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Scheduling delegate's final decisions: ACCS, August 2014

Scheduling medicines and poisons

7 August 2014

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Part A - Final decisions on matters referred to an expert advisory committee (ACCS) 1.1-1.7

1. Scheduling proposals referred to the March 2014 meeting of the Advisory Committee on Chemicals Scheduling (ACCS#10)

1.1 1-butanol

Scheduling proposal

On 29 August 2013, the National Industrial Chemicals and Notification Assessment Scheme (NICNAS) under the Inventory Multi-tiered Assessment Prioritisation (IMAP) process requested that the delegate consider a proposal to include spray preparations containing 5 per cent or more of 1-butanol in Schedule 5. This proposal was first notified to the delegate in September 2013 at which time it was determined that expert advisory committee advice may not be required for this proposal. However, due to the complexity of the proposal, expert advice on this substance is being sought.

The delegate considered the proposal in the NICNAS IMAP report which focuses on the potential for eye damage and inhalation toxicity associated with the use of 1-butanol in cosmetics and various spray-on products used in a domestic setting. The issues raised have much in common with those in the 1-propanol IMAP report, and they could be considered together. In view of the potential impact on existing products, the delegate considers that advice is needed from the ACCS, with an appropriate public notice alerting the industry to the proposed scheduling action. Since the advice from the TGA is that 1-butanol is used as an excipient (in printing ink only) there is no need to refer the matter to a joint ACCS/ACMS meeting. The inclusion of 1-butanol (as an excipient) in one AgVet product should be considered by the ACCS.

The delegate asked the following specific questions:

  • The principal issue raised by the NICNAS IMAP report is the potential for eye irritancy associated with concentrations of 1-butanol above 5 per cent, with more serious eye damage expected at 10 per cent and above. The Report also notes the potential for skin damage at higher concentrations and effects on the CNS associated with inhalation of vapours. The NICNAS report notes relevant exposure scenarios associated with the use of 1-butanol in cosmetics, domestic cleaners and in particular, spray-on products.
  • The skin-eye toxicity can be attributed to the solvent and de-fatting effects of 1-butanol, and this would be expected of any short-chain alkyl alcohol, including ethanol. It is noted that ethanol is currently included in Appendix B for all uses.
  • Does the ACCS consider that the toxicity potential for 1-butanol and its potential use in the listed products warrants inclusion in Schedule 6, with exemptions to Schedule 5 at x? per cent, and exempt below y? per cent?
  • If scheduling is recommended, should this be limited to certain specific product types in the retail market? If so, what wording is recommended to achieve such limitations?
  • If scheduling is recommended, is the preferred nomenclature 1-butanol, n-butanol or butyl alcohol (consistent with the naming style for ethyl alcohol used in the Appendix B entry)? Should any of these names be cross-referenced in the SUSMP index (as per ethyl alcohol)?
  • What Appendix E & F statements are recommended for any scheduled products?
  • What regulatory impacts on existing products would be expected for any of the above scheduling options, and to what extent should this be considered in setting an implementation date?
Substance summary

Please refer to the NICNAS IMAP Human Health Tier II Assessment Report for 1-butanol, which is available on from the NICNAS website.

Scheduling status

1-Butanol is not specifically scheduled.

Scheduling history

1-Butanol has not been previously considered for scheduling therefore scheduling history is not available.

Pre-meeting public submissions

Four public submissions were received.

The first submission indicated that 1-butanol is listed in the TGA's ARTG ingredient list as n-butyl alcohol BP, indicating that it may have uses in therapeutic goods, although specific uses are not defined. This ingredient may have been used as a propellant in certain aerosol dosage forms for medicines. The submission noted that the delegate's proposal was not limited to cosmetic or industrial preparations containing 1-butanol, and no cut-off is proposed. It is concerned about the possibility that including 1-butanol in a schedule may have some impact on therapeutic goods, and requested that consideration should be given to exempt from scheduling for therapeutic goods containing 1-butanol.

The second submission indicated that it did not support scheduling of 1-butanol. If, however, 1-butanol is considered for inclusion in a schedule, it should be considered by the joint ACMS & ACCS consideration to ensure that therapeutic use of 1-butanol is not inadvertently affected. The submission asserted the Cosmetic Ingredient Review (CIR) found that that cosmetic preparations containing 1- butanol are safe therefore cosmetics preparations containing 1-butanol be exempted from scheduling.

The third submission noted that 1-butanol is currently used in therapeutic and cosmetic products, therefore the proposal should be considered by the joint ACCS & ACMS. The submission asserted that it is not aware of any issues using 1-butanol in aerosol products intended for cosmetic or therapeutic use. Based on the CIR Ingredient Status Report and publically available data, 1-butanol has been classified as safe for use in various cosmetic products. These types of products therefore should be exempted from the proposed Schedule 5 and/or 6 entry/s.

The fourth submission noted that 1-butanol is also used in therapeutic goods therefore the scheduling proposal should be considered by the joint ACCS and ACMS. The submission indicated that publically available data has shown that 1-butanol is recognized as safe for use in cosmetic products. If a Schedule 5 and/or Schedule 6 entry is considered appropriate, the entry should exempt from scheduling for cosmetic and therapeutic products containing 1-butanol. If a concentration cut-off is applied, the cut-off should be set at a concentration where current cosmetic and therapeutic products in the market will not be impacted.

ACCS advice to the delegate

The ACCS recommended that preparations containing 1-butanol at concentrations greater than 10 per cent be included in Schedule 6 except when in Schedule 5 and except for preparations containing 5 per cent or less of 1-butanol. Cosmetics and therapeutics to be exempted. The committee also recommends appropriate Appendix E and F statements for 1-butanol.

The ACCS recommended an implementation date of 12 months.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the committee included: (c) the toxicity of the substance.

The reasons for the recommendation comprised the following:

  • Potential for moderate to severe eye damage or respiratory irritation consistent with the SPF factors for Schedule 5 or Schedule 6 depending on concentration and use.
Delegate's interim decision

The delegate accepts the advice of the ACCS to include 1-butanol in Schedules 5 and 6. The critical toxicological endpoints driving this categorisation (potential for inhalation toxicity, skin irritancy and severe eye irritancy) are consistent with SPF criteria for listing in Schedule 6, with the public health risk sufficiently ameliorated for products between 5 and 10 per cent to be included in Schedule 5, and to be exempt from scheduling when less than 5 per cent. The delegate notes, but does not accept, the ACCS recommendation that cosmetics and therapeutic products be specifically exempted. There appear to be no therapeutic goods or cosmetics where the concentration of 1-butanol would be likely to exceed the 5 per cent cut-off to exempt, and if there are any such products, the warnings associated with the proposed schedule entries would be applicable and suitable.

The delegate agrees with the implementation date being 1 July 2015. The ACCS suggested that at least twelve months may be needed to implement the required label changes.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: b) the purposes for which a substance is to be used and the extent of use of a substance and c) the toxicity of a substance.

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.
Public submissions on the interim decision

One submission was received. The submission indicated that 1-butanol does not require a schedule listing and requested the delegate to defer the final decision to seek reconsideration from the ACCS.

Edited versions of these submissions are available at Public submissions on scheduling matters.

Delegate's final decision

The delegate notes the submissions received in response to publication of the interim decision and has determined to set aside the interim decision and to seek further advice.

The delegate notes that the potential for eye irritation/damage at high concentrations is the principal driver for scheduling. Moreover, consistent with advice from the ACCS, the delegate has now formed the view that scheduling controls over the use of 1-butanol in cosmetics and therapeutic goods are unnecessary, given the safety evaluation profiles that have been undertaken for the existing range of products in these classes (or would be in the case of new therapeutic goods). If 1-butanol is to be scheduled, these products should be specifically exempt, as originally recommended by the ACCS.

The delegate also notes the apparent inconsistency of current and past committee advice relating to the need to schedule solvent-type materials with low toxicity profiles, but with properties that could result in similar eye irritation (e.g. ethanol, tetrahydrofuran). The delegate has therefore decided to refer the matter back to the ACCS to consider a range of product types containing 1-butanol that would specifically warrant scheduling to protect against eye damage, and whether these should include such products as aerosol or spray products (except in therapeutic goods), and/or arts & craft materials, where there may be a greater risk of being taken into the eye.

The matter is to be referred back the ACCS for further consideration. A new and appropriate implementation time can be determined after reconsideration of the scheduling proposal by the ACCS.

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1.2 1-propanol

Scheduling proposal

On 29 August 2013, the National Industrial Chemicals and Notification Assessment Scheme (NICNAS) under the Inventory Multi-tiered Assessment Prioritisation (IMAP) process requested that the delegate consider a proposal to include cosmetics and domestic preparations, such as arts, craft and hobby material, containing 1-propanol in an appropriate schedule. This proposal was first notified to the delegate in September 2013 at which time it was determined that expert advisory committee advice may not be required for this proposal. However, due to the complexity of the proposal, expert advice on this substance is being sought.

The delegate noted that the NICNAS IMAP report focuses on the potential for eye damage associated with the use of 1-propanol in cosmetics and other products used in a domestic setting. It proposes inclusion in Schedule 6, with cut-offs to Schedule 5 and exempt. In view of the potential impact on existing products, the delegate considered that advice was needed from the ACCS, with an appropriate public notice alerting the industry to the proposed scheduling action. Since the advice from the APVMA and TGA was that 1-propanol had not been used in products they regulate, there was no need to refer the matter to a joint ACCS/ACMS meeting.

The delegate asked the following questions:

  • The principal issue raised by the NICNAS IMAP report is the potential for eye irritancy associated with concentrations of 1-propanol above 5 per cent, with more serious eye damage expected at 10 per cent and above. The Report also notes the potential for skin damage at higher concentrations and effects on the CNS associated with inhalation of vapours. The NICNAS report notes relevant exposure scenarios associated with the use of 1-propanol in cosmetics, domestic cleaners and in particular, arts, craft and hobby materials.
  • The skin-eye toxicity can be attributed to the solvent and de-fatting effects of 1-propanol, and this would be expected of any short-chain alkyl alcohol, including ethanol. It is noted that ethanol is currently included in Appendix B for all uses.
  • Does the ACCS consider that the toxicity potential for 1-propanol and its potential use in the listed products warrants inclusion in Schedule 6, with exemptions to Schedule 5 at x? per cent, and exempt below y? per cent?
  • If scheduling is recommended, should this be limited to certain specific product types in the retail market? If so, what wording is recommended to achieve such limitations?
  • If scheduling is recommended, is the preferred nomenclature 1-propanol, n-propanol or propyl alcohol (consistent with the naming style for ethyl alcohol used in the Appendix B entry)? Should any of these names be cross-referenced in the SUSMP index (as per ethyl alcohol)?
  • What Appendix E & F statements are recommended for any scheduled products?
  • What regulatory impacts on existing would be expected for any of the above scheduling options, and to what extent should this be considered in setting an implementation date?
Substance summary

Please refer to the NICNAS Inventory Multi-tiered Assessment Prioritisation (IMAP) Human Health Tier II Assessment Report for 1-propanol, which is publically available on the NICNAS website.

Scheduling status

1-propanol is not specifically scheduled.

Scheduling history

1-propanol has not been considered previously therefore scheduling history is not available.

Pre-meeting public submissions

Four public submissions were received.

The first submission indicated that 1-propanol is listed in the ARTG as propan-1-ol BP, and is allowed in therapeutic goods in products for dermal use up to a maximum concentration of 18 per cent w/v. The submission indicated that the delegate's proposal was not restricted to cosmetic or industrial products, and no cut-off was proposed. The submission was concerned about the possibility that there may be some impact on therapeutic goods, and requested that consideration should be given to exempt from scheduling for therapeutic goods containing 1-propanol.

The second submission indicated that NICNAS did not provide any evidence to suggest that current uses of some preparations containing up to 60 per cent of 1-propanol were causing public health and safety concerns. The submissions indicated that it did not support scheduling of 1-propanol, however, if a schedule listing for 1-propanol was considered appropriate, the proposal should be considered by the joint ACMS & ACCS to ensure that therapeutic uses of 1-propanol were not inadvertently captured.

The third submission indicated that 1-propanol is currently used in therapeutic and cosmetic products therefore the proposal should be considered by the joint ACCS & ACMS. The submission asserted that based on the CIR Ingredient Status report and publically available data, 1-propanol had been considered safe for use in various cosmetic products as currently used.

The fourth submission indicated that as therapeutic goods may contain 1-propanol, the scheduling proposal should be considered by the joint ACCS & ACMS. The submission asserted that the CIR Expert Panel has assessed the safety profile of certain cosmetic preparations containing 0.002 to 100 per cent of 1-propanol and concluded that 1-propanol was considered to be safe. The submission requested that if 1-propanol was to be included in Schedule 5 and/or Schedule 6, cosmetic and therapeutic products containing 1-propanol be exempted from the scheduling. If a concentration cut-off was applied, the cut-off should be set at a concentration where current cosmetic and therapeutic products in the market would not be impacted.

ACCS advice to the delegate

The ACCS recommended that preparations containing 1-propanol at concentrations greater than 10 per cent be in Schedule 6, between 5 and 10 per cent in Schedule 5, and exempt for preparations containing 5 per cent or less of 1-propanol. Cosmetics and therapeutics are to be exempted.

The ACCS recommended an extended implementation period of 12 months.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the committee included: (c) the toxicity of the substance.

The reasons for the recommendation comprised the following:

  • Potential for moderate to severe eye damage consistent with Schedule 5 or Schedule 6 depending on concentration and use.
Delegate's interim decision

The delegate accepts the advice of the ACCS to include 1-propanol in Schedules 5 and 6. The critical toxicological endpoints driving this categorisation (potential for inhalation toxicity, skin irritancy and severe eye irritancy) are consistent with SPF criteria for listing in Schedule 6, with the public health risk sufficiently ameliorated for products between 5 and 10 per cent to be included in Schedule 5, and to be exempt from scheduling when less than 5 per cent. The delegate notes, but does not accept, the ACCS recommendation that cosmetics and therapeutic products be specifically exempted. There appear to be no therapeutic goods or cosmetics where the concentration of 1-propanol would be likely to exceed the 5 per cent cut-off to exempt, and if there are any such products, the warnings associated with the proposed schedule entries would be applicable and suitable.

The delegate agrees with the implementation date being 1 July 2015. The ACCS suggested that at least twelve months may be needed to implement the required label changes.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: b) the purposes for which a substance is to be used and the extent of use of a substance and c) the toxicity of a substance.

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 factors2;
  • Other relevant information.
Public submissions on the interim decision

One submission was received. The submission indicated that 1-butanol 1-propanol does not require a schedule listing and requested the delegate to defer the final decision to seek reconsideration from the ACCS.

Edited versions of these submissions are available at Public submissions on scheduling matters.

Delegate's final decision

The delegate notes the submissions received in response to publication of the interim decision and has determined to set aside the interim decision and to seek further advice.

The delegate notes that the potential for eye irritation/damage at high concentrations is the principal driver for scheduling. Moreover, consistent with advice from the ACCS, the delegate has now formed the view that scheduling controls over the use of 1-propanol in cosmetics and therapeutic goods are unnecessary, given the safety evaluation profiles that have been undertaken for the existing range of products in these classes (or would be in the case of new therapeutic goods). If 1-propanol is to be scheduled, these products should be specifically exempt, as originally recommended by the ACCS.

The delegate also notes the apparent inconsistency of current and past committee advice relating to the need to schedule solvent-type materials with low toxicity profiles, but with properties that could result in similar eye irritation (e.g. ethanol, tetrahydrofuran). The delegate has therefore decided to refer the matter back to the ACCS to consider a range of product types containing 1-propanol that would specifically warrant scheduling to protect against eye damage, and whether these should include such products as alcohol-based handrubs, and/or arts & craft materials, where the 1-propanol concentrations are likely to be substantively higher than the proposed scheduling cut-offs.

The matter is to be referred back the ACCS for further consideration. A new and appropriate implementation time can be determined after reconsideration of the scheduling proposal by the ACCS.

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1.3 2,4-diaminophenoxyethanol sulfate

Scheduling proposal

On 29 August 2013, the National Industrial Chemicals and Notification Assessment Scheme (NICNAS) under its New Chemicals Assessment process, requested that the delegate consider a proposal to include 2,4-diaminophenoxyethanol sulfate in Schedule 6 and Appendix F entries. This proposal was first notified to the delegate in September 2013 at which time it was determined that expert advisory committee advice may not be required for this proposal. However, due to the complexity of the proposal, expert advice on this substance is being sought.

The delegate considered the proposal that the toxicity profile of 2,4-diaminophenoxyethanol sulphate includes moderate to high acute toxicity, moderate skin irritancy, severe eye irritancy and potential genotoxicity. Its proposed use is as a component of oxidative hair colouring products at up to 4 per cent. Its toxicity and use profiles are similar to an oxidative hair dye considered at the November 2013 ACCS meeting (2-amino-5-ethylphenol). ACCS advice is required to determine whether a similar scheduling approach should be used for 2,4-diaminophenoxyethanol sulfate (Schedule 6 with exempt cut-off with reverse scheduling label statements for exempt products) and are Appendix E & F statements required?

Substance summary

2,4-diaminophenoxyethanol sulfate is used as an ingredient of oxidative hair colouring products at a maximum final (on-head) concentration of 2.0 per cent, after mixing the hair dye formulation with a hydrogen peroxide preparation typically in 1:1 proportions3.

Figure 1.Structure of 2,4-diaminophenoxyethanol sulfate

Structure of 2,4-diaminophenoxyethanol sulfate.

The delegate noted that the NICNAS report indicated that the main analogue used in the assessment of 2,4-diaminophenoxy ethanol sulfate is ethanol, 2-(2,4-diaminophenoxy)-, dihydrochloride; CAS number: 66422-95-5 (INCI name: 2,4-diaminophenoxyethanol HCl). This differs from 2,4-diaminophenoxyethanol sulfate only in the counter ion of the salt, with the free base of the analogue and the notified chemical being identical. The structure of ethanol, 2-(2,4-diaminophenoxy)- is provided below (Figure 2). The water solubility and partition coefficient of the notified chemical and the analogue chemical are within similar ranges and thus absorption of the two chemicals across biological membranes is not expected to be significantly different. The NICNAS report concluded that it is reasonably considered that the analogue and 2,4-diaminophenoxyethanol sulfate will have comparable physical/chemical and toxicological properties.

Figure 2. Structure of ethanol, 2-(2,4-diaminophenoxy)-, dihydrochloride

Structure of ethanol, 2-(2,4-diaminophenoxy)-, dihydrochloride

Acute toxicity

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

Toxicity Species 2,4-diaminophenoxyethanol sulfate SPF* classification
Acute oral toxicity LD50 (mg/kg bw) Rat 1 000- 1 113 Schedule 6
Acute dermal toxicity LD50 (mg/kg bw) Mouse 1 160-1 745 Schedule 6
Acute inhalational toxicity LC50 (mg/m3/4h) Not supplied Not supplied Unable to assess
Skin irritation Rabbit Slight irritant
Eye irritation Rabbit Irritant
Skin sensitisation (adjuvant test) Guinea pig Sensitiser

*Scheduling Policy Framework for Medicines and Chemicals (2010)

Repeat-dose toxicity

In a 90-day oral repeat dose study, both male and female rats were exposed to the analogue chemicals at 0, 4, 20 and 100 mg/kg bw/day. At 100 mg/kg bw/day, excessive salivation was observed in both males and females and lower body weight gains were noted for males. The presence of urinary bilirubin, nitrites and glucose in the coloured urine (marked coloration from yellow to yellow-brown in both males and females) was detected at the end of the treatment period. The presence of these chemicals in the urine may have been due to an analytical interference, as there were no changes observed in the plasma levels of these chemicals. An increase in relative kidney weights was observed in males and females dosed with 100 mg/kg bw/day.

Deposition of brownish pigment in the thyroid (mainly in follicular epithelial cells) as well as brownish colouration of the thyroid was observed in all animals given 100 mg/kg bw/day. An augmented degree of spleen haemosiderosis (deposition of haemosiderin, a protein that stores iron) was also observed for most animals given 100 mg/kg bw/day. The microscopic changes to the thyroid and spleen were still observed at the end of the recovery period.

Plasma levels of the test substance were determined from samples taken on day 1 and week 13 of the study. Systemic exposure was found to increase proportionally with the dose level.

A no observed adverse effect level (NOAEL) of 20 mg/kg bw/day was established.

Mutagenicity

Based on these studies the analogue chemical is considered to be an in vitro mutagen/genotoxin. However, the results obtained from tests conducted in vivo, which explored the endpoints found to be positive in vitro, indicate that the test substance cannot be classified as an in vivo mutagen or genotoxin.

Bacterial gene mutation assay positive in one strain (Salmonella typhimurium) in the presence of S9 metabolic activation.

Genotoxicity

Several genotoxicity studies on the analogue chemical had been conducted. These include a number of bacterial cell assays, with some positive results in certain strains and/or conditions/concentrations, as well as negative results. There are also in vitro assays with some positive and some negative results, and in vivo assays, with negative results.

Carcinogenicity

In a 2-year study, rats exposed to 0, 0.05 and 0.1 per cent (corresponding intake levels: 0, 20.9 and 35.5 mg/kg bw/day for male rats and 0, 27.8 and 60.9 mg/kg bw/day for female rats) to the analogue chemical. Body weight gain was decreased for males and females in both treatment groups. Tumour incidences in control and treated groups were generally the same. Pigment deposition in the epithelial cells of thyroid follicles of both males and females was observed in the highest dose groups, though their distribution did not correlate with the occurrence of tumours. An increase in the C-cell adenoma was observed in the thyroid gland of male rats. The NICNAS report noted that the study authors indicated that this increase was not toxicologically significant as C-cell adenomas are common in old F344 rats. However, historical control values were not provided. The NICNAS report indicated that no conclusion regarding the carcinogenicity of the analogue chemical could be made on the basis of this study.

The NICNAS report noted that there was no sufficient evidence of carcinogenicity therefore no conclusion can be drawn from this study.

In another 2-year study, mice were exposed to 0, 0.04 and 0.07 per cent in water, ad libitum (corresponding intake levels: 0, 35.8 and 62.8 mg/kg bw/day for male mice and 0, 44.6 and 81.4 mg/kg bw/day for female mice). Tumour incidences in control and treated groups were the same. Pigment deposition in the epithelial cells of thyroid follicles of both males and females was observed in the highest dose groups. The distribution of the deposits did not correlate with the tumour occurrence.

Reproduction and developmental toxicity

In a reproductive toxicity study, rats were exposed to 0, 4, 20, 125 mg/kg bw/day of the analogue chemical. Clinical signs of maternal toxicity, such as salivation, reduced body weight gain and food consumption, in the dam were noted in the 125 mg/kg bw/day dose group.

Moreover, at 125 mg/kg bw/day there was a statistically significant reduction in the mean foetal weight also observed. This corresponded with a statistically significant increased incidence of foetuses showing incomplete ossification of thoracic vertebra centrum or supernumerary short 14th rib.

Prenatal developmental toxicity (rat) NOAEL for maternal toxicity and embryo-foetal development is 20 mg/kg bw/day. In a developmental toxicity study, rats were exposed to 0, 50, 100, 200 mg/kg bw/day of the analogue chemical. In the 200 mg/kg bw/day dose groups, there was a significant dose related increase in the incidence of skeletal anomalies and skeletal variants. Lower litter weights and foetal mean weight were also observed at this dose. Clinical signs of toxicity, such as salivation, fur loss and reduced body weight gain, in the dam were noted in the 200 mg/kg bw/day dose group.

In another developmental toxicity trial, mice were exposed to 15, 150, 1500 mg/kg bw (dermal application) of the analogue chemical. No teratogenic effects, no significant difference in skeletal development compared to negative controls were observed.

Observation in humans

Not supplied.

Public exposure

Salon application

Some of the products containing 2,4-diaminophenoxyethanol sulfate are designed for the salon market and intended for one application per bottle. For such products, public exposure to hair colorant products containing the notified chemical is likely to be intermittent (based on use pattern) and widespread. In these products, the notified chemical (up to 4 per cent) will be diluted 1:1 to 1:2 with developer, leading to maximal exposure concentrations of up to 2 per cent. The hair dye will be used at a maximum of approximately once per month, at up to 2.6 g of the notified chemical (4 per cent in 65 mL liquid product) each application. It is estimated that consumers will be exposed to these hair dye products for up to one hour daily, 12 days per year primarily by dermal route (mainly on the scalp), with the possibility of accidental ocular and oral exposure.

Home application

Some hair dye products containing the notified chemical (up to 4 per cent) may also be used by members of the public in home settings. The application instructions of products designed for home application typically indicate that gloves must be worn when using the dye, though it is unknown whether the gloves provided are of the most suitable type to ensure minimal breakthrough of the notified chemical. In addition, the instructions indicate that an allergy patch test must be performed 48 hours before use.

The method of application used by consumers is likely to be similar to that used by salon workers. As such, exposure is expected to be similar, though slightly higher, than experienced by consumers when the products are applied in salons, due to the greater potential for dermal (particularly to the hands) and accidental ocular exposure when application takes place by members of the public. Dermal exposure to the notified chemical would reduce if wearing gloves are worn during use.

There are a number of additional types of hair dye products for home use containing 2,4-diaminophenoxyethanol sulfate (up to 4 per cent) with different use instructions to those used by hair salon workers. Examples of products may include shampoo-in hair colour and brush-in colour gels. The products are mainly recommended for grey hair and for use by men. Typically, for each product the colour base containing 2,4-diaminophenoxyethanol sulfate at up to 4 per cent concentration will be diluted with developer (hydrogen peroxide solution) in a ratio of 1:1, so that the final maximum concentration of 2,4-diaminophenoxyethanol sulfate applied will be 2 per cent.

Shampoo-in products

The mixture will be applied to the head and lathered evenly into the hair similarly to shampoo. The quantity used per application will be dependent upon the length of the hair and as such, the entire mixture may not be used. In this case, users are directed to discard any unused mixture. Up to 1.2 g of the notified chemical (4 per cent in 30 mL liquid product) will be used per application. The mixture will be kept in the hair for 5 minutes and then rinsed out, followed by shampooing of the hair. Typically reapplication will occur on a monthly basis. The method of reapplication (i.e. application to grey roots) differs from the first time application described above. The mixture will be applied to the roots only and after 4 minutes it will be combed through the hair followed by rinsing. The mixture may also be used on grey sideburns or hair on the temple by applying for a few seconds and subsequently wiping away.

Brush-in colour gel

Hair

The product containing 2,4-diaminophenoxyethanol sulfate (up to 4 per cent) and the developer will be contained in separate resealable tubes. Up to 1.6 g of 2,4-diaminophenoxyethanol sulfate (4 per cent in 40 g liquid product) will be used per application. It will be squeezed along one side of the applicator brush, with an approximately equal amount of developer on the separate and opposite side of the brush. Mixing with the developer does not occur prior to application to the hair. Rather, the brush will be run through the hair, resulting in some mixing on the hair (though it may not be complete or thorough). As such, the scalp may be exposed to concentrations of the notified chemical up to 4 per cent. It will be kept on the hair for up to 10 minutes, followed by rinsing with warm water. Reapplication is expected to occur approximately once per month.

Facial hair

Up to 0.56 g of 2,4-diaminophenoxyethanol sulfate (4 per cent in 14 g liquid product) will be used per application. The mixed product (containing 2,4-diaminophenoxyethanol sulfate at up to 2 per cent) will be applied to facial hair using an applicator brush, left on the hair for up to 5 minutes, and then rinsed out, followed by shampooing. It is anticipated that reapplication would occur no more than once a week. It is also noted that the product instructions imply that the provided gloves should be reused during subsequent applications when the remaining contents of the tubes are used. This practice may lead to increased levels of exposure to 2,4-diaminophenoxyethanol sulfate due to the possible presence of residues on the gloves.

For each of the above types of products outlined above, exposure to the public will be primarily dermal through the scalp, beard area of face, and hands (if gloves are not used properly), but some accidental ocular or oral exposure is also possible. The public will be exposed to the notified chemical at a concentration of up to 4 per cent from dermal contact with the hair dye during dilution and typically up to a concentration of 2 per cent from contact of the hair dye with the scalp and face (beard area) during the dyeing process (note that there is some potential for the scalp to be exposed to concentrations of up to 4 per cent of 2,4-diaminophenoxyethanol sulfate when using brush-in colour gel designed for the hair, due to possible incomplete mixing with the developer).

International regulations

The European Union Cosmetics Directive lists the chemical in Annex III Part 1 List of substances provisionally allowed, after mixing under oxidative conditions, the maximum concentration applied to hair must not exceed 2 per cent (as hydrochloride).

Scheduling status

2,4-diaminophenoxyethanol sulfate is not specifically scheduled.

Scheduling history

2,4-diaminophenoxyethanol sulfate has not been previously considered for scheduling therefore scheduling history is not available.

Pre-meeting public submissions

Two submissions were received.

One submission indicated that NICNAS new chemical report is not sufficiently clear as to whether this ingredient is used in any therapeutic goods, as the report pertains to its use in hair dyes. The submission requested that if 2,4-diaminophenoxyethanol sulfate is listed in a schedule, it should exclude therapeutic preparations containing 2,4-diaminophenoxyethanol sulfate.

The other submission indicated that while 2,4-diaminophenoxyethanol sulfate is not specifically scheduled, the Schedule 6 and Appendix C entries of phenylenediamine would capture 2,4-diaminophenoxyethanol sulfate. The submission asserted that as the schedule entry for phenylenediamine adequately address the risks of 2,4 diaminophenoxyethanol sulfate, there is no need for a separate listing for 2,4 diaminophenoxyethanol sulfate. If there is a need for a specific listing for 2,4-diaminophenoxyethanol sulfate, the new schedule entry should clearly indicate that the limitations imposed relate to the on-head concentration of the mixture containing 2,4-diaminophenoxyethanol and not the product containing the substance.

ACCS advice to the delegate

The ACCS recommended that that hair dye preparations containing more than 4 per cent 2,4-diaminophenoxyethanol sulfate be included in Schedule 6 and recommends appropriate Appendix E and F statements.

The ACCS recommended an implementation date of 1 October 2014.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (c) the toxicity of a substance.

The reasons for the recommendation comprised the following:

  • The toxicity profile of the substance meets the criteria of Schedule 6. The labelling requirements warrant the specified exemptions.
Delegate's interim decision

The delegate accepts ACCS advice that new entries be created in Schedule 6 and Appendices E & F, to regulate the use of 2,4-diaminophenoxyethanol sulfate in hair dyes. The main source of exposure is expected to be associated with this use and the schedule wording is specific for this use, to reduce the likelihood of inadvertent capture of other types of products. Furthermore, consistent with Schedule 6 entries for some other hair dye ingredients with a similar toxicological profile, and previous recommendations made by the ACCS, an exemption from Schedule 6 has been provided for products that meet specific labelling requirements.

The wording of these proposed entries in Schedule 6 and Appendices E & F is consistent with that used for other hair dye components with a similar toxicological profile. The delegate notes that 2,4 diaminophenoxyethanol may be covered by the existing Schedule 6 entry for hair dyes containing phenylenediamines, but that creating a new specific entry allows for an exemption clause (at 4 per cent) to be included, with similar labelling conditions mandated.

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 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.

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 factors4;
  • Other relevant information.
Public submissions on the interim decision

One submission was received. The submission noted that although 2,4-diaminophenoxyethanol sulfate is not specifically scheduled, it would be captured by the phenylenediamines schedule entry. As there appear to have been no discussions at the ACCS meeting, nor in the delegate's interim decision on whether 2,4-diaminophenoxyethanol sulfate poses a higher risk than other phenylenediamines, 2,4-diaminophenoxyethanol sulfate's schedule entry therefore should mirror the phenylenediamines schedule entry.

Edited versions of these submissions are available at Public submissions on scheduling matters.

Delegate's final decision

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

The delegate notes that, contrary to the opinion in the public submission that 2,4-diaminophenoxyethanol sulfate would be captured by the phenylenediamines schedule entry, this differs from the advice provided by the ACCS in recommending a separate Schedule 6 entry. Furthermore, the ACCS advice is consistent with advice relating to another hair dye ingredient (2-amino-5-ethylphenol) considered at the November 2013 meeting. The ACCS advice relating to both of these recent decisions allows for the Schedule 6 entry to be specific for use in hair dyes, with a cut-off to exempt at an appropriate concentration (4% in the case of 2,4-diaminophenoxyethanol). The warning statements relating to skin/eye irritation would apply to products both covered by and exempted from Schedule 6.

The later implementation date of 1 July 2015 is intended to allow for orderly re-labelling of products already on the Australian market.

Schedule entry

Schedule 6 - New entry

2,4-DIAMINOPHENOXYETHANOL in hair dye preparations except in preparations containing 4 per cent or less of 2,4-diaminophenoxyethanol when the immediate container and primary pack are labelled with the following

KEEP OUT OF REACH CHILDREN

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

Written in letters not less than 1.5 mm in height.

Appendix E, Part 2 - New entry
Poisons Standard statements
2,4-Diaminophenoxyethanol

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 - New entry
Poison Warning statement Safety direction
2,4-Diaminophenoxyethanol 21- WARNING - this product contains ingredients which may cause skin irritation to certain individuals. A preliminary test according to the accompanying directions should be made before use. This product must not be used for dying eyelashes and eye brow; to do so may be injurious to the eye.

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1.4 2-ethylhexyl 2 ethylhexanoate or hexanoic acid, 2-ethyl-, 2-ethylhexyl ester

Scheduling proposal

On 10 December 2013, the National Industrial Chemicals and Notification Assessment Scheme (NICNAS) under its Inventory Multi-tiered Assessment and Prioritisation (IMAP) programme requested that the delegate consider a proposal to include cosmetic preparations and/or domestic preparations containing hexanoic acid, 2-ethyl-, 2-ethylhexyl ester in Schedule 6 entry with a low concentration exemption cut-off for cosmetic preparations and/or domestic preparations containing hexanoic acid, 2-ethyl-, 2-ethylhexyl ester.

The delegate's reason for referring this scheduling proposal to the ACCS is that, the NICNAS IMAP report focuses on the potential for reproductive toxicity associated with the hydrolysis of this ester to known reproductive toxicants, 2-ethylhexanol and 2-ethylhexanoic acid. The NICNAS report notes its potential use in leave-on cosmetic products with a concentration level up to 8.3 per cent, and that the use of such products is associated with a relatively small Margin of Exposure (MOE) estimate. The issues raised have much in common with current Schedule 6 arrangements for ethylene glycol monoalkyl ethers and their acetates. In view of the potential impact on existing products, the delegate considers that advice is needed from the ACCS, with an appropriate public notice alerting the industry to the proposed scheduling action.

The delegate asked the following specific questions:

  • Since the current Schedule 6 entry for ethylene glycol monoalkyl ethers and their acetates does not appear to specifically capture the 2-ethylhexyl 2-ethylhexanoate, does the ACCS support the creation of a separate Schedule 6 entry for this chemical?
  • Is the Schedule 6 listing decision on hexyloxyethanol from the July 2013 ACCS meeting a suitable template for the schedule wording, with the associated recommendations for entries in Appendices E & F?
  • Should the listing of 2-ethylhexyl 2-ethylhexanoate in Schedule 6 be specific to cover use in cosmetics only?
  • What is the preferred name for listing in the Schedules?
  • Should the exemption cut-off be set at 10 per cent, consistent with the other ethylene glycol monoalkyl ethers, or at 8.3 per cent (the putative upper limit in cosmetics products), or at some lower level, given the adverse findings of the MOE calculation?
  • What weight should be given to the NICNAS comment on the Cosmetics Ingredient Review (CIR) 2013 proposal that the reproductive toxicity potential of the ester may be limited by the rate of hydrolysis?
Substance summary

Please refer to the NICNAS IMAP Human Health Tier II Assessment for hexanoic acid, 2-ethyl-, 2-ethylhexyl ester and NICNAS IMAP Human Health Tier II Assessment for hexanoic acid, 2-ethyl-, which are are publically available on the NICNAS website.

Scheduling status

2-Ethylhexyl 2-ethylhexanoate is not specifically scheduled.

Scheduling history

2-Ethylhexyl 2-ethylhexanoate has not been previously considered for scheduling therefore scheduling history is not available.

Pre-meeting public submissions

Two submissions were received.

One submission indicated that the EU and the USA had extensively considered the risks posed by the substance and had not imposed any restriction on the use of the substance. The submission asserted that there was no need to schedule 2-ethylhexyl 2-ethylhexanoate.

The second submission indicated that there does not appear to be an entry in TGA e-BS. It was unclear from the scheduling proposal whether the proposed scheduling of the substance may have impact on therapeutic goods, noting that the wording of the scheduling proposal did not exclude therapeutic goods. The submission requested that the schedule listing should exclude therapeutic preparations containing the substance.

ACCS advice to the delegate

The ACCS recommended that preparations containing more than 10 per cent of 2-ethylhexyl 2-ethylhexanoate be listed in Schedule 6. The committee, in addition to recommending a Schedule 6 listing, also recommended appropriate Appendix E and F statements for 2-ethylhexyl 2-ethylhexanoate.

The ACCS recommended an implementation date of 1 October 2014.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (c) the toxicity of the substance.

The reasons for the recommendation comprised the following:

  • Potential reproductive toxicity consistent with criterion for Schedule 6.
Delegate's interim decision

The delegate accepts the advice of the ACCS to include 2-ethylhexyl 2-ethylhexanoate in Schedule 6, with an exemption cut-off at 10 per cent. While its acute oral toxicity is low and there is sparse information on skin-eye irritancy and sensitisation potential, the critical toxicological endpoint is reproductive/developmental toxicity associated with its ready hydrolysis to the known reproductive toxicants, 2-ethylhexanol and 2-ethylhexanoic acid. The NICNAS risk assessment suggests that a Margin of Exposure (MoE) estimate (26) associated with use in leave-on cosmetics (at 8.3 per cent) to be unacceptable. However, this MoE estimate was not based on studies using 2-ethylhexyl 2-ethylhexanoate and includes conservative assumptions (rapid and complete hydrolysis, 100 per cent absorption and a LOAEL-derived additional 3x safety factor). The delegate concludes that the 10 per cent cut-off to exempt recommended by the ACCS is appropriate in these circumstances, and that it is consistent with Schedule 6 exempt cut-offs for compounds with similar reproductive toxicity potential (e.g. ethylene glycol monoalkyl ethers).

The delegate welcomes further comment on the suitability of the proposed 10 per cent exemption cut-off, and whether a lower cut-off (e.g. 2 per cent) should be developed to be specifically applied to leave-on cosmetics.

The delegate also supports the ACCS recommendation to require an Appendix F warning statement (No. 53) relating to this reproductive toxicity potential. This warning statement would only apply to products that meet Schedule 6 criteria.

The delegate proposes a more extended implementation date 1 July 2015 to allow for further consultation on the proposed exemption cut-off (including referral back to the November 2014 ACCS meeting if necessary), and to allow an appropriate time for product re-labelling to occur.

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 a substance, b) the purposes for which a substance is to be used and the extent of use of a substance and c) the toxicity of a substance.

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 factors5;
  • Other relevant information.
Public submissions on the interim decision

One submission was received. The submission noted that although the delegate's proposed schedule entry for the substance would capture its salts and derivatives, the metabolites of 2-ethylhexyl 2-ethylhexanoate, such as 2-ethylhexanol and 2-ethyhexanoic acid may not be captured by this entry. The submission requested the delegate defer the final decision on this substance and re-consult a proposal for the two separate schedule entries, i.e. 2-ethylhexanol and 2-ethyhexanoic acid.

Edited versions of these submissions are available at Public submissions on scheduling matters.

Delegate's final decision

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

The delegate notes the proposal in the public submission that consideration be given to developing separate schedules for 2-ethylhexanol and 2-ethyhexanoic acid, the hydrolysis products of 2-ethylhexyl hexanoate in which the developmental toxicity potential resides. This is a matter that could be considered at a future meeting of the ACCS, although there is no indication that either of these chemicals is included in the Australian Inventory of Chemical Substances (AICS) and should therefore not be available in Australia.

No specific comment has been received on the proposed cut-off to exempt at 10%.

The delegate confirms the proposed implementation date 1 July 2015 to allow an appropriate time for product re-labelling to occur.

Schedule entry

Schedule 6 - New entry

2-ETHYLHEXYL 2-ETHYLHEXANOATE except in preparations containing 10 per cent or less of 2-ethylhexyl 2-ethylhexanoate.

Appendix E, Part 2 - New entry
Poisons Standard statements
2-Ethylhexyl 2-ethylhexanoate 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).
Appendix F, Part 3 - New entry
Poison Warning statement Safety direction
2-Ethylhexyl 2 ethylhexanoate 53. CAUTION - 2-ethylhexyl 2-ethylhexanoate should not be used by pregnant women.

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1.5 Benzoic acid, 2-hydroxy-, (3Z)-1-methyl-3-hexen-1-yl ester

Scheduling proposal

On 29 August 2013, the National Industrial Chemicals and Notification Assessment Scheme (NICNAS) under its New Chemicals Assessment process, requested that the delegate consider a proposal to create a new Schedule 6 and Appendix F listing for benzoic acid, 2-hydroxy-, (3Z)-1-methyl-3-hexen-1-yl ester. This proposal was first notified to the delegate in September 2013 at which time it was determined that expert advisory committee advice may not be required for this proposal. However, due to the complexity of the proposal, expert advice on this substance is being sought.

The reasons for this recommendation include:

  • Benzoic acid, 2-hydroxy-, (3Z)-1-methyl-3-hexen-1-yl ester is a moderate to severe skin sensitiser and meets the Scheduling Policy Framework's Schedule 6 factors.
  • A quantitative risk assessment for dermal sensitisation indicated that an acceptable risk to the public was associated with use of the chemical at no more than 0.2 per cent in deodorants, 0.37 per cent in fine fragrances, 0.51 per cent in other leave on cosmetic products and 0.96 per cent in rinse-off cosmetic, fabric care and household cleaning products.
  • The delegate's reason for referring this scheduling proposal to the ACCS is that, while the NICNAS evaluation report proposes listing this new chemical in Schedule 6, the ACCS advice is needed on whether inclusion in the SUSMP is the most appropriate control measure, given its proposed use in low concentrations in fragrances, cosmetics, household cleaners and fabric care products.

The delegate asked the following specific questions:

  • The pure chemical has relatively low acute toxicity, is weakly positive as a skin/eye irritant and is a sensitiser in animal studies, but not in human studies. Public exposure is only likely to occur through its use as a fragrance containing up to 4.8 per cent, in cosmetics containing up to 1 per cent and household cleaning products containing up to 0.12 per cent. Does the ACCS consider that listing in the SUSMP is appropriate? If so, in which schedule should it be listed, and can the ACCS recommend a low cut-off concentration to exempt?
  • Should there be different cut-off concentrations for different product classes (e.g. fragrances; leave-on and rinse-off cosmetics; deodorants; household cleaners)?
  • If scheduled, what name should be used in the listing - the chemical name - benzoic acid, 2-hydroxy-, (3Z)-1-methyl-3-hexen-1-yl ester, or an alternative name, such as (Z)-hept-4-en-2-yl 2-hydroxybenzoate?
  • Are Appendix E & F statements required?
Substance summary

Benzoic acid, 2-hydroxy-, (3Z)-1-methyl-3-hexen-1-yl ester is intended to be used as a component of fragrances for a variety of cosmetic and household cleaning products (proposed usage concentration: ≤4.8 per cent in fine fragrances, ≤0.96 per cent in other cosmetic products and ≤0.12 per cent in fabric care and household cleaning products).

The end-use products (containing ≤4.8 per cent benzoic acid, 2-hydroxy-, (3Z)-1-methyl-3-hexen-1-yl ester) may be used by consumers and professionals, such as hairdressers, workers in beauty salons or cleaners. Depending on the nature of the product, these could be applied in a number of ways, such as by hand, using an applicator or sprayed.

Figure 3. Structure of benzoic acid, 2-hydroxy-, (3Z)-1-methyl-3-hexen-1-yl ester

Structure of benzoic acid, 2-hydroxy-,(3Z)-1-methyl-3-hexen-1-yl ester

Acute toxicity

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

Toxicity Species Benzoic acid, 2-hydroxy-, (3Z)-1-methyl-3-hexen-1-yl ester SPF* Classification
Oral LD50 (mg/kg bw) Rat >2000 Schedule 5
Dermal LD50 (mg/kg bw) Rat >2000 Schedule 5
Inhalational LC50 (mg/m3/4h) Not provided Not provided Unable to assess
Skin irritation Rabbit Slight irritant
Eye irritation Rabbit Slight irritant
Skin sensitisation (Local lymph node assay and Modified Local lymph node assay) Mouse Sensitiser
Skin sensitisation (Repeat insult patch test [15 per cent]) Human Non-sensitiser

*Scheduling Policy Framework for Medicines and Chemicals (2010)

Repeat-dose toxicity

In a 28-day oral toxicity study, rats (5/sex/dose) were administered benzoic acid, 2-hydroxy-, (3Z)-1-methyl-3-hexen-1-yl ester at 0, 100, 300 or 1000 mg/kg bw/day. There were no mortalities during the study and the treatment related effects were, in general, limited to increased liver weights and minimal to mild hepatocellular hypertrophy in 1000 mg/kg bw/day males (2/5) and females (2/5), and in 300 mg/kg bw/day males (2/5). There was slight-moderate salivation and dyspnea in one subject at 1000 mg/kg bw/day. The liver effects were not considered to be adverse, thus the NOAEL established by the study authors was 1000 mg/kg bw/day.

Mutagenicity

Benzoic acid, 2-hydroxy-, (3Z)-1-methyl-3-hexen-1-yl ester was not mutagenic in a bacterial reverse mutation assay and was not clastogenic in an in vitro chromosome aberration assay in Chinese hamster V79 cells.

Genotoxicity

The substance was non genotoxic in an in vitro chromosome aberration assay.

Carcinogenicity

Information not supplied.

Reproduction and developmental toxicity

Information not supplied.

Observation in humans

Information not supplied.

International regulations

No known international restrictions identified.

Scheduling status

Benzoic acid, 2-hydroxy-, (3Z)-1-methyl-3-hexen-1-yl ester is not specifically scheduled.

Scheduling history

Benzoic acid, 2-hydroxy-, (3Z)-1-methyl-3-hexen-1-yl ester has not been previously considered for scheduling therefore scheduling history is not available.

Pre-meeting public submissions

Two submissions were received.

One submission indicated that the information provided in the scheduling proposal and in the NICNAS report was not sufficiently clear as to whether this ingredient was used in any therapeutic goods. The submission requested that if the substance was listed in a schedule, consideration be given to specifically exclude therapeutic good preparations containing benzoic acid, 2-hydroxy-, (3Z)-1-methyl-3-hexen-1-yl ester.

The other submission noted that NICNAS assessment report indicates that this substance had a low toxicity profile therefore it did not support a schedule listing for this substance.

ACCS advice to the delegate

The ACCS recommended benzoic acid, 2-hydroxy-, (3Z)-1-methyl-3-hexen-1-yl ester does not require a schedule listing.

The reasons for the recommendation comprised the following:

  • The fragrance ingredient based on the evidence before the committee do not require scheduling.
Delegate's interim decision

The delegate accepts ACCS advice that the fragrance ingredient benzoic acid, 2-hydroxy-, (3Z)-1-methyl-3-hexen-1-yl ester does not require scheduling.

The delegate notes that sensitisation potential is the toxicological finding that could justify inclusion in the schedules, and that the ACCS has made similar recommendations at this and previous meetings on the need to schedule fragrance chemicals where sensitisation potential is the main driver. The delegate also notes that there was extensive discussion at ACCS on the interpretation of positive in vivo rodent-based sensitisation tests, such as the Local Lymph Node Assay (LLNA), particularly where human studies fail to confirm a sensitisation. This information has been supplemented by NICNAS, including information on how the tests may be quantitatively interpreted to determine sensitisation potency and to derive a possibly useful estimate of an appropriate scheduling cut-off. Using this approach, benzoic acid, 2-hydroxy-, (3Z)-1-methyl-3-hexen-1-yl ester could be classified as a weak sensitiser, possibly explaining why it proved negative in a human study with a limited number of subjects. Since there were no other toxicological factors that would justify scheduling, and the use of benzoic acid, 2-hydroxy-, (3Z)-1-methyl-3-hexen-1-yl ester as a fragrance ingredient in products on the Australian market is likely to be at concentrations of no more than 1 per cent, the delegate confirms that no schedule listing is proposed.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: b) the purposes for which a substance is to be used and the extent of use of a substance and c) the toxicity of a substance.

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 factors6;
  • Other relevant information.
Public submissions on the interim decision

No public 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 reasons for the final decision are in keeping with those for the interim decision.

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1.6 Dibutyl phthalate

Scheduling proposal

On 10 December 2013, the National Industrial Chemicals and Notification Assessment Scheme (NICNAS), under the Priority Existing Chemical (PEC) program, requested that the delegate consider including cosmetic and personal care preparations containing dibutyl phthalate (DBP) in Appendix C.

The reasons for this recommendation are:

  • Estimate of margin of exposure (MoE) for use of DBP in cosmetics indicates that the risk of reproductive toxicity for the general population from the use of cosmetics containing DBP is unacceptable. Repeat-dose toxicity studies on multiple generations of rodents showed testicular toxicity. Both fertility and development are affected in the parents and following generations. The toxicity in male rodents involves overt effects on the reproductive tract organs. DBP also affects testosterone synthesis in male rodents;
  • Reproductive toxicity induced by DBP might have serious long-term health effects and affect the development and reproduction of future populations if the exposure is within a critical window of human health development;
  • A cautious approach to the potential risks associated with DBP is warranted, given the level of uncertainty regarding both the health effects and levels of exposure for different population groups; and
  • Currently there are no restrictions in Australia on the use of DBP in cosmetics and there is a potential for introduction and widespread use of cosmetic products containing DBP.

The delegate referred the proposal to the ACCS. The reason for referring the proposal to the ACCS is that NICNAS recommended specific uses of DBP, i.e. cosmetics and personal care products, be restricted by listing in Appendix C. The Scheduling Policy Framework (SPF) indicates that advice from the ACCS should be sought for such restrictive scheduling. Since the proposal is specific for cosmetic and personal care products, it should have no impact on therapeutic goods regulated by the TGA, so there appears to be no need to refer the matter to a joint meeting of the ACCS-ACMS.

The delegate asked the following questions.

  • Noting the difficulties and uncertainties associated with the assignment of a NOAEL for reproductive toxicity and the exposure estimates, does the ACCS agree that the relatively small margin of exposure (MoE) calculations associated with the uses of DBP in cosmetic and personal care products warrant restrictive scheduling?
  • Based on similar toxicological concerns, previous decisions of the NDPSC and ACCS in relation to restrictions on the use of diethyl phthalate (DEP), dimethyl phthalate (DMP) and diethylhexyl phthalate (DEHP) have resulted in listing in Appendix C for various products deliberately applied to human skin. Does the ACCS support a parallel entry for DBP?
  • The NICNAS exposure calculations indicate that the products contributing most to estimates of DBP systemic exposure would fit the definition of 'cosmetics'. This suggests that a parallel entry for DEHP could act as a template. Is there a need to expand the proposed Appendix C entry to include sunscreens, personal insect repellents and body lotions, with a cut-off at 0.5 per cent, as in the current DMP and DEP entries?
  • None of the phthalate esters currently listed in Appendix Care separately listed in any schedules of the SUSMP. While the NICNAS evaluations only recommend controls on the use of some phthalate esters in cosmetics and personal care products, do other use patterns of the more toxic phthalates suggest a need to consider scheduling to control a broader range of products?
Substance summary

Please refer to the NICNAS PEC assessment report for dibutyl phthalate and its related compounds, which is publically available on the NICNAS website. The report number is PEC/26.

Scheduling status

Dibutyl phthalate is not specifically scheduled. Other phthalates such as diethylhexyl phthalate, diethylphthalate and dimethylphthalate are listed in Appendix C. Diethylhexyl phthalate for cosmetic use is listed in Appendix C and dimethylphthalate and diethylphthalate in sunscreens or personal insect repellents for human use (except in preparations containing 0.5 per cent or less of dimethylphthalate and diethylphthalate) is currently listed in Appendix C.

APPENDIX C

DIETHYLHEXYL PHTHALATE for cosmetic use.

APPENDIX C

DIETHYLPHTHALATE in sunscreens, personal insect repellents or body lotion preparations for human use except in preparations containing 0.5 per cent or less of diethylphthalate.

APPENDIX C

DIMETHYLPHTHALATE in sunscreens, personal insect repellents or body lotion preparations for human use except in preparations containing 0.5 per cent or less of dimethylphthalate.

Scheduling history

In August 2001, the National Drugs and Poisons Scheduling Committee (NDPSC) considered foreshadowed proposal (from August 2000) including dimethylphthalate (DMP) and diethylphthalate (DEP) in Appendix C when used in insect repellents or sunscreens for human use. The committee agreed that the potential reproductive hazard to males of the short-chain phthalates, dimethyl- and diethylphthalate when applied to large areas of the skin, warranted prohibition of these substances in products such as sunscreens and insect repellents. A cut-off limit of 0.5% was also supported as dermal exposure at or below this level was unlikely to present a risk.

In June 2011, the chemicals scheduling delegate decided to list diethylhexyl phthalate in Appendix C when in preparations for cosmetic use.

Pre-meeting public submissions

Two submissions were received.

One submission indicated that dibutyl phthalate is listed in TGA e-BS site with use as an active ingredient restricted to topical prescription preparations, and use allowed as an excipient in registered and listed medicines. The submission requested that only cosmetic preparations containing dibutyl phthalate should be listed in a schedule.

The other submission indicated that cosmetic preparations containing dibutyl phthalate be included in Appendix C. The submission noted that dibutyl phthalate is listed in Annex II (substances banned in cosmetics) of the EU Cosmetics Directive.

ACCS advice to the delegate

The ACCS recommended that cosmetic preparations containing dibutyl phthalate be included in Appendix C.

The ACCS recommended an implementation date of 1 October 2014.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (c) the toxicity of a substance.

The reasons for the recommendation comprised the following:

  • The potential for irreversible reproductive toxicity warrants banning in cosmetic preparations.
Delegate's interim decision

The delegate accepts ACCS advice that a new Appendix C entry be created to restrict dibutylphthalate use in cosmetics. Reproductive toxicity is the toxic effect noted in animal studies that drives the risk assessment and the Margin of Exposure (MoE) estimate for this specific use is considered unacceptable. Inclusion of such products in Appendix C is considered to be the most effective way to prevent the use of dibutylphthalate in cosmetic products, and it is consistent with the listing of other phthalate esters with similar reproductive toxicity potential in Appendix C.

The delegate agrees with the implementation date being 1 October 2014. An early implementation date is warranted since the objective is to remove any such products from the Australian market on safety grounds.

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 a substance, b) the purposes for which a substance is to be used and the extent of use of a substance and c) the toxicity of a substance and d) the dosage, formulation, labelling, packaging and presentation of a substance.

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 factors7;
  • Other relevant information.
Public submissions on the interim decision

No public 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 reasons for the final decision are in keeping with those for the interim decision.

The proposed new entry in Appendix C is consistent with that proposed in the interim decision.

Schedule entry

Appendix C - New entry

DIBUTYLPHTHALATE for cosmetic use.

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1.7 2-phenoxyethanol or ethanol, 2-phenoxy-

Scheduling proposal

On December 2013, the National Industrial Chemicals and Notification Assessment Scheme (NICNAS) under its Inventory Multi-tiered Assessment and Prioritisation (IMAP) process requested that the delegate consider including cosmetic preparations containing more than 1 per cent of ethanol, 2-phenoxy- in Schedule 5.

The delegate's reason for referring this scheduling proposal to the ACCS is that 2-phenoxyethanol is an ethylene glycol aryl ether, so it would not be captured by the current Schedule 6 entry for monoalkyl ethers. Its toxicity profile, as summarised in the IMAP report, does not appear to include the reproductive toxicity potential of some of the monoalkyl ethers, but its potential for eye irritancy and sensitisation warrants consideration for listing in the SUSMP schedules. The IMAP report draws particular attention to its use in cosmetics, and proposes a Schedule 5 entry, with an exemption cut-off in cosmetics at 1 per cent. In view of the potential impact on existing products, the delegate considers that advice is needed from the ACCS, with an appropriate public notice alerting the industry to the proposed scheduling action.

The delegate asked the following specific questions:

  • Does the ACCS support the creation of a Schedule 5 entry for 2-phenoxyethanol? If so, should the listing name be: 2-phenoxyethanol, phenylglycol ether, or ethylene glycol monophenyl ether?
  • Should the listing be specific to cover use in cosmetics or domestic products only? Such specific scheduling may be needed if there are uses (as noted by the Secretariat) in veterinary products.
  • Should there be separate cut-offs to exempt for different product classes? - e.g. 1 per cent for cosmetics and 15 per cent for other domestic products?
  • Is the Schedule 6 listing decision on hexyloxyethanol from the July 2013 ACCS meeting a more suitable template for the schedule wording, with the associated recommendations for entries in Appendices E & F?
Substance summary

Please refer to the NICNAS Inventory Multi-tiered Assessment Prioritisation (IMAP) Human Health Tier II Assessment Report for ethanol, 2-phenoxy-, which is publically available on the NICNAS website.

Scheduling status

2-Phenoxyethanol is not specifically scheduled.

Ethylene glycol monoalkyl ethers and their acetate are listed in Schedule 6 and Appendices E, F and I.

In October 2013, the delegate decided to create a new Schedule 6 entry for preparations containing 10 per cent or less of hexyloxyethanol. The delegate also included hexyloxyethanol in Appendix E and F entries.

Scheduling history

Scheduling history of ethylene glycol monoalkyl ethers and their acetates.

In November 1984, the Poisons Schedule (Standing) Committee (PSC) considered scheduling of ethylene glycol monoalkyl ethers and their acetates. The PSC noted that ethylene glycol monomethyl- and monoethyl ethers were the most toxic of the series which demonstrated significant testicular effects, reproductive toxicity and haematological effects and were toxic at inhalation levels at the threshold limit value (TLV). The PSC also noted that other alkyl ethers of demonstrated haematological effects which increased with chain lengths. The PSC therefore decided to include preparations containing 5 per cent or less of ethylene glycol monoalkyl ethers and their acetates in Schedule 6.

In February 1985, the PSC reconsidered the November 1984 decision and decided to raise the Schedule 6 ethylene glycol monoalkyl ethers and their acetates exemption cut-off from 5 per cent to 10 per cent.

In October 2013, the delegate, based on ACCS advice and public submission received in regards to the delegate's proposal, decided to create a new Schedule 6 entry for preparations containing 10 per cent or less of hexyloxyethanol. The delegate also included hexyloxyethanol in Appendix E and F entries. The delegate's decision to include hexyloxyethanol in Schedule 6 was based on its toxicity profile, in particular, hexyloxyethanol’s moderate to high acute oral (LD50 738 mg/kg bw) and dermal toxicity (LD50 721 mg/kg bw), and its potential corrosivity to skin.

Pre-meeting public submissions

Three submissions were received.

The first submission indicated that the delegate's scheduling proposal refers to cosmetic preparations containing the substance. The submission indicated that it supports a clear distinction between cosmetics/personal care products and therapeutic goods in the drafting of scheduling proposals.

The second submission indicated that EU Cosmetic Directive allows cosmetic preparations containing up to 1 per cent of 2-phenoxyethanol as a preservative. In Australia, up to 1 per cent of 2-phenoxyethanol was used in cosmetics preparations. The submission requested that consideration therefore be given to include cosmetic preparations containing more than 1 per cent of 2-phenoxyethanol in a schedule.

The third submission indicated that it would make further submission based on delegate's interim decision.

ACCS advice to the delegate

The ACCS recommended that cosmetic preparations containing more than 1 per cent of 2-phenoxy-ethanol and other preparations containing more than 15 per cent of 2-phenoxy- ethanol be included in Schedule 6.

The ACCS recommended an implementation date of 1 October 2014.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (c) the toxicity of a substance.

The reasons for the recommendation comprised the following:

  • The acute oral toxicity profile is consistent with the SPF factors for Schedule 6.
Delegate's interim decision

The delegate accepts the advice of the ACCS to include 2-phenoxyethanol in Schedules 5 and 6. The critical toxicological endpoints driving this categorisation (potential for acute oral and dermal toxicity, skin/eye irritancy and sensitisation) are consistent with SPF criteria for listing in Schedule 6, with the public health risk sufficiently ameliorated for products containing 15 per cent or less, and cosmetic products containing 1 per cent or less.

The delegate agrees with the implementation date being 1 October 2014. An early implementation date is proposed, based on advice that there should be minimal impact on products currently in the Australian market.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: b) the purposes for which a substance is to be used and the extent of use of a substance and c) the toxicity of a substance.

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 factors8;
  • Other relevant information.
Public submissions on the interim decision

No public 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 reasons for the final decision are in keeping with those for the interim decision.

Schedule entry

Schedule 6 - New entry

2-PHENOXYETHANOL except:

  1. in cosmetic preparations containing 1 per cent or less of 2-phenoxyethanol; or
  2. in other preparations containing 15 per cent or less of 2-phenoxyethanol.
Appendix E, Part 2 - New entry
Poisons Standard statements
2-Phenoxyethanol

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 eye, wash out immediately with water.

Appendix F, Part 3 - New entry
Poison Warning statement Safety direction
2-Phenoxyethanol 5. Irritant 1. Avoid contact with eyes.

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Footnotes

  1. Scheduling Policy Framework for Medicines and Chemicals (SPF, 2010)
  2. Scheduling Policy Framework for Medicines and Chemicals (SPF, 2010)
  3. Opinion on 2,4-diaminophenoxy ethanol dihydrochloride and sulfate (pdf,225kb). European Commission's Scientific Committee on Consumer Safety
  4. Scheduling Policy Framework for Medicines and Chemicals (SPF, 2010)
  5. Scheduling Policy Framework for Medicines and Chemicals (SPF, 2010)
  6. Scheduling Policy Framework for Medicines and Chemicals (SPF, 2010)
  7. Scheduling Policy Framework for Medicines and Chemicals (SPF, 2010)
  8. Scheduling Policy Framework for Medicines and Chemicals (SPF, 2010)

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