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Scheduling delegate's final decisions: ACCS, November 2015

Scheduling medicines and poisons

19 November 2015

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2.7 Carcinogenic amines (azo dyes)

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

2. Scheduling proposals referred to the August 2015 ACCS meeting

2.7 Carcinogenic amines (azo dyes)

Scheduling proposal

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

  • In April 2015 the delegate received a request to consider new entries for various dyes that could release selected carcinogenic amines and/or aromatic amine precursors for listing in Schedule 7 or Schedule 10/Appendix C.
Scheduling application

The reasons for the request were:

  • that whilst 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;
    • 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 scheduling of these dyes would be consistent with scheduling decisions on other azo dyes that have the potential to be metabolised to known carcinogens;
  • that restrictions on using some of these chemicals exist overseas, with some restrictions based on the absence of adequate data to demonstrate safety; and
  • that trace levels of the aromatic amines used in the production of the dyes could be technologically inevitable.
Delegate's reasons for referring this to the committee

This is a complex scheduling matter that proposes listing in Schedule 7. The SPF recommends that such matters be referred to an advisory committee. Furthermore, the way the chemicals are listed for scheduling and the potential regulatory impacts are both matters on which the delegate requests ACCS advice.

The delegate asked the committee the following questions:

  • The NICNAS proposals for listing all the specified aromatic amines in Schedule 7 and/or Schedule 10, is to capture their use in dyes that may be metabolised to the listed aromatic amines. All are alleged to have genotoxic and/or carcinogenic properties that warrant restrictive scheduling. Does the ACCS agree that the genotoxic/carcinogenic potential of all the dyes supports such actions, and if not, which ones should be included in either Schedule 7 or 10?
  • Note that one of the specified amines (4-chloro-o-toluidine) is already listed in Schedule 7, but there is no indication in scheduling records of when, or why, this listing was made. Depending on how the ACCS proposes actions on the other listed amines, is there a need to amend the current S7 listing of 4-chloro-o-toluidine for consistency?
  • If they are to be included in Schedules 7/10, is the most appropriate way to list them individually, as in the public notice, or to create an entry analogous to that recommended at the November 2013 and 2014 ACCS meetings, where specific azo dyes that could be metabolised to benzidine or benzidine-congeners were listed in Schedule 7 under generic entries.
  • Note that the ACCS recommendation on dyes that could be metabolised to benzidine was based on knowledge that benzidine is a known human carcinogen. Is the strength of evidence for carcinogenicity for the listed aromatic amines in this current scheduling proposal of the same compelling nature?
  • To what extent could the REACH approach to classification in Annex XVII inform the way that these dyes could be listed in the SUSMP schedules?

Unless specifically included in the schedule wording, listing in Schedules 7 or 10 implies that the entries would capture products that contain the chemicals as an impurity or residual reaction product. What regulatory impact would such listing impose on products with residual contaminants if the ACCS recommends listing of the individual aromatic amines? Is there any basis for recommending scheduling cut-offs below which the restrictive scheduling would not apply?

Substance summary

Refer to the NICNAS Inventory Multi-tiered Assessment Prioritisation (IMAP) human health Tier II assessment reports for:

The critical concern for this group of chemicals relates to potential carcinogenic effects following exposure. Toxicological data are available for several of the chemicals: Solvent Red 24; Solvent Red 23; Solvent Red 1; Solvent Red 19; Orange Oil SS; Basic Red 76; Acid Red 73; Acid Red 35; Disperse Yellow 7; CAS No. 56358-09-9; and CAS No. 70879-65-1, which are considered representative of the potential for toxicity due to azo cleavage for all chemicals in this group. The data from the structurally-related chemicals and aromatic amines (azo cleavage products), the p-aminoazobenzene; o-anisidine; o-toluidine; 4-toluenediamine; o-aminoazotoluene; 5-nitro-o-toluidine; 4-chloro-o-toluidine; and p-chloroaniline are also included.

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.

Carcinogenicity

The chemicals identified by CAS No. 85136-74-9; CAS No. 108225-03-2; and CAS No. 118658-99-4 are classified as hazardous - Category 2 carcinogenic substances - with the risk phrase 'May cause cancer' (T; R45) in the HSIS (Safe Work Australia). No experimental data are available to evaluate or to support an amendment to this classification.

Limited data are available on the chemicals in this group. The carcinogenic potential of Solvent Red 23 (p-aminoazobenzene-based); Solvent Red 19 (p-aminoazobenzene-based); Disperse Yellow 7 (CAS No. 6300-37-4) (p-aminoazobenzene-based); Solvent Red 24 (o-anisidine-based); and Orange Oil SS (o-toluidine-based) have been examined in long-term oral and dermal studies in mice and rats.

The strongest evidence for carcinogenicity was reported for Orange Oil SS. The chemical was found to be carcinogenic in mice, with intestinal and local tumours identified following oral and subcutaneous administration, respectively. The chemical also produced tumours in the mouse urinary bladders following bladder implantation. Studies in rats were inadequate for evaluation. Whilst both positive and negative results have been observed for other chemicals in this group, studies generally were considered inadequate for evaluation (IARC, 1975; Government of Canada, 2011; Government of Canada, 2013a).

The aromatic amine o-toluidine that could be formed following azo bond reductive cleavage in some of the chemicals in this group, is recommended for classification as a category 1 carcinogenic substance based on the evidence for carcinogenicity in humans.

Seven of these aromatic amines (p-aminoazobenzene; o-anisidine; o-toluidine; 2-4-toluenediamine; o-aminoazotoluene; 4-chloro-o-toluidine; and p-chloroaniline) are classified as hazardous (Category 2 carcinogenic substance) with the risk phrase 'May cause cancer' (T; R45) in the HSIS (Safework Australia). The chemical 5-Nitro-o-toluidine is classified as hazardous (Category 3 carcinogenic substance) with the risk phrase 'Limited evidence of carcinogenic effect' (Xn; R40) (Safe work Australia).

The available experimental data (animal studies) for these aromatic amines identifies a number of chemically-induced multi-organ tumours. These include benign and malignant tumours in the urinary bladder, spleen, subcutaneous tissues, kidneys, adrenal gland, liver, mammary glands, skin, blood and blood vessels, thyroid, lungs, gallbladder and renal pelvis.

Findings from several cohort studies involving factory workers have provided strong evidence for an increased risk of urinary bladder cancer associated with long-term occupational exposure to o-toluidine.

The mechanism of action underlying the carcinogenicity of these aromatic amines is still not fully understood. However, metabolic activation to produce nitrenium ion metabolites, which cause DNA adduct formation and induction of DNA damaging effects, has been suggested. A genotoxic mode of action cannot be dismissed.

Overall, based on the potential for the chemicals to be metabolised to form classified carcinogens, classification is considered appropriate.

Public exposure - Cosmetic and domestic

Some of the chemicals in this group (Solvent Red 23; Solvent Red 24; CAS No. 131-79-3; Solvent Red 1; Orange Oil SS; CAS No. 4482-25-1; CAS No. Acid Red 73; CAS No. Acid Red 35; CAS No. 8005-78-5; and Basic Red 76) have been identified as having potential cosmetic use. In Australia, Acid Red 35 and Basic Red 76 have reported use in hair dyes. A recent international use of Solvent Red 23 and Orange Oil SS in hair dyes was also reported. Some of the potential cleavage products or impurities of the chemicals in this group (aromatic amines) such as o-toluidine; p-aminoazobenzene; o-aminoazotoluene; and p-chloroaniline have been detected in a number of cosmetic products. The chemical o-toluidine was detected in permanent hair dyes and commercial henna samples (colours not specified). Hence, the public could potentially be exposed to classified carcinogens as an impurity in, or through the release of, these aromatic amines derived from the chemicals in this group. In addition, o-aminoazotoluene in decorative colouring (alta) used by Asian women on their feet has been reported. 'Certain imported products with cultural significance in some communities may result in increased risk for these populations'.

Based on the available data, widespread domestic use is not expected; however, the introduction of these dyes for home use cannot be excluded.

International regulations

Cosmetic

Based on the information obtained from Galleria Chemica, the chemicals Solvent Red 24 (CAS Nos. 85-83-6) and Solvent Red 23 are listed in the Health Canada List of prohibited and restricted cosmetic ingredients (the cosmetic ingredient "Hotlist").

The chemicals Solvent Red 24; Solvent Red 23; Solvent Red 1; CAS No. 4482-25-1; CAS No. 5413-75-2; CAS No. 5421-66-9; CAS No. 8005-78-5; CAS No. 85136-74-9; CAS No. 68425-18-3; CAS No. 118658-98-3; CAS No. 118658-99-4 are listed in the:

  • 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 Cosmetics Regulation 1223/2009 Annex II—List of substances prohibited in cosmetic products; and
  • New Zealand Cosmetic Products Group Standard—Schedule 4: Components cosmetic products must not contain.

The chemicals Solvent Red 24; CAS No. 85136-74-9; CAS No. 108225-03-2; and CAS No. 118658-99-4 are prohibited for all uses, whereas the other chemicals are prohibited when used as a substance in hair dye products.

The chemical Solvent Red 23 (identified as CI 26100) is listed in the:

  • ASEAN Cosmetic Directive Annex IV Part 1 - List of colouring agents allowed for use in cosmetic products;
  • EU Cosmetics Regulation 1223/2009 Annex II - List of colourants allowed in cosmetic products; and
  • New Zealand Cosmetic Products Group Standard - Schedule 6 - Colouring agents cosmetic products may contain with restriction.

In the above directives, the chemical is specified as 'not to be used in products applied to mucus membranes'; purity criteria also apply.

The Scientific Committee on Cosmetic Products and Non-Food Products (SCCNFP 2002) concluded that 'azo dyes which may release one or more carcinogenic aromatic amines, poses a risk to the health of the consumer'. In 2004, the SCCNFP concluded that several of the dyes cannot be considered safe for hair dyeing purposes, unless they are regarded as such on the basis of an adequate safety dossier. These include:

  • Solvent Red 1 (o-anisidine-based);
  • Solvent 23 and Acid Red 73 (p-aminoazobenzene-based); and
  • CAS No. 8005-78-5 and CAS No. 4482-25-1 (2,4-toluenediamine-based).

Basic Red 76 is listed in the EU Cosmetics Regulation 1223/2009 Annex III - List of substances which cosmetic products must not contain except subject to the restrictions laid down. The chemical is allowed in non-oxidative hair dye products at a maximum concentration of 2 %.

In 2011, the European Scientific Committee on Consumer Safety (SCCS) concluded that 'Basic Red 76 containing up to 18% methyl sulphate does not pose a risk to the health of the consumer when used as a non-oxidative hair dye with a maximum on-head concentration of 2.0%.' (SCCS, 2011). However, this opinion did not directly consider the release of o-anisidine from reductive cleavage of the azo linkage. Whilst quantitative risk calculations conducted by the Government of Canada estimated a margin of exposure of 10000 for cancer effects for the use of Solvent Red 1 in hair conditioner (concentration 0.1%) (Government of Canada, 2013a), in the absence of Australian specific use data, it is not possible to extrapolate this finding for Australia.

The chemicals Solvent Red 24; Solvent Red 23; and CAS No. 131-79-3 are listed in the Philippines Restricted Ingredients For Use In Cosmetics - List of substances which must not form part of the composition of cosmetic products.

Other

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

'1. Azodyes 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.'

The chemicals o-anisidine; o-toluidine; p-aminoazobenzene; 2,4-toluenediamine; o-aminoazotoluene; 5-nitro-o-toluidine; p-chloroaniline; and 4-chloro-o-toluidine are listed in Appendix 8 of EU REACH Annex XVII.

The chemicals identified by CAS No. 85136-74-9; CAS No. 108225-03-2; and CAS No. 118658-99-4 are restricted under Annex XVII to the REACH Regulations. 'The chemical cannot be used in substances and preparations placed on the market for sale to the general public in individual concentrations 0.1 %' (European Parliament and Council 1999; European Parliament and Council 2006; European Parliament and Council 2008).

Scheduling status

The chemicals proposed for scheduling consideration are not currently specifically scheduled. However, other azo dyes that have the potential to be metabolised to known carcinogens have previously been considered for scheduling and listed in Schedule 7. These other azo dyes include:

BENZIDINE-BASED AZO DYES being:

  • 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
  • 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
Scheduling history

In April 2014, the delegate, based on ACCS advice, made a decision to list 11 benzidine-based dyes in Schedule 7. The delegate indicated that inclusion of benzidine-based dyes in Schedule 10/Appendix C was not the most appropriate way of regulating the use of these substances. The delegate also noted that some of the dyes may have use as laboratory and analytical reagents. While there are stringent existing controls under Model Work Health and Safety legislation, and industry advises that they have been largely phased out of many uses, their carcinogenic potential, via conversion to benzidine (a known human carcinogen), indicates they should not be used in products available in the domestic market.

The delegate confirmed a proposed implementation date of 1 June 2015 for the following benzidine-based dyes:

Schedule 7 - New entry

BENZIDINE-CONGENER (3,3'-disubstituted) AZO DYES.

Schedule 7 - Amend Entry

BENZIDINE-BASED AZO DYES being:

C. I. ACID BLACK 29. CAS No. 12217-14-0

Note that the amendment to the current Schedule 7 BENZIDINE-BASED AZO DYES entry is to add the chemical C.I. Acid Black 29 to the existing list.

Public pre-meeting submissions

One public submission was received. The submission stated concern for the sheer number of compounds being considered for scheduling and that there is a lack of resources for a thorough consideration of each. Scheduling is posed to be delayed to enable more time for this. Two dyes were singled-out in the submission, CAS# 85-85-9 and CAS# 68391-30-0, where each are allowed, in some degree, in the EU. These dyes, and any others that may also be permitted in any degree, be exempt from Appendix C listing.

The public submissions are available at Public submissions on scheduling matters.

Summary of ACCS advice to the delegate

The committee recommended a new Schedule 7 be created for azodyes that are derivatives by diazotisation from the substances listed in the resolution.

The committee recommended an implementation date of 1 February 2016.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (a) the risks and benefits of the use of a substance; and (c) the toxicity of a substance.

The reasons for the recommendations comprised the following:

  • Potential widespread ability to substitute.
  • Carcinogenic potential.
Delegate's interim decision

The NICNAS IMAP program has referred for possible listing in Schedule 7, a number of azo dyes that can be reduced by azo reductases to carcinogenic components. The delegate has previously considered, and agreed to, Schedule 7 listing a number of benzidine-and benzidine-congener azo dyes. The current proposal seeks to regulate azo dyes that can be reduced by azo reductases to 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). One of these (4-chloro-o-toluidine) is already listed in Schedule 7 under the name used in connection with its use as a pesticide (chlordimeform). The others are not currently scheduled, presumably because they are only used in industrial processes, and not in products available to the public. Some of these substances are listed in Appendix 8 of EU REACH Annex XVII, suggesting that actions will be taken by industry to phase out many of their uses.

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 a generic listing (like the current Schedule 7 entries for benzidine-congener azo dyes) could achieve this objective. Simply listing the 7 specified aromatic amines in Schedule 7 as separate entries would not necessarily capture the parent azo dyes as 'derivatives'.

Schedule 7 - New 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)
  • 4-chloro-o-toluidine (CAS No. 95-69-2).

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; (c) the toxicity of a substance.

Proposed implementation date is 1 February 2016. This implementation date is warranted since the objective is to remove any such products from the Australian market on safety grounds.

The reasons for the interim decision comprised the following:

This wording specifically captures azo dyes that can be reduced by azo reductases to aromatic amines that could pose a cancer risk to the general public through their use in consumer products (e.g textiles, leathers, fabrics). At this time, there appears to be no need to list the individual aromatic amines in Schedule 7 in the absence of any information that they are used in consumer products in their own right.

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.
Public submissions on the interim decision

One submission was received. The submission did not support the delegate's interim decision. The submission states the implementation date is problematic for industry as it does not allow sufficient time for manufacturers to identify products that will be affected by the scheduling decision and allow a time to implement a substitute colourant. The submission was also concerned with two listed azo dyes in particular, CAS numbers 85-85-9 and 68391-30-0, that are permitted in for use in Europe and that there is insufficient evidence to include these in Schedule 7. Furthermore, the submission is concern that the scheduling entry is broadly worded—referring to 'diazotisation' reaction—and may capture substances that are listed elsewhere in the SUSMP.

Edited versions of the 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 the most pragmatic approach to controlling the substances under consideration. The delegate believes that a generic entry, similar to that previously used for the Schedule 7 entry for benzidine-congener azo dyes is preferable to individually listing all the affected dyes. The delegate notes the concerns that substances described in the generic entry may be difficult for industry to identify, but points to the NICNAS IMAP report that lists all 72 dyes on the Australian Inventory of Chemical Substances (AICS) that would be included in the generic entry.

The submission lists two dyes (CAS 85-85-9 and Basic Red 76 CAS 6831-30-0) that are on an EU list of substances allowed in hair dye products, with a maximum concentration proposed. Only Basic Red 76 is on the NICNAS list, and would be affected by the proposed Schedule 7 entry. The delegate suggests that if this dye is of importance to the Australian industry, a submission should be made to exempt this specific substance from the proposed Schedule 7 generic entry, with proposals on how it should be regulated. The submission also states that hair dyes based on 4-amino-m-cresol (CAS 2835-99-6) would be captured by the generic entry. This is not the case, since it is not an azo dye listed in the NICNAS IMAP report, and it is not one of the three o-toluidine amines listed as potential products of azoreduction of the dyes that are subject to the NICNAS report.

The submission also requests a longer implementation period to allow for re-formulation of products containing the affected azo dyes. However, consistent with the previous decisions relating to benzidine- and benzidine congener-based azo dyes, the delegate confirms that an early implementation date is required for the protection of public health from potentially carcinogenic amines that could be released by these azo dyes.

The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.


Footnotes

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

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