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Scheduling delegate's final decisions, March 2017

Scheduling medicines and poisons

23 March 2017

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1.2 3-Nitro-p-hydroxyethylaminophenol (4-[(2-hydroxyethyl)amino]-3-nitrophenol)

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

Advisory Committee on Chemicals Scheduling (ACCS#18)

1.2 3-Nitro-p-hydroxyethylaminophenol
(4-[(2-hydroxyethyl)amino]-3-nitrophenol)

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 4-[(2-hydroxyethyl)amino]-3-nitrophenol in hair dye and eyelash/eyebrow colouring products and to determine whether an appropriate exemption cut-off is required.

Scheduling application

This was a general application. The applicant's proposed amendments to the Poisons Standard are as follows:

Schedule 6 - New Entry

4-[(2-HYDROXYETHYL)AMINO]-3-NITROPHENOL except when used in hair dye colouring preparations containing 3 per cent or less of 4-[(2-hydroxyethyl)amino]-3-nitrophenol under oxidising conditions (after mixing with hydrogen peroxide), or containing 1.85 per cent or less of 4-[(2-hydroxyethyl)amino]-3-nitrophenol under non-oxidising conditions, and in ready to use preparations 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.

written in letters not less than 1.5 mm in height.

Appendix E, Part 2 - New Entry

4-[(2-HYDROXYETHYL)AMINO]-3-NITROPHENOL

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

Appendix F, Part 3 - New Entry

4-[(2-HYDROXYETHYL)AMINO]-3-NITROPHENOL

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

The applicant's reasons for the request are:

  • 4-[(2-Hydroxyethyl)amino]-3-nitrophenol is reported to be used in permanent and semi-permanent cosmetic hair dye preparations in Australia;
  • 4-[(2-Hydroxyethyl)amino]-3-nitrophenol is an extreme skin sensitiser with a local lymph node assay (LLNA) EC3 value (estimated concentration required to produce a three-fold increase in lymphocyte proliferation) of 0.07%;
  • 4-[(2-Hydroxyethyl)amino]-3-nitrophenol is a potential developmental toxin;
  • There are overseas restrictions and labelling requirements for use of 4-[(2-hydroxyethyl)amino]-3-nitrophenol in hair dyes;
  • The existing overseas restrictions are currently under review by the European Commission's Scientific Committee on Consumer Safety (SCCS), to take into account the sensitisation potential of the chemical; and
  • When 4-[(2-hydroxyethyl)amino]-3-nitrophenol is used as a hair dye, there is a potential risk of for skin sensitisation, which may be controlled through concentration restrictions and warning labels, as have previously been applied to other sensitising hair dyes considered for inclusion in the SUSMP.
Current scheduling status and relevant scheduling history

4-[(2-Hydroxyethyl)amino]-3-nitrophenol is not currently scheduled and has not been previously considered for scheduling; therefore, scheduling history is not available.

International regulations

The chemical is listed on the following:

  • The EU Regulation (EC) No 344/2013 Annex III- List of substances which cosmetic products must not contain except subject to the restrictions laid down: '(a) hair dye substance in oxidative hair dye products; (a) after mixing under oxidative conditions the maximum concentration applied to hair must not exceed 3.0%; (b) hair dye substance in non-oxidative hair dye products; (b) the maximum concentration in ready for use preparation is 1.85%; and for (a) and (b): - do not use with nitrosating agents, - maximum nitrosamine content: 50 µg/kg, - keep in nitrite-free containers' - when concentrations do not exceed the maximum concentration listed in (a) and (b), it must be labelled with the following: hair colourants can cause severe allergic reactions, read and follow instructions.
  • New Zealand Cosmetic Products Group Standard-Schedule 5: Components cosmetic products must not contain except subject to the restrictions and conditions laid down: '(a) the maximum authorised concentration in the finished cosmetic product as a hair dye substance in non-oxidative hair dye products is 1.85%; (b) in combination with hydrogen peroxide the maximum use concentration upon application is 3.0%; (c) do not use with nitrosating systems; (d) maximum nitrosamine content: 50 µg/kg; and (e) keep in nitrate-free containers'.
  • The Association of South East 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: '(a) the maximum authorised concentration in the finished cosmetic product as a hair dye substance in non-oxidative hair dye products is 1.85%; (b) after mixing under oxidative conditions the maximum concentration applied to hair must not exceed 3.0%; (c) do not use with nitrosating systems; (d) maximum nitrosamine content: 50 µg/kg; and (e) keep in nitrate-free containers.'
Substance summary
Table 1.2A: Chemical information
Property 4-[(2-Hydroxyethyl)amino]-3-nitrophenol
CAS No. 65235-31-6
Alternative names Phenol, 4-[(2-Hydroxyethyl)amino]-3-nitro- (CAS); 3-nitro-p-hydroxyethylaminophenol (INCI); 1-hydroxy-3-nitro-4-(ß-hydroxyethyl)-aminobenzene; 3-nitro-4-n-(beta-hydroxyethyl)aminophenol; 4-((2-hydroxyethyl)amino)-3-nitrophenol
Chemical structure Chemical structure of 4-[(2-Hydroxyethyl)amino]-3-nitrophenol
Molecular formula C8H10N2O4
Molecular weight 198.2 g/mol

The following information has been extracted from the NICNAS IMAP Human Health Tier II assessment report for Phenol, 4-[(2-hydroxyethyl)amino]-3-nitro-.1

Table 1.2B: Acute toxicity end-points for 4-[(2-hydroxyethyl)amino]-3-nitrophenol
Toxicity Species 4-((2-hydroxyethyl)amino)-3-nitrophenol SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bw) Sprague Dawley (SD) rats >2000 Schedule 5

Acute dermal toxicity LD50 (mg/kg bw)

No dermal absorption data is available

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 Non-irritant at 4 and 6% N/A
Eye irritation New Zealand White Rabbits Slight irritant at 4 and 6% N/A
Skin sensitisation CBA/J Mice Strong sensitiser Schedule 6
Acute toxicity

4-((2-Hydroxyethyl)amino)-3-nitrophenol is considered to have low acute oral toxicity. The available LD50 of >2000 mg/kg bw supports this conclusion. No data are available for dermal or inhalation toxicity.

Irritation

Based on the limited data available, 4-((2-hydroxyethyl)amino)-3-nitrophenol is not considered to be a skin irritant. However, it is considered to be a slight eye irritant:

  • In two eye irritation studies 4-((2-hydroxyethyl)amino)-3-nitrophenol was instilled into the conjunctival sacs of New Zealand White rabbits at 4 and 6%, and was reported to be slightly irritating to the eyes based on the observation of slight chemosis and conjunctival redness, which were fully reversed after five days; the observation of folded irises reversed after 48 hours.
Sensitisation

Based on the available data, the chemical is considered to be an extreme skin sensitiser:

  • In a local lymph node assay (LLNA) conducted according to OECD TG 429, 4-((2-hydroxyethyl)amino)-3-nitrophenol was applied to the dorsal surface of both ear lobes of female CBA/J mice (4 animals/group) in dimethylformamide once daily for three consecutive days. 4-((2-Hydroxyethyl)amino)-3-nitrophenol, at test concentrations of 0.03, 0.09, 0.28, 0.83 or 2.5%, produced stimulation indices (SI) of 2.18, 3.54, 6.36, 7.61 or 11.22, respectively. The estimated concentration needed to produce a three-fold increase in lymphocyte proliferation (EC3) was calculated to be 0.07%, indicating extreme skin sensitisation potential.
Repeat-dose toxicity

Apart from developmental effects, 4-((2-hydroxyethyl)amino)-3-nitrophenol is not considered to cause to adverse health effects following repeated oral exposure (NOAEL 200 mg/kg). No data are available for repeated dermal and inhalation toxicity.

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 test were negative.

Carcinogenicity

No animal toxicity data are available on the carcinogenicity of 4-((2-hydroxyethyl)amino)-3-nitrophenol. Based on the available genotoxicity data, it is not considered to be genotoxic carcinogenic.

Reproduction and developmental toxicity

Limited data are available. The available data indicate that 4-((2-hydroxyethyl)amino)-3-nitrophenol may have potential for developmental toxicity following oral exposure:

  • In a prenatal development toxicity study conducted according to OECD TG 414, pregnant SD rats (20 animals/group) were administered 0, 100 or 1000 mg/kg bw/day of 4-((2-hydroxyethyl)amino)-3-nitrophenol daily by oral gavage on gestational days (GDs) 6-15. All rats were euthanised on GD 20. Red discoloured urine was observed in all animals due to the dyeing properties of the chemical. In the 1000 mg/kg bw/day group, the number of viable foetuses was slightly decreased. Two foetuses in this group had malformations including external astomia (congenital absence) of the face and brain, and polydactyly of the digits. External astomia is known to occur spontaneously in rats of this strain at a low incidence and the presence of polydactyly could not be confirmed by a re-examination of the specimen; therefore, the effects were considered as artifactual events. No other adverse effects were observed. The European Commission's Scientific Committee on Consumer Products (SCCP) 2006 Opinion considered 'the no observed adverse effect level (NOAEL) for developmental toxicity to be 100 mg/kg/day and the NOAEL for maternal toxicity 1000 mg/kg/day, which suggests that teratogenic (external astomia) and embryotoxic (decreased number of live foetuses) effects occurred at dose levels which were not toxic to the pregnant dams.
Public exposure

4-((2-Hydroxyethyl)amino)-3-nitrophenol is reported to be used in permanent and semi-permanent hair dye preparations in Australia.

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 4-((2-hydroxyethyl)amino)-3-nitrophenol be entered in Schedule 6 as the INCI name, 3-nitro-p-hydroxyethylaminophenol, in the Poisons Standard as follows:

Schedule 6 - New Entry

3-NITRO-p-HYDROXYETHYLAMINOPHENOL except:

  1. in non-oxidative hair dye preparations containing 1.85 per cent or less of 3-nitro-p-hydroxyethylaminophenol 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; or

  2. in oxidative hair dye preparations containing 3 per cent or less of 3-nitro-p-hydroxyethylaminophenol after mixing under oxidative conditions 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 recommended appendix and index entries be created as follows:

Appendix F, Part 3 - New Entry

3-NITRO-p-HYDROXYETHYLAMINOPHENOL

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

Index - New Entry

3-NITRO-p-HYDROXYETHYLAMINOPHENOL
cross reference: 4-[(2-hydroxyethyl)amino]-3-nitrophenol

Schedule 6
Appendix F, Part 3

The committee also advised an implementation date of 1 June 2017.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the advice comprised the following:

  • 3-Nitro-p-hydroxyethylaminophenol is used in hair dyes, and dermal contact is unavoidable.
  • 3-Nitro-p-hydroxyethylaminophenol is an extreme skin sensitiser, and meets the factors for Schedule 6.
  • The risk of skin sensitisation when exposed to 3-nitro-p-hydroxyethylaminophenol can be managed with mandatory warning statements and concentration cut-offs for hair dye products to be exempted from Schedule 6 .
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal
  • ACCS advice
  • Public Submission 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 4-((2-hydroxyethyl)amino)-3-nitrophenol under the INCI name, 3-nitro-p-hydroxyethylaminophenol.

The wording for the schedule, appendix and index entries are as follows:

Schedule 6 - New Entry

3-NITRO-p-HYDROXYETHYLAMINOPHENOL except:

  1. in non-oxidative hair dye preparations containing 1.85 per cent or less of 3-nitro-p-hydroxyethylaminophenol 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; or

  2. in oxidative hair dye preparations containing 3 per cent or less of 3-nitro-p-hydroxyethylaminophenol after mixing under oxidative conditions 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 F, Part 3 - New Entry

3-NITRO-p-HYDROXYETHYLAMINOPHENOL

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

Index - New Entry

3-NITRO-p-HYDROXYETHYLAMINOPHENOL
cross reference: 4-[(2-hydroxyethyl)amino]-3-nitrophenol

Schedule 6
Appendix F, Part 3

The proposed implementation date is 1 June 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; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the interim decision are the following:

  • The delegate acknowledges the committee's advice.
  • 3-Nitro-p-hydroxyethylaminophenol is used in hair dyes, and dermal contact is unavoidable.
  • 3-Nitro-p-hydroxyethylaminophenol is an extreme skin sensitiser, and meets the factors for Schedule 6.
  • The risk of skin sensitisation when exposed to 3-nitro-p-hydroxyethylaminophenol can be managed with mandatory warning statements and concentration cut-offs for hair dye products to be exempted from Schedule 6.
Public submissions on the interim decision

One (1) submission was received which supported the delegate's interim decision with amendments. The main point in support was that the proposed schedule entry would be in alignment with international regulations in the EU. The main points were:

  • No Appendix E Standard Statements are proposed. The submission suggests that Standard Statements should be applied in a way that is consistent with other existing entries for scheduled hair dye substances.
  • The submission questions the use of the warning statement, 'This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye' and whether the reason for its inclusion is eye irritancy or sensitisation.
  • The appropriateness of the proposed 'earliest possible implementation date' of 1 June 2017. The submission stresses that an adequate transition period of at least 12 months must be allowed for any labelling changes and/or reformulation that may be required where no immediate risk has been identified; and that there is no evidence to suggest immediate action is required for the risk management of this substance.
Delegate's final decision

The delegate's final decision is to create new Schedule 6, Appendices E & F and Index entries for 4-((2-hydroxyethyl)amino)-3-nitrophenol under the INCI name, 3-nitro-p-hydroxyethylaminophenol as follows:

Schedule 6 - New Entry

3-NITRO-p-HYDROXYETHYLAMINOPHENOL except:

  1. in non-oxidative hair dye preparations containing 1.85 per cent or less of 3-nitro-p-hydroxyethylaminophenol after mixing 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; or

  2. in oxidative hair dye preparations containing 3 per cent or less of 3-nitro-p-hydroxyethylaminophenol after mixing under oxidative conditions 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

3-NITRO-p-HYDROXYETHYLAMINOPHENOL

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

Appendix F, Part 3 - New Entry

3-NITRO-p-HYDROXYETHYLAMINOPHENOL

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

Index - New Entry

3-NITRO-p-HYDROXYETHYLAMINOPHENOL
cross reference: 4-[(2-hydroxyethyl)amino]-3-nitrophenol

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

The implementation date has been extended to 1 February 2018.

The delegate confirms that the reasons for the final decision are the same as those provided from the interim decision. Additional reasons for the final decision include:

  • The warning statement 'This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye' has been included as the chemical is a slight eye irritant at concentrations 4 and 6% and likely to be irritating at exempted concentrations when used in hair dye preparations.
  • Appendix E Standard Statements apply to the scheduled substance and not the exemptions (as specified in a) and b) of the Schedule 6 entry for 3-nitro-p-hydroxyethylaminophenol)). 3-Nitro-p-hydroxyethylaminophenol is a slight eye irritant at 4 and 6% which is likely to become more severe at higher concentrations; therefore Standard Statement E1 (if in eyes wash out immediately with water) is appropriate.
  • The words 'after mixing' have been added to the schedule entry for clarity
  • The delegate notes that a longer implementation time is required to allow for labelling changes and/or reformulation.

1 Publicly available on the NICNAS website at: https://www.nicnas.gov.au/chemical-information/imap-assessments/imap-assessment-details?assessment_id=1799

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