investigated in a local lymph node assay (LLNA). A solution containing the chemical at 0.25, 0.5, 1, 2.5 or 5 % was applied (25 µL) to the dorsal surface of both ears of CBA/J mice, once daily for three days. The treated animals were monitored daily for mortality and clinical signs. The study reported a dose-related increase in the stimulation index (SI), with 2.5 % and 5 % concentrations, exceeding the value of three. The effective concentration needed to produce a three-fold increase in lymphocyte proliferation (EC3) was calculated to be 2.2 %, indicating the chemical as a moderate to severe skin sensitiser.
In a skin sensitisation test, albino Hartley guinea pigs (n = 10/sex) were treated topically (occlusive, behind the right shoulder blade) with 0.5 g of p-methylaminophenol, three times per week for three weeks and once on week four. The animals also received two intradermal injections of Freund's complete adjuvant on days one and 10. Twelve days after induction, the untreated left flank was challenged with 0.5 g of the chemical for 48 hours under occlusion. No skin reactions were observed.
Although a guinea pig skin sensitisation study with p-methylaminophenol gave negative results, based on the positive results observed for p-methylaminophenol sulfate in a more reliable assay, both chemicals are expected to be skin sensitisers.
Based on the data available for p-methylaminophenol sulfate, the chemicals are expected to cause serious damage to health from repeated oral exposure. In a 13-week oral gavage study, SD rats were dosed with p-methylaminophenol sulfate (suspended in 0.5 % carboxymethylcellulose) at 0, 3, 10, or 30 mg/kg bw/day. A no observed adverse effect level (NOAEL) of 10 mg/kg bw/day was reported based on tubular epithelial degeneration/single cell necrosis in the kidneys of most males and in half of the female rats at 30 mg/kg bw/day. In addition, some males of this group had higher urinary volumes with lower specific gravity. However, these changes were reported as completely reversible within the four-week recovery period.
No information was available for repeated dose toxicity by inhalation route and dermal routes.
The available data are not sufficient to derive a conclusion on the genotoxicity of the chemicals.
Only limited data are available. The chemicals are not expected to be carcinogenic via dermal exposure at 1 % concentration.
Based on the limited data available, the chemicals are not known to cause reproductive or developmental toxicity.
Considering the use of these chemicals in permanent hair dyes in Australia, the main route of public exposure is expected to be through the skin.
The Association of Southeast Asian Nations (ASEAN), European Union (EU) and New Zealand have restricted the use of these chemicals in cosmetics. Following a safety evaluation, the SCCP (2006) concluded that the 'use of p-methylaminophenol sulphate itself as an oxidative hair dye at a maximum concentration of 0.68% in the finished cosmetic product (after mixing with hydrogen peroxide) does not pose a risk to the health of the consumer, apart from its sensitising potential.'
Currently, there are no restrictions in Australia on using these chemicals in cosmetics or hair dyes. In the absence of any regulatory controls, the characterised critical health effects (skin sensitisation) have the potential to pose an unreasonable risk for the uses identified.
The chemicals are listed on the following:
p-Methylaminophenol and its sulfate are not specifically scheduled.
p-Methylaminophenol and its sulfate have not been previously considered for scheduling; therefore, scheduling history is not available.
One public submission was received.
No objections to aligning with EU were raised. It was noted in the submission that it is important to maintain "in-use" concentrations for hair dye preparations, due to the mode of use being mixing with an oxidising substance prior to use.
The public submission is available at Public submissions on scheduling matters.
The Committee recommended that new Schedule 6 and Appendix F entries for p-methylaminophenol be created with exceptions or cut-offs as follows:
Schedule 6 - New Entry
p-METHYLAMINOPHENOL except when used in hair dye and eyebrow/eyelash colouring products at a concentration of 1 per cent or less after mixing for use when the immediate container and primary pack are labelled with the following statements:
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use.
Written in letters not less than 1.5 mm in height.
Appendix F - New Entry
p-METHYLAMINOPHENOL
Part 1, Warning Statement: 28
The ACCS recommended an implementation date of 1 June 2016.
The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included (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 recommendations comprised the following:
The delegate considered the following in regards to this proposal:
Oxidative hair dyes of the aromatic diamine and aminophenolic classes have some common toxicological properties that warrant controls over scheduling. These features are primarily skin-eye irritancy and sensitization potential. These toxicological properties generally align with SPF criteria for listing in Schedule 6. Several of these dyes (e.g. phenylenediamines, toluenediamines; aminophenols) have already been listed in Schedule 6, but previous scheduling policies have allowed for some products to be exempted where there are label statements warning of the potential for skin irritancy and sensitization, and recommending testing for individual susceptibility before use. This approach is commonly called ‘reverse scheduling’. Where there is potential mutagenicity, or the need to prevent uses for skin colouration (tattooing) or use to dye eyebrows or eyelashes, some of these substances have been listed in Schedule 10 to prevent such uses.
This is one of six oxidant hair dyes that were referred to the November 2015 meeting of the ACCS for advice to the delegate on scheduling. The key issues were whether their toxicological profiles sufficiently match the SPF criteria for inclusion in Schedule 6 and whether product exemptions based on 'reverse scheduling' could be applied, consistent with labelling provisions applied to other oxidative hair dyes. Given that some products containing oxidative hair dyes require mixing with an oxidant, such as hydrogen peroxide, before application to the hair, consideration was given to appropriate exemption cut-off concentrations that take account of the final concentration applied to the hair.
The delegate notes, and accepts, ACCS advice that p-methylaminophenol should be listed in Schedule 6, with an exemption cut-off at 1%, provided products are labelled with the warning statements about potential skin sensitisation that have been required for similar oxidative hair dyes. The delegate also notes ACCS advice that warning statements relating to use for dyeing eyebrows and eyelashes are not needed, because the substance is not a strong irritant. The delegate also notes ACCS advice that p-methylaminophenol is the INCI name and is the preferred name for listing in Schedule 6.
A later implementation date is proposed to allow for an orderly process of re-labelling of products already on the market.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance; d) the dosage, formulation, labelling, packaging and presentation of a substance.
p-METHYLAMINOPHENOL except when used in hair dye and eyebrow/eyelash colouring products at a concentration of 1 per cent or less of p-methylaminophenol after mixing for use when the immediate container and primary pack are labelled with the following statements:
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use.
Written in letters not less than 1.5 mm in height.
p-METHYLAMINOPHENOL
Part 1, Warning Statement: 28
One submission was received. The submission supported the delegate's interim decision.
Edited versions of public submissions are available at Public submissions on scheduling matters.
The delegate notes the submission received in response to publication of the interim decision and confirms the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.
p-METHYLAMINOPHENOL except when used in hair dye and eyebrow/eyelash colouring products at a concentration of 1 per cent or less of p-methylaminophenol after mixing for use when the immediate container and primary pack are labelled with the following statements:
KEEP OUT OF REACH OF CHILDREN, and
WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use.
Written in letters not less than 1.5 mm in height.
p-METHYLAMINOPHENOL
Warning Statement: 28
The proposed implementation date is 1 October 2016.
Scheduling medicines and poisons
The chemicals scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS):
The reasons for the request were:
The SPF requires consultation with the States/territories on amendments to Parts 1-3 of the Poisons Standard. At the time of referral, the delegate believed that such consultation could be achieved via referral to a meeting of the ACCS. The ACCS advice was that a more formal consultative proposal may be needed. The delegate had raised the following issues in the referral to the ACCS.
The delegate asked the committee the following questions:
If the ACCS does support the proposed amendment, what implementation date is proposed to allow for an orderly re-labelling of existing products?
Currently paints and tinters that contain only Schedule 5 poisons are exempt from the labelling requirements of Section 1.3 of the Poisons Standard. As such, the predominate hazard information on a consumer paint tin is the Dangerous Goods information.
The paint industry is going through a relabelling exercise to meet the 1 January 2017 deadline for all industrial/commercial products to be labelled according to Globally Harmonised System (GHS) of Classification and Labelling of Chemicals as required by the model Work Health and Safety. GHS labelling information is more prominent than existing labelling requirements as it contains both written and pictorial hazard information.
In the paint industry, products are commonly split-fills where the same product is sold to both consumer and trade markets in different labelled tins. Looking at how a tin of paint will be labelled for the workplace vs a tin labelled for consumer the applicant believes that the difference is getting so large that a consumer may be provided with a false sense of security.
The applicant contends that, to the consumer, the paint looks "safe" just like the old fashion oil based paints, but to the worker the paint looks highly hazardous and full PPE and precautions are required. The applicant believes that the consumer will be complacent in it use and expose themselves to unnecessary risk and a worker will be more inclined to purchase consumer labelled products as they appear safer and will miss receiving appropriate hazard information.
The three outcomes that are foreseen by the applicant as occurring if Part 2 is amended as proposed are:
1.5.8 Paints
Two public submissions were received. There were no contentions with the application to amend Part 2, 1.5.8 Paints. Both submissions asked for a long implementation date to allow for any changes to labelling.
The public submission is available at Public submissions on scheduling matters.
The Committee suggested that the current scheduling of Schedule 5 Paints remains appropriate, although it declined to make a firm recommendation to the Delegate, pending the outcome of formal negotiations on scheduling policy issues related to amendment of Parts 1-3 of the Poisons Standard.
The delegate considered the following in regards to this proposal:
The delegate has decided to defer making a decision on this issue, pending formal consultation with the States/Territories, as required in the new AHMAC Scheduling Policy Framework for amendments to Parts 1-3 of the Poisons Standard.
One submission was received. The submission supported the delegate's interim decision. Edited versions of public submissions are available at Public submissions on scheduling matters.
The delegate notes the submission received in response to publication of the interim decision and confirms the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.
Scheduling medicines and poisons
The chemicals scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS):
The reasons for the request were:
The delegate asked the committee the following questions:
To what extent is the toxicity of topramezone consistent with that of other HPPD inhibitors (e.g. mesotrione - listed in Schedule 5 in 2011)?
Figure 1. Chemical structure of topramezone (BAS 670 H)
The acute toxicity end-points for topramezone are listed in the below table.
Toxicity | Species | Topramezone | SPF* Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Wistar Rat | >2000 (no deaths) | Appendix B |
Acute dermal toxicity LD50 (mg/kg bw) | Wistar Rat | >2000 (no deaths) | Appendix B |
Acute inhalational toxicity LC50 (mg/m3/4h) | Wistar Rat | >5050 (no deaths) | Appendix B |
Skin irritation | NZW rabbit | Slight irritant | Schedule 5 |
Eye irritation | NZW rabbit | Slight irritant | Schedule 5 |
Skin sensitisation (GPMT) | Guinea pig | Non-sensitising | Appendix B |
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
For full summaries and discussion of other endpoints, please see the OCS evaluation report for topramezone. An abridged overview is included below.
In repeat-dose toxicity studies, the rat appeared to be the most sensitive species, with the thyroid gland (increased incidence and/or severity of flaky colloid, follicular cell hypertrophy and follicular cell hyperplasia), pancreas (diffuse degeneration) and eyes (corneal opacity) as target organs for toxicity in this species, but not mice or dogs. Increased kidney and/or liver weights, generally in the absence of histopathological lesions, was evident in mice and/or dogs. Serum chemistry (all species) and urinalysis findings (rats and dogs; not assessed in mice) consistent with the pharmacological action of topramezone (4-HPPD inhibition) included elevated serum tyrosine levels and increased urinary ketone levels. While reversibility of effects was not always assessed, the nature of the toxicity findings indicates reversibility is possible. Overall, the repeat-dose toxicity profile of topramezone is very similar to other 4-HPPD inhibitors, such as mesotrione.
There was no evidence of a mutagenic/genotoxic potential of topramezone in vitro with and without metabolic activation, or a genotoxic potential in vivo.
There was no evidence of a carcinogenic potential in an 18-month carcinogenicity study in mice by dietary administration up to and including the highest dose tested of 1903/2467 mg/kg bw/day (8000 ppm) for males/females, respectively.
In a rat dietary oral carcinogenicity study, an increased incidence of thyroid gland tumours (follicular cell adenoma and carcinoma; both sexes) with an increased incidence of follicular cell hyperplasia was observed in females only. The Mode of Action data did indicate that topramezone treatment causes a perturbation of thyroid-pituitary hormone homeostasis, which is a potentially underlying cause for thyroid tumour formation in rats. Thyroid tumours in rodents that occur as a result of alterations to thyroid hormone levels are generally not considered to be relevant to human subjects. Therefore, topramezone is unlikely to pose a carcinogenic risk to human subjects.
Fertility was unaffected in mice and rats in three and two generation reproduction studies, respectively.
Topramezone crossed the placenta in rabbits and elevated foetal serum levels of tyrosine were observed. There were no adverse embryofoetal developmental effects observed in mice. Similar foetal skeletal variations (delayed ossification and supernumerary ribs and/or vertebrae) were seen in rats and rabbits. These variations occurred in the absence of maternotoxicity and are considered to be secondary to the pharmacological effects of topramezone. Similar foetal skeletal effects were observed with other 4-HPPD inhibitors, such as mesotrione. These effects alone were not considered sufficient to warrant labelling of mesotrione as a developmental toxicant.
However, in both rats and rabbits, topramezone appeared to have adverse effects on kidney genesis and development in foetuses/pups following maternal exposure. Foetuses lacking a kidney/ureter were seen in developmental studies with rabbits, while F1 pups adults and with renal pelvic dilation (a malformation) were seen in a reproductive study in rats; kidney anatomical maturation occurs postnatally in rodents.
The data from two species (rats and rabbits) suggests topramezone treatment has an irreversible effect on the developing kidney. Irreversible foetal kidney lesions have not been reported in developmental/reproductive studies with other 4-HPPD inhibitors. With the available data, this effect cannot be ruled out as not being relevant to humans. Unlike other members of the 4-HPPD inhibitor class, topramezone should be considered as a developmental toxicant.
No evidence of neurotoxicity was seen in an acute and repeat dose developmental neurotoxicity study.
Topramezone was not investigated for immunotoxic potential.
No information was provided.
At this time, no agricultural use product containing topramezone has been proposed.
Topramezone as an active constituent as well as a SC herbicidal product containing topramezone have been approved/registered by the US EPA (2005, conditional approval), EFSA (2014) and Health Canada (2006, as a temporary approval).
Topramezone is not specifically scheduled.
Topramezone has not been previously considered for scheduling; therefore, scheduling history is not available.
One public submission was received. The submission was a comment on the OCS Technical Report. The submission refers to the dilated renal pelvis findings stating that these occur at maternal toxic concentrations and should be considered a variation, rather than a malformation, and are secondary to tyrosinemia. The dilated renal pelvis findings are proposed not to be human-relevant and should not be used for the derivation of reference values. The NOAEL from the developmental rabbit studies should be used instead.
The public submission is available at Public submissions on scheduling matters.
The committee recommended that a new Schedule 5 entry be created for topramezone as follows:
TOPRAMEZONE
The Committee recommended an implementation date of 1 June 2016.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (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.
The reasons for the recommendations comprised of the following:
The delegate considered the following in regards to this proposal:
The delegate notes, and accepts, ACCS advice that topramezone be listed in Schedule 5, with no cut-off to exempt at this time in light of there being no product information. The delegate agrees that the overall toxicological profile of topramezone is consistent with SPF criteria for listing in Schedule 5. The equivocal nature of the foetal developmental effects, including the apparently flat dose-response relationship and their possible relationship to the elevated tyrosine levels associated with treatment with this HPPD inhibitor, were considered insufficient to require listing in Schedule 6.
The earliest practicable implementation of the scheduling decision will facilitate approval of the substance by the APVMA.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: c) the toxicity of the substance.
TOPRAMEZONE
No public submissions were received.
The delegate has confirmed the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.
TOPRAMEZONE
The proposed implementation date is 1 June 2016.
Scheduling medicines and poisons
Substance | Final decision |
---|---|
Bismuth oxychloride | The delegate's final decision is that the current scheduling for bismuth oxychloride remains appropriate |
Naproxen |
APPENDIX H - New entryProposed implementation date: 1 June 2016 |
Paracetamol |
The delegate has deferred making a final decision at this time regarding the scheduling of paracetamol when combined with ibuprofen. This is due to a late submission received during the most recent consultation period, and allows the submission to be given due consideration before the delegate makes a final decision. The final decision will be made before the end of April. |
Piracetam | The delegate's final decision is that the current scheduling of piracetam remains appropriate. |
Lansoprazole, omeprazole and rabeprazole |
The delegate's final decision is to include lansoprazole, omeprazole, rabeprazole in Schedule 2: LansoprazoleSchedule 2 - New entryLANSOPRAZOLE in oral preparations containing 15 mg or less of lansoprazole per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 7 days' supply. Schedule 3 - AmendmentLANSOPRAZOLE in oral preparations containing 15 mg or less of lansoprazole per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 14 days' supply except when included in Schedule 2. Schedule 4 - AmendmentLANSOPRAZOLE except when included in Schedule 2 or 3. OmeprazoleSchedule 2 - New entryOMEPRAZOLE in oral preparations containing 20 mg or less of omeprazole per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 7 days' supply. Schedule 3 - AmendmentOMEPRAZOLE in oral preparations containing 20 mg or less of omeprazole per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 14 days’ supply except when included in Schedule 2. Schedule 4 - Amend entryOMEPRAZOLE except when included in Schedule 2 or 3. RabeprazoleSchedule 2 - New entryRABEPRAZOLE in oral preparations containing 10 mg or less of rabeprazole per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 7 days' supply. Schedule 3 - AmendmentRABEPRAZOLE in oral preparations containing 10 mg or less of rabeprazole per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 14 days' supply except when included in Schedule 2. Schedule 4 - AmendmentRABEPRAZOLE except when included in Schedule 2 or 3. Proposed implementation date: 1 June 2016 |
Flubromazolam |
Schedule 9 - New entryFLUBROMAZOLAM Proposed implementation date: 1 June 2016 |
Thymosin Beta 4 (Thymosin β4) |
Schedule 4 - New entriesTHYMOSIN BETA 4 (THYMOSIN Β4) TB-500 FIBROBLAST GROWTH FACTORS Appendix D, Item 5 - New entriesTHYMOSIN BETA 4 (THYMOSIN Β4) TB-500 FIBROBLAST GROWTH FACTORS Proposed implementation date: 1 June 2016 |
Scheduling medicines and poisons
The medicines scheduling delegate (the delegate) has referred the following scheduling proposal for consideration by the Advisory Committee on Medicines Scheduling (ACMS):
The applicant has provided the following information regarding Bismuth Oxychloride:
Bismuth oxychloride is a synthetically prepared white or nearly white amorphous or finely crystalline powder. Bismuth oxychloride is used in formulations of many cosmetic and personal care products, including make-up, nail products, cleansing products, fragrances and hair colouring products. Bismuth oxychloride imparts a white colour to cosmetics and personal care products.
The United States Food and Drug Administration (FDA) lists bismuth oxychloride as a colour additive exempt from certification. The FDA requires that bismuth oxychloride conforms to the following specifications and shall be free from impurities other than those named (to the extent that such other impurities may be avoided by good manufacturing practice): Volatile matter, not more than 0.5%; Lead (as Pb), not more than 20 ppm; Arsenic (as As), not more than 3 ppm; Mercury (as Hg), not more than 1 ppm; Bismuth oxychloride, not less than 98%. Bismuth oxychloride is permitted to be used to colour externally applied drugs, including those intended for use in the area of the eye. Use in lipsticks is permitted. The FDA considers that certification of bismuth oxychloride is not necessary for protection of public health.
Toxicological data presented in a journal article in 1975 provided the following summary: The pearlescent white pigment, bismuth oxychloride, which is used as a colouring agent for decorative cosmetics, was administered to BD rats in the diet in a concentration of 1, 2 or 5% for two years. Neither carcinogenic activity nor other toxic effect attributable to the test compound was detected in the animals, which were maintained on a control diet from the termination of treatment until their death.
Bismuth oxychloride was included on the Australian Register of therapeutic Goods (ARTG) in July 2002. TGA currently permits its use as an active ingredient in biologicals, and as an excipient in biologicals or medical devices. The ARTG states that bismuth oxychloride "will not be available as a starting material for OTC (products)" - this is consistent with the current scheduling of bismuth oxychloride (Schedule 4 for human therapeutic use).
The TGA regulates some sunscreens as therapeutic goods. These include primary sunscreens with SPF 4 or more, secondary sunscreens (except those regulated as cosmetics), and primary or secondary sunscreens with SPF 4 or more that contain an insect repellent. Products that contain an ingredient with sunscreening properties where the primary purpose of the product is neither sunscreening nor therapeutic ('cosmetic sunscreens') are regulated as cosmetics by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS). Bismuth oxychloride is not used as a UV filter, but may be included as an excipient in cosmetic products (e.g. to give makeup a shimmering effect), including cosmetic sunscreens.
In Australia, the NICNAS Inventory multi-tiered assessment and prioritisation (IMAP) framework lists the status of bismuth oxychloride (bismuthine, chlorooxo-) for cosmetic use as Tier I Final (chemicals that are not considered to pose an unreasonable risk to the health of workers and public health on the basis of the Tier I assessment).
Bismuth Oxychloride is currently covered under entries for 'BISMUTH COMPOUNDS' in Schedule 4.
BISMUTH COMPOUNDS for cosmetic use, except:
BISMUTH COMPOUNDS for human therapeutic use, except bismuth formic iodide or bismuth subiodide in dusting powders containing 3 per cent or less of bismuth.
Poisons Standard (Standing) Committee: May 1979
The PSSC considered concerns that had been raised by the Australian Drug Evaluation Committee (ADEC) regarding the unrestricted availability of bismuth compounds (particularly the subnitrate and tripotassium dicitrata-bismuthate) and their potential to cause neurotoxicity. The PSSC considered Schedule 4 appropriate, in view of limited published data on mechanism of action of bismuth compounds. The PSSC recommended that bismuth subgallate should be deleted from Schedule 4, and that 'Bismuth compounds for human oral use' should be inserted as a new entry in Schedule 4.
Poisons Standard (Standing) Committee: February 1984
The PSSC considered the scheduling of bismuth, including a proposal to exempt bismuth oxychloride from Schedule 4 when used as a pearlescent in cosmetics for external use (item 4.36). The PSSC had noted that the Japanese Government Advisory Scientific Medical Committee (the only other country that had imposed restrictions on bismuth oxychloride in cosmetics) had withdrawn its restrictions (see item 3.6). The PSSC supported exempting bismuth oxychloride from scheduling when used in cosmetics, and recommended that the Schedule 4 entry for 'Bismuth' should be amended to 'Bismuth, compounds of, for human therapeutic or cosmetic use, except: (a) bismuth citrate when incorporated in hair colorant preparations in concentrations of 0.5% w/w or less; (b) bismuth oxychloride in cosmetics; (c) bismuth formic iodide in dusting powder containing 3% or less of bismuth.
National Drugs and Poisons Scheduling Committee: August 1999
The NDPSC considered recommendations from the Trans-Tasman Harmonisation of Scheduling Working Party (June 1999), and agreed that the Schedule 4 entry for Bismuth compounds should be replaced by two separate entries, covering bismuth compounds for cosmetic use and bismuth compounds for therapeutic use (it was noted that the New Zealand schedule only regulates medicines). The NDPSC therefore decided to create the following Schedule 4 new entries: 'Bismuth compounds for cosmetic use except: (a) bismuth citrate when incorporated in hair colourant preparations in concentrations of 0.5 per cent or less; or (b) bismuth oxychloride'; and 'Bismuth compounds for human therapeutic use, except bismuth formic iodide or bismuth subiodide in dusting powders containing 3 per cent or less of bismuth'.
National Drugs and Poisons Scheduling Committee: November 1999
The NDPSC supported the August 1999 decision regarding the new Schedule 4 entries for bismuth compounds.
Two submissions were received.
The supporting submission made the following main point:
The opposing submission made the following main points:
The public submissions are available at Public submissions on scheduling matters.
The ACMS recommended that the current scheduling 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; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the recommendations comprised the following:
The delegate considered the following in regards to this proposal:
The delegate's interim decision is that the current scheduling for bismuth oxychloride remains appropriate.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: a) the risks and benefits of the use of the substance; b) the purposes for which a substance is to be used and the extent of use of a substance; and c) the toxicity of the substance.
The reasons for the recommendation comprised the following:
The delegate considered the following in regards to this proposal:
No public submissions were received.
The delegate has confirmed the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the final decision and reasons are in keeping with those for the interim decision.
Scheduling medicines and poisons
The medicines scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Medicines Scheduling (ACMS):
The applicant has provided the following information regarding Naproxen:
Naproxen, a propionic acid derivative, is a non-steroidal anti-inflammatory drug (NSAID). Naproxen is used in musculoskeletal and joint disorders such as ankylosing spondylitis, osteoarthritis, and rheumatoid arthritis including juvenile idiopathic arthritis. It is also used in dysmenorrhoea, headache including migraine, postoperative pain, soft-tissue disorders, acute gout, and to reduce fever. Naproxen is usually given orally as the free acid or as the sodium salt (550 mg of naproxen sodium is equivalent to about 500 mg of naproxen).
NAPROXEN is currently listed in Schedules 2, 3 and 4, and in Appendix F.
NAPROXEN in divided preparations containing 250 mg or less of naproxen per dosage unit in packs of 30 or less dosage units.
NAPROXEN in a modified release dosage form of 600 mg of naproxen or less per dosage unit in packs of 16 or less dosage units when labelled not for the treatment of children under 12 years of age.
NAPROXEN except when included in Schedule 3 or in Schedule 2.
Delegate decision: July 2014
The ACMS considered a proposal to include naproxen in Schedule 2 in a modified release (extended release) dosage form containing 600 mg or less of naproxen per dosage unit in packs of 16 or less dosage units, when labelled not for treatment of children under 12 years of age. The ACMS recommended, and the delegate confirmed, that those modified release naproxen preparations should be included in Schedule 3. The ACMS also recommended that the SUSMP Appendix F warnings current at that time for naproxen should apply to the new Schedule 3 dosage form for naproxen. The implementation date for the delegate's decision was 1 October 2014.
Delegate decision: March 2015
The ACMS considered a proposal to include naproxen (when in Schedule 3) in Appendix H. The ACMS recommended, and the delegate confirmed, that the current scheduling of naproxen remained appropriate. Reasons for the delegate's March 2015 decision included that: Schedule 2 naproxen products can be advertised to consumers and there does not appear to be any additional benefit in advertising modified release naproxen; concern that advertising Schedule 3 products might encourage consumers to request the modified release product when conventional lower dose product might be more appropriate; and that modified release naproxen had only recently been included in Schedule 3, and there were no Schedule 3 naproxen products on the ARTG and consequently no experience with their marketing/use in Australia.
Four public submissions were received.
The main points of the supporting decisions were:
The main point of the opposing submission was:
The ACMS recommended that naproxen should be listed in Appendix H.
The committee recommended an implementation date of 1 June 2016.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: a) the risks and benefits of the use of the substance; b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance; d) the dosage, formulation, labelling, packaging and presentation of a substance; e) the potential for abuse of a substance; and f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the recommendation comprised the following:
The delegate considered the following in regards to this proposal:
The delegate's interim decision is to include Naproxen in Appendix H.
The proposed implementation date is 1 June 2016.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: a) the risks and benefits of the use of the substance; b) the purposes for which a substance is to be used and the extent of use of a substance; and c) the toxicity of the substance.
The reasons for the recommendation comprised the following:
The delegate considered the following in regards to this proposal:
One public submission (ASMI) was received which supported the delegate's interim decision.
The delegate has confirmed the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the final decision and reasons are in keeping with those for the interim decision.
The implementation date is 1 June 2016.
Scheduling medicines and poisons
The medicines scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Medicines Scheduling (ACMS):
The delegate's interim decision is available at Reasons for scheduling delegate's interim decision and invitation for further comment for the ACCS and ACMS meetings, November 2015
The delegate considered the following in regards to this proposal:
Four public submissions were received. All supported the delegate's interim decision to amend the S2 entry, however 2 submissions requested an amendment to part (a) of the proposed entry into the Poisons Standard as follows:
PARACETAMOL for therapeutic use:
The delegate has deferred making a final decision at this time regarding the scheduling of paracetamol when combined with ibuprofen. This is due to a late submission received during the most recent consultation period, and allows the submission to be given due consideration before the delegate makes a final decision. The final decision will be made before the end of April.
Scheduling medicines and poisons
The medicines scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Medicines Scheduling (ACMS):
The applicant has provided the following information regarding Piracetam:
Piracetam acts on the central nervous system (CNS) and has been described as a nootropic; it is said to protect the cerebral cortex against hypoxia. It is also reported to inhibit platelet aggregation and reduce blood viscosity at high doses. Piracetam is used as an adjunct in the treatment of myoclonus of cortical origin, and has also been used in dementia. Other disorders or states in which it has been tried (on the basis of a supposed ‘cerebrocortical insufficiency’ responsive to piracetam) include alcoholism, vertigo, cerebrovascular accidents, dyslexia, behavioural disorders in children, and after trauma or surgery.
In cortical myoclonus, piracetam is given in oral doses of 7.2 g daily, increasing by 4.8 g daily every three or four days up to a maximum of 24 g daily. It is given in two or three divided doses. Once the optimal dose of piracetam has been established, attempts should be made to reduce the dose of other drugs.
Piracetam has been given for various other disorders in a usual oral dose of up to 2.4 g daily in 2 or 3 divided doses; doses of up to 4.8 g daily or higher have been used in severe cases. In severe disorders it has also been given by intramuscular or intravenous injection.
Although piracetam is used in some countries in the management of cognitive impairment and dementia, a systematic (Cochrane) review concluded that the evidence from the published literature did not support this use.
Piracetam is reported to produce insomnia or somnolence, weight gain, hyperkinesia, nervousness and depression. Other reported adverse effects include gastrointestinal disorders such as abdominal pain, diarrhoea, nausea and vomiting, hypersensitivity reactions, ataxia, vertigo, confusion, hallucinations, angioedema and rashes. Piracetam should not be given to patients with hepatic impairment or with severe renal impairment (creatinine clearance less than 20 mL/minute); dosage reduction is recommended for those with mild to moderate renal impairment. Therapy with piracetam should not be withdrawn abruptly in myoclonic patients due to the risk of inducing seizures. When used to treat cortical myoclonus, piracetam is contraindicated in patients with cerebral haemorrhage, and should be used with caution after major surgery and in those with haemostatic disorders or severe haemorrhage.
Piracetam is rapidly and extensively absorbed from the gastrointestinal tract; peak plasma concentrations are reached within 1.5 hours after oral doses. The plasma half-life is reported to be five hours, and piracetam crosses the blood-brain barrier. Piracetam is excreted almost completely in the urine. It crosses the placenta and is distributed into breast milk.
Piracetam is currently listed in Schedule 4.
The NDPSC agreed to include piracetam in Schedule 4, on the grounds of harmonisation with New Zealand.
The New Zealand Medicines Classification Committee (MCC) considered the classification of a number of new chemical entities, including piracetam, at its meeting on 17 May 2001. The MCC agreed that, in view of the indications and as it was a new chemical entity, piracetam should be classified as prescription medicine.
Two public submissions were received. These were opposed to the proposal.
They made the following main points:
The public submissions are available at Public submissions on scheduling matters.
The ACMS recommended that the current scheduling of piracetam remains appropriate.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: a) the risks and benefits of the use of the substance; b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance; d) the dosage, formulation, labelling, packaging and presentation of a substance; e) the potential for abuse of a substance; and f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the recommendation comprised the following:
The delegate considered the following in regards to this proposal:
The delegate's interim decision is that the current scheduling of piracetam remains appropriate.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: a) the risks and benefits of the use of the substance; b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance; d) the dosage, formulation, labelling, packaging and presentation of a substance; e) the potential for abuse of a substance; and f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the recommendation comprised the following:
The delegate considered the following in regards to this proposal:
No public submissions were received.
The delegate has confirmed the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the final decision and reasons are in keeping with those for the interim decision.
Scheduling medicines and poisons
The medicines scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Medicines Scheduling (ACMS):
Esomeprazole, lansoprazole, omeprazole, pantoprazole and rabeprazole are proton pump inhibitor (PPI) medicines. PPIs reversibly reduce gastric acid secretion by specifically inhibiting the gastric enzyme H+, K+-ATPase proton pump in gastric parietal cells.
PPIs are used in conditions where inhibition of gastric acid secretion may be beneficial, such as the management of peptic ulcer disease, relief of acid-related dyspepsia, treatment of gastro-oesophageal reflux disease (GORD), treatment of NSAID-associated ulceration and treatment of pathological hypersecretory states such as Zollinger-Ellison syndrome.
Over-the-counter (OTC - i.e. Schedule 2 or 3) PPIs are indicated for the relief of heartburn and other symptoms of GORD, when given once daily for at least seven days, and up to 14 days. OTC PPIs appear to have consistent safety and efficacy profiles when used short-term for the relief of symptoms of GORD (OTC use is limited to 14 days except on medical advice, and OTC PPIs are not approved for use in children or adolescents under 18 years of age).
LANSOPRAZOLE is currently listed in Schedules 3 and 4.
LANSOPRAZOLE in oral preparations containing 15 mg or less of lansoprazole per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 14 days' supply.
LANSOPRAZOLE except when included in Schedule 3.
RABEPRAZOLE is currently listed in Schedules 3 and 4.
RABEPRAZOLE in oral preparations containing 10 mg or less of rabeprazole per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 14 days' supply.
RABEPRAZOLE except when included in Schedule 3.
PANTOPRAZOLE is currently listed in Schedules 2, 3 and 4.
PANTOPRAZOLE in oral preparations containing 20 mg or less of pantoprazole per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 7 days' supply.
PANTOPRAZOLE in oral preparations containing 20 mg or less of pantoprazole per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 14 days’ supply except when included in Schedule 2.
PANTOPRAZOLE except when included in Schedule 2 or 3.
ESOMEPRAZOLE is currently listed in Schedules 3 and 4. However, the delegate has proposed, in an October 2015 interim decision, to reschedule esomeprazole, so that it will be listed in Schedules 2, 3 and 4, as follows (with a proposed implementation date of 1 February 2016).
ESOMEPRAZOLE in oral preparations containing 20 mg or less of esomeprazole per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 7 days' supply.
ESOMEPRAZOLE in oral preparations containing 20 mg or less of esomeprazole per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 14 days' supply except when included in Schedule 2.
ESOMEPRAZOLE except when included in Schedule 2 or 3.
The NDPSC included the PPI, pantoprazole, in Schedule 3, in oral preparations containing 20 mg or less of pantoprazole for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 14 days' supply (the NDPSC subsequently amended the implementation date until 1 May 2008).
The NDPSC agreed to down-schedule rabeprazole to Schedule 3 in oral preparations containing 10 mg or less of rabeprazole per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 14 days' supply (i.e. with pack size and indication restrictions similar to those for pantoprazole).
The NDPSC decided to schedule lansoprazole and omeprazole similarly to pantoprazole and rabeprazole, to harmonise with New Zealand.
Delegate's decision: March 2014
ACMS considered an application to down-schedule from Schedule 4 to Schedule 3 esomeprazole in oral preparations containing 20 mg or less per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 14 days' supply. ACMS recommended, and the delegate confirmed, that esomeprazole should be down-scheduled to Schedule 3, as requested.
Delegate's decision: March 2015
The ACMS recommended, and the delegate confirmed, a new entry in Schedule 2 for pantoprazole when supplied in oral preparations containing 20 mg or less of pantoprazole per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 7 days of supply. The implementation date for this decision was 1 June 2015.
Delegate's interim decision: October 2015
The ACMS recommended a new entry in Schedule 2 for esomeprazole when supplied in oral preparations containing 20 mg or less of esomeprazole per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 7 days of supply.
The ACMS also proposed that the medicines delegate consider initiating a proposal to create new Schedule 2 entries for lansoprazole, omeprazole and rabeprazole in packs containing not more than 7 days' supply (consistent with the current Schedule 2 entry for pantoprazole, and the proposed Schedule 2 entry for esomeprazole).
The delegate's interim decision supported these ACMS recommendations. The proposed implementation date for the inclusion of esomeprazole in Schedule 2 is 1 February 2016.
One public submission was received which made the following main points:
The public submission is available at Public submissions on scheduling matters.
The ACMS recommended that lansoprazole, omeprazole and rabeprazole be down-scheduled from Schedule 3 to Schedule 2 as follows:
The ACMS recommended an implementation date of 1 June 2016.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: a) the risks and benefits of the use of the substance; b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance; and d) the dosage, formulation, labelling, packaging and presentation of a substance.
The reasons for the recommendation comprised the following:
The delegate considered the following in regards to this proposal:
The delegate's interim decision is to include lansoprazole, omeprazole, rabeprazole in Schedule 2 as proposed below - see "Schedule Entry".
The proposed implementation date is 1 June 2016.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: a) the risks and benefits of the use of the substance; b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance; and d) the dosage, formulation, labelling, packaging and presentation of a substance.
The reasons for the recommendation comprised the following:
Schedule 2 - New entry
LANSOPRAZOLE in oral preparations containing 15 mg or less of lansoprazole per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 7 days' supply.
Schedule 3 - Amendment
LANSOPRAZOLE in oral preparations containing 15 mg or less of lansoprazole per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 14 days' supply except when included in Schedule 2.
Schedule 4 - Amendment
LANSOPRAZOLE except when included in Schedule 2 or 3.
Schedule 2 - New entry
OMEPRAZOLE in oral preparations containing 20 mg or less of omeprazole per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 7 days' supply.
Schedule 3 - Amendment
OMEPRAZOLE in oral preparations containing 20 mg or less of omeprazole per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 14 days' supply except when included in Schedule 2.
Schedule 4 - Amendment
OMEPRAZOLE except when included in Schedule 2 or 3.
Schedule 2 - New entry
RABEPRAZOLE in oral preparations containing 10 mg or less of rabeprazole per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 7 days' supply.
Schedule 3 - Amendment
RABEPRAZOLE in oral preparations containing 10 mg or less of rabeprazole per dosage unit for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 14 days' supply except when included in Schedule 2.
Schedule 4 - Amendment
RABEPRAZOLE except when included in Schedule 2 or 3.
The proposed implementation date is 1 June 2016.
The delegate considered the following in regards to this proposal:
No public submissions were received.
The delegate has confirmed the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the final decision and reasons are in keeping with those for the interim decision.
The implementation date is 1 June 2016.
Scheduling medicines and poisons
The medicines scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Medicines Scheduling (ACMS):
The applicant has provided the following information regarding flubromazolam:
Flubromazolam is a benzodiazepine derivative. It is a triazolo analogue of the designer benzodiazepine, flubromazepam.
Benzodiazepines enhance the activity of gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain. This results in anxiolytic, sedative, hypnotic, muscle relaxant and antiepileptic effects.
Molecular formula: C17H12BrFN4
CAS Number: 612526-40-6
IUPAC name: 8-bromo-6-(2-fluorphenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a]benzodiazepine.
Flubromazolam has high potency, and can cause strong sedation and amnesia at oral doses as low as 500 micrograms. Flubromazolam has an onset of effect of 30 minutes, and duration of effect of 12-18 hours. After-effects are experienced for ≥ 24 hours. There is a risk of fatal overdose if benzodiazepines such as flubromazolam are combined with other central nervous system depressants such as opioid analgesics, alcohol and 4-hydroxybutanoic acid (GHB).
There is a risk of unintended over-dosing. People who use flubromazolam for its psychoactive properties reported compulsive re-dosing. Abrupt discontinuation of flubromazolam following regular dosing over several days can result in a withdrawal phase that includes rebound symptoms such as increased anxiety and insomnia.
Flubromazolam has recently become available online (products available for sale online include the pure substance and 250 microgram pellets).
Flubromazolam has no currently established therapeutic use and is likely to present a high risk of dependency, abuse, misuse or illicit use. The dangers associated with flubromazolam are such as to warrant limiting use to strictly controlled medical and scientific research. On this basis, flubromazolam meets two of the factors for inclusion in Schedule 9 of the Poisons Standard.
Flubromazolam is a triazolo analogue of the designer benzodiazepine, flubromazepam (7- bromo-5-(2-fluorphenyl)-1,3-dihydro-1,4-benzodiazepine-2-one). Flubromazepam has a much longer time to onset of effect (4 hours) and much longer duration of effect (3 days) than flubromazolam.
Flubromazolam is currently not specifically scheduled.
Flubromazolam is a benzodiazepine derivative, and is therefore currently covered by the entries for 'Benzodiazepine derivatives' in Schedule 4 and Appendix D.
BENZODIAZEPINE derivatives except when separately specified in these Schedules.
Paragraph 5 - Poisons for which possession without authority is illegal (e.g. possession other than in accordance with a legal prescription)
BENZODIAZEPINE DERIVATIVES, including those separately specified in Schedule 4 and Schedule 8.
[The additional controls on possession or supply specified in Appendix D only apply to the substances listed when included in Schedule 4 and Schedule 8.]
OTHER BENZODIAZEPINES - Specific schedule entries
Schedule 4 includes specific entries for the following benzodiazepines (in addition to the entry for benzodiazepine derivatives): bromazepam; chlordiazepoxide; clobazam; clonazepam; clorazepate; diazepam; flurazepam; ketazolam; loprazolam; lorazepam; lormetazepam; medazepam; midazolam; motrazepam; nitrazepam; oxazepam; prazepam; quazepam; temazepam; triazolam; zolazepam.
The benzodiazepines, alprazolam and flunitrazepam, are currently listed in Schedule 8.
Currently, there do not appear to be entries for any benzodiazepines in Schedule 9.
FLUBROMAZOLAM
Flubromazolam has not previously been considered for scheduling.
BENZODIAZEPINES
In May 1982, the general class of benzodiazepines was included in Schedule 4. In May 1986, some individual benzodiazepine substances were listed in Schedule 4 (bromazepam, diazepam). Other individual benzodiazepine substances have subsequently been listed in Schedule 4.
In February 1997, the NDPSC considered a proposal to include flunitrazepam in Schedule 9, in response to representations from the Chairman of the Australian Health Ministers’ Advisory Council (AHMAC). The NDPSC decided that the scheduling of flunitrazepam should be considered in May 1997. In May 1997, the NDPSC foreshadowed a Schedule 8 entry for flunitrazepam, on the basis of its abuse and the harmful effects associated with abuse. The NDPSC agreed, in August 1997, to defer further consideration until the November 1997 meeting. The NDPSC agreed, in November 1997, that there was an on-going public health issue associated with the abuse and misuse of flunitrazepam, and decided to reschedule it from Schedule 4 to Schedule 8. The NDPSC confirmed this decision in February 1998.
The November 1997 NDPSC meeting had decided that a review of the scheduling of benzodiazepines was appropriate, following a decision to include flunitrazepam in Schedule 8, due to its known abuse and public health concerns associated with this abuse. The NDPSC considered the submissions received in response to the decision to undertake the review at its August 1998 meeting, and agreed that it was appropriate that those benzodiazepines currently included in Schedule 4 of the Standard for uniform scheduling of drugs and poisons should remain in Schedule 4.
Delegate decision: August 2010
The NDPSC considered the scheduling of alprazolam, following a request that it be rescheduled to Schedule 8, in response to concerns about misuse and abuse. The NDPSC decided that the current scheduling of alprazolam (Schedule 4) remained appropriate. The delegate confirmed this decision in August 2010.
Delegate decision: June 2013
The ACMS considered a proposal to reschedule benzodiazepines from Schedule 4 to Schedule 8 in March 2013. The ACMS recommended that alprazolam be rescheduled from Schedule 4 to Schedule 8. The ACMS recommended that the current scheduling of other benzodiazepines remained appropriate, and that benzodiazepines should be included in Appendix D, paragraph 5.
Reasons for the recommendation to include alprazolam in Schedule 8 included public health concerns, increased morbidity and mortality in overdose, abuse and misuse (particularly in association with opioids) and evidence of widespread misuse of alprazolam.
The delegate decided to include alprazolam in Schedule 8. The delegate also decided to include a new entry in Appendix D, paragraph 5, for "Benzodiazepine derivatives, including those separately specified in Schedule 4 and Schedule 8".
No public submissions were received.
The ACMS recommended flubromazolam be included in Schedule 9.
The ACMS recommended an implementation date of 1 June 2016.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: a) the risks and benefits of the use of the substance; b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance; d) the dosage, formulation, labelling, packaging and presentation of a substance; e) the potential for abuse of a substance; and f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the recommendation comprised the following:
The delegate considered the following in regards to this proposal:
The delegate's interim decision is to include Flubromazolam in Schedule 9.
The proposed implementation date is 1 June 2016.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: a) the risks and benefits of the use of the substance; b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance; d) the dosage, formulation, labelling, packaging and presentation of a substance; e) the potential for abuse of a substance; and f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the recommendation comprised the following:
The delegate considered the following in regards to this proposal:
No public submissions were received.
The delegate has confirmed the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the final decision and reasons are in keeping with those for the interim decision.
The implementation date is 1 June 2016.
Scheduling medicines and poisons
The medicines scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Medicines Scheduling (ACMS):
The applicant has provided the following information regarding Performance and image enhancing drugs:
Thymosin Beta 4 (Thymosin β4) is a growth factor affecting muscle, tendon or ligament, vascularisation and regenerative capacity. Thymosin Beta 4 is a 43 amino acid peptide – the molecular structure is shown in the diagram below where each letter indicates one of the 20 different amino acids.
TB-500 is a short peptide analogue of Thymosin Beta 4. TB-500 is presumed by design to have the same properties as Thymosin Beta 4.
These substances are currently used illicitly to enhance sporting performance and more broadly across the community often for body building and image enhancement purposes. The substances are banned by the World Anti-Doping Agency (WADA Prohibited List, 2015) for use by athletes, both in and out of competition.
Fibroblast Growth Factors (FGFs) are a family of growth factors involved in angiogenesis, wound healing, embryonic development and various endocrine signalling pathways. FGFs also have a role in the processes of proliferation and differentiation of wide variety of cells and tissues (Thisse & Thisse, 2005; Turner & Grose, 2010).
Thymosin Beta 4, Tb-500 and Fibroblast Growth Factors are currently not listed in the schedules or appendices in the Standard for uniform scheduling of medicines and poisons (SUSMP).
Delegate's decision: March 2015
The ACMS considered a proposal to include new entries in Schedule 4 and Appendix D for a number of performance and image enhancing drugs. The ACMS recommended, and the delegate confirmed, that the following substances should be included in Schedule 4 and in Appendix D, Item 5 [Poisons for which possession without authority is illegal (e.g. possession other than in accordance with a legal prescription)]:
The ACMS recommended similarly for new individual substance entries for:
No public submissions were received.
The ACMS recommended that:
The ACMS recommended an implementation date of 1 June 2016.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: a) the risks and benefits of the use of the substance; b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance; d) the dosage, formulation, labelling, packaging and presentation of a substance; e) the potential for abuse of a substance; and f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the recommendation comprised the following:
The delegate considered the following in regards to this proposal:
The delegate's interim decision is to include Thymosin Beta 4, TB-500 and Fibroblast Growth Factors in Schedule 4 and Appendix D item as per the below proposed wording for the schedule entries.
The proposed implementation date is 1 June 2016.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: a) the risks and benefits of the use of the substance; b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance; d) the dosage, formulation, labelling, packaging and presentation of a substance; e) the potential for abuse of a substance; and f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the recommendation comprised the following:
Thymosin Beta 4 (Thymosin β4)
TB-500
Fibroblast Growth Factors
Poisons for which possession without authority is illegal (e.g. possession other than in accordance with a legal prescription)
Thymosin Beta 4 (Thymosin Β4)
TB-500
Fibroblast Growth Factors
The delegate considered the following in regards to this proposal:
No public submissions were received.
The delegate has confirmed the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the final decision and reasons are in keeping with those for the interim decision.
The implementation date is 1 June 2016.
Scheduling medicines and poisons
Substance | Final decision |
---|---|
Sarolaner |
Schedule 5 - New EntrySAROLANER for the treatment, prevention and control of fleas and ticks in dogs in oral divided preparations each containing 120 mg or less of sarolaner per dosage unit. Schedule 6 - New EntrySAROLANER except when included in Schedule 5. Implementation date: 1 June 2016 |
Cloquintocet |
Schedule 5 - Amended EntryCLOQUINTOCET MEXYL - delete the word MEXYL Implementation date: 1 June 2016 |
Clothianidin |
Schedule 6 - Amend EntryCLOTHIANIDIN except
Schedule 5 - Amend EntryCLOTHIANIDIN in preparations containing 20 per cent or less of clothianidin except in gel preparations dispensed in sealed cartridges containing 1 per cent or less of clothianidin. Implementation date: 1 June 2016 |
Mandestrobin |
Schedule 5 - New EntryMANDESTROBIN except in preparations containing 25 per cent or less of mandestrobin. Implementation date: 1 June 2016 |
Scheduling medicines and poisons
In December 2015 the Office of Chemical Safety (OCS), based on an application made to the Australian Pesticides and Veterinary Medicines Authority (APVMA) for the approval of sarolaner as a new active constituent, and the registration of a product line Sarolaner Palatable Chews for Dogs, containing sarolaner in a chewable tablet formulation, requested that the Delegate consider creating a new entry for sarolaner in Schedule 6 of the SUSMP. An exemption to Schedule 5 for sarolaner when in oral divided preparations each containing 120 mg or less of sarolaner per dosage unit for the treatment, prevention and control of fleas and ticks in dogs has been proposed by OCS.
The applicant proposed a new Schedule 5 entry for sarolaner.
The Applicant, as part of an application to the APVMA, has requested that the Delegate consider submitted a data package seeking approval of the new active constituent sarolaner, and registration of the new product line Sarolaner Palatable Chews for Dogs containing sarolaner in a chewable tablet formulation. The largest tablet contains a maximum single dose of 120 mg of sarolaner. The product is intended to be administered once per month for the treatment and control of fleas and ticks in dogs.
The applicant has proposed that sarolaner be listed in Schedule 5 of the SUSMP, "consistent with the recent APVMA approvals of afoxolaner and sarolaner...as a substance with a low potential for causing harm, the extent of which can be reduced through the use of appropriate packaging with simple warnings and safety directions on the label."
Sarolaner belongs to the isoxazoline class of parasiticides; similar chemicals previously considered by the Delegate/ACCS include afoxolaner and fluralaner.
Figure 12. Chemical structure of sarolaner
The acute toxicity end-points for this chemical are listed in the below table.
Toxicity | Species | Sarolaner | SPF* Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | 550 < LD50 < 2000 (point estimate 783) | Schedule 6 |
Acute dermal toxicity LD50 (mg/kg bw) | Rat | > 2000 | N/A |
Acute inhalational toxicity LC50 (mg/m3/4h) | N/A | N/A | N/A |
Skin irritation | Rabbit | Non-irritant | N/A |
Eye irritation | Rabbit | Slight irritant | Schedule 5 |
Skin sensitisation (LLNA method) | Mouse | Non-sensitiser |
* Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
No acute toxicity data on the formulated product were submitted. Acute toxicity estimations indicated that the product line Sarolaner Palatable Chews for Dogs is expected to be of low acute oral and dermal toxicity, not skin or eye irritant, and not a skin sensitiser.
See acute toxicity table above.
See acute toxicity table above.
Sarolaner was evaluated for repeated dose toxicity in rats and dogs. In rats, both 30- and 90-day studies were conducted to evaluate the potential toxicity of sarolaner. In the 30-day study, key treatment-related effects were elevated adrenal gland weight at 2.233 and 22.33 mg/kg bw/d, elevated ovaries/oviducts weights at 22.33 mg/kg bw/d, with corresponding pathology effects. The adrenal glands at 22.33 mg/kg bw/d were enlarged, an effect that was characterized by enlargement of cells of the zona fasciculata and cytoplasmic vacuolation of the adrenal cortex. In the ovaries, there was apparent hypertrophy of the interstitial cells, which followed a dose response at ≥2.233 mg/kg bw/d and was considered moderately severe at 22.33 mg/kg bw/d. Based on these findings, the NOEL for Sarolaner in the 30-day rat repeated dose toxicity study was 0.223 mg/kg bw/d, based on adverse effects occurring at 2.233 mg/kg bw/d. Similar effects were identified in the 90-day study, with a NOEL for this study established at 0.25 mg/kg bw/d.
In dogs, three studies were conducted with repeated dosing structures, intended to evaluate the margin of safety of administration of Sarolaner to dogs. The first was an exploratory study, conducted over approximately 2 months; this study was non-GLP compliant and did not follow any specific guideline. In addition to the initial exploratory study, a tolerance study was conducted in dogs over approximately 5 weeks. The third was a 9-month dosing study in young beagle dogs; this study was GLP-compliant and followed guidelines specified under VICH GL43. Across the three studies, results suggested that sarolaner is well-tolerated in dogs, up to 20 mg/kg bw. However, in the margin of safety study in young beagle dogs, mild tremors and ataxia were noted at ≥12 mg/kg bw, suggesting that sarolaner administration can elicit a mild neurotoxic effect. This is supported by range-finding information from an oral toleration study in dogs, where tremors, seizures, unsteady gait, stiff/jerky movement, and soft stool were noted at 62.5 mg/kg bw. However, conventional functional observation battery evaluations in the repeat-dose rat toxicity studies did not show functional changes at the doses tested, suggesting that the dog may be more sensitive for neurological effects.
Sarolaner was negative for genotoxic potential in both in vitro (bacterial and mammalian cell) and in vivo (mammalian) testing. It is considered unlikely that sarolaner is genotoxic.
No information was provided.
No multi-generation reproductive toxicity studies were available for evaluation.
Sarolaner was tested for developmental toxicity in both rats and rabbits. Sarolaner did not cause developmental malformations in either species under the test conditions. The results indicated that sarolaner is unlikely to cause developmental toxicity in the absence of maternal toxicity.
No information was provided.
The OCS, as part of their evaluation, has considered the potential public exposure and risks associated with use of the product Sarolaner Palatable Chews for Dogs.
Exposure to sarolaner during dosing is unlikely to result in a toxicologically significant exposure. The presentation of Sarolaner Palatable Chews for Dogs (containing up to 120 mg sarolaner/chew), with mostly non-toxic excipients will limit exposure to sarolaner. While dermal exposure to sarolaner could be increased if tablets were crushed or broken to be mixed with food rather than placed whole into food or administered directly, such contact is not expected to notably increase the exposure and risks associated with dermal contact with sarolaner in the palatable chew.
Adults may be exposed to small amounts of sarolaner following dosing of dogs, via contact with wet or partly macerated chews, or from contact with vomitus or urine/faeces. Contact with excreta is unlikely to result in toxicologically significant exposure. Any dermal, oral or ocular exposure via excreta is likely to be infrequent and sporadic, and could be considered as a limited acute exposure event.
In accidental exposure scenarios involving children, as a worst case scenario, it was presumed that a child (infant and toddler) gains access to a 6 pack containing the largest tablet size containing 120 mg sarolaner per tablet. In this event, the resulting accidental exposure would be 65.45 mg/kg bw for an infant weighing 11 kg and 48 mg/kg bw for a toddler weighing 15 kg. Compared with the lower limit of the acute oral toxicity LD50 range for the active constituent sarolaner of 550 mg/kg bw (a dose associated with clinical signs of toxicity), these doses provide a margin of safety of 8 for infants and 11 for toddlers. In the event of exposure to a single tablet of the highest available dose, the comparable exposures would be 10.9 mg/kg bw for an infant weighing 11 kg and 8 mg/kg bw for a toddler weighing 15 kg. Compared to the lower limit of the acute oral toxicity range for the active constituent, the margin of safety would be 50 for infants and 68 for toddlers.
In both cases, the margin of safety would normally be considered insufficient to protect against effects from accidental ingestion. Furthermore, the OCS notes that the available toxicity information in the tolerance study in young beagle dogs reported mild tremors and ataxia as treatment-related effects after a single dose of 12 mg/kg bw, suggesting the possibility that there are acute toxicity risks associated with an accidental exposure event.
However, the OCS notes that the proposed product will be packaged in foil blister packs which are considered to be child resistant. Additionally, to provide adequate warning regarding the potential risks associated with product use, the OCS recommends the following precautionary statements:
In addition, the safety directions "do not swallow" and "wash hands after use" are recommended.
Sarolaner has been considered by the European Medicines Agency's Committee for Medicinal Products for Veterinary Use (CVMP), see Attachment B, which has recommended the granting of a marketing authorisation for veterinary medicinal product Simparica, containing sarolaner at up to 120 mg per chewable tablet.
Sarolaner is not specifically scheduled.
Sarolaner has not been previously considered for scheduling; therefore, scheduling history is not available.
SAROLANER for the treatment, prevention and control of fleas and ticks in dogs in oral divided preparations each containing 120 mg or less of sarolaner per dosage unit.
SAROLANER except when included in Schedule 5.
The delegate considered the relevant matters under subsection 52E (1) of the Therapeutic Goods Act 1989: (c) the toxicity of a substance; and (d) the dosage, formulation, packaging and presentation of the substance.
The reasons for the interim decision comprised the following:
The delegate considered the following in regards to this proposal:
The applicant had no objections to the Delegate's interim decision.
The delegate has confirmed the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.
SAROLANER for the treatment, prevention and control of fleas and ticks in dogs in oral divided preparations each containing 120 mg or less of sarolaner per dosage unit.
SAROLANER except when included in Schedule 5.
Implementation date: 1 June 2016.
Scheduling medicines and poisons
In December 2015 the Office of Chemical Safety (OCS), based on an application made to the Australian Pesticides and Veterinary Medicines Authority (APVMA) for the approval of cloquintocet acid as a new active constituent, recommended that the delegate consider creating a new entry for cloquintocet acid in Schedule 5 of the SUSMP. No cut-off exemptions for cloquintocet acid were proposed by OCS and no registration application has been received for a product containing cloquintocet acid.
The applicant has submitted a data package seeking approval of the new active constituent cloquintocet acid. The applicant has asked that cloquintocet acid be considered for exemption from scheduling and listing in Appendix B to the SUSMP.
Figure 1. Structure of cloquintocet acid
Cloquintocet acid is a crop safener and is not classified in a chemical class. The role of a crop safener is to prevent the phytotoxic action of the accompanying herbicide with which it is mixed. Cloquintocet acid is currently not listed in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP).
Cloquintocet acid is the primary in vivo mammalian metabolite of cloquintocet-mexyl and hydrolysis of the mexyl occurs rapidly in vivo so that systemic exposure is primarily to cloquintocet acid. The toxicological assessment of cloquintocet acid was limited to the conduct of key studies to confirm toxicological equivalence to cloquintocet-mexyl and allow bridging to the toxicological database already available for cloquintocet-mexyl for human health assessment.
The acute toxicity end-points for this chemical are listed in the below table.
Toxicity | Species | Cloquintocet Acid | SPF* Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat |
LD50 >2000 mg/kg bw no deaths or treatment related clinical signs Low oral toxicity |
N/A |
Acute dermal toxicity LD50 (mg/kg bw) | Rat |
LD50 >5000 mg/kg bw no deaths or treatment related clinical signs Low dermal toxicity |
N/A |
Acute inhalational toxicity LC50 (mg/m3/4h) | Rat |
4-hr LC50 > 6110 mg/m3 no deaths Low inhalational toxicity |
N/A |
Skin irritation | Rabbit | Non irritating | N/A |
Eye irritation | Rabbit |
Conjunctival redness (scores 1-2) resolved by 72h Slight eye irritant |
Schedule 5 |
Skin sensitisation (LLNA) | Mice | Non sensitising (concentrations ≤50% active ingredient) | N/A |
* Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
Cloquintocet acid:
Not irritating to the skin of rabbits. Slightly irritating to the eye of rabbits.
Not a skin sensitiser in mice up to 50% w/v (LLNA test).
No guideline short-term toxicity studies were submitted. Short-term (7-14 day) studies in rats were carried out either as probe studies or to establish palatability in the test diet and these studies were not suitable for establishing NOELs for cloquintocet acid. The repeat dose studies indicated there were palatability issues with test diets containing high concentrations of cloquintocet acid, often resulting in transient effects on body weights and food consumption.
In a guideline-compliant subchronic (13 week) study in rats, cloquintocet acid was administered at dietary concentrations of up to 2100ppm (116/127 mg/kg bw/d in males/females). Effects on body weight, body weight gain and food consumption were attributed to the palatability of the test diet. Cloquintocet acid did not induce deaths, changes in clinical signs, ophthalmoscopy or treatment-related findings in functional tests, prothrombin time, serum thyroid hormone parameters or gross pathological or histopathological alterations. Slight but statistically significantly increased platelet counts in females administered cloquintocet acid at 2100 ppm were not considered toxicologically relevant. A number of other findings at the high dose were dismissed due to lack of dose response relationship or lack of correlation with other relevant toxicological findings. A slight but statistically significant decrease in absolute and relative spleen weights at 2100 ppm cloquintocet acid with no corresponding gross or histopathological changes was not considered to be toxicologically significant. The no-observed-effect level (NOEL) for the Crl:WI(Han) rat was the highest dose tested, a targeted concentration of 2100 ppm X204558 (equivalent to time-weighted average concentrations of 116 or 127 mg/kg bw/day in males and females, respectively).
Genotoxicity assays for gene mutation in vitro in bacterial cells (reverse mutation using five strains of S. typhimurium) and mammalian cells (forward mutation in CHO K1 cells) and a cytogenetic assay in vitro using human peripheral lymphocytes, were negative, with and without metabolic activation for cloquintocet acid (X204558). Based on the uniform negative findings, cloquintocet acid (X204558) is not mutagenic or genotoxic.
No carcinogenicity studies with cloquintocet acid were provided.
In a screening oral one-generation (reduced) reproductive toxicity study (Ellis-Hutchings, 2014b), groups of 10 male and 10 female Crl:CD(SD) rats were administered cloquintocet acid at 0, 105, 700 or 2100 ppm, equivalent to 0, 7.38, 48.2 or 123 mg/kg/day for males and 0, 6.98-11.1, 48.9-75.5 or 125-227 mg/kg/day for females given 0, 105, 700, or 2100 ppm during the pre-breeding gestation and lactation phases of the study, respectively. There were no treatment related and toxicologically significant effects in parental animals. Body weight and/or body weight gain and food consumption were initially lower (greatest on days 1-2) and attributed to the decreased palatability of the test diets) in males and females in the mid (700 ppm) and high dose (2100 ppm) groups. There were no treatment-related effects on clinical signs, litter size (survival) or pup body weights. At the pup necropsy at LD 4 there were no macroscopic changes or findings of gross external morphological alterations attributed to treatment following exposure to cloquintocet acid. The reproductive and offspring NOEL were both identified at the highest dose of cloquintocet acid tested (2100 ppm or 123/125-127 mg/kg bw/day, M/F) based on the lack of treatment-related and toxicologically significant effects in adult males, dams and pups. A parental (systemic) NOEL was also identified at 2100 ppm (equivalent to time-weighted average concentrations of 123 or 125-227 mg/kg bw/day in males and females, respectively) based on the lack of toxicologically significant effects in adults (both sexes) and dams up to and including the high dose of 2100 ppm cloquintocet acid.
Noting the screening nature of the study, under the conditions of the study, OCS considers that cloquintocet acid is unlikely to be a reproductive or developmental toxicant in rats, and is likely to share comparable reproductive and developmental toxicity potential with cloquintocet-mexyl.
No dedicated neurotoxicity studies were submitted. However, cloquintocet acid did not show signs of neurotoxicity in rats in submitted acute toxicity studies or in a FOB in a subchronic (dietary) 90 day toxicity study.
No information provided.
No information provided. No product proposed at this time.
No information provided.
CLOQUINTOCET ACID is not specifically scheduled.
CLOQUINTOCET MEXYL included in Schedule 5 of the SUSMP.
CLOQUINTOCET ACID has not been previously considered for scheduling; therefore, scheduling history is not available.
CLOQUINTOCET MEXYL - delete the word MEXYL
The reasons for the interim decision comprised the following:
The delegate's interim decision is to amend the current Schedule 5 entry for Cloquintocet mexyl, removing reference to the mexyl ester so that cloquintocet and all its salts and esters are captured by the entry. The delegate notes that cloquintocet acid lacks the weak sensitisation potential of the mexyl ester, but that otherwise, the toxicological profile of the acid and mexyl ester are comparable, and consistent with SPF criteria for listing in Schedule 5, based on eye irritancy.
The OCS evaluation report notes that cloquintocet acid has a low toxicity profile, with slight eye irritancy the only toxicity endpoint that is consistent with SPF criteria for listing in Schedule 5. The OCS report also notes that cloquintocet acid is a metabolite of cloquintocet mexyl, a substance already included in Schedule 5 on the basis of slight eye irritancy and weak sensitisation potential. The delegate proposes to accept the OCS recommendation to also list cloquintocet acid in Schedule 5, but to do so by amending the current entry for cloquintocet mexyl, noting that this ester would still be considered a Schedule 5 substance because of the Part 1 para 2(c) definition that an entry in the schedules includes all salts, esters, ethers or derivatives of listed substances. The delegate does not see a need to have two entries in Schedule 5 for cloquintocet and its mexyl ester. Accordingly, the scheduling proposal is to amend the current entry as shown.
The delegate considered the relevant matters under subsection 52E (1) of the Therapeutic Goods Act 1989: (c) the toxicity of a substance.
The delegate considered the following in regards to this proposal:
The applicant had no objections to the Delegate's interim decision.
The delegate has confirmed the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.
CLOQUINTOCET MEXYL - delete the word MEXYL
Implementation date: 1 June 2016.
Scheduling medicines and poisons
In November 2015 the Office of Chemical Safety (OCS), based on an application made to the Australian Pesticides and Veterinary Medicines Authority (APVMA) for registration of a new insecticide product, requested that the delegate consider amending the entry for clothianidin in Schedule 5. The recommended amendment is as follows:
CLOTHIANIDIN in preparations containing 20 per cent or less of clothianidin except in gel preparations dispensed in sealed cartridges containing 1 per cent or less of clothianidin.
The applicant has applied for a reconsideration of the scheduling entry for clothianidin, proposing that Maxforce Activ Cockroach Gel be exempt from scheduling. In support of the proposal for exemption from scheduling, the applicant stated that the product represents a limited risk to human health due to the:
Figure 14. Chemical structure of clothianidin
Clothianidin belongs to the neonicotinoid group of compounds and is thought to bind to the postsynaptic nicotinic acetylcholine receptor in insects. Insect death results from nerve excitation and paralysis.
Toxicity | Species | Clothianidin |
---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | LD50 >5000 |
Mice | LD50=465/389 (male/female) | |
Acute dermal toxicity LD50 (mg/kg bw) | Rat | LD50 >2000 |
Acute inhalational toxicity LC50 (mg/m3) | Rat | LC50 >6140 |
Skin irritation | Rabbits | Non-irritant |
Eye irritation | Rabbit | Non-irritant |
Skin sensitisation LLNA | Mice | Non-sensitiser |
Target/critical effect: Reduced food consumption and body weight gain (rats, mice and dogs) and increased plasma K+ and Na+ (mice) and haemoglobin (rats).
Lowest relevant oral NOEL (mg/kg bw/d): 90 (4-wk, mouse): based on reduced bodyweight gain and food consumption in both sexes, elevated plasma K+ and Na+ in females at 190 mg/kg bw/d.
Lowest relevant dermal NOEL (mg/kg bw/d): 300 (28-d, rat)
Lowest relevant inhalation NOEC (mg/m3): No inhalational study submitted.
Target/critical effect: Reduced plasma ALT. Increased hepatocellular hypertrophy and increased incidence of ovarian interstitial cell hyperplasia.
Increased hepatocellular hypertrophy (male mice) and increased incidence of ovarian interstitial cell hyperplasia (rats).
Reproduction target/critical effect: Reduced bodyweight gains, higher food consumption, preputial separation and vaginal opening delayed in F1 pups, reduced sperm motility, increased incidences of still births, reduced thymus and spleen weights.
Reduced bodyweight gain in F1 pups.
Lowest relevant reproductive NOEL (mg/kg bw/d): Parental NOEL: 32.7 (2-gen, rats, oral)
Neonatal NOEL: 10.2 (2-gen, rats, oral)
Developmental target/critical effect: Maternal: Reduced bodyweight gain and food consumption (rats). Death proceeded by weight loss, reduced food consumption, reduced faecal output, orange urine, decreased activity, loss of righting reflex (rabbits).
Developmental: Higher incidence of absent intermediate lobe of the lung (rabbits).
Lowest relevant developmental NOEL (mg/kg bw/d): Maternal NOEL: 10 (rabbit, oral)
Developmental NOEL: 25 (rabbit, oral)
No acute inhalational study was submitted on the formulated product. Information available indicate that inhalational exposure to the product is not expected to occur based on the non-volatile nature of clothianidin (vapour pressure: 3.8 × 10-11 Pa at 20°C) and the formulation type (gel). The active constituent, clothianidin, has low inhalational toxicity (LC50 >6140 mg/m3) in rats.
Toxicity endpoint | Maxforce Activ Cockroach Gel |
---|---|
Oral | Low toxicity* |
Dermal | Low toxicity* |
Inhalational | Low toxicity# |
Skin irritation | Non-irritant* |
Eye irritation | Non-irritant* |
Skin sensitisation | Non-sensitiser* |
*Based on toxicological studies on the product - see Attachment A, Appendix II #Based on toxicological studies on clothianidin - see Attachment A, Section 3.1 |
No information was provided.
The qualitative exposure estimate determined that the potential for exposure during product use was low, and most likely based on dermal exposure to the product. The product is packaged as a ready-to-use formulation and applied using a specific type of equipment (e.g. a bait or calking gun). It is therefore considered that while the use pattern of the proposed product will potentially involve regular and ongoing application by professional applicators, it is expected to result in only limited dermal exposure. Based on the current qualitative exposure assessment a precautionary statement has been recommended when using the product (i.e. wash hands after use). This statement has been included in the recommended safety directions for the proposed product.
The occupational re-entry risks associated with the use of the product are expected minimal due to the intended use pattern of the product and limited post-application activities associated with the product.
The product will be applied by professional pest control operators in publicly accessible areas (e.g. domestic premises, food processing establishments, food storage facilities (except where grain is stored), food preparation areas, public buildings, small-scale animal housing and transportation vehicles).
The draft product label contains the statement 'Gel should be applied out of reach of children'. Furthermore, according to the applicant, the proposed product will be placed in 'locations which are usually not accessible for children' (where insects hide, where high transit of insects is expected). Accidental exposure to members of the public is therefore not expected to occur under the proposed conditions of use as described by the draft product label and the directions for use.
Consistent with the risk assessment considerations and to provide adequate warning regarding the potential risks associated with product use, the OCS recommended the following Precautionary/Warning Statements:
"Do not place bait in areas accessible to children"
No information was provided.
CLOTHIANIDIN is currently listed in Schedules 5 and 6.
CLOTHIANIDIN was first considered for scheduling at the October 2002 meeting of the NDPSC. On the basis of its high acute oral toxicity in mice, clothianidin was included in Schedule 6. A cut-off was not established as the product considered at the time also had an acute toxicological profile consistent with inclusion in Schedule 6. Clothianidin first appeared in the SUSDP in June 2005.
CLOTHIANIDIN was subsequently considered by the scheduling committee in October 2006 in relation to a new product formulation. In that meeting, members considered a proposal for a new entry for CLOTHIANIDIN in Schedule 5 with a 20% cut-off, and consequential amendment of the existing Schedule 6 entry. At the product concentration proposed it was considered the toxicity profile was consistent with inclusion in Schedule 5.
CLOTHIANIDIN except
CLOTHIANIDIN in preparations containing 20 per cent or less of clothianidin except in gel preparations dispensed in sealed cartridges containing 1 per cent or less of clothianidin.
Implementation date: 1 June 2016.
The reasons for the final decision comprised the following:
The delegate considered the following in regards to this proposal:
Scheduling medicines and poisons
In December 2015, the Office of Chemical Safety (OCS), based on an application made to the Australian Pesticides and Veterinary Medicines Authority (APVMA) for registration of a new fungicide product, has referred the following scheduling proposal to be considered by the delegate:
The Applicant has submitted a data package seeking approval of the new active constituent mandestrobin, a member of the strobilurin fungicide class of chemicals, a mitochondrial respiration inhibitor of fungal pathogens. As a new chemical for AgVet use, it will require consideration for scheduling prior to final registration of products containing this active constituent.
Figure 15. Structure of Mandestrobin (S-2200TG)
The acute toxicity end-points for mandestrobin are listed in the below table.
Toxicity | Species | Mandestrobin (S-2200) |
SPF* Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | >2000 (no deaths) | Appendix B |
Acute dermal toxicity LD50 (mg/kg bw) | Rat | >2000 (no deaths) | Appendix B |
Acute inhalational toxicity LC50 (mg/m3/4h) | Rat | >4964 (no deaths) | Appendix B |
Skin irritation | Rabbit | Non-irritant | Appendix B |
Eye irritation | Rabbit | Moderate irritant | Schedule 5 |
Skin sensitisation (Maximization Test) | Guinea pigs | Non-sensitiser | Appendix B |
* Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
Acute oral toxicity studies were conducted for technical grade mandestrobin (S-2200TG). Mandestrobin (S-2200TG) was found to be of low acute oral (LD50 of > 2000 mg/kg bw/d), low acute dermal (LD50 of >2000 mg/kg bw/d) and low acute inhalation (LC50 of >4964 mg/m3) toxicity.
Mandestrobin was found to be a moderate irritant of the eye, and non-irritating to skin.
Mandestrobin was found to be non-sensitising to skin.
The systemic toxicity of mandestrobin in dietary studies consisted primarily of decreased bodyweight and bodyweight gain, liver toxicity such as increased liver weight and centrilobular hepatocellular hypertrophy with associated clinical chemistry seen at higher doses. This systemic toxicity profile was observed in subchronic and chronic studies in rats (54/61.1 mg/kg bw/d, M/F), mice (807.3/1111.2, mg/kg bw/d, M/F) and dogs (90.9/102.7, mg/kg bw/d, M/F), with the available data indicating that the rat was the most sensitive species. No short term oral studies were submitted for mandestrobin. No treatment-related adverse effects were seen in a short-term dermal toxicity study in the rat at the limit dose.
Study duration | Species & Route | Doses (mg/kg bw/d) |
NOEL/NOEC (mg/kg bw/d) |
LOEL & Toxic End-point (mg/kg bw/d) |
---|---|---|---|---|
Short-term/Sub-chronic | ||||
28 days | Rat, dermal | 0, 100, 300, 1000 | 1000 | No treatment-related effects observed |
13 weeks | Rat, dietary |
800, 4000, 10,000, 20000 ppm (0, 54/62, 283/320, 743/789, 1545/1887 M/F) |
800 ppm Males: 54.0 Females: 61.6 |
4000 ppm (283 mg/kg bw/d) and above for dose related clinical signs of including increased absolute and relative liver weight, large mottled liver, and hepatocyte proliferation, in both sexes. |
13 weeks | Mouse, dietary |
0, 1750, 3500, 7000 ppm (0, 204/252, 405/529, 807/1111 M/F) |
7000 ppm Males: 807.3 Females: 1111.2 |
No treatment-related effects observed |
13 weeks | Dogs |
4000, 12000, 40000 ppm (0, 90.9/102.7, 267.8/304.4, 933.1/820.4 M/F) |
4000 ppm Males: 90.9 Females: 102.7 |
12000 ppm (268/304 (M/F) mg/kg bw/d) and above for liver organ weight and liver histopathological findings. |
Chronic | ||||
52 weeks | Dog, dietary |
0, 200, 800, 4000, 8000 ppm (0, 4.3/4.5, 19.2/20.4, 92/92, 18.07/225.7 M/F) |
800 ppm Males: 19.2 Females: 20.4 |
4000 ppm (92 mg/kg bw/d M&F) for dark liver, centrilobular hepatocyte hypertrophy and pigmented hepatocytes |
78 weeks | Mouse, dietary |
0, 700, 2000, 7000 ppm (main group: 0, 82.5/99.2, 238.8/280.3, 823.9/99.4 M/F) (satellite group: 0, 88.4/104.0, 255.0/325.0, 883.3/1045.1 M/F) |
7000 ppm Males: 883 Females: 1045 |
No treatment related effects |
104 weeks | Rat, dietary |
400, 2000, 7000, 15000 ppm (0, 21/26.7, 105/135, 375.6/475, 804/1016 M/F) |
Males: 2000 ppm (105.1) Females: 400 ppm (26.7) |
7000 ppm (376 mg/kg bw/d, males) and above for hepatocyte hypertrophy, correlating with increases in relative liver weights and macroscopic findings of large liver. Increased total cholesterol. 2000 ppm (135 mg/kg bw/d, females) and above for decreased body weights and body weight gain. Hepatocyte hypertrophy in males, correlating with increases in relative liver weights and macroscopic findings of large liver. |
Mandestrobin was not genotoxic in a bacterial reverse mutation test, and the results from the in vitro gene mutation assay (in Chinese Hamster V79 cells), chromosomal aberration (in Chinese Hamster lung cells CHL/IU) and micronucleus test (Mice bone marrow cells) were negative both with and without metabolic activation. Overall, mandestrobin is not considered genotoxic. There was no evidence of a mutagenic/genotoxic potential of mandestrobin or its primary metabolites in vitro with and without metabolic activation.
No evidence of oncogenic potential was observed in mice treated with diets containing concentrations up to 7000 ppm or rats up to 15000 ppm. An increase in the sex-cord stromal tumours in the ovary of female rats was observed in animals offered 7000 or 15000 ppm. This was considered to be part of a continuum of change that was associated with sex-cord stromal hyperplasia. The sex-cord stromal hyperplasia was not statistically significant during pairwise comparison of treatment groups with controls; however, the incidence of benign sex cord stromal tumours were statistically significant in the treated versus control rats (p=0.005).
Study duration | Species & Route | Doses (mg/kg bw/d) |
NOEL/NOEC (mg/kg bw/d) |
LOEL & Toxic End-point (mg/kg bw/d) |
---|---|---|---|---|
78 weeks | Mouse, dietary |
0, 700, 2000, 7000 ppm (main group: 0, 82.5/99.2, 238.8/280.3, 823.9/99.4 M/F) (satellite group: 0, 88.4/104.0, 255.0/325.0, 883.3/1045.1 M/F) |
7000 ppm Males: 883 Females: 1045 |
No treatment related effects |
104 weeks | Rat, dietary |
400, 2000, 7000, 15000 ppm (0, 21/26.7, 105/135, 375.6/475, 804/1016 M/F) |
Males: 2000 ppm (105.1) Females: 400 ppm (26.7) |
7000 ppm (376 mg/kg bw/d, males) and above for hepatocyte hypertrophy, correlating with increases in relative liver weights and macroscopic findings of large liver. Increased total cholesterol. 2000 ppm (135 mg/kg bw/d, females) and above for decreased body weights and body weight gain. Hepatocyte hypertrophy in males, correlating with increases in relative liver weights and macroscopic findings of large liver. |
Mandestrobin was not a reproductive or developmental toxicant. However, in the reproductive toxicity study in the rats, systemic toxicity signs including increased relative liver weights, moderate diffuse hepatocyte hypertrophy, increased thyroid weights in F0 males (3000 ppm). Significantly decreased relative and absolute spleen weight in males F1 pups at weaning were observed at >3000 ppm.
Study duration | Species & Route | Doses (mg/kg bw/d) |
NOEL/NOEC (mg/kg bw/d) |
LOEL & Toxic End-point (mg/kg bw/d) |
---|---|---|---|---|
Reproductive, (range-finding) | Rat, dietary |
0, 5000, 10000, 20000 ppm (F0 male: 318, 636, 1253 F0 female: 335, 667, 1326) |
Not established | 5000 ppm (equivalent to 244.1 mg/kg bw/d in males and 781.7 mg/kg bw/d in lactating females) based on treatment-related and toxicologically significant findings in liver and thyroid organ weight and histopathology in males. |
Reproductive, 2-Generation | Rat, dietary |
0, 1000, 3000, 10000 ppm (F0 male: 56.2, 166.3, 559 F0 female: 62.5, 195, 629 F1 male: 84.7, 254.5, 881 F1 female: 90, 274.9, 929.3) |
Reproductive F0/F1 10000 ppm male: 560/629 female: 881/930 Systemic F0/F1 1000 ppm male: 56/62 female: 85/90 Developmental F1/F2 weanlings 1000 ppm |
Reproductive No reproductive toxicity was observed in F0 or F1 parental animals up to 10000 ppm. General 3000 ppm (166 mg/kg bw/d) for increased relative liver weights, moderate diffuse hepatocyte hyopertrophy, increased thyroid weights in F0 males. Developmental ≥ 3000 ppm (255/275 mg/kg bw/d, M/F) for significantly decreased relative and absolute spleen weight in males F1 pups at weaning |
Developmental GD 6-19 |
Rat, gavage | 0, 250, 500, 1000 | 1000 | No significant adverse signs of maternal or embryo-foetal toxicity. |
Developmental GD 7-28 |
Rabbit, gavage | 0, 250, 500, 1000 |
Maternotoxicity 500 Developmental 1000 |
Maternotoxicity 1000 for decreased food intake. Developmental No effect of treatment on the mean incidence of external foetal variations and malformations. |
Developmental GD 6-19 |
Rat, gavage | 0, 100, 300, 1000 |
Maternotoxicity 300 Developmental 1000 |
Maternotoxicity 1000 for decreased food intake. Developmental No effect of treatment on the mean incidence of external foetal variations and malformations. |
Developmental GD 7-28 |
Rabbit, gavage | 0, 100, 300, 1000 |
Maternotoxicity/Developmental 1000 |
No treatment related effects. |
While no neurotoxic effects were observed in the short-term (28-days) and sub-chronic (90-days) dietary study in rats, the acute oral (gavage) neurotoxicity study identified neuro-functional changes, including decreased locomotor activity at peak effect time at the highest dose level of 2000 mg/kg bw tested in the acute neurotoxicity study, though no treatment-related neuro-histological changes were observed. Overall, when considered with the decreased locomotor activity noted in the rat acute neurotoxicity study in rats, the available data suggests that mandestrobin has mild neurotoxic potential.
Study duration | Species & Route | Doses (mg/kg bw/d) |
NOEL/NOEC (mg/kg bw/d) |
LOEL & Toxic End-point (mg/kg bw/d) |
---|---|---|---|---|
28 days (screening study) | Rat, dietary |
0, 1500, 5000, 15000 ppm (0, 135, 436, 1340) |
Immunotoxicity 15000 ppm (1340) Neurotoxicity 15,000 ppm 1200(M)/1305(F) |
No treatment-related immunotoxic/neurotoxic effects. |
28 days immunotoxicity | Rat, dietary |
0, 1500, 5000, 15000 ppm (0, 147, 471, 1419) |
Immunotoxicity 15000 ppm (1419) |
No treatment-related immunotoxic effects. |
Acute Neurotoxicity | Rats, gavage | 0, 300, 1000, 2000 | 2000 | No treatment-related neurotoxic effects. |
Acute Neurotoxicity | Rat, gavage | 0, 500, 1000, 2000 | 1000 | 2000 for decreased locomotor activity at peak effect time (8 hours post dose on Day 0. |
90 days Neurotoxicity | Rat, dietary |
0, 1500, 5000, 15000 ppm (Males: 0, 99, 338, 1024) (Females: 0, 122, 415, 1223) |
Females: 15000 ppm (1223) Males: 5000 ppm (388) Neurotoxicity 15000 ppm (1024/1223 M/F) |
15000 ppm (1024 mg/kg bw/d, males) for significantly decreased bodyweight and bodyweight gain. No treatment-related neurotoxicity effects observed. |
Mechanistic studies suggest that mandestrobin is a hepatic enzyme inducer via CAR activation in rat similar to phenobarbital.
The applicant has provided discussion and analysis of the MOA data for evaluating higher incidence of ovarian sex-cord stromal tumour in female rats treated with S-2200TG in a 2-year carcinogenicity study. As there was no evidence of interaction with hormone receptors in mechanistic studies, no genotoxic effect, and the top dose level exceeded the maximum tolerated dose in the two-year chronic/carcinogenicity study, the sex-cord stromal lesions and tumours in female rat were not considered toxicologically significant.
Study type | Method and doses | Results (focussing on liver and thyroid changes) and conclusions |
---|---|---|
Effects of S-2200TG and its metabolites on human oestrogen receptor alpha and human androgen receptor (Suzuki 2012) |
10, 100 pM 1, 10, 100 nM 1, 10 100, µM |
No agonist or antagonist effects were observed. Cytotoxicity apparent in HeLa cells treated with ≥ 6 µM 24 - 48 hours. |
Effects of S-2200TG androgen and oestrogen levels in vitro (Kubo 2012) |
Steroidogenesis assay 10, 100, 300 nM 1, 3, 10, 30, 100 µM |
Cytotoxicity was observed at 100 µM dose level. No effects on production of oestrogen or testosterone in human adrenocortical cells up to 30 µM in culture. |
Dose response, time course, and reversibility for short-term study for mode of action analysis for rat liver and thyroid findings with S-2200TG (Asano 2012e) | 0, 400, 2000, 7000, 15000 ppm | At the highest dose (15000 ppm), a significant increase in absolute and relative liver weight with diffuse hepatic hypertrophy. Increased CYP2B activity. Increased thyroid weight in females at 7000 and 15000 ppm with diffuse thyroid follicular cell hypertrophy. |
Toxicological relevance of liver and thyroid alterations in rats (Yamada 2012a) | - | Liver is the target organ in all species. Thyroid effects have been observed in the rat, but not in the mouse or dog. The observations in the both the liver and the thyroid have been limited to organ-specific hypertrophy. No carcinogenic findings for either of these target organs have been reported in rat or mouse carcinogenicity studies. Liver and thyroid hypertrophy were induced by S-2200TG treatment in experimental animals, the findings from a MOA analysis allow for the conclusion that S-2200TG does not pose a hazard to humans. |
Dose-response, time course and reversibility of alterations at an early phase of treatment with S-2200TG (Yamada 2012b) | 7000 ppm | No effects on DNA replication in hepatocytes. Significant increase in relative liver weights, CYP2B activity and total liver protein. Visual changes in gross liver pathology in 3/10 treated animals. S-2200 is a weak CAR activator at 7000 ppm. |
Interpretation of higher incidence of ovarian sex-cord stromal tumour in female rats treated with s-2200tg in a 2-year carcinogenicity study (Yamada and Miyata 2012) | 0, 400, 2000, 7000, 15000 ppm |
The aetiology of ovarian tumours (including SCST) may involve hormonal perturbations/interactions. S-2200TG was negative in both an oestrogen receptor reporter gene assay and an assay for steroidogenesis. In addition there was no evidence that S-2200TG causes endocrine disruption, nor was any abnormality observed in the rat reproduction study. It is unlikely that S-2200 is carcinogenic. |
None of the metabolites of S-2200; 2-COOH-S-2200, 5-COOH-S-2200, 2-CH2OH-S-2200, 4-OH-S-2200 and De-Xy-S-2200 were considered to be mutagenic. All the metabolites except 5-COOH-S-2200 were of low acute oral toxicity (LD50>2000 mg/kg bw/d). 5-COOH-S-2200 was of moderate acute oral toxicity (300<LD50<2000 mg/kg bw/d).
No information was provided.
At this time, the proposed agricultural use of mandestrobin is not expected to result in general public (i.e. domestic) exposure. Spray drift considerations have not been considered.
Mandestrobin is currently under registration review by the US EPA in a joint review with Health Canada. The EFSA has reviewed mandestrobin as an active constituent, with the peer review document published in 2015.
MANDESTROBIN is not specifically scheduled.
MANDESTROBIN has not been previously considered for scheduling; therefore, scheduling history is not available.
MANDESTROBIN except in preparations containing 25 per cent or less of mandestrobin.
Implementation date: 1 June 2016.
The reasons for the final decision comprised the following:
The delegate considered the following in regards to this proposal:
Scheduling medicines and poisons
The TGA is updating names of ingredients in a number of medicines approved for use in Australia to align with names used internationally. The following changes are part of this process. Further information on these changes is available from the TGA website at: Updating medicine ingredient names
For each ingredient listed below:
Old name used in SUSMP | New name |
---|---|
8-hydroxyquinoline | oxyquinoline |
acriflavine | acriflavinium chloride |
amoxycillin | amoxicillin |
amphotericin | amphotericin |
chlorbutol | chlorobutanol |
cholestyramine | colestyramine |
colaspase | asparaginase |
di-N propyl isocinchomeronate | di-n-propyl isocinchomeronate |
ethanolamine | monoethanolamine |
triethanolamine | trolamine |
bretylium tosylate | bretylium tosilate |
butyl aminobenzoate | butamben |
chlorthalidone | chlortalidone |
cisatracurium besylate | cisatracurium besilate |
cyclosporin | ciclosporin |
delavirdine mesylate | delavirdine mesilate |
di-iodohydroxyquinoline | diiodohydroxyquinoline |
disodium etidronate | etidronate disodium |
disodium pamidronate | pamidronate disodium |
eformoterol | formoterol |
ethacrynic acid | etacrynic acid |
ethinyloestradiol | ethinyestradiol |
glutaraldehyde | glutaral |
guaiphenesin | guaifenesin |
hexachlorophane | hexachlorophene |
hydroxyurea | hydroxycarbamide |
indomethacin | indometacin |
lignocaine | lidocaine |
methylphenobarbitone | methylphenobarbital |
oestradiol | estradiol |
oestriol | estriol |
oestrogens | estrogens |
oestrone | estrone |
oxpentifylline | pentoxifylline |
pentamidine isethionate | pentamidine isetionate |
pericyazine | periciazine |
phenobarbitone | phenobarbital |
procaine penicillin | procaine benzylpenicillin |
salcatonin | calcitonin salmon |
tetracosactrin | tetracosactide |
For the following ingredients, a new cross reference only will be included in the Index: