You are here

Scheduling delegate's final decisions: ACCS/ACMS, April 2014

Scheduling medicines and poisons

14 April 2014

Book pagination

Part A - Final decisions on matters referred to an expert advisory committee (ACCS) - 1.18-1.21

1.18 Zinc lactate

Scheduling proposal

On 13 September 2013, NICNAS under the New Chemicals Assessment scheme has requested that the delegate consider a proposal to include the preparations containing more than 2.5 per cent zinc lactate in Schedule 6 with strong warnings listed in Appendix F of the SUSMP and use of distinctive packaging. The basis for this recommendation is that it has moderate to high acute oral toxicity and eye irritancy. The maximum permitted concentration of the chemical in any product intended for human use (or in toothpastes) should not exceed 2.5 per cent.

The delegate considered the proposal for inclusion of zinc lactate to Schedule 6.

The delegate's reason for referring this scheduling proposal to the ACCS was that zinc lactate is a chemical referred by NICNAS following evaluation as a new chemical. Its proposed use is as an ingredient in toothpastes. Other potential uses that could result in public exposure have not been identified. The NICNAS recommendation is that inclusion in Schedule 6 is warranted on the basis of its acute toxicity profile, particularly its irritancy potential, but notes that use in toothpastes at up to 2.5 per cent should not produce adverse health effects. The NICNAS notes that this conclusion also applies to chronic exposure to absorbed zinc from the use of toothpastes. ACCS advice is needed on how to use scheduling to limit the use and concentration of this chemical in toothpastes.

The delegate sought the following specific advice from the ACCS:

  • Does the ACCS support inclusion of zinc lactate in Schedule 6, based on its acute toxicity profile, including its irritancy potential, with a cut-off to exempt at 2.5 per cent when an ingredient of toothpastes?
  • Since this chemical is a complex of zinc with lactic acid, is zinc lactate the most appropriate name for listing in the schedule (there are precedents for specifically listing other inorganic and organic zinc compounds)?
  • Is there a need to include a specific entry in Appendix C to limit its use in toothpastes, or is the Schedule 6 entry sufficient to control this use?
  • What Appendix E & F statements should be applied to scheduled products containing zinc lactate (if any, given that a secondary notification and NICNAS assessment would be required if other uses are contemplated)?
  • Are there likely to be any uses of zinc lactate inadvertently captured by the Schedule 6 entry, and should the 2.5 per cent exemption for toothpastes be a general exemption (in all products) at and below this concentration? If the exemption applies only to toothpastes, should it also specify the age range (adults and children over 12) to which the risk assessment applies?
  • Is there any need for a consequential amendment to the current Schedule 4 entry for zinc compounds (it currently applies only to preparations for internal human use)?
Substance details

Zinc lactate is used as a component of toothpaste. It can also be used as a dietary supplement20 and can be found in mouthwash, facial cleansers, breath fresheners, body wash and liquid hand soaps.21 However, it cannot be established that such products are available in Australia or what the concentration of zinc lactate is in these products, though it is expected to be minimal22.

Figure 5. Structural formula of zinc lactate.
Figure 5. Structural formula of zinc lactate.

End-point of acute toxicity Zinc lactate SPF*
Acute oral toxicity LD50 (mg/kg bw) 500 - 2000 Moderate to high
Acute dermal toxicity LD50 ( (mg/kg bw) No data
Acute inhalational toxicity LC50 (mg/L/4h) No data
Skin irritation Not irritant
Eye irritation Irritant
Skin sensitisation No data

*Scheduling Policy Framework for Medicines and Chemicals (2010)

Repeated dose toxicity

No repeated dose toxicity studies on the notified chemical were provided. Several studies on zinc compounds have been conducted via the oral route, in both humans and animals. In the EU report of zinc distearate (EC, 2004), a NOAEL of 50 mg Zn2+/day (0.83 mg/kg bw/day) from human studies was chosen for risk assessment purposes, based on noted effects at higher dosage levels, in particular disruption of copper homeostasis.

The Recommended Dietary Intake (RDI) for zinc is 12 mg (4.5 mg for children aged 1-3 years). Zinc lactate is a permitted form (FSANZ, 2000).

Mutagenicity

No data on the mutagenicity potential for the notified chemical was provided.

Carcinogenicity

Limited studies on the carcinogenicity potential of zinc compounds are available. It is noted in the EU report (EC, 2004) that zinc deficiency or supplementation may influence carcinogenesis, but that there is no evidence for a direct carcinogenic action of zinc.

Reproductive toxicity

In the EU report (EC, 2004), a NOAEL of >19.9 mg Zn2+/kg bw/day was adopted for developmental toxicity in animals. It is noted that a zinc deficiency results in an impairment of fertility and foetal development. Therefore, zinc was determined not to be of concern with respect to reproductive toxicity in humans.

This risk to the public associated with the use of zinc lactate at concentrations of 2.5 per cent or less when used by adults and children aged 12 years or older is not considered to be unreasonable.

Scheduling status

Zinc lactate is not currently scheduled. A Schedule 4 entry exists for Zinc compounds for human internal use, however as the use for this substance is not for human internal use this entry does not apply.

Scheduling history

There is no scheduling history for zinc lactate.

Public pre-meeting submissions

Three public submissions were received.

The first submission indicated that currently medicines containing zinc compounds for human internal use are excluded from scheduling requirements if the recommended daily dose in preparations is 25 mg or less of zinc. If the recommended daily dose is between 25 mg and 50 mg, the preparations are exempted when compliant with the requirements of the Required Advisory Statements for Medicine Labels (RASML). The product notified to the NICNAS contained 2.5 per cent of zinc lactate, or approximately 0.75 per cent of zinc. At this concentration level, even if dilution factors are not taken into account, i.e. the full average daily amount of toothpaste used (2.75 g) is ingested, the zinc intake would be below 25 mg (approximately 20 mg). Medicines containing zinc compounds that are intended to be ingested are unscheduled when the daily dose of zinc is 25 mg or less of zinc (based on the information above). The submission indicated that zinc lactate as an ingredient in cosmetics does not require scheduling.

The second submitter indicated that there are some inconsistencies with the Australian Register of Therapeutic Goods (ARTG) entry restrictions for this ingredient when used in toothpastes. The ARTG entry for the ingredient also proposes a usage limit of 2.0 per cent or less of zinc lactate for dermal use.

The third submission did not provide comments regarding the delegate's proposal and indicated that it will provide comments, if required, based on delegate's interim decision.

ACCS advice to the delegate

The committee recommends that zinc lactate be included in Schedule 6 with an exception cut-off to unscheduled for a) preparations containing 2.5 per cent or less of zinc lactate; and b) if in tooth paste labelled 'not recommended for children under 12 years of age', with an implementation date of 1 June 2014.

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

The reasons for the recommendation comprised the following:

  • Maintaining stability in relevant products, e.g. preservatives. Risk of ingestion of excessive amount of zinc.
  • Toxicity risk related to children's use of adult toothpaste. Ocular toxicity of zinc lactate.
Delegate's interim decision

The delegate partially accepts the advice of the ACCS. The delegate notes that the primary purpose behind the recommendation in the NICNAS report on zinc lactate was to restrict the concentration in toothpastes to 2.5% and, based on risk assessment calculations of daily zinc systemic intake, to limit the use of toothpastes exceeding 2.5% to adults and children aged >12 years. The Schedule 6 proposal is also partly based on the imprecise estimate of the acute lethal dose of zinc lacate, and an uncertain characterisation of its eye irritancy potential. The delegate disagrees with ACCS advice that the Schedule 6 entry be generic, with exemptions for toothpastes <2.5%. There is insufficient evidence of its potential uses and public health hazards other than in toothpastes, and unknown implications for restricting use in a broader range of products. Therefore, the delegate has decided to limit the Schedule 6 entry to toothpastes containing 2.5% or more of zinc lactate and to apply an age exemption to products labelled with the warning 'not recommended for children under 12 years of age'.

The delegate agrees with the implementation date of 1 June 2014.

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) 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 factors23;
  • Other relevant information.
Submissions on interim decision

Three public submissions were received. One of the submitter (indicated below as the third submission) did not submit a public submission for the delegates' proposal inviting public comments.

The first submission indicated that the proposed concentration cut-off for toothpaste preparations containing 2.5% or less of zinc lactate was lower than orally ingested complementary medicines which do not require RASML statements. The submission therefore requested the delegate consider either increasing exemption cut-off from 2.5% to 3% or not scheduling zinc lactate for use in toothpastes. The submission also indicated that the exemption from the proposed Schedule 6 entry age exemption to products labelled with the warning 'not recommended for children under 12 years of age' was not clear and this needs to be amended.

The second submission noted that it had no further comments on delegate's interim decision on zinc lactate.

The third submission indicated that the delegate's interim decision on zinc lactate appears to be that toothpastes containing more than 2.5% zinc lactate is in Schedule 6, and that toothpastes containing 2.5% or less of zinc lactate should be labelled "Not recommended for children under 12 years of age". The submission noted that the Schedule 6 entry would be clearer if it were to read along the following lines:

ZINC LACTATE in toothpastes except in toothpaste preparations containing 2.5 per cent or less of zinc lactate and labelled with the statement:

  • Not recommended for children under 12 years of age.

The submission also noted that including an entry in Appendix F Part 1 along the lines "Not recommended for children under 12 years of age", and an entry in Part 3 for zinc lactate in toothpastes.

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 refer the matter back to the Advisory Committee on Chemicals Scheduling for further advice. Issues raised in the consultation process that need further consideration include:

  • Estimates of zinc intake associated with toothpaste use and the basis for the risk assessments for systemic zinc exposure in relation to other sources of zinc, including therapeutic uses.

Clarification of the basis for labelling toothpastes as 'not recommended for children under 12 years of age' and an appropriate schedule wording to achieve this objective.

Since a final decision has been deferred, the delegate reserves further consideration of reasons under Section 52E(1).

Scheduling entry
Schedule 6 - new entry

ZINC LACTATE in toothpastes except

  1. in toothpaste preparations containing 2.5 per cent or less of zinc lactate; and
  2. when in toothpaste labelled 'not recommended for children under 12 years of age'.

In response to submissions requesting clarification of the proposed Schedule 6 entry, the delegate has withdrawn the proposed schedule entry. The matter will be referred back to the Advisory Committee on Chemicals Scheduling for further advice.

1.19 Triethanolamine

Scheduling proposal

On 13 September 2013, NICNAS under the Inventory Multi-tiered Assessment Prioritisation (IMAP) process, requested that the delegate consider a proposal to reschedule triethanolamine listed in Schedule 5 to provide a cut-off to except cosmetic leave-on preparations containing 2.5 per cent or less of triethanolamine.

NICNAS recommendation for public health

The NICNAS in their IMAP report recommended that an amendment to the current listing of the chemical in the SUSMP be considered. Matters to be taken into consideration include:

  • a concern for irritation with leave on cosmetic products where the product contains ≥2.5 per cent of triethanolamine;
  • a concern for nitrosamine formation with use of the chemical in cosmetic products under certain conditions such as when used with nitrosating systems, particularly for leave-on cosmetic products;
  • pH of the cosmetic product and concentration of triethanolamine salts affecting free triethanolamine levels; and the intradermal application of the chemical is more likely to result in skin irritation, such as when used in certain tattoo removal procedures requiring intradermal administration. Therefore, it is recommended that regulatory controls to prevent the use of intradermal application of the chemical in certain tattoo removal cosmetics be considered.

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

The delegate's reason for referring this scheduling proposal to the ACCS was that, in accordance with section 4.2 of the Scheduling Policy Framework for Medicines and Chemicals24 (SPF, 2010), advice is required to be obtained from an expert advisory committee for all rescheduling proposals. The NICNAS IMAP report is a public document and it contains sufficient information for ACCS to provide advice. Furthermore, its recommendations would be known to industry.

Triethanolamine is already included in Schedule 5 with a cut-off to exempt for preparations containing less than 5 per cent. The NICNAS IMAP report addresses the potential for skin irritation to occur at concentrations above 2.5 per cent and recommends amending the Schedule 5 entry to include such preparations in the Schedule 5 entry (i.e. add an additional sub-clause to the exemption specific for leave-on (and other?) cosmetic preparations.

The NICNAS IMAP report also requests consideration of scheduling action to restrict preparations used by intradermal injection for tattoo removal.

The delegate sought the following specific advice from the ACCS:

  • Does the ACCS support the proposed amendment to the Schedule 5 cut-off for cosmetic preparations containing more than 2.5 per cent of triethanolamine?
  • Should this amended cut-off apply only to leave-on cosmetic preparations, or all cosmetic preparations?
  • Is the 5 per cent cut-off for other triethanolamine preparations (e.g. cleaners) still appropriate?
  • Should the current Appendices E & F statements be applied to the new clause; in particular, is a new set of Appendix F Statements needed for cosmetic products, deleting reference to Safety Direction No. 4 'avoid contact with skin'.
  • What scheduling actions could best give effect to the NICNAS recommendation to restrict the use of triethanolamine applied intradermally for tattoo removal? Would this be a specific listing in Appendix C, or a new entry in Schedule 4 (similar to that for ethanolamine)?
  • Does the ACCS have concerns about the potential for triethanolamine to promote the formation of nitrosamines, and is there any control that could be placed on this via scheduling?
Substance details
Use of triethanolamine

The chemical is listed on the 2006 High Volume Industrial Chemicals List (HVICL) with a total reported volume of 1 000 - 9 999 tonnes. The following Australian uses were reported under previous mandatory and/or voluntary calls for information:

  • Cosmetic use i.e. pH control and neutralising agent or in tattoo removal cream
  • Domestic use i.e. neutralising and emulsifying agent in laundry detergents and household cleaning products
  • Commercial use i.e. in solvents, construction material, corrosion inhibitor and in paint and printing inks
  • Site-limited use i.e. manufacturing other chemicals, explosives manufacture and in waste oil treatment

The identified international uses of triethanolamine include:

  • Domestic use i.e. detergents (laundry powders), cleaning and polishing products (bathroom cleaners, leather and car waxes) and disinfectants (in aerosol disinfectant air fresheners).
  • Commercial use i.e. lubricants, corrosion inhibitors and paints
  • Site-limited use i.e. extracting hydrogen sulphide gas, producing other chemicals (piperazine) and as a chelating agent.
Toxicity end-points

The NICNAS IMAP report notes that the critical health effects for risk characterisation of triethanolamines include acute toxicity (oral, dermal, inhalation, eye, skin and respiratory irration) and harmful effects following repeated oral exposure.

End-point of acute toxicity Triethanolamine SPF*
Acute oral toxicity LD50 (mg/kg bw) 5200 - 11 300 Low
Acute dermal toxicity LD50 (mg/kg bw) >2000 Low
Acute inhalational toxicity LC50 (mg/L/4 h) 1800 Moderate to high
Skin irritation Not irritant
Skin irritation (humans) Irritant
Eye irritation Irritant
Skin sensitisation (Maximisation test and Lymph node assay) Not a sensitiser

*Scheduling Policy Framework for Medicines and Chemicals (2010)

Respiratory irritation

Based on the available information a classification for respiratory irritation is warranted (refer to Repeat dose toxicity-inhalation).

Observation in humans

The CIR (2013) reported that, in clinical provocative tests using 5-10 'hyperreactors,' 100 per cent triethanolamine produced an irritant reaction on non-scarified skin, 10 per cent triethanolamine was a marked irritant on scarified skin and 5 per cent triethanolamine in ethanol was slightly irritating to scarified skin (CIR, 2013).

In studies testing formulations containing 0.45-2.4 per cent of the chemical, no irritation was observed (CIR, 2013). According to the CIR expert panel, formulations containing 0.83-20.04 per cent triethanolamine were irritating. However, given the absence of detailed information regarding the formulations, this opinion is difficult to interpret.

Repeat dose toxicity

Oral

In the only available well reported study, the no observed adverse effect level (NOAEL) was >1000 mg/kg bw/day. Based on the available data, the chemical does not meet the factors for classification for repeated dose toxicity through the oral route.

Dermal

The chemical is reported to cause local (acanthosis, inflammation and ulceration of the skin) and systemic (increased kidney weights and nephropathy in female rats) effects following repeated dermal exposure.

The NOAEL for systemic renal effects was 250 mg/kg bw/day in female rats only (NTP, 1999). The systemic effects were observed at concentrations that do not warrant a hazard classification.

Inhalation

Based on the available information, no hazard classification for repeated dose inhalation toxicity is recommended. However, a classification for respiratory irritation is warranted.

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

Considering the animal studies conducted, there is no evidence of carcinogenicity through the oral route and equivocal evidence of carcinogenicity through the dermal route. The available data do not warrant hazard classification.

The International Agency for Research on Cancer (IARC) has classified the chemical as 'not classifiable as to its carcinogenicity to humans' (Group 3), based on inadequate evidence for carcinogenicity in humans and experimental animals (IARC, 2000).

The Cosmetic Ingredient Review (CIR) Expert Panel reported that while the chemical does not directly react with N-nitrosating agents to form nitrosamines, the chemical could undergo hydrolytic cleavage that results in diethanolamine. This in turn can be N-nitrosated to chemicals that may be carcinogenic. Therefore, the chemical should not be used in consumer products where N-nitroso compounds could be formed (CIR, 2013).

Reproductive and developmental toxicity

The chemical does not show specific reproductive or developmental toxicity through the dermal route and is equivocal through the oral route. The available data do not warrant a hazard classification.

International restrictions include

European Union (EU) cosmetic restriction III/6225: Authorised use in leave-on products at a maximum concentration of 2.5 per cent in the finished product. Furthermore, for both leave-on and rinse-off products the following restrictions apply:

  • do not use with nitrosating systems;
  • minimum purity: 99 per cent;
  • maximum secondary amine content: 0.5 per cent (applies to raw materials);
  • maximum nitrosamine content: 50 microgram/kg; and
  • keep in nitrite-free containers.
Scheduling status

This chemical (excluding its salts and derivatives, except in preparations containing 5 per cent or less of triethanolamine) is listed in Schedule 5 of the SUSMP.

Triethanolamine is included in Appendix E with standard statement of 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),' G3 'If swallowed, do NOT induce vomiting', E1 'If in eyes was out immediately with water' and S1 'If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water' and in Appendix F with a warning statement 'Irritant' and safety directions of 'Avoid contact with eyes' and 'Avoid contact with skin'.

Scheduling history

The toxicological information relating to triethanolamine, and other ethanolamines (diethanolamine and monoamine) have been considered by the NDPSC over several meetings in 1995, 1996 and 2000.

Public pre-meeting submissions

Four submissions were received.

One submitter indicated that the main concern for triethanolamine is the irritation potential. Based on the information in the NICNAS IMAP report on triethanolamine, irritation is likely to be induced by chemical reaction between triethanolamine and the skin and eyes rather than through other mechanisms e.g. TRPV1 receptor agonist. The irritation potential should therefore relate to the un-neutralised triethanolamine and not the salts of the triethanolamine, which could also the rationale for the current schedule entry. The submission indicated that re-scheduling of triethanolamine is unwarranted. The submission further noted that it was unaware of any concerns raised with consumer or cosmetic products containing triethanolamine with the current scheduling controls. This may be partly due to triethanolamine being used at levels lower than allowed by current scheduling.

Another submission did not provide comments regarding the delegates' proposal and indicated that it will provide comments, if required, based on the delegates' interim decision.

A third submission supported that the scheduling of triethanolamine remains as per the current schedule, and that the current allowable concentration in unscheduled products of up to 5 per cent remains unchanged. This submission commented that the regulatory restriction on concentration of triethanolamine in cosmetics was not consistent across overseas jurisdictions with restrictions in the European Union but not in the US or Canada.

The fourth submitter noted that some therapeutic goods contain triethanolamine salicylate as an active ingredient and requested that any scheduling amendment should exclude salts and derivatives from scheduling. The current Schedule 5 entry for the substance excludes salts and derivatives therefore for consistency, the proposed amendment should also excludes salts and derivatives of the substance.

ACCS advice to the delegate

The committee recommends that the current scheduling of triethanolamine remains appropriate, except when used for tattoo removal.

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

  • the risks and benefits of the use of a substance.

The reasons for the recommendation comprised the following:

  • evidence of significant adverse health effects when use in tattoo removal. This use potentially requires medical supervision.
Delegate's interim decision

The delegate accepts ACCS advice that the current listing of triethanolamine in Schedule 5 remains appropriate and that there is insufficient evidence of a public health concern to lower the exemption threshold from 5% to 2.5%. The delegate notes concerns raised about the potential for adverse effects associated with the use of chemical products containing triethanolamine in tattoo removal. While listing such preparations in Schedule 4 may be the most appropriate way to control this use, the delegate accepts ACCS advice such use be referred for advice from a joint meeting of the ACCS and ACMS before taking any scheduling action.

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 purpose for which the 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 factors26;
  • Other relevant information.
Submissions on interim decision

Three public submissions were received.

Two submissions indicated that they support the delegate's decision of not to amend the current schedule triethanolamine listing. Both submissions indicated that it would be appropriate to refer this proposal either to the joint ACCS & ACMS or to the ACMS.

One submission indicated that as the delegate's interim decision on this item had no effects on therapeutic goods, it had no further comments on this issue.

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.

1.20 Trisiloxane, 1,1,1,3,5,5,5-heptamethyl-3-[(trimethylsilyl)oxy]-

Scheduling proposal

On 17 September, NICNAS under the New Chemicals Assessment process has recommended that the delegate consider including trisiloxane, 1,1,1,3,5,5,5-heptamethyl-3-[(trimethylsilyl)oxy]- in Schedule 6 except when in make-up, face care products and rinse-off products at or below 34 per cent and in lip products at or below 20 per cent in which case the chemical should be included in Schedule 5.

The basis for this recommendation is:

  • The chronic, carcinogenicity and reproductive toxicity data indicate the chemical has a moderate risk of producing irreversible toxicity which meets the scheduling factors for Schedule 6.
  • A quantitative risk assessment based on repeat dose toxicity potential of the analogue substances (D4 and D5), indicated that body lotion should be excluded from the possible product types and the concentration of the chemical in lip products should be no more than 20 per cent.

The delegate's reason for referring this scheduling proposal to the ACCS was that this is one of several NICNAS-referred chemicals where the primary public exposure is likely to be via use of cosmetic products. The delegate requested the Advisory Committee on Chemicals Scheduling (ACCS) advice on how to best manage the scheduling aspects of such submissions.

The delegate sought the following specific advice from the ACCS:

  • Given the relatively low toxicity profile of this chemical, and the fact that public exposure is only likely to occur through the use of cosmetic products containing up to 34 per cent of this organosilane chemical, does the ACCS consider that listing in the SUSMP is appropriate? If so, in which schedule should it be listed?
  • If scheduled, what name should be used in the listing (1,1,1,3,5,5,5-heptamethyl-3-[(trimethylsilyl)oxy]-trisiloxane or methyl trimethicone)?
  • If scheduled, what is an appropriate cut-off to a lower schedule or to exempt? Should this be 34 per cent for all cosmetic uses, or different cut-offs for different product types?
  • Can the ACCS advise on whether it is possible to implement, through scheduling, the NICNAS recommendation that the chemical should not be used in body lotions or aerosols?
  • Is there a need for Appendices E and F statements, given that public exposure to the pure chemical is unlikely to occur, and cosmetic products containing 34 per cent or less would not appear to warrant warning statements?
  • While there is no indication cosmetic products containing this organosilane will be injected or implanted, is there any need to amend the current Appendix C entry that prohibits such use for silicones?
Substance details

Organosilicones, such as trisiloxane, has been used in various industrial applications due to their unique active surface properties. In aqueous systems, hydrophilically substituted trisiloxane derivatives function as excellent wetting agents. Trisiloxane surfactants have been used as adjuvants in agricultural applications for a long time27.

Trisiloxane is used in the manufacture of various products, including resin, synthetic rubber, artificial synthetic fibers and filaments, pharmaceuticals and medicines, paints, coatings, adhesives, soap, cleaning compounds, toilet preparations, and household appliances28.

Trisiloxane, 1,1,1,3,5,5,5-heptamethyl-3-[(trimethylsilyl)oxy]- will be used at ≤34 per cent concentration in a range of cosmetics, including facial cleansers, shampoos, conditioners, shower gels, make-up removers and lip products29.

Figure 6. Structure of trisiloxane, 1,1,1,3,5,5,5-heptamethyl-3-[(trimethylsilyl)oxy]
Figure 6. Structure of trisiloxane, 1,1,1,3,5,5,5-heptamethyl-3-[(trimethylsilyl)oxy]

End-points of acute toxicity Species Trisiloxane, 1,1,1,3,5,5,5-heptamethyl-3-[(trimethylsilyl)oxy]- SPF*
Acute oral toxicity LD50 (mg/kg bw) Rat >2000 Low toxicity
Acute dermal toxicity** Not provided Not provided Not provided
Acute inhalational toxicity** Not provided Not provided Not provided
Skin irritation Rabbit Non-irritant
Eye irritation Rabbit Non-irritant
Skin sensitisation Guinea pig Non-sensitiser

*Scheduling Policy Framework for Medicines and Chemicals (2010)

**Based on studies conducted on analogue substances, namely octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5), low acute dermal and inhalation toxicity is expected for the notified chemical.

Repeat-dose toxicity

A 28-day repeat-dose oral toxicity study was conducted on the notified chemical in rats. No deaths or clinical effects were recorded for this study. While this study established a no observed effect level (NOEL) of 1 500 mg/kg bw/day, only one dose of the test substance was administered and no haematological or clinical chemistry measurements were made.

Mutagenicity

Trisiloxane was not mutagenic in a bacterial reverse mutation study and was not clastogenic in an in vitro mammalian chromosome aberration test.

Genotoxicity

Trisiloxane was not a genotoxic.

Reproductive toxicity

No reproductive toxicity studies were provided on trisiloxane. Studies on an analogue substance (D4) have been conducted and this chemical is classified under category 3 for reproductive toxicity (R62 Possible risk of impaired fertility; HSIS). Reproductive toxicity effects were noted in rats following inhalation. These included an increase in pre-implantation loss, increased post-implantation loss suppression of luteinising hormone surge, reductions in corpora lutea and in the number of pups born to exposed dams. While the relevance of these findings to humans and to the notified chemical is uncertain, the possibility of chronic effects following repeated, long term exposure to the notified chemical via inhalation cannot be ruled out.

Carcinogenicity

No carcinogenicity studies on trisiloxane were provided. In chronic/carcinogenicity studies conducted on analogue chemicals (D4 and D5) in rats via inhalation, endometrial adenomas were observed at the highest dose level and were concluded to be due to threshold effects on the rat endocrine system (which was also supported by the lack of genotoxic potential). However, the relevance of these effects to humans and to the notified chemical is uncertain.

Public health

At the proposed use concentration of ≤34 per cent notified chemical in cosmetic products, acute toxicity effects are not expected. The repeated dose toxicity effects of the notified chemical have not been determined. However, based on the observation of adverse effects in analogue chemicals, D4 and D5, particularly with respect to reproductive toxicity and carcinogenicity, similar effects in the notified chemical cannot be ruled out.

Repeat dose toxicity potential was estimated by calculation of the margin of exposure (MOE) of the notified chemical using the worst case exposure scenario of 0.52 mg/kg bw/day and the no observed adverse effect level (NOAEL) of 17.8 mg/kg bw/day, which was established in toxicity studies involving the analogues D4 and/or D5. A MOE value ≥100 is considered acceptable to account for intra- and inter-species differences. Using the abovementioned NOAEL, a MOE of 34 was estimated. Thus, the risk to the public from use of the notified chemical at 34 per cent concentration in cosmetic products, including facial cleansers, shampoos, conditioners, shower gels, make-up removers and lip products is considered to be unreasonable.

In the exposure estimate, the greatest contributors were body lotion (based on the large daily exposure amount and large skin surface area) and lipstick (based on ingestion of the notified chemical). Exclusion of body lotion from the possible product types and reduction of the concentration of the notified chemical in lipstick products from 34 per cent to 20 per cent, allows recalculation of the combined internal dose to 0.182 mg/kg bw/day. A MOE of 98 is then estimated.

In light of the conservative parameters used, the risk to the public associated with the use of the notified chemical at ≤34 per cent concentration in make-up, face care products and rinse off products and ≤20 per cent in lip products is not considered to be unreasonable.

Scheduling status

Trisiloxane, 1,1,1,3,5,5,5-heptamethyl-3-[(trimethylsilyl)oxy]- is not specifically scheduled.

Scheduling history

Not applicable.

Public pre-meeting submissions

Two public submissions were received.

One submission raised concerns with a number of aspects of the NICNAS assessment of methyl trimethicone and the scheduling proposal from scientific assessment and risk management viewpoints. The human health assessment, particularly the setting of the MOE was based on the NOAEL of "analogues" D4 (octamethylcyclotetrasiloxane) and/or D5 (Decamethylcyclopentasiloxane). It was NICNAS' decision to assign D4 and D5 as "analogues" of methyl trimethicone. The submission indicated that it failed to see the structural similarity between methyl trimethicone and D4/D5. All of these substances are silicone based and are similar in molecular weight [mass], however this is where the similarities appear to end. Without providing scientific justification for assigning D4/D5 as analogues of methyl trimethicone (e.g. mode of action for D4/D5 is known and it is likely, based on scientific logic that can be explained, that methyl trimethicone will also trigger the same toxicological response as D4/D5), the use of D4/D5 data for risk assessment of methyl trimethicone is inappropriate. There is no scientific justification in the public reports of NICNAS assessments. The only justification NICNAS put forward for the use of D4/D5 as analogues is that the three substances have similar molecular weight [mass], water solubility, partition co-efficient and vapour pressure. The submission did not support scheduling of methyl trimethicone, D4 or D5 based on all available information on these substances.

The other did not provide comments regarding the delegate's proposal and indicated that it will provide comments, if required, based on delegate's interim decision.

ACCS advice to the delegate

The committee recommends that trisiloxane, 1,1,1,3,5,5,5-heptamethyl-3-[(trimethylsilyl)oxy]- does not require a schedule listing.

Delegate's interim decision

The delegate accepts ACCS advice that trisiloxane, 1,1,1,3,5,5,5-heptamethyl-3-[(trimethylsilyl)oxy] does not require scheduling, either under this name, or its INCI name, methyl trimethicone. The toxicity profile of this chemical suggests sufficiently low acute toxicity to not warrant scheduling. However, the delegate notes and agrees with concerns raised by both the ACCS and in an industry submission, that inferring a reproductive toxicity potential for this chemical, based on 'read-across' from studies with cyclic siloxanes of similar molecular weight, provides insufficient evidence of relevant toxicity for this to be considered in the scheduling process.

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 purpose for which the 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 factors30;
  • Other relevant information.
Submissions on interim decision

Two public submissions were received.

One submission indicated that it supports the delegate's decision of not to include the substance in a schedule.

The other submission noted that as the delegate's decision had not impact on therapeutic goods, it had no further comments on this issue.

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.

1.21 C11-C15-secondary, ethoxylated, oxirane and oxirane, ethyl (oxirane)

Scheduling proposal

On 29 August 2013, the delegate received an application proposing the inclusion of C11-C15-secondary, ethoxylated, oxirane and oxirane, ethyl in Schedule 6. The basis for this recommendation is that the substance's high acute oral toxicity and the slight to moderate eye irritancy. The acute oral LD50 for the neat chemical was 550 - 2000 mg/kg in rats. Eye irritation was slight to moderate in rabbits based on the level of corneal opacity, iritis and conjunctival irritation observed.

The delegate's reason for referring this scheduling proposal to the ACCS was that although substance's proposed uses are mainly industrial and there is little likelihood that any products containing a high enough concentration to warrant scheduling would appear in the retail marketplace, it would be useful to have ACCS's advice.

The delegate sought the following specific advice from the ACCS:

  • While the toxicity profile of this polymer appears to be consistent with Schedule 6 factors in the Scheduling Policy Framework, is this sufficient reason to consider including it in the SUSMP, given that the proposed use pattern is mainly industrial and there appears to be limited likelihood that products entering the domestic retail market would have concentrations high enough to warrant scheduling?
  • If scheduling is warranted, is there sufficient information on acute toxicity and/or irritancy potential to determine a cut-off to a lower schedule or to exempt?
  • If inclusion in Schedule 6 is supported by the ACCS, please indicate wording that would identify this specific polymeric chemical in the schedules, and suggest appropriate Appendix E (First Aid) and Appendix F (warning statements and safety directions) statements?
Substance details

The polymer contains alcohols, C11-C15-secondary, ethoxylated, oxirane and oxirane, ethyl (the polymer). The polymer is a non-ionic surfactant that will be used at up to 1 per cent concentration in products for a range of applications, including coatings (40 per cent of total import volume), industrial hard surface cleaners (25 per cent), food and non-dairy beverage cleaning (25 per cent), inks (5 per cent), and adhesives (5 per cent).

End-points of acute toxicity Species C11-C15-secondary, ethoxylated, oxirane and oxirane, ethyl (oxirane) SPF*
Acute oral toxicity LD50 (mg/kg bw) Rat 550-2000; Moderate to high toxicity
Acute oral toxicity LD50 (mg/kg bw) Rat >2000; Low toxicity
Acute dermal toxicity LD50 (mg/kg bw) Rat >2000 Low toxicity
Skin irritation Rabbit Slightly irritating
Eye irritation Rabbit Irritating
Skin sensitisation* Human No evidence of sensitisation

*Scheduling Policy Framework for Medicines and Chemicals (2010)

**Study performed on an analogue polymer.

Acute oral toxicity study

In the main study 3/4 animals treated at 2000 mg/kg bw died within 1-day of dosing, with notable signs of toxicity in these animals including hypoactivity, hunched posture and/or ano-genital staining. Red discolouration of the intestines was noted at necropsy in the animals that died during the observation period. No abnormalities were noted at necropsy in animals treated at the lower doses (550 and 175 mg/kg bw).

In a second acute oral toxicity study, the notified polymer was determined by the study authors to have an LD50 >2000 mg/kg bw. However, it is noted that 2/5 animals tested at 2000 mg/kg bw died within 1-day of dosing, with hypoactivity and/or ano-genital staining noted in these animals prior to death. Red discolouration of the intestines or lungs was noted at necropsy in the animals that died during the observation period.

Repeated dose toxicity

No repeated dose toxicity data were submitted for the notified polymer. However, reports from three studies (90-day feeding studies) conducted on an analogue polymer in rats (treated at 62.5, 125, 250 and 500 mg/kg bw/day) and dogs (treated at 82, 154 and 354 mg/kg bw/day) were submitted.

While limited details were provided (and/or limited parameters were tested), the results indicated statistically significant mean body weight gain reductions in male and female rats dosed with the test substance at ≥125 mg/kg bw/day. The absolute liver and kidney weights were statistically significantly decreased in rats dosed with the test substance at 500 mg/kg bw/day; however, the relative weights were not significantly reduced. The no observed adverse effect level (NOAEL) in rats was established by the study authors as between 62.5 and 125 mg/kg bw/day.

In dogs, doses of 354 mg/kg bw/day resulted in severe mean body weight losses and the subsequent halting of treatment at week 6. These animals re-gained weight on the control diet by the study completion. Statistically significantly reduced haemoglobin was noted in one dog receiving the test substance at 354 mg/kg bw/day. Hydrocephalus was noted in 1 male and 2 female dogs treated with the test substance at 354 mg/kg bw/day, however, this was considered to be non-treatment related by the study authors, on the basis that it is a common lesion in dogs (although in this study, control group dogs did not have any evidence of hydrocephalus). The NOAEL in dogs, for the notified polymer has been estimated to between 150 and 350 mg/kg bw/day.

Genotoxicity

The notified chemical was not mutagenic in a bacterial reverse mutation study and was not clastogenic in an in vitro mammalian chromosome aberration test.

Toxicity for reproduction

No reproductive and developmental toxicity data were submitted for the notified polymer. A reproductive and developmental toxicity study that was conducted on an analogue polymer in rats (treated at 60, 168 and 470 mg/kg bw/day) was submitted. The results of the study indicated that there were no adverse effects in foetuses, but there was some systemic toxicity in male and female adults (reductions in mean body weight, food consumption and clinical signs were noted) at doses ≥168 mg/kg bw/day. Therefore, a no observed effect level (NOEL) for parental toxicity of 60 mg/kg bw/day was established and a NOAEL for reproductive/developmental toxicity was established as ≥470 mg/kg bw/day.

Public health

The public may be exposed to the notified polymer when applying the paint containing <1 per cent notified polymer by brush or roller. Spray application is not anticipated, as this requires the use of special tools. DIY use is expected to be infrequent and users may wear some PPE to minimise exposure. In addition, painting is expected to occur in ventilated environments.

The public may come into contact with products to which the coatings, adhesives and inks containing the notified polymer have been applied. However, the polymer will be bound in a matrix and will be unavailable for exposure.

Therefore, under the proposed use scenarios, the risk to public health is not considered to be unreasonable.

Scheduling status

The polymer is not specifically scheduled.

Scheduling history

Not applicable.

Public pre-meeting submissions

Two public submissions were received.

One submission indicated that the substance name [C11-C15- secondary, ethoxylated, oxirane and oxirane, ethyl (oxirane)] did not appear to represent a chemical structure. Firstly, "ethoxylated" means reacted with oxirane (synonym for oxirane is ethylene oxide). It was noted in the submission that oxirane may have been accidentally repeated but noticed that "oxirane, ethyl" which is assumed to refer to butylene oxide, is not referenced in the substance name (e.g. butoxylated). Further the word "secondary" should refer to an alkyl chemical structure such as alcohols e.g. secondary ethoxylated alcohol - this does not appear to be the case. The submitter will be interested in any scheduling proposals for ethoxylated alcohols or scheduling amendment proposals for ethylene oxide.

The second submission did not provide comments regarding the delegate's proposal and indicated that it will provide comments, if required, based on delegate's interim decision.

ACCS advice to the delegate

The committee recommends that a polymer which contains alcohols, C11-C15-secondary, ethoxylated, oxirane and oxirane, ethyl- does not require a schedule listing.

Delegate's interim decision

The delegate accepts ACCS advice that this polymer does not need to be included in any schedules of the SUSMP. While the polymer itself may have toxicological properties that appear to satisfy SPF factors for inclusion in Schedule 6, the likelihood is low that the public could be exposed to concentrations high enough to constitute a health hazard when it is used as a component of paints and coatings.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (b) the purpose for which the 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 factors31;
  • Other relevant information.
Submissions on interim decision

Two public submissions were received.

One submission indicated that it supported the delegate's interim decision of not to include the substance in a schedule.

The other submission indicated that as the delegate's interim decision on this polymer had no impact on therapeutic goods, it had no further comments regarding delegate's interim decision on this polymer.

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.


Footnotes

  1. Zinc Lactate Dihydrate Purified Powder
  2. Zinc Lactate Guide
  3. NICNAS's Public Report on Zinc lactate. STD/1388
  4. Scheduling Policy Framework for Medicines and Chemicals (2010)
  5. National Coordinating Committee on Therapeutic Goods, 2010, Scheduling Policy Framework for Medicines and Chemicals
  6. Regulation (EC) No 1223/2009 of the European Parliament and of the Council of 30 November 2009 on Cosmetic Products
  7. Scheduling Policy Framework for Medicines and Chemicals (2010)
  8. Trisiloxane Surfactants - Mechanisms of Spreading and Wetting . Venzmeir et al
  9. Trisiloxane, 1,1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]- (M4Q).
  10. NICNAS's Public Report on Trisiloxane, 1,1,1,3,5,5,5-heptamethyl-3-[(trimethylsilyl)oxy]- (INCI Name: Methyl Trimethicone). LTD/1637
  11. Scheduling Policy Framework for Medicines and Chemicals (2010)
  12. Scheduling Policy Framework for Medicines and Chemicals (2010)

Book pagination