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

Scheduling medicines and poisons

12 May 2016

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1.1 Crystal violet and related dyes

Part A - Interim decisions on scheduling proposals referred to an advisory committee (March 2016)

1. Advisory Committee on Chemicals Scheduling (ACCS#16)

1.1 Crystal violet and related dyes

Referred scheduling proposal
  • In response to issues raised in a NICNAS IMAP Human Health Tier 2 assessment report on crystal violet and related dyes, the scheduling proposal is to create a new group Schedule 6 entry for Crystal violet (methylrosanilinium chloride) and related dyes to regulate their use in hair dye products and to provide appropriate exemptions.
Scheduling application

The reasons for the request are:

  • Appropriate scheduling and labelling should be undertaken to preclude the use of crystal violet and related dyes in hair dye products. Crystal violet is already listed in Schedule 4 of the SUSMP. Due to the similarities in their toxicity profiles, the dyes related to crystal violet (CAS Nos: 1694-09-3; 2390-59-2; 2390-60-5; 2580-56-5 and 72102-55-7) should also be restricted from use in hair dye products. These chemicals also have industrial uses which should be appropriately controlled provided that the IMAP worker health and safety recommendations are implemented.
  • The chemicals are suspected of being carcinogenic. Whilst data are limited for some of the chemicals in the group, crystal violet (CAS No. 548-62-9) and benzyl violet (CAS No. 1694-09-3) are classified as having 'Limited evidence of carcinogenic effect'.
  • The chemicals are acutely toxic and cause serious eye damage; and
  • The chemicals, 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 dyes in Australia.
Specific issues/questions raised by the delegate

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.

  • Does the ACCS agree that the toxicological profile of Crystal Violet (acute toxicity, severe eye irritancy, but lacking reliable data on skin irritancy and sensitisation potential) warrants controls over use in cosmetics and consumer products?
  • What weight should be given to the listing of Crystal Violet in various international cosmetic regulations where its use is prohibited?
  • What weight should be given to the limited evidence of genotoxicity, and potential carcinogenicity, in deciding the most appropriate controls over the use of Crystal Violet?
  • There appear to be non-cosmetic uses that could result in consumer exposure (e.g. in domestic dyes and colourants, and in antibacterial preparations). Should a Schedule listing be specific to control use in hair dyes or cosmetic products (as for some other hair dye ingredients), or should the entry be broader in order to capture these other uses? Should a schedule entry include an exception clause that refers to its listing in Schedule 4?
  • Does a listing under the generic name CRYSTAL VIOLET (or GENTIAN VIOLET) necessarily capture all the dyes listed in the NICNAS IMAP report? Should a generic entry contain the additional words '... and other triarylmethane dyes'?
  • Is there a need for specific entries in Appendices E and F to manage labelling of scheduled products?
Substance summary

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

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)

Acute toxicity

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.

Skin irritation

No reliable data are available for the chemicals in this group.

Eye irritation

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.

Sensitisation

No data are available.

Repeat-dose toxicity

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.

Genotoxicity and mutagenicity

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.

Carcinogenicity

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.

Reproduction and developmental toxicity

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.

Observation in humans

There are limited data indicating that crystal violet causes mild skin irritation in humans; however, very few experimental details were provided.

Public exposure

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).

International regulations

The chemicals are listed on the following:

  • EU Cosmetics Regulation 1223/2009 Annex II—List of substances prohibited in cosmetic products (CAS No. 548-62-9; CAS No. 1694-09-3; CAS No. 2390-59-2; CAS No. 2390-60-5; CAS No. 2580-56-5)
  • New Zealand Cosmetic Products Group Standard—Schedule 4: Components cosmetic products must not contain (CAS No. 548-62-9; CAS No. 1694-09-3; CAS No. 2580-56-5);
  • Health Canada List of prohibited and restricted cosmetic ingredients (The Cosmetic Ingredient ‘Hotlist’) (CAS No. 548-62-9; CAS No. 1694-09-3; CAS No. 2390-59-2; CAS No. 2390-60-5; CAS No. 2580-56-5); and
  • The Association of Southeast Asian Nations (ASEAN) Cosmetic Directive Annex II Part 1: List of substances which must not form part of the composition of cosmetic products (CAS No. 548-62-9; CAS No. 1694-09-3; CAS No. 2580-56-5).

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.

Current scheduling status

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.

Relevant scheduling history

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.

Pre-meeting public submissions

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.

ACCS advice to the delegate

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

  • Crystal Violet (CAS No. 548-62-9)
  • Acid Violet 49 (CAS No. 1694-09-3)
  • Ethyl Violet (CAS No. 2390-59-2)
  • Basic Blue 7 (CAS No. 2390-60-5)
  • Basic Blue 26 (CI 44045) (CAS No. 2580-56-5)

Schedule 6 – New entries

METHYLROSANILINIUM CHLORIDE AND THE FOLLOWING TRIARYLMETHANE DYES

  • Crystal Violet (CAS No. 548-62-9)
  • Acid Violet 49 (CAS No. 1694-09-3)
  • Ethyl Violet (CAS No. 2390-59-2)
  • Basic Blue 7 (CAS No. 2390-60-5)
  • Methylium, 4-(dimethylamino)phenylbis4-(ethylamino)-3-methylphenyl-, acetate (CAS No. 72102-55-7)
    • except when in Schedule 4 or when used as a dermal marker

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"

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 factors1;
  • Other relevant information.
Delegate's interim decision

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

  • Acid Violet 49 (CAS No. 1694-09-3)
  • Ethyl Violet (CAS No. 2390-59-2)
  • Basic Blue 7 (CAS No. 2390-60-5)
  • Basic Blue 26 (CI 44045) (CAS No. 2580-56-5)

Schedule 6 – New entries

METHYLROSANILINIUM CHLORIDE (formerly known as crystal violet CAS No. 548-62-9) AND THE FOLLOWING TRIARYLMETHANE DYES

  • Acid Violet 49 (CAS No. 1694-09-3)
  • Ethyl Violet (CAS No. 2390-59-2)
  • Basic Blue 7 (CAS No. 2390-60-5)
  • Methylium, 4-(dimethylamino)phenylbis4-(ethylamino)-3-methylphenyl-, acetate (CAS No. 72102-55-7)
    • except when included in Schedules 4 or 10

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


Footnotes

  1. Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)

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