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Scheduling delegate's final decisions: ACCS, November 2015

Scheduling medicines and poisons

19 November 2015

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1.1 2-ethylhexanoic acid and its derivatives

Part A - Final decisions on matters referred to an expert advisory committee (ACCS#13)

1. Scheduling proposals referred to the March 2015 meeting of the Advisory Committee on Chemicals Scheduling (ACCS#13)

1.1 2-ethylhexanoic acid and its derivatives

Scheduling proposal

The Chemicals Scheduling Delegate (the delegate) referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS):

  • That a new entry be created in Schedule 6 for 2-ethylhexanoic acid and its derivatives, with appropriate low concentration exemption cut-off in cosmetic and/or domestic preparations containing esters that hydrolyse and/or metabolise to 2-ethylhexanoic acid.

In December 2014, the National Industrial Chemicals Notification and Assessment Scheme (NICNAS), under its Inventory Multi-tiered Assessment Prioritisation (IMAP) programme, referred the following proposal to be considered by the chemicals scheduling delegate:

  • That a new entry be created in Schedule 6 for 2-ethylhexanoic acid and its derivatives, with appropriate low concentration exemption cut-off in cosmetic and/or domestic preparations containing esters that hydrolyse and/or metabolise to 2-ethylhexanoic acid.

The reasons for the request were:

  • 2-Ethylhexanoic acid is not directly used in cosmetic or domestic products in Australia. Ester derivatives of the chemical readily hydrolyse to form 2-ethylhexanoic acid via chemical or enzymatic processes, and this was accepted by the Delegate as a basis for scheduling 2-ethylhexyl 2-ethylhexanoate at concentrations above 10% (which is broadly equivalent to 5% 2-ethylhexanoic acid). The Cosmetic Ingredient Review's (CIR) assessment of alkyl ethylhexanoates (CIR, 2013) indicates that alkyl ethylhexanoates have widespread use in cosmetic products overseas. It is expected that these ester derivatives have similar uses in cosmetic products in Australia.
  • Sixteen cosmetic ingredients which metabolise to 2-ethylhexanoic acid are identified from CIR, 2013. These compounds are best scheduled as derivatives of 2-ethylhexanoic acid, which is the toxic species of concern.
  • Scheduling the derivatives based on the percentage that can be metabolized to 2-ethylhexanoic acid will result in uniform treatment.
  • The critical health effects of 2-ethylhexanoic acid include systemic long-term effects (fertility and developmental toxicity) based on observations in laboratory animals. Fertility effects (reduction in sperm motility, abnormal sperm, and dose-dependent delays in mating) were reported in rats. Developmental toxicity effects were noted in the absence of maternal toxicity from several studies in rats following exposure to the chemical via the oral route. The lowest observed adverse effect level (LOAEL) was reported to be 100 mg/kg bw/day based on skeletal variations (wavy ribs) and skeletal malformations (club foot) of the foetuses.
  • There are currently no labelling requirements for products containing the chemical and its derivatives (apart from 2-ethylhexyl 2-ethylhexanoate) in Australia. However, the characterised critical health effects (fertility and developmental toxicity) have the potential to pose an unreasonable risk to the public under the uses identified.
Delegates reasons for referring this to the committee

The related substance, 2-ethylhexyl 2-ethylhexanoate was considered by the ACCS at the July 2014 meeting. The key toxicological issue was reproductive toxicity associated with the hydrolysis of this ester to known reproductive toxicants, 2-ethylhexanol and 2-ethylhexanoic acid. The current IMAP report recommends making a separate Schedule 6 entry, with appropriate low-level cut-offs to regulate the use of 2-ethylhexanoic acid, but more particularly, esters that hydrolyse to form this known reproductive toxin.

The delegate asked the ACCS the following questions:

  • The NICNAS IMAP report suggests there are likely to be few products where 2-ethylhexanoic acid may be a direct ingredient, but there are potentially more esters used in cosmetic and domestic products. The 2013 US CIR Expert Panel report lists some 16 alkyl esters of 2-ethylhexanoic acid used in cosmetic products that could be hydrolysed to 2-ethylhexanoic acid. Does the ACCS support a Schedule 6 listing that captures all these esters? What wording of the Schedule 6 entry would best capture such a generic listing?
  • The current Schedule 6 entry for 2-ethylhexyl 2-ethylhexanoate is: 2-ETHYLHEXYL 2-ETHYLHEXANOATE except in preparations containing 10 per cent or less of 2-ethylhexyl 2-ethylhexanoate. There are also entries in Appendices E & F. These entries would become redundant in the light of a generic entry. Should they be deleted or retained?
  • The 10% cut-off to exempt has apparently been recommended for consistency with the 10% exemption in the generic S6 entry for ethylene glycol monoalkyl ethers and their acetates (also a reproductive toxicity issue). Is this cut-off suitable for a generic entry for 2-ethyhexanoates? The 10% cut-off recommended for 2-ethylhexyl 2-ethylhexanoate would represent approximately 5% of the hydrolysed acid. Is it possible to word a generic S6 entry so that it only captures the hydrolysis products of esters at a relevant concentration?
  • The CIR report suggest that current uses of alkyl esters of 2-ethylhexanoic acid used in cosmetic products at concentrations up to 77% in rinse-off products and 53% in leave-on products is 'safe'. What impact does this report have on a proposal to develop a generic listing with one or more exemption cut-offs for leave-on or rinse-off cosmetic products?
  • If a generic listing is impractical, would a simple entry for 2-ethylhexanoic acid and its derivatives, with a 5% exemption cut-off, have any regulatory effect? Would such an entry capture any or all of the alkyl esters as 'derivatives'?
Substance summary

Refer to the NICNAS IMAP human health Tier II assessment report for Hexanoic acid, 2-ethyl-. This report is publicly available on the NICNAS website: NICNAS IMAP assessment report ID 787. A summary is provided below.

In addition, the CIR assessment of alkyl ethylhexanoates (CIR, 2013) is publicly available from:

How to access a pdf document

Repeat-dose toxicity

In a 90-day dietary study in rats, a LOAEL of 917 mg/kg bw/day was reported based on reduced body weight gain in conjunction with reduced feeding (Canada, 2011). A lowest observed effect level (LOEL) of 303 mg/kg bw/day was also reported based on increased relative liver weight and hepatocyte hypertrophy.

In a 90-day dietary study in mice, a LOAEL of 1040 mg/kg bw/day was reported based on reduced body weight (Canada, 2011; REACH). A LOEL of 885 mg/kg bw/day was also reported based on effects including increased relative liver weight, hepatocyte hypertrophy, kidney effects and forestomach lesions.

Reproduction and developmental toxicity

The chemical is classified as hazardous as a Category 3 reproductive toxin with the risk phrase 'Possible risk of harm to the unborn child' (Xn; R63) in Safe Work Australia's Hazardous Substances Information System (HSIS). There is also sufficient evidence to classify the chemical as potentially toxic in relation to fertility.

The chemical was reported to cause developmental toxicity in several studies in rats following exposure via the oral route (Canada, 2011; Pennan et al., 1992; REACH). These effects were noted in the absence of signs of maternal toxicity. The lowest developmental toxicity LOAEL was reported to be 100 mg/kg bw/day.

In a developmental toxicity study, pregnant female Wistar rats were administered the chemical on gestation days 6-19 via drinking water at 0, 100, 300 or 600 mg/kg bw/day (Canada, 2011; Pennan et al., 1992; REACH). Skeletal variations in foetuses were observed at the lowest dose. A dose-dependent increase in club foot was observed in foetuses of the treatment group (statistically significant at the highest and intermediate dose); this anomaly was not observed in any foetuses of the control group. A statistical increase in wavy ribs was also observed in the foetuses of all treatment groups compared to controls. A dose-dependent increase in malformation of the legs, reported as 'flabby legs (external, slightly paralysed)' was also observed in foetuses of all treatment groups; this was not observed in any foetuses of the control group. While a maternal toxicity LOAEL of 600 mg/kg bw/day (highest dose) was reported from this study, based on decreased maternal body weight gain (Canada, 2011; Pennan et al., 1992), a REACH dossier reported maternal toxicity (slightly lower pregnancy rates and reduced body weights) at 300 mg/kg bw/day. A developmental LOAEL of 100 mg/kg bw/day was determined from this study in both reports.

Foetal skeletal variations, malformations, reduced foetal body weights and early foetal deaths have also been reported in several other developmental toxicity studies in rats following oral exposure to the chemical (Canada, 2011; REACH). For each of these studies, developmental effects were observed in the absence of maternal toxicity.

In a reproductive toxicity study in Wistar rats, the sodium salt of the chemical was administered via drinking water at 100, 300 or 600 mg/kg bw/day (Pennan et al., 1993; REACH). Males were exposed to the chemicals for 10 weeks prior to mating and for three weeks during mating; females were exposed for two weeks prior to mating and throughout the entire gestation and lactation period. Effects on the male reproductive system (reduction in sperm motility) were observed at 100 mg/kg bw/day, and increases in abnormal sperm were observed at 300 and 600 mg/kg bw/day. Dose-dependent delays in mating at 300 and 600 mg/kg bw/day were also reported, in addition to some animals being reported to be 'totally infertile'.

Public exposure

While use of the chemical in domestic products in Australia is not known, it is reported to be used in domestic products overseas. Limited information with regard to concentration in domestic products is available from the US National Library of Medicine's Household Products Database, which indicated use of the chemical in:

  • liquid form auto products (antifreeze) at up to 8%;
  • a home maintenance product (paint drier) at up to 5%; and
  • an arts and craft stain product at less than 4%.

An approximate margin of exposure (MOE) was calculated by Canada (2011) based on domestic use of the chemical in similar types of products identified in this report (alkyd paints), using similar levels of bioavailability, and LOAELs. The calculations resulted in the determination that the MOE was acceptable, particularly given the expected episodic exposure of the general population to the chemical from normal use of these products.

However, since esters that hydrolyse and/or metabolise to 2-ethylhexanoic acid are widely available to the general public, appropriate restrictions on the chemical and its derivatives are needed.

International regulations

The chemical is listed on the following:

  • European Union Cosmetic Directive 76/768/EEC Annex II: List of Substances which must not form part of the composition of cosmetic products.
  • New Zealand Cosmetic Products Group Standard - Schedule 4: Components cosmetic products must not contain.
Scheduling status

2-Ethylhexanoic acid is not specifically scheduled.

Scheduling history

2-Ethylhexanoic acid has not been previously considered for scheduling; therefore, scheduling history is not available.

However, a chemical belonging to the same group of chemicals, namely 2-ethylhexyl 2-ethylhexanoate was considered by the ACCS in March 2014. The delegate decided to include this chemical in Schedule 6 due to reproductive/developmental toxicity associated with its ready hydrolysis to the known reproductive toxicants, 2-ethylhexanol and 2-ethylhexanoic acid.

Schedule 6

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

Appendix E, Part 2
Poisons Standard statements
2-Ethylhexyl 2-ethylhexanoate A - For advice, contact a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor (at once).
Appendix F, Part 3
Poisons Warning statements Safety direction
2-Ethylhexyl 2-ethylhexanoate 53. CAUTION - 2-ethylhexyl 2-ethylhexanoate should not be used by pregnant women.
Pre-meeting public submissions

One public submission was received. The submission proposed that 2-ethylhexanoic acid should be included in Schedule 6, except when in concentrations of 10% or less, to be consistent with the scheduling decision for 2-ethylhexyl-2-ethylhexanoate (2-EHEH) made in August 2014. The submission noted that the Appendix E and F statements used for 2-EHEH are also relevant for 2-ethylhexanoic acid and should be maintained. The following schedule entry for esters of 2-ethylhexanoic acid was also proposed:

ALKYL ETHYLHEXANOATES (excluding derivatives) in preparations containing 10 percent or more alkyl ethylhexanoate calculated as 2-ethylhexanoate.

Summary of ACCS advice to the delegate

The committee recommended that a new Schedule 6 entry be created for 2-ethylhexanoic acid with exceptions in preparations containing 5 per cent or less of as calculated as 2-ethylhexanoic acid.

The committee also recommended a new Appendix E, Part 2 entry (standard statement A) and a new Appendix F, Part 3 entry (warning statement 53).

In addition, the committee recommended the current Schedule 6 and Appendices E and F entries for 2-ethylhexyl 2-ethylhexanoate be deleted.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the recommendation comprised the following:

  • Developmental toxicant.
  • Alkyl esters are used in cosmetic products which in vivo hydrolyse to the acid which is the toxin.
Delegate's interim decision

The delegate accepts ACCS advice that the recent scheduling decision to include 2-ethylhexyl-2-ethylhexanoate in Schedule 6, because of the reproductive toxicity potential of its hydrolysed acid and alcohol components, needs to be broadened to capture all the alkyl 2-ethylhexanoate esters that can yield 2-ethylhexanoic acid via hydrolysis. The delegate notes the advice from NICNAS and the actions by other regulators to limit the concentrations of such esters in cosmetic products that are applied directly to human skin. The issue considered by the ACCS was how to word a generic entry in Schedule 6 to capture these esters. ACCS advice was that, while 2-ethylhexanoic acid was unlikely to be used in cosmetics or other products as itself, including its alkyl esters in the entry could ensure that all the substances of concern would be captured. The exemption cut-off (5%) could then be based on the amount of 2-ethylhexanoic acid able to be released by complete hydrolysis. It is possible that a simple Schedule 6 entry for 2-ethylhexanoic acid could capture the alky esters as ‘derivatives’, consistent with guidance in Part 1 of the Poisons Standard, but the proposed wording should be clearer in its coverage and provide a consistent exemption cut-off for substances that contain 2-ethylhexanoic acid in different proportions based on molecular weights.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (c) the toxicity of the substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

Schedule entry
Schedule 6 - New Entry

2-ETHYLHEXANOIC ACID and its alkyl esters except in preparations containing 5 per cent or less calculated as 2-ethylhexanoic acid.

Appendix E, Part 2 - New Entry
Poison Standard statements
2-ethylhexanoic acid and its alkyl esters A - For advice, contact a Poisons Information Centre (e.g. phone Australia 13 1126; New Zealand 0800 764 766) or a doctor (at once).
Appendix F, Part 3 - New Entry
Poison Warning statements Safety direction
2-ethylhexanoic acid and its alkyl esters 53 - CAUTION - (Name of substance) should not be used by pregnant women.
Schedule 6, Appendix E and Appendix F - Delete Entries

2-Ethylhexyl 2-ethylhexanoate.

Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • Public submissions received;
  • ACCS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors1;
  • Other relevant information.
Public submissions on the interim decision

One submission was received. The submission did not object to the delegate's interim decision.

An edited version of the submission is available on the TGA website at: Public Submissions ACCS#13 March 2015

Delegate's final decision

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

The proposed implementation date is 1 February 2016. This is the earliest date of which the projected publication of an update to the SUSMP would allow for implementation in the State/Territory legislation.


Footnotes

  1. Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)

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