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Scheduling delegate's final decisions, January 2017

Scheduling medicines and poisons

16 January 2017

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1.2. 1,3-Benzenediol

Final decisions on matters not referred to an expert advisory committee

1. Chemicals not referred to the November 2016 ACCS

1.2. 1,3-Benzenediol

Referred scheduling proposal

An application was submitted to create a new Schedule 6 entry for 1,3-benzenediol for restriction in cosmetic and domestic products.

Current scheduling status and relevant scheduling history

1,3-Benzenediol is not currently scheduled and has not been previously considered for scheduling; therefore, a scheduling history is not available. However, an isomer of 1,3-benzenediol, 1,2 benzenediol is currently scheduled as follows:

Schedule 6

1,2-BENZENEDIOL.

Appendix E − 1,2-BENZENEDIOL (catechol)

Standard statements: A, E1, S1

Appendix F − 1,2-BENZENEDIOL (catechol)

Warning statements: 51, 59.

Safety directions: 1, 4, 8.

Australian regulatory information

1,3-Benzenediol was reported to be used in permanent hair dye preparations in Australia (NICNAS, 2007) and in overseas hair lotions and shampoos.

Currently, there are no restrictions in Australia on using this chemical in hair dyes, hair lotions and shampoos. In the absence of any regulatory controls, the characterised critical health effects (skin and eye irritation, and skin sensitisation) have the potential to pose an unreasonable risk under the identified uses. The risk could be mitigated by implementing concentration limits and labelling requirements for use in hair dyes, hair lotions and shampoos.

International regulations

The EU has restricted the use of this chemical in oxidative hair colouring products at a maximum concentration of 2.5%. It is mixed with hydrogen peroxide in a 1:1 ratio just prior to use, which corresponds to a concentration of 1.25% when applied to hair (SCCS, 2010). Restricted use in hair lotions and shampoos was also reported to be the maximum authorised concentration in the finished cosmetic product of 0.5%.

1,3-Benzenediol is listed on the EU Cosmetic Directive 76/768/EEC Annex III Part 1: List of substances which cosmetic products must not contain except subject to the restrictions and conditions laid down below (Galleria Chemica): (a) Hair dye substance in oxidative hair dye products for general and professional use-after mixing under oxidative conditions the maximum concentration applied to hair must not exceed 1.25% (w/w); and (b) Hair lotions and shampoos- maximum authorised concentration in the finished cosmetic product of 0.5% (w/w).

1,3-Benzenediol is also listed on the following:

  • 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;
  • 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;
  • Health Canada List of prohibited and restricted cosmetic ingredients (The Cosmetic Ingredient 'Hotlist'); and
  • Chile list of Cosmetic Ingredients with limited use or concentration.
Scheduling application

General application.

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

Schedule 6 − New Entry

1,3-BENZENEDIOL except:

  1. in hair dye preparations containing 1.25 per cent or less of 1,3-benzenediol after mixing for use 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.

    written in letters not less than 1.5 mm in height; or

  2. in hair lotions/shampoo products containing 0.5 per cent or less of 1,3-benzenediol and when the immediate container and primary pack are labelled with the following statement:

    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 E1,3-BENZENEDIOL

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

Appendix F1,3-BENZENEDIOL

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

The applicant's reasons for the request are:

  • 1,3-Benzenediol is used in permanent hair dye preparations in Australia (NICNAS, 2007) and in hair lotions and shampoos overseas (refer to Import, Manufacture and Use section of IMAP Tier II report);
  • 1,3-Benzenediol has moderate oral toxicity and has been shown to cause skin and eye irritation as well as skin sensitisation;
  • 1,3-Benzenediol has existing overseas restrictions in European Union (EU) for oxidative hair colouring products at a maximum concentration of 2.5%, with labelling requirements at lower concentrations. It is mixed with hydrogen peroxide in a 1:1 ratio just prior to use, resulting in a concentration of 1.25% when applied to hair (SCCS, 2010). Use of the chemical is also restricted in hair lotions and shampoos with a maximum authorised concentration in the finished cosmetic product of 0.5%; and
  • When 1,3-benzenediol 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.
Substance summary

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 Safety (SCCS) report.

Figure 1.2: Chemical structure of 1,3-benzenediol
Figure 1.2: Chemical structure of 1,3-benzenediol

Table 1.2A: Chemical properties and identifiers of 1,3-benzenediol
Property/identifier 1,3-Benzenediol
Molecular formula C6H6O2
Molecular weight 110.1°g/mol
CAS name 1,3-Benzenediol
CAS number 108-46-3
IUPAC and/or common and/or other names Resorcinol (INCI name); benzene-1,3-diol (IUPAC); 1,3-dihydroxybenzene; and 3-hydroxyphenol.
Table 1.2B: Acute toxicity end-points for 1,3-benzenediol
Toxicity Species 1,3-Benzenediol SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bodyweight (bw)) Rats (Sprague Dawley) 200-980 mg/kg bw/day. N/A
Acute dermal toxicity LD50 (mg/kg bw) Rabbits > 2000 mg/kg bw/day. N/A
Acute inhalational toxicity LC50 (mg/m3/4h) Rats (Harlan Wistar)

> 7800 mg/m 3/1–hour (equivalent to 7.8 mg/L or 1732 ppm); and

> 2800 mg/m 3/8–hours (equivalent to 2.8 mg/L or 622 ppm)

N/A
Skin irritation Rabbit (albino) Slight to severe skin irritant in diluted and semi-solid state, respectively (flaked and industrial grade). Schedule 6
Rabbit (New Zealand White) Not irritating to skin (2.5% solution in water; 98.8% purity)
Eye irritation Rabbit (albino) Severe eye irritant (see below) Schedule 6
Skin sensitisation (Guinea Pig Maximisation Test: GPMT) Guinea pigs (Pirbright white) Sensitiser (relative incidence of the positive reactions in animals was > 30%) (99.9% purity) Schedule 6
Skin sensitisation (mouse local lymph node assay: LLNA) Mice (CBA/Ca)

Moderate sensitiser with EC = 1.4 and 6.3%

(unspecified purity)

Acute toxicity

The acute toxicity end-points of 1,3-benzenediol are summarised in Table 1.2B.

Skin irritation

Based on the weight of evidence, the chemical is considered to be slightly to severely irritating to skin when administered diluted in an aqueous solution or in semi-solid state (flaked or industrial grade):

  • In a non-guideline (Federal Hazardous Substance Labelling Act (FHSLA)) skin irritation study, 0.5 g of the chemical (flaked grade) in saline was applied to the clipped belly skin (abraded and intact) of albino rabbits (six males) for 24 hours under occlusive patches. Observations were made at 24 and 72 hours post-treatment, and animals were kept under observation for a maximum of two weeks. Treatment-related effects were moderate irritation on intact skin and necrosis on abraded skin. Effects were more pronounced at 72 hours post-treatment. In the two week recovery period, necrotic areas were still encrusted or scarred. The primary dermal irritation index (PDII) was reported to be 4.4;
  • In similar non-guideline (FHSLA) studies, a 24-hour occluded application of the chemical (flaked and industrial grade) at 0.5 g to the bellies of male albino rabbits produced moderate irritation on intact skin and necrosis on abraded sites. The chemical (industrial grade) was reported to cause slight to severe irritation of the intact areas, and from severe irritation to necrosis of the abraded areas, 24 hours after exposure. In the 2-week post-recovery period, necrotic areas were still encrusted or scarred. The primary dermal irritation index (PDII) for the chemical was reported to be 4.4 (flaked grade) and 5.4 (industrial grade); and
  • In a study conducted according to the OECD Test Guideline 404 (acute dermal irritation/corrosion), 0.5 mL of the chemical (2.5% aqueous solution) (98.8% purity) was applied to the clipped back skin of New Zealand White rabbits (three males/group) for four hours under semi-occlusive patches. Observations were made at one, 24, 48 and 72 hours post-treatment. No adverse cutaneous reactions were reported at this low concentration.
Eye irritation

Data from one study using the chemical (flaked and industrial grade diluted in an aqueous solution and semi-solid state, respectively) indicated that the chemical should be considered a severe eye irritant:

  • In a non-guideline (FHSLA) study, 0.1 g of the chemical (flaked and industrial grade) was instilled into the eyes of albino rabbits (6 males). Treatment-related effects upon administration included inflamed conjunctivae, opaque corneas and visible discomfort in animals. At 24 hours post-exposure, observations included severe conjunctivitis, iritis, corneal opacity occluding most of the iris and corneal ulcerations. Irreversible effects on the eyes were reported and by day 14, all treated eyes had kerataconus (thinning of and irregularly shaped cornea) and pannus (abnormal layer of fibrovascular tissue or granulation tissue over the cornea) formation. Total mean eye irritation Draize scores were reported to be 105/110 at 24, 48 and 72 hours and the chemical was considered to be a severe eye irritant;
  • The chemical was mildly irritating in six albino rats administered 0.1 g of the chemical (dry powder). Reported mean irritation scores were 56.3, 45.0 and 39.9 out of 110 over the observation period at 24, 48 and 72 hours, respectively. No further study details were available; and
  • In a study conducted according to OECD TG 405 (acute eye irritation/corrosion), 0.1 mL of the chemical (2.5% solution in water (98.8% purity)) was instilled into the eyes (conjunctival sacs) of New Zealand White rabbits (three males) and left for 72 hours. Mean scores of zero were reported for chemosis, iris lesions and corneal opacity over 24, 48 and 72 hours. For redness of the conjunctivae, a mean score of 0.1 was reported.
Skin sensitisation

Based on the available animal and human data, the chemical is considered to be a moderate to strong contact skin sensitiser and is recommended for classification:

  • In a GPMT conducted in accordance with OECD TG 406, Pirbright white guinea pigs (treatment group 10 animals, control group 5 animals and accompanying group 20 animals used for range finding) were administered 2% (w/v) solution of the chemical (99.9% purity as white flakes in sodium chloride) by intradermal injection followed by occlusive, epicutaneous application of 25% the chemical. At the challenge exposure using 25% of the chemical (occlusive epicutaneous application), very slight to distinct erythema was observed on the skin of 2-3 animals at 24 and 48 hours observation periods. At the second challenge and compared to the control group, very slight to distinct erythema was reported in 7/10 guinea pigs at 24 hours and on 5/10 guinea pigs at 48 hours and minor swelling was also observed in one animal at 24 hours after patch removal. The relative incidence of the positive reactions in animals was over the threshold value of 30% and the chemical was considered to be a skin sensitiser;
  • In a study conducted in accordance with OECD TG 429, positive skin sensitisation was reported in LLNA studies in two independent experiments. A positive control of a-hexyl cinnamaldehyde (HCA), a moderate sensitiser, at the concentration of 25% (v/v) in DMF was used. In the first experiment (range finding), female CBA/J mice (four animals/dose including negative and positive controls) were administered 25 μL of the chemical (in vehicle dimethylformamide at 2.5, 5, 10, 25 or 50%) applied to the dorsal surface of each ear, once daily for three consecutive days. Stimulation indices (SI) of 3.83, 4.14, 3.97, 3.51 and 3.30 were reported, respectively. Positive lymphoproliferative responses (SI > 3) were reported at all concentrations, but no clear dose-response relationship was observed. In the second experiment, mice (four/dose) were administered daily applications of 0.1, 0.5, 1, 5 or 25% chemical (w/v). Treatment resulted in stimulation indices of 1.58, 2.87, 1.97, 3.51 and 5.74, respectively. A dose-related increase in SI was seen and the threshold positive value of three was exceeded. The effective concentration at which a three-fold increase in SI was achieved (EC3) was reported to be 1.4% and the chemical was considered to be a moderate skin sensitiser; and
  • The chemical (purity unspecified) was not reported to be sensitising according to two non-guideline skin sensitisation (LLNA) studies in mice (concentrations of up to 2.5% and 25% w/v were tested, respectively). No further study details were available and the reliability of both studies was questioned due to out-dated study methods (OECD, 2008). However, the chemical was reported to be a sensitiser in mice in a LLNA study (OECD TG 429). A group of CBA/Ca female mice (four/dose) were treated at daily concentrations of 0, 1, 5, 10, 25 and 50% (w/v) of the chemical (purity unspecified) in acetone/olive oil (ratio of 4:1). SIs of 1.0, 0.7, 2.2, 5.2, 8.4 or 10.4 were measured respectively, and an EC value of 6.3% was determined (REACH; OECD, 2008).
Observation in humans

Human patch-testing using 1,3-benzenediol elicited allergic skin reactions in 0.7–0.8% of 1694 dermatitis patients. In further case histories of 34 dermatitis patients, the chemical was reported to cause reactions after epicutaneous testing.

No dermatitis of the hands was reported for 42 workers from a tyre factory after an epicutaneous test with the chemical.

In human patch tests with the chemical (2% in petrolatum), four out of 302 hairdressers suffering from contact dermatitis reported a positive reaction. No further details were available. In another case, one patient who developed contact dermatitis after application of paint to the skin was patch tested with the chemical (5% in petrolatum) and showed a positive result after 48 hours. In a third case, three female patients suffering from acne and contact dermatitis gave a positive patch test for the chemical (2% in petrolatum) after 48 and 72 hours.

Repeat-dose toxicity

Based on the weight-of-evidence, the chemical is not considered to cause serious damage to health from repeated oral exposure.

No information was available for repeated dose toxicity by the dermal route.

There is insufficient evidence to evaluate repeated dose 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.

Carcinogenicity

Based on the available data, the chemical is not considered to be carcinogenic.

Reproduction and developmental toxicity

Based on the available data, the chemical is not considered to be a reproductive or developmental toxin.

Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • NICNAS IMAP Tier II Report;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling Policy Framework (SPF 2015) criteria; and
  • Other relevant information.
Delegate's final decision

The delegate's final decision is to create a new Schedule 6 entry for 1,3-benzenediol with a 1.25 per cent exemption cut-off in hair dye preparations as follows:

Schedule 6 − New Entry

RESORCINOL except:

  1. in hair dye preparations containing 1.25 per cent or less of resorcinol 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.

    written in letters not less than 1.5 mm in height; or

  2. in hair lotions/shampoo products containing 0.5 per cent or less of resorcinol when the immediate container and primary pack are labelled with the following statement:

    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 on the eyelashes or eyebrows; to do so may be injurious to the eye.

    written in letters not less than 1.5 mm in height.

Appendix E, Part 2 – RESORCINOL

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).

Appendix F, Part 3 – RESORCINOL

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

Index – New Entry

RESORCINOL
cross reference: 1,3-benzenediol

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

The delegate notes that the main routes of exposure to resorcinol is through the skin and eyes from products applied to the hair and scalp. The skin and eye irritation and skin sensitisation of resorcinol are consistent with Schedule 6 criteria. Recent decisions for previously considered similar sensitising hair dyes have allowed for some products to be exempted where there are label statements warning of the potential for skin irritancy and sensitisation, and recommending testing for individual susceptibility before use. This scheduling decision is in alignment with international regulations for resorcinol and is consistent with recent decisions agreed on previously considered similar sensitising hair dyes.

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 the substance; (b) the purposes for which the substance is to be used and (c) the toxicity of the substance.

The implementation date is 1 February 2017.

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