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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) 1.12-1.14

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

1.12 Oxalic acid

Scheduling proposal

The chemicals scheduling delegate considered a proposal to amend the current Schedule 6 oxalic acid entry to exempt from scheduling preparations containing 8 per cent or less oxalic acid for household and domestic cleaning.

The delegate referred the proposal to the ACCS as the submission sought amendment of the current Schedule 6 entry for oxalic acid, to exempt a specific range of cleaning products containing up to 8 per cent oxalic acid. The Scheduling Policy Framework (SPF) suggests that proposals for re-scheduling require advice from an advisory committee. Furthermore, the history of scheduling of oxalic acid is somewhat obscure and there appears to have been little or no contemporary consideration given to exempting products containing low concentrations of oxalic acid.

The delegate asked the following specific questions to the ACCS:

  • The scheduling history for oxalic acid is not very informative. It was first listed in the (then) schedules Schedule 2 and Schedule 5 in May 1956, when the schedules were first being established. The original wording for these entries was:
  • Schedule 2: Substances which are dangerous to human life if misused or carelessly handled
  • OXALIC ACID and metallic oxides, except in laundry blue and polishes.
  • Schedule 5: Domestic poisons
  • OXALIC ACID AND METALLIC OXALATES IN POLISHES.
  • There are no records of when the current Schedule 6 entry was promulgated. The only records of further consideration are in November 1985 when the (then) Schedule 6 entry was amended to clarify the status of sodium salts and in February 1986, when a submission to require child resistant closures was considered, and rejected. It appears that the intent of the original scheduling was to exempt some types of cleaning products, but this appears to have been lost during subsequent re-organisation of the schedules.
  • The current submission seeks to exempt a range of cleaning products containing up to 8 per cent oxalic acid. The submission acknowledges that oxalic acid is systemically toxic, despite being formed as a normal metabolite within the body, with some dietary intake also contributing to oxalate concentrations in the body. Current label warning statement emphasise the corrosive potential associated with high concentrations of oxalic acid.
  • Can the ACCS advise on whether a cut-off clause should be added to the current Schedule 6 entry (to either exempt or to Schedule 5) to address this submission seeking re-scheduling of cleaning products containing up to 8 per cent oxalic acid? If so, what specific wording changes to the current entry are suggested?
  • Current SUSMP Appendix E First Aid statement emphasise the risks of skin, eye and respiratory irritancy. Are these still suitable for cleaning products containing up to 8 per cent oxalic acid?
  • Current SUSMP Appendix F entries for oxalic acid require safety warning statement 2 (corrosive) and safety directions 4 (attacks eyes - protect eyes when using) and 8 (avoid breathing dust (or) vapour (or) spray mist) while the entry for metallic oxalates requires only safety directions 4 and 8. There is no record of when either the Appendix E or F entries were promulgated, and they appear inconsistent with the range of label warning statements used on the applicant's cleaning products sold overseas. Does the ACCS consider that the current Appendix E and F entries for oxalic acid should be modified, and are there different Appendix entries required if the recommendation is to down-schedule these cleaning products to Schedule 5?
  • Can the ACCS advise on whether there might be inadvertent implications for other types of products containing oxalic acid if scheduling changes are recommended?
Substance summary

Oxalic acid is an odourless, colourless powder or granular solid that is slightly soluble in water16. It is present in many plants and vegetables, notably in those of the Oxalis and Rumex families, where it occurs in the cell sap of the plant as the potassium or calcium salt17.

Oxalic acid is endogenously produced in humans and excreted at amounts of about 25 mg daily via urine. Normal concentrations of oxalates in plants were in the range of 5 to 200 000 mg/kg dry weight18.

Figure 6. Structure of oxalic acid

Structure of oxalic acid

Acute toxicity

The summary of acute toxicity studies is shown in the table below.

Toxicity Species Oxalic acid SPF* classifaction
Oral LD50 (mg/kg bw) Rat 475 to 375 Moderate to high toxicity
Dermal LD50 (mg/kg bw) Not supplied Low toxicity Unable to assess
Inhalational LC50 (mg/m3/4h) Not supplied Not supplied Unable to assess
Skin irritation Not provided Irritant
Eye irritation Not provided Irritant
Skin sensitisation Not provided Not provided
Skin sensitisation Non-sensitiser Sensitiser

*Scheduling Policy Framework for Medicines and Chemicals (2010)

The US EPA (2005) indicates that acute oral exposure (LD50 = 300 mg/kg in gravid rats and 7500 mg/kg in rats) in rats and dogs causes gastric haemorrhage, central nervous system depression, convulsion, coma and kidney damage in experimental animals.

The US EPA (1992) notes that it is corrosive to the eyes, skin and has been placed in Toxicity Category I (indicating the highest degree of toxicity) for acute eye and skin irritation effects. Moreover, oxalic acid is also highly irritating and damaging to the respiratory system if inhaled. Acute exposure also cause stomach irritation, lowered calcium levels, effects to the nervous system and kidney damage in humans. The Merck Index also indicates that oxalic acid is caustic and corrosive to the human skin and mucous membranes.

Repeat-dose toxicity

In two studies, groups of male and female rats were fed diets supplemented with 0, 25 and 50 g/kg (equivalent to 0, 2000 and 5000 mg/kg bw/day) oxalic acid for 70 days. The high dose levels depressed the growth rate. This was accompanied by renal toxicity (increased water intake, increased kidney weight, abnormal gross appearance of kidneys at necropsy and stone formation) and reduced thyroid function. In a non-invasive screening test for the detection of renal disease, sodium oxalate administrated subcutaneously to rats at 25, 50 and 75 mg/kg bw/day for 2, 3 and 1 weeks respectively, caused mainly haematuria, with increase in the excretion into urine of white blood cells, epithelia and casts. Histopathological examination of kidneys indicated a small number of oxalate deposits in animals treated with sodium oxalate. The report indicated that these effects were indicative of a mild nephrotoxicity due to tubular obstruction following the administration of subcutaneous doses of oxalic acid greater than or equal to 25 mg/kg bw/day, for 5 days a week for 2 weeks.

The US EPA (1992) notes that a subchronic inhalation study in rats showed decreased body weights, restricted growth and disrupted oestrous cycles. At the highest dose, the test animals also had reduced thyroid weights and changes in iodine and hormone levels. Metabolism studies show that excess levels of oxalic acid cause kidney damage in mammals. Chronic oral intake in animals produces kidney damage and disturbances in the metabolism of calcium. A multi-generation mouse reproduction study showed reproductive effects and parental toxicity at the highest dose level.

Mutagenicity

There are no studies which address the mutagenic potential of oxalic acid in vivo. The negative results of the relevant in vitro studies and the data from a chronic toxicity study suggests that oxalic acid has no carcinogenic potential in rats. Therefore further mutagenic studies are not required for a risk assessment of residues of the compound.

Genotoxicity

The results of the various Ames test indicate that oxalic acid is clearly negative in the Salmonella typhimurium assay.

Carcinogenicity

In a carcinogenicity study, male and female rats were administered with 1000, 5000, 8000 and 12 000 ppm (corresponding to 50 to 600 mg/kg bw/day) of oxalic acid for 2 years. There were no effects of the treatment on body weight, body weight gain and food consumption during the first 52 weeks. There was no significant difference between the mortality rate at any dosage level in the treated groups and in the controls. The report indicated that within limitations of the study, which did not meet the criteria of current guidelines, there was no evidence of carcinogenicity in rats given approximately 50 to 600 mg/kg bw/day.

Reproduction and developmental toxicity

In a reproductive toxicity study, mice were exposed to dietary doses of 0, 0.05, 0.1 and 0.2 per cent (89, 162 and 275 mg/kg bw/day) oxalic acid. In the F0/F1 generations the number of litters in fertile pairs, live pup weight and prostate gland weight decreased significantly at 0.2 per cent in the diet, while all other parameters were unaffected. In the F1-generation the total number of live pups decreased, and prostate gland weight decreased significantly. Decreased water consumption was induced in the F1 0.1 and 0.2 per cent dose groups. Relative kidney weight of F2 females and the incidence of abnormal sperm in F2 males were increased. The report concluded that oxalic acid is a weak reproductive toxicant in mice at dose of 0.2 per cent in drinking water corresponding to about 275 mg/kg bw/day.

Oxalic acid did not induce overt teratogenic effects or postnatal toxicity. A no observed effect level (NOEL) was not determined since the data from the 0.05 and 0.1 per cent dose level groups were not recorded for the second generation.

Two teratogenicity studies were conducted in rats and sheep. In the rat study 10 females were administered with 0, 159, 205 mg/kg bw/day by gavage from day 7 post conception up to the day of parturition. Higher doses of 227 and 272 mg/kg bw/day had proven fatal within 7 days in a pilot study, while 136 mg/kg bw/day had led to marked vacuolation in cells of proximal tubules and tubular nephrosis in the pups. Neither gross malformation nor tubular nephroses was observed in offspring in the main study.

Observation in humans

Intravenous doses of 25 mg/kg bw oxalic acid inadvertently administered to human patients have led to kidney failure, cardiac arrest and death in spite of intensive care. High oral intake via a diet rich oxalic acid has also occasionally led to severe poisoning and deaths. Oral fatal doses of oxalic acid were reported to range from 3 to 30 g/person. The susceptibility of individuals varies greatly, depending on prior kidney damage, certain intestinal disease states or genetic abnormalities such as primary hperoxaluria.

Determination of individual oxalate intake of 3 volunteers maintaining food records over days suggest high average ingestion (152 ± 83 mg/day, range 44 to 351 mg/day) of normal consumers. On the basis of huge variations of oxalic acid content in the diet it may be assumed that occasional intake may reach and exceed 1 g/day, in particular in vegetarians. The report noted that it is believed, that similar to rodents and ruminants, bacterial decomposition of oxalic acid in the human intestine may largely increase with high prolonged oxalate exposure via diet, leading to reduced bioavailability and consequently lowered toxicity. Therefore adverse reactions are not common in humans in spite of daily intake occasionally reaching potentially dangerous levels.

Public exposure

The US EPA (1992) indicates that the potential for significant eye and dermal exposure exists when homeowners apply bathroom disinfectant products containing oxalic acid and other active and inert ingredients. These products are liquid and granular formulations applied using brushes, swabs or mops. Exposure, especially to the concentrated formulations, can cause chemical burns to the skin and severe to permanent damage to the eyes.

Although they contain only a small amount of oxalic acid and a much greater amount of other active and inert ingredients, oxalic acid products as formulated and registered for use as bathroom disinfectants can be highly irritating and damaging to the eyes, skin and mucous membranes. Exposure to the concentrated formulations can result in chemical burns to the skin and severe to permanent eye damage. However, these risks should be low as long as product label directions and precautions are followed.

International regulations

An internet search regarding international regulation of oxalic acid did not provide comprehensive information. Various Material Safety Data Sheets (MSDS) for products marketed in European Union have relevant label warning statements, such as 'Harmful', 'Harmful in contact with skin and if swallowed', 'Keep out of reach of children' and 'Avoid contact with skin and eyes'. These MSDS also notes: "Classification and labelling have been performed according to EU directives 67/548/EEC, 88/379/EEC".

Scheduling status

Oxalic acid is listed in Schedule 6, Appendices E and F.

SCHEDULE 6

OXALIC ACID except its derivatives and insoluble salts.

Appendix E
Poisons Standard statements
Oxalic acid

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).

E2 - If in eyes, hold eyelids apart and flush the eye continuously with running water. Continue flushing until advised to stop by a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor, or for at least 15 minutes.

G3 - If swallowed, do NOT induce vomiting.

S1 - If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water.

Appendix F
Poisons Warning statements Safety direction
Oxalic acid

2. Avoid contact with eyes.

4. Avoid contact with skin.

8. Avoid breathing dust (or) vapour (or) spray mist

Scheduling history

Oxalic acid was first considered in May 1956 by the Poisons Schedule Committee (PSC) and PSC decided to include oxalic acid and metallic oxalates in Schedule 5.

In November 1985, the PSC decided to amend the Schedule 6 oxalic acid entry to exempt its derivatives and insoluble salts from the Schedule 6 entry.

Pre-meeting public submissions

Four submissions were received.

The first submission requested that consideration of this proposal be broadened in such a way to exclude therapeutic mouthwash preparations containing less than 3 per cent of potassium oxalate.

The second submission noted that it did not object to the delegate's proposal in principle. The submission suggested that the current Schedule 5 listing of the oxalic acid entry should remain the same (i.e. "oxalic acid except its derivatives and insoluble salts") so that it excludes the oxalate salt of some registered medicines, such as escitalopram oxalate (which is in Schedule 4).

The third submission indicated that it supports the delegate's proposal to exempt from scheduling oxalic acid in domestic cleaning preparations containing 8 per cent or less oxalic acid. The submission requested that the ACCS and the delegate consider exempting from scheduling dental products including mouthwashes containing 3 per cent or less of soluble salts of oxalic acid.

The fourth submission requested that mouth wash preparations, intended for use in the symptomatic relief treatment of sensitive teeth, containing up to 3 per cent of oxalic acid’s salt potassium oxalate be exempted from scheduling.

ACCS advice to the delegate

The ACCS recommended that the current scheduling of oxalic acid remains appropriate.

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:

Insufficient evidence to change the scheduling of the chemical.

Delegate's interim decision

The delegate confirms that the toxicity profile of oxalic acid is consistent with SPF Schedule 6 criteria and accepts ACCS advice that the current listing of oxalic acid in Schedule 6 remains appropriate. The label signal heading, First Aid statements (Appendix E), Safety Directions and Warning Statements (Appendix F) remain appropriate for the type of cleaning products in the re-scheduling submission. The delegate also notes ACCS advice that the available information is insufficient to develop an exemption threshold for the Schedule 6 entry at this time. The delegate notes the proposals in public submissions that scheduling therapeutic goods containing oxalates is not appropriate, but concludes that the current entry (excepting derivatives and insoluble salts) should not apply to derivatives used in medicines. The matter of providing an exemption threshold for the use of soluble oxalates in mouthwashes requires further consideration and it will be referred back to a future meeting of the ACCS/ACMS.

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 factors19;
  • Other relevant information.
Public submissions on the interim decision

One submission was received. The submission indicated that mouthwash preparations containing potassium oxalate is currently marketed in the UK and several other European countries as a Class IIa medical device for dental sensitivity. It requested that consideration be given to specifically exempt from scheduling for mouthwash preparations containing oxalic acid and if deemed necessary with an appropriate concentration cut-off to enable this preparation to be supplied in Australia.

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 current Schedule 6 listing for oxalic acid in relation to its use in cleaning products. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.

However, the delegate also confirms the need to consider whether mouthwashes or other therapeutic goods containing soluble oxalates should be captured by the current entry. In accordance with SPF guidance that such re-scheduling matters be referred to an advisory committee, and that advice on this matter was not provided by the ACCS, the delegate proposes to refer this specific issue back to a joint meeting of the ACCS/ACMS.

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1.13 PPG-1-PEG-9 lauryl glycol ether or glycols, 1,2-, C12-16, ethoxylated propoxylated

Scheduling proposal

On 29 August 2013, the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) under its New Chemicals Assessment process, requested that the delegate consider a proposal to include PPG-1-PEG-9 lauryl glycol ether in Schedule 5 and Appendix F.

The basis for this recommendation is that:

  • PPG-1-PEG-9 lauryl glycol ether is a slight to moderate skin and eye irritant therefore the substance meets the factors in the Scheduling Policy Framework (SPF) for Schedule 5.
  • Repeat dose toxicity data indicate PPG-1-PEG-9 lauryl glycol ether is unlikely to produce irreversible toxicity therefore the substance meets the factors in the SPF for 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 that although this is a reasonably straightforward proposal to create a parent entry for this chemical polymer in Schedule 5, with appropriate exemption for low concentration products, it requires ACCS advice in relation to whether scheduling is the most appropriate control mechanism, and what cut-offs to apply if the chemical is to be listed.

The delegate asked the following specific questions:

  • The chemical has a relatively low acute and chronic toxicity profile, with minimal skin/eye irritancy and no evidence of sensitisation potential. Public exposure is only likely to occur through its use as an emulsifier for fragrances in cosmetic products. Does the ACCS consider that listing in the SUSMP is appropriate? If so, is Schedule 5 the most appropriate?
  • The proposed use pattern suggests that 2-3 per cent is the likely concentration in products, but 10 per cent is the possible maximum level. At these concentrations, the polymer appears to be sufficiently non-toxic to warrant exemption from Schedule 5. If the ACCS recommends inclusion of the pure chemical in a schedule, does the ACCS support a cut-off concentration to exempt at 10 or 3 per cent?
  • The Margin of Exposure calculations suggest that the estimated maximum daily dose (3.8 mg/kg/d) for products containing 10 per cent is well within the rat 90-day NOAEL of 80 mg/kg/d, although less than 100. Does this add support for an exemption cut-off of 10 per cent?
  • If scheduled, what name should be used in the listing - the INCI name of PPG-1-PEG-9 lauryl glycol ether, or the chemical name - glycols, 1,2-, C12-16, ethoxylated propoxylated?
  • If the ACCS recommends inclusion in a Schedule, does the toxicity profile warrant development of entries in either Appendices E or F?
Substance summary

PPG-1-PEG-9 lauryl glycol ether will be used as a component of cosmetic products at up to 10 per cent concentration (with a typical usage concentration of 2-3 per cent). PPG-1-PEG-9 lauryl glycol ether is intended for use as a fragrance emulsifier and will therefore be used in cosmetic products that require addition of a fragrance.

The finished products containing PPG-1-PEG-9 lauryl glycol ether (at up to 10 per cent concentration) may be used by consumers and professionals such as hairdressers or beauty salon workers. Depending on the nature of the product, these could be applied in a number of ways, such as by hand, using an applicator or by spray.

Acute toxicity

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

Toxicity Species PPG-1-PEG-9 lauryl glycol ether SPF* classification
Acute oral toxicity LD50 (mg/kg bw) Rat 2560 Schedule 5 classification
Acute dermal toxicity LD50 (mg/kg bw) Not provided Not provided Unable to assess
Acute inhalational toxicity LC50 (mg/m3/4h) Not provided Not provided Unable to assess
Skin irritation Rabbit Slight irritant
Eye irritation Rabbit Slight irritant
Skin sensitisation (non-adjuvant test) Guinea pig Non-sensitiser

*Scheduling Policy Framework for Medicines and Chemicals (2010)

Repeat-dose toxicity

Repeated dose toxicity information on PPG-1-PEG-9 lauryl glycol ether was not provided. Upon repeated oral (gavage) exposure of rats (90 day exposure period) to an analogue polymer, the NOAEL was established by the authors as 80 mg/kg bw/day, based on the main findings (at the high dose, 150 mg/kg bw/day) of lesions present in the stomachs at histopathology, reduced weight gain and reduction in food intake, in combination with findings such as nasal respiratory epithelium lesions and organ weight effects (in-particular on the kidneys, thymus and spleen). While effects were noted at lower doses (50 and 80 mg/kg bw/day; especially the effects on the nasal respiratory epithelium), they were considered by the study authors to be due to a local irritant effect of the analogue polymer and/or were not considered to be adverse at the lower dosage levels.

Mutagenicity

PPG-1-PEG-9 lauryl glycol ether was reportedly not mutagenic in a bacterial reverse mutation test in the presence and absence of metabolic activation.

Genotoxicity

No information provided.

Carcinogenicity

No information provided.

Reproduction and developmental toxicity

A reproduction test on Daphnia magna using 0.15, 0.47, 1.5, 4.8 and 15.4 mg/L of PPG-1-PEG-9 lauryl glycol ether did not have long lasting harmful effects on aquatic invertebrates.

Observation in humans

No information provided.

Public exposure

The general public will be repeatedly exposed to PPG-1-PEG-9 lauryl glycol ether during the use of cosmetic products containing PPG-1-PEG-9 lauryl glycol ether (proposed to be used at up to 10 per cent concentration, noting that the typical usage concentration will be 2-3 per cent).

Local effects

Based on the information available, PPG-1-PEG-9 lauryl glycol ether is considered to be a skin and eye irritant. However, PPG-1-PEG-9 lauryl glycol ether will be present in cosmetic products at concentrations ≤10 per cent, skin and eye irritation effects are considered much less likely. Based on the limited available repeated dose toxicity data on an analogue polymer, the risk of adverse nasal irritancy effects cannot be ruled out.

Systemic effects

The potential systemic exposure to the public from the use of PPG-1-PEG-9 lauryl glycol ether in cosmetic products was estimated to be 3.80 mg/kg bw/day. Using a NOAEL of 80 mg/kg bw/day, which was derived from a repeated dose toxicity study on an analogue polymer, the margin of exposure (MOE) was estimated to be 21. A MOE value greater than or equal to 100 is considered acceptable to account for intra- and inter-species differences, therefore, the MOE is considered to be unacceptable.

Reducing the concentration of PPG-1-PEG-9 lauryl glycol ether in leave-on cosmetic products to 2 per cent and in rinse-off products to 3 per cent gives a recalculated combined internal dose of 0.78 mg/kg bw/day. An acceptable MOE of 102 is then estimated.

Therefore, based on the information available, the risk to the public associated with the use of PPG-1-PEG-9 lauryl glycol ether at ≤2 per cent in leave-on cosmetic products and ≤3 per cent in rinse-off cosmetic products is not considered to be unreasonable.

International regulations

No international regulations identified.

Scheduling status

PPG-1-PEG-9 lauryl glycol ether is not specifically scheduled.

Scheduling history

PPG-1-PEG-9 lauryl glycol ether has not been previously considered for scheduling therefore scheduling history is not available.

Pre-meeting public submissions

Two submissions were received.

One submission questioned the basis for NICNAS's proposed restrictions on the substance and indicated that there is no need to schedule this substance. The toxicity profile and its use pattern does not warrant a schedule listing, particularly when only a maximum of 1000kg of the polymer is allowed in Australia per year. The submission asserted that if scheduling is deemed necessary, it should align with other scheduled surfactants such as sodium lauryl sulfate.

The second submission indicated that PPG-1-PEG-9 lauryl glycol ether is listed in TGA eBS website, with the synonym Eumulgin LG. The concentration of this ingredient is not to exceed 5 per cent in the final finished product and is not to be included in topical products intended for use on the eye. The compound is also found in the International Cosmetic Ingredient Dictionary as an emulsifying agent/surfactant. The submission requested that, if the delegate decides to schedule the substance, therapeutic preparations containing the substance be excluded from the schedule listing.

ACCS advice to the delegate

The ACCS recommended that that PPG-1-PEG-9 lauryl glycol ether does not require a schedule listing.

The reasons for the recommendation comprised the following:

  • Low toxicity profile coupled with the use pattern does not warrant scheduling control.
Delegate's interim decision

The delegate accepts ACCS advice that PPG-1-PEG-9 lauryl glycol ether does not require a schedule listing.

The delegate notes that the ACCS considered the NICNAS calculation deriving a Margin of Exposure (MoE) of 21 to be overly conservative. The MoE was based on exposure estimates from simultaneous multiple product use, it used a reduced dermal absorption factor (15.6 per cent), partly based on read-across from a different lauryl glycol ether, and the NOAEL used was from a 90-day rat study with an analogue glycol ether. The delegate also notes ACCS advice that other PPG-1-PEG-9 lauryl ether analogues (none of which are scheduled in the SUSMP) have been used widely in cosmetic and other products (including therapeutic goods) for some time without apparent adverse health effects. The delegate notes that the slight skin/eye irritancy potential and low acute oral toxicity are consistent with SPF criteria for listing in Schedule 5, but concludes that public health concerns associated with proposed uses in products at quite low concentrations are insufficient to warrant scheduling the chemical.

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 factors20;
  • Other relevant information.
Public submissions on the interim decision

No public submissions were received.

Delegate's final decision

The delegate 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.

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1.14 4,4-dimethyl-1-cyclohexene-1-propanal

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 4,4-dimethyl-1-cyclohexene-1-propanal in Schedule 6 and Appendix F.

The reasons for this request are:

  • 4,4-dimethyl-1-cyclohexene-1-propanal has moderate to high acute oral toxicity which may cause death or severe injury if taken internally which meets the Scheduling Policy Framework’s (SPF) Schedule 6 factors.
  • It is a severe eye irritant with corneal opacity noted in all treated eyes which meets the factors in the SPF for Schedule 6.
  • It is a moderate to severe skin sensitiser which meets the factors in the SPF for Schedule 6.
  • A quantitative risk assessment determined that the risk from repeated exposure to the chemical, skin irritation, eye irritation and skin sensitisation is acceptable at concentrations no more than 1.0 per cent in fine fragrances, 0.1 per cent in other leave-on cosmetic products, 0.5 per cent in rinse-off cosmetic products and 0.9 per cent in household products.

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 that while the NICNAS evaluation report proposes listing this new chemical in Schedule 6, 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 and household products.

The delegate asked the following questions:

  • Given the relatively moderate toxicity profile of this chemical, and the fact that public exposure is only likely to occur through its use as a fragrance in cosmetic and household cleaning products containing up to 5 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?
  • Noting that the pure chemical is a skin/eye irritant and a potential sensitiser, but there is limited information on these toxicities at the low concentrations proposed for consumer products, is this toxicity potential sufficient to warrant inclusion of the substance in Schedule 6? Are Appendix E & F statements required?
Substance summary

The substance is intended to be used as a component of fragrances for a variety of cosmetic and household products (proposed usage concentration: ≤1.15 per cent concentration in fine fragrances, ≤2.5 per cent in other cosmetic products and ≤5 per cent in household products).

The finished products containing the substance 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 7: Structure of 4,4-dimethyl-1-cyclohexene-1-propanal

Structure of 4,4-dimethyl-1cyclohexene-1-propanal

Acute toxicity

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

Toxicity Species 4,4-dimethyl-1-cyclohexene-1-propanal SPF* Classification
Acute oral toxicity LD50 (mg/kg bw) Rats 300 - 2000 Consistent with Schedule 6
Acute dermal toxicity LD50 (mg/kg bw) Rats >2000 Consistent with Schedule 5
Acute inhalational toxicity LC50 (mg/m3/4h) Not provided Not provided Unable to assess
Skin irritation Rabbits Irritant
Eye irritation Rabbits Severe irritant
Skin sensitisation (local lymph node assay) Mice Sensitiser

*Scheduling Policy Framework for Medicines and Chemicals (2010)

Repeat-dose toxicity

A 28-day repeat-dose study by oral gavage was conducted in rats. There were no overt clinical signs of toxicity noted for animals at up to 300 mg/kg bw/day. However, organ weight and histopathological changes were noted in animals treated at this dose.

There were no treatment related macroscopic findings in any organ at necropsy. However, absolute and relative liver and kidney weights were increased in males in the low, mid and high dose groups and females in the high dose group only. While liver weights returned to normal following the recovery period, kidney weights remained elevated for males receiving 300 mg/kg bw/day (the only dose measured in the recovery group). The organ weight effects in both sexes to be non-adverse due to increased water intake, resulting in an adaptive response in organ weights.

Gastro-intestinal tract lesions and inflammation were noted in males receiving 300 mg/kg bw/day. Chronic ulceration was also noted at the conclusion of the study (following the recovery period) in one animal. These effects were attributed to 4,4-dimethyl-1-cyclohexene-1-propanal. Based on the adverse gastro-intestinal results of this study, a no observed adverse effect level (NOAEL) of 150 mg/kg bw/day was derived.

Mutagenicity

4,4-dimethyl-1-cyclohexene-1-propanal was not mutagenic in a bacterial reverse mutation study and was not clastogenic in an in vitro mammalian chromosome aberration test.

Genotoxicity

4,4-dimethyl-1-cyclohexene-1-propanal was a not genotoxic in in vitro mammalian chromosome aberration.

Carcinogenicity

No information provided.

Reproduction and developmental toxicity

No information provided.

Observation in humans

Irritation

An in vitro skin irritation study conducted using a reconstituted human epidermis model (EpiSkin), indicated that 4,4-dimethyl-1-cyclohexene-1-propanal was borderline non-irritating.

An in vitro eye irritation study conducted using a reconstituted human corneal epithelium model (SkinEthic) indicated that 4,4-dimethyl-1-cyclohexene-1-propanal was non-irritating to the eyes.

Public exposure

Repeated-dose toxicity

Members of the public may experience repeated exposure to 4,4-dimethyl-1-cyclohexene-1-propanal (at ≤5 per cent concentration) through the use of the cosmetic and household products. The principal route of exposure will be dermal. Ocular and inhalation exposure is also possible, particularly if products are applied by spray.

The repeat-dose toxicity potential was estimated by calculation of the margin of exposure (MoE) of 4,4-dimethyl-1-cyclohexene-1-propanal using the worst case exposure scenario from use of multiple products of 7.3 mg/kg bw/day and the NOAEL of 150 mg/kg bw/day, which was established in a 28-day repeated dose toxicity study on 4,4-dimethyl-1-cyclohexene-1-propanal. A MoE value ≥300 is considered acceptable to account for intra- and inter-species differences, and to account for long-term exposure (noting that the NOAEL was derived from a 28-day study). Using the abovementioned NOAEL, a MoE of 21 was estimated, which is considered to be unacceptable.

Reducing the concentration of 4,4-dimethyl-1-cyclohexene-1-propanal in fine fragrances to 1.0 per cent, all other leave-on cosmetic products to 0.1 per cent, rinse-off cosmetic products to 0.5 per cent and household products to 0.9 per cent allows recalculation of the combined internal dose to 0.5 mg/kg bw/day. An acceptable MoE of 300 is then estimated.

Irritation

4,4-dimethyl-1-cyclohexene-1-propanal is considered to be a skin irritant and cause serious damage to eyes. Skin irritation effects are not expected from use of the notified chemical at the revised (lowered) concentrations in cosmetic and household products. However, the potential for eye irritation (namely, from use of household products and fine fragrances, which will contain a higher concentration of the notified chemical) is of concern.

Ocular exposure is only expected to occur in the unlikely event of an accident, and, in the case of household products, the products may be diluted with water at the time of eye contact. The potential for eye irritation may be further minimised by the inclusion of appropriate labelling and directions for use to warn against eye contact.

Sensitisation

4,4-dimethyl-1-cyclohexene-1-propanal is considered to have the potential to cause skin sensitisation. Methods for the quantitative risk assessment of dermal sensitisation have been proposed and been the subject of significant discussion. Using a fine fragrance (containing 1.0 per cent notified chemical) as an example product that may contain 4,4-dimethyl-1-cyclohexene-1-propanal, as a worst case scenario, the Consumer Exposure Level (CEL) is estimated to be 37.5 μg/cm2. When tested in an LLNA study, 4,4-dimethyl-1-cyclohexene-1-propanalwas a skin sensitiser with an EC3 value of 54.6 per cent. Consideration of the study details and application of appropriate safety factors allowed the derivation of an Acceptable Exposure Level (AEL) of 41.8 μg/cm2. In this instance, the factors employed included an inter-species factor (3.16), intra-species factor (10), a matrix factor (3.16) and a use and time factor (3.16), giving an overall safety factor of >300 (300 used for calculations).

As the AEL>CEL, the risk to the public of the induction of sensitisation that is associated with the use of fine fragrances (a worst case example of a leave-on cosmetic product) at ≤1.0 per cent concentration is not considered to be unreasonable. Based on the significantly lower expected exposure level from other leave-on cosmetic products (containing ≤0.1 per cent 4,4-dimethyl-1-cyclohexene-1-propanal), rinse-off products (containing ≤0.5 per cent 4,4-dimethyl-1-cyclohexene-1-propanal) and household products (≤0.9 per cent of 4,4-dimethyl-1-cyclohexene-1-propanal), by inference, the risk of induction of sensitisation associated with the use of these products is also not considered to be unreasonable. It is acknowledged that consumers may be exposed to multiple products containing 4,4-dimethyl-1-cyclohexene-1-propanal and a quantitative assessment based on the aggregate exposure has not been conducted.

Therefore, based on the information available, the risk to the public associated with the use of 4,4-dimethyl-1-cyclohexene-1-propanal at ≤1.0 per cent in fine fragrances, ≤0.1 per cent in other leave-on cosmetic products, ≤0.5 per cent in rinse-off cosmetic products and ≤0.9 per cent in household products, is not considered to be unreasonable.

International regulations

A search on the internet did not provide any information on the international regulation of 4,4-dimethyl-1-cyclohexene-1-propanal or the substance.

Scheduling status

4,4-dimethyl-1-cyclohexene-1-propanal is not specifically scheduled.

Scheduling history

4,4-dimethyl-1-cyclohexene-1-propanal has not been previously considered for scheduling therefore scheduling history is not available.

Pre-meeting public submissions

Two submissions were received.

One submission questioned the dermal absorption value used in the NICNAS assessment report (i.e. 100 per cent dermal absorption was assumed), and the use of the worst case scenario i.e. the use of 4,4-dimethyl-1-cyclohexene-1-propanal by a single person in maximum concentrations in 10 product types (body lotion, face cream, hand cream, fine fragrances, deodorant spray, shampoo, conditioner, shower gel, hand soap and hair styling products). Further, the submission argued that the use of 300 as the acceptable Margin of Exposure (MoE) value for 4,4-dimethyl-1-cyclohexene-1-propanal when 100 was used for PPG-1-PEG-9 lauryl glycol ether. The submission requested that the ACCS and the delegate to determine whether the methods and data used by NICNAS to derive the acceptable use pattern of 4,4-dimethyl-1-cyclohexene-1-propanal is appropriate. If the ACCS and delegate consider it is necessary to schedule 4,4-dimethyl-1-cyclohexene-1-propanal, a further consultation which includes the proposed exemption cut-off from scheduling is required.

The second submission indicated that 4,4-dimethyl-1-cyclohexene-1-propanal is used as a fragrance in cosmetic and household products. The submission also indicated that 4,4-dimethyl-1-cyclohexene-1-propanal is not appears to be listed on the ingredient list of the ARTG.

ACCS advice to the delegate

The ACCS recommended that preparations containing more than 1 per cent of 4,4-dimethyl-1-cyclohexene-1-propanal/4,4-dimethyl-1-cyclohexene-1-propanal, be listed in Schedule 6 and that the substance requires inclusion in Appendix E and F.

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:

  • Toxicity profile (skin sensitisation, eye irritation and acute oral toxicity) consistent with criteria of Schedule 6 above 1 per cent.
Delegate's interim decision

The delegate accepts ACCS advice that 4,4-dimethyl-1-cyclohexene-1-propanal should be listed in Schedule 6. While the acute toxicity profile (oral and dermal lethal dose estimates) is reasonably low, the severe eye-irritancy is consistent with SPF criteria for Schedule 6. This is reinforced by evidence of sensitisation potential (categorised as weak with EC3 value of 54.6 per cent).

The delegate notes that NICNAS has calculated Margin of Exposure (MoE) estimates for systemic toxicity based on conservative exposure factors and using an additional 3x factor to account for the limited data on repeated dose toxicity (NOAEL of 150 mg/kg bw/d in a 28 day study in rats). The delegate notes the point made in a public submission that such an additional factor was not used in estimating the MoE for another chemical considered by the ACCS at the meeting (where a the NOAEL from a 90-day rat study was used), but the delegate accepts that inclusion of the additional 3x factor is consistent with standard toxicological practice and reasonable in these circumstances. The NICNAS MoE estimate of 21 based on multiple product exposure and the highest estimated product concentrations was considered unacceptable. Considering both the risk assessment calculations for both sensitisation and systemic toxicity, NICNAS estimated that an acceptable MoE could only be achieved where the concentration of 4,4-dimethyl-1-cyclohexene-1-propanal was restricted to 0.9 per cent in household products, 0.5 per cent in rinse-off cosmetics and 0.1 per cent in leave-on cosmetics.

Accordingly, while the delegate accepts ACCS advice that a cut-off to exempt at 1 per cent would be reasonable for most products, the delegate proposes lower cut-offs for cosmetic products, as recommended in the NICNAS report.

Since there may already be products containing 4,4-dimethyl-1-cyclohexene-1-propanal on the Australian market, the delegate proposes a longer implementation time (1 July 2015) to allow for product-re-labelling and for more extensive consultation on the proposed exemption cut-offs.

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 factors21;
  • 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 delegate confirms the longer implementation time (1 July 2015) to allow for product-re-labelling, since there may already be products containing 4,4-dimethyl-1-cyclohexene-1-propanal on the Australian market.

Schedule entry

Schedule 6 - New entry

4,4-DIMETHYL-1-CYCLOHEXENE-1-PROPANAL except:

  1. in leave-on cosmetic preparations containing 0.1 per cent of less of 4,4-dimethyl-1-cyclohexene-1 propanal;
  2. in rinse-off cosmetic preparations containing 0.5 per cent of less of 4,4-dimethyl-1-cyclohexene-1 propanal; or
  3. in other preparations containing 1 per cent of less of 4,4-dimethyl-1-cyclohexene-1 propanal.
  4. Appendix E, Part 2 - New entry
    Poison Standard statement
    4,4-dimethyl- 1-cyclohexene-1-propanal

    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).

    E2 - If in eyes, hold eyelids apart and flush the eye continuously with running water. Continue flushing until advised to stop by a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor, or for at least 15 minutes.

    Appendix F, Part 3 - New entry
    Poison Warning statement Standard statement
    4,4-dimethyl-1-cyclohexene-1-propanal

    5. Irritant.

    28. (Over) (Repeated) exposure may cause sensitisation.

    1. Avoid contact with eyes.

    2. Avoid contact with skin.

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    Footnotes

    1. The United States Environmental Protection Agency's (US EPA, 2005) Inert Reassessment - Oxalic Acid.
    2. The Merck Index (1996) An encyclopedia of chemicals, drugs and biologicals - 7043. Oxalic acid. Twelfth Edition, pp 10 330.
    3. European Agency for the Evaluation of the Medicinal Product's (EMEA, 2003) Oxalic acid summary report (EMEA/MRL/891/03-final).
    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)

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