Scheduling medicines and poisons
This consultation closed on 26 May 2016
A delegate of the Secretary to the Department of Health hereby gives notice of delegates' interim decisions for amending the Poisons Standard (commonly referred to as the Standard for the Uniform Scheduling of Medicines and Poisons - SUSMP) under subsections 42ZCZP the Therapeutic Goods Regulations 1990 (the Regulations). This notice also provides the reasons for each decision and the date of effect (the implementation date) of the decision.
The delegates' interim 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 11 November 2015 and 10 December 2015 (medicines) and 20 January 2016 (chemicals and medicines) on the TGA website at: Scheduling advisory committees invitations for public comment.
Redacted versions of public submissions received in response to the request for public comment will be published on or after the date of this notice on the TGA website at: Public submissions on scheduling matters.
This notice provides the interim decisions of the delegates, the reasons for those decisions and invites further submissions from the applicant and parties who made valid submissions in response to the original invitations for submissions (published on 11 November 2015 and 20 January 2016 at: Scheduling advisory committees invitations for public comment).
Further submissions must be relevant to the proposed amendment, must address a matter mentioned in section 52E of the Therapeutic Goods Act 1989 and be received by the closing date 26 May 2016.
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, need not be considered by the delegate.
Please note that all valid submissions received on or before the closing date will be published following removal of confidential information. It is up to the person making the submissions to highlight any information which they wish to be considered as confidential. Material claimed to be commercial-in-confidence will be considered against the guidelines for the use and release of confidential information set out in Chapter 6 of the Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015), issued by the Australian Health Ministers' Advisory Council (AHMAC). The SPF is accessible at: AHMAC - Scheduling policy framework for medicines and chemicals.
Persons making submissions are strongly encouraged to lodge submissions in electronic format (word or unsecured PDF preferred) via the email address provided below. Submissions, preferably in electronic format, should be made to:
Chemicals.Scheduling@tga.gov.au for items referred to the Advisory Committee on Chemicals Scheduling; and
Medicines.Scheduling@tga.gov.au for items referred to the Advisory Committee on Medicines Scheduling.
The closing date for further submissions is 26 May 2016.
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Scheduling medicines and poisons
Abbreviation | Name |
---|---|
AAN | Australian Approved Name |
AC | Active constituent |
ACCC | Australian Competition and Consumer Commission |
ACCM | Advisory Committee on Complementary Medicines (formerly Complementary Medicine Evaluation Committee [CMEC]) |
ACNM | Advisory Committee on Non-prescription Medicines (formerly Medicines Evaluation Committee [MEC]) |
ACPM | Advisory Committee on Prescription Medicines (formerly Australian Drug Evaluation Committee [ADEC]) |
ACSOM | Advisory Committee on the Safety of Medicines (formerly Adverse Drug Reactions Advisory Committee [ADRAC]) |
ADEC | Australian Drug Evaluation Committee (now Advisory Committee on Prescription Medicines [ACPM]) |
ADI | Acceptable daily intake |
ADRAC | Adverse Drug Reactions Advisory Committee (now Advisory Committee on the Safety of Medicines [ACSOM]) |
AHMAC | Australian Health Ministers' Advisory Council |
APVMA | Australian Pesticides and Veterinary Medicines Authority |
AQIS | Australian Quarantine and Inspection Service |
ARfD | Acute reference dose |
ASCC | Australian Safety and Compensation Council |
ASMI | Australian Self-Medication Industry |
ARTG | Australian Register of Therapeutic Goods |
CAS | Chemical Abstract Service |
CHC | Complementary Healthcare Council of Australia |
CMEC | Complementary Medicine Evaluation Committee (now Advisory Committee on Complementary Medicines [ACCM]) |
CMI | Consumer Medicine Information |
COAG | Councils of Australian Governments |
CRC | Child-resistant closure |
CTFAA | Cosmetic, Toiletry & Fragrance Association of Australia |
CWP | Codeine Working Party |
DAP | Drafting Advisory Panel |
ECRP | Existing Chemicals Review Program |
EPA | Environmental Protection Authority |
ERMA | Environmental Risk Management Authority (New Zealand) |
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 of 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 | Interim decision |
---|---|
Crystal violet and related dyes |
Schedule 10 - new entryMETHYLROSANILINIUM CHLORIDE (formerly known as crystal violet CAS No. 548-62-9) AND THE FOLLOWING TRIARYLMETHANE DYES - for use in hair dyes
Schedule 6 - New entriesMETHYLROSANILINIUM CHLORIDE (formerly known as crystal violet CAS No. 548-62-9) AND THE FOLLOWING TRIARYLMETHANE DYES
BASIC BLUE 26 (CAS No. 2580-56-5) except when used as a colourant in cosmetics not intended to be in contact with mucous membranes. Schedule 4 - Amend entryCRYSTAL VIOLET for human use except when used as a dermal marker. - replace "CRYSTAL VIOLET" with "METHYLROSANILINIUM CHLORIDE" Index entries:Crystal violet - see methylrosanilinium chloride Gentian violet - see methylrosanilinium chloride Proposed implementation date: 1 October 2016. |
Disperse yellow 3 |
Schedule 10 - New entryDISPERSE YELLOW 3 - for use in hair dyes Schedule 6 - New entryDISPERSE YELLOW 3 - except when in Schedule 10 Appendix E, Part 2 - New entryDISPERSE YELLOW 3 Standard statements: A, S1 Appendix F, Part 3 - New entryDISPERSE YELLOW 3 Warning Statement: 28 Safety direction: 4 Proposed implementation date: 1 October 2016. |
Chrysoidine base |
Schedule 6 - New entryCHRYSOIDINE except when in Schedule 10 Schedule 10 - New entryCHRYSOIDINE in preparations for use in hair dyes. Appendix E, Part 3 - New entryCHRYSOIDINE Standard statements: A, S1, E1 Proposed implementation date: 1 October 2016. |
p-Aminophenol |
Schedule 6 - New entryp-AMINOPHENOL except when used in hair dye and eyebrow/eyelash colouring products at a concentration of 1 per cent or less of p-aminophenol after mixing for use when the immediate container and primary pack are labelled with the following statements: KEEP OUT OF REACH OF CHILDREN, and WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use. Written in letters not less than 1.5 mm in height. Appendix E, Part 2 - New entryp-AMINOPHENOL Standard statements: A, S1 Appendix F, Part 3 - New entryp-AMINOPHENOL Warning Statement: 28 Proposed implementation date: 1 June 2017. |
2-Methylresorcinol |
Schedule 6 - New entry2-METHYLRESORCINOL except:
Appendix E, Part 2 - new entry2-METHYLRESORCINOL Standard statements: A, E1 Appendix F, Part 3 - new entry2-METHYLRESORCINOL Safety direction: 1 Proposed implementation date: 1 June 2017. |
2,4-Diamino-5-methylphenetole |
The current scheduling remains appropriate. Index - new entry2,4-DIAMINO-5-METHYLPHENETOLE Proposed implementation date: 1 October 2016. |
2-Chloro-5-nitro-N-hydroxyethyl-p-phenylenediamine |
The current scheduling remains appropriate. Index - new entry2-CHLORO-5-NITRO-N-HYDROXYETHYL-p-PHENYLENEDIAMINE Proposed implementation date: 1 October 2016. |
BIS-Isobutyl PEG/PPG |
Schedule 6 - New entryBIS-ISOBUTYL PEG/PPG-20/35/AMODIMETHICONE COPOLYMER except in rinse-off cosmetic products containing 1 per cent or less of bis-isobutyl PEG/PPG-20/35/amodimethicone copolymer. Appendix E, Part 2 - New entryBIS-ISOBUTYL PEG/PPG-20/35/AMODIMETHICONE COPOLYMER Standard statements: A, E1 Appendix F, Part 3 - New entryBIS-ISOBUTYL PEG/PPG-20/35/AMODIMETHICONE COPOLYMER Safety direction: 1 Proposed implementation date: 1 June 2017. |
Propamocarb | The current scheduling remains appropriate. |
Fluopicolide |
Appendix B, Part 3 - New entryFLUOPICOLIDE Part 1 - Reasons for Entry - a) low toxicity Part 2 - Area of Use - 1.3 Fungicide Proposed implementation date: 1 October 2016. |
Nonanoic acid |
Schedule5 - New entryNONANOIC ACID except in preparations containing 10 per cent or less of nonanoic acid Proposed implementation date: 1 February 2017. |
Di-bak Parkinsonia |
Schedule 5 - New entriesLASIODIPLODIA PSEUDOTHEOBROMAE except when used as a herbicide in capsule preparations at a concentration of 16 CFU or less per capsule. NEOSCYTALIDIUM NOVAEHOLLANDIAE except when used as a herbicide in capsule preparations at a concentration of 16 CFU or less per capsule. MACROPHOMINA PHASEOLINA except when used as a herbicide in capsule preparations at a concentration of 16 CFU or less per capsule. Proposed implementation date: 1 October 2016. |
Streptomyces lidicus |
Appendix B, Part 3 - New entrySTREPTOMYCES LYDICUS WYEC 108 Part 1 - Reasons for Entry - a) low toxicity Part 2 - Area of Use - 1.3 Fungicide Proposed implementation date: 1 October 2016. |
Isopyrazam |
Schedule 6 - New entryISOPYRAZAM Proposed implementation date: 1 October 2016. |
4,5-Dichloro-2-N-octyl-3(2H)-Isothiazolone | The current scheduling remains appropriate. |
Methyldibromo glutaronitrile |
Schedule 6 - Amend entryMETHYLDIBROMO GLUTARONITRILE except when in Schedule 10 Schedule 10 - Amend entryMETHYLDIBROMO GLUTARONITRILE in preparations intended to be in contact with the skin, including cosmetic use Proposed implementation date: 1 October 2016. |
Potassium hydroxide and Sodium hydroxide |
Schedule 6 - Amend entryPOTASSIUM HYDROXIDE (excluding its salts and derivatives) except:
SODIUM HYDROXIDE (excluding its salts and derivatives) except:
Proposed implementation date: 1 October 2016. |
Scheduling medicines and poisons
The reasons for the request are:
Crystal violet is currently listed in Schedule 4 (for human therapeutic use), except when used a skin marker. The current NICNAS referral relates primarily to its use in cosmetics, specifically hair dyes, and requests appropriate controls via listing in Schedule 6. The delegate requires advice from the ACCS to determine the most appropriate scheduling action.
The chemicals in this group are synthetic organic compounds, used extensively as colourants in various applications. They are chemically similar in that they all possess a triarylmethane backbone with similar chemical chromophores without any clear toxicological differences. For matters relating to scheduling and classification, the chemicals could be considered as chemical class or group.
Figure 1: Chemical structures
The toxicity end-points for Crystal violet and related dyes are summarised in the table below.
Toxicity | Species | Result | SPF* Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bodyweight (bw)) | Rat | Ranging from 90-650 | 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 | Human | Limited, unreliable data | - |
Eye irritation | Rabbit | Severe irritant | Schedule 6 |
Skin sensitisation | N/A | No data | - |
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
Crystal violet was found to have moderate to high acute toxicity based on results from animal tests following oral exposure. The median lethal dose (LD50) in rats ranges from 90 mg/kg bw to 650 mg/kg bw for chemicals in this group. Data on ethyl violet indicate similar toxicity. As the chemicals in this group are close analogues of crystal violet or ethyl violet, the classification should apply to all the members of this group.
No reliable data are available for the chemicals in this group.
Crystal violet is classified as hazardous with the risk phrase 'Risk of serious damage to eyes' (Xi; R41) in the HSIS (Safe Work Australia). The available data support this classification. In eye irritation studies, crystal violet caused serious eye damage and the effects were not reversible within the observation periods. The other chemicals in this group are likely to have similar irritation effects.
No data are available.
Studies suggest that the chemicals in this group do not represent a significant concern for repeated dose toxicity. Crystal violet was assessed for carcinogenicity in B6C3F1 mice in a life-time dosing study.
Positive results were reported for crystal violet in two in vitro point mutation assays (Ames test) in Salmonella typhimurium strains TA 98, TA 1535 and TA 1538, with or without metabolic activation. Positive results were also observed in several other in vitro assays conducted with the chemical. However, while there is a concern for mutagenicity, in the absence of clear positive in vivo data, the available data are insufficient to conclude that these chemicals are genotoxic.
The chemicals, crystal violet (CAS No. 548-62-9) and benzyl violet (CAS No. 1694-09-3) are classified as hazardous—Category 3 carcinogenic substance—with the risk phrase 'Limited evidence of carcinogenic effect' (Xn; R40) in the HSIS (Safe Work Australia). The available data support this classification and an extension of this classification to the other chemicals in the group.
Crystal violet was assessed for carcinogenicity in B6C3F1 mice in a life-time dosing study. Mice(150 mice/sex/dose) were dosed with the chemical by dietary administration at 0, 100, 300 or 600 ppm (equivalent to 0, 5, 15 or 30 mg/kg bw/day). Hepatocellular adenomas and carcinomas were the most common lesions, with significant dose-related increases found at 24 months in males and at both 18 and 24 months in females. The females also showed statistically significant dose-related increases in adenoma of the Harderian gland and in type A reticulum cell sarcoma in the urinary bladder, uterus, ovaries and vagina. Under these test conditions, the chemical was found to be carcinogenic in mice in several different organs.
In a reproduction study, male and female weanling rats were dosed with crystal violet at 0, 100, 300 or 600 ppm in diet for 80 days. During dosing, females and males from the same dose level were mated. Two males and two females were selected from each litter at random (F1a generation). The F1a pups continued on the same dose levels as their respective parents. In total, 570 male and 570 female F1a rats were fed crystal violet 0, 100, 300 or 600 ppm diet (equal to approximately 0, 30/40, 8/1000 or 160/200 mg/kg bw/day for males/females, respectively) for 24 months. Food consumption, body weights and clinical signs were recorded weekly. Complete necropsy, histopathological examination and clinical chemistry analysis were performed on selected animals at 12, 18 and 24 months. The majority of neoplastic lesions were observed only at the 24-month necropsy. Increases in the incidence of follicular cell adenocarcinomas of the thyroid were statistically significant in males in the highest dose group, and in females in the two highest dose groups. Hepatocellular adenomas were significantly increased at 24 months in males in the 300 ppm and 600 ppm feed groups.
There are limited data indicating that crystal violet causes mild skin irritation in humans; however, very few experimental details were provided.
The chemicals, C.I. basic blue 7 (CAS No. 2390-60-5) and C.I. basic blue 26 (CAS No. 2580-56-5) have reported cosmetic use in hair colourant formulations in Australia.
The chemicals have reported cosmetic use as hair colourants overseas (CAS No. 548-62-9; CAS No. 2390-59-2; CAS No. 2580-56-5; CAS No. 2390-60-5).
The chemicals are listed on the following:
The chemicals (CAS No. 548-62-9; CAS No. 2580-56-5) are listed on the candidate list of substances of very high concern for eventual inclusion in Annex XIV (ECHA, 2014). In the EU, companies could have legal obligations if the chemical that they produce, supply or use is included on the candidate list whether on its own, in mixtures, or present in articles.
The chemical crystal violet (CAS No. 548-62-9) is listed in schedule 4 as follows:
Schedule 4
CRYSTAL VIOLET for human use except when used as a dermal marker.
No other chemicals in this group are listed in the Poisons Schedule.
Note: The current crystal violet entry will be updated in the 1 June 2016 update to reflect the internationally agreed name methylrosanilinium chloride, regardless of this scheduling proposal.
Crystal violet was included in Schedule 4 in August 1989. The Committee noted the opinion of ADEC that crystal violet is a carcinogen and should not be available for use in humans. The Committee determined that crystal violet may be used as a surgical marker, as it did not present a long term hazard, but its use as a marker on the skins of food-producing animals may present a public health risk.
Two public submissions were received. The first submission noted that Crystal Violet is used in topical antiseptic products and is entered in the ARTG as a 1% topical antiseptic solution and therefore therapeutic goods should be exempted from any proposed Schedule 6 entry for Crystal Violet.
The second submission did not object to aligning scheduling controls with those in the European Union, but questioned whether this could be achieved in a single schedule entry. They noted four of the six CAS numbers in the NICNAS IMAP list are on the EU Cosmetics Regulations Annex II (i.e. banned from cosmetic use): 548-62-9, 1694-09-3, 2390-59-2 and 2390-60-5. They had no objections to these being added to Schedule 10, similar to the Benzidine-based azo-dyes schedule entry. They further noted one substance in the IMAP list, CI 44045 (CAS number 2580-56-5) is listed in EU Cosmetics Regulations Annex IV, colourants allowed in cosmetics, with a restriction that it is not to be used in products applied to mucous membranes, and not allowed in hair dyes. They believe schedule entry for this one should allow continued use in cosmetics, except hair dyes and products which contact with mucous membranes. They also stated that for the substance CAS number 72102-55-7, no information on use in cosmetics or any restrictions in consumer products was available, but that it may be used in newsprints, and scheduling controls therefore should focus on this specific use.
The public submission is available at: Public submissions on scheduling matters.
The Committee advised a new Schedule 10 entry for methylrosanilinium chloride (crystal violet) and specified related dyes for use in hair dyes, as well as a new Schedule 6 entry for other uses of related dyes. Members also advised a separate entry for the dye Basic Blue 26 except when used as a colourant in cosmetics not intended to be in contact with mucous membranes or when, in Schedule 4 or used as a dermal marker.
Members advised the Delegate to consider the appropriate chemical name for the schedule entry and conventions for listing of CAS numbers in the Standard, and to have regard to the implementation date and reasons given for benzidine-based dyes considered previously which have similar safety concerns.
Reasons given by the Committee for the advice were: b) to prevent use in cosmetics and in hair dyes; c) acutely toxic, strong eye irritant with potential for eye damage, consistent with S6; f) alignment with EU restrictions. The chemical name is consistent with that used internationally.
The committee advised the following amendments to the Poisons Standard:
Schedule 10 – new entry
METHYLROSANILINIUM CHLORIDE AND THE FOLLOWING TRIARYLMETHANE DYES– for use in hair dyes
Schedule 6 – New entries
METHYLROSANILINIUM CHLORIDE AND THE FOLLOWING TRIARYLMETHANE DYES
BASIC BLUE 26 (CAS No. 2580-56-5) except when used as a colourant in cosmetics not intended to be in contact with mucous membranes or when in Schedule 4 or when used as a dermal marker.
Schedule 4 – Amend entry
CRYSTAL VIOLET for human use except when used as a dermal marker. – replace " CRYSTAL VIOLET" with "METHYLROSANILINIUM CHLORIDE"
The delegate considered the following in regards to this proposal:
The delegate notes, and accepts, the advice of the ACCS to create new listings for crystal violet and related triarylmethane dyes in Schedules 6 and 10. The listings are to be made under the name methylrosanilinium chloride, in accordance with an agreement to standardise entries in the Poisons Standard in line with the International Harmonisation of Ingredient Names. The former common names crystal violet and gentian violet are to be cross-referenced in the Index, and for further clarity, the Schedule 6 and 10 entries will include CAS numbers of the specific triarylmethane dyes captured by the entries. A consequent amendment to the current Schedule 4 entry for crystal violet adopts the new nomenclature.
The purpose of the Schedule 10 entry is to restrict use in hair dyes preparations, in alignment with similar restrictions in international cosmetics regulations (EU, NZ, Canada and ASEAN). The toxicological basis for this restriction is the acute toxicity profile, including strong skin irritancy potential. The Schedule 10 entry also captures three related triarylmethane dyes with similar toxicological potential. For all other uses (except human therapeutic use covered under the existing Schedule 4 entry), the substances are listed under a new entry in Schedule 6. A further separate entry in Schedule 6 has been created for Basic Blue 26 (CAS No. 2580-56-5) to align with international regulations, where restrictions on cosmetic use only apply to preparations applied directly to mucous membranes. There was insufficient information, and no recommendation from the ACCS, for the delegate to consider any low concentration exemptions from the proposed entries.
The delegate notes the industry submission that draws attention to the potential human use of gentian violet as a topical antiseptic. However, this use is covered by the existing Schedule 4 entry, which is only changed in relation to the listing name used.
The proposed implementation date is 1 October 2016. An early implementation date is proposed in order to bring the regulation of these ingredients in cosmetic sold in Australia into alignment with international regulations.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.
Schedule 10 – new entry
METHYLROSANILINIUM CHLORIDE (formerly known as crystal violet CAS No. 548-62-9) AND THE FOLLOWING TRIARYLMETHANE DYES– for use in hair dyes
Schedule 6 – New entries
METHYLROSANILINIUM CHLORIDE (formerly known as crystal violet CAS No. 548-62-9) AND THE FOLLOWING TRIARYLMETHANE DYES
BASIC BLUE 26 (CAS No. 2580-56-5) except when used as a colourant in cosmetics not intended to be in contact with mucous membranes.
Schedule 4 – Amend entry
CRYSTAL VIOLET for human use except when used as a dermal marker. – replace "CRYSTAL VIOLET" with "METHYLROSANILINIUM CHLORIDE"
Index entries:
Crystal violet – see methylrosanilinium chloride
Gentian violet – see methylrosanilinium chloride
Scheduling medicines and poisons
The reasons for the request are:
The reasons for the request were:
Disperse yellow 3 is one of several oxidative hair dye ingredients that have been referred for scheduling in the past three years. Generally, these have been listed in either schedules 5 or 6, with cut-offs to exempt at a relevant concentration that minimises the risks of skin sensitisation and/or irritancy. In some cases, scheduling exemptions have been allowed via ‘reverse scheduling', where products labelled with specified warning statements may be exempted from the generic scheduling controls of Schedule 5 or 6.
Further restrictions may have been applied where products are used in eyebrow/eyelash tints as well as in hair dyes. Additional restrictions (Schedule 10 listing) have been placed where there is a significant risk of genotoxicity and/or carcinogenicity, or where precluded use in products for skin colouration (tattooing) have been required. In some cases where there was no evidence of significant use in Australia, the delegate's decision was not to schedule the substance (e.g. o-aminophenol from the July 2014 meeting).
The Delegate sought advice from the Committee on the following questions:
Please refer to the NICNAS assessment report for Acetamide, N-[4-[(2-hydroxy-5-methylphenyl)azo]phenyl]-
Figure 2. Structure of Disperse Yellow 3
Toxicity | Species | Disperse Yellow 3 | SPF* Classification |
---|---|---|---|
Acute oral toxicity LD50 | Rat | > 5000 mg/kg bw | Not classified |
Skin sensitisation - LLNA challenge and loose-fit coculture-based sensitisation assay (LCSA)) | positive | Schedule 6 |
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
This chemical is classified as hazardous with the risk phrase ‘May cause sensitisation by skin contact' (R43) in the Hazardous Substance Information System (HSIS) (Safe Work Australia). The positive results reported in a modified LLNA in mice and skin patch tests in humans (see Observation in humans section) support this classification.
The standard and modified (sensitisation—challenge) LLNA were used to test the sensitising potential of Disperse Yellow 3 and its aromatic amine metabolites, 4-Aminoacetanilide and 2-amino-p-cresol (Stahlmann et al., 2006). In the standard LLNA Disperse Yellow 3 and 4-aminoacetanilide were negative, but 2-amino-p-cresol showed a clear positive reaction. However, when the protocol was modified to a sensitisation—challenge assay, all three chemicals produced sensitisation reactions.
Compared with controls, significant increases in lymph node weights, cellularity and in the number of lymphocytes carrying A1 epitopes were observed in animals exposed to Disperse Yellow 3 (10 % and 30 % concentration) and 4-aminoacetanilide (30 % concentration). These results indicated sensitisation reactions. However, stronger sensitisation was induced by 2-amino-p-cresol.
Based on the weight of evidence from the available in vitro and in vivo genotoxicity studies, the chemical is considered to be genotoxic.
A number of in vitro genotoxicity tests gave positive results, and Disperse Yellow 3 also induced DNA damage in vivo. The aromatic amine metabolites are also genotoxic in vivo and/or in vitro.
The chemical is classified as hazardous—Category 3 carcinogenic substance - with the risk phrase ‘Limited evidence of carcinogenic effect' (Xn; R40 in the HSIS (Safe Work Australia)). The available data support this classification.
In long-term feeding studies (103 weeks) exposure to the chemical caused tumours in male Fischer (F344) rats and male and female B6C3F1 mice. The liver was the main target organ of carcinogenicity in male rats. In these animals, dose-dependent significant increases in hepatocellular adenomas and combined hepatocellular adenomas and carcinomas were observed in treated males (dose). In addition, combined rare adenoma, mucinous adenocarcinoma and sarcoma, and combined squamous cell papilloma and fibrosarcoma were also identified in the glandular and non-glandular portions of the stomach of the exposed male rats. No tumours were reported in exposed female rats.
There is a lack of epidemiological data to indicate specific links between occupational exposure to the chemical and tumour development.
The mechanism of action underlying the chemical's carcinogenic potential is not fully understood. However, the available data suggest a genotoxic mode of action.
No data are available.
A number of reports indicate sensitisation potential of the chemical. Allergic, contact-type dermatitis was reported in individuals with exposure to textiles coloured with dyes containing Disperse Yellow 3 (IARC, 1990; HSDB). The chemical has been identified as a disperse dye known to cause occupational contact allergic dermatitis in the textile industry (Office of Environmental Health Hazard Assessments, OEHHA, 2012).
Epicutaneous testing of the chemical (1% in petroleum) was conducted in 12 eczema patients with suspected contact allergy to textile dyes. The result showed that five patients had positive reactions to the chemical (Cosmetic Ingredient Review, CIR, 1996).
In another study, a number of patients who tested positive for Disperse Yellow 3 were also positive for the aromatic amine metabolites 4-aminoacetanilide and 2-amino-p-cresol. In this study, 6/10 patients tested with a dilution series of the chemical showed positive reactions. In addition, four patients showed positive reactions at 0.01 % of the chemical. These patients also showed a positive reaction to 4-aminoacetanilide (3/6) and 2-amino-p-cresol (6/6) (Malinauskiene et al., 2012).
Positive results in a patch test performed with a purified form of the dye indicated that it is the chemical and not the impurities that is responsible for the sensitisation response (CIR, 1996).
In a recent review on contact dermatitis from textiles, Malinauskiene et al. (2013) reported that a considerable number of patients showed positive patch test reactions to Disperse Yellow 3 (1 % in petrolatum). Positive responses were seen in approximately 7 % (averaged over 18 studies) of patients suspected or thought likely to have contact dermatitis caused by disperse dye allergy (aimed patch testing). In routine patch testing that included textile dyes (screening testing), a 0.8 % prevalence rate for Disperse Yellow 3 was reported (averaged over 12 studies). In Italy, Disperse Yellow 3 was also found to be one of the prevalent contact allergens in children (Malinauskiene et al., 2013).
No specific Australian use, import or manufacturing information has been identified.
The chemical has reported cosmetic use in oxidative hair dyes. No information is available on the concentrations used. Use of the chemical in cosmetics in the United States of America (USA) was reported in 1992, but there was no documented use in 2011 (Personal Care Product Council, 2011).
The chemical is listed on the following (Galleria Chemica):
The chemical is also in the EU's list of 179 substances banned for use in hair dye products (European Commission, 2010).
Disperse Yellow 3 is not specifically scheduled.
Disperse Yellow 3 has not been previously considered for scheduling; therefore, scheduling history is not available.
One public submission was received. The submission did not object to aligning the scheduling controls for this substance with the EU. They noted Disperse Yellow 3 is listed in Annex II of the EU Cosmetics Regulations and cannot be used in cosmetics in the EU.
The public submission is available at: Public submissions on scheduling matters.
In relation to the Delegate's questions the committee agreed that the sensitisation and carcinogenic potential warrants control in cosmetic and consumer products and should not be used in hair dyes. The committee agreed it was appropriate to have both a Schedule 6 entry for disperse yellow 3 for general use and a Schedule 10 entry to specifically prohibit use in hair dyes, noting the schedule 6 entry effectively prohibits use in cosmetics. Members further agreed that appropriate warning statements for general use to advise of the skin sensitization potential was warranted. The committee advised that the name Disperse Yellow 3 be used in any Schedule entry with a cross-reference to the chemical name 4-(2-hydroxy-5-methylphenylazo)acetanilide in the index. Members agreed that the substance is not captured by the existing benzidine azo dye entries or azo dyes derivatised by diazotisation and therefore should be listed separately in the Standard.
The committee agreed on the following amendments to the Poisons Standard:
Schedule 10 - New entry
DISPERSE YELLOW 3 - for use in hair dyes
Schedule 6 - New entry
DISPERSE YELLOW 3- except when in Schedule 10
Appendix E, Part 2 - new entry
DISPERSE YELLOW 3
Standard statements: A, S1
Appendix F, Part 3 - new entry
DISPERSE YELLOW 3
Warning Statement: 28
Safety direction: 4
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: b) to prevent its use in hair dyes but allow use in other dye situations (e.g. fabrics); and c) toxicity - skin sensitization consistent with Schedule 6 listing.
The delegate considered the following in regards to this proposal:
The delegate notes, and accepts, the advice of the ACCS to create new listings for Disperse Yellow 3 in Schedules 6 and 10, and in Appendices E and F. The listings are to be made under the name Disperse Yellow 3, with the chemical name 4-(2-hydroxy-5-methylphenylazo)acetanilide, cross-referenced in the index. The delegate notes that this substance would not be captured under any existing Schedule entries for phenylenediamines or azo dyes.
The purpose of the Schedule 10 entry is to restrict use in hair dyes preparations, in alignment with similar restrictions in international cosmetics regulations (EU, NZ and ASEAN). The toxicological basis for this restriction is the acute toxicity profile, including skin sensitisation potential shown in both toxicological testing and in human studies. For use in products other than hair dyes, the listings in Schedule 6 and Appendices E and F should provide suitable warnings to product users, including the requirement for the signal heading POISON on product labels. There was insufficient information, and no recommendation from the ACCS, for the delegate to consider any low concentration exemptions from the proposed entries.
The proposed implementation date is 1 October 2016. An early implementation date is proposed in order to bring the regulation of this oxidative hair dye ingredient in products sold in Australia into alignment with international regulations.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.
Schedule 10 - New entry
DISPERSE YELLOW 3 - for use in hair dyes
Schedule 6 - New entry
DISPERSE YELLOW 3- except when in Schedule 10
Appendix E, Part 2 - new entry
DISPERSE YELLOW 3
Standard statements: A, S1
Appendix F, Part 3 - new entry
DISPERSE YELLOW 3
Warning Statement: 28
Safety direction: 4
Scheduling medicines and poisons
Currently, there are no restrictions on introducing or using these chemicals in Australia. In the absence of any regulatory controls, the characterised critical health effects (particularly carcinogenicity and mutagenicity) have the potential to pose an unreasonable risk if the chemical is used in cosmetic products. Whilst domestic use of the chemicals will result in lower levels of exposure, given that the chemicals are genotoxic there is sufficient uncertainty regarding the safety of such products to warrant some restriction. Matters to be taken into consideration include:
The chemicals are prohibited for use in hair dye products in a number of overseas countries.
The delegate's reasons for the request are: The toxicity profile of chrysoidine base and its salts suggest that scheduling is required to regulate exposures to products containing them, particularly in view of its potential acute toxicity, skin/eye irritancy, sensitisation potential, genotoxicity and carcinogenicity.
The delegate sought advice from the Committee on the following questions:
The NICNAS IMAP Tier II Human Health Report on Chrysoidine base and its salts, the p-aminobenzene IMAP report and the o-aminoazotoluene IMAP Report are available from the NICNAS website.
The chemicals in this group include chrysoidine base (Solvent Orange 3—CAS No. 495-54-5) and various salts of chrysoidine.
Figure 3. Structure of chrysoidine base
The critical concern for this group of chemicals relates to the potential for carcinogenic effects following exposure, due to the presence of the chrysoidine base. The chemicals are all classified as genotoxic.
Data are available for Basic orange 2 which is the hydrochloride salt of chysoidine base and structurally-related azo aromatic amines, p-aminoazobenzene (CAS No. 60-09-3), o-aminoazotoluene (CAS No. 97-56-3) and phenazopyridine hydrochloride (CAS No. 136-40-3).
The acute toxicity end-points for chrysoidine base are listed in the table below.
Toxicity | Species | Result | SPF* Classification |
---|---|---|---|
Acute oral toxicity LD50 | Rat | 1532 mg/kg bw | Schedule 6 |
Skin irritation | Irritant (limited data) | Schedule 5 | |
Eye irritation | Severe (limited data) | Schedule 6 | |
Skin sensitisation | Analogue data – skin sensitiser | Schedule 5 |
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
The chemicals are classified as hazardous with the risk phrase 'Harmful if swallowed' (Xn; R22) in the Hazardous Substance Information System (HSIS) (Safe Work Australia). Based on test results, the chemicals have low to moderate acute oral toxicity in rats. Chrysoidine base has a median lethal dose (LD50) in the range warranting classification and there is insufficient evidence to determine the LD50 for the remaining chemicals.
The chemicals are classified as hazardous with the risk phrase 'Irritating to skin' (Xi; R38) in the HSIS (Safe Work Australia). No data are available to evaluate this classification.
All the chemicals in this group (except Solvent Orange 3: CAS No. 495-54-5) are currently classified as hazardous with the risk phrase 'Risk of serious damage to eyes' (Xi; R41) in the HSIS (Safe Work Australia). No data are available to evaluate this classification. However, in the absence of information, and as the classification is not clearly related to extremes of pH, this hazard classification is also considered appropriate for Solvent Orange 3.
No data on skin sensitisation are available for the chemicals. The structurally-related chemicals, p-aminoazobenzene (CAS No. 60-09-3) and o-aminoazotoluene (CAS No. 97-56-3), are considered to be sensitisers based on observations in animals and humans. In addition, the chemicals in this group have the potential to form benzenamine (CAS No. 62-53-3) due to potential azo reduction by the skin microflora. Benzenamine is classified as a sensitiser in the HSIS with available animal data to support this classification. Overall a classification is considered to be warranted.
The data for repeated dose toxicity for this chemical group are limited. However, repeated dose exposure of rats to 160 mg/kg bw/day of Basic Orange 2 for 21 days resulted in pathological changes to blood and stomach tissue. Whilst effects are not sufficient for classification, effects in the blood are consistent with those observed with the structurally related chemical, p-aminoazobenzene (CAS No. 60-09-3), and its potential metabolite, benzenamine and, therefore, the blood is considered to be a likely target for systemic toxicity for this group of chemicals.
The chemicals are classified as hazardous (Category 3 mutagenic substances) with the risk phrase 'Possible risk of irreversible effects' (Xn; R68) in HSIS (Safe Work Australia). The positive in vitro and in vivo genotoxicity data on some of the chemicals of this group (Solvent Orange 3, Basic Orange 2 and chrysoidine monoacetate—CAS No. 75660-25-2) and the metabolite chemicals support this classification.
Limited data are available for the chemicals. Based on the weight of evidence from available data on one of the chemicals in the group (Basic Orange 2), similar azo aromatic amines, p-aminoazobenzene, o-aminoazotoluene and phenazopyridine hydrochloride, and the metabolite chemical (benzenamine), the chemicals are considered carcinogenic. This is supported by the available genotoxicity data for the chemicals and information available from Quantitative Structure Activity Relationship modelling.
Basic Orange 2 was tested for carcinogenicity in single experiments in mice and rats using oral administration (IARC, 1987). Significantly increased incidences of liver adenomas and adenocarcinomas (72 %) and leukaemia and reticular cell sarcomas (with a combined incidence of 27 %) compared with controls were observed in C57BL mice that were fed a low-vitamin diet containing 0.2 % chrysoidine (equivalent to 260 mg/kg bw/day) for 13 months. Metastases of the liver tumours to the lungs were also observed. The second experiment on rats was inadequately reported. No tumours occurred in a group of 10 rats fed a diet containing 0.1 % chrysoidine (equivalent to 50 mg/kg bw/day) for 51–366 days. However, the experiment was performed with only a low dose administered to a small number of animals with short exposure and observation periods, and, therefore, may not have fully explored the carcinogenic potential of the chemical in rats.
The structurally-related azo aromatic amines, p-aminoazobenzene (CAS No. 60-09-3), o aminoazotoluene (CAS No. 97-56-3) and phenazopyridine hydrochloride (CAS No. 136-40-3), are all reported to cause liver tumours in rats and/or mice. Other sites of tumour formation include the lung (p-aminoazobenzene and o-aminoazotoluene), the colon (phenazopyridine hydrochloride) and urinary bladder, gall bladder, and mammary gland (o-aminoazotoluene). The chemicals, p aminoazobenzene and o-aminoazotoluene, are classified as hazardous (Category 2 carcinogenic substances) with the risk phrase ‘May cause cancer' (T; R45) in the HSIS (Attachments B and C The metabolite benzenamine (CAS No. 62-53-3) is carcinogenic to rats (albeit at higher doses and with effects observed in the spleen) and is classified as a Category 3 carcinogenic substance in the HSIS.
QSAR modelling for the Solvent Orange 3 using OASIS-TIMES, gave positive predictions for carcinogenicity. However, the chemical structure was out of the applicable domain of the QSAR models indicating greater uncertainty about the reliability of the positive predictions.
The chemicals may undergo metabolism to produce reactive nitrenium ions as an initial step in the carcinogenic mechanism of action. This usually involves N-hydroxylation of the aromatic amines to an N-hydroxylamine and eventual formation of the pro-carcinogenic nitrenium ions. The highly reactive nitrenium ions may covalently bind to DNA provided that they are sufficiently stabilised to not undergo further reactions. It was shown in an Ames test (with metabolic activation) that the stability of the nitrenium ions is correlated with mutagenicity (Benigni and Bossa, 2011). The non-fused conjugated ring polycyclic aromatic amine component of the chemical is postulated to stabilise the formation of the reactive nitrenium ions. The other chemicals in this group, being salts of Solvent Orange 3, are expected to behave similarly.
No data are available for the chemicals.
Human evidence of carcinogenicity, based on exposure to chrysoidine, is considered to be limited (IARC, 1987). Reports of bladder cancer from oral exposure in three amateur fishermen in the United Kingdom exposed to chrysoidine-dyed maggots led to an additional four cases being reported and two case–control studies. A bladder cancer case-control study involving approximately 900 case-control pairs found a relative risk of 0.7 based on five cases for bronze maggots and 2.0 based on nine cases for yellow maggots (Cartwright et al., 1983). A smaller study (202 case-control pairs) showed more bladder cancers following the use of dyed maggots (14 % cases, 8 % controls), with a 3-fold risk when bronze maggots were used for more than five years (Sole and Sorahan, 1985).
Although the uses of these chemicals in cosmetic and/or domestic products in Australia are not known, the chemicals are reported to be used in products overseas such as shoe polish and hair dyes, which might result in exposure of the general population. The introduction of these dyes for home use cannot be excluded.
The chemicals are listed on the following (Galleria Chemica):
In the above directives, the chemicals are listed as 'm-phenylenediamine, 4-(phenylazo)-, and its salts, when used as a substance in hair dye products'.
In 2004, the Scientific Committee on Cosmetic Products and Non-Food Products intended for consumers (SCCNFP) concluded that Basic Orange 2 cannot be considered safe for hair dyeing purposes, unless these purposes are regarded as safe on the basis of an adequate safety dossier (SCCNFP, 2004).
Chrysoidine base is not specifically scheduled.
Chrysoidine base has not been previously considered for scheduling; therefore, scheduling history is not available.
One public submission was received. The submission raised no objections to aligning the scheduling controls for this substance with the EU and noted all of the substances identified in the NICNAS IMAP report are listed in Annex II of the EU Cosmetics Regulations and cannot be used in cosmetics in the EU. They believe the schedule entry should specifically identify the following CAS numbers to ensure no other substances are inadvertently captured. CAS No. 495-54-5; 532-82-1; 63681-54-9; 75660-25-2; 79234-33-6; and 94247-67-3, consistent with the entry for Benzidine based azo-dyes.
The public submission is available at: Public submissions on scheduling matters.
The committee provided the following advice in response to the Delegate’s questions:
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: c) toxicity - Acute toxicity data are consistent with Schedule 6 criteria; f) other – There was concern with potential for eye irritation. Recommended schedule amendments would apply regulatory controls consistent with those in place internationally.
The committee advised that a combination of a Schedule 6 entry with a Schedule 10 entry be created for Chrysoidine with appropriate specifications as follows:
Schedule 6 - New entry
CHRYSOIDINE except when in Schedule 10
Schedule 10 - New entry
CHRYSOIDINE in preparations for use in hair dyes.
Appendix E, Part 3 – new entry
CHRYSOIDINE
Standard statements: A, S1, E1
The delegate considered the following in regards to this proposal:
The delegate notes, and accepts, the advice of the ACCS to create new listings for Chrysoidine in Schedules 6 and 10, and in Appendix E. The delegate notes the industry submission that requests the inclusion of CAS numbers for the six substances that would be captured by these entries, but also notes ACCS advice that listing under the name chrysoidine would automatically capture all the salts and derivatives listed in the NICNAS IMAP report, under the provisions of clause 2(c) of Part 1 of the Poisons Standard. The delegate also notes that this substance would not be captured under any existing Schedule entries for phenylenediamines or azo dyes.
The purpose of the Schedule 10 entry is to restrict use in hair dyes preparations, in alignment with similar restrictions in international cosmetics regulations (EU, NZ and ASEAN). The toxicological basis for this restriction is the acute toxicity profile, including skin sensitisation potential and limited evidence of genotoxicity and carcinogenicity. For use in products other than hair dyes, the listings in Schedule 6 and Appendix E should provide suitable warnings to product users, including the requirement for the signal heading POISON on product labels. There was insufficient information, and no recommendation from the ACCS, for the delegate to consider any low concentration exemptions from the proposed entries.
The proposed implementation date is 1 October 2016. An early implementation date is proposed in order to bring the regulation of this hair dye ingredient in products sold in Australia into alignment with international regulations.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance;
Schedule 6 - New entry
CHRYSOIDINE except when in Schedule 10
Schedule 10 - New entry
CHRYSOIDINE in preparations for use in hair dyes.
Appendix E, Part 3 – new entry
CHRYSOIDINE
Standard statements: A, S1 (wash off skin), E1 (wash out of eyes)
Scheduling medicines and poisons
The reasons for the request are:
The critical health effects for risk characterisation are mutagenicity and skin sensitisation. Given the potential for mutagenicity and skin sensitisation, the risk would be better controlled by inclusion of warning statements on the label for preparations containing the chemical at any concentration. This chemical has similar use and hazard profile to a number of chemicals which have been listed in Schedule 6 with reverse scheduling requirements.
The Delegate's reasons for referring this to the Committee include the following: p-aminophenol is one of several oxidative hair dye ingredients that have been referred for scheduling in the past three years. Generally, these have been listed in either schedules 5 or 6, with cut-offs to exempt at a relevant concentration that minimises the risks of skin sensitisation and/or irritancy. In some cases, scheduling exemptions have been allowed via ‘reverse labelling’, where products labelled with specified warning statements may be exempted from the generic scheduling controls of Schedule 5 or 6. Further restrictions may have been applied where products are used in eyebrow/eyelash tinters as well as in hair dyes. Additional restrictions (Schedule 10 listing) have been placed where there is a significant risk of genotoxicity and/or carcinogenicity, or where precluded use in products for skin colouration (tattooing) have been required. In some cases where there was no evidence of significant use in Australia, the delegate’s decision was not to schedule the substance (e.g. o-aminophenol from the July 2014 meeting).
The delegate sought advice from the Committee on the following questions:
Please refer to the NICNAS IMAP Tier II report for p-aminophenol that is publicly available on the NICNAS website.
Figure 4. Structure of p-aminophenol
The acute toxicity end-points for p-aminophenol are listed in the table below.
Toxicity | Species | Result | SPF* Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | 671 (SD rats) | Schedule 6 |
Acute dermal toxicity LD50 (mg/kg bw) | Rat | >5000 | N/A |
Acute inhalational toxicity LC50 (mg/m3/4h) | Rat | >3.42 mg/L | N/A |
Skin irritation | Rabbit | Slight irritant | Schedule 5 |
Eye irritation | Rabbit | Slight irritant | Schedule 5 |
Skin sensitisation (maximisation test and Buehler test) | Guinea pig | Skin sensitiser | Schedule 6 |
Skin sensitisation (human data) | Human |
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
The chemical has moderate acute oral toxicity and low acute dermal toxicity. The available data for inhalation were inconclusive.
Based on the available information, p-aminophenol is a slight skin and eye irritant.
Based on the available animal and human data, p-aminophenol is a skin sensitiser.
In a study similar to the Buehler test, Pirbright Dunkin Hartley guinea pigs were treated with 0.1, 0.5, 1 or 2 % preparations of p-aminophenol. Dose-dependent, positive skin responses were observed in 3/10, 5/10, 6/10 and 9/10 animals, respectively.
Freund's complete adjuvant tests were conducted in guinea pigs using two methods of induction. In the first method, Freund's adjuvant was injected alone before 0.18 mmol/L of p-aminophenol was topically administered twice (over two days); p-aminophenol did not induce any skin sensitisation reactions. In the second method, Freund's adjuvant was injected with 0.18 mmol/L of p-aminophenol (ratio 1:1) (induction), followed by a 0.09 mmol/L of p-aminophenol 16 days later (challenge). The treatment induced positive reactions in 40 % of the animals.
P-aminophenol gave positive skin reactions in patch tests in 25 % (1/4) and 17 % (2/12) of patients with dermatitis (among 13 beauticians and 33 hairdressers respectively, tested for occupational dermatitis).
Among 24 hairdressers and eight barbers patch tested for occupational allergic contact dermatitis, p-aminophenol induced positive reactions in 25 % (2/8) of patients with dermatitis.
The application of p-aminophenol at 1 % gave positive results in 3 % (11/372) of patients patch tested with the chemical.
Based on the available data, p-aminophenol may cause severe effects from repeated oral exposure. The kidney is the target organ for repeated oral toxicity in rats, with nephrosis seen at doses of 30 mg/kg bw/day and above. However, there are uncertainties about the reversibility of kidney effects.
Based on the available in vitro and in vivo data, p-aminophenol may have mutagenic properties. Most of the in vivo tests conducted gave positive results for genotoxicity on somatic cells, including:
Based on the limited information available, p-aminophenol is not expected to be carcinogenic.
Based on the available data, p-aminophenol is not expected to have reproductive or developmental toxicity. The foetal effects observed in rats at high doses (133 and 467 mg/kg bw/day) are considered secondary to maternal toxicity.
The chemical was reported to be used in permanent hair dyes in Australia in 2007.
Currently, there are no restrictions in Australia on using p-aminophenol in hair dyes. In the absence of any regulatory controls, the characterised critical health effects, particularly skin sensitisation and mutagenicity, have the potential to pose an unreasonable risk under the identified use. The risk could be mitigated by implementing restrictions for the use of the chemical in hair dyes.
Using p-aminophenol in hair dyes in the EU is subject to the restrictions described in EU Regulation Annex III (amended by Regulation (EC) No 1197/2013): after mixing under oxidative conditions the maximum concentration applied to hair must not exceed 0.9 %.
p-Aminophenol is not specifically scheduled.
p-Aminophenol has not been previously considered for scheduling; therefore, scheduling history is not available.
One public submission was received. The submission raised no objections to aligning the scheduling controls with EU. They note substance is included in Annex III of the EU Cosmetics Regulations, restricting its use to oxidative hair dyes with in-use concentration not exceeding 0.9%. They propose schedule entry consistent with recent decisions on oxidative hair dye ingredients. They also request a later implementation date to allow time for relabelling of products already on the market.
The public submission is available at: Public submissions on scheduling matters.
The committee advised that the toxicological profile of p-aminophenol warrants controls over use in cosmetics and consumer products, as well as other products. Members agreed that a Schedule 6 entry is appropriate according to SPF criteria. On the evidence supporting a cut off concentration, the committee agreed there was sufficient data to recommend a 1% cut off concentration. The committee did not consider the evidence for mutagenicity was sufficient to recommend a higher schedule.
The committee advised that the appropriate name for use in the SUSMP was p-aminophenol and a new Schedule 6 entry be created for p-aminophenol with appropriate exemptions and cut off as follows:
Schedule 6 - New entry
p-AMINOPHENOL except when used in hair dye and eyebrow/eyelash colouring products at a concentration of 1 per cent or less of p-aminophenol after mixing for use when the immediate container and primary pack are labelled with the following statements:
KEEP OUT OF REACH OF CHILDREN, and
WARNING – This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use.
Written in letters not less than 1.5 mm in height.
Appendix E, Part 2– New entry
p-AMINOPHENOL
Standard statements: A, S1
Appendix F, Part 3 – New entry
p-AMINOPHENOL
Warning Statement: 28
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: a) risk of skin sensitisation is reduced by limiting maximum concentration in bottle and after mixing. c) toxicity - the acute oral toxicity and skin sensitisation are consistent with Schedule 6 criteria. d) The positive skin sensitisation is dose-dependent and therefore Schedule 6 with appropriate RASML is appropriate.
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.
p-Aminophenol is one of four oxidant hair dyes that were referred to the March 2016 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-aminophenol should be listed in Schedule 6, with an exemption cut-off at 1%, provided products are labelled with the warning statements about skin sensitisation potential that have been required for similar oxidative hair dyes. The delegate also notes ACCS advice that the potential for eye irritation is not sufficient to require warning statements relating to use for dyeing eyebrows and eyelashes.
The proposed implementation date is 1 June 2017. A later implementation date is proposed to allow for an orderly process of re-labelling of products already on the market.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.
Schedule 6 - New entry
p-AMINOPHENOL except when used in hair dye and eyebrow/eyelash colouring products at a concentration of 1 per cent or less of p-aminophenol after mixing for use when the immediate container and primary pack are labelled with the following statements:
KEEP OUT OF REACH OF CHILDREN, and
WARNING – This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use.
Written in letters not less than 1.5 mm in height.
Appendix E, Part 2– New entry
p-AMINOPHENOL
Standard statements: A, S1
Appendix F, Part 3 – New entry
p-AMINOPHENOL
Warning Statement: 28
Scheduling medicines and poisons
The reasons for the request are:
The critical health effects for risk characterisation are mutagenicity and skin sensitisation. Given the potential for mutagenicity and skin sensitisation, the risk would be better controlled by inclusion of warning statements on the label for preparations containing the chemical at any concentration. This chemical has similar use and hazard profile to a number of chemicals which have been listed in Schedule 6 with reverse scheduling requirements.
The delegate's reasons for referring this to the committee include the following: 2-methylresorcinol is one of several oxidative hair dye ingredients that have been referred for scheduling in the past three years. Generally, these have been listed in either schedules 5 or 6, with cut-offs to exempt at a relevant concentration that minimises the risks of skin sensitisation and/or irritancy. In some cases, scheduling exemptions have been allowed via 'reverse labelling', where products labelled with specified warning statements may be exempted from the generic scheduling controls of Schedule 5 or 6.
Further restrictions may have been applied where products are used in eyebrow/eyelash tinters as well as in hair dyes. Additional restrictions (Schedule 10 listing) have been placed where there is a significant risk of genotoxicity and/or carcinogenicity, or where precluded use in products for skin colouration (tattooing) have been required. In some cases where there was no evidence of significant use in Australia, the delegate's decision was not to schedule the substance (e.g. o-aminophenol from the July 2014 meeting).
The Delegate sought advice from the committee on the following questions:
Please refer to the NICNAS IMAP assessment report for 1,3-benzenediol, 2-methyl-. This report is publicly available on the NICNAS website.
Figure 5. Structure of 1,3-benzenediol, 2-methyl- (2-methylresorcinol)
The acute toxicity end-points for 2-methylresorcinol are listed in the table below.
Toxicity | Species | Result | SPF* Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Mice | 390 | 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 | Mild irritant | Schedule 5 |
Eye irritation | Rabbit | Severe irritant | Schedule 6 |
Skin sensitisation (local lymph node assay (LLNA)) | Mice | Weak sensitiser (EC3 = 50 %) | Schedule 5/6 |
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
Based on available data, the chemical has moderate acute oral toxicity. No data are available on acute dermal and inhalation toxicity.
2-Methylresorcinol is considered to be slightly irritating to skin. In an OECD Guideline 404 compliant study, 0.5 g of the test material was moistened and applied to the intact, shaved back skin of rabbits (three males/group) for four hours under semi-occlusive patches. Very slight erythema developed in one animal after one hour.
2-Methylresorcinol is a severe eye irritant. In a OECD guideline 405 study, 0.1 mL of undiluted test chemical (equivalent to 50.6 mg) was instilled into one eye of one rabbit and left for 24 hours. The test chemical caused corneal opacity (maximum grade 3) and epithelial damage (maximum 100 % of the corneal surface). These effects were not fully reversible within the observation period. Iridial irritation (grade 1) was observed for the first seven days of observation. Conjunctival irritation (consisting of erythema and chemosis) was observed. The nictitating membrane and eyelids exhibited white discolouration, consistent with necrosis.
2-Methylresorcinol is a weak skin sensitiser, according to a LLNA assay conducted CBA mice (5/group) had 25 µL of the test material (at 1, 10, 25 or 50 %) applied to the dorsal surface of each ear, once daily for three consecutive days. Five days after the first topical application, all mice were administered radiolabelled thymidine (3HTdR), draining lymph nodes were excised and thymidine incorporation into the lymph node cells was assessed. Stimulation Indices (SI) of 0.7, 0.6, 1.1 and 3 were calculated for the 1, 10, 25 and 50 % groups, respectively. An EC 3 of 50 % was determined accordingly.
Based on the data available, 2-methylresorcinol 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 weight of evidence from the available well-conducted in vitro and in vivo genotoxicity studies, 2-methylresorcinol is not considered to be genotoxic.
No data were available.
Based on the available data, 2-methylresorcinol is not expected to have reproductive or developmental toxicity.
2-Methylresorcinol is reported to be used in permanent hair dye preparations in Australia.
Currently, there are no restrictions in Australia on using this chemical in cosmetics/hair dyes or eyelash colouring products. In the absence of any regulatory controls, the characterised critical health effects (skin sensitisation) have the potential to pose an unreasonable risk to public under the uses identified.
The following international regulations apply:
2-Methylresorcinol is not specifically scheduled.
2-Methylresorcinol has not been previously considered for scheduling; therefore, scheduling history is not available.
One public submission was received. The submission had no objections to aligning the scheduling controls for this substance with the EU. The submission noted that 2-methylresorcinol is included in Annex III of the EU Cosmetics Regulations, restricting its use to hair dyes with in-use concentration not exceeding 1.8%. They proposed a specific Schedule entry in line with recent decisions on hair dye products. They also sought a later implementation date to allow relabelling of existing products.
The public submission is available at: Public submissions on scheduling matters.
In response to the Delegate's questions, the Committee advised that the toxicological profile of the substance warrants controls over use in hair dye products, including warning statements indicating products should not be used for dying eyebrows/eye lashes. The committee advised the toxicity profile of the substance was consistent with inclusion in Schedule 6.
In regards to the sensitization potential of the substance, the committee advised that, with a suitable cut off concentration consistent with that in the EU, the risk of sensitization from use of the hair dye products was low. As such, the Committee recommended a cut off concentration of 1.8%.
Members agreed 2-methylresorcinol was an appropriate name and consistent with the INCI name.
The committee recommended that a new Schedule 6 entry be created for 2-methylresorcinol with appropriate exemptions and cut off as follows:
Schedule 6 - New entry
2-METHYLRESORCINOL except:
KEEP OUT OF REACH OF CHILDREN, and
WARNING –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 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 entry
2-METHYLRESORCINOL
Standard statements: A, E1
Appendix F, Part 3 – new entry
2-METHYLRESORCINOL
Safety direction: 1
The committee recommended a late implementation date (1 February 2017) to allow relabelling of existing products on the market.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: a) Potential for severe eye damage when used as a hair dye, particularly eyebrow and eyelash tinting products; c) It is a severe eye irritant and has an acute LD50 of 390mg/kg bw which warrants a Schedule 6 entry. Exposure would occur to the public and professional users of hair colourants; d) Restricted to 1.8% for hair dye only.
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.
2-methylresorcinol is one of four oxidant hair dyes that were referred to the March 2016 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-methylresorcinol should be listed in Schedule 6, with an exemption cut-off at 1.8% in products either without, or after, mixing with an oxidant , provided products are labelled with the warning statements about skin sensitisation potential that have been required for similar oxidative hair dyes. The delegate also notes ACCS advice that the potential for eye irritation is sufficient to require additional warning statements relating to use for dyeing eyebrows and eyelashes.
The delegate also notes ACCS advice that 2-methylresorcinol is the INCI name and is the preferred name for listing in Schedule 6.
The proposed implementation date is 1 June 2017. A later implementation date is proposed to allow for an orderly process of re-labelling of products already on the market.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.
Schedule 6 - New entry
2-METHYLRESORCINOL except:
KEEP OUT OF REACH OF CHILDREN, and
WARNING –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 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 entry
2-METHYLRESORCINOL
Standard statements: A, E1
Appendix F, Part 3 – new entry
2-METHYLRESORCINOL
Safety direction: 1
Scheduling medicines and poisons
The reasons for the request are:
The critical health effect for risk characterisation is skin sensitisation. Given the potential for skin sensitisation, the risk would be better controlled by inclusion of warning statements on the label of preparations containing the chemical at any concentration. Similar chemicals have been listed in Schedule 6 of the SUSMP with reverse scheduling requirements.
The Delegate's reasons for referring this to the Committee were as follows: 2,4-diamino-5-methylphenetole is one of several oxidative hair dye ingredients that have been referred for scheduling in the past three years. Generally, these have been listed in either schedules 5 or 6, with cut-offs to exempt at a relevant concentration that minimises the risks of skin sensitisation and/or irritancy. In some cases, scheduling exemptions have been allowed via 'reverse labelling', where products labelled with specified warning statements may be exempted from the generic scheduling controls of Schedule 5 or 6. Further restrictions may have been applied where products are used in eyebrow/eyelash tinters as well as in hair dyes.
Additional restrictions (Schedule 10 listing) have been placed where there is a significant risk of genotoxicity and/or carcinogenicity, or where precluded use in products for skin colouration (tattooing) have been required. In some cases where there was no evidence of significant use in Australia, the delegate’s decision was not to schedule the substance (e.g. o-aminophenol from the July 2014 meeting).
The delegate has sought advice from the Committee on the following questions:
Please refer to the publicly available report on the NICNAS website.
Figure 6. Structure of 2,4-diamino-5-methylphenetole.
The acute toxicity end-points for 2,4-diamino-5-methylphenetole are listed in the table below.
Toxicity | Species | Result | SPF* Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat and mouse | Approximately 200-2000 | Schedule 6 |
Acute dermal toxicity LD50 (mg/kg bw) | N/A | No data | N/A |
Acute inhalational toxicity LC50 (mg/m3/4h) | N/A | No data | N/A |
Skin irritation | Guinea pig | Not an irritant at 3 % concentration | N/A |
Eye irritation | Guinea pig | Not an irritant at 3 % concentration | N/A |
Skin sensitisation: QSAR - LLNA | N/A | Skin sensitiser (predicted EC3 = 5.1) | Schedule 6 |
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
Based on the available data, 2,4-diamino-5-methylphenetole has been reported to have moderate acute oral toxicity, although the data are not sufficient to validate this conclusion. No information was available for acute toxicity by dermal and inhalation routes.
Based on the available data, 2,4-diamino-5-methylphenetole is not irritating to the skin and eyes at a 3 % concentration.
Based on the available data, 2,4-diamino-5-methylphenetole is expected to be a skin sensitiser.
Ten female guinea pigs were induced with a 0.1 % solution of 2,4-diamino-5-methylphenetole in Ringer's solution via intradermal injection to the clipped shoulder region, followed by a topical application of a 40 % solution of 2,4-diamino-5-methylphenetole. After two weeks, the animals were challenged with a 30 % solution of the chemical. Two of 10 test animals showed slight to moderate erythema (EC SCC, 2000). The SCCNFP (1999) reported that this study used an intradermal induction concentration that was too low. The cosmetic product containing the chemical was reported to have a label warning for risk of sensitisation (SCCNFP, 1999).
The sensitisation potency of 2,4-diamino-5-methylphenetole was predicted in a study on 229 hair dye substances using a QSAR model based on the LLNA. The study predicted the chemical to be a moderate to strong sensitiser, with an estimated concentration needed to produce a 3-fold increase in lymphocyte proliferation (EC3) value of 5.1 (Sosted et al., 2004).
Based on the available data, 2,4-diamino-5-methylphenetole 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, 2,4-diamino-5-methylphenetole is not considered to be genotoxic.
No animal toxicity data are available on the carcinogenicity of 2,4-diamino-5-methylphenetole. Based on the available genotoxic data and information available from QSAR modelling, the chemical is not considered to be carcinogenic.
Limited data are available and are not sufficient to derive a conclusion on the reproductive and developmental toxicity of 2,4-diamino-5-methylphenetole.
No information was available.
2,4-diamino-5-methylphenetole was not reported to be used in hair dye preparations in Australia in 2007. It has overseas use in hair dye preparations at a maximum concentration of 2 % (maximum concentration of 1 % when mixed with hydrogen peroxide) (SCCNFP, 1999).
The Association of South East Asian Nations (ASEAN), European Union (EU) and New Zealand Cosmetic Products Group Standard have prohibited the use of this chemical in cosmetics. 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 if used in cosmetics.
The chemical is listed on the following:
2,4-diamino-5-methylphenetole is not specifically scheduled.
2,4-diamino-5-methylphenetole has not been previously considered for scheduling; therefore, scheduling history is not available.
One public submission was received. In that submission no objections to aligning the scheduling controls for this substance with the EU were raised. The submission notes that 2,4-diamino-5-methylphenetole is listed in Annex II of the EU Cosmetics Regulations and cannot be used in cosmetics in the EU.
The public submission is available at: Public submissions on scheduling matters.
In response to the Delegate's questions, the Committee advised the toxicity profile of the substance warrants control over use in cosmetics and consumer products. The committee agreed a Schedule 6 entry for phenylenediamines was appropriate and with no exemption cut off concentration specified. The committee advised that inclusion in Schedule 6 effectively prohibits use of 2,4 diamino 5 methylphenetole in cosmetics.
The committee advised that 2,4-diamino-5-methylphenetole does not require separate scheduling, as the substance is considered to already be captured by the existing entries for phenylenediamines. However the Committee advised that the substance should be included in the index with cross reference to the general entry to provide clarity for industry on its scheduling. This editorial change will be included in the next update of the SUSMP.
The Committee recommended an early implementation date for the index amendment.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: a) low risk with oral toxicity as it is for topical use; b) Chemical has reported use overseas in cosmetic preparations. No reports of use in Australia; c) substance demonstrates skin sensitisation and acute oral toxicity consistent with Schedule 6 criteria; d) appropriate to use labelling similar to that used by other Schedule 6 oxidative hair colourant chemicals; f) the committee considered the substance was already captured by the existing entry for phenylenediamine and does not warrant separate scheduling.
The delegate considered the following in regards to this proposal:
2,4-Diamino-5-methylphenetole is one of four oxidant hair dyes that were referred to the March 2016 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 the toxicity profile of 2,4-diamino-5-methylphenetole is consistent with other phenylenediamine-based hair dye ingredients and that it could be considered to be covered by the generic Schedule 6 listing for PHENYLENEDIAMINES. Accordingly, the only scheduling action proposed is to cross-reference 2,4-diamino-5-methylphenetole in the index with the generic entry.
An implementation date is not relevant, since the substance is already covered by the generic PHENYLENEDIAMINES entry. The addition of the index cross-reference should be done at the earliest possible time.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.
Index – new entry
2,4-DIAMINO-5-METHYLPHENETOLE
cross reference: PHENYLENEDIAMINES
Scheduling medicines and poisons
The reasons for the request are:
The critical health effect is the potential for skin sensitisation, and this risk would be better controlled by inclusion of warning statements on the label of preparations containing 2 chloro 5 nitro N hydroxyethyl p-phenylenediamine at any concentration. Similar chemicals have been listed in Schedule 6 of the SUSMP with reverse scheduling requirements.
The Delegate's reasons for referring the application to the Committee were: 2-chloro-5-nitro-N-hydroxyethy p-phenylenediamine is one of several oxidative hair dye ingredients that have been referred for scheduling in the past three years. Generally, these have been listed in either schedules 5 or 6, with cut-offs to exempt at a relevant concentration that minimises the risks of skin sensitisation and/or irritancy. In some cases, scheduling exemptions have been allowed via 'reverse labelling', where products labelled with specified warning statements may be exempted from the generic scheduling controls of Schedule 5 or 6.
Further restrictions may have been applied where products are used in eyebrow/eyelash tinters as well as in hair dyes. Additional restrictions (Schedule 10 listing) have been placed where there is a significant risk of genotoxicity and/or carcinogenicity, or where precluded use in products for skin colouration (tattooing) have been required. In some cases where there was no evidence of significant use in Australia, the delegate's decision was not to schedule the substance (e.g. o-aminophenol from the July 2014 meeting).
The Delegate sought advice from the Committee on the following questions:
The report, containing more detailed information about the substance, is publicly available on the NICNAS website.
Figure 7. Structure of 2-chloro-5-nitro-N-hydroxyethyl p-phenylenediamine
The acute toxicity end-points for 2-chloro-5-nitro-N-hydroxyethyl p-phenylenediamine are listed in the table below.
Toxicity | Species | Result | SPF* Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Mice | 2850 | 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 | Guinea pig | Not irritating at 0.25 % concentration | N/A |
Eye irritation | Guinea pig | Slightly irritating at 0.25 % concentration | Schedule 5 |
Skin sensitisation: QSAR prediction based on LLNA | N/A | Skin sensitiser (predicted EC3= 2.7) | Schedule 6 |
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
2-chloro-5-nitro-N-hydroxyethyl p-phenylenediamine has low acute oral toxicity in female CF1 mice. There are no data on acute dermal and inhalation toxicity.
Only limited data are available in guinea pigs. 2-chloro-5-nitro-N-hydroxyethyl p-phenylenediamine at a 0.25 % concentration is not irritating to the skin. The chemical at a 0.25 % concentration is slightly irritating to the eyes.
Although the animal data (two limited quality non-guideline studies) indicate that the chemical is not a skin sensitiser, predictions from QSAR modelling indicated that the chemical was a moderate to strong skin sensitiser.
A 0.5 % solution of 2-chloro-5-nitro-N-hydroxyethyl p-phenylenediamine (in 50 % ethanol) was administered as intracutaneous injections (0.1 mL) to the shaved skin of 15 female guinea pigs, twice/day, 6 days/week for three weeks. A control group of five female guinea pigs was used. After four weeks, the animals were challenged with an intracutaneous injection (0.1 mL) containing a 0.5 % solution of the chemical (in 50 % ethanol) at dilutions of 1:10, 1:100, 1:500 and 1:1000 in Ringer's solution. Severe erythema was observed 24 hours after challenge in both treated and control animals, which reduced to slight-well-defined erythema after 48 hours. 2-chloro-5-nitro-N-hydroxyethyl p-phenylenediamine was reported to have 'shined through the skin' during the challenge phase, making it difficult to evaluate. However, this effect was not mentioned during the induction phase. The chemical was reported as non-sensitising (EC SCC, 2000).
In another study, guinea pigs (10/sex/dose) were induced with two intradermal injections (0.05 mL each); one containing Freund's complete adjuvant (FCA) (1:1 with distilled water) and the other containing a 3 % solution of 2-chloro-5-nitro-N-hydroxyethyl p-phenylenediamine in water. The animals were then treated with a dermal application of 10 % sodium lauryl sulfate in white vaseline (unoccluded) on the following day. This was followed by (6-8 hours later) an occluded application (0.5 mL) of the chemical at 3 % in white vaseline. Forty-eight hours after the first induction, two intradermal injections (0.05 mL each) were given with 3 % of the chemical in FCA (diluted with 1:1 arachis oil). The animals were challenged 14 days later using a patch test (occluded for 24 hours) using 0.5 mL of 1, 2 or 3 % of the chemical in FCA (1:1 in arachis oil). No primary irritation or sensitisation was observed in the animals, either immediately after the challenge or 24 hours later, when compared with the control group (EC SCC, 2000). However, the EC SCC (2000) reported that the test protocol deviated from the OECD Test Guidelines for the Magnusson-Kligman test.
The sensitisation potency of 2-chloro-5-nitro-N-hydroxyethyl p-phenylenediamine was predicted in a study on 229 hair dye substances using a QSAR model based on the local lymph node assay (LLNA). The study predicted the chemical to be a moderate to strong skin sensitiser, with an estimated concentration needed to produce a three-fold increase in lymphocyte proliferation (EC3) value of 2.7 (Sosted, 2004).
Skin sensitisation prediction using the OECD QSAR Toolbox v3.2 model was negative for the parent chemical—there were no protein binding alerts. However, of the nine possible chemical metabolites, three were predicted to be skin sensitisers. Potential protein binding reactions of the metabolites were Michael additions or Schiff Base formation.
Skin sensitisation prediction using OASIS-TIMES v2.27.14 (Optimized Approach based on Structural Indices Set-Tissue Metabolism Simulator) modelling was also negative for the parent chemical, although the model prediction was out of applicability domain, which indicates greater uncertainty about its reliability. The possible metabolites of the chemical, based on the metabolism simulators of OASIS-TIMES, were predicted to be strong skin sensitisers.
Based on a 90-day study in rats, 2-chloro-5-nitro-N-hydroxyethyl p-phenylenediamine is not expected to cause serious damage to health from repeated oral exposure. Only limited data were available on repeated dose dermal toxicity and no data were available on repeated dose inhalation toxicity.
Based on the available data from in vitro and in vivo genotoxicity studies, the chemical is not expected to be genotoxic.
Only limited animal data were available. Based on the available genotoxicity data, mitigating factors relating to the mechanisms of aromatic amine carcinogenicity and due to its chemical structure, this chemical is not considered to be carcinogenic.
Only limited data were available and are not sufficient to derive a conclusion on reproductive or developmental toxicity of the chemical.
The chemical is reported to be used in permanent and semi-permanent hair dye preparations in Australia (NICNAS, 2007). Many countries, including those in the European Union, have banned the use of this chemical in cosmetics.
Currently, there are no restrictions in Australia on using this chemical in cosmetics. 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 under the identified uses.
The chemical is listed on the following:
2-Chloro-5-nitro-N-hydroxyethyl p-phenylenediamine is not specifically scheduled.
2-Chloro-5-nitro-N-hydroxyethyl p-phenylenediamine has not been previously considered for scheduling; therefore, scheduling history is not available.
One public submission was received. The submission had no objections to aligning the scheduling controls for this substance with the EU. It noted that 2-chloro-5-nitro-N-hydroxyethyl-p-*phenylenediamine is listed in Annex II of the EU Cosmetics Regulations and cannot be used in cosmetics in the EU.
The public submission is available at: Public submissions on scheduling matters.
In response to the Delegate's questions, the Committee advised that the substance warrants control over use in cosmetics and hair dye products consistent with other similar hair dyes (specifically phenylenediamine entry in Schedule 6) on the basis of potential for skin sensitisation.
The committee advised that 2-chloro-5-nitro-N-hydroxyethyl p-phenylenediamine does not require a separate schedule entry, as the substance was considered to be captured by the existing general entry for phenylenediamines in Schedule 6. However, the committee recommended inclusion of the substance in the index with cross reference to the general entry. This editorial change to the index will be made during the next update of the SUSMP.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: a) risk of skin sensitisation resulting from use as hair colourant; b) used in permanent and semi-permanent hair dyes in Australia and in concentrations of up to 2% and 1% overseas for oxidative and semi-permanent hair dyes, respectively. Many countries including EU have banned use in cosmetics; c) toxicity of the substance including predicted moderate to strong skin sensitisation potential from QSAR modelling; d) Labelling as per similar Schedule 6 chemicals used in oxidative hair colourant process; f) The committee noted the data was not sufficient to warrant consideration in a lower schedule.
The delegate considered the following in regards to this proposal:
2-Chloro-5-nitro-N-hydroxyethyl p-phenylenediamine is one of four oxidant hair dyes that were referred to the March 2016 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 the toxicity profile of 2 chloro 5 nitro N hydroxyethyl p-phenylenediamine is consistent with other phenylenediamine-based hair dye ingredients and that it could be considered to be covered by the generic Schedule 6 listing for PHENYLENEDIAMINES. Accordingly, the only scheduling action proposed is to cross-reference 2-chloro-5-nitro-N-hydroxyethyl p-phenylenediamine in the index with the generic entry.
An implementation date is not relevant, since the substance is already covered by the generic PHENYLENEDIAMINES entry. The addition of the index cross-reference should be done at the earliest possible time.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.
Index – new entry
2-CHLORO-5-NITRO-N-HYDROXYETHYL-p-PHENYLENEDIAMINE
cross reference: PHENYLENEDIAMINES
Scheduling medicines and poisons
The reasons for the request are:
Similar to other surfactant chemicals previously considered for Scheduling, the key risk is the eye irritation, particularly when considered in the context of the use in hair care products.
The NICNAS risk assessment determined that there was no unreasonable risk to the public when used at 1% concentration in rinse-off hair care products (the maximum concentration proposed by the notifier). However, there remains uncertainty as to the actual concentration cut-off at which eye damage may occur, as eye irritation data was only available for a solution containing the polymer at 30-50% concentration.
The Delegate's reasons for referring this substance to the Committee were: the key scheduling issues, on which the delegate requires ACCS advice, is whether the weak skin irritancy and severe eye irritancy potential of this silicone co-polymer warrants inclusion in either Schedule 5 or 6 because of its potential use in rinse-off cosmetic hair care products.
The Delegate sought advice from the Committee on the following questions:
Please refer to the New Chemical assessment report for Siloxanes and Silicones, 3-[(2-aminoethyl)amino]propyl Me, di-Me, hydroxy- and methoxy-terminated, polymers with polyethylene-polypropylene glycol bis(2-methyl-2-propen-1-yl) ether (Word,77kb). This report is publicly available on the NICNAS website.
The toxicological investigations were conducted on the polymer at 30-50% concentration, unless stated otherwise. The acute toxicity end-points for bis-Isobutyl PEG/PPG-20/35/Amodimethicone Copolymer are listed in the below table.
Toxicity | Species | Result | SPF* Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | > 2,000 | Schedule 5 |
Acute dermal toxicity LD50 (mg/kg bw) | Not provided | Not provided | - |
Acute inhalational toxicity LC50 (mg/m3/4h) | Not provided | Not provided | - |
Skin irritation | Rabbit | Slightly irritating (at 10% concentration)** | Schedule 5 |
Eye irritation | Rabbit | Severely irritating | Schedule 6 |
Skin sensitisation | Not provided | Not provided | - |
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
** A 10% suspension of the product (containing the polymer at 30-50% concentration) was used as a test substance in the study.
In a study conducted on rabbits the polymer at 30-50% was determined to be severely irritating to eyes, based primarily on conjunctival irritation, including effects which had not reversed by the end of the observation period.
A 10% suspension of the product (containing the polymer at 30-50% concentration) was found to be slightly irritating to the skin when tested on rabbits.
No information was provided.
The polymer was not mutagenic in a bacterial reverse mutation study and it was not clastogenic in an in vitro mammalian chromosome aberration test.
No information was provided.
No information was provided.
No information was provided.
There will be repeated exposure of the public to the polymer (at up to 1% concentration) through the use as a surfactant in rinse off hair care products, such as shampoos and conditioners. The principal routes of exposure will be dermal, while ocular and oral exposures are also possible.
No information was provided.
Bis-Isobutyl PEG/PPG is not specifically scheduled.
Bis-Isobutyl PEG/PPG has not been previously considered for scheduling, therefore scheduling history is not available.
One public submission was received. The submission noted the substance is intended for use in dilute, rinse off cosmetic products. They agree the hazard profile merits scheduling consideration but questioned whether the risks require risk mitigation through scheduling and if they would deliver safety benefits for the end user. They believe use of first aid statement E1 "If in eyes wash out immediately with water." normally applied to severe eye irritants is redundant, because under the intended use situation (rinse-off cosmetic, e.g. shampoo or conditioner), if the product was to enter the eye, the user would instinctively wash the eye immediately under water. They note there are no restrictions on the use of this polymer internationally. They suggest that if any scheduling restrictions are considered, the focus should be on uses that are not its current intended use to deter unintended uses, and allow this polymer to remain unscheduled when in rinse-off cosmetic preparations.
The public submission is available at: Public submissions on scheduling matters.
In response to the Delegate's questions, the Committee has advised that the toxicity of the substance warrants a Schedule 6 entry with an exemption for rinse off hair products below 1%, and entries in Appendix E and F.
The committee recommends that a new Schedule 6 entry be created Bis-Isobutyl PEG/PPG-20/35/Amodimethicone Copolymer as follows:
Schedule 6 - New entry
BIS-ISOBUTYL PEG/PPG-20/35/AMODIMETHICONE COPOLYMER except in rinse-off hair products containing 1 per cent or less of bis-isobutyl PEG/PPG-20/35/amodimethicone copolymer.
Appendix E, Part 2 – New entry
BIS-ISOBUTYL PEG/PPG-20/35/AMODIMETHICONE COPOLYMER
Standard statements: A, E1
Appendix F, Part 3 – New entry
BIS-ISOBUTYL PEG/PPG-20/35/AMODIMETHICONE COPOLYMER
Safety direction: 1 (avoid contact with eyes)
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: c) There are minimal risks to the user if the product containing the polymer is used as directed; b) The substance is used in rinse off cosmetics specifically shampoos and conditioners. It is widely used by the public and the hairdressing profession; c) The substance is a severe eye irritant consistent with schedule 6 criteria.
The delegate considered the following in regards to this proposal:
The delegate notes, and accepts, ACCS advice that a new listing for this silicone copolymer be created in Schedule 6, with appropriate listings in Appendices E and F to require relevant label First Aid and Warning Statements. The preferred name for listing is the INCI name Bis-Isobutyl PEG/PPG-20/35/Amodimethicone Copolymer. While the acute toxicity profile is possibly consistent with SPF criteria for listing in Schedule 5, the delegate agrees that a primary listing in Schedule 6 is more appropriate, given the strong eye irritancy potential. The delegate agrees to include a specific exemption to the Schedule 6 entry only for use in rinse-off cosmetic products at concentrations of 1% or less.
The delegate has broadened the schedule entry recommended by the ACCS to include an exemption for all rinse-off cosmetic products, not just those used in preparations formulated for use on the hair.
The delegate notes the points raised in the industry submission, that scheduling does not achieve any useful risk mitigation because of the reduced potential for eye irritancy in dilute preparations and the lack of international controls over use in cosmetics. However, the delegate considers that the exemptions in the proposed Schedule 6 entry address these concerns and mandate appropriate labelling of products where the use pattern and higher concentrations that may be used could be associated with a higher potential for eye damage. The eye warning statement prescribed in Appendix F will only be applied to products that do not meet the Schedule 6 exemption.
The proposed implementation date is 1 June 2017. A later implementation date is proposed to allow for an orderly process of re-labelling of products already on the market.
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.
Schedule 6 - New entry
BIS-ISOBUTYL PEG/PPG-20/35/AMODIMETHICONE COPOLYMER except in rinse-off cosmetic products containing 1 per cent or less of bis-isobutyl PEG/PPG-20/35/amodimethicone copolymer.
Appendix E, Part 2 – New entry
BIS-ISOBUTYL PEG/PPG-20/35/AMODIMETHICONE COPOLYMER
Standard statements: A, E1
Appendix F, Part 3 – New entry
BIS-ISOBUTYL PEG/PPG-20/35/AMODIMETHICONE COPOLYMER
Safety direction: 1
Scheduling medicines and poisons
In December 2015, the Australian Pesticides and Veterinary Medicines Authority (APVMA) referred the following proposal to be considered by the delegate:
The reasons for the request are:
New data provided by the applicant includes:
The majority of these studies were conducted after the ADI for propamocarb was set in 1987. The analysis of these new data supports the removal of propamocarb from Schedule 5 to an Appendix B listing in the Poisons Standard.
The Delegate's reasons for referring this to the Committee were as follows: While the toxicological profile of propamocarb is reasonably straightforward, and could be considered for a scheduling decision to be made by the delegate, ACCS advice is sought on whether the newly submitted data is sufficient to justify deletion of propamocarb from Schedule 5, and listing in Appendix B.
The Delegate sought advice from the Committee on the following questions:
Figure 8. Structure of propamocarb (HCl salt)
The acute toxicity end-points for propamocarb are listed in the below table.
Toxicity | Species | Result | SPF* Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | SD Rat | > 2000 | Low toxicity |
Wistar Rat | > 5000 | ||
Acute dermal toxicity LD50 (mg/kg bw) | Rat | > 5000 | Low toxicity |
Acute inhalational toxicity LC50 (mg/m3/4h) | Rat | 5540 | Low toxicity |
Skin irritation | Rat | Non-irritant | Non-irritant |
Eye irritation | Rabbit | Non-irritant | Non-irritant |
Skin sensitisation (LLNA and maximisation) | Guinea pig | Sensitiser | Sensitiser |
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
In the short-term toxicity studies, the critical effect was vacuolation of the choroid plexus in the brain and other tissues/glands, which was observed in a 28-day mouse dietary study at 172 mg/kg bw/d. The relevant short-term toxicity NOEL was set at the next lowest dose at 100 mg/kg bw/d.
In the sub-chronic toxicity studies, the critical effects observed were consistent with the effects found in the short-term studies. In rats reduced body weight gain and vacuolar changes in the choroid plexus and the lacrimal glands were observed. In dog dietary studies, wide spread vacuolation in secretary glands was observed and the sub-chronic NOEL was set at 131 mg/kg bw/d.
Consistent with the critical effects found in short-term and sub-chronic toxicity studies, vacuolation of multiple tissues was observed in 52-week dog dietary study. While vacuolation was seen at every dose level, there was a dose-related response in the severity of vacuolation. The NOEL for chronic toxicity was 39 mg/kg bw/d.
Propamocarb was not genotoxic in the battery of in vivo and in vitro genotoxicity studies.
Propamocarb was not carcinogenic.
In the 2-generation reproductive toxicity study in rats, female survival was decreased in both generations, female fertility index was slightly lowered and in males, a decreased sperm motility and count was observed at the highest dose level tested (1000 mg/kg bw/d). Consistent with the findings in other rat toxicity studies, vacuolation of tissues was also observed at the higher dose levels. The NOEL for parental toxicity was set at 50 mg/kg bw/d. The NOEL of 200 mg/kg bw/d was set for pup development based on decreased pup viability at the highest dose. The overall NOEL for reproduction toxicity was set at 200 mg/kg bw/d based on the adverse effects on sperm parameters.
Propamocarb was not a teratogen in the tested animals. In rats, a reduced body weight gain and increased mortality of dams were the basis for a NOEL of 680 mg/kg bw/d for maternal toxicity. The NOEL for foetal toxicity was set at 204 mg/kg bw/d based on slightly increased number in foetal deaths and retarded ossification.
Propamocarb was not acutely neurotoxic. In a sub-chronic study a vacuolation of choroid plexus in the ventricles of cerebrum and cerebellum was observed but these studies did not show any functional deficits in the tested animals and therefore the biological significance of vacuolation is unknown.
Not explored by the APVMA in this report. Propamocarb is been registered for use in the USA and European Union.
Propamocarb is currently listed in Schedule 5.
Propamocarb has been considered for scheduling in May 1979 and July 1987. In the 1979 meeting the committee noted the limited toxicological data that were available but agreed to include the substance in Schedule 5 for the proposed, limited use (soil fungicide in ornamental plants).
In the 1987 meeting the committee considered additional studies and noted the low acute toxicity of the substance, that it was slightly irritating to the eye (rabbit) but non-irritating to the skin (rabbit). It did not cause skin sensitization (guinea pig), showed negative genotoxic, carcinogenic or teratogenic potential but was embryotoxic at maternotoxic doses. A schedule 5 entry was deemed appropriate.
No public submissions were received.
In response to the Delegate’s questions the Committee advised that it was appropriate to retain the current listing for propamocarb in Schedule 5 due to concerns with the neurotoxicity in dogs and skin sensitisation potential, and therefore an Appendix B entry was not supported.
The committee advised that the current scheduling of propamocarb remains appropriate.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: c) toxicity of the substance: Acute oral toxicity (effects in dogs), skin sensitisation.
The delegate considered the following in regards to this proposal:
The delegate notes, and accepts, ACCS advice that the current listing of propamocarb in Schedule 5 remains appropriate. The extension of the toxicological database provided in newly submitted studies confirms the relatively low toxicity of this fungicide, but the findings of slight skin sensitisation, neurotoxicity and lethality observed with acute oral dosing in dogs, and vacuolations observed in the brain and other tissues in chronic and repeat-dosing studies, albeit observed only at quite high dosing rates, nevertheless suggest that retaining the current listing in Schedule 5 is suitably precautionary.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (c) the toxicity of a substance.
Scheduling medicines and poisons
In December 2015, the Australian Pesticides and Veterinary Medicines Authority (APVMA) referred the following proposal to be considered by the delegate:
The reasons for the request are:
The Delegate referred the substance to the Committee for advice on the following issues:
Figure 9. Chemicals structure of fluopicolide.
The acute toxicity end-points for fluopicolide are listed in the following table.
Toxicity | Species | Result | SPF* Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | > 5000 | Low toxicity |
Acute dermal toxicity LD50 (mg/kg bw) | Rat | > 5000 | Low toxicity |
Acute inhalational toxicity LC50 (mg/m3/4h) | Rat | 5160 | Low toxicity |
Skin irritation | Rat | Non-irritant | Non-irritant |
Eye irritation | Rabbit | Slight irritant | Slight irritant |
Skin sensitisation | Guinea pig | Non-sensitiser | Non-sensitiser |
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
In the short-term toxicity studies, the target/critical effect was liver pathology, which was observed in a 28-day dietary mouse study. The NOEL was set at 10.4 mg/kg bw/d based on increased liver weights associated with centrilobular hepatocellular hypertrophy at a LOEL (640 ppm).
In sub-chronic toxicity studies, critical effects were seen in the liver of rats. Histopathological effects observed in the 3-month rat dietary study included centrilobular hepatocellular hypertrophy in males at the LOEL (1400 ppm). An increase in the severity and incidence of trabecular hyperostosis of the bone joint was observed in females at the same dose level. A NOEL was set at 7.4 mg/kg bw/day (100 ppm).
Consistent with the liver pathology seen in the short-term and sub-chronic toxicity studies, liver pathology was the target organ in a chronic toxicity study in rats. A NOEL was set at 7.9 mg/kg bw/d (50 ppm) based on the increased absolute and relative liver weights associated with hepatocellular hypertrophy at the LOEL and highest does (400 and 3200 ppm, respectively). A markedly increased incidence of hepatocellular adenoma was observed at 3200 ppm.
Fluopicolide was not genotoxic based on a battery of in vivo and in vitro genotoxicity assays.
Carcinogenicity studies showed an increased incidence of hepatocellular adenoma at the highest dose level (3200 ppm) in a 78-week mouse dietary study and a NOEL was set at 400 ppm. The incidence of hepatocellular carcinoma was unaffected by the treatment. Mechanistic studies demonstrated a mouse specific mechanism for the liver adenoma. It was concluded that the benign liver tumours observed in mice were not relevant to humans.
Fluopicolide was not a reproductive toxicant. A NOEL of 25.5 mg/kg bw/d for males and 32.9 mg/kg bw/d for females (500 ppm) was set based on increased liver and kidney weights, adverse kidney histopathology findings and reduced weight gains at the next highest dose tested. A reproduction NOEL of 103.4 mg/kg b/d (2000 ppm) was set at the highest dose tested in a 2-generation dietary study in rats.
Fluopicolide was not a teratogen in developmental studies in rats and rabbits. In rats, a NOEL for maternal and foetal toxicity was set at 60 mg/kg bw/d. This was based on reduced weight gain in dams and delayed development in foetuses observed at the dose level of 700 mg/kg bw/d. A NOEL for teratogenesis was set at the highest dose level 1000 mg/kg bw/day. In rabbits, fluopicolide killed the majority of the dams and their pups at the highest dose tested (60 mg/kg bw/d). At this dose level, a high level of premature delivery, body weight loss and decreases in food consumption were observed. The NOEL for maternal and foetal toxicity was 20 mg/kg bw/d and the NOEL for foetal development was 60 mg/kg bw/d.
Neurotoxicity studies conducted in rats demonstrated that fluopicolide was not neurotoxic.
Not explored by the APVMA in this report. Fluopicolide has been approved for use in the European Union since 2006.
Fluopicolide is not specifically scheduled.
Fluopicolide has not been previously considered for scheduling; therefore, scheduling history is not available.
No public submissions were received.
In response to the Delegate's request the Committee has advised that the toxicity profile of fluopicolide is sufficiently low to support it being included in Appendix B. The Committee noted the slight and transient eye irritation effects of the substance.
The committee advised the following amendments to the Poisons Standard:
Appendix B, Part 3 - New entry
FLUOPICOLIDE
Part 1 – Reasons for Entry
a) low toxicity
Part 2 - Area of Use
1.3
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: c) Toxicity of the substance - Slight and transient eye irritation effects.
The delegate considered the following in regards to this proposal:
The delegate notes, and accepts, the ACCS advice that the toxicity profile of fluopicolide is not consistent with SPF criteria for listing in any of the schedules. Accordingly, the delegate proposes to list fluopicolide in Appendix B, to designate that it has at least been considered for scheduling.
The proposed implementation date is 1 October 2016. Since listing in Appendix B is not equivalent to a decision to list a substance in a schedule, an implementation date is not strictly relevant. However, early advice to the APVMA of this decision will facilitate prompt registration of products under consideration by the APVMA. Accordingly, amendment of Appendix B at the earliest revision of the Poisons Standard is recommended.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (c) the toxicity of a substance.
Appendix B, Part 3 - New entry
FLUOPICOLIDE
Part 1 – Reasons for Entry - a) low toxicity
Part 2 - Area of Use - 1.3
Scheduling medicines and poisons
On 2 December 2015 the APVMA referred the following proposal to be considered by the delegate:
The reasons for the request are:
The evaluation also considered that other medium chain fatty acids and their derivatives are not listed as scheduled poisons.
The Delegate's reasons for referring this substance to the Committee for advice were: Although the toxicological profile of this substance is relatively straightforward, with mucosal, skin and eye irritancy as the principal drivers of any scheduling proposal, the delegate requires advice from the ACCS on how to word a schedule entry that does not capture non-agricultural uses, including use in cosmetics, sanitisers, as a food additive or as a naturally occurring fatty acid in various fruits and plants.
The Delegate has sought advice on the following questions:
Please refer to publically available reports on nonanoic acid (potassium salt)(pdf,87kb) on NICNAS website for nonanoic acid.
Figure 10. Structure of nonanoic acid
Nonanoic acid (NNA; also frequently referred to as pelargonic acid) is a naturally occurring carboxylic acid with a carbon chain-length of nine, belonging to the chemical class saturated fatty acids commonly referred to as medium chain fatty acids (C8 to C12).
It is a clear, colourless liquid with a weak odour. NNA is soluble in aqueous solution however it can readily form esters and partially dissociate into the pelargonate anion (CH3(CH2)7COO-) and the hydronium cation (H3O+) in an aqueous solution (NICNAS IMAP, 2015). The molecular weight (158.24 g/mol) and octanol-water partition coefficient (3.4 logPow) of NNA suggest that dermal penetration is possible.
Oral, dermal or inhalation absorption studies are not available. The default of 100% is assumed for oral, dermal and inhalation absorption. NNA has low systemic toxicity and is not corrosive. The acute oral and dermal toxicity (rat) is greater than 2000 mg/kg. Acute inhalation median lethal concentration (LC50)(rat) is more than 3000 mg/m3 (4 h).
The human clinical data for skin irritation indicates reversible moderate irritation. Eye irritation is slight to moderate and nonanoic acid is not classifiable as a skin sensitiser. The eye irritation is considered reversible although corneal opacity has been reported in some older rabbit studies. NNA did not cause marked organ toxicity in repeat dose toxicity studies. It did cause gastrointestinal irritation. It is unlikely to produce significant toxicity (organ damage, respiratory sensitisation, mutagenicity, carcinogenicity, reproductive toxicity).
For occupational margin of exposure assessment the selected no observed adverse effect level (NOAEL) is from a 28-day oral study in male and female Wistar rats. NNA was administered by gavage at doses of 0, 50, 150 or 1000 mg/kg bw/d in concentrations of 1, 3 or 20% in propylene glycol as a vehicle. Treatment related effects were minimal except for gastrointestinal irritation. An irregular surface of the forestomach was noted in all high dose animals. In this dose group, histopathological examination showed slight to marked hyperplasia of the squamous epithelium of the forestomach. These latter effects were also noticed in 2 from 10 animals of the mid-dose group but these were considered to be without any toxicological relevance since they were minimal and occurred in the absence of (other) functional or morphological disturbances or clinical signs. Therefore a local oral (i.e. for gastric effect) NOAEL of 150 mg/kg bw/d was established (ECHA 2013). The ECHA did not establish a systemic NOAEL.
Given the effects are local and not systemic for home garden assessments the potential for skin and eye contact and the magnitude of skin and eye irritation should be the focus. The threshold for slight to moderate skin irritation is between 3 and 10% w/w NNA. At 10% skin irritation is transient and mild.
For occupational margin of exposure assessment the selected NOAEL is from a 28-day oral study in Wistar rats (ECHA 2013). A local irritation effect was noted, with an oral NOAEL of 150 mg/kg bw/d; general systemic toxicity was not observed. The NOAEL is based on slight to marked hyperplasia of the squamous epithelium of the forestomach, a local irritant effect rather than a systemic effect. In this case the presence or absence of skin and eye irritation is the primary considerations for the home garden health risk assessment but also for occupational risk assessment.
Based on skin and eye irritation the evaluation proposes that NNA be included in Schedule 5 of the SUSMP with a cut off of 3%.
The following table summarises the toxicological information for nonanoic acid.
Study type | Species / Test System | Result | Reference |
---|---|---|---|
Acute Oral Toxicity | Wistar rat, Crl:(WI) BR (outbred, SPFQuality), 3/sex/dose | LD50 >2000 mg/kg bw | ECHA 2013 |
Acute Dermal Toxicity | Wistar rat, Crl:(WI) BR (outbred, SPFQuality), 5/sex/dose | LD50 >2000 mg/kg bw | ECHA 2013 |
Acute Inhalation Toxicity | Details not provided in summary | LC50 (4 h) >5.3 mg/L | ECHA 2013 |
Skin irritation | Human and Rabbits (NZW) | Irritating | ECHA 2013 |
Eye irritation | Human experience and Rabbits (NZW) | Irritating | ECHA 2013a, b, c |
Skin sensitisation | Albino Guinea pigs, Dunkin Hartley strain (SPF-quality), 10 females per test item group. Maximisation test. | No evidence of sensitisation | ECHA 2013 |
Respiratory sensitisation | No information | No evidence of sensitisation | ECHA 2013 |
Carcinogenicity | Non-standard dermal carcinogenicity study | No evidence for carcinogenicity | ECHA 2013 |
Mutagenicity -Genetic toxicity | Bacterial gene mutation test, mammalian in vitro chromosomal aberration test and in vivo mouse micronucleus assay | No evidence for genotoxicity or mutagenicity | ECHA 2013 |
Toxicity to reproduction - fertility |
47 week Rat, McCollum-Wisconsin. A casein diet, containing 18.5% medium chain triglyceride (MCT) The MCT contained about 51% octanoic acid and 35% decanoic acid resulting in an octanoic acid dietary dose of about 4700 mg/kg bw/d and a decanoic acid dietary dose of about 3200 mg/kg bw/d. |
No concern for reproductive toxicity. Overall LOEL of ≥ 8000 mg/kg bw d |
ECHA 2013 |
Toxicity to reproduction - development | |||
Toxicity to reproduction - breastfed babies. Effects on or via lactation | |||
Specific Target Organ Toxicity - Repeat Dose | 28 day study with Wistar rat, Crl:(WI) BR (outbred, SPF-Quality), 5 males and 5 females per dose group |
NOAEL - 150 mg/kg bw/d Based on the observation of macroscopic irregular surface of the forestomach (hyperplasia of the squamous epithelium) at 1000 mg/kg bw/d |
ECHA 2013 |
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
The technical report notes that NNA was listed on the 2007 OECD list of high production volume chemicals, meaning that the chemical was produced or imported levels greater than 1,000 tonnes per year in at least one member country/region (OECD 2007).
The principal uses for NNA are in cosmetics and conventional pesticides. NNA is used in cosmetics for skin-conditioning, fragrance, surfactant-cleansing, and surfactant-emulsifying (Johnson et al., 2011). It is an active ingredient of antimicrobial agents (e.g. surface sanitiser), blossom thinners (formulations that decrease flower load and improve fruit yields), biopesticides and conventional pesticides registered with the US Environmental Protection Agency (US EPA) (US EPA, 2010, US EPA, 2000). The US EPA-registered products contain NNA in the range 0.96-57%. It is also used in lacquers, plastics, lubricants, metalworking fluids, photographic plate development and in the manufacture of plastics and pharmaceuticals (US EPA, 2010). In Australia NNA has reported domestic use as a surface-active agent (NICNAS IMAP, 2015).
Fatty acids are a significant part of a person’s normal daily diet with NNA being naturally present in fruits, vegetables, dairy products, meat and grains at levels ranging from 0.2 - 400 mg/kg (Marin Water, 2010). Natural levels of NNA include 1.4 mg/kg in dried mushrooms, 0.03-0.04 mg/kg in beer, and 2.5-20.5 mg/kg in coffee (Council of Europe, 2000).
The APVMA report notes that no known Australian or international restrictions were identified in their review or by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS IMAP, 2015).
The US Food and Drug Administration (FDA) has approved NNA for use as a direct food additive under the synthetic flavouring substances and adjuvants category at the minimum quantity required to produce their intended effect (21CFR172, 2015), and as an indirect additive as a surface sterilant on food-processing equipment and utensils and dairy-processing equipment (21CFR178, 2015), at the amount reasonably required to accomplish its intended physical, nutritive, or other technical effect in food. FDA approval has also been reported for use in cosmetics, shampoos and other personal care products and in transdermal drug delivery systems (US EPA, 2010).
It was also noted the primary metabolite of NNA is azelaic acid, which is approved by the Therapeutic Goods Administration as an over the counter acne treatment.
Nonanoic acid is not specifically scheduled.
Nonanoic acid has not been previously considered for scheduling; therefore, scheduling history is not available.
Two public submissions were received. The first submission did not support the scheduling proposal. It was claimed that at the concentration of the ready-to-use product, the pH was sufficiently low to not require scheduling. A cut off concentration of 4% was suggested. The second submission did not support the proposal. They noted the substance is listed in the ARTG ingredient list and may have a use as an excipient in fragrances. Therefore, they request that the ACCS considers exemption for the use of the substance as an excipient in therapeutic goods, with a suitable cut off concentration if appropriate.
The public submissions are available at: Public submissions on scheduling matters.
In response to the Delegate's request, the Committee have advised that the irritant properties of the substance meet the criteria for inclusion in Schedule 6 rather than Schedule 5. In relation to the Delegate’s questions, the Committee noted the broad use pattern of NNA and given its irritancy, the schedule entry should not be restricted to agricultural uses only to capture other areas of potential public exposure.
The Committee advised that a 10% cut off for the substance was appropriate, below which the substance would not be scheduled. This cut off concentration was considered appropriate to avoid capturing its use in food additives and cosmetics.
The Committee recommended use of the IUPAC name of nonanoic acid for scheduling.
The committee recommended the following amendments to the Poisons Standard:
Schedule 6 - New entry
NONANOIC ACID except in preparations containing 10 per cent or less of nonanoic acid
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: c) The substance has severe eye irritation potential that meet Schedule 6 criteria; f) The committee considered the eye irritancy/damage of the substance warranted schedule 6 entry. It was noted currently available products (non-agricultural) would be below 10%.
The delegate considered the following in regards to this proposal:
Nonanoic acid was referred by the APVMA for consideration of scheduling because if its use as an adjuvant in AgVet products. This substance is a naturally occurring fatty acid and it may also be used as a food additive and in therapeutic goods. As such, it represents a challenge to devise a scheduling proposal that provides appropriate controls over uses where suitable warning statements are necessary, while exempting uses where such controls are inappropriate.
The delegate notes the advice from the ACCS, that a new Schedule 6 entry be created for nonanoic acid, with a cut-off to exempt in preparations containing 10% or less. The advice for a primary listing in Schedule 6 is based primarily on the potential for severe eye damage associated with exposure to this fatty acid, while most of the other toxicological criteria are consistent with SPF criteria for listing in Schedule 5. The delegate notes comments made by the ACCS that the evaluation of the eye irritancy studies presented lacked rigour and that there is some uncertainty about the severity and reversibility of the lesions associated with concentrated solutions of the acid. The delegate also notes submissions from industry, suggesting the lack of concern for dilute preparations and that the ACCS did not recommend any entries in Appendices E or F, to provide for any First Aid or label Warning Statements for products that would be captured by the schedule listing.
The delegate has decided to create a primary listing for nonanoic acid (the preferred IUPAC name) in Schedule 5, with an exemption for products containing 10% or less. There is sufficient evidence that, at concentrations below 10%, that should cover most uses and natural occurrences of nonanoic acid in products available to the public, the risks of eye damage are sufficiently ameliorated to warrant scheduling controls unnecessary.
The proposed implementation date is 1 February 2017. While an early implementation date would facilitate registration of new products by the APVMA, there is some doubt as to whether any existing products regulated by the APVMA could be affected, and require re-labelling. Accordingly, an intermediate implementation date is proposed.
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.
Schedule5 - New entry
NONANOIC ACID except in preparations containing 10 per cent or less of nonanoic acid
The delegate has determined that listing in Schedule 5 is more consistent with SPF criteria and provides adequate controls for any preparations in current use that would contain more than 10% of nonanoic acid.
Scheduling medicines and poisons
In December 2015 the Office of Chemical Safety (OCS), based on an application made to the APVMA to approve three new biological active constituents, requested that the Delegate consider creating new entries for Lasiodiplodia pseudotheobromae (strain NT039), Neoscytalidium novaehollandiae (strain QLD003) and Macrophomina phaseolina (strain NT094) in Schedule 5 of the SUSMP with cut off exemptions. The proposed new entries are as follows:
The reasons for the request are:
The delegate's reasons for referring this to the Committee were to seek ACCS advice to determine whether the toxicity data package is sufficiently comprehensive to make a scheduling decision, and whether the evidence of potential infectivity justifies listing in Schedule 5, with an exemption for a product containing low levels of the three fungal strains.
The Delegate has sought advice on the following questions:
Di-Bak Parkinsonia is a new biological herbicide consisting of three fungal species - Lasiodiplodia pseudotheobromae, Neoscytalidium novaehollandiae and Macrophomina phaseolina – combined with a millet substrate in gelatine capsule formulation.
The acute toxicity end-points for Di-Bak Parkinsonia are listed below.
Toxicity | Species | Result | SPF* Classification |
---|---|---|---|
Acute intraperitoneal toxicity/pathogenicity LD50 | Rat | > 16 CFU/strain/animal^ | N/A |
"Acute" oral toxicity LD50 (mg/kg bw)^ | Rat | > 2g/kg bw/d^ | [Unscheduled] |
Acute dermal toxicity LD50 (mg/kg bw) | n/a | ||
Acute inhalational toxicity LC50 (mg/m3/4h) | n/a | ||
Skin irritation | n/a | ||
Eye irritation | n/a | ||
Skin sensitisation LLNA^ | Mice | Unlikely to be a skin sensitiser^ | [Unscheduled] |
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
^ Study has reduced regulatory value
Repeat-dose studies were not undertaken; however it is considered that the proposed formulation and intended use pattern of the product present a low potential for the active constituents to cause harm.
No information was provided.
Mycoses by M. phaseolina and L. pseudotheobromae appear generally to be cutaneous or subcutaneous in nature and often follow some sort of trauma or injury. However, cases of severe eye and sinus infection by L. pseudotheobromae in humans have been recorded in the academic literature where no obvious mode of acquisition or underlying medical condition was present.
No information was provided.
No domestic (general public) exposure is expected for Lasiodiplodia pseudotheobromae, Neoscytalidium novaehollandiae and Macrophomina phaseolina. The intended use of Di-Bak Parkinsonia Bioherbicide is as a bioherbicide for Parkinsonia aculeata trees present in grazing land. The OCS notes that Lasiodiplodia pseudotheobromae, Neoscytalidium novaehollandiae and Macrophomina phaseolina fungal species are already present in trees native to Australia.
No information was provided.
Di-Bak Parkinsonia Bioherbicide or its component fungal species are not specifically scheduled.
Di-Bak Parkinsonia Bioherbicide or its component fungal strains have not been previously considered for scheduling; therefore, scheduling history is not available.
No public submissions were received.
In response to the Delegate's request, the Committee has advised that the product warrants inclusion in Schedule 5 due to infectivity potential, despite exposure risks being minimal due to the formulation presentation and the presence of the fungi in the natural environment. It was noted the fungi are present in concentrated form and thus increases the risks. The Committee advised that warning statements recommended for inclusion under APVMA registration requirements would sufficiently ameliorate risks.
The committee advocated for a new Schedule 5 entries be created for Lasiodiplodia pseudotheobromae, Neoscytalidium novaehollandiae and Macrophomina phaseolina with appropriate exemptions and cut off as follows:
Schedule 5 - New entries
LASIODIPLODIA PSEUDOTHEOBROMAE except when used in capsule preparations at a concentration of 16 CFU or less per capsule.
NEOSCYTALIDIUM NOVAEHOLLANDIAE except when used in capsule preparations at a concentration of 16 CFU or less per capsule.
MACROPHOMINA PHASEOLINA except when used in capsule preparations at a concentration of 16 CFU or less per capsule.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: c) Potential for the substance to be infective in some individuals; d) the presentation of the active ingredient in capsule form sufficiently reduces exposure to the extent that scheduling is not required if in capsules and labelled in accordance with APVMA labelling requirements.
The delegate considered the following in regards to this proposal:
The delegate notes, and accepts, ACCS advice that the three fungal spores contained in the referred biological herbicide product be listed in Schedule 5, with an exemption cut-off at 16CFU or less in an encapsulated dose form. The delegate notes that this advice is primarily based on the potential infectivity to humans of these naturally-occurring fungi, and that there is no specific SPF guidance on the use of infectivity and/or pathogenicity data in making a scheduling decision. It was also noted that the proposed method of use (insertion of capsules into holes bored in trees) further reduces the risk of exposure to the public, and justifies exempting the specific product from the schedule entry. While these proposals would lead to the scheduling capture of any other product formulated with these three fungi, it is not envisaged that the natural occurrence of any of these fungal strains in the environment would be captured by the schedule entry.
The delegate thinks it necessary to further specify the type of agricultural use as a herbicide, as well as specifying the encapsulated nature of the product, in the schedule entry.
The proposed implementation date is 1 October 2016. An early implementation for this scheduling proposal will facilitate registration of the product by the APVMA.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.
Schedule 5 - New entries
LASIODIPLODIA PSEUDOTHEOBROMAE except when used as a herbicide in capsule preparations at a concentration of 16 CFU or less per capsule.
NEOSCYTALIDIUM NOVAEHOLLANDIAE except when used as a herbicide in capsule preparations at a concentration of 16 CFU or less per capsule.
MACROPHOMINA PHASEOLINA except when used as a herbicide in capsule preparations at a concentration of 16 CFU or less per capsule.
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 Streptomyces lydicus WYEC 108 as a new active constituent and the registration of a product, Actinovate BioFungicide, containing Streptomyces lydicus WYEC 108, recommends that the delegate consider creating a new entry for Streptomyces lydicus WYEC 108 in Schedule 6 of the SUSMP with cut-off exemptions (to unscheduled) when used in preparations containing 0.037 per cent or less of Streptomyces lydicus WYEC 108 for agricultural use.
The reasons for the request are:
The OCS assessment concluded that the product Actinovate BioFungicide containing 0.037% (w/w) Streptomyces lydicus WYEC 108 did not meet the Scheduling Policy Framework criteria, and as such, an exemption cut-off was proposed at 0.037 per cent or less for agricultural use.
The delegate's reasons for referring this to the Committee for advice were: the overall low toxicity profile of this biological pesticide suggests that scheduling is not required, but seeks advice from the ACCS to determine whether there is sufficient evidence of skin/respiratory sensitisation potential to justify listing in Schedule 6, with an exemption for a product containing 0.037% or less of Streptomyces lydicus WYEC 108.
The Delegate has sought advice from the Committee on the following questions:
The acute toxicity end-points for Streptomyces lydicus WYEC 108 are listed below.
Toxicity | Species | Results | SPF* Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat |
>5050 (~ 2.5 x 109 CFU/kg bw) No deaths |
N/A |
Acute dermal toxicity LD50 (mg/kg bw) | Rat |
>5050 (~ 9.95 x 109 CFU/kg bw) No deaths |
N/A |
Acute inhalation toxicity | Estimated | Low | N/A |
Acute pulmonary toxicity/ pathogenicity | Rat |
LD50 > 9.1 x 108 CFU/rat No deaths Not a pulmonary toxicant/pathogen |
N/A |
Acute intravenous injection toxicity/pathogenicity | Rat |
LD50 > 9.33 x 108 CFU/rat No deaths Non-toxic/Non-pathogenic |
N/A |
Skin irritation | Rabbit | Non-irritant | N/A |
Eye irritation | Rabbit | Slight eye irritant | N/A |
Skin and respiratory sensitisation | Estimated | Potential sensitiser | Schedule 6 |
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
The acute toxicity end-points for Actinovate BioFungicide are listed in the below table.
Toxicity | Species | Results | SPF* Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat (F only) |
LD50 >5000 No deaths |
N/A |
Acute dermal toxicity LD50 (mg/kg bw) | Rat |
LD50 >5050 1 death |
N/A |
Acute inhalation toxicity | Estimated | Low | N/A |
Skin irritation | Rabbit | Non-irritant | N/A |
Eye irritation | Rabbit | Non-irritant | N/A |
Skin and respiratory sensitisation | Estimated | Non-sensitising | N/A |
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
In a pulmonary toxicity/pathogenicity and infectivity study, no mortalities were observed in rats following intra-tracheal injection at dose of 9.1 x 108 CFU of Streptomyces lydicus strain WYEC 108 per animal. No treatment-related signs of toxicity were observed. The microbial pest control agent (MPCA) was detected in the kidney, liver, mesenteric lymph nodes and in the lungs of treatment test animals up to Day 21, but had cleared by Day 28 or earlier. Streptomyces lydicus WYEC 108 was not considered to be toxic/pathogenic when administered via intra-tracheal injection to rats at 9.1 x108 CFU/animal.
In an intravenous injection infectivity study, no mortalities or significant signs of toxicity were observed in rats following injection with Streptomyces lydicus WYEC 108 at 9.33 x 108 CFU per animal. Streptomyces lydicus WYEC 108 was detected in the blood, brain, kidney, mesenteric lymph nodes, lungs, liver and spleen up to Day 21, but cleared from all test animals by Day 28 or earlier. Streptomyces lydicus WYEC 108 was not considered to be toxic/pathogenic when administered via intravenous injection to rats at 9.33 x 108 CFU/animal.
Acute inhalation toxicity on Streptomyces lydicus WYEC 108 was not provided. Extrapolating from the pulmonary toxicity/pathogenicity and infectivity study, the OCS considered that Streptomyces lydicus WYEC 108 was a low acute inhalation toxicant in rats as no treatment-related effects were observed. However, the study was not suitable to establish an acute inhalational LC50.
No information was provided.
At this time, the proposed agricultural use of Streptomyces lydicus WYEC 108 is not expected to result in general public exposure. Spray drift considerations have not been considered.
Products similar to, and containing Streptomyces lydicus WYEC 108 at the same concentration as Actinovate BioFungicide, are available in the USA, Canada and New Zealand.
Streptomyces lydicus strain WYEC 108 is not specifically scheduled. Dihydrostreptomycin and streptomycin are both listed in Schedule 4 of the Poisons Standard.
Streptomyces lydicus strain WYEC 108 has not been previously considered for scheduling; therefore, scheduling history is not available.
No public submissions were received.
In response to the Delegate's request, the Committee have advised that there is insufficient evidence of skin and respiratory sensitisation potential to warrant inclusion of the substance in Schedule 6, and advocated for the substance to be included in Appendix B.
The committee recommended the following amendments to the Poisons Standard:
Appendix B, Part 3 - New entry
STREPTOMYCES LYDICUS WYEC 108
Part 1 - Reasons for Entry - a) low toxicity
Part 2 - Area of Use - 1.3 - Fungicide
The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: a) low risk of adverse effects compatible with Appendix B; b) to be used in the agricultural setting, as a fungicide and soil supplement; c) Low toxicity and infectivity potential; d) Product to be used in agricultural and industrial setting.
The delegate considered the following in regards to this proposal:
The delegate notes, and accepts, ACCS advice that this biofungicidal preparation, containing the bacterium Streptomyces lydicus strain WYEC 108, does not satisfy any of the SPF criteria for listing in the schedules and should be listed in Appendix B. It is noted that the evidence for potential skin sensitisation and irritancy was considered by the ACCS to be insufficient to warrant scheduling, and that no other toxicity, infectivity or pathogenicity was apparent from the studies presented.
The proposed implementation date is 1 October 2016. Since listing in Appendix B is not equivalent to a decision to list a substance in a schedule, an implementation date is not strictly relevant. However, early advice to the APVMA of this decision will facilitate prompt registration of products under consideration by the APVMA. Accordingly, amendment of Appendix B at the earliest revision of the Poisons Standard is recommended.
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.
Appendix B, Part 3 - New entry
STREPTOMYCES LYDICUS WYEC 108
Part 1 - Reasons for Entry - a) low toxicity
Part 2 - Area of Use - 1.3 - Fungicide
Scheduling medicines and poisons
In December 2015, the Office of Chemical Safety (OCS) has referred the following scheduling proposal to be considered by the delegate:
The reasons for the request are:
The Delegate's reasons for referring this substance to the Committee were: to seek advice on whether it supports the OCS recommendation to list isopyrazam in Schedule 6, with no exemption cut-off for the proposed product.
The Delegate has sought advice from the Committee on the following questions:
Isopyrazam is a new carboxamide broad-spectrum foliar fungicide with an inhibitory mode of action on the enzyme succinate dehydrogenase (complex II) within the fungal mitochondrial respiration chain. The proposed product is intended for the control of black spot (Venturia inaequalis) and powdery mildew (Podosphaera leucotricha) in apples, and for control of black spot (Venturia pirina) in pears. Isopyrazam contains two diastereoisomers, designated syn and anti-isomers. Both of the isomers are biologically active.
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The European Food Safety Authority has also published a report on the risk assessment for isopyrazam (pdf,522kb) .
Figure 11. Structure of Isopyrazam
The majority of metabolism and toxicology studies submitted were performed with Syn:Anti material with a ratio of around 93:7, but there were also a number of studies performed with material with an isomeric ratio of around 70:30 and a number of comparative studies where the test materials ranged from 100% Syn through to 100% Anti-isomer to help determine if the isomeric ratio had an influence on the mammalian toxicity of the test material.
The acute toxicity end-points for isopyrazam are listed in the following table.
Toxicity | Species | Result | SPF* Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | 550 > LD50 ≤ 2000 | Schedule 6 |
Acute dermal toxicity LD50 (mg/kg bw) | Rat | LD50 > 5000 | Appendix B |
Acute inhalational toxicity LC50 (mg/m3/4h) | Rat | LD50 > 5000 | Appendix B |
Skin irritation | Rabbit | Non irritant | Appendix B |
Eye irritation | Rabbit | Slight irritant | Schedule 5 |
Skin sensitisation (LLNA) | Mouse | Sensitiser | Schedule 6 |
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
The acute toxicity end-points for Seguris Flexi (containing 12.5% isopyrazam) are listed in the table below.
Toxicity | Species | Result | SPF* Classification |
---|---|---|---|
Acute oral toxicity LD50 (mg/kg bw) | Rat | 1750 | Schedule 6 |
Acute dermal toxicity LD50 (mg/kg bw) | Rat | LD50 > 5000 | Appendix B |
Acute inhalational toxicity LC50 (mg/m3/4h) | Rat | LD50 > 2710 (no deaths) | Appendix B |
Skin irritation | Rabbit | Moderate irritant | Schedule 5 |
Eye irritation | Rabbit | Severe irritant | Schedule 6 |
Skin sensitisation (LLNA) | Mouse | Non-sensitiser | Appendix B |
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
Isopyrazam active constituent was found to be of low acute oral toxicity (550 < LD50 < 2000 mg/kg bw), low acute dermal toxicity (LD50 > 5000 mg/kg bw) and low acute inhalational toxicity (LC50 > 5280 mg/m3/4h).
Isopyrazam was found to be a slight irritant to the eye, and non-irritating to skin in rat studies.
Isopyrazam was found to be a sensitiser in local lymph node assay in mice.
The systemic toxicity of isopyrazam in oral studies consisted primarily of decreased bodyweight and bodyweight gain, liver toxicity such as increased liver weight, hepatocellular hypertrophy with associated changes in clinical chemistry. The LOEL or NOEL established in chronic studies for the different species were: rats (LOEL = 5.5/6.9 mg/kg bw/d, M/F, 104-week), mice (NOEL = 7.8/9.9 mg/kg bw/d, M/F, 80-week study) and dogs (NOEL = 25 mg/kg bw/d, 52-week study).
Isopyrazam was neither mutagenic nor genotoxic in an array of studies including Ames test, cytogenetic assay, chromosomal aberration test and mouse lymphoma mutation assay in vitro, and UDS assay and micronucleus test in vivo. 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 isopyrazam concentrations up to 3500 ppm (432.6/553.6 mg/kg bw/d, M/F). Isopyrazam is considered to be carcinogenic in rats at a dose of 3000 ppm (173.5/232.8 mg/kg bw/d, M/F), based on the treatment related increase in uterine adenocarcinomas, thyroid follicular cell adenomas in males and hepatocellular adenomas in females (Milburn GM, 2008). The NOEL for carcinogenicity was 500 ppm (27.6/34.9 mg/kg bw/d, M/F) in this study.
Multiple mechanisms of action (MOA) studies were submitted by the applicant postulating mechanism by which isopyrazam induced liver tumours. The available data was analysed using IPCS framework and it was established that isopyrazam-induced rat liver tumours occurs via a MOA that is similar to phenobarbital which is known to be non-genotoxic, a CAR (constitutive androstane receptor) activator, inducer of liver CYP2B isoforms and induce hepatocellular tumours in rodents but is not a human carcinogen.
The key factors in the weight of evidence evaluation for the carcinogenicity of isopyrazam are: (a) there were no carcinogenic findings in mice in a study where the top dose produced a highly significant decrease in body weight gain (up to 40% in males and up to 20% in females); (b) treatment-related increases in tumour incidence (liver and uterus) were only observed in one sex, one species and confined to a significantly toxic dose level i.e. greater than the MTD (defined as a greater than 10% reduction in body weight gain); (c) isopyrazam was shown not to be oestrogenic in the rat thus excluding the most obvious potential mode of action for uterine tumours; and (d) clear NOELs have been established for liver and uterine tumours indicating that these are a high-dose threshold-based phenomenon.
Isopyrazam was not a reproductive or developmental toxicant. The NOEL for reproductive or fertility parameters was 3000 ppm (217.4 mg/kg bw/d) in a two generation rat study.
No neurotoxic effects were observed in the acute (single dose) and sub-chronic (90-days) studies in rats. No immunotoxicity findings were observed up to a dose of 5000 ppm (127 mg/kg bw/d) in a 28-day dietary Crl:CD1 female mouse study.
No information was provided.
No information was provided.
Isopyrazam is conditionally approved in the European Union. The United States Environmental Protection Agency (US EPA) has established tolerances for residues of isopyrazam in or on apples and peanuts for which there are no accompanying United States registrations. Isopyrazam is a fungicide not currently registered for use in Canada, however a maximum residue limit (MRL) has been proposed by the Health Canada’s Pest Management Regulatory Agency (PMRA) for isopyrazam on bananas to permit the import and sale of foods containing such residues.
Isopyrazam is not specifically scheduled.
Isopyrazam has not been previously considered for scheduling; therefore, scheduling history is not available.
No public submissions were received.
In response to the Delegate’s request, the Committee has advised the substance meets Schedule 6 criteria, on the basis of acute oral toxicity and potential developmental toxicity being consistent with Schedule 6 factors.
In relation to different isomer mixtures used in testing, the Committee advised that the isomer ratio has an impact on the acute toxicity of isopyrazam but appears to have little influence on repeat-dose effects. The available studies were considered adequate to characterise the toxicity potential of the substance.
In relation to the mode of action for the carcinogenic effects in rats, the Committee advised that the proposed mode of action had not been conclusively demonstrated. However, isopyrazam was not an in vivo genotoxicant, and NOELs were identified for tumour findings which were only seen at the top dose levels which exceeded the maximum tolerated dose. The Committee noted the observed tumours in rats were associated with high doses and are not a relevant consideration for scheduling.
The committee advised that a new Schedule 6 entry be created for Isopyrazam as follows:
Schedule 6 - New entry
ISOPYRAZAM
The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: c) Acute oral toxicity and concern for potential developmental toxicity.
The delegate considered the following in regards to this proposal:
The delegate notes, and accepts, ACCS advice that a new entry for isopyrazam be created in Schedule 6. The delegate notes that this advice is primarily based on the acute toxicity profile, including potential skin sensitisation, being consistent with SPF scheduling criteria for listing in Schedule 6. Also noted are some concerns about the developmental eye defects (microphthalmia) seen in some rabbit studies, although not consistently found in other studies.
The proposed implementation date is 1 October 2016. An early implementation for this scheduling proposal will facilitate registration of the product by the APVMA.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (c) the toxicity of a substance.
Schedule 6 - New entry
ISOPYRAZAM
Scheduling medicines and poisons
The reasons for the request are:
The reasons the Delegate has referred this substance to the Committee were: The key issue to be considered in relation to this re-scheduling application is whether the proposed Schedule 6 concentration cut-off in a product matrix is protective against the demonstrated sensitizing potential for this isothiazolinone biocide. In support of the re-scheduling application, the applicant has provided additional sensitisation studies for the substance in water-based paints, and proposes a slight alteration to the wording to specify that the exemption be limited to water-based acrylic or silicone paints. The issue of whether the biocidal use pattern falls within the general exemption for biocides in Appendix A was not resolved in the delegate's original decision, and remains unresolved in the current submission.
The Delegate has sought advice on the following questions:
Figure 12: Structure of 4,5-Dichloro-2-N-octyl-3(2H)-isothiazolone.
The relevant sensitisation data for 4,5-Dichloro-2-N-octyl-3(2H)-isothiazolone are listed in the table below:
Study | Vehicle | 4,5-Dichloro-2-N-octyl-3(2H)-isothiazolone Concentration ppm (%) |
Outcome | Test type |
---|---|---|---|---|
O'Hara and Anderson 2002a Reference 3 |
Paint | 300 (0.03) | Sensitiser |
Buehler (Guinea Pigs) |
500 (0.05) | Sensitiser | |||
800 (0.08) | Sensitiser | |||
O'Hara and Anderson 2002b Reference 4 |
Paint | 1150 (.12) | Sensitiser |
Buehler (Guinea Pigs) |
Sanders 2007 Reference 5 |
Paint | 300 (0.03) | Non sensitiser | LLNA (mouse) |
600 (0.06) | Non sensitiser | |||
900 (0.09) | Non sensitiser | |||
1120 (0.11) | Sensitiser | |||
Acetone | 300 (0.03) | Sensitiser | ||
600 (0.06) | Sensitiser | |||
900 (0.09) | Sensitiser | |||
1120 (0.11) | Sensitiser | |||
McMillan 2002 Reference 7 |
Paint | 95 (0.0095) | Non sensitiser | LLNA (mouse) |
478 (0.048) | Non sensitiser | |||
718 (0.072) | Non sensitiser | |||
947 (0.095) | Non sensitiser | |||
1094 (0.11) | Non sensitiser | |||
Acetone | 95 (0.0095) | Sensitiser | ||
478 (0.048) | Sensitiser | |||
718 (0.072) | Sensitiser | |||
947 (0.095) | Sensitiser | |||
1094 (0.11) | Sensitiser | |||
Sanders 2009 Reference 8 |
Paint | 600 (0.06) | Non sensitiser | LLNA (mouse) |
900 (0.09) | Non sensitiser | |||
1200 (0.12) | Sensitiser | |||
Acetone/olive oil (4:1) | 1200 (0.12) | Sensitiser | ||
Acetone | 1200 (0.12) | Sensitiser | ||
Hall 2012 Reference 9 |
Water based paint | 1200 (0.12) | Non sensitiser |
Buehler (Guinea Pigs) |
Silicone based paint | 1200 (0.12) | Non sensitiser | ||
Acetone | 800 (0.08) | Sensitiser |
No information was provided.
No information was provided.
As discussed in the previous OCS advice to the delegate, the European Commission (EC) assessment report for 4,5-Dichloro-2-N-octyl-3(2H)-isothiazolone as a biocide ingredient in wood preservatives found the chemical to be a skin sensitiser at 0.01% (100 ppm; 4.4 g a.i./cm2) based on the study considered in March 2015, and recommended that a lower specific concentration limit (lower than the default cut off for skin sensitisers of 1%) should be considered even for classification, labelling and packaging (CLP) for this chemical based on the Guidance to Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures (ECHA, 2009). A classification as an extreme sensitizer with a specific concentration of 0.001% was recommended.
The classification, labelling and packaging (CLP) for the chemical based on the Guidance to Regulation (EC) No 1272/2008 applies for occupational use when risk management control measures are expected to be in place at work sites. The extension to use of the products containing the chemical by non-professional painters and possibly the general public would warrant more stringent measures.
4,5-dichloro-2-N-octyl-3(2H)-isothiazolone is currently listed in Schedule 6.
In February 1995, the NDPSC, considered toxicological data for 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone. No metabolic, sub-chronic or chronic animal data was provided. In a 28-day repeat dose study, gastrointestinal irritation was the major toxic effect. Developmental and genotoxicity studies did not show evidence of teratogenicity or genotoxicity. The committee considered that based on its skin and eye corrosion and skin sensitisation potential, it was appropriate to include 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone in Schedule 6.
In June 2008, the NDPSC noted that the toxicology data provided in support of past considerations were very old and that no new data were submitted with the current submission and agreed to defer consideration in order to seek further advice regarding these studies. They agreed however that it was appropriate to proceed with consideration of the applicant's request and decided to broaden the current Schedule 6 exemption of ≤1% in paint by also including ≤1% in jointing compounds and sealants.
In July 2014, the delegate received the following application to be considered for rescheduling:
The applicant's reasons for the request were:
In June 2015 the interim decision of the Delegate was published noting that the current Schedule 6 entry was appropriate. In response to the Delegate's interim decision, the applicant provided additional toxicology studies to be considered by the Delegate and/or the committee and a revised proposal for the chemical, limiting the exception to water based/acrylic/silicone paints, jointing compounds and sealants containing 0.1% or less of the chemical.
One public submission was received. The submission supports the proposed amendments and notes skin contact for paints is incidental during use, and do not remain on the skin thus sensitization risks are minimal.
The public submission is available at: Public submissions on scheduling matters.
In response to the Delegate's request, the committee has advised there is insufficient evidence to support the proposed cut off for exemption. New animal studies indicate that skin sensitisation can occur at levels either around or below the cut off proposed by the applicant. Skin exposure during the use of the paint is highly likely in the domestic setting with a significant risk of skin sensitisation necessitating label warnings and the substance retention in Schedule 6.
On the weight that should be given to the applicant’s contention that the substance is substantially retained in the paint matrix and is therefore not available for absorption into the skin, the Committee advised this was most relevant for applied and dried paint. However, it was noted studies provided indicate up to 20% of the substance was available for absorption and, given the very low concentrations that elicited a response in the animal tests, the reduced absorption does not eliminate the risk of skin sensitisation.
On the Delegate’s question about LLNA and Buehler tests, the Committee advised that positive test results from one method should not automatically be dismissed in favour of negative findings using the other method. The Committee noted no testing results were provided for product types other than paint, such as jointing compounds and sealants.
The committee advised that the current Schedule 6 entry for 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone remains appropriate.
The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: b) Incidental dermal exposure is likely with inclusion of the substance as a biocide in paints, jointing compounds and sealants, particularly when these products are used by the general public.; c) Animal studies suggest skin sensitisation is possible at very low concentrations and therefore the substance, at all concentrations, continues to meet the criteria for Schedule 6.
The delegate considered the following in regards to this proposal:
The delegate notes the advice from the ACCS based on evaluation of additional information submitted by the applicant since this matter was considered at the March 2015 ACCS meeting. The delegate agrees that the new studies suggest a reduction in sensitisation potential when 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone is incorporated in a paint matrix, but that they do not resolve the question of where an appropriate exemption cut-off could be applied to such products. Findings that sensitisation reactions have been demonstrated at and below the proposed cut-off concentrations support the ACCS advice that current scheduling remains appropriate, and that the sensitisation warning statements and POISON signal heading on such products provide appropriate advice to product users.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.
Scheduling medicines and poisons
On 30 November 2015 the chemicals Delegate identified possible ambiguity in the current SUSMP entries for the chemical. The proposal is to amend the Schedule 6 entry to remove the exception clause "except in preparations intended to be in contact with the skin, including cosmetic use".
The reasons the Delegate has referred this substance to the Committee were to seek advice on appropriate amendments to remove ambiguity in the current Schedule 6 and 10 entries for MDBG.
In previous versions of the SUSMP, listing in Appendix C was used to designate specific uses of substances that should be prohibited. The previous heading of Appendix C was:
SUBSTANCES, OTHER THAN THOSE INCLUDED IN SCHEDULE 9, OF SUCH DANGER TO HEALTH AS TO WARRANT PROHIBITION OF SALE, SUPPLY AND USE.
In some cases, this message was directed to the relevant regulatory agency (e.g. TGA for therapeutic uses), while it is understood that some State/Territory jurisdictions automatically applied controls analogous to those of Schedule 7 to control those uses of substance listed in Appendix C.
Previous versions of the Poisons Standard (SUSMP4 and 5, 2013-2014) used a 'dagger' to designate substances in Schedules 4, 5 and 6 that were also listed in Appendix C, with a page header that drew attention to those listings ('Substances marked † are listed in Appendix C'). When Appendix C was transitioned to Schedule 10 in SUSMP6 (2015), the 'dagger' designation was discontinued. Instead, exception clauses were added to Schedule 10 listings for substances where the primary listing was in Schedules 4, 5 or 6. The addition of these exception clauses was designed to follow the 'cascading principle' where listing of a substance in the most restrictive schedule is used as the primary listing, with cross-references to listings in other less restrictive schedules designated by exception clauses.
The delegate is concerned that the cascading principle may be inappropriate for substances listed in Schedule 10, that was intended to apply quite selective controls, and that the use of exception clauses in Schedule 10 could introduce ambiguities.
The Delegate has sought advice on the following questions:
Please refer to the NICNAS Chemical assessment report for methyldibromo glutaronitrile (pdf,293kb) which is available from the NICNAS website.
Figure 13. Structure of methyldibromo glutaronitrile
Methyldibromo Glutaronitrile is currently listed in Schedules 6 and 10 and Appendix F.
Schedule 6
METHYLDIBROMO GLUTARONITRILE except in preparations intended to be in contact with the skin, including cosmetic use.
Schedule 10
METHYLDIBROMO GLUTARONITRILE in preparations intended to be in contact with the skin, including cosmetic use except when in Schedule 6.
Appendix F, Part 3
Warning statement 28
Safety directions 1, 4, 7
Methyldibromo glutaronitrile (MDBG) was first considered for scheduling in June 2008. Due to an administrative error the substance was reconsidered at the October 2008 meeting.
The Committee decided: to include MDBG in Appendix C when in preparations intended to be in contact with the skin, including cosmetic use; and in Schedule 6 except when in preparations intended to be in contact with the skin, including cosmetic use. Appendix F warning statement 28 and Safety directions 1, 4 and 7 were also agreed.
The current wording of the Schedule 10/Appendix C entry was published in the first version of the Standard in 2015 <https://www.legislation.gov.au/Details/F2015L00128>.
Two public submissions were received. The first submission did not support the proposed amendments. They noted that MDBG is entered in the ARTG ingredient list and is allowed in therapeutic goods as an excipient in OTC medicines. They requested that the ACCS considers exemptions (from either Schedule 6 or Schedule 10, as appropriate) for the use of the substance as an excipient in therapeutic goods, with a suitable cut-off concentration if appropriate. The second submission supports clarification of the current Schedule entries and included proposed wording for an amended Schedule 6 entry.
The public submissions are available at: Public submissions on scheduling matters.
In response to the Delegate's request, the Committee advised that the current schedule entries for MDBG were ambiguous. They recommended that the entries could be improved by simplifying the cross reference between the entries as follows; for the schedule 6 entry, replacing the exception clause with “except when in Schedule 10”, and for the Schedule 10 entry, referring to the use that is subject to prohibition and deletion of reference to the Schedule 6 entry.
The Committee recommended the following amendments to the Poisons Standard:
Schedule 6 - Amend entry
METHYLDIBROMO GLUTARONITRILE except when in Schedule 10
Schedule 10 – Amend entry
METHYLDIBROMO GLUTARONITRILE in preparations intended to be in contact with the skin, including cosmetic use.
The Committee recommended an early implementation date (1 October 2016).
The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: f) amendments clarify which uses are subject to prohibition in Schedule 10.
The delegate considered the following in regards to this proposal:
The delegate notes, and accepts, ACCS advice to amend the Schedule 6 and 10 entries for methyldibromo glutaronitrile , since they appeared to contain mutually exclusive exemption clauses. The purpose of the Schedule 10 entries was to prevent the availability of products that would be directly applied to human skin. Retaining the existing Schedule 6 entry would be consistent with SPF criteria for such a listing and would ensure that labelling and supply restrictions for other types of products are retained.
The delegate notes the industry submission that seeks an exemption from the entries where the substance may be used in therapeutic goods. The chemicals scheduling delegate has therefore referred the matter to the medicines scheduling delegate for further consideration.
The proposed implementation date is 1 October 2016. This is a clarification of existing schedule entries, so it should be implemented in the earliest revision of the Poisons Standard.
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.
Schedule 6 - Amend entry
METHYLDIBROMO GLUTARONITRILE except when in Schedule 10
Schedule 10 – Amend entry
METHYLDIBROMO GLUTARONITRILE in preparations intended to be in contact with the skin, including cosmetic use
Scheduling medicines and poisons
On 30 November 2015 the Chemicals Scheduling Delegate identified ambiguity in the current entries for sodium and potassium hydroxide in relation to the use in food additive preparations. The proposal is to delete the exception clause c) in the Schedule 6 entries for potassium hydroxide and sodium hydroxide.
The reason for the request is:
In previous versions of the SUSMP, listing in Appendix C was used to designate specific uses of substances that should be prohibited. The previous heading of Appendix C was:
SUBSTANCES, OTHER THAN THOSE INCLUDED IN SCHEDULE 9, OF SUCH DANGER TO HEALTH AS TO WARRANT PROHIBITION OF SALE, SUPPLY AND USE.
In some cases, this message was directed to the relevant regulatory agency (e.g. TGA for therapeutic uses), while it is understood that some State/Territory jurisdictions automatically applied controls analogous to those of Schedule 7 to control those uses of substance listed in Appendix C.
Previous versions of the Poisons Standard (SUSMP4 and 5, 2013-2014) used a 'dagger' to designate substances in Schedules 4, 5 and 6 that were also listed in Appendix C, with a page header that drew attention to those listings ('Substances marked † are listed in Appendix C'). When Appendix C was transitioned to Schedule 10 in SUSMP6 (2015), the 'dagger' designation was discontinued. Instead, exception clauses were added to Schedule 10 listings for substances where the primary listing was in Schedules 4, 5 or 6. The addition of these exception clauses was designed to follow the 'cascading principle' where listing of a substance in the most restrictive schedule is used as the primary listing, with cross-references to listings in other less restrictive schedules designated by exception clauses.
The delegate is concerned that the cascading principle may be inappropriate for substances listed in Schedule 10, that was intended to apply quite selective controls, and that the use of exception clauses in Schedule 10 could introduce ambiguities. The concerns about possible ambiguities are spelled out in the delegate questions.
Please refer to the NICNAS assessment reports for sodium hydroxide and potassium hydroxide available on the NICNAS website.
Sodium hydroxide and potassium hydroxide are currently listed in Schedules 5, 6 and 10 of the SUSMP. They are also included in Appendix E and F.
Schedule 5
POTASSIUM HYDROXIDE (excluding its salts and derivatives) in preparations containing 5 per cent or less of potassium hydroxide being:
SODIUM HYDROXIDE (excluding its salts and derivatives) in preparations containing 5 per cent or less of sodium hydroxide being:
Schedule 6
POTASSIUM HYDROXIDE (excluding its salts and derivatives) except:
SODIUM HYDROXIDE (excluding its salts and derivatives) except:
Schedule 10
POTASSIUM HYDROXIDE (excluding its salts and derivatives), in liquid or semi-solid food additive preparations, for domestic use, the pH of which is more than 11.5.
SODIUM HYDROXIDE (excluding its salts and derivatives), in liquid or semi-solid food additive preparations, for domestic use, the pH of which is more than 11.5.
Potassium and sodium hydroxides were first considered for scheduling at the May 1956 and January 1955 meetings, respectively. They have since been considered a number of times, most recently at the February 2010 meeting. At this meeting the Committee discussed the inherent properties of lye water and its poisoning risk – particularly consequences of accidental ingestion by children. It was noted that the lye water accidental poisoning issue was considered at previous meetings and at that time the Committee had decided that the risks from lye water with a pH of more than 11.5 were adequately addressed through a CRC requirement (along with public education and labelling). Several Members asserted that the information now before the Committee was sufficient to establish that this existing level of control had not been sufficient, noting lye water accidental ingestions and injuries had continued to occur since the mandating of CRCs.
Members generally agreed that, for lye water preparations with a pH of more than 11.5, the extremely alkaline nature, even in small amounts, could cause life threatening caustic injuries. A Member noted, however, that the risk of ingestion was most significant with regard to use in the domestic setting. The Member argued that there appeared to be scope for continuing to allow non-domestic access (such as restaurants or industrial food processing) to high strength lye water products. Another Member noted that there appeared to be alternative preparations available with pH of 11.5 or less which should be sufficient for domestic use. The Committee therefore agreed to restrict the domestic availability of lye water by capturing domestic food additive preparations, with pH of more than 11.5, through specific entries to this effect for alkaline salts, sodium hydroxide and potassium hydroxide in Appendix C.
One public submission was received. That submission supported the proposed amendments to remove ambiguity in those entries. The submission provided suggested wording for the revised entry.
The public submissions are available at: Public submissions on scheduling matters.
In response to the Delegate's request, the Committee have advised that the KOH and NaOH entries are ambiguous, and that amendment to the Schedule 6 entries would provide greater clarity.
The Committee advised that, with the availability of an electronic version of the SUSMP it was now easy for users to do a search of the document to find all relevant entries and inserting a dagger was now unnecessary.
The Committee recommended that the current Schedule 6 entries for potassium hydroxide and sodium hydroxide be amended as follows:
Schedule 6 - Amend entry
POTASSIUM HYDROXIDE (excluding its salts and derivatives) except:
SODIUM HYDROXIDE (excluding its salts and derivatives) except:
The Committee recommended an early implementation date (1 October 2016).
The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: f) Amendment further clarifies existing entries.
The delegate considered the following in regards to this proposal:
The delegate notes, and accepts, ACCS advice to amend the Schedule 6 entries for sodium and potassium hydroxides, since they appeared to contain an exemption clause that contradicts the purpose of the Schedule 10 entry. The purpose of the Schedule 10 entries was to prevent the availability of such strongly alkaline solutions for use as food additives in the domestic market. The proposed cross-reference in the Schedule 6 entries to the entries in both Schedules 5 and 10 should clarify the intent of these controls. The delegate notes that the proposed amendments are supported by the submission from industry.
The proposed implementation date is 1 October 2016. This is a clarification of existing schedule entries, so it should be implemented in the earliest revision of the Poisons Standard.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.
Schedule 6 - Amend entry
POTASSIUM HYDROXIDE (excluding its salts and derivatives) except:
SODIUM HYDROXIDE (excluding its salts and derivatives) except:
Scheduling medicines and poisons
Substance | Interim decision |
---|---|
Symphytum spp. (Comfrey) |
Schedule entrySCHEDULE 10 - Amend entry SYMPHYTUM spp. (Comfrey) in preparations for human or animal use except when in Schedule 5. SCHEDULE 5 - Amend entry SYMPHYTUM spp. (Comfrey) in preparations for dermal therapeutic or dermal cosmetic use. Proposed implementation date: 1 October 2016. |
Scheduling medicines and poisons
The chemicals scheduling delegate has referred the following scheduling proposal for consideration by the Joint sitting of the Advisory Committees on Chemicals and Medicines Scheduling (ACCS-ACMS):
SYMPHYTUM spp. (Comfrey) in preparations for internal use.
Delegate-initiated application. The reasons for the request were:
The delegate asked the committee the following questions:
SYMPHYTUM spp. (Comfrey) is currently listed in Schedules 5 and 10/Appendix C and in Appendix F.
Schedule 10/Appendix C
SYMPHYTUM spp. (Comfrey) for therapeutic or cosmetic use except when included in Schedule 5.
Schedule 5
SYMPHYTUM spp. (Comfrey) for dermal use.
Appendix F
SYMPHYTUM spp. (Comfrey) when included in Schedule 5.
Safety directions: 31, 32
SYMPHYTUM spp. (Comfrey) has been considered by previous scheduling committees on a number of occasions.
It was first considered in May 1978 to be low risk except where consumption of large quantities was involved and was not scheduled.
In November 1983, the committee noted that while human poisonings had not been recorded, comfrey contained a carcinogenic alkaloid shown to produce a cumulative toxic effect. The committee agreed to include comfrey prepared and packed for internal use in humans as a new Schedule 1 entry for comfrey of:
In May 1992, the committee considered submissions in relation to the proposed exemption for topical applications of comfrey due to the low level of pyrrolizidine alkaloids (PAs) in the plants and the low level of dermal absorption. A 1988 review by the Commonwealth Health Department noted that "creams that contain Symphytum officinale extract are not considered to be a significant source of the intake of comfrey in view of the low dermal absorption of the pyrrolizidine alkaloids".
The committee considered that while theoretically an element of risk of liver damage and cancer due to low levels of exposure to PAs in man could not be denied, the likelihood following exposure to small amounts of PAs of the kind present in comfrey was extremely low, even in the case of exposure involving un-braided skin. The committee could not justify the prohibition of the use of the plant in approved external use formulations. The committee examined the list of ointment bases provided by the Traditional Medicines Evaluation Committee and considered that they would not increase the dermal absorption of comfrey to a level which would have toxicological concerns. The substance was included in Schedule 5 with two new Appendix F warnings as follows:
Appendix C
SYMPHYTUM spp. (Comfrey) for therapeutic use except when included in Schedule 5.
Schedule 5
SYMPHYTUM spp. (Comfrey) in ointments and creams for dermal use.
Appendix F, Part 3
Symphytum spp. (Comfrey) when included in Schedule 5.
Safety Directions: 31. Do not use on broken skin. 32. Do not use under occlusive dressing.
In May 1998, the committee considered a submission to allow the sale of comfrey when in dermal preparations such as sprays. It noted the Schedule 5 entry included creams and ointments for dermal use and all other therapeutic preparations were covered by the Appendix C entry.
The 1998 committee noted that at the previous consideration percutaneous absorption of comfrey, with hepatotoxic PAs was a major issue in the consideration of an exemption for comfrey in dermal preparations. It also noted that to achieve therapeutic effects, some absorption would be required and if vehicles such as DMSO were used, enhanced absorption would be expected. The current scheduling did not preclude the use of specific vehicles and that the issue of inappropriate formulations could be an issue to be considered by the TGA at the time of registration. The committee agreed that the restriction for 'creams and ointments' should be deleted from the Schedule 5 entry. The Appendix F warning statements were considered appropriate.
The committee agreed that there was potential for confusion in the interpretation of the entries for use in cosmetics, as the Appendix C entry specifically mentioned therapeutic use, but the Schedule 5 entry did not. The committee agreed that the toxicity associated with topical comfrey in either therapeutic or cosmetic use was the same. The committee agreed the Appendix C entry should clarify that it was its intention that comfrey for cosmetic use should be controlled in the same way as therapeutic preparations.
No change was made to the Appendix F warnings. The current schedule 5 and 10 (then Appendix C) entries were set in May 1998.
Three submissions were received. Two submissions supported the proposal, and one opposed the proposal.
Schedule 10/Appendix C - Amend entry
SYMPHYTUM spp. (Comfrey) in preparations for human or animal use except when in Schedule 5
Schedule 5 – Amend entry
SYMPHYTUM spp. (Comfrey) in preparations for dermal therapeutic or dermal cosmetic use
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 delegates note, and accept, the advice from the joint meeting of the ACCS and ACMS, and agree to amend the current entries for symphytum spp (comfrey) in schedules 5 and 10. The delegates note that previous considerations by the NDPSC, in regard to the scheduling of products containing symphytum spp, had been mainly concerned with limiting human exposures via routes that could result in significant systemic exposures (except via food, which is not regulated by poison scheduling). The intent of the current schedule entries is to use the Schedule 5 entry to allow only certain types of dermal exposures (in therapeutic and cosmetic products applied topically). The proposed amendments aim to clarify that only topically applied therapeutic products and dermally applied cosmetics would be allowed under the Schedule 5 entry. The existing Warning Statement in Appendix F reinforces this message.
The proposed implementation date is 1 October 2016. The proposed edits to existing entries in Schedules 5 and 10 do not constitute an intent to change the current scheduling arrangements; merely to clarify the entries. Accordingly, an early implementation date is appropriate.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance.
Schedule entry
SCHEDULE 10 - Amend entry
SYMPHYTUM spp. (Comfrey) in preparations for human or animal use except when in Schedule 5.
SCHEDULE 5 - Amend entry
SYMPHYTUM spp. (Comfrey) in preparations for dermal therapeutic or dermal cosmetic use.
Scheduling medicines and poisons
Substance | Interim decision |
---|---|
Cannabis | The Delegate's interim decision on Cannabis and Tetrahydrocannabinol has been published separately. |
Codeine | The Delegate's decision relating to scheduling of codeine will be made after June 2016. |
Benzodiazepines |
Schedule 9 - New entriesDICYCLAZEPAM PYRAZOLAM CLONAZOLAM DESCHLOROETIZOLAM FLUBROMAZEPAM NIFOXIPAM MECLONAZEPAM Proposed implementation date: 1 October 2016. |
Ketoprofen | The current scheduling remains appropriate |
Naproxen | The current scheduling remains appropriate |
Paracetamol |
Schedule 2 – Amend entryPARACETAMOL for therapeutic use:
Schedule 4 – Amend entryPARACETAMOL:
Proposed implementation date: 1 October 2016. |
Loratadine |
Schedule 2 – Amend entryLORATADINE in preparations for oral use except in divided preparations for the treatment of seasonal allergic rhinitis in adults and children 12 years of age and over when:
Schedule 4 – Amend entryLORATADINE except:
Proposed implementation date: 1 October 2016. |
Scheduling medicines and poisons
The Delegate's interim decision on Cannabis and Tetrahydrocannabinol has been published separately.
Scheduling medicines and poisons
The Delegate's decision relating to scheduling of codeine will be made after June 2016.
Scheduling medicines and poisons
Delegate-initiated application. The reasons for the request were:
Benzodiazepines are the major group of drugs used as anxiolytics and hypnotics, with some also used for their muscle relaxant and anticonvulsant properties. Benzodiazepines may be helpful in the short-term management of anxiety and sleep disturbances, but they must be used with caution because of the risk of dependence and abuse, even when used at therapeutic doses for short periods. Some commonly used benzodiazepines include diazepam, oxazepam, nitrazepam and temazepam.
The delegate asked the committee; for benzodiazepines not specifically specified in Schedule 8 or Schedule 9 what would be the appropriate scheduling to achieve the ACMS suggested outcome?
A class entry for Benzodiazepine derivatives is currently listed in Schedule 4, except when separately specified in the Schedules. The majority of individually listed benzodiazepines are in Schedule 4.
Benzodiazepines were added to the standard in Schedule 4 as a class entry, ensuring new benzodiazepine derivatives, including those prepared by simple manipulation of drug molecules, would be captured by the existing Schedule entry, in accordance with the nited Nations Convention on Psychotropic Substances 1971 (the Convention).
In May 1986 in response to a request from the Western Australian Health Department, the Committee agreed to include 10 separate benzodiazepine substances in Schedule 4 and amend the benzodiazepine class entry to exclude those that were separately specified.
In February 1987, the individual benzodiazepine substances were listed in Appendix K as drugs required to be labelled with warning statements.
In February 1996, the Committee considered a report of an overdose resulting in death and the New South Wales State Coroner concerns regarding the appropriateness of the current benzodiazepines scheduling. The Committee considered the new information, and concluded that rescheduling of the drugs would not have prevented the overdose, noting that the States and Territories have procedures in place to deal with such matters and that the appropriate prescription and dispensing of Schedule 4 drugs to be the professional responsibility of medical practitioners and pharmacists. The Committee considered that benzodiazepines were appropriately scheduled in Schedule 4 and that strategies other than those available via the scheduling mechanism were more appropriate.
In November of 1997, the benzodiazepine substance flunitrazepam was rescheduled from Schedule 4 to Schedule 8 due to public health concerns. The committee agreed that, while from a scientific standpoint flunitrazepam is no different from other substances in the benzodiazepine class, the health concerns related to the use and accessibility of flunitrazepam lead to its inclusion in Schedule 8.
In August of 1998, a class review of benzodiazepines based on the up-scheduling of flunitrazepam was conducted by the committee. The Committee recognised that benzodiazepines were useful therapeutic products and generally there are no suitable substitutes for their legitimate therapeutic uses. The Committee also noted that rescheduling would impose additional difficulties and costs for manufacturers, pharmacists, patients and the PBS system. A majority of the public submissions received advocated for the retention of benzodiazepines in Schedule 4, resulting in no change to the scheduling. The appropriateness of the scheduling was again reaffirmed in 1999.
Alprazolam was scheduled in November 1981, and was added to Appendix K in November 1987 as it was included in a list of substances of concern by the Australian Federal Police. In October 2007, the Department of Health in Tasmania introduced monthly reporting requirements of Alprazolam due to concerns of misuse. Rescheduling Alprazolam as a Schedule 8 substance was considered in June 2010. However, there was insufficient evidence to support a Schedule 8 restriction for alprazolam, and advised that the Schedule 4 entry remained appropriate.
In November 1971, temazepam is individually specified in Schedule 4, with appendix K entry added in February 1987. At the February and June 2004 meetings, the committee considered a proposal to reschedule temazepam soft gel capsules to Schedule 8 due to illicit drug abuse market. Following the deferral from the February meeting, the sponsor of the product voluntarily withdrew the gelcap products from the ARTG, with temazepam remaining in Schedule 4.
The following benzodiazepines were included in Schedule 4 by individual specification between 1965 and 1998 without an Appendix K entry: Bromazepam, Chlordiazepoxide, Clonazepam, Clorazepate, Clobazam, Diazepam, Flurazepam, Ketazolam, Loprazolam, Lorazepam, Lormetazepam, Medazepam, Midazolam, Nitrazepam, Oxazepam, Prazepam, Quazepam and Triazolam.
In 2013, the Committee considered a proposal to reschedule benzodiazepines from Schedule 4 to Schedule 8. The Committee recommended: (1) that alprazolam be rescheduled from Schedule 4 to Schedule 8; (2) that the scheduling of the remaining benzodiazepines remained appropriate; and (3) that benzodiazepines be included in Appendix D, paragraph 5.
Nil.
The ACMS recommended that the following substances, not previously scheduled, be separately specified in Schedule 9: dicyclazepam, pyrazolam, clonazolam, deschloroetizolam, flubromazepam, nifoxipam and meclonazepam. They also recommended that the current scheduling of benzodiazepine derivative (Class entry) otherwise 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 advice comprised the following:
The delegate considered the following in regards to this proposal:
The delegate has considered and agrees with the advice and reasons of the ACMS.
The proposed implementation date is 1 October 2016.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
Schedule entry
Schedule 9 - New entries
DICYCLAZEPAM
PYRAZOLAM
CLONAZOLAM
DESCHLOROETIZOLAM
FLUBROMAZEPAM
NIFOXIPAM
MECLONAZEPAM
Scheduling medicines and poisons
The applicant's reasons for the request were:
The delegate asked the committee the following questions:
Ketoprofen, a propionic acid derivative, is non-steroidal anti-inflammatory drug (NSAID) and has been marketed for the treatment of rheumatoid arthritis and osteoarthritis in various forms (standard release capsules, sustained release capsules, suppositories and topical gels).
KETOPROFEN is currently listed in Schedules 3 and 4.
Schedule 3
KETOPROFEN in divided preparations for oral use containing 25 mg or less of ketoprofen per dosage unit in a pack containing 30 or less dosage units.
Schedule 4
KETOPROFEN except:
Ketoprofen has been available in Australia since 1981 in orally administered dose forms.
In 1999, the Committee decided to harmonise with New Zealand in regard to oral ketoprofen preparations, and dermal preparations of ketoprofen – creating the Schedule 3 entry for 25 mg or less of ketoprofen per dosage unit in a pack containing 30 or less dosage units.
Two submissions were received. Both submissions opposed the proposal due to increased risks of gastrointestinal and cardiovascular adverse effects compared to other NSAIDs available over the counter (i.e. ibuprofen, diclofenac and naproxen).
The committee advised that the current scheduling of ketoprofen 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; 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:
The delegate has considered and agrees with the advice and reasons of the ACMS, that the current scheduling of ketoprofen remains appropriate.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance.
Scheduling medicines and poisons
The applicant's reasons for the request were:
The delegate asked the committee the following questions:
Naproxen is an arylpropionic acid derivative related to the arylacetic acid class of medicines. It has analgesic, anti-inflammatory and antipyretic properties. It is unrelated to salicylates and the corticosteroid hormones. Naproxen therapeutic indications include treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis; symptomatic treatment of primary dysmenorrhoea and relief of acute and/or chronic pain states in which there is an inflammatory component as well as an analgesic in acute migraine attack.
Naproxen is a non-selective non-steroidal anti-inflammatory drug (NSAID) inhibiting both COX-1 and COX-2 and it exhibits a pharmacologic profile similar to other compounds in the NSAID class, such as ibuprofen. Naproxen has been widely used as a prescription and OTC medicine for many years, and its safety profile has been well-characterised.
NAPROXEN is currently listed in Schedules 2, 3 and 4, and in Appendix F. The delegate in March 2016 decided that from 1 June 2016, naproxen will also be in Schedule H.
Schedule 2
NAPROXEN in divided preparations containing 250 mg or less of naproxen per dosage unit in packs of 30 or less dosage units.
Schedule 3
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.
Schedule 4
NAPROXEN except when included in Schedule 3 or in Schedule 2.
Appendix F
Poison | Warning Statements |
---|---|
Naproxen |
101: Don't use [this product/name of the product]: If you have a stomach ulcer. In the last 3 months of pregnancy. [This statement may be omitted in preparations used exclusively for the treatment of dysmenorrhoea.] f you are allergic to (name of substance) or anti-inflammatory medicines. 104: Unless a doctor has told you to, don't use [this product/name of the product]: For more than a few days at a time. With other medicines containing (name of substance) or other anti-inflammatory medicines. If you have asthma. If you are pregnant. [This statement may be omitted in preparations used exclusively for the treatment of dysmenorrhoea.] |
A detailed history of scheduling of naproxen can be found on the TGA website.
Naproxen was first included in Schedule 4 of the Poisons Standard in June 1982.
In February 1983, the Poisons Scheduling Committee agreed to reschedule naproxen from Schedule 4 to Schedule 3 when supplied in packs of 12 tablets for the treatment of the symptoms of dysmenorrhea.
In August 1989, a new Schedule 2 entry for naproxen was supported by the Scheduling Committee when labelled for the treatment of spasmodic dysmenorrhoea in packs of 12 or less on the grounds that it did not present an apparent public health hazard.
In November 1998, the NDPSC amended the Schedule 2 entry for naproxen to allow preparations containing 250 mg or less per dosage unit in packs of 20 or less dosage units.
In November 1999, the NDPSC rescheduled the Schedule 3 entry to Schedule 2 on the basis that the safety data was similar to that of other NSAIDs already listed in Schedule 2. An Appendix F warning was linked to the Schedule 2 entry.
In August 2001, the committee considered a proposal to exempt naproxen when in 250 mg or less per dosage unit, in packs of 24 or less dosage units, for the short-term analgesic therapy of dysmenorrhoea. The committee decided that the Schedule 2 entry remained appropriate given concerns around lack of evidence regarding safety and the need to access advice and counselling.
In May 2005 warning statements 101 and 104 were included in Appendix F.
In March 2014 (delegate decision July 2014), the ACMS considered a proposal to include naproxen in Schedule 2 in a new 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 advised, and the delegate decided, that those modified release naproxen preparations should be included in Schedule 3. The ACMS also advised that the existing Appendix F warnings for naproxen should apply to the new Schedule 3 dosage form for naproxen. This was implemented on 1 October 2014.
In November 2014, the ACMS rejected a proposal to include naproxen (when in Schedule 3, which covers only modified release naproxen) in Appendix H, citing 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.
In November 2015, the ACMS advised, and the delegate agreed, to include naproxen in Appendix H. The implementation date is 1 June 2016.
Three submissions were received. Of these, one submission supported the proposal. Main points:
The other two submissions opposed the proposal. Main points:
The committee advised that the current scheduling of naproxen 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; 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 has considered and agrees with the advice and reasons of the ACMS, that the current scheduling of naproxen remains appropriate.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
Scheduling medicines and poisons
To amend the Schedule 2 entry of paracetamol to:
OTC Medicines Evaluation (OTCME, Department of Health) application. The reasons for the request were:
The delegate asked the committee the following questions:
Paracetamol, also known as acetaminophen, is an analgesic substance used to treat pain and fever. It is typically used for treatment of mild to moderate pain and is often sold in combination with other ingredients in cold medications.
Products containing paracetamol in combination with ibuprofen are currently included in Schedules 3 or 4.
PARACETAMOL is currently listed in Schedules 2, 3 and 4, and in Appendix F.
SCHEDULE 2
PARACETAMOL for therapeutic use except:
Schedule3
PARACETAMOL when combined with ibuprofen in a primary pack containing 30 dosage units or less.
Schedule 4
PARACETAMOL:
Appendix F
Poison | Warning Statements |
---|---|
Paracetamol | 97: Adults: Keep to the recommended dose. Don't take this medicine for longer than a few days at a time unless advised to by a doctor. and/or |
98: Children and adolescents: Keep to the recommended dose. Do not give this medicine for longer than 48 hours at a time unless advised to by a doctor. | |
99: If an overdose is taken or suspected, ring the Poisons Information Centre (Australia 13 11 26; New Zealand 0800 764 766) or go to a hospital straight away even if you feel well because of the risk of delayed, serious liver damage. | |
100: Do not take with other products containing paracetamol, unless advised to do so by a doctor or pharmacist. |
Four submissions were received all supporting the proposal. The main points were:
The committee advised that the Schedule 2 (and Schedule 4) entry for paracetamol be amended to:
Schedule 2
PARACETAMOL for therapeutic use:
Schedule 4
PARACETAMOL:
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 advice comprised the following:
Other matters considered relevant by ACMS were:
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The delegate considered the following in regards to this proposal:
The delegate has considered and agrees with the advice and reasons of the ACMS, to amend the current schedule 2 and 4 entries for paracetamol.
The proposed implementation date is 1 October 2016.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
Schedule entry
Schedule 2 – Amend entry
PARACETAMOL for therapeutic use:
Schedule 4 – Amend entry
PARACETAMOL:
Scheduling medicines and poisons
General application. The reasons for the request were:
The delegate asked the committee the following question:
Loratadine is a potent, long-acting tricyclic antihistamine with selective peripheral H1-receptor antagonistic activity1-2. Its efficacy as a first line treatment for the symptomatic treatment of allergic rhinitis and allergic skin conditions such as urticaria (hives) has long been established. Once-daily treatment as an effective control for allergic rhinitis has been available in Australia and globally for more than 20 years.
LORATADINE is currently listed in Schedules 2 and 4.
SCHEDULE 2
LORATADINE in preparations for oral use except in divided preparations for the treatment of seasonal allergic rhinitis in adults and children 12 years of age and over when:
SCHEDULE 4
LORATADINE except:
At the May 1992 National Drugs and Poisons Scheduling Committee (NDPSC) meeting, the Committee recommended Loratadine be included in Schedule 4.
In November 1992, the NDPSC declined a proposal to reschedule loratadine from Schedule 4 to Schedule 3, due to concerns about cardiac side effects.
In April 1994, the NDPSC rescheduled loratadine tablets to Schedule 3, and loratadine syrup to Schedule 3 in November 1995.
In May 1997, the NDPSC deferred a down-scheduling application for loratadine from Schedule 3 to Schedule 2, due to an article that was published in the Lancet, raising concerns of cardiovascular safety. In August 1997 meeting, the NDPSC confirmed the current Schedule 3 entry.
In February 1999, the NDPSC considered the rescheduling of loratadine from Schedule 3 to Schedule 2. The NDPSC agreed that loratadine in preparations for oral use should be rescheduled, and that the restriction to ‘only therapeutically active ingredient’ should no longer apply. In November 1999, the NDPSC confirmed the down-scheduling of loratadine to Schedule 2.
After discussions in February 2012, the Schedule 2 and Schedule 4 entries were amended to exempt solid dose oral preparations containing 10 mg or less of loratadine in packs containing no more than 5 dosage units for the treatment of seasonal allergic rhinitis. The exemption for treatment is for adults and children over the age of 12 years.
In July 2013, the ACMS considered a proposal to reschedule loratadine from Schedule 2 to unscheduled in oral preparations containing 10 mg or less in packs containing not more than 5 daily doses for the treatment of seasonal allergic rhinitis in adults and children 6 years of age and over, with a warning label recommending a daily dose not exceeding 10 mg loratadine for adults and children with body weight over 30 kg, or recommended daily dose not exceeding 5 mg loratadine for children with body weight 30 kg and under. The Committee recommended that the current scheduling of loratadine remained appropriate, due to the risk of inappropriate use and delay in correct diagnosis, the lack of data on adverse effects/experiences/poisoning in Australia, no substantial public health benefit in exempting from schedules and a complicated dosage regimen with risk of inappropriate dosing.
Five submissions were received. Three submissions supported the proposal. The main points were:
Two submissions opposed the proposal. The main points were:
The committee advised that the Schedule 2 and Schedule 4 entries for loratadine be amended to increase the unscheduled loratidine dosage from 5 dosage units to 10 dosage units in divided oral preparations when used in adults and children 12 years of age and over for the treatment of seasonal allergic rhinitis. The members noted that the voluntary labelled statement to seek medical advice after 5 days of treatment is inconsistent with a 10 day pack size.
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; 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:
The delegate has considered and agrees with the advice and reasons of the ACMS, to amend the current schedule 2 and 4 entries for loratadine.
The proposed implementation date is 1 October 2016.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance.
Schedule 2 - Amend entry
LORATADINE in preparations for oral use except in divided preparations for the treatment of seasonal allergic rhinitis in adults and children 12 years of age and over when:
Schedule 4 - Amend entry
LORATADINE except: