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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, July 2016
Scheduling medicines and poisons
3.1 Direct Red 254
Red strikethrough textindicates text that has been deleted.
- Green italicised text indicates text that has been added.
Referred scheduling proposal
An application was submitted to create a new Schedule 7 entry for Direct Red 254 while providing consistency with the current scheduling of other azo-based dyes.
Current scheduling status and relevant scheduling history
Direct red 254 has not been previously considered for scheduling and is not separately listed in the SUSMP. There is a group entry for specific azo dyes in Schedule 7. There is a group entry for phenylenediamine and its derivatives in Schedule 6 and 10, and Appendix E and F.
Other azo dyes have been considered for scheduling on two separate occasions. At the August and November 2015 Advisory Committee on Chemicals Scheduling (ACCS) meetings, the committee advised that a range of azo dyes requires scheduling. The delegate agreed with the ACCS advice, and a group entry for azo dyes was included in Schedule 7 in the SUSMP in 2016. The fundamental reasons for the scheduling of the azo dyes were due to the potential to be metabolised to carcinogenic and/or genotoxic aromatic amines.
The azo dyes considered by the delegate and published in November 2015, include derivatives by diazotisation of o-anisidine, o-toluidine, p-aminoazobenzene, o-aminoazotoluene, 2,4-toluenediamine, 5-nitro-o-toluidine, p-chloroaniline and 4-chloro-o-toluidine, to be included in Schedule 7 and implemented on 1 February 2016. Further information is available at: Scheduling delegate's final decisions: ACCS, November 2015.
The azo dyes considered by the delegate and published in March 2016, include derivatives by diazotisation of 2-napthylamine, 2,4,5-trimethylaniline and 6-methoxy-m-toluidine (p-cresidine) to be included in Schedule 7 and implemented on 1 June 2016. Further information is available at: Scheduling delegate's final decisions, March 2016.
The application's proposed amendments to the SUSMP are as follows:
Schedule 5 - New Entry
DIRECT RED 254.
The applicant's reasons for the request are:
- An application to register a product 'Envirodye' containing Direct Red 254, an azo dye derivative;
- Direct Red 254 has an estimated oral LD50 of 750 mg/kg bw (low toxicity). On this basis the applicant sought a Schedule 6 classification for the substance; and
- Although Direct Red 254 is an azo dye, it is not listed as a benzidine based azo dye, but a sulphonated dye and as such, is considered to have a low potential for genotoxicity and carcinogenicity. Therefore, the APVMA instead suggested a Schedule 5 classification.
Direct Red 254 has been put forward for scheduling by the APVMA in relation to an application for the registration of an AgVet product. Direct Red 254 is a sulfonated diazo dye, and is intended for use in a liquid marking dye for use in non-crop situations with herbicide spray solutions to assist in clearer identification of sprayed areas.
The APVMA proposed a Schedule 5 entry based on the submitted acute oral toxicity studies supporting the combined toxicity of the product being of low acute toxicity. The proposal does not include a cut-off.
Direct Red 254 (Figure 3.1) is a sulfonated diazo dye with a molecular weight of approximately 826 g/mol. It is a water soluble substance with sulfonic acid substituents and amine / hydroxyl functional groups that are ionisable. The following information has been extracted from the HHRA technical report for toxicology of the Direct Red 254.
Figure 3.1: Structures of Direct Red 254 as the disodium salt (CAS No. 6300-50-1) and as the triethanolamine salt (CAS No. 64683-40-5)
The acute toxicity end-points for Direct Red 254 (CAS No. 64683-40-5) are listed in Table 3.1. The toxicological database for Direct Red 254 is limited to acute toxicity and genotoxicity studies. However the toxicological database for the group of azo dyes to which Direct Red 254 belongs (Direct / Reactive Dyes, PMRA 2015) is considered sufficient to determine the toxicological profile of Direct Red 254 and characterise the risk to humans.
The toxicology assessment of Direct / Reactive Dyes was conducted by Health Canada (2015).
|Toxicity||Species||Results||SPF (2015) Classification|
|Acute oral toxicity LD50 (mg/kg bw)||Rat||>5000||N/A|
|Acute dermal toxicity LD50 (mg/kg bw)||No data||No data||N/A|
|Acute inhalational toxicity LC50 (mg/m3/4h)||No data||No data||N/A|
|Skin irritation||Rabbit||Non-irritant||Appendix B|
|Eye irritation||Rabbit||Slight irritant||Schedule 5|
|Skin sensitisation||Guinea pig||Non-sensitive||Schedule 5|
Aqueous solutions (8.7% and 15%) have been tested for acute toxicity (LD50 > 5000 mg/kg bw).
Dermal and inhalation toxicity studies were not available. Direct Red 254 was not a skin irritant in rabbits but is a slight eye irritant in the same species. Direct Red 254 was not a dermal sensitiser in the guinea pig maximisation test.
Subacute, chronic, developmental and in vivo genotoxicity studies were not submitted for Direct Red 254. A Health Canada (2015) evaluation of direct dyes included consideration of data for 37 diazo direct dyes within their evaluation. The Health Canada evaluation was used to consider missing endpoints (repeat dose toxicity, reproductive toxicity and developmental toxicity) and to source acute and repeat dose NOAELs suitable for conducting a worker risk characterisation. Direct Red 254 is not intended for crop uses.
Health Canada concluded a low carcinogenic and genotoxic potential for sulfonated aromatic amines (Direct Red 254 can be reduced to a sulfonated aromatic amine). In particular Health Canada state: Available data indicate that sulfonated aromatic amines generally have low carcinogenic and genotoxic potential owing to their high electronegativity and water solubility (Marchisio et al. 1976; Lin and Solodar 1988; Jung et al. 1992; OECD QSAR Toolbox 2013).
Health Canada considered a range of subacute, chronic, developmental and reproductive toxicity studies for direct and reactive dyes. A range of NOAELs, 26 - 300 mg/kg bw/d, was identified from oral repeat-dose toxicity studies for Direct Orange 39 and the six additional substances. Data from the dermal route were limited; only a single test dose level was used in each of the available short-term and chronic dermal toxicity studies.
Pre-meeting public submissions
No pre-meeting submissions were received for Direct Red 254.
Summary of ACCS advice to the delegate
The committee advised that Direct Red 254 should remain unscheduled and an Appendix B entry for Direct Red 254 was appropriate with a cross reference in the index.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the committee included: (b) the purposes for which a substance is to be used and the extent of use of a substance; and (c) the toxicity of a substance.
The reasons for the advice comprised the following:
- Toxicity is low via the oral and dermal routes due to the high molecular weight, water solubility and electronegativity of Direct Red 254 in comparison to some other azo-dyes;
- Health Canada have previously identified sulfonated aromatic amines to have low carcinogenic and genotoxic potential and Direct Red 254 does not form carcinogens as part of the metabolism pathways; and
- Its use pattern as a molecular dye for application of herbicides to vegetation suggests that the already low toxicity profile of Direct Red 254 is further mitigated by the use of appropriate personal protective equipment (PPE).
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); and
- Other relevant information:
- Following the ACCS meeting in July 2016, the APVMA submitted further information (19 August 2016) to help inform the delegate's interim decision.
- The APVMA confirmed the following CAS numbers for Direct Red 254:
- CAS 64683-40-5 = Direct Red 254 (triethanolamine salt)
- CAS 101380-00-1 = Direct Red 254
- The new proposal for Direct Red 254 suggested by the APVMA:
- Schedule 6 with a cut-off at 30% (w/v) into Schedule 5.
- This proposal is based on the theoretical oral LD50 of 750 mg/kg bw for Direct Red 254 which was calculated from the oral LD50 of 5000 mg/kg bw for a diluted formulation containing Direct Red 254 at a concentration of 15% (i.e. 5000 mg/kg bw x 15% = 750 mg/kg bw).
Delegate's interim decision
The delegate notes the ACCS advice and reasons to keep Direct Red 254 unscheduled, however the theoretical oral LD50 of 750 mg/kg bw for Direct Red 254 is consistent with the criteria for Schedule 6 in the SPF. The acute toxicity data is only available for a diluted formulation of Direct Red 254 (8.7-5%) and not for the active ingredient alone. Skin sensitisation and genotoxicity studies were performed using Direct Red 254 in 'powdered' form which in some cases was stated to be 'pure' however the exact concentration of active is unknown. The interim decision to create new entries for Direct Red 254 in Schedule 5 and Schedule 6 is appropriate based on SPF criteria with the new schedules providing adequate control for any preparations in current use that would contain more than 30% of Direct Red 254.
The proposed implementation date is 1 February 2017.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (b) the purposes for which a substance is to be used and the extent of use of a substance; and (c) the toxicity of a substance.
Schedule 6 - New Entry
DIRECT RED 254 except when included in Schedule 5.
Schedule 5 - New Entry
DIRECT RED 254 in preparations containing 30 per cent or less of Direct Red 254.
Index - New Entry
DIRECT RED 254
cross reference: 2-NAPHTHALENESULFONIC ACID, 7-AMINO-4-HYDROXY-3-[[P-[(P-SULFOPHENYL)AZO]PHENYL]AZO]-, BIS(TRIETHANOLAMINE) SALT