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

Scheduling medicines and poisons

3 February 2016

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1.9 Dyes that could release selected carcinogenic amines (not listed on AICS)

Part A - Interim decisions on matters referred to an expert advisory committee

1. Scheduling proposals referred to the November 2015 meeting of the Advisory Committee on Chemicals Scheduling (ACCS#15)

1.9 Dyes that could release selected carcinogenic amines (not listed on AICS)

Scheduling proposal

The chemicals scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS):

  • To create a new entry for various dyes that could release selected carcinogenic amines (not listed on AICS) and/or the aromatic amine precursors in Schedule 7 or Appendix C.
Scheduling application

The reasons for the request were:

  • Although the data for the actual dyes are limited, the chemicals are all considered to have the potential to be metabolised to the following carcinogenic and/or genotoxic aromatic amines through reductive cleavage of the azo linkage:
    • 2-naphthylamine (CAS No. 91-59-8);
    • 2,4,5-trimethylaniline (CAS No. 137-17-7); and
    • 6-methoxy-m-toluidine (p-cresidine) (CAS No. 120-71-8).
  • Although the commercial production of Ponceau 3R and dyes based on 2-naphthylamine is restricted in some countries, this does not appear to be the case for dyes based on p-cresidine. In addition, commercial production in other countries such as India and China is not known.
  • The scheduling of these dyes would be consistent with scheduling decisions on other azo dyes that have the potential to be metabolised to known carcinogens.
  • Trace levels of the aromatic amines used in dye production could be technologically inevitable.
  • The delegate's reason for referring this scheduling proposal to the ACCS is that, in accordance with section 4.2 of the Scheduling Policy Framework (SPF), advice is required to be obtained from an expert advisory committee for all proposals to list in Schedule 7, and this will also offer industry an opportunity to provide comment on potential regulatory impacts.
Specific issues/questions raised by the Delegate

The delegate asked the committee the following questions:

  • Noting the scheduling approaches to the restrictions on benzidine-based azo dyes and benzidine congener (3,3'-disubstituted) based azo dyes from the 2013 and 2014 November ACCS meetings, and for other azo dyes that can be de-azotised to carcinogenic aromatic amines at the August 2015 ACCS meeting, does the ACCS support creation of an additional listing for five azo dyes listed in the NICNAS IMAP report?
  • Should this listing be in Schedule 7 or 10? Should the listing(s) be for the named substances, along with their CAS numbers, or should they be added to the generic entry developed at the August 2015 ACCS meeting? If the substances are named individually, should they be listed as the sodium salts (as in the IMAP report), or named such as to capture all salts?
Substance summary

Please refer to the NICNAS Inventory Multi-tiered Assessment Prioritisation (IMAP) human health Tier II assessment report for Dyes that could release selected carcinogenic amines (not listed on AICS).

The critical concern for this group of chemicals and the focus of this assessment relates to the potential carcinogenic effects following exposure. The toxicological data for the chemicals in this group are limited. However, these azo compounds could undergo reductive cleavage of their azo bonds, releasing the following aromatic amines that have known carcinogenic potential: 2-naphthylamine; 2,4,5-trimethylaniline; and p-cresidine. These aromatic amines, are classified carcinogens in Australia. In addition, 2-naphthylamine (cleavage product of CAS No. 85186-64-7 and CAS No. 85186-66-9), is identified as a prohibited carcinogen (Table 10.1, Schedule 10) in Workplace Health and Safety legislation (WHS Regulations, 2011). Whilst these aromatic amines are not listed on the AICS, they are reported to be used overseas. Therefore, these chemicals could potentially be present as impurities in products imported into Australia.

This group of dyes represents the fourth such submission arising from IMAP. The previous three, for dyes based on benzidine, dyes based on benzidine congeners, and dyes based on other carcinogenic amines listed on AICS, have resulted in ACCS recommendations and/or Delegate's decisions for Schedule 7 listing. The current group completes the set of dyes based on "EU 22" amines forwarded for scheduling. The critical fact that separates this group from the previously (August 2015) considered group is that, as the amines are not on AICS, there are no IMAP reports on the amines available for reference, and so consideration of the carcinogenicity of the amines is contained within the assessment of the dyes (see IMAP report).

Genotoxicity

Based on the limited data available, it is not possible to draw a definite conclusion regarding the genotoxicity of the chemicals in this group. Although available data are neither sufficient nor adequately comprehensive for classification, a genotoxic mode of action cannot be ruled out. Studies on the aromatic amines that are potential cleavage products of the chemicals in this group (2-naphthylamine, 2,4,5-trimethylaniline and p-cresidine) demonstrated genotoxicity/mutagenicity in a number of in vitro and in vivo assays (see IMAP report for more details).

Carcinogenicity

Limited data are available for the carcinogenic potential of the chemicals in this group.

Ponceau 3R is reported to produce tumours in rat livers and mouse urinary bladders. Long-term oral exposure (feeding studies) to Ponceau 3R of up to two years with 0.5-5 % doses in the diet) produced liver tumours in rats (Wistar, Osborne-Mendel, Bethesda Black). These include hepatomas, hepatic adenomas, bile duct adenoma, and adenomatous or nodular hyperplasia (Grice et al., 1961; Mannell, 1964; Aiso et al., 1966; IARC, 1975). The authors suggested that the component compounds present in the chemical, such as 2,4,5-trimethylaniline, contributed to the observed carcinogenic activity of Ponceau 3R (Mannell, 1964). In mice, Ponceau 3R produced bladder tumours on implantation in the urinary bladder (IARC, 1975 (referenced in the IMAP report)).

The International Agency for Research on Cancer (IARC) has classified Ponceau 3R as 'Possibly carcinogenic to humans' (Group 2B), based on inadequate evidence for carcinogenicity in humans, but sufficient evidence for carcinogenicity in animal testing (IARC, 1987 (referenced in the IMAP report)).

Although data are not available for the other chemicals in this group, the aromatic amines that could be released following the azo bond reductive cleavage of these chemicals are known carcinogens.

The aromatic amine, 2-naphthylamine, is classified as hazardous - Category 1 carcinogenic substance - with the risk phrase 'May cause cancer by inhalation' (T; R45) in the (HSIS) (Safe Work Australia).

The IARC has classified 2-naphthylamine as 'known to be a human carcinogen based on the sufficient evidence of carcinogenicity from studies in humans'. A number of studies reported a significant increase in human urinary bladder tumours caused by occupational exposure. Experimentally, urinary bladder tumours were also seen in several species of laboratory animals (rat, hamster, dog and monkey) following repeated exposures to 2-napthylamine via a number of routes including oral, dermal, subcutaneous, intraperitoneal, intravesicular implantation and bladder-instillation (IARC, 2010 (referenced in the IMAP report)). Liver and lung tumours were also observed in mice.

The aromatic amines, p-cresidine and 2,4,5-trimethylaniline are classified as Category 2 carcinogenic substances - with the risk phrase 'May cause cancer' (T; R45) in HSIS (Safe Work Australia). These aromatic amines are considered as 'reasonably anticipated to be human carcinogens based on sufficient evidence of carcinogenicity from studies in experimental animals' (IARC, 1982; NTP, 2011 (referenced in the IMAP report)).

Long-term oral exposure to p-cresidine produced malignant and benign tumours in the urinary bladder and liver of rats and mice, and nasal cancer in rats (NTP, 2011). Chronic exposure of rats and mice to 2,4,5-trimethylaniline caused lung and liver tumours (NCI, 1979; NTP; Wiley VCH (referenced in the IMAP report)).

Metabolic activation of aromatic amines to produce nitrenium ion metabolites, which cause DNA adduct formation and induction of DNA damaging effects, has been postulated to be the likely mechanism of action for their carcinogenicity (SCCNFP, 2002 (referenced in the IMAP report)). The IARC concluded that 'there is strong mechanistic evidence that the carcinogenicity of 2-napthylamine operates by a genotoxic mechanism of action' (IARC, 2010 (referenced in the IMAP report)).

Public exposure

Although the commercial production of Ponceau 3R and dyes based on 2-naphthylamine is restricted in some countries, this does not appear to be the case for dyes based on p-cresidine and 2,4,5-trimethylaniline. In addition, commercial production in other countries such as India and China is not known. Therefore the introduction of these dyes for home use cannot be excluded.

International regulations

Cosmetic

The chemicals are restricted by the EU Annex XVII to EU Regulation as follows:

  1. Azo dyes which, by reductive cleavage of one or more azo groups, may release one or more of the aromatic amines listed in Appendix 8, in detectable concentrations, i.e. above 30 ppm in the finished articles or in the dyed parts thereof, according to the testing methods listed in Appendix 10, shall not be used in textile and leather articles which may come into direct and prolonged contact with the human skin or oral cavity, such as:
    • clothing, bedding, towels, hairpieces, wigs, hats, nappies and other sanitary items, sleeping bags;
    • footwear, gloves, wristwatch straps, handbags, purses/wallets, briefcases, chair covers, purses worn round the neck;
    • textile or leather toys and toys which include textile or leather garments; and
    • yarn and fabrics intended for use by the final consumer.
  2. Furthermore, the textile and leather articles referred to in paragraph 1 above shall not be placed on the market unless they conform to the requirements set out in that paragraph'.

Appendix 8 is the list of the "EU 22" aromatic amines.

Scheduling status

None of the dyes listed above are not specifically scheduled.

Scheduling history

None of the dyes listed above have been previously considered for scheduling; therefore, scheduling history is not available.

Pre-meeting public submissions

One public submission was received. No general objections to proposal, however they note that changing labelling may require a period of transition.

The public submission is available at Public submissions on scheduling matters.

ACCS advice to the delegate

The Committee recommended that the group Schedule 7 entry for AZO DYES that are derivatives by diazotisation of any of the following substances be amended to include the additional following highlighted in red:

Schedule entry
Schedule 7 - Amend Entry

AZO DYES that are derivatives by diazotisation of any of the following substances:

  • o-anisidine (CAS No. 90-04-0)
  • o-toluidine (CAS No. 95-53-4)
  • p-aminoazobenzene (CAS No. 60-09-3)
  • o-aminoazotoluene (CAS No. 97-56-3)
  • 2,4-toluenediamine (CAS No. 95-80-7)
  • 5-nitro-o-toluidine (CAS No. 99-55-8)
  • p-chloroaniline (CAS No. 106-47-8)
  • 2-naphthylamine (CAS No. 91-59-8)
  • 2,4,5-trimethylaniline (CAS No. 137-17-7)
  • 6-methoxy-m-toluidine (p-cresidine) (CAS No. 120-71-8)

The committee recommended an implementation date of 1 June 2016.

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

The reasons for the recommendations comprised the following:

  • To be consistent with previous decisions made on azo-based dyes
  • Azo-dyes are considered to be carcinogenic in animal data and in-vitro testing
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • Public submissions received;
  • ACCS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors9;
  • Other relevant information.
Delegate's interim decision

The NICNAS IMAP program has previously referred for possible listing in Schedule 7, a number of azo dyes based on the known human carcinogen benzidine, as well as some dyes based on benzidine congeners and those that can be reduced by azo reductases to carcinogenic amine components. Following referral to the August 2015 meeting of the ACCS, the delegate agreed to Schedule 7 listing for azo dyes that can be reduced by azoreductases to yield 8 specific carcinogenic aromatic amines: o-anisidine (CAS No. 90-04-0); o-toluidine (CAS No. 95-53-4); p-aminoazobenzene (CAS No. 60-09-3); o-aminoazotoluene (CAS No. 97-56-3); 2,4-toluenediamine (CAS No. 95-80-7); 5-nitro-o-toluidine (CAS No. 99-55-8);p-chloroaniline (CAS No. 106-47-8);and 4-chloro-o-toluidine (CAS No. 95-69-2). The current proposal seeks to extend the list of carcinogenic amines is this generic entry, in order to capture some additional potentially carcinogenic amines, specifically 2-naphthylamine (CAS No. 91-59-8); 2,4,5-trimethylaniline (CAS No. 137-17-7); and 6-methoxy-m-toluidine(p-cresidine) (CAS No. 120-71-8).

The delegate accepts ACCS advice that the dyes referred in the current submission should also be controlled for use in consumer products by listing in Schedule 7, and agrees that adding them to the current generic listing for AZO DYES that are derivatives by diazotisation of any of the following substances: ... would achieve this objective. The delegate notes a point raised in a public submission that some of the listed aromatic amines may be present as manufacturing impurities in the relevant azo dyes. However, since the objective is to control the parent dyes themselves, and the resultant aromatic amines are not specifically listed as individual substances in Schedule 7, this should not be a problem.

The proposed implementation date is 1 June 2016.

The earliest practicable implementation date is warranted since the objective is to remove any such products from the Australian market on safety grounds.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: c) the toxicity of the substance.

Schedule entry
Schedule 7 - Amend Entry

AZO DYES that are derivatives by diazotisation of any of the following substances:

  • o-anisidine (CAS No. 90-04-0)
  • o-toluidine (CAS No. 95-53-4)
  • p-aminoazobenzene (CAS No. 60-09-3)
  • o-aminoazotoluene (CAS No. 97-56-3)
  • 2,4-toluenediamine (CAS No. 95-80-7)
  • 5-nitro-o-toluidine (CAS No. 99-55-8)
  • p-chloroaniline (CAS No. 106-47-8)
  • 2-naphthylamine (CAS No. 91-59-8)
  • 2,4,5-trimethylaniline (CAS No. 137-17-7)
  • 6-methoxy-m-toluidine (p-cresidine) (CAS No. 120-71-8)

Footnotes

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

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