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Scheduling delegates' interim decisions and invitation for further comment: ACCS/ACMS, November 2017

Scheduling medicines and poisons

5 February 2018

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3.4. Silver Oxide

Referred scheduling proposal

An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to consider silver oxide for scheduling in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) – the Poisons Standard.

Scheduling application

This was a general application. The applicant’s proposed amendments to the Poisons Standard are:

  • Appendix B – New Entry
  • SILVER OXIDE

The applicant's reasons for the request are:

  • Data from (soluble) silver compounds were used to establish a toxicology profile for this silver salt, mainly on silver and silver nitrate which are listed in the Poisons Standard.
  • However, not only is the silver concentration in the proposed product below the Poisons Standard cut-offs for the scheduling of both silver and silver nitrate, but both the presentation/packaging and use pattern restricts hazard.
  • The product's presentation/packaging restricts hazard and the product's use pattern (spa pool sanitiser) restricts hazard.
  • There is no identified public health risk for silver oxide.

The majority of studies used to establish a toxicological profile for silver oxide (soluble silver) were conducted with silver nitrate that is included on the APVMA list of actives not requiring evaluation. Therefore, it is recommended that consideration is given to include silver oxide on this list.

Current scheduling status

SILVER OXIDE is not specifically scheduled.

Related silver scheduling:

  • Schedule 6
  • SILVER NITRATE except:
  1. when included in or expressly excluded from Schedule 2; or
  2. in preparations containing 1 per cent or less of silver.
  • Schedule 2
  • SILVER for therapeutic use except:
    1. in solutions for human oral use containing 0.3 per cent or less of silver when compliant with the requirements of the Required Advisory Statements for Medicine Labels; or
    2. in other preparations containing 1 per cent or less of silver.
  • Appendix E, Part 2
  • Silver salts: A, E2.
  • Silver oxide is not currently scheduled and has not been previously considered for scheduling. Therefore a scheduling history is not available.

    Australian regulatory information

    Silver oxide is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017.

    Silver oxide is not an excipient or active ingredient in any medicines on the ARTG.

    International regulations
    European Union

    Silver substances currently approved for use in Europe include silver oxide, silver chloride, metallic silver, silver citrate and silver nitrate. Functions of these silver containing substances vary from deodorising and antimicrobial to preserving and skin conditioning.

    Silver oxide is the silver source in cosmetic grade Nolla™ in Europe. Other silver substances such as metallic silver and silver chloride can be used when regulations allow it outside Europe. All approved cosmetic ingredients in Europe can be found on the database maintained by the European Commission.

    ECHA
    • Disilver oxide. IUPAC name: silver oxide.
    • EC/List no.: 243-957-1.
    • Trade names: G-58 C and OleMax types.
    • Hazard classification and labelling: Danger! According to the classification provided by companies to ECHA in REACH registrations this substance is very toxic to aquatic life, with long lasting effects, may cause fire or explosion (strong oxidiser) and causes serious eye damage.
    • This substance is manufactured and/or imported in the European Economic Area in 100 - 1 000 tonnes per year. This substance is used in articles by professional workers (widespread uses), in formulation or re-packing, at industrial sites and in manufacturing.
    • Consumer Uses: ECHA has no publicly registered data indicating in which chemical products the substance might be used. ECHA has no publicly registered data on the routes by which this substance is most likely to be released to the environment.
    • Article service life: Release to the environment of this substance is likely to occur from industrial use: in the production of articles. Other releases to the environment of this substance is likely to occur from: outdoor use in long-life materials with low release rate (e.g. metal, wooden and plastic construction and building materials) and indoor use in long-life materials with low release rate (e.g. flooring, furniture, toys, construction materials, curtains, foot-wear, leather products, paper and cardboard products, electronic equipment). This substance can be found in complex articles, with no release intended: machinery, mechanical appliances and electrical/electronic products (e.g. computers, cameras, lamps, refrigerators, washing machines), electrical batteries and accumulators and vehicles. This substance can be found in products with material based on: metal (e.g. cutlery, pots, toys, jewellery).
    • Widespread uses by professional workers: ECHA has no public registered data indicating whether or in which chemical products the substance might be used. ECHA has no public registered data on the types of manufacture using this substance. Release to the environment of this substance is likely to occur from industrial use: in the production of articles.
    • Formulation or re-packing: ECHA has no publicly registered data indicating whether or in which chemical products the substance might be used. Release to the environment of this substance is likely to occur from industrial use: formulation of mixtures.
    • Uses at industrial sites: This substance is used in the following products: biocides (e.g. disinfectants, pest control products), laboratory chemicals, water treatment chemicals and pH regulators and water treatment products. This substance is used for the manufacture of: chemicals, fabricated metal products and electrical, electronic and optical equipment. Release to the environment of this substance is likely to occur from industrial use: in the production of articles.
    • Manufacture: Release to the environment of this substance is likely to occur from industrial use: manufacturing of the substance.
    United States of America (USA)

    Code of Federal Regulations, Sec. 310.548 Drug products containing colloidal silver ingredients or silver salts offered over the counter (OTC) for the treatment and/or prevention of disease.

    Colloidal silver ingredients and silver salts have been marketed in OTC drug products for the treatment and prevention of numerous disease conditions. There are serious and complicating aspects to many of the diseases these silver ingredients purport to treat or prevent. Further, there is a lack of adequate data to establish general recognition of the safety and effectiveness of colloidal silver ingredients or silver salts for OTC use in the treatment or prevention of any disease. These ingredients and salts include, but are not limited to, silver proteins, mild silver protein, strong silver protein, silver, silver ion, silver chloride, silver cyanide, silver iodide, silver oxide, and silver phosphate.

    Canada

    Natural health products ingredients database – homeopathic substance:

    List of the natural health products ingredients database – homeopathic substance.
    Ingredient Proper Name(s) Common Name(s)
    EHP_Argentum oxydatum
    (Homeopathic Substance)
    • Argentum oxydatum
    • Oxyde d'argent
    • Silver oxide
    • Argentum oxydatum
    • Oxyde d'argent
    • Silver oxide
    New Zealand
    • Silver oxide approval number: HSR001346.
    • Synonyms: disilver oxide.
    Substance summary
    Table 3.4.1: Chemical information for Silver oxide
    Property Silver oxide
    CAS name Silver oxide
    CAS number 20667-12-3
    Chemical structure chemical structure of
    Molecular formula Ag2O
    Molecular weight 231.7 g/mol
    IUPAC and/or common and/or other names

    Silver monoxide; Argentous oxide; Silver rust

    InChI: 1S/2Ag.O

    IUPAC: Silver (I) oxide

    The following information was extracted from the AVPMA human health risk assessment (HHRA) technical report for the toxicology of silver oxide.

    Table 3.4.2: Acute toxicity end-points for silver oxide
    Toxicity Species [Silver oxide] SPF (2015) Classification
    Acute oral toxicity LD50 (mg/kg bw)

    Rat

    Mouse

    280 (for ionic silver)

    32 (ionic silver)
    Schedule 6
    Acute dermal toxicity LD50 (mg/kg bw) - No data -
    Acute inhalational toxicity LC50 (mg/m3/4h) - No data -
    Respiratory irritation - Respiratory irritant (>20%) -
    Skin irritation - No data -
    Eye irritation - No data -
    Skin sensitisation (Buehler) Guinea pig Non-sensitiser N/A
    N/A

    Since no studies were available for silver oxide (the salt source of soluble silver), the toxicological profile for silver oxide was determined using data on soluble silver compounds from published reviews. Many of the studies reported in these reviews were conducted prior to the principles of GLP being established by the OECD in 1978. However, as a toxicological profile was established for registration of the product and not approval of the active constituent, the data that also included information on human exposure to silver compounds were considered to be sufficient for risk assessment purposes.

    The majority of studies used to establish a toxicological profile for silver oxide (soluble silver) were conducted with silver nitrate that is included on the APVMA list of actives not requiring evaluation. Therefore, the APVMA recommends that consideration is given to include silver oxide on this list.

    Silver oxide is formed in the manufacturing process for the product the proposed product. Silver oxide is present in the proposed product at 1% of which 0.93% is silver. The proposed product is a spa pool product intended for domestic use, whose sanitising effects are due to the gradual release of silver from the silver oxide over time. The product's formulation type, presentation and packaging means that direct user exposure to the product would not be considered to occur under normal conditions of use (i.e. presentation/packaging restricts hazard).

    The qualitative determination of exposure and risk undertaken indicates that the acute and repeated risks from swimming in the proposed product treated spa pools are considered to be low to negligible and therefore acceptable (i.e. use pattern restricts hazard).

    Silver and silver nitrate that established the toxicology profile are both currently scheduled in the Poisons Standard.

    Acute toxicity

    For soluble silver, the oral and dermal absorption in humans was 21% and <1% respectively, and it was of moderate acute oral toxicity in the rat (LD50 280 mg/kg bw). No acute dermal or inhalation studies were available. Skin and ocular "burns" have been reported with occupational exposure to silver nitrate, though such findings are likely due to the corrosive effect of nitrate rather than by silver itself. The most frequent abnormal ocular finding in workers was argyrosis which was also observed in rats. Silver was not considered a skin sensitiser. Human and animal data indicate it was a respiratory irritant. The limited systemic findings in rats do not warrant scheduling.

    The product the proposed product was estimated to have low acute oral, dermal and inhalation toxicity, moderate skin irritation, severe eye irritation, and neither a skin sensitiser or respiratory irritant. The estimated skin and eye irritant potential were attributed to product constituents other than silver oxide.

    Mutagenicity; reproduction and developmental toxicity

    In vitro, silver was not mutagenic in bacteria but was clastogenic in mammalian cells causing chromosome aberrations and DNA strand breaks. No in vivo studies were available. There is no historical evidence of silver having a carcinogenic potential. It was concluded that silver is unlikely to pose a carcinogenic risk to humans. The findings in the one generation study were not considered to provide robust evidence that silver is a reproductive toxicant. Silver was not teratogenic, neurotoxic or immunotoxic in rats.

    Observation in humans

    The only data reported on silver oxide in the published reviews were for occupational exposure, with co-exposure to silver nitrate also reported to occur. In humans, the main reported effect after long-term inhalation or ingestion to high doses of silver was the development of argyria and/or argyrosis, with the evidence suggesting the pigmentation does not interfere with the normal functioning of organs. Respiratory irritation and argyrosis were reported to occur, along with abdominal pain in one study. However, the limited reporting detail for these studies meant they were not reliable for risk assessment purposes.

    Pre-meeting public submissions

    One (1) submission was received for silver oxide that supported the proposal. The main point was:

    • Silver oxide is used as a biocide in spa and tool sanitiser products. An entry in Appendix B would be a straightforward way to ensure that there are no unintended effects on the regulatory status of other silver compounds and/or derivatives which may be used in other sectors.

    The public submission will be made available on the TGA website.

    Summary of ACCS advice to the delegate

    The committee recommended that silver oxide does not require scheduling and should therefore be included in Appendix B, as follows:

    Appendix B – New Entry

    SILVER OXIDE

    Reasons for Entry: b (Use pattern restricts hazard)
    Areas of Use: 7.14 (Spa/pool sanitiser)

    The committee also recommended an implementation date of 1 June 2018 as this is the earliest practicable implementation date.

    Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

    The reasons for the recommendation comprised the following:

    1. the risks and benefits of the use of a substance:
    • Risks: As presented, the benefits of silver oxide are likely to greatly outweigh the risks.
    • Benefits: silver oxide reduces bacterial levels in spas.
  • the purposes for which a substance is to be used and the extent of use of a substance:
    • The use of silver oxide as a spa pool sanitiser will allow for the soluble silver to be dissolved into the spa.
    • Minimal exposure to silver is expected.
  • the toxicity of a substance:
    • Toxicity of silver oxide is not well characterised.
    • The presentation restricts the potential for respiratory irritancy.
  • the dosage, formulation, labelling, packaging and presentation of a substance:
    • Formulation as an integral part of a silicate glass, which is further contained, is the key to the low risk, more than simply the low solubility of silver oxide.
    • Silver oxide present in a product for the domestic market is at 1% (<1% silver), allowing for gradual release of silver over time.
  • the potential for abuse of a substance:
    • Nil
  • any other matters that the Secretary considers necessary to protect public health
    • There is insufficient data for a Schedule 6 entry.
    Delegate's considerations

    The delegate considered the following regarding this proposal:

    • Scheduling proposal
    • ACCS advice
    • Public submission received
    • Section 52E of the Therapeutic Goods Act 1989
    • Scheduling Policy Framework (SPF 2015)
    Delegate's interim decision

    The delegate’s interim decision is that silver oxide does not require scheduling and to include it in Appendix B of the Poisons Standard. The proposed decision is:

    Appendix B – New Entry

    SILVER OXIDE

    Reasons for Entry: b (Use pattern restricts hazard)
    Areas of Use: 7.14 (Spa/pool sanitiser)

    The proposed implementation date is 1 June 2018. This is the earliest practicable implementation date.

    The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (a) the risks and benefits of the use of the substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of the substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and( f) any other matters that the Secretary considers necessary to protect public health.

    The reasons for the interim decision are the following:

    1. the risks and benefits of the use of a substance:
    • Risks: As presented, the benefits of silver oxide are likely to greatly outweigh the risks.
    • Benefits: silver oxide reduces bacterial levels in spas.
  • the purposes for which a substance is to be used and the extent of use of a substance:
    • The use of silver oxide as a spa pool sanitiser will allow for the soluble silver to be dissolved into the spa.
    • Minimal exposure to silver is expected.
  • the toxicity of a substance:
    • Toxicity of silver oxide is not well characterised.
    • The presentation restricts the potential for respiratory irritancy.
  • the dosage, formulation, labelling, packaging and presentation of a substance:
    • Formulation as an integral part of a silicate glass, which is further contained, is the key to the low risk, more than simply the low solubility of silver oxide.
    • Silver oxide present in a product for the domestic market is at 1% (<1% silver), allowing for gradual release of silver over time.
  • the potential for abuse of a substance:
    • Nil
  • any other matters that the Secretary considers necessary to protect public health
    • There is insufficient data for a Schedule 6 entry.

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