3.1 2-chloro-p-phenylenediamine

3. Advisory Committee on Chemicals Scheduling (ACCS #23)

3.1 2-chloro-p-phenylenediamine

On this page: Delegate's interim decision | Materials considered | Scheduling proposal | Background information for solvent yellow

Delegate's interim decision

Materials considered

In making this interim decision, I have considered the following material:

• The application to amend the current Poisons Standard with respect to naphthalene;
• The public submissions received before the first closing date;
• The advice received from the Joint Advisory Committees on Medicines and Chemicals Scheduling (Joint ACMS-ACCS #20);
• The Australian Health Ministers' Advisory Council's Scheduling Policy Framework (SPF 2018); and
• Section 52E of the Therapeutic Goods Act 1989, in particular (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; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

Scheduling proposal

The pre-meeting scheduling proposal for 2-chloro-p-phenylenedaime was published on the TGA website on 31 August 2018 at Consultation: Proposed amendments to the Poisons Standard - ACCS, ACMS and Joint ACCS/ACMS meetings, November 2018.

Background information for solvent yellow

In this section: Delegate's referral to ACCS-ACMS | Applicant's scheduling proposal and reasons | Current scheduling status | Scheduling history | Australian regulations | International regulations | Substance summary | Pre-meeting public submissions | Joint ACMS-ACCS advice

Delegate's referral to ACCS

An application was submitted by National Industrial Chemicals Notification and Assessment Scheme (NICNAS), as part of its Inventory Multi-tiered Assessment and Prioritisation (IMAP) program to amend the Poisons Standard with respect to the group entry for Phenylenediamines. The application proposes to amend the existing Schedule 6 and Schedule 10 group entries for Phenylenediamines in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) to include the halogenated derivatives, 2-chloro-p-phenylenediamine and its sulfate.

Applicant's scheduling proposal and reasons

The applicant's proposed amendments to the Poison Standard are:

The applicant's reasons for the proposal are:

• the chemical and its sulfate is reported to have international use in cosmetics for dyeing hair, eyebrows and eyelashes, and in domestic products. It is expected they are used in similar products in Australia;
• the chemicals are strong skin sensitisers;
• there is evidence of severe allergic reactions in humans when 2-chloro-p-phenylenediamine is used to dye eyebrows and eyelashes; and
• the chemicals are acutely toxic following oral exposure.
• similar to other phenylenediamine derivatives, the potential for skin sensitisation clearly presents a risk when the chemicals are used in cosmetic products for dyeing hair, eyebrows and eyelashes. This risk can be controlled by imposition of concentration restrictions and warning labels, as have previously been applied to other sensitising phenylenediamine derivatives in the SUSMP for use in hair, eyebrows and eyelashes dyeing products.

Current scheduling status

2-chloro-p-phenylenediamine/2-chloro-p-phenylenediamine sulfate are not currently scheduled in the current Poisons Standard.

Phenylenediamines are listed in the Poisons Standard as follows:

Scheduling history

2-chloro-p-phenylenediamine/2-chloro-p-phenylenediamine sulfate are not specifically scheduled and has not been previously considered for scheduling; therefore a scheduling history is not available.

In January 1955, the Committee on Poisons Schedule decided to list phenylene toluene and other alkylated benzene diamines in Schedule 2. At that time Schedule 2 substances were considered to be Poisons, the sale of which was restricted to certain specified categories of vendors and which were subject to identical packing and labelling requirements to those of Schedule 1 but which were not required to be entered in a Poisons Register.

In March 1980, the Poisons Schedule Committee (PSC) decided to delete the Schedule 6 aromatic amines entry and amend the Schedule 6 phenylene diamines entry to include alkylated phenylene diamines.

In May 1985, the PSC noted that a number of phenylene diamines in Schedule 6 listing were individually listed as well as being included in the general entry for phenylene diamines. The PSC agreed that the individual entries were not required in addition to the general entry for phenylene diamines and decided to delete the individual entries. The PSC agreed that no change was required to the Schedule 2 phenylene diamines entry.

In August 2000, the NDPSC agreed to exempt hair dye products containing phenylenediamines or toluenediamines from scheduling, conditional upon specified labelling.

In February and June 2004, the NDPSC considered the outcomes of investigations into incorrectly packed and labelled eyelash/brow tints containing phenylenediamines/toluenediamine and in October 2004, the NDPSC agreed to foreshadow amendments to prohibit use for eyelash/brow tinting. This proposal was varied by the February 2005 NDPSC meeting which instead agreed to foreshadow two options: to allow either salon use only, or all domestic use, of these eyelash/brow tints as Schedule 6 products (when compliant with the specified labelling).

In June 2005, the NDPSC concluded that the potential risk of causing a strong allergic response in a small number of individuals could be minimised through appropriate labelling. The NDPSC therefore agreed to that eyelash/brow tints were Schedule 6 poisons when appropriately labelled.

In June 2006, the NDPSC considered a request for flexibility in applying the mandatory labelling for eyelash/brow tints containing phenylenediamine and toluenediamine. The NDPSC indicated that, as the main risk was sensitisation, which in this case did not demonstrate a clear dose response, strong label warnings were required before such products could be available as Schedule 6. As there was a risk of separation of an outer pack from the immediate container, it was appropriate that all mandatory labelling continued to be applied to the immediate container, regardless of pack size. That the Schedule 6 warning statement would need to be applied, whether the use was domestic or industrial, or the product would default to Appendix C. The NDPSC further confirmed that the introduction to both Appendix E and F provided sufficient flexibility to allow for variation of product use and formulation.

In February 2007, the NDPSC considered the labelling requirements for single use composite pack hair preparations, including those containing phenylenediamines or toluenediamine, in view of amending various references to 'hair dyes' to 'hair preparations'. The NDPSC decided not to amend these references as there was potential for inadvertent capture of products for non-dying use patterns.

In February 2008, the NDPSC considered the scheduling of phenylenediamine and toluenediamine in eyelash/brow tints including restrict non-professional supply to ≤ 5 mL and limit non-professional supply to 'complete kit' forms (i.e. all reagents). The NDPSC agreed that it was not appropriate to address separate supply of a developer for eyelash/brow tinting through the scheduling process as there was little evidence of an actual public health risk from products not being sold in 'complete kit' form. The NDPSC also agreed that there was little evidence to support a pack size restriction on the availability of eyelash/brow tints containing phenylenediamine / toluenediamine.

Australian regulations

2-chloro-p-phenylenediamine (CAS 615-66-7) and 2-chloro-p-phenylenediamine sulfate (CAS 6219-71-2) are present on the Australian Inventory of Chemical Substances (AICS).

2-chloro-p-phenylenediamine and 2-chloro-p-phenylenediamine sulfate are not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 5 of 2017.

2-chloro-p-phenylenediamine and 2-chloro-p-phenylenediamine sulfate are not excipients or active ingredients in any medicine on the Australian Register of Therapeutic Goods (ARTG).

International regulations

The chemicals in this group have the following international restrictions (Galleria Chemica):

• The New Zealand Inventory of Chemicals (NZIoC) allows for possible use as a component in a product covered by a group standard but is not approved for use as a chemical in its own right.
• 2-chloro-p-phenylenediamine was registered under Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) as of 17 August 2016. The registration dossier was updated on 5 July 2018, following compliance checks by the European Chemicals Agency (ECHA).
• 2-chloro-p-phenylenediamine sulfate was registered under REACH as of 9 January 2018.

The chemicals in this group are listed as hair dyes in the European Commission (EU) Cosmetic Ingredients and Substances (CosIng) database, and as hair colourants in the United States (US) Personal Care Product Council International Cosmetic Ingredients (INCI) Directory.

The free base (CAS No. 615-66-7) is used in oxidative hair dye formulations at concentrations up to 4.6% and for dyeing eyebrows and eyelashes, mixed with 3% hydrogen peroxide solution in a 1:1 ratio prior to use in both applications (SCCS, 2013). The sulfate salt (CAS No. 6219-71-2) is used in hair dyes at concentrations up to 2% (before dilution) (CIR, 2011).

Other international uses have been identified for the chemicals through the US Department of Health and Human Services Household Products Database (US HPD) and the EU Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) dossiers.

The free base has reported domestic use in the following:

• anti-bacterial hand wash.

The free base has reported non-industrial use in the following:

• weed killer/pesticides; and
• pharmaceuticals.

The free base is not commercially produced in the US (US National Library of Medicine's Hazardous Substances Data Bank (HSDB)). The sulfate salt seems to have limited use in the US with the Compilation of Ingredients Used in Cosmetics in the US (CIUCUS), 2011 listing the sulfate salt in only one product.

The Scientific Committee on Consumer Products (SCCP) concluded that it is of the opinion that the use of 2-chloro-p-phenylenediamine (CAS No. 615-66-7) for dyeing hair, eyelashes and eyebrows is not safe for the consumer (SCCS, 2013). However, this recommendation was made primarily due to the inability to calculate margin of safety for use in oxidative hair dye formulations for eyebrows and eyelashes for a maximum use concentration of 4.6%. This does not preclude the scheduling changes proposed for the chemical and its sulfate to manage skin sensitisation risk.

Substance summary

Table 1: Chemical information for 2-chloro-p-phenylenediamine

Element	2-chloro-p-phenylenediamine /2-chloro-p-phenylenediamine sulfate
CAS name	1,4-benzenediamine, 2-chloro-	1,4-benzenediamine, 2-chloro-, sulfate
CAS Number	615-66-7	6219-71-2
Chemical structure
Molecular formula	C6H7ClN2	C6H7ClN2.xH2O4S
Molecular weight	140.60 g/mol	240.70 g/mol
IUPAC and/or common and/or other names	2-chloro-p-phenylenediamine (INCI) 2-chlorobenzene-1,4-diamine (IUPAC) 3-chloro-4-aminoaniline; Ursol Brown O; C.I. 76065	2-chloro-p-phenylenediamine sulfate (INCI) 2-chlorobenzene-1,4-diammonium sulfate (IUPAC) C.I. 76066; C.I. Oxidation Base 13A; Rodol Brown SO

As the toxicokinetics and toxicity of the phenylenediamine derivative (free base; CAS No. 615-66-7) and its sulfate salt (CAS No. 6219-71-2) are expected to be similar, they have been grouped together for purposes of the human health risk assessment. While there may be differences between the sulfate salt and the free base with respect to local effects, the speciation of the chemicals in biological fluids will be dependent on pH but independent of the original chemical form (SCCS, 2013).

Table 2: Acute toxicity end-points for 2-chloro-p-phenylenediamine

Toxicity	Species	2-chloro-1,4-benzenediamine	SPF (2018) Classification
Acute oral toxicity LD50 (mg/kg bw)	Rat	729-1190 mg/kg bw	Schedule 6
Acute dermal toxicity LD50 (mg/kg bw)	-	No data	N/A
Acute inhalational toxicity LC50 (mg/m3/4h)	-	No data	N/A
Skin irritation	Rabbit	Not irritating	N/A
Eye irritation	Rabbit	Slight-moderately irritating	Schedule 5
Skin sensitisation (non-guideline guinea pig test)	Guinea pig	Skin sensitising	Schedule 6

Acute toxicity

The chemicals in this group are considered to have moderate acute toxicity following oral exposure with a median lethal dose (LD₅₀) between 729-1190 mg/kg bw based on data available on 2-chloro-p-phenylenediamine.

Irritation

Based on available data, 2-chloro-p-phenylenediamine is not irritating to skin under the test conditions. No data are available for the sulfate salt. However, since the local irritation effects of the salt are not expected to be greater than those of the free base, the sulfate salt is not likely to be irritating to skin based on data available for the free base.

Sensitisation

The chemicals in this group are considered to be sensitising to skin based on data available on 2-chloro-p-phenylenediamine.

In a non-guideline test, 2-chloro-p-phenylenediamine was reported to be a strong sensitiser producing a reaction in 9 out of 15 guinea pigs within 24 hours of challenge (SCCS, 2013). Although the test was described as 'Magnusson-Kligman protocol' (SCCS, 2013), study details showed that it was not a guinea pig maximisation test (GPMT). Female Pirbright white guinea pigs (n=10-15/group) were intracutaneously induced with the chemical at 3% for 5 consecutive days. After 4 weeks of induction, the animals were challenged with topical application of the chemical at up to 0.3%. Use of Freund's Complete Adjuvant (FCA) is not mentioned.

Quantitative structure-activity relationship (QSAR) modelling using OECD QSAR Toolbox showed protein binding alerts for 2-chloro-p-phenylenediamine and its metabolites for skin sensitisation. One QSAR modelling study based on local lymph node assay (LLNA) data and topological substructural molecular descriptors (TOPS-MODE) predicted a sensitisation potency of 1.6 for the free base (close to p-phenylenediamine with a predicted score of 1.8), identifying 2-chloro-p-phenylenediamine as a strong/moderate sensitiser (Søsted et al., 2004).

Repeat-dose toxicity

The chemicals in this group are not expected to cause serious damage to health following repeated oral exposure at low doses based on available data.

Mutagenicity / Genotoxicity

The chemicals in this group are not expected to be genotoxic based on available data. Although 2-chloro-p-phenylenediamine tested positive for gene mutations in vitro, it was negative for genotoxicity in vivo. Furthermore, read-across data on 1,4-benzenediamine (CAS No. 106-50-3) and its analogues indicate that the chemicals in this group are not likely to be genotoxic.

Carcinogenicity

The chemicals are not expected to be carcinogenic based on available data.

Reproduction and developmental toxicity

The chemicals in this group are not expected to have specific developmental toxicity based on the limited data available on 2-chloro-p-phenylenediamine. No data is available for reproductive toxicity.

Observation in humans

The following three individual case reports give evidence of severe allergic reactions/contact dermatitis produced within 24 hours of dyeing eyelashes and eyebrows with a dye containing 2-chloro-p-phenylenediamine:

• itchy dermatitis on eyebrows;
• itchy dermatitis on eye lids; and
• swollen eyelids, watering, itchiness and redness in both eyes, followed by severe inflammation of eye lids and conjunctival chemosis (swelling).

Public exposure

Since the expected use of the chemicals in Australia is in cosmetic products for dyeing hair, eyebrows and eyelashes, the main route of public exposure is expected to be through the skin.

Pre-meeting public submissions

One public submission, which was supportive of the scheduling proposal, was received before the first closing date in response to an invitation published on 31 August 2018 under regulation 42ZCZK of the Regulations.

The main points provided in support of the amendment were:

• The proposal provides clarification and confirmation that halogenated derivatives of the entries for phenylenediamines are captured by the existing scheduling entries.
• The proposal is not expected to result in any significant regulatory impact.

ACCS advice

The committee recommends that the current Schedule 6 entry and Schedule 10 entries for PHENYLENEDIAMINES be amended as follows:

The committee also recommended an implementation date of 1 June 2018.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (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; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the advice included:

1. the risks and benefits of the use of a substance:
   • Strong sensitisers and evidence in humans of severe allergic reactions when used as a dye for eyebrow and eyelashes.

     Management of risk through appropriate concentration restrictions and labelling.

   • The critical health effects for risk characterisation include:
     • local effects- eye irritation and skin sensitization; and
     • systemic acute effects- acute toxicity by oral, dermal and inhalation routes.
2. the purposes for which a substance is to be used and the extent of use of a substance:
   • Not reported to be used in Australia.
   • Internationally used in cosmetics, hair dyes and dye for eyelash and eyebrow tints.
   • The chemicals are primarily used in cosmetics. 2-chloro-p-phenylenediamine (CAS No. 615-66-7) is reported to also have domestic and industrial use.
3. the toxicity of a substance:
   • Skin sensitiser.
   • The halogenated derivatives exhibit toxicities consistent with other members of the schedule entry.
4. the dosage, formulation, labelling, packaging and presentation of a substance:
   • Nil.
5. the potential for abuse of a substance
   • Nil.
6. any other matters that the Secretary considers necessary to protect public health
   • Draft Amendment to EU Regulations inclusion of 2-Chloro-p-Phenylenediamine and sulfate and dihydrochloride salts to prohibited substances.