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Scheduling delegate's final decisions, March 2016

Scheduling medicines and poisons

17 March 2016

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1.8 C.I. Direct Orange 1

Part A - Final 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)

1.8 C.I. Direct Orange 1

Scheduling proposal

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

  • In August 2015, the National Industrial Chemicals Notification and Assessment Scheme (NICNAS), under its Inventory Multi-tiered Assessment and Prioritisation (IMAP) Programme, referred a proposal to amend the entry for BENZIDINE-BASED AZO DYES in Schedule 7 to include C.I. Direct Orange 1 in the Poison Standard by the delegate.
Scheduling application

The reasons for the request were:

  • That whilst the data for the actual chemical are limited, C.I. Direct Orange 1 has been identified as a benzidine-based azo dye.
  • Benzidine based-dyes have been shown to be metabolised to benzidine, a known human carcinogen.
  • In June 2013, NICNAS completed an assessment of a number of azo dyes which may break down to produce the potent carcinogen, benzidine. The chemicals were recommended for scheduling to prohibit their sale, supply and use in consumer products (NICNAS). The scheduling delegate decided to list the chemicals in Schedule 7 of the Poisons Standard (effective as of 1 June 2014). In the absence of similar regulatory controls, this chemical could also pose an unreasonable risk to the public.
  • In November 2014, a similar proposal for scheduling C. I. Acid Black 29, another benzidine-based dye not included in the original NICNAS assessment, was agreed by ACCS.
  • The scheduling of this chemical would be consistent with scheduling decisions with other benzidine-based dyes.
  • The proposal is to add C.I. Direct Orange 1 to the existing BENZIDINE-BASED AZO DYES entry in Schedule 7. The SPF recommends that proposals to list in S7 be referred to the ACCS, 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:

  • Does the ACCS agree that the toxicological profile of C.I .Direct Orange 1 is consistent with other benzidine-based azo dyes, and therefore warrants addition to that entry? Adding C.I. Direct Orange 1 to the current list of substances covered by this generic entry would be consistent with the way that listing of C.I. Acid Black was recommended at the November 2014 ACCS meeting.
  • Should the entry list both the common name (C.I Direct Orange 1) and the CAS number? As a secondary issue, does the ACCS support a recommendation to the TGA that the current formatting of the BENZIDINE-BASED AZO DYES entry in Poisons Standard July 2015 be addressed, so that CAS numbers are appropriately aligned with the substances to which they refer, and missing CAS numbers are re-inserted?
Substance summary

Please refer to the NICNAS Inventory Multi-tiered Assessment Prioritisation (IMAP) human health Tier II assessment report for C.I. Direct Orange 1.

The critical concern for this chemical and the focus of this assessment relates to the potential carcinogenic effects following exposure. Data are available for four benzidine-based dyes; Direct Red 28 (CAS No. 573-58-0), Direct Blue 6 (CAS No. 2602-46-2), Direct Black 38 (CAS No. 1937-37-7) and Direct Brown 95 (CAS No. 16071-86-6). Based on the common metabolite, benzidine, the data are considered representative for C.I. Direct Orange 1. These data can be found on the NICNAS website.

Toxicokinetics

Metabolism of benzidine-based dyes to free benzidine and its metabolites have been observed in both humans and animals.

In vivo, azo reduction of benzidine-based substances, liberating free benzidine, occurs by an enzyme-mediated reaction. The intestinal microflora have been shown to be particularly active in azo dye reduction, but hepatic enzymes can also catalyse the reductive cleavage.

Bacteria on the skin have also been shown to possess azoreductase activity.

Genotoxicity

No data are available for the chemical. However, a dose-related increase in the number of circulating peripheral lymphocytes displaying chromosomal aberrations was observed in workers exposed to benzidine and benzidine-based dyes (Direct Black 38 and Direct Blue 6). The highest frequencies of aberrant lymphocytes were associated with the highest airborne dust concentrations of benzidine (0.42–0.86 mg/m3) or benzidine-based dyes (7.8–32.3 mg/m3), and with the highest mean levels of benzidine found in the urine (1.8–2.3 µg/L). The frequency of polyploid lymphocytes was also elevated in workers when compared with controls (ATSDR, 2001; IARC 2010 (referenced in C.I. Direct Orange 1 IMAP report)).

Carcinogenicity

No data are available for the chemical. However, the related chemicals Direct Red 28, Direct Black 38, Direct Blue 6 and Direct Brown 95 are currently classified as hazardous as Category 2 carcinogens with the risk phrase 'May cause cancer' (T; R45) in HSIS (Safe Work Australia). Several other benzidine-based dyes are recommended for classification for carcinogenicity (refer to the IMAP report).

Three benzidine-based dyes (Direct Black 38, Direct Blue 6 and Direct Brown 95) have been tested for carcinogenicity in animals. The International Agency for Research on Cancer (IARC) concluded that there was sufficient evidence for the carcinogenicity of all dyes metabolised to benzidine on the basis of these studies. Observed effects included increased incidence of hepatocellular carcinomas and liver neoplastic nodules with all three dyes, and mammary gland cancers with Direct Black 38. A slight increase in transitional cell carcinoma of the urinary bladder was observed in an implantation study with Direct Blue 6. Hepatocellular carcinomas and liver neoplastic nodules were observed for all three dyes, despite a relatively short exposure period of 13 weeks (NTP, 2011; IARC, 2012; Government of Canada, 2013 (referenced in C.I. Direct Orange 1 IMAP report)).

The evidence of bladder cancer for workers exposed to benzidine-based dyes was not consistent across studies. There were limitations in the studies, including coexposure to known carcinogens in humans. Despite this, IARC has classified dyes metabolised to benzidine as carcinogenic to humans (Group 1) and the US National Toxicology Program has also classified dyes metabolised to benzidine as 'known to be human carcinogens'. The classification was based on findings that:

  • benzidine is known to be a human carcinogen;
  • the metabolism of benzidine-based dyes results in the release of free benzidine and the induction of chromosomal aberration in humans; and
  • benzidine exposure from exposure to benzidine-based dyes is equivalent to exposure to equimolar doses of benzidine.
Reproductive and developmental toxicity

No data are available for the chemical. However, the related chemicals Direct Red 28, Direct Black 38 and Direct Blue 6 are classified as hazardous - Category 3 substances toxic to reproduction - with the risk phrase 'Possible risk of harm to the unborn child' (T; R63) in HSIS (Safe Work Australia). Several other benzidine-based dyes are recommended for classification for developmental toxicity (see the IMAP report).

Public exposure

Whilst the use of benzidine-based dyes is being phased out in some countries, use of the chemical as a dye has been reported internationally. The introduction of this chemical for home use cannot be excluded.

International regulations

Cosmetics

No known restrictions have been identified for the chemical. However, the related benzidine-based dyes, Direct Red 28 (CAS No. 573-58-0), Direct Black 38 (CAS No. 1937-37-7), Direct Blue 6 (CAS No. 2602-46-2) and Direct Brown 95 (CAS No. 16071-86-6) are listed on the following (Galleria Chemica):

  • Association of South East Asian Nations (ASEAN) Cosmetic Directive Annex II Part 1: List of substances which must not form part of the composition of cosmetic products;
  • EU Regulation (EC) No 1223/2009 of the European Parliament and of the Council of 30 November 2009 on cosmetic products - Annex II - List of Substances Prohibited in Cosmetic Products; and
  • New Zealand Cosmetic Products Group Standard - Schedule 4: Components cosmetic products must not contain.

Other

Access to benzidine-based dyes for home use is no longer permitted in the USA (NTP, 2011).

The chemical is restricted by Annex XVII to REACH 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.'
Scheduling status

CI. Direct Orange 1 is not specifically scheduled.

Scheduling history

CI. Direct Orange 1 has not been previously considered for scheduling; therefore, scheduling history is not available.

Pre-meeting public submissions

One public submission was received. There was no objection to the proposal.

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

ACCS advice to the delegate

The Committee recommended that the following amendments (highlighted in red) be made to the Schedule 7 entry for BENZIDINE-BASED AZO DYES to include C.I. Direct Orange 1 (CAS No. 545779-28-1) and insert any missing CAS numbers as follows:

Schedule 7 - Amend Entry

BENZIDINE-BASED AZO DYES

  • 2,2'-[[1,1'-biphenyl]-4,4'-diylbis(azo)]bis[N-(4-chlorophenyl)-3-oxobutanamide] (CAS No. 94249-03-3)
  • Acid Red 85 (Acid Fast Red A)
  • 1,3-Naphthalenedisulfonic acid, 7-hydroxy-8-[[4'-[[4-[[(4-methylphenyl)sulfonyl]oxy]phenyl]azo][1,1'-biphenyl]-4-yl]azo]-, disodium salt (CAS No. 3567-65-5)
  • C.I. Acid Black 29 (CAS No. 12217-14-0)
  • C.I. Direct Orange 1 (CAS No. 54579-28-1)
  • Direct Black 38
  • 2,7-Naphthalenedisulfonic acid, 4-amino-3-[[4'-[(2,4-diaminophenyl)azo][1,1'-biphenyl]-4-yl]azo]-5-hydroxy-6-(phenylazo)-, disodium salt (CAS No. 1937-37-7)
  • Direct Blue 2
  • 2,7-Naphthalenedisulfonic acid, 5-amino-3-[[4'-[(7-amino-1-hydroxy-3-sulfo-2-naphthalenyl)azo][1,1'-biphenyl]-4-yl]azo]-4-hydroxy-, trisodium salt (CAS No. 2429-73-4)
  • Direct Blue 6
  • 2,7-Naphthalenedisulfonic acid, 3,3'-[[1,1'-biphenyl]-4,4'-diylbis(azo)]bis[5-amino-4-hydroxy-, tetrasodium salt (CAS No. 2602-46-2)
  • Direct Brown 2
  • 5-[[4'-[(7-amino-1-hydroxy-3-sulfo-2-naphthalenyl)azo][1,1'-biphenyl]-4-yl]azo]-2-hydroxy- benzoic acid disodium salt (CAS No. 2429-82-5)
  • Direct Brown 95
  • Cuprate(2-), [5-[[4'-[[2,6-dihydroxy-3-[(2-hydroxy-5-sulfophenyl)azo]phenyl]azo][1,1'-biphenyl]-4-yl]azo]-2-hydroxybenzoato(4-)]-, disodium salt (CAS No. 16071-86-6)
  • Direct Green 1
  • 2,7-Naphthalenedisulfonic acid, 4-amino-5-hydroxy-3-[[4'-[(4-hydroxyphenyl)azo][1,1'-biphenyl]-4-yl]azo]-6-(phenylazo)-, disodium salt (CAS No. 3626-28-6)
  • Direct Green 6
  • 2,7-Naphthalenedisulfonic acid, 4-amino-5-hydroxy-6-[[4'-[(4-hydroxyphenyl)azo][1,1'-biphenyl]-4-yl]azo]-3-[(4-nitrophenyl)azo]-, disodium salt (CAS No. 4335-09-5)
  • Direct Red 28 (Congo Red)
  • 1-Naphthalenesulfonic acid, 3,3'-[[1,1'-biphenyl]-4,4'-diylbis(azo)]bis[4-amino-, disodium salt (CAS No. 573-58-0)
  • Direct Red 37
  • 1,3-Naphthalenedisulfonic acid, 8-[[4'-[(4-ethoxyphenyl)azo][1,1'-biphenyl]-4-yl]azo]-7-hydroxy-, disodium salt (CAS No. 3530-19-6)

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 factors8;
  • Other relevant information.
Delegate's interim decision

The delegate notes that a number of benzidine-based azo dyes were listed in Schedule 7 as an outcome of advice from the February 2014 meeting of the ACCS. The listed dyes warrant stringent controls because of their carcinogenic potential via conversion to benzidine (a known human carcinogen). The delegate therefore accepts ACCS advice that CI Direct Orange 1 shares the carcinogenic potential of the already listed benzidine-based azo dyes and that it should be added to the list of such dyes in the current Schedule 7 listing.

Only the dye name/number and CAS number are to be included in the listing, without the chemical name as for other listings, since it appears that C.I Direct Orange 1 may be a mixture of three different substances. In addition, as an editorial amendment, the missing CAS number for C.I. Acid Black 29 is to be included.

This is the earliest practicable date on which this schedule can be implemented in the Poisons Standard.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: a) the risks and benefits of the use of the substance; b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance.

Schedule entry
Schedule 7 - Amend Entry

BENZIDINE-BASED AZO DYES

  • 2,2'-[[1,1'-biphenyl]-4,4'-diylbis(azo)]bis[N-(4-chlorophenyl)-3-oxobutanamide] (CAS No. 94249-03-3)
  • Acid Red 85 (Acid Fast Red A)
  • 1,3-Naphthalenedisulfonic acid, 7-hydroxy-8-[[4'-[[4-[[(4-methylphenyl)sulfonyl]oxy]phenyl]azo][1,1'-biphenyl]-4-yl]azo]-, disodium salt (CAS No. 3567-65-5)
  • C.I. Acid Black 29 (CAS No. 12217-14-0)
  • C.I. Direct Orange 1 (CAS No. 54579-28-1)
  • Direct Black 38
  • 2,7-Naphthalenedisulfonic acid, 4-amino-3-[[4'-[(2,4-diaminophenyl)azo][1,1'-biphenyl]-4-yl]azo]-5-hydroxy-6-(phenylazo)-, disodium salt (CAS No. 1937-37-7)
  • Direct Blue 2
  • 2,7-Naphthalenedisulfonic acid, 5-amino-3-[[4'-[(7-amino-1-hydroxy-3-sulfo-2-naphthalenyl)azo][1,1'-biphenyl]-4-yl]azo]-4-hydroxy-, trisodium salt (CAS No. 2429-73-4)
  • Direct Blue 6
  • 2,7-Naphthalenedisulfonic acid, 3,3'-[[1,1'-biphenyl]-4,4'-diylbis(azo)]bis[5-amino-4-hydroxy-, tetrasodium salt (CAS No. 2602-46-2)
  • Direct Brown 2
  • 5-[[4'-[(7-amino-1-hydroxy-3-sulfo-2-naphthalenyl)azo][1,1'-biphenyl]-4-yl]azo]-2-hydroxy- benzoic acid disodium salt (CAS No. 2429-82-5)
  • Direct Brown 95
  • Cuprate(2-), [5-[[4'-[[2,6-dihydroxy-3-[(2-hydroxy-5-sulfophenyl)azo]phenyl]azo][1,1'-biphenyl]-4-yl]azo]-2-hydroxybenzoato(4-)]-, disodium salt (CAS No. 16071-86-6)
  • Direct Green 1
  • 2,7-Naphthalenedisulfonic acid, 4-amino-5-hydroxy-3-[[4'-[(4-hydroxyphenyl)azo][1,1'-biphenyl]-4-yl]azo]-6-(phenylazo)-, disodium salt (CAS No. 3626-28-6)
  • Direct Green 6
  • 2,7-Naphthalenedisulfonic acid, 4-amino-5-hydroxy-6-[[4'-[(4-hydroxyphenyl)azo][1,1'-biphenyl]-4-yl]azo]-3-[(4-nitrophenyl)azo]-, disodium salt (CAS No. 4335-09-5)
  • Direct Red 28 (Congo Red)
  • 1-Naphthalenesulfonic acid, 3,3'-[[1,1'-biphenyl]-4,4'-diylbis(azo)]bis[4-amino-, disodium salt (CAS No. 573-58-0)
  • Direct Red 37
  • 1,3-Naphthalenedisulfonic acid, 8-[[4'-[(4-ethoxyphenyl)azo][1,1'-biphenyl]-4-yl]azo]-7-hydroxy-, disodium salt (CAS No. 3530-19-6)
Public submissions on the interim decision

One submission was received. The submission supported the delegate's interim decision.

Edited versions of public submissions are available at Public submissions on scheduling matters.

Delegate's final decision

The delegate notes the submission received in response to publication of the interim decision and confirms the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.

Schedule entry
Schedule 7 - Amend Entry

BENZIDINE-BASED AZO DYES

  • 2,2'-[[1,1'-biphenyl]-4,4'-diylbis(azo)]bis[N-(4-chlorophenyl)-3-oxobutanamide] (CAS No. 94249-03-3)
  • Acid Red 85 (Acid Fast Red A)
    1,3-Naphthalenedisulfonic acid, 7-hydroxy-8-[[4'-[[4-[[(4-methylphenyl)sulfonyl]oxy]phenyl]azo][1,1'-biphenyl]-4-yl]azo]-, disodium salt
    (CAS No. 3567-65-5)
  • C.I. Acid Black 29
    (CAS No. 12217-14-0)
  • C.I. Direct Orange 1
    (CAS No. 54579-28-1)
  • Direct Black 38
    2,7-Naphthalenedisulfonic acid, 4-amino-3-[[4'-[(2,4-diaminophenyl)azo][1,1'-biphenyl]-4-yl]azo]-5-hydroxy-6-(phenylazo)-, disodium salt
    (CAS No. 1937-37-7)
  • Direct Blue 2
    2,7-Naphthalenedisulfonic acid, 5-amino-3-[[4'-[(7-amino-1-hydroxy-3-sulfo-2-naphthalenyl)azo][1,1'-biphenyl]-4-yl]azo]-4-hydroxy-, trisodium salt
    (CAS No. 2429-73-4)
  • Direct Blue 6
    2,7-Naphthalenedisulfonic acid, 3,3'-[[1,1'-biphenyl]-4,4'-diylbis(azo)]bis[5-amino-4-hydroxy-, tetrasodium salt
    (CAS No. 2602-46-2)
  • Direct Brown 2
    5-[[4'-[(7-amino-1-hydroxy-3-sulfo-2-naphthalenyl)azo][1,1'-biphenyl]-4-yl]azo]-2-hydroxy- benzoic acid disodium salt
    (CAS No. 2429-82-5)
  • Direct Brown 95
    Cuprate(2-), [5-[[4'-[[2,6-dihydroxy-3-[(2-hydroxy-5-sulfophenyl)azo]phenyl]azo][1,1'-biphenyl]-4-yl]azo]-2-hydroxybenzoato(4-)]-, disodium salt
    (CAS No. 16071-86-6)
  • Direct Green 1
    2,7-Naphthalenedisulfonic acid, 4-amino-5-hydroxy-3-[[4'-[(4-hydroxyphenyl)azo][1,1'-biphenyl]-4-yl]azo]-6-(phenylazo)-, disodium salt
    (CAS No. 3626-28-6)
  • Direct Green 6
    2,7-Naphthalenedisulfonic acid, 4-amino-5-hydroxy-6-[[4'-[(4-hydroxyphenyl)azo][1,1'-biphenyl]-4-yl]azo]-3-[(4-nitrophenyl)azo]-, disodium salt
    (CAS No. 4335-09-5)
  • Direct Red 28 (Congo Red)
    1-Naphthalenesulfonic acid, 3,3'-[[1,1'-biphenyl]-4,4'-diylbis(azo)]bis[4-amino-, disodium salt
    (CAS No. 573-58-0)
  • Direct Red 37
    1,3-Naphthalenedisulfonic acid, 8-[[4'-[(4-ethoxyphenyl)azo][1,1'-biphenyl]-4-yl]azo]-7-hydroxy-, disodium salt
    (CAS No. 3530-19-6)

The proposed implementation date is 1 June 2016.


Footnotes

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

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