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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, July 2016

Scheduling medicines and poisons

15 September 2016

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2.2 Hexachlorophene

Note

  • Red strikethrough text indicates text that has been deleted.
  • Green italicised text indicates text that has been added.
Referred scheduling proposal

An application was submitted to create a new Schedule 10 entry to prohibit the use of hexachlorophene in cosmetics.

Scheduling history

Hexachlorophene was originally considered for scheduling in March 1972 by the National Health and Medical Research Council's Poisons Schedule Sub-committee and has been considered a number of times since. In March 1972, the committee considered and advised on new entries for hexachlorophene in Schedules 3 and Schedule 4 with an Appendix A statement given its use as a topical antiseptic. Appendix A imposed a warning statement 'for external washing only, rinse skin thoroughly after use', for preparations other than that for use on infants, containing 0.75 per cent or less for skin cleansing purposes. In July 1972, the Poisons Schedule Sub-committee considered topical uses of hexachlorophene and advised a new Schedule 2 entry. In November 1974, the Poisons Schedule Sub-committee agreed to amend the existing Schedule 3 and 4 entries and create a new Schedule 6 entry for veterinary use of hexachlorophene. Amendments to the Appendix A warning statements were advised, where the concentration was raised from 0.75 per cent to 3 per cent.

In November 1980, the National Health and Medical Research Council's Poisons Schedule (standing) committee (PSStC) agreed to amend the Schedule 3 entry by removing the clause relating to use as a preservative and an inclusion of a new pregnancy warning statement in Appendix A (women likely to become pregnant should avoid the use of this product) was considered. In May 1981, the PSStC noted a report by PHAC that there was an absence of detailed data on absorption through intact skin and teratogenicity of hexachlorophene. The PSStC also considered that a mandatory warning on products containing hexachlorophene may result in their withdrawal from the market, which was of concern due to their use in hospitals as surgical preparations.

In November 1983, PSStC again considered advising on a 15 ppb limit for TCDD in hexachlorophene to align with the British Pharmacopoeia Commission. However in the absence of data on the practicalities of production or the toxicological implications of various levels, no agreement was made.

In August 1984, PSStC considered amending Schedule 2 to limit hexachlorophene to 3 per cent or less in skin cleansing products, and Schedule 4 in preparations for use on infants. In November 1984, the PSStC noted that Victorian Poisons Advisory Committee advised on the inclusion of a warning statement on hexachlorophene products for use in pregnancy, which had been previously raised several times (considerations of teratogenicity and risks to women of child-bearing age were considered in the November 1978, August 1980, February 1982 and November 1983 meetings). The PSStC decided that no alteration to the scheduling of hexachlorophene was warranted.

Current scheduling status

Hexachlorophene is currently listed in Schedules 2, 4 and 6 and Appendix E and F as follows:

Schedule 6

HEXACHLOROPHENE in preparations for the treatment of animals.

Schedule 4

HEXACHLOROPHENE:

  1. in preparations for use on infants; or
  2. in other preparations except:
    1. when included in Schedule 2 or 6; or
    2. in preparations containing 0.75 per cent or less of hexachlorophene.

Schedule 2

HEXACHLOROPHENE in preparations for human use containing 3 per cent or less of hexachlorophene except:

  1. in preparations containing 0.75 per cent or less of hexachlorophene; or
  2. in preparations for use on infants, as specified in Schedule 4.

Appendix E - HEXACHLOROPHENE when included in Schedule 6.

Standard statement: A [for advice, contact a Poisons Information Centre (e.g. phone Australia 131126; New Zealand 0800 764 766) or a doctor (at once)]

Appendix F - HEXACHLOROPHENE in preparations for skin cleansing purposes containing 3 per cent or less of hexachlorophene.

Warning statement: 24 (for external washing only. Rinse skin thoroughly after use)

Other relevant regulations

Public exposure

Although use in cosmetic and domestic products in Australia is not clearly known, hexachlorophene is available for use in consumer products (not intended for infants) at concentrations up to 0.75% as per the current SUSMP entries.

Non-industrial use is reported for hexachlorophene in Australia, including in medicinal cleansing lotions.

Internationally, the use of hexachlorophene in cosmetics is prohibited in several countries, while use of hexachlorophene as a preservative (at up to 0.1%) in cosmetics is conditionally permitted in the United States of America.

Non-industrial uses of hexachlorophene have been identified internationally, including therapeutic use as a topical anti-bacterial medicine, veterinary use as an anthelminthic (parasite treatment) drug in animals, and agricultural use as a soil fungicide.

Historical use of hexachlorophene as an anti-bacterial ingredient in soaps, lotions and detergents is reported. However, this use is now prohibited in several countries. Notable historical use in detergents is also reported in hospital settings for surgical scrubbing and for washing newborn babies to reduce bacterial infections.

International regulations

Hexachlorophene is prohibited for use in cosmetic products in several countries as according to inclusion in the following listings:

  • European Union (EU) Cosmetics Regulation 1223/2009 Annex II - List of substances prohibited in cosmetic products;
  • New Zealand Cosmetic Products Group Standard - Schedule 4: Components cosmetic products must not contain; and
  • Health Canada List of prohibited and restricted cosmetic ingredients (The Cosmetic Ingredient 'Hotlist').

Additionally, there are severe restrictions on use of hexachlorophene in cosmetics in the United States, as according to the following listing by the United States Food and Drug Administration (US FDA):

'Hexachlorophene may be used as a preservative in cosmetic products other than those which in normal use may be applied to mucous membranes or which are intended to be used on mucous membranes, at a level that is no higher than necessary to achieve the intended preservative function, and in no event higher than 0.1 percent. Such use of hexachlorophene shall be limited to situations where an alternative preservative has not yet been shown to be as effective or where adequate integrity and stability data for the reformulated product are not yet available'.

Scheduling application

General application.

The applicant's proposal is to amend the entries in the SUSMP for hexachlorophene to prohibit its use in cosmetic products.

The applicant's reasons for the request are:

  • The potential for use of hexachlorophene in cosmetic products in Australia (up to 0.75 % concentration is currently unscheduled);
  • Hexachlorophene causes neurotoxic effects following short-term or repeated oral and dermal exposure;
  • Hexachlorophene is a suspected developmental toxin;
  • Hexachlorophene is acutely toxic following oral or dermal exposure; and
  • Hexachlorophene is prohibited for use in cosmetic products in Canada, New Zealand and the European Union, with severely restricted use in cosmetics in the United States of America.
Substance summary

Hexachlorophene (CAS No. 70-30-4) is a white to light-tan, odourless, crystalline powder. While no specific Australian industrial use, import, or manufacturing information has been identified for hexachlorophene, the TGA has identified several non-industrial uses of hexachlorophene in Australia including in medicinal cleansing lotions.

Figure 2.2: Structure of hexachlorophene

Figure 2.2: Structure of hexachlorophene

Acute toxicity

The acute toxicity end-points for hexachlorophene (Figure 2.2) are listed in the Table 2.2 and are publically available in the NICNAS IMAP Human Health Tier II assessment report for phenol, 2,2'-methylenebis[3,4,6-trichloro-. Briefly, hexachlorophene is classified as hazardous for both oral and dermal exposure routes, with the risk phrases 'Toxic if swallowed' (T; R25) and 'Toxic in contact with skin' (T; R24) in the HSIS. The available data (LD50 values and observations in humans) support these classifications. Additionally, hexachlorophene is reported to cause severe (irreversible) sub-lethal effects following short-term oral or dermal exposure to products containing hexachlorophene (at 3 - 6.3 % concentrations). There is no acute inhalation toxicity data available for hexachlorophene and limited data from animal studies and human observations which indicate that hexachlorophene is a potential skin irritant. There is no reliable data available for eye irritation or skin sensitisation. There are several repeat insult patch tests conducted with hexachlorophene in humans, however specific study details are limited. While skin irritation is reported in these studies, no significant effects indicative of skin sensitisation have been observed.

Based on the weight of evidence from the available in vitro and in vivo genotoxicity assays, hexachlorophene is not considered to be genotoxic; and based on the available data, there is no evidence to indicate that hexachlorophene is carcinogenic.

Toxicity Species Result SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bw) Rat 56 - 66 Schedule 6
Acute dermal toxicity LD50 (mg/kg bw) Rat 1180
Acute inhalation toxicity LC50 (mg/m3/4h) N/A No data -
Skin irritation Human, rabbit, guinea pig Insufficient data -
Eye irritation N/A No data -
Skin sensitisation Human Insufficient data* -
Genotoxicity Mice, Human Not genotoxic* -
Carcinogenicity Rats, Mice Not carcinogenic* -

* See the NICNAS IMAP Human Health Tier II assessment report for phenol, 2,2'-methylenebis[3,4,6-trichloro-. for more information

Reproduction and developmental toxicity

Hexachlorophene does not show specific reproductive toxicity based on the available information. The reproductive effects were only observed at maternally toxic dose levels. However, based on the available data from experimental studies in animals, hexachlorophene has the potential to cause developmental effects. Reduced survival rate of offspring, in addition to the detection of lesions in the brain of offspring (similar to those reported in repeated oral and dermal toxicity studies in animals and observations in humans), support this conclusion.

Observation in humans

Cases of poisoning, caused by ingestion of products containing hexachlorophene, have been reported. In one case, a product containing hexachlorophene at 3 % in emulsion was mistakenly swallowed by 10 preoperative patients. Reported toxic effects included food aversion, nausea, vomiting, abdominal cramps and diarrhoea. Severe dehydration was also observed.

Dermal application of hexachlorophene to patients with burns, or to infants, has resulted in circulatory failure, effects on the central nervous system (twitching and convulsions) and, in some cases, death. In one notable incident in 1972, hexachlorophene was reported to have been inadvertently added to a talc baby powder product at 6.3 %. Encephalopathy (displayed symptoms of brain dysfunction) and skin lesions were observed in 204 infants and small children exposed to the product, with deaths occurring in 36 children within a few days of exposure. Similar to findings reported in animal studies, brain lesions were commonly reported following autopsy of children that have died following exposure to hexachlorophene.

There are several studies that have examined the prevalence of birth defects and malformations in children of hospital staff who had been regularly exposed to hexachlorophene through hand washing. Some concluded that exposure-related association was observed, while others concluded that there is no association between exposure to hexachlorophene and malformations at birth. However, deficiencies in the study methodologies have been noted in most cases.

Use of hexachlorophene in cosmetic and domestic products in Australia is not known.

Repeat dose toxicity

There are consistent reports of neurotoxic effects following exposure to hexachlorophene (leg weakness in animals, and tremors and convulsions in humans). Additionally, brain lesions were commonly reported at necropsy in animal exposure studies, including in the offspring of animals exposed to hexachlorophene (in reproductive or developmental toxicity studies), and at autopsy of children that have died following exposure to hexachlorophene.

Pre-meeting public submissions

One (1) public submission was received that supported the scheduling proposal.

The public submission is available on the TGA website.

Summary of Joint ACMS/ACCS advice to the delegates

The committee advised that the proposal to create a new Schedule 10 entry for hexachlorophene was inappropriate. The committee advised that the current hexachlorophene Schedule 6 and Schedule 2 entries for hexachlorophene in the SUSMP be amended as follows:

Schedule 6 - Amend Entry

HEXACHLOROPHENE:

  1. in preparations for the treatment of animals; or
  2. for cosmetic use.

Schedule 2 - Amend Entry

HEXACHLOROPHENE in preparations for human use containing 3 per cent or less of hexachlorophene except:

  1. in preparations containing 0.75 per cent or less of hexachlorophene; or
  2. in preparations for use on infants, as specified in Schedule 4; or
  3. when separately specified in these Schedules.

The committee suggested an implementation date of 1 February 2017.

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

The reasons for the advice included:

  • Hexachlorophene is considered hazardous and acutely toxic;
  • Human adverse events have been recorded from both oral and dermal exposure showing neurotoxic side effects (leg weakness in animals, twitching ad convulsions in humans), poisoning (resulting nausea, vomiting, abdominal cramps, diarrhoea and severe dehydration) and death;
  • Hexachlorophene is used as a disinfectant and a preservative; and
  • The chemical is prohibited for use in cosmetic products in Canada, New Zealand, the European Union, and severely restricted for use in cosmetics in the United States, a similar level of restriction in Australia to mitigate the risks would be appropriate.
Delegates' considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • ACCS/ACMS advice;
  • Public submissions received;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling Policy Framework (SPF 2015); and
  • Other relevant information.
Delegates' interim decision

The delegates note and accept the ACCS-ACMS advice to amend the Schedule 6 and Schedule 2 entries for hexachlorophene. Given hexachlorophene is considered hazardous and acutely toxic - with human adverse events recorded from both oral and dermal exposure showing neurotoxic side effects (leg weakness in animals, twitching ad convulsions in humans), poisoning (resulting nausea, vomiting, abdominal cramps, diarrhoea and severe dehydration) and death - adding a restriction to preclude its use in cosmetics is appropriate. Furthermore, the amendment to the Schedule 6 entry for hexachlorophene will align Australian regulations for this chemical in regards to its use in cosmetics, with Canada, New Zealand, the United States and the European Union.

The proposed implementation date is 1 February 2017.

The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (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 (f) any other matters that the Secretary considers necessary to protect public health.

Schedule 6 - Amend Entry

HEXACHLOROPHENE:

  1. in preparations for the treatment of animals; or
  2. for cosmetic use.
Schedule 2 - Amend Entry

HEXACHLOROPHENE in preparations for human use containing 3 per cent or less of hexachlorophene except:

  1. in preparations containing 0.75 per cent or less of hexachlorophene; or
  2. in preparations for use on infants, as specified in Schedule 4; or
  3. when separately specified in these Schedules.
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