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Scheduling delegate's final decisions, June 2016

Scheduling of medicines and poisons

23 June 2016

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1.3 Chrysoidine base

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

1. Scheduling proposals referred to the March 2016 meeting of the Advisory Committee on Chemicals Scheduling (ACCS#16)

1.3 Chrysoidine base

Referred Delegate's scheduling proposal
  • In response to issues raised in a NICNAS IMAP Human Health Tier 2 assessment report on chrysoidine base and its salts, the scheduling proposal is to create a new Schedule 6 entry for chrysoidine base to regulate its use in domestic and cosmetic products.
Applicant's application and scheduling proposal

In December 2015, NICNAS under its Inventory Multi-tiered Assessment and Prioritisation (IMAP) programme referred the following proposal to be considered by the delegate:

Appropriate scheduling and labelling should be undertaken to mitigate risk when chrysoidine base and its salts are used in domestic and cosmetic products. Due to their toxicity profile, these chemicals should be considered for listing in Schedule 6 of the SUSMP.

The reasons for the request were as follows:

  • Currently, there are no restrictions on introducing or using these chemicals in Australia. In the absence of any regulatory controls, the characterised critical health effects (particularly carcinogenicity and mutagenicity) have the potential to pose an unreasonable risk if the chemical is used in cosmetic products. Whilst domestic use of the chemicals will result in lower levels of exposure, given that the chemicals are genotoxic there is sufficient uncertainty regarding the safety of such products to warrant some restriction.
  • Although use in cosmetic and/or domestic products in Australia is not known, the chemicals are reported to be used in cosmetic and/or domestic products overseas, such as shoe polish and hair dyes that could result in exposure of the general population.
  • The chemicals are classified as genotoxic.
  • Whilst data for carcinogenicity of the chemicals themselves is limited, chrysoidine hydrochloride (Basic Orange 2) has produced liver tumours in mice. Solvent Orange 3 is predicted to be carcinogenic based on QSAR modelling.
  • Three structurally-related azo aromatic amines are considered to be carcinogenic, all producing liver tumours in rats and/or mice as well as tumours in other organs. Where comparisons could be made using the available data, the chemicals being assessed had similar genotoxicity profiles to these structurally-related azo aromatic amines.
  • Azo dyes derived from two of the three structurally related aromatic amines (p-aminoazobenzene and o-aminoazotoluene) have recently had a decision published for their inclusion in Schedule 7.

The chemicals are prohibited for use in hair dye products in a number of overseas countries.

Substance summary

The NICNAS IMAP Tier II Human Health Report on Chrysoidine base and its salts, the p-aminobenzene IMAP report and the o-aminoazotoluene IMAP Report are available from the NICNAS website.

The chemicals in this group include chrysoidine base (Solvent Orange 3 - CAS No. 495-54-5) and various salts of chrysoidine.

Figure 3. Structure of chrysoidine base
Figure 3. Structure of chrysoidine base

The critical concern for this group of chemicals relates to the potential for carcinogenic effects following exposure, due to the presence of the chrysoidine base. The chemicals are all classified as genotoxic.

Data are available for Basic orange 2 which is the hydrochloride salt of chysoidine base and structurally-related azo aromatic amines, p-aminoazobenzene (CAS No. 60-09-3), o-aminoazotoluene (CAS No. 97-56-3) and phenazopyridine hydrochloride (CAS No. 136-40-3).

Acute toxicity

The acute toxicity end-points for chrysoidine base are listed in the table below.

Toxicity Species Result SPF* Classification
Acute oral toxicity LD50 Rat 1532 mg/kg bw Schedule 6
Skin irritation Irritant (limited data) Schedule 5
Eye irritation Severe (limited data) Schedule 6
Skin sensitisation Analogue data - skin sensitiser Schedule 5

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

The chemicals are classified as hazardous with the risk phrase 'Harmful if swallowed' (Xn; R22) in the Hazardous Substance Information System (HSIS) (Safe Work Australia). Based on test results, the chemicals have low to moderate acute oral toxicity in rats. Chrysoidine base has a median lethal dose (LD50) in the range warranting classification and there is insufficient evidence to determine the LD50 for the remaining chemicals.

Irritation

The chemicals are classified as hazardous with the risk phrase 'Irritating to skin' (Xi; R38) in the HSIS (Safe Work Australia). No data are available to evaluate this classification.

All the chemicals in this group (except Solvent Orange 3: CAS No. 495-54-5) are currently classified as hazardous with the risk phrase 'Risk of serious damage to eyes' (Xi; R41) in the HSIS (Safe Work Australia). No data are available to evaluate this classification. However, in the absence of information, and as the classification is not clearly related to extremes of pH, this hazard classification is also considered appropriate for Solvent Orange 3.

Sensitisation

No data on skin sensitisation are available for the chemicals. The structurally-related chemicals, p-aminoazobenzene (CAS No. 60-09-3) and o-aminoazotoluene (CAS No. 97-56-3), are considered to be sensitisers based on observations in animals and humans. In addition, the chemicals in this group have the potential to form benzenamine (CAS No. 62-53-3) due to potential azo reduction by the skin microflora. Benzenamine is classified as a sensitiser in the HSIS with available animal data to support this classification. Overall a classification is considered to be warranted.

Repeat-dose toxicity

The data for repeated dose toxicity for this chemical group are limited. However, repeated dose exposure of rats to 160 mg/kg bw/day of Basic Orange 2 for 21 days resulted in pathological changes to blood and stomach tissue. Whilst effects are not sufficient for classification, effects in the blood are consistent with those observed with the structurally related chemical, p-aminoazobenzene (CAS No. 60-09-3), and its potential metabolite, benzenamine and, therefore, the blood is considered to be a likely target for systemic toxicity for this group of chemicals.

Genotoxicity

The chemicals are classified as hazardous (Category 3 mutagenic substances) with the risk phrase 'Possible risk of irreversible effects' (Xn; R68) in HSIS (Safe Work Australia). The positive in vitro and in vivo genotoxicity data on some of the chemicals of this group (Solvent Orange 3, Basic Orange 2 and chrysoidine monoacetate - CAS No. 75660-25-2) and the metabolite chemicals support this classification.

Carcinogenicity

Limited data are available for the chemicals. Based on the weight of evidence from available data on one of the chemicals in the group (Basic Orange 2), similar azo aromatic amines, p-aminoazobenzene, o-aminoazotoluene and phenazopyridine hydrochloride, and the metabolite chemical (benzenamine), the chemicals are considered carcinogenic. This is supported by the available genotoxicity data for the chemicals and information available from Quantitative Structure Activity Relationship modelling.

Data for the chemicals

Basic Orange 2 was tested for carcinogenicity in single experiments in mice and rats using oral administration (IARC, 1987). Significantly increased incidences of liver adenomas and adenocarcinomas (72 %) and leukaemia and reticular cell sarcomas (with a combined incidence of 27 %) compared with controls were observed in C57BL mice that were fed a low-vitamin diet containing 0.2 % chrysoidine (equivalent to 260 mg/kg bw/day) for 13 months. Metastases of the liver tumours to the lungs were also observed. The second experiment on rats was inadequately reported. No tumours occurred in a group of 10 rats fed a diet containing 0.1 % chrysoidine (equivalent to 50 mg/kg bw/day) for 51-366 days. However, the experiment was performed with only a low dose administered to a small number of animals with short exposure and observation periods, and, therefore, may not have fully explored the carcinogenic potential of the chemical in rats.

Analogue data

The structurally-related azo aromatic amines, p-aminoazobenzene (CAS No. 60-09-3), o aminoazotoluene (CAS No. 97-56-3) and phenazopyridine hydrochloride (CAS No. 136-40-3), are all reported to cause liver tumours in rats and/or mice. Other sites of tumour formation include the lung (p-aminoazobenzene and o-aminoazotoluene), the colon (phenazopyridine hydrochloride) and urinary bladder, gall bladder, and mammary gland (o-aminoazotoluene). The chemicals, p aminoazobenzene and o-aminoazotoluene, are classified as hazardous (Category 2 carcinogenic substances) with the risk phrase 'May cause cancer' (T; R45) in the HSIS (Attachments B and C The metabolite benzenamine (CAS No. 62-53-3) is carcinogenic to rats (albeit at higher doses and with effects observed in the spleen) and is classified as a Category 3 carcinogenic substance in the HSIS.

QSAR/mechanistic data

QSAR modelling for the Solvent Orange 3 using OASIS-TIMES, gave positive predictions for carcinogenicity. However, the chemical structure was out of the applicable domain of the QSAR models indicating greater uncertainty about the reliability of the positive predictions.

The chemicals may undergo metabolism to produce reactive nitrenium ions as an initial step in the carcinogenic mechanism of action. This usually involves N-hydroxylation of the aromatic amines to an N-hydroxylamine and eventual formation of the pro-carcinogenic nitrenium ions. The highly reactive nitrenium ions may covalently bind to DNA provided that they are sufficiently stabilised to not undergo further reactions. It was shown in an Ames test (with metabolic activation) that the stability of the nitrenium ions is correlated with mutagenicity (Benigni and Bossa, 2011). The non-fused conjugated ring polycyclic aromatic amine component of the chemical is postulated to stabilise the formation of the reactive nitrenium ions. The other chemicals in this group, being salts of Solvent Orange 3, are expected to behave similarly.

Reproduction and developmental toxicity

No data are available for the chemicals.

Observation in humans

Human evidence of carcinogenicity, based on exposure to chrysoidine, is considered to be limited (IARC, 1987). Reports of bladder cancer from oral exposure in three amateur fishermen in the United Kingdom exposed to chrysoidine-dyed maggots led to an additional four cases being reported and two case-control studies. A bladder cancer case-control study involving approximately 900 case-control pairs found a relative risk of 0.7 based on five cases for bronze maggots and 2.0 based on nine cases for yellow maggots (Cartwright et al., 1983). A smaller study (202 case-control pairs) showed more bladder cancers following the use of dyed maggots (14 % cases, 8 % controls), with a 3-fold risk when bronze maggots were used for more than five years (Sole and Sorahan, 1985).

Public exposure

Although the uses of these chemicals in cosmetic and/or domestic products in Australia are not known, the chemicals are reported to be used in products overseas such as shoe polish and hair dyes, which might result in exposure of the general population. The introduction of these dyes for home use cannot be excluded.

International regulations

The chemicals are listed on the following (Galleria Chemica):

  • EU Cosmetics Regulation 1223/2009 Annex II (Ref # 1293): List of substances which cosmetic products must not contain (CosIng).
  • New Zealand Cosmetic Products Group Standard - Schedule 4 (Ref # 1293): Components cosmetic products must not contain; and
  • 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.

In the above directives, the chemicals are listed as 'm-phenylenediamine, 4-(phenylazo)-, and its salts, when used as a substance in hair dye products'.

In 2004, the Scientific Committee on Cosmetic Products and Non-Food Products intended for consumers (SCCNFP) concluded that Basic Orange 2 cannot be considered safe for hair dyeing purposes, unless these purposes are regarded as safe on the basis of an adequate safety dossier (SCCNFP, 2004).

Current scheduling status

Chrysoidine base is not specifically scheduled.

Scheduling history

Chrysoidine base has not been previously considered for scheduling; therefore, scheduling history is not available.

Pre-meeting public submissions

One public submission was received. The submission raised no objections to aligning the scheduling controls for this substance with the EU and noted all of the substances identified in the NICNAS IMAP report are listed in Annex II of the EU Cosmetics Regulations and cannot be used in cosmetics in the EU. They believe the schedule entry should specifically identify the following CAS numbers to ensure no other substances are inadvertently captured. CAS No. 495-54-5; 532-82-1; 63681-54-9; 75660-25-2; 79234-33-6; and 94247-67-3, consistent with the entry for Benzidine based azo-dyes.

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

Summary of ACCS advice to the delegate

The committee provided the following advice in response to the Delegate's questions:

  • The committee agreed there was insufficient evidence of genotoxicity and carcinogenicity to warrant a Schedule 7 entry. Acute toxicity data were consistent with Schedule 6 rather than Schedule 7. The committee agreed it was better to have a specific entry for this chemical rather than capturing it in the other scheduled dyes entries. Further it was noted that there is evidence of use in the hobby industry, and this should be considered when scheduling the substance.
  • The committee noted that inclusion of the substance in Schedule 6 will effectively preclude use of chrysoidine and its salts in cosmetics (due to the requirement for POISON labelling), but this would not prevent use of these substances in hair dye products, noting that there are many hair dye products that contain other substances in the consumer market with the POISON signal heading.
  • The committee agreed that given the information before them, Schedule 6 and Schedule 10 entries are warranted to prohibit use in hair dyes with Appendix E statements in relation to skin and eyes.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: c) toxicity - Acute toxicity data are consistent with Schedule 6 criteria; f) other - There was concern with potential for eye irritation. Recommended schedule amendments would apply regulatory controls consistent with those in place internationally.

The committee advised that a combination of a Schedule 6 entry with a Schedule 10 entry be created for chrysoidine with appropriate specifications as follows:

Schedule 6 - New Entry

CHRYSOIDINE except when in Schedule 10.

Schedule 10 - New Entry

CHRYSOIDINE in preparations for use in hair dyes.

Appendix E, Part 3 - New Entry

CHRYSOIDINE.

Standard statements: A, E1.

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

The delegate notes and accepts, the advice of the ACCS to create new listings for Chrysoidine in Schedules 6 and 10, and in Appendix E. The delegate notes the industry submission that requests the inclusion of CAS numbers for the six substances that would be captured by these entries, but also notes ACCS advice that listing under the name chrysoidine would automatically capture all the salts and derivatives listed in the NICNAS IMAP report, under the provisions of clause 2(c) of Part 1 of the Poisons Standard. The delegate also notes that this substance would not be captured under any existing Schedule entries for phenylenediamines or azo dyes.

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 and ASEAN). The toxicological basis for this restriction is the acute toxicity profile, including skin sensitisation potential and limited evidence of genotoxicity and carcinogenicity. For use in products other than hair dyes, the listings in Schedule 6 and Appendix E should provide suitable warnings to product users, including the requirement for the signal heading POISON on product labels. There was insufficient information, and no recommendation from the ACCS, for the delegate to consider any low concentration exemptions from the proposed entries.

The proposed implementation date is 1 October 2016. An early implementation date is proposed in order to bring the regulation of this hair dye ingredient in products 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 6 - New Entry

CHRYSOIDINE except when in Schedule 10

Schedule 10 - New Entry

CHRYSOIDINE in preparations for use in hair dyes.

Appendix E, Part 3 - New Entry

CHRYSOIDINE.

Standard statements: A, S1 (wash off skin), E1 (wash out of eyes)

Public submissions on the interim decision

No submissions were received.

Delegate's final decision

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

The implementation date is 1 October 2016.


Footnote

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

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