You are here

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

Scheduling medicines and poisons

5 February 2018

Book pagination

2.2. Salts of Boric Acid

Referred scheduling proposal

An application was submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) to amend the current entry for boric acid in Schedule 5, to remove “excluding its salts”, so salts of boric acid are captured by 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:

Schedule 5 – Amend Entry

BORIC ACID (excluding its salts) and BORAX except:

  1. when included in Schedule 4;
  2. in preparations, other than insect baits, containing 1 per cent or less of boron; or
  3. in hand cleaning preparations.

The applicant’s reasons for the request are:

  • Data from animals indicate that boric acid and its salts are reproductive and developmental toxins.
  • Boric acid and its salts are reported to be used in cosmetic and domestic products overseas and are therefore, likely to be used in similar products in Australia.
  • Boric acid and its salts have international restrictions on their use.
Current scheduling status

The salts of boric acid are captured by the Schedule 4 entry for BORON in the current Poisons Standard as follows:

Schedule 4

BORON, including boric acid and borax, for human therapeutic use except:

  1. in preparations for internal use containing 6 mg or less of boron per recommended daily dose;
  2. in preparations for dermal use containing 0.35 per cent or less of boron, which are not for paediatric or antifungal use; or
  3. when present as an excipient.

Boric acid is included in Schedule 5 and Appendix E, Part 2. However, salts of boric acid are specifically excluded as follows:

Schedule 5

BORIC ACID (excluding its salts) and BORAX except:

  1. when included in Schedule 4;
  2. in preparations, other than insect baits, containing 1 per cent or less of boron; or
  3. in hand cleaning preparations.

Appendix E, Part 2

BORIC ACID

Standard statements: A (For advice, contact a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor (at once)).

Index

BORON
cross reference: BORATES, BORAX, BORIC ACID, BORON COMPOUNDS

Schedule 4

Scheduling history

The scheduling history for boron compounds dates back to July 1968. The most recent scheduling considerations are highlighted below.

May and August 2001 National Drugs and Poisons Schedule Committee (NDPSC)

The May and August 2001 NDPSC Meetings agreed to revise the boron Schedule 4 entry to exempt a daily oral dose of 3 mg and to exempt dermal preparations containing 0.35 per cent or less to harmonise with the New Zealand (NZ) classification for dermal use. However, the committee did not agree to harmonise on other use patterns. This outcome was referred to NZ's Medicines Classification Committee (MCC) for consideration.

February 2006 National Drugs and Poisons Schedule Committee (NDPSC)

The February 2006 NDPSC Meeting:

  • Noted that NZ had toxicity concerns regarding the use of high strength boron for nappy rash in babies under occlusive conditions.
  • Noted that NZ products only contained boric acid and that boron was not listed as an ingredient in medicines. In contrast, registered ingredients for Australian therapeutic products include either boron or boric acid. A Member also noted that the boron scheduling excluded excipients and that this may need to be reviewed on the basis of the substance's toxicity.
  • Recommended that NZ consider harmonising with the scheduling of boron and that MCC consider submitting a proposal to the NDPSC regarding appropriate nomenclature for harmonisation.
June 2007 National Drugs and Poisons Schedule Committee (NDPSC)

The June 2007 NDPSC Meeting agreed that consideration of the scheduling of boron should be deferred, pending information from NZ regarding a potential proposal to set a new exemption cut-off, and the reasons for any such recommendation.

December 2007 NZ Medicines Classification Committee (MCC)

At the December 2007 Meeting, the MCC agreed that boron, including boric acid and borax, should be a prescription medicine except when for internal use in medicines containing 6 mg or less per recommended daily dose; for dermal use other than paediatric use in medicines containing 0.35 per cent or less or when present as an excipient.

February and June 2008 National Drugs and Poisons Schedule Committee (NDPSC)

The February and June 2008 NDPSC Meetings, following reconsideration of the issues (including the reasons for the adoption by New Zealand of a 6 mg cut-off for internal use), agreed to foreshadow the following amendments to the Schedule 4 boron entry (including capture of all paediatric use as Schedule 4) to allow stakeholders a further opportunity to comment, and to help identify any potential unintended consequences:

  • Broadening the entry, particularly regarding topical use, by amending from an inclusive to an exclusive form.
  • Increasing the internal use cut-off from 3 mg to 6 mg.
  • Capturing all dermal paediatric use in Schedule 4 (i.e. remove the current allowance for dermal paediatric use, when not a dusting powder and ≤ 0.35 per cent, to be unscheduled).
  • Removing the exemption for antifungal preparations for dermal use (i.e. these will be captured in Schedule 4).
  • Adding the expression "including boric acid and borax" and changing 'milligrams' in part (a) to 'mg'.
  • “Schedule 4 – Foreshadowed amendment
  • BORON – Amend entry to read:
  • BORON, including boric acid and borax, for human therapeutic use except:
  1. in preparations for internal use containing 6 mg or less of boron per recommended daily dose;
  2. in preparations for dermal use containing 0.35 per cent or less of boron, other than preparations other than preparations for paediatric or antifungal use; or
  3. when present as an excipient."
Australian regulatory information

Boric acid is an ingredient in 80 products on the ARTG including eye drops, antifungal treatments, contact lens solution, detergents and vitamins.

Boric acid is listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017 as follows:

Ingredient Name Purpose of the ingredient in the medicine Specific requirements
890 BORIC ACID A, H Boron is a mandatory component of Boric acid. The percentage of Boron from Boric acid should be calculated based on the molecular weight of Boric acid

The maximum recommended daily dose must provide no more than 6mg of Boron.

In preparations for dermal use, which are not for paediatric or antifungal use, the concentration of boron in the medicine must be no more than 3500 mg/kg or 3500 mg/L or 0.35%

The indication 'For mineral (may state the mineral) supplementation' is only permitted for use when the medicine is for oral or sublingual use.

Some members of this group (CAS Nos. 1330-43-4, 12267-73-1, 13840-56-7) are classified as hazardous for reproductive and developmental toxicity – Category 1B; H360FD (May damage fertility. May damage the unborn child) in the HCIS (Safe Work Australia).

Boric acid (CAS No. 10043-35-3) is classified as a hazardous for reproductive and developmental toxicity – Category 1B; H360FD (May damage fertility. May damage the unborn child) in the HCIS (Safe Work Australia).

International regulations

Boric acid, disodium salt and boric acid, dipotassium salt are listed on the following:

  • European Union (EU) Regulation (EC) No 1223/2009 of the European Parliament and of the Council of 30 November 2009 on cosmetic products—Annex III— "List of substances which cosmetic products must not contain except subject to the restrictions laid down" with specific conditions on maximum in-use concentrations for talc (5%), oral products (0.1%) and other products (3%). Other conditions include restrictions and label statements to the effect of "Not to be used in products for children under 3 years of age".
    • The 2013 EU SCCS opinion on "the safety of boron compounds in cosmetic products" recommended further risk management, however this recommendation has not yet been implemented in legislation.
  • The chemicals boric acid, disodium salt, MEA-borate and MIPA-borate are listed on the Health Canada List of prohibited and restricted cosmetic ingredients (The Cosmetic Ingredient "Hotlist").
Substance summary

1330-43-4

Boric acid (H2B4O7), disodium salt; Boron sodium oxide, (B4Na2O7) (CAS); Sodium borate (INCI); disodium tetraborate; sodium borate anhydrous; disodium tetraborate, anhydrous

1332-77-0

Boric acid (H2B4O7), dipotassium salt; Boron potassium oxide (B4K2O7) (CAS); potassium tetraborate; potassium borate; dipotassium tetraborate

26038-87-9

Boric acid (H3BO3), compd. with 2-aminoethanol; monoethanolamine, boric acid salt; Boric acid (H3BO3), compd. with 2-aminoethanol (1:?) (CAS); MEA-borate (INCI)

26038-90-4

Boric acid (H3BO3), compd. with 1-amino-2-propanol (1:?) (CAS); MIPA-borate (INCI); 1-aminopropan-2-ol, compound with orthoboric acid; boric acid, monoisopropanolamine salt; orthoboric acid isopropanolamine salt

68003-13-4

Boric acid (H3BO3), compd. with 1-amino-2-propanol (1:1) (CAS); MIPA-borate (INCI); Isopropanolamine borate; (2 hydroxypropyl)ammonium dihydrogen orthoborate

The following information was extracted from the NICNAS IMAP Human Health Tier II assessment report for salts of boric acid.

Table 2.2.1: Acute toxicity end-points for salts of boric acid
Toxicity Species Salts of boric acid SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bw) Rat >2000 mg/kg bw (for suitable analogues) Schedule 5
Acute dermal toxicity LD50 (mg/kg bw) Rat >2000 mg/kg bw (for suitable analogues) Schedule 5
Acute inhalational toxicity LC50 (mg/m3/4h) Rat >2000 mg/m3 (for suitable analogues) Schedule 5
Skin irritation Rabbit Suitable analogue chemicals non-irritating. Schedule 5
Eye irritation Rabbit Suitable analogue chemicals produced mild irritation in some studies Schedule 5
Skin sensitisation Guinea pig Suitable analogue chemicals are non-sensitising Schedule 5
General statement

The Scientific Committee on Consumer Safety (SCCS) has recently concluded that substances such as borates, tetraborates, and octaborates as well as other boric acid salts/esters (MEA-borate, MIPA-borate, potassium borate, trioctyldodecyl borate and zinc borate reported in the CosIng database) produce boric acid following contact with water. Therefore, as these compounds have chemical, biological and toxicological properties similar to boric acid, the general restrictions applicable to boric acid for safe use in cosmetic products should apply to the whole group of borates (SCCS, 2013).

Acute toxicity
Oral

Limited data was provided for the chemicals in this group. The information available for sodium borate, anhydrous (CAS No. 1330-43-4) and analogues boric acid (CAS No. 10043-35-3), borax (CAS No. 1303-96-4) and zinc borates suggest that the chemicals in this group are likely to have low acute toxicity in animal tests following oral exposure. The median lethal dose (LD50) in rats for the tested chemicals in the group and the analogue chemicals is >2000 mg/kg bw. The boric acid amine salts are also expected to have low acute oral toxicity (>2000 mg/kg bw).

Dermal

No data was provided for the chemicals in this group.

Data available for the analogue chemicals, boric acid (CAS No. 10043-35-3), borax (CAS No. 1303-96-4) and zinc borates indicate that the chemicals in this group are likely to have low acute toxicity in animal tests following dermal exposure. The dermal LD50 in rats is >2000 mg/kg bw for each of these analogues. It is also noted that the dermal absorption through intact skin is very low (dermal absorption rate of 0.5% was assumed for borates. [52][53][54]

Inhalation

No data was provided for the chemicals in this group.

Information available on the analogues boric acid (CAS No. 10043-35-3), borax (CAS No. 1303-96-4) and zinc borates indicates that the chemicals in this group are likely to have low acute toxicity in animal tests following inhalational exposure. The highest achievable inhalational dose produced no mortalities in these studies.

Observation in humans

There is a large database of accidental or intentional poisoning in humans following exposure to borates. A review of more than 700 cases of acute boric acid exposures in adults and children found 88.3% of cases were without symptoms. Although the report provided only limited information on dose response, dose ranges of 0.1–55 g and 0.01–89 g of boric acid were reported for symptomatic and asymptomatic cases, respectively. There are case reports of lethal oral exposures in humans involving accidental or intentional ingestion of high doses of boric acid. While oral lethal doses for boric acid have been quoted as 2–3 g for infants, 5–6 g for children, and 15–30 g for adults, the data are largely unsubstantiated. Further difficulty in making an appropriate quantitative judgment about a lethal dose was also noted due to medical intervention in most cases. Following ingestion of a formula accidentally prepared with a 2.5% aqueous solution of boric acid, 5 infants became lethargic, developed vomiting and diarrhoea, and died within 3 days of exposure (estimated dose of 4.5–14 g boric acid). Deaths have also occurred in a 77-year-old man following ingestion of 30 g of boric acid and in a 45-year-old man following ingestion of approximately 280 g of boric acid. In both instances, clinical signs were similar: vomiting, diarrhoea, erythema, cyanotic extremities, acute renal failure, cardiopulmonary hypertension and death from heart failure.

Irritation
Skin

Although the data for the chemicals in this group are limited, the available information on the analogues, boric acid (CAS No. 10043-35-3), borax (CAS No. 1303-96-4), and on zinc borates indicate that the chemicals in this group are not likely to be skin irritants.

Eye

Limited data was provided on the chemicals in this group. In an eye irritation study, potassium pentaborate (CAS No. 11128-29-3) (0.1 g) was placed in the conjunctival sac of the right eye of each of the three New Zealand White (NZW) rabbits and treated eyes were rinsed with water 24 hours after administration of the test substance. The untreated left eye of each rabbit served as a control. As significant eye irritation scores were not observed in any animal throughout the study, the chemical was classified as non-irritant to the eyes. Slight eye irritant effects were reported in animal studies for the analogues: boric acid (CAS No. 10043-35-3); borax (CAS No. 1303-96-4) and on zinc borates. The reported effects were not sufficient to warrant hazard classification for the chemicals in this group.

Respiratory

The limited data indicate that the chemicals in this group are unlikely to be specific respiratory irritants.

Sensitization

Although no information is available on the skin sensitisation potential of chemicals in this group, based on the available information on the analogue chemicals, the chemicals in this group are not likely to be skin sensitisers.

Observation in humans

No evidence of skin or respiratory sensitisation in humans occupationally exposed to borates has been reported.

Repeat-dose toxicity
Oral

No data was provided for the chemicals in this group.

The available information on boron-containing compounds indicates that the chemicals in this group are not likely to cause serious damage to health from repeated oral exposure.

Dermal

No data was provided.

Inhalation

No data was provided.

Genotoxicity

Although the data for the chemicals in this group are limited, the available information on boric acid (CAS No. 10043-35-3) and zinc borates indicates that the chemicals in this group are not likely to have a mutagenic or genotoxic potential.

Carcinogenicity

Limited data are available on the chemicals in this group. Available information on other inorganic borates and on zinc borates indicates that the chemicals in this group are not likely to have a carcinogenic potential. The chemicals in this group are also not considered to have a mutagenic or genotoxic potential.

Reproduction and developmental toxicity

No data was provided regarding reproductive or developmental effects of chemicals in this group in animals and humans, although there are studies on the analogues boric acid and borax. While the appropriate data are not available for chemicals in this group, information on boron-containing compounds (boric acid) in animals is sufficient to support classification for all chemicals in this group.

The testes and the developing foetus have been identified as the most sensitive targets of boron toxicity in animal studies, with the rat being the most sensitive species. The reported testicular effects included reduced organ weight and organ:body weight ratio; atrophy and degeneration of the spermatogenic epithelium; impaired spermatogenesis; and reduced fertility. The reported developmental effects included high prenatal mortality; reduced foetal body weight; and malformations and variations of the eyes, central nervous system, cardiovascular system and axial skeleton. The NOAEL for fertility of 100 mg/kg bw/day of boric acid (equivalent to 17.5 mg boron/kg bw/day) has been determined from two-year and three-year generational studies in rats, based on testicular effects. The critical NOAEL for developmental effects has been determined as 55 mg/kg bw/day of boric acid (equivalent to 9.6 mg boron/kg

As the chemicals in this group dissociate in water and give rise to boric acid, these results are applicable to borate salts.

Public exposure

Although specific use in cosmetic products in Australia is not known, the chemicals are reported to be used in cosmetic products overseas as buffering agents and viscosity controlling agents.

Pre-meeting public submissions

Two (2) public submissions were received for salts of boric acid, which opposed the scheduling proposal.

Main points opposed:
  • The five salts of boric acid identified are used at very low concentrations in cosmetics as buffering/viscosity controlling agents (sodium borate), as enzyme stabilisers in domestic detergent products and as corrosion inhibitors in industrial products.
  • Borax is present in many preparations for internal use containing 6 mg or less of boron per recommended daily dose as per the Schedule 4 entry. There are also many non-therapeutic products (for example dental adhesive products) which contain borax (as a preservative and viscosity controlling agent) that will be adversely affected by the proposal.
  • The current EU concentration cut-offs for cosmetics (talc (5%), oral products (0.1%) and other products (3%)) should be used in the current Schedule 5 entry for boric acid and borax.
  • Request a decision deferral pending a thorough investigation of scheduling impact, or an appropriate transition period of 24 to 30 months be applied to allow for any reformulation and/or labelling changes that would be required.

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

Summary of ACCS-ACMS advice to the delegates

The committee recommended that the Schedule 5 and Index entries of boric acid be amended as follows:

Schedule 5 – Amend Entry

BORIC ACID (excluding its salts) and BORAX except:

  1. when included in Schedule 4; or
  2. in preparations, other than insect baits, containing 1 per cent or less calculated as of boron; or
  3. in hand cleaning preparations.

Index – Amend Entry

BORIC ACID
cross reference: BORAX, BORON

The committee also recommended an implementation date of 1 October 2018 to allow time for industry to accommodate the changes.

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; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the recommendation comprised the following:

  1. the risks and benefits of the use of a substance:
  • The risks of boric acid and its salts is that the data indicates that the hazard is considered:
    • low to moderate effects in humans with normal use;
    • can cause only minor adverse effects to the human being in normal use;
    • requires caution in handling, storage, or use (S5); and
    • may cause death or severe injury if ingested (S6).
  • The benefit of boric acid and its salts is that it is used as an excipient to improve products.
  • the purposes for which a substance is to be used and the extent of use of a substance:
    • Boric acid and its salts are used in a wide range of cosmetics and personal products (antiseptics/astringents/skin lotions/some eyewash solutions/enamels and glazes).
    • They are also used in domestic and industrial cleaning products, including dishwashing and laundry liquids.
  • the toxicity of a substance:
    • There are reproductive and developmental effects in sensitive animals.
      • Testes and the developing foetus have been identified as the most sensitive targets of boron toxicity in animal studies.
    • Toxicity in humans:
      • No or limited data of oral, dermal and inhalation toxicity and genotoxicity or carcinogenicity.
      • Overall, evidence from studies considered shows toxicity in these areas is low in humans.
      • No appropriate data available for analogues boric acid and borax.
    • Salts of boric acid are readily converted to boric acid in aqueous solutions.
  • the dosage, formulation, labelling, packaging and presentation of a substance:
    • Appropriate Warning for:
      • Repeated Use;
      • Ingestion ; and
      • Developmental and Reproductive toxicity.
    • Labelling and packaging should restrict use in children and child access to products with higher concentrations.
  • the potential for abuse of a substance:
    • Nil.
  • any other matters that the Secretary considers necessary to protect public health
    • Nil.
    Delegate's considerations

    The delegate considered the following in regards to this proposal:

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

    The delegates’ interim decision is to amend the Schedule 5 and index entries for boric acid. The proposed Schedule and index entries are:

    Schedule 5 – Amend Entry

    BORIC ACID except:

    1. when included in Schedule 4; or
    2. in preparations, other than insect baits, containing 1 per cent or less calculated as boron; or
    3. in hand cleaning preparations.

    Index – Amend Entry

    BORIC ACID
    cross reference: BORAX, BORON

    The proposed implementation date is 1 October 2018. This is to allow time for industry to accommodate the changes.

    The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989 (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

    The reasons for the interim decision are the following:

    1. the risks and benefits of the use of a substance:
    • The risks of boric acid and its salts is that the data indicates that the hazard is considered:
      • low to moderate effects in humans with normal use;
      • can cause only minor adverse effects to the human being in normal use;
      • requires caution in handling, storage, or use (S5); and
      • may cause death or severe injury if ingested (S6).
    • The benefit of boric acid and its salts is that it is used as an excipient to improve products.
  • the purposes for which a substance is to be used and the extent of use of a substance:
    • Boric acid and its salts are used in a wide range of cosmetics and personal products (antiseptics/astringents/skin lotions/some eyewash solutions/enamels and glazes).
    • They are also used in domestic and industrial cleaning products, including dishwashing and laundry liquids.
  • the toxicity of a substance:
    • There are reproductive and developmental effects in sensitive animals.
      • Testes and the developing foetus have been identified as the most sensitive targets of boron toxicity in animal studies.
    • Toxicity in humans:
      • No or limited data of oral, dermal and inhalation toxicity and genotoxicity or carcinogenicity.
      • Overall, evidence from studies considered shows toxicity in these areas is low in humans.
      • No appropriate data available for analogues boric acid and borax.
    • Salts of boric acid are readily converted to boric acid in aqueous solutions.
  • the dosage, formulation, labelling, packaging and presentation of a substance:
    • Appropriate Warning for:
      • Repeated Use;
      • Ingestion ; and
      • Developmental and Reproductive toxicity.
    • Labelling and packaging should restrict use in children and child access to products with higher concentrations.
  • the potential for abuse of a substance:
    • Nil.
  • any other matters that the Secretary considers necessary to protect public health
    • Nil.

    Footnotes

    1. National Industrial Chemicals Notification and Assessment Scheme (NICNASb). Tier II human health assessment for boric acid (CAS No. 10043-35-3). Australian Government Department of Health. Available at http://www.nicnas.gov.au
    2. National Industrial Chemicals Notification and Assessment Scheme (NICNASc). Tier II human health assessment for borax (CAS No. 1303-96-4). Australian Government Department of Health. Available at http://www.nicnas.gov.au
    3. National Industrial Chemicals Notification and Assessment Scheme (NICNASd). Tier II human health assessment for zinc borate (CAS No. 1332-07-6). Australian Government Department of Health. Available at http://www.nicnas.gov.au

    Book pagination