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

Scheduling medicines and poisons

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2 February 2017

1.4 HC Blue 16 (1,3-bis(2,4-diaminophenoxy)propane tetrahydrochloride)

Part A - Interim decisions on matters referred to an expert advisory committee (November 2016)

Advisory Committee on Chemicals Scheduling (ACCS #18)

1.4 HC Blue 16, (1,3-bis(2,4-diaminophenoxy)propane tetrahydrochloride)

Referred scheduling proposal

An application was submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) to create a new Schedule 6 entry for 1,3-bis(2,4-diaminophenoxy)propane tetrahydrochloride in hair dyes and eyebrow/eyelash colouring products and to determine whether an appropriate exemption cut-off is required.

Scheduling application

General application.

The applicant's proposed amendments to the Poisons Standard are as follows:

Schedule 6 - New entry

1,3-BIS(2,4-DIAMINOPHENOXY)PROPANE TETRAHYDROCHLORIDE except when used in hair dye colouring products at a concentration of 1.8 per cent or less of 1,3-bis(2,4-diaminophenoxy)propane tetrahydrochloride, or 1.2 per cent or less of 1,3-bis(2,4-diaminophenoxy)propane (the free base), and when the immediate container and primary pack are labelled with the following statements:

KEEP OUT OF REACH OF CHILDREN; and

WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use, and

Written in letters not less than 1.5mm in height.

Appendix E, Part 2 - New Entry

1,3-BIS(2,4-DIAMINOPHENOXY)PROPANE TETRAHYDROCHLORIDE

Standard statements: E1 (if in eyes wash out immediately with water).

Appendix F, Part 3 - New Entry

1,3-BIS(2,4-DIAMINOPHENOXY)PROPANE TETRAHYDROCHLORIDE

Warning statements: 28 ((over) (repeated) exposure may cause sensitisation).

The applicant's reasons for the request are:

  • 1,3-Bis(2,4-diaminophenoxy)propane tetrahydrochloride is an eye irritant; a moderate skin sensitiser with a local lymph node assay (LLNA) EC3 value of 14.7%.
  • 1,3-Bis(2,4-diaminophenoxy)propane tetrahydrochloride has existing overseas restrictions, including a maximum allowable concentration of 1.8% in cosmetics, with warnings of sensitisation at lower concentrations, in the European Union (EU).
Current scheduling status and relevant scheduling history

1,3-Bis(2,4-diaminophenoxy)propane tetrahydrochloride is not currently scheduled and has not been previously considered for scheduling; therefore, scheduling history is not available. There is however, a derivative of 1,3-bis(2,4-diaminophenoxy)propane tetrahydrochloride, 1,3-benzenediamine that is currently listed in the SUSMP in Schedule 10 as follows:

Schedule 10

1,3-BENZENEDIAMINE in preparations for cosmetic use and skin colouration (including tattooing).

Australian regulatory information

The chemical is reported to be used in permanent hair dye preparations in Australia. Currently, there are no restrictions in Australia on using this chemical in cosmetics/hair dyes or eyelash colouring products. In the absence of any regulatory controls, the characterised critical health effects (skin sensitisation) have the potential to pose an unreasonable risk to the public under the uses identified.

International regulations

The chemical is listed on the following:

  • EU Cosmetics Regulation 1223/2009 Annex III-List of substances which cosmetic products must not contain except subject to the restrictions laid down: maximum concentration in cosmetic formulation must not exceed 1.2 % calculated as free base (1.8 % as tetrahydrochloride salt). The Cosmetics Regulation also mandates label warning statements relating to the sensitisation potential of the chemical;
  • The Association of Southeast Asian Nations (ASEAN) Cosmetic Directive Annex III-Part 1—List of substances which cosmetic products must not contain except subject to restrictions and conditions laid down; and
  • New Zealand Cosmetic Products Group Standard-Schedule 5-Table 1: Components cosmetic products must not contain except subject to the restrictions and conditions laid down.
Substance summary
Structure of 1,3-bis(2,4-diaminophenoxy)propane tetrahydrochloride

Figure 1.4: Structure of 1,3-bis(2,4-diaminophenoxy)propane tetrahydrochloride

Table 1.4A: Chemical information
Property 1,3-bis(2,4-diaminophenoxy)propane tetrahydrochloride
CAS name 1,3-Bis(2,4-diaminophenoxy)propane tetrahydrochloride
CAS number 74918-21-1
INCI name 1,3-Bis-(2,4-Daiminophenoxy)propane HCl
IUPAC and/or common and/or other names HC Blue 16; 1,3-Benzenediamine, 4,4'-[1,3-propanediylbis(oxy)]bis-, tetrahydrochloride

The following toxicology information was extracted from the NICNAS IMAP Human Health Tier II assessment. Further information can also be found in the European Commission Scientific Committee on Consumer Products (pdf,246kb) (SCCP) report.

Table 1.4B: Acute toxicity end-points for 1,3-bis(2,4-diaminophenoxy)propane tetrahydrochloride
Toxicity Species 1,3-bis(2,4-diaminophenoxy)propane tetra hydrochloride SPF (2015) Classification
Acute oral toxicity median lethal dose (LD50) (mg/kg bodyweight (bw)) Wistar rat 3570 Schedule 5
Acute dermal toxicity LD50 (mg/kg bw) N/A No data N/A
Acute inhalational toxicity LC50 (mg/m3/4h) N/A No data N/A
Skin irritation New Zealand White rabbits Mild skin irritant Schedule 5
Eye irritation New Zealand White rabbits Moderate eye irritation Schedule 5
Skin sensitisation (LLNA) CBA/J mice The chemical is a moderate skin sensitiser (EC3 value of 14.7%) Schedule 6
Acute toxicity

The chemical has low acute toxicity based on results from animal tests following oral exposure. The LD50 in rats is 3570 mg/kg bw.

The chemical was assessed in a non-guideline acute oral toxicity study in male Wistar rats (10 animals/group). The animals were dosed by oral gavage at 2510, 3160, 3570, 3980 or 5010 mg/kg bw. Animals were observed for 14 days. Mortalities occurred in the groups as follows: 0/10 (2510 mg/kg bw), 2/10 (3160 mg/kg bw), 5/10 (3570 mg/kg bw), 8/10 (3980 mg/kg bw), and 9/10 (5010 mg/kg bw). An LD50 of 3570 mg/kg bw was determined from this study.

Skin irritation

The chemical was reported in a study to cause mild, transient skin irritation in New Zealand White rabbits:

  • In an OECD TG 404 (acute dermal irritation/corrosion) study, 0.5 g of the moistened substance was applied to the intact, shaved back skin of three New Zealand White rabbits. The test chemical was left in place for four hours under a semi-occlusive patch. The application resulted in slight erythema on the exposed skin of all rabbits at one hour after treatment. No oedema was observed and no evidence of irreversible damage was apparent. Under these test conditions, 1,3-bis(2,4-diaminophenoxy)propane tetrahydrochloride caused minimal and transient irritation of the skin.
Eye irritation

The chemical was reported to irritate the eyes when tested according to OECD TG 405 (acute eye irritation/corrosion). The average corneal, iridial, conjunctival redness and conjunctival chemosis scores were given as (1/1/3/4). The effects were reversible within 14 days of application.

In a study conducted according to OECD TG 405, the chemical (approximately 45.2 mg as an undiluted solution) was instilled into the conjunctival sac of one eye each of three New Zealand White rabbits and left for 24 hours. The chemical caused corneal injury including opacity (maximum grade 1 in all animals up to 72 hours after instillation) and epithelial damage (maximum 65% of the corneal surface, 24 hours after instillation). Corneal injury resolved within 72 hours. Iridial irritation (grade 1) was observed in all animals but resolved during the observation period. Conjunctival irritation consisted of redness (up to grade 3), chemosis (up to grade 4) and discharge (up to grade 2) and had completely resolved in one animal within seven days and in the other animals within 14 days. No mortalities or evidence of systemic toxicity were observed. Under the conditions of the study, the test substance was irritating to rabbit eyes.

Sensitisation

The chemical is considered to be a moderate skin sensitiser based on the positive results seen in a single LLNA. The EC3 (estimated concentration required to produce a three-fold increase in lymphocyte proliferation) was 14.7%.

The potential for the chemical to promote sensitisation was investigated in a study conducted according to OECD TG 429 (skin sensitisation: local lymph node assay). Female CBA/J mice (five animals/group) were topically administered the chemical in solution on the dorsal surface of each ear lobe once daily, for three consecutive days at 5, 25 and 50% (in ethanol/water mixture (7/3, volume/volume)). The rate of radio-labelled thymidine incorporation in the lymph nodes was used to calculate stimulation indices. Even at the highest concentration, no local effects were observed on the skin of the ears. The SI for the different dose groups were 1.2 ± 1.0 (5%), 4.9 ± 1.1 (25%) and 4.3 ± 1.0 (50%), respectively. An EC3 value of 14.7% was calculated. On the basis of this finding, the test chemical is considered to be a skin sensitiser.

Oral repeat-dose toxicity

In a 90-day oral gavage study in rats, a no observed adverse effect level (NOAEL) of 40 mg/kg bw/day was reported.

The chemical was assessed for toxicity following repeated oral dosing in a study conducted according to OECD TG 408 (repeated dose 90-day oral toxicity study in rodents). Crl:(WI)BR Wistar rats (12 animals/sex/group) were dosed with the chemical by gavage for 13 weeks at 0, 40, 130 or 360 mg/kg bw/day. Discolouration and brown staining was evident in several tissues in the high dose group. Some ocular pathology was evident in the mid and high dose groups. Reduced weight gain was also evident in high dose males. The mid and high dose groups also exhibited significant changes in organ weights (thymus, adrenal glands, spleen and kidneys). Some cardiac degeneration was evident in the mid and high dose groups. Two mortalities were recorded in the two highest dose groups; however, evaluation at necropsy showed no clear cause of death. Minor haematological changes were reported for the low dose group; however, these were not considered adverse effects associated with treatment. There were no treatment-related changes in food consumption in any group. On the basis of these findings, an NOAEL of 40 mg/kg bw/day was established.

Genotoxicity

Based on the weight of evidence from the available in vitro and in vivo genotoxicity studies, the chemical is not considered to be genotoxic. All in vivo genotoxicity tests were negative.

Reproduction and developmental toxicity

Based on the results, a reported NOAEL of 180 mg/kg bw/day was determined for maternal and foetal toxicity.

In a non-guideline study, female Sprague Dawley rats (21 animals/group) were administered the chemical by oral gavage on gestation days 6-15, at 0, 20, 60 or 180 mg/kg bw/day. No maternal deaths occurred during the study and dams did not exhibit any evidence of a toxic response to the test chemical at any dose. There was no evidence that the test chemical had any influence on the outcome of pregnancy. Resorption rates and post-implantation losses were not affected by treatment. No foetal effects of treatment were observed. On the basis of these findings, an NOAEL of 180 mg/kg bw/day, was determined for foetal and maternal toxicity.

Pre-meeting public submissions

One (1) pre-meeting submission was received in support. The main points were that the new schedule entry would be in alignment with international regulators in the EU, ASEAN and NZ.

Summary of ACCS advice to the delegate

The committee advised that a new Schedule 6 entry for 1,3-bis(2,4-diaminophenoxy)propane tetrahydrochloride be created under the common name, HC Blue 16, with an exemption cut-off of 1.2% in the Poisons Standard as follows:

Schedule 6 - New entry

HC BLUE 16 (including its salts) except when in hair dye preparations containing 1.2 per cent or less of HC Blue 16 when the immediate container and primary pack are labelled with the following statements:

KEEP OUT OF REACH OF CHILDREN, and

WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use. This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye, and

Written in letters not less than 1.5 mm in height.

The committee also advised that appendix and index entries be created as follows:

Appendix E, Part 2 - New Entry

HC BLUE 16

Standard statements: A (For advice, contact a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor (at once)), E1 (if in eyes wash out immediately with water), S1 (If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water).

Appendix F, Part 3 - New Entry

HC BLUE 16

Warning statements: 28 ((over) (repeated) exposure may cause sensitisation), 79 (Will irritate eyes).

Safety directions: 1 (Avoid contact with eyes).

Index - New entry

HC BLUE 16
cross reference: 1,3-bis(2,4-diaminophenoxy)propane tetrahydrochloride

Schedule 6
Appendix E, Part 2
Appendix F, Part 3

The committee recommended an implementation date of 1 June 2017.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health. The reasons for the advice comprised the following:

  • As a cosmetic in many other countries, Australian consumers will also have access to the effective cosmetic, HC Blue 16;
  • While the risk of skin sensitisation is real, the risk is attenuated by the consumer product being available in low strength, and the consumer product being labelled appropriately to warn consumers of skin sensitisation risk;
  • HC Blue 16 is used as a precursor for hair care products, including hair dyes. Such products may be used widely;
  • HC Blue 16 is uses in hair dyes, and dermal contact is unavoidable;
  • HC Blue 16 has a moderate skin sensitisation potential, which is consistent with Schedule 6 factors;
  • HC Blue 16 should only be exempt from Schedule 6 at a lower concentration of 1.2% of the free base, and when it is labelled with appropriate warnings regarding skin sensitisation; and
  • Placing scheduling restrictions on HC Blue 16 would align Australian standards with those in other developed economies.
Delegate's considerations

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)
  • Other relevant information.
Delegate's interim decision

The delegate's interim decision is to create a new Schedule 6 entry for 1,3-bis(2,4-diaminophenoxy)propane tetrahydrochloride under the common name, HC Blue 16, with an exemption cut-off of 1.2 per cent.

The proposed Schedule entry is as follows:

Schedule 6 - New entry

HC BLUE 16 (including its salts) except when in hair dye preparations containing 1.2 per cent or less of HC Blue 16 when the immediate container and primary pack are labelled with the following statements:

KEEP OUT OF REACH OF CHILDREN, and

WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use. This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye, and

Written in letters not less than 1.5 mm in height.

Appendix E, Part 2 - New Entry

HC BLUE 16

Standard statements: A (For advice, contact a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor (at once)), E1 (if in eyes wash out immediately with water), S1 (If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water).

Appendix F, Part 3 - New Entry

HC BLUE 16

Warning statements: 28 ((over) (repeated) exposure may cause sensitisation), 79 (Will irritate eyes).

Safety directions: 1 (Avoid contact with eyes).

Index - New entry

HC BLUE 16
cross reference: 1,3-bis(2,4-diaminophenoxy)propane tetrahydrochloride

Schedule 6
Appendix E, Part 2
Appendix F, Part 3

The proposed implementation date is 1 June 2017.

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; d) the dosage, formulation, labelling, packaging and presentation of a substance; and f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the recommendation comprised the following:

  • The delegate acknowledges the committee's advice.
  • As a cosmetic in many other countries, Australian consumers will also have access to the effective cosmetic, HC Blue 16.
  • While the risk of skin sensitisation is real, the risk is attenuated by the consumer product being available in low strength, and the consumer product being labelled appropriately to warn consumers of skin sensitisation risk.
  • HC Blue 16 is used as a precursor for hair care products, including hair dyes. Such products may be used widely.
  • HC Blue 16 is used in hair dyes, and dermal contact is unavoidable.
  • HC Blue 16 has a moderate skin sensitisation potential, which is consistent with Schedule 6 factors.
  • HC Blue 16 should only be exempt from Schedule 6 at a lower concentration of 1.2% of the free base, and when it is labelled with appropriate warnings regarding skin sensitisation.
  • Placing scheduling restrictions on HC Blue 16 would align Australian standards with those in other developed economies.
  • Earliest possible implementation date.

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