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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, March 2017

Scheduling medicines and poisons

17 May 2017

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3.2 Climbazole

3. Advisory Committee on Chemicals Scheduling (ACCS #19)

3.2. Climbazole

Referred scheduling proposal

An application was submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) to amend the current entries for climbazole in Schedules 5 and 6, to restrict its use in cosmetic products except at concentrations below 0.5% in leave-on hair and face cosmetics, and up to 2% for rinse-off hair cosmetics.

Current scheduling status

Climbazole is in Schedule 5 and Schedule 6 of the Poisons Standard as follows:

Schedule 6

CLIMBAZOLE except:

  1. when included in Schedule 5; or
  2. in preparations containing 2 per cent or less of climbazole.

Schedule 5

CLIMBAZOLE in preparations containing 40 per cent or less of climbazole except in preparations containing 2 per cent or less of climbazole.

Climbazole is also listed in Appendix E as follows:

Appendix E, Part 2

CLIMBAZOLE

Standard statement: 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).].

Scheduling history

Climbazole was first considered for scheduling by the Poisons Schedule Committee (PSC) in November 1980. Although the original application specified use as a household and industrial fungicide, at that time the committee decided that the absence of chronic toxicological data warranted restrictions for human use, and that Schedule 4 was appropriate.

In November 1985 the Poisons Schedule Committee (PSC) considered rescheduling climbazole from Schedule 4 to Schedule 5 (for human use), to permit its use in an antidandruff shampoo. However, the committee did not accept this rescheduling application given the lack of chronic toxicological data.

In November 1986 the Drugs and Poisons Scheduling Committee (DPSC) considered an amended application to the one received in November 1985 to reschedule climbazole from Schedule 4 to Schedule 5 (for human use) in order to permit its use in an antidandruff shampoo. In its deliberations, the committee noted that climbazole would be incorporated into the proposed Australian Cosmetic Standard at 0.5% or less. The committee agreed to delete the Schedule 4 entry for climbazole and create: a new Schedule 5 entry for preparations containing 40% or less except in preparations containing 2% or less (as in the current Schedule 5 entry); and a new Schedule 6 entry with an exemption for preparations containing 2% or less of climbazole (as in the current Schedule 6 entry).

Scheduling application

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

Schedule 6 - Amend Entry

CLIMBAZOLE except:

  1. when included in Schedule 5; or
  2. in leave-on hair and face cosmetic preparations containing 0.5 per cent or less of climbazole; or in preparations containing 2 per cent or less of climbazole.
  3. in rinse-off hair and face cosmetic preparations containing 2 per cent or less of climbazole.

Schedule 5 - Amend Entry

CLIMBAZOLE in preparations containing 40 per cent or less of climbazole except in preparations containing 2 per cent or less of climbazole.:

  1. in leave-on hair and face cosmetic preparations containing 0.5 per cent or less of climbazole; or
  2. in rinse-off hair and face cosmetic preparations containing 2 per cent or less of climbazole.

The applicant's reasons for the request are:

  • Climbazole is readily bioavailable following oral exposure and has moderate acute oral toxicity;
  • Climbazole is not an eye irritant at 0.5% and not a skin irritant at 2%;
  • Climbazole has been selected as a candidate for the European Union (EU) Community Action Rolling Plan (CoRAP) initiative for further evaluation of reproductive and developmental toxicity;
  • Climbazole is reported to be used in cosmetic products overseas (as a preservative or antimicrobial agent); in the absence of Australian specific data, this is assumed to be representative of its use in Australia; and
  • According to the SCCP Opinion (2009), climbazole is 'regulated in the Cosmetics Directive as a preservative in Annex [V], with a maximum authorized concentration of 0.5%' and 'is used as an anti-dandruff active agent in hair cosmetic preparations up to a maximum concentration of 2.0% in rinse-off products or up to a maximum concentration of 0.5% in leave-on products. In addition, it is used in leave-on face creams up to a maximum concentration of 0.5%'.
Australian regulatory information

Climbazole is permitted to be used as both an excipient and active ingredient in biological and prescription medicines; however a search of the Australian Register of Therapeutic Goods (ARTG) found it is not currently used in any listed products.

Climbazole is not listed on the Therapeutic Goods (Permissible Ingredients) Determination No. 1 of 2017.

The use of climbazole was approved by the Medicines Evaluation Committee (MEC) in 2004 for dermal use only. Climbazole can be used in hair care products at concentration of up to 0.5% for leave-on products and up to 2% for rinse-off products.

International regulations

Climbazole is listed on the EU Cosmetics Regulation 1223/2009 Annex V - List of preservatives allowed in cosmetic products. The maximum concentration allowed is 0.5% in ready for use preparations.

The SCCS has concluded (SCCS 2013) that climbazole 'may be used as a preservative (or non-preservative) ingredient up to a maximum concentration of 0.5% in leave-on hair and face cosmetics. Its non-preservative use in rinse-off hair cosmetics up to a maximum concentration of 2% was also considered to be safe. Its use in leave-on products other than those mentioned above was, however, not considered safe'. Furthermore, 'the non-preservative use of Climbazole either in foot care cosmetics alone at a concentration of up to 0.5% or in combination with either shampoo (at a maximum concentration of 2%) or face cream (at a maximum concentration of up to 0.5%) or with hair lotion (at a maximum concentration of up to 0.5%), does not pose a risk to the health of the consumer. In the case, however, that 3 products, although each safe when used separately, are combined, the combinations of either shampoo, hair lotion and a foot care product or face cream, hair lotion and a foot care product (all containing Climbazole at the maximum requested concentration) cannot be considered safe for the consumer'.

Substance summary

Climbazole is an imidazole topical antifungal agent commonly used in the treatment of human fungal skin infections such as dandruff, eczema and Seborrheic dermatitis.[76],[77]

Figure 3.2: Chemical structure of Climbazole

Figure 3.2: Chemical structure of Climbazole

Table 3.2A: Chemical information for climbazole
Property Climbazole
CAS name 2-butanone, 1-(4-chlorophenoxy)-1-(1H-imidazol-1-yl)-3,3-dimethyl-
CAS number 38083-17-9
IUPAC and/or common and/or other names climbazole (INCI and AAN); Crinipan AD; Baypival; (RS)-1-(4-Chlorophenoxy)-1-imidazol-1-yl-3,3-dimethylbutan-2-one (IUPAC); 1-[(4-chlorophenoxy)(tert-butylcarbonyl)methyl; 1-(4-chlorophenoxy)-1-(1H-imidazolyl)-3,3-dimethyl-2-butanone
Molecular formula C15H17ClN2O2
Molecular weight 292.76 g/mol

The following data was extracted from the NICNAS IMAP Human Health Tier II report for climbazole. [78],

Table 3.2B: Acute toxicity end-points for climbazole
Toxicity Species Result SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bw) Mouse (male CF1/W68) 664 Schedule 6
Rat (Wistar) 400
Rabbit (female Chinchilla) 250
Dog (Beagle) 250-500
Acute dermal toxicity LD50 (mg/kg bw) Rat >5000 Schedule 5
Acute inhalational toxicity LC50 (mg/m3/4h) N/A No data N/A
Skin irritation Rabbit Slightly irritating at 0.5% concentration Limited data
Guinea pig Irritating at 10% concentration
Human volunteers Not a skin irritant at 2% concentration
Eye irritation Rabbit Not irritating at 0.5% concentration Limited data
Chicken Enucleated Eye Test Negative results up to 2% concentration
Hen's Egg Test-Chorioallantoic Membrane (HET-CAM) assay Negative results for the neat chemical
Skin sensitisation

Mouse (LLNA)

Guinea pig (GPMT)

Guinea pig (Buehler)

Not sensitising N/A
Acute toxicity

Based on the available data, climbazole has moderate acute oral toxicity and low acute dermal toxicity. No data is available for acute inhalation toxicity.

Skin irritation

No skin irritation data are available using neat climbazole however, climbazole at 0.5% concentration was slightly irritating to the skin of New Zealand White rabbits, and an irritant in female Bor:DHPW guinea pigs at 10% concentration. In patch tests, climbazole was not a skin irritant at 2% concentration in human volunteers (SCCP 2009).

Eye irritation

No in vivo eye irritation studies are available using neat climbazole, however climbazole was not irritating to rabbit eyes at 0.5% concentration. A Chicken Enucleated Eye Test (screening assay) gave negative results for climbazole up to 2% concentration. A Hen's Egg Test-Chorioallantoic Membrane (HET-CAM) assay showed negative results for neat climbazole; however, this assay detects only strong eye irritants (SCCP 2009).

Climbazole is not expected to be an eye irritant in humans at 2% concentration (SCCP 2009).

Skin sensitisation

Based on the results of a local lymph node assay (LLNA) in CBA/J mice (OECD TG 429), climbazole up to 20% concentration does not have potential to induce skin sensitisation (SCCP 2009).

Climbazole gave negative results for skin sensitisation in two non-guideline studies (Magnusson Kligman Guinea Pig Maximisation test and Buehler test) in female guinea pigs (Bor:DHPW and Hartley). [However, it should be noted that the SCCP report stated that these studies were either not valid or impossible to assess.]

Repeat-dose toxicity

Based on the available data in rats and dogs, climbazole is not considered to cause severe effects following repeated oral or inhalation exposure. However, repeated dose oral toxicity studies in rats showed increased liver enzyme activity from doses at or above 15 mg/kg bw/day. No data are available on repeated dose dermal toxicity.

The SCCP report stated that the available studies were conducted between 1975 and 1983, before GLP-regulations were in place. The descriptions were brief and the raw data incomplete. For ethical reasons and after a thorough re-examination of the available information, the SCCP proposed to accept the use of a cautious NOEL-value of 5 mg/kg bw/day, deduced from the 90 day oral study with the rat. This No observed effect level (NOEL) was used in the margin of safety (MoS) calculations for the specific use scenarios of climbazole.

The SCCP report calculated the MoS to be 701 for a 60 kg person using an anti-dandruff shampoo containing 2% climbazole, using an in vitro dermal penetration rate of 0.297 µg/cm2 (0.15%) through human skin. This indicates that climbazole at 2% is safe for use in anti-dandruff shampoo (rinse-off products). The MoS for a 60 kg person using hair lotions, face cream and leave-on body lotion (all containing 0.5% climbazole) were calculated to be 189, 425 and 13, respectively, using in vitro dermal penetration rates of 1.10 µg/cm2 (2.23%) or 1.25 µg/cm2 (3.46%) through pig skin. Considering these MoS values, using a leave-on body lotion containing 0.5% climbazole for whole body (area of 18,000 cm2) was not considered safe as the MoS was calculated to be <100. The SCCP concluded that, 'To generate an acceptable MoS (≥ 100), the treated surface area for leave-on products containing 0.5% Climbazole should not exceed 2400 cm2.'

Genotoxicity

Based on the results from the available in vitro and in vivo genotoxicity studies, climbazole is not considered to be genotoxic. Some in vitro genotoxicity tests indicated positive results, but all in vivo tests were negative.

Reproduction and developmental toxicity

Based on the available data, climbazole is not considered to cause specific reproductive or developmental toxicity, as effects were only observed secondary to maternal toxicity. However, climbazole is a candidate for the EU CoRAP initiative for further evaluation of reproductive and developmental toxicity.

Public exposure

Climbazole is reported to be used in cosmetic products overseas as a preservative or antimicrobial agent. In the absence of Australian specific data, this is assumed to be representative of its use in Australia.

Pre-meeting public submissions

Two (2) public submissions were received. Both submissions did not support the proposal. The submissions noted that there should be alignment with EU regulations for use in cosmetics but special consideration should then be made for domestic preparations. Currently EU regulations permits up to 0.5% in cosmetics; however there is ongoing assessment by the SCCS in Europe and therefore the rescheduling should be deferred until a decision is made by the SCCS in Europe. A delayed Poisons Standard entry of 12 months to allow implementation was requested.

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

Summary of ACCS advice to the delegate

The committee recommends that the current Schedule 6 and 5 entries for climbazole be amended as follows:

Schedule 6 - Amend Entry

CLIMBAZOLE except:

  1. when included in Schedule 5; or
  2. in preparations containing 2 per cent or less of climbazole in leave-on hair, face and foot cosmetic preparations containing 0.5 per cent or less of climbazole; or
  3. in other preparations (that are not leave-on cosmetic preparations) containing 2 per cent or less of climbazole.

Schedule 5 - Amend Entry

CLIMBAZOLE in preparations containing 40 per cent or less of climbazole except in preparations containing 2 per cent or less of climbazole.:

  1. in leave-on hair, face and foot cosmetic preparations containing 0.5 per cent or less of climbazole; or
  2. in other preparations (that are not leave-on cosmetic preparations) containing 2 per cent or less of climbazole.

The committee also recommended an implementation date of 1 June 2018 to allow adequate time for industry to make the necessary labelling 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; and (c) the toxicity of a substance.

The reasons for the advice comprised the following:

  • Climbazole is an effective fungicidal preservative.
  • Moderate acute oral and low acute dermal toxicity, but high dermal absorption.
  • There is a risk of toxicity if climbazole is used at concentrations up to the maximum unscheduled cut-off and/or simultaneous use of multiple preparations for different purposes; especially if preparations are intended to be left on the skin/hair. However this risk can be mitigated by the reduced exposure dermally for exempted products.
Delegate's considerations

The delegate considered the following in regards to this proposal:

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

The delegate's interim decision is to amend the current Schedule 6 and 5 entries for climbazole. The proposed Schedule entry is as follows:

Schedule 6 - Amend Entry

CLIMBAZOLE except:

  1. when included in Schedule 5; or
  2. in leave-on hair, face and foot cosmetic preparations containing 0.5 per cent or less of climbazole; or
  3. in other preparations (that are not leave-on cosmetic preparations) containing 2 per cent or less of climbazole.

Schedule 5 - Amend Entry

CLIMBAZOLE in preparations containing 40 per cent or less of climbazole except:

  1. in leave-on hair, face and foot cosmetic preparations containing 0.5 per cent or less of climbazole; or
  2. in other preparations (that are not leave-on cosmetic preparations) containing 2 per cent or less of climbazole.

The proposed implementation date is 1 June 2018.

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.

The reasons for the interim decision are the following:

  • The delegate acknowledges the committee's advice.
  • Climbazole is an effective fungicidal preservative.
  • Moderate acute oral and low acute dermal toxicity, but high dermal absorption.
  • There is a risk of toxicity if climbazole is used at concentrations up to the maximum unscheduled cut-off and/or simultaneous use of multiple preparations for different purposes; especially if preparations are intended to be left on the skin/hair. However this risk can be mitigated by the reduced exposure dermally for exempted products.
  • A long implementation date is proposed in order to allow adequate time for industry to make the necessary labelling changes.

Footnotes

  1. Pérez-Rivera, Alex A., et al., "Evaluation of the genotoxicity of the imidazole antifungal climbazole: comparison to published results for other azole compounds." Mutation Research/Genetic Toxicology and Environmental Mutagenesis 672.1 (2009): 27-39.
  2. Youn H, Kim S, Ahn K, et al., Efficacy and Safety of Cream Containing Climbazole/Piroctone Olamine for Facial Seborrheic Dermatitis: A Single-Center, Open-Label Split-Face Clinical Study. Annals Of Dermatology [serial online]. December 2016;28(6):733-739
  3. This report is publicly available on the NICNAS website at Human Health Tier II Assessment for 2-Butanone, 1-(4-chlorophenoxy)-1-(1H-imidazol-1-yl)-3,3-dimethyl-.

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