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Scheduling delegate's final decisions, June 2017

Scheduling medicines and poisons

29 June 2017

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3.1 Ethyl hexanediol

Part A - Final decisions on matters referred to an expert advisory committee

Advisory Committee on Chemicals Scheduling (ACCS #19)

3.1 Ethyl hexanediol

Referred scheduling proposal

An application was submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) to amend the scheduling of ethyl hexanediol by replacing the Schedule 10 entry with a Schedule 6 entry to allow for human use.

Scheduling application

This was a general application. The applicant's proposed amendments to the Poisons Standard are as follows:

Schedule 10 – Delete Entry

ETHYLHEXANEDIOL for human use.

Schedule 6 – New Entry

ETHYL HEXANEDIOL.

Schedule 4 – Current Entry

ETHYL HEXANEDIOL for animal use.

Appendix E, Part 2

ETHYL HEXANEDIOL

Standard statement: 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).

The applicant's reasons for the request are:

  • There are concerns about developmental toxicity for the current Schedule 10 entry for ethyl hexanediol (National Drugs and Poisons Scheduling Committee (NDPSC), 2012); however, publicly available data on reproductive toxicity indicated effects at high doses only and/or concurrent with maternal toxicity;
  • The only critical health effect identified and classified was eye irritation;
  • There are no international restrictions;
  • International sources have determined that ethyl hexanediol is a safe cosmetic ingredient (Cosmetic Ingredient Review (CIR), 2011);
  • Cosmetic and/or domestic use is considered to be limited; and
  • Structurally similar chemicals, 2-ethylhexanoic acid (and its alkyl esters) and 2-ethylhexanol (and its derivatives), have similar uses but higher potency for critical health effects. 2-Ethylhexanoic acid is in Schedule 6 with a 5% exemption cut-off and 2-ethylhexanol is currently being considered by NICNAS as to whether Schedule 6 with appropriate low-level cut-offs are required.
Current scheduling status and relevant scheduling history

Ethyl hexanediol is currently listed in Schedules 4 and 10 as follows:

Schedule 10

ETHYLHEXANEDIOL for human use.

Schedule 4

ETHYLHEXANEDIOL for animal use.

The structurally similar chemical 2-ethylhexanoic acid is in Schedule 6 and Appendices E and F as follows:

Schedule 6

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

2-ETHYLHEXANOIC ACID

Standard statements: A (For advice, contact a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor (at once)).

Appendix F, Part 3

2-ETHYLHEXANOIC ACID

Warning statements: 53 (CAUTION – (Name of substance) should not be used by pregnant women).

Prior to 1991, ethyl hexanediol was listed in Appendix B of the then SUSDP. In November 1991, the Drugs and Poisons Scheduling Sub-Committee (DPSSC) considered a request from a member to remove ethyl hexanediol from Appendix B in view of reports linking the insect repellent to teratogenic effects. The committee advised deletion from Appendix B, while establishing whether the substance is used in Australia.

From February - May 1993, the DPSSC reviewed the toxicology of ethyl hexanediol following a US EPA cancellation of registrations prohibiting sale, distribution or use of existing stocks of ethyl hexanediol., At its November 1991 meeting, the DPSSC had requested that the Chemicals Safety Unit (CSU) establish whether ethyl hexanediol was used in Australia, and if so request relevant data from sponsors in order to establish a schedule. At that meeting, the DPSSC had advised that ethyl hexanediol be deleted from Appendix B. The committee considered and created a new Appendix C entry for ethyl hexanediol, following concerns about malformations evident in rat studies, which appeared to be dose-related.

In February 2000, the National Drugs and Poisons Schedule Committee (NDPSC) considered an exemption from Appendix C for cosmetic use. The committee did not support exemption of ethyl hexanediol from Appendix C because of unacceptable risk of teratogenicity associated with the use of the substance.

In October 2006, the NDPSC included ethyl hexanediol in Schedule 4 to harmonise with New Zealand. In February 2007 the NDPSC agreed that a Schedule 4 entry for ethyl hexanediol would conflict with the then existing Appendix C (now Schedule 10) entry. The committee agreed that the Schedule 4 entry was only intended to capture animal therapeutic use, and that it remained appropriate for human therapeutic use to be captured by Appendix C. The February 2007 NDPSC Meeting confirmed that the Schedule 4 entry was intended to capture animal therapeutic use only.

The overlap between entries was considered by the NDPSC from June - October 2008. The NDPSC confirmed that the Appendix C entry for ethyl hexanediol captured all human use.

In February 2009, the NDPSC amended the Schedule 4 entry to reflect its use in animal treatment only with the addition 'for animal treatment'.

Australian regulatory information

Ethyl hexanediol is not listed on the Therapeutic Goods (Permissible Ingredients) Determination No. 1 of 2017, and a search of the Australian Register of Therapeutic Goods (ARTG) found it is neither an excipient nor active in any listed medicines.

Ethyl hexanediol is not in any currently registered products regulated by the APVMA.

International regulations

Ethyl hexanediol was listed as a hazardous substance by the EPA in New Zealand in December 2006 (HSNO Approval Code HSR003694).

Substance summary
Table 3.1A: Chemical information
Property Ethyl hexanediol

CAS name

1,3-hexanediol, 2-ethyl-

CAS number

94-96-2

Chemical structure

Chemical structure of ethyl hexanediol

IUPAC and/or common and/or other names

Ethyl hexanediol (INCI); 1,3-hexanediol, 2-ethyl- (CAS); hexanediol; octylene glycol; ethohexadiol (AAN); 2-ethylhexane-1,3-diol (IUPAC)

Molecular formula

C8H18O2

Molecular weight

146.3 g/mol

The following information was extracted from the NICNAS IMAP Human Health Tier II assessment report for ethyl hexanediol.

Table 3.1B: Acute toxicity end-points for ethyl hexanediol
Toxicity Species Result SPF (2015) Classification

Acute oral toxicity LD50 (mg/kg bw)

Rats (strain not specified)

2710-9210

Schedule 5

Acute dermal toxicity LD50 (mg/kg bw)

Rabbits (strain not specified)

8960-18700

Schedule 5

Acute inhalational toxicity LC50 (mg/m3/4h)

Rats (strain not specified)

>3800

Schedule 5

Skin irritation

New Zealand White rabbits
Guinea pigs (Strain not specified)
Swiss mice

Mildly irritating (neat chemical)

Schedule 5

Eye irritation

New Zealand White rabbits

Irritating

Schedule 6

Skin sensitisation (Mangusson and Kigman maximisation test and Kodak footpad method)

Guinea pigs (strain not specified; Hartley)

No positive reactions

N/A

Acute toxicity

Based on the available oral, dermal and inhalation data, ethyl hexanediol has low acute toxicity.

Skin irritation

Ethyl hexanediol is reported to slightly irritate skin:

  • In an acute dermal irritation/corrosion study conducted according to OECD TG 404 in New Zealand White rabbits (n = 3/sex), 0.5 mL of undiluted ethyl hexanediol was applied occlusively to clipped dorsal trunk skin for a duration of 4 h and animals were observed for 14 days. Five animals were reported to show slight local erythema (redness) and one showed well-defined local oedema (swelling). All the effects were fully reversed within 24–48 h. The study was concluded that ethyl hexanediol was slightly irritating to skin.
  • In another study, 0.5 mL of undiluted ethyl hexanediol was applied occlusively to the shaved dorsal skin of guinea pigs (n = 5), nine times over 11 days. Slight erythema (in 2/5 animals) was observed after three applications and slight to moderate erythema (in 3/5 animals) was observed by the end of the study.
  • In an acute toxicity study conducted on New Zealand White rabbits (n = 5/sex/group), undiluted ethyl hexanediol was applied once under occlusive patches to the clipped skin of the trunks for 24 h at a dose of 8, 11.3 or 16 mL/kg bw in males and 4, 8 or 16 mL/kg bw in females. The rabbits were observed for 14 days. There were signs of inflammation, redness and swelling at the dosing site. Redness and swelling reversed by day seven, but desquamation (skin peeling) was still evident at the end of the study.
  • In a lifetime study in female Swiss mice (n = 50/dose), 0.2 mL of ethyl hexanediol at concentrations of 10, 50 or 100% in acetone was applied to shaved dorsal skin, twice weekly. Minimal local inflammatory changes including moderate dermatitis were observed.
Eye irritation

Based on the available data, ethyl hexanediol is considered to cause serious eye damage:

  • In an ocular irritation study conducted in female rabbits (n = 3), 0.1 mL of undiluted ethyl hexanediol was applied into the conjunctival sac of the eyes. Clouding of the cornea, irritation of the iris and reddening and swelling of the conjunctiva were observed within one hour of administration. Effects on the cornea reversed within one week, effects on the conjunctivae reversed after 10 days, while the iris irritation remained after 21 days. Ethyl hexanediol was reported to be moderately irritating, with a Draize score of 35/110. Similar effects were reported in another two studies. No further details are available.
  • In an acute eye irritation study (similar to OECD TG 405) conducted in New Zealand White rabbits (n = 6/treatment), ethyl hexanediol was instilled into the conjunctival sac (0.1 mL) in one group and onto the cornea of the eye (0.01 or 0.005 mL) in two other groups. Animals were examined after 1 h, 24 h and 2, 3 and 7–14 days. The animals treated with 0.1 mL developed mild to severe conjunctivitis, mild to severe chemosis and mild to marked discharge. Moderate iris inflammation and moderate corneal injury were observed. Animals that were administered 0.01 or 0.005 mL had moderate to severe conjunctivitis at the 24 h observation. An overall irritation score of 80/110 was reported for the 1 h observation time point, with all effects being fully reversed within seven days.
  • In another study conducted using New Zealand White rabbits (n = 6), 0.1 mL of neat ethyl hexanediol was instilled into the conjunctival sac of one eye; the eyes of three rabbits were washed immediately after chemical instillation, whilst the eyes of the other three rabbits remained unwashed. Both groups were observed immediately and after 1, 24, 48 and 72 h and 7 and 14 days after instillation. Fluorescein staining of the eyes was undertaken 24 h after dosing. Moderate to severe erythema and oedema of the conjunctivae and nictitating membranes (inner eyelids); slight erythema and oedema of the eyelids; slight corneal opacity; and discharge were observed in the unwashed eyes at 24 h. Irritation was less severe in the rinsed eyes, with slight to moderate erythema observed in the conjunctivae and nictitating membranes of the eyes at 1 h. Signs of irritation were reduced by seven days, and fully reversed by 14 days.
Sensitization

Based on the available data, ethyl hexanediol is not expected to be a skin sensitiser.

Repeat-dose toxicity

Based on available data ethyl hexanediol is not considered to cause serious health effects from repeated oral (NOAEL of 480 mg/kg bw/day was reported in rats) or dermal exposure (NOAEL of 1884 mg/kg bw/day was determined in rats). No data are available for inhalation repeat-dose toxicity.

Genotoxicity

Based on the weight of evidence from the available in vitro and in vivo genotoxicity studies, ethyl hexanediol is not considered to be genotoxic.

Carcinogenicity

The limited available data do not indicate that ethyl hexanediol is a carcinogen.

Reproduction and developmental toxicity

Ethyl hexanediol shows specific developmental toxicity, but only at high doses.

  • In a developmental toxicity study (similar to OECD TG 414) in pregnant SD rats (n = 8/dose), ethyl hexanediol (in corn oil) was administered by gavage at 500, 1000, 2000 or 4000 mg/kg bw/d on GD 6-15. The NOAEL for maternal and developmental toxicity was reported to be 1000 mg/kg bw/d. Mortalities were reported in the dams at 2000 mg/kg bw/d (1/8) and 4000 mg/kg bw/d (7/8). At doses 32000 mg/kg bw/d, signs of weakness, respiratory difficulty, dehydration, sialorrhoea (excess salivation), gait disturbances, nasal discharge, porphyrin tears, diarrhoea, decreased volume of faeces and unkempt coats were observed in the dams. Hypothermia, partially closed eyes and excessive tearing were observed in the high dose group only. Lesions at necropsy showed that ethyl hexanediol had the greatest effect in the stomach and duodenum; there was excess mucous in the caecum and atrophy of the thymus and adipose tissue. In foetuses from the 2000 mg/kg bw/d group, the incidences of malformations significantly increased (rudimentary or filamentous tails, malformation of rear limbs and joints, shortened trunk and umbilical hernia); and there were also increases in the incidence of haematoma (nine foetuses out of four litters). Two foetuses from different litters exposed to ethyl hexanediol at 1000 mg/kg bw/d and one in the 500 mg/kg bw/d group had rudimentary tails.
  • In a developmental toxicity study (similar to OECD TG 414) in pregnant SD rats (n = 25 mated females/dose), ethyl hexanediol was dermally applied (occlusively) at 0, 1, 2 or 4 mL/kg bw/day (equivalent to 0, 935, 1870 and 3740 mg/kg bw/d) for 6 h per day on gestation days (GD) 6–15. Animals were euthanised on GD 21. The NOAEL for maternal reproductive toxicity was reported to be >3768 mg/kg bw/d based on no reported variations in the number of pregnancies, foetal body weights or reproductive factors. At the highest dose, terminal maternal body weights were decreased, and absolute liver weights were significantly increased. Mild skin irritation with exfoliation and crusting were observed in a few females at the mid and high doses. The NOAEL for developmental toxicity was reported to be 942 mg/kg bw/d based on a statistically significant but non-dose-dependent increase in the incidences of skeletal malformation (related to reduced ossification) in the foetuses from the mid and high dose groups, and visceral malformation (e.g. unilateral hydroureter) in the foetuses from the high dose groups. It was concluded that ethyl hexanediol is a weak developmental toxicant (CIR, 1994; Ballantyne, 2005; REACH). In two developmental toxicity studies (similar to OECD TG 414) in pregnant SD rats (n=8 – 25/dose), ethyl hexanediol was administered by gavage at 500, 1000, 2000 or 4000 mg/kg bw/day or occlusively 6 h/day at 0, 1, 2 or 4 mL/kg bw/day (equivalent to 0, 935, 1870 and 3740 mg/kg bw/day), on gestation days 6-15.
Observation in humans

Irritation

Slight irritation was observed in humans:

  • Mild skin irritation was seen in humans administered ethyl hexanediol under semi-occlusive and occlusive conditions for 24 h, repeated 15 times over 21 consecutive days;
  • Barely perceivable erythema was observed in 1/106 human subjects under occlusive and semi-occlusive conditions when exposed to ethyl hexanediol at 5%;
  • Barely perceivable erythema in 2/30 under semi-occlusive and 4/30 under occlusive conditions were observed immediately and 24 h after application of ethyl hexanediol at 100%. One subject had definite erythema after 72 h.

Skin sensitisation

Ethyl hexanediol was reported to be a weak skin sensitiser following a human repeated insult patch test. Undiluted ethyl hexanediol was applied occlusively for 24 h, three times per week for three weeks. They were challenged with ethyl hexanediol two weeks later, on an untreated area of skin for 24 h and observed after 24-48 h. There were two incidences of definite erythema 48 h after the challenge patch was removed. Further testing, showed that one of these subjects had a definite sensitisation response.

Public exposure

Ethyl hexanediol is reported to be used in cosmetic and/or domestic products overseas. Cosmetic use is reported to be limited overseas and domestic use is prohibited in Australia (currently listed in Schedule 10 of the SUSMP). The cosmetic use overseas is assumed to be representative of its potential use in Australia. Existing controls are such that ethyl hexanediol cannot be used in such products in Australia.

Pre-meeting public submissions

Two (2) public submissions were received. Both submissions supported the scheduling proposal. The main points were:

  • Ethyl hexanediol does not require scheduling control when in human use preparations as the only health concern is eye irritancy (developmental toxicity has been shown to no longer be an issue).
  • Scheduling of ethyl hexanediol should align with EU regulations for use in cosmetics.
  • There should be low concentration cut-offs for cosmetic and domestic use preparations. If an exemption for cosmetic use at 5% is made, then household products not intended for contact with skin should be exempted at a higher cut-off concentration. This is due to the risk of accidental eye contact being less in domestic products than cosmetics.

The public submissions will be made available on the TGA website.

Summary of ACCS advice to the delegate

The committee recommends that the current Schedule 10 and 4 entries for ethyl hexanediol be deleted and that a new Schedule 6 entry be created as follows:

Schedule 10 – Delete Entry

ETHYLHEXANEDIOL for human use.

Schedule 6 – New Entry

ETHYL HEXANEDIOL except in preparations containing 5 per cent or less of ethyl hexanediol.

Schedule 4 – Delete Entry

ETHYL HEXANEDIOL for animal use.

The committee recommended Appendix E/F entries be created as follows:

Appendix E, Part 2 – New Entry

ETHYL HEXANEDIOL

  • Standard statements: A (For advice, contact a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor (at once)), 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

ETHYL HEXANEDIOL

Warning Statements: 79 (will irritate eyes).

Safety directions: 1 (avoid contact with eyes).

The committee also advised an implementation date of 1 October 2017.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the advice comprised the following:

  • The substance is used as an ingredient in cosmetic and domestic products internationally, and down-scheduling will allow for this use in Australia.
  • It is likely to be in imported products or used in Australia for such purposes if re-scheduled.
  • Ethyl hexanediol causes serious eye damage and poses a risk to public health if certain controls are not in place.
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal
  • ACCS advice
  • Public Submissions received
  • Section 52E of the Therapeutic Goods Act 1989
  • Scheduling Policy Framework (SPF 2015)
  • Other relevant information
Delegate's interim decision

The delegate's interim decision is that the current Schedule 10 and 4 entries for ethyl hexanediol be deleted and that a new Schedule 6 entry be created. The proposed Schedule entry is as follows:

Schedule 10 – Delete Entry

Schedule 6 – New Entry

ETHYL HEXANEDIOL except in preparations containing 5 per cent or less of ethyl hexanediol.

Schedule 4 – Delete Entry

Appendix E, Part 2 – New Entry

ETHYL HEXANEDIOL

Standard statements: A (For advice, contact a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor (at once)), 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

ETHYL HEXANEDIOL

Warning Statements: 79 (will irritate eyes).
Safety directions: 1 (avoid contact with eyes).

The proposed implementation date is 1 October 2017, as this is the earliest possible implementation date.

The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of 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.

The reasons for the interim decision are the following:

  • The delegate acknowledges the committee's advice.
  • The substance is used as an ingredient in cosmetic and domestic products internationally, and down-scheduling will allow for this use in Australia.
  • It is likely to be in imported products or used in Australia for such purposes if re-scheduled.
  • Ethyl hexanediol causes serious eye damage and poses a risk to public health if certain controls are not in place.
Public submissions on the interim decision

One (1) submission was received that opposed the delegate's interim decision. The main points were:

  • Although the maximum concentration of 5% as stated in the interim decision is in alignment with the US CIR recommendation, there are no restrictions on the use of ethyl hexanediol in cosmetics in the EU, NZ or ASEAN;
  • The Schedule 6 entry should be limited to cosmetic preparations as ethyl hexanediol is not restricted for use in non-cosmetic products anywhere else in the world;
  • The concentration cut-off to exempt from scheduling of 5% is considered too low for products that are not intended for skin contact as accidental eye exposure is unlikely;
  • Ethyl hexanediol does not require scheduling control when in human use preparations as the only health concern is eye irritancy (developmental toxicity has been shown to no longer be an issue); and
  • Salts and derivatives should be specifically excluded due to difficulty in interpreting which substances are meant to be captured by the Poisons Standard entry (no examples of inappropriately captured substances were given).
Delegate's final decision

The delegate notes the submission, however as ethyl hexanediol is to be down-scheduled from Schedule 10, it is inappropriate that all uses except for cosmetic use are exempt from scheduling. This may be reconsidered if new data is provided to the delegate and committee. Furthermore, due to the chemical structure of ethyl hexanediol, and the presence of hydroxy groups within the structure, salts and derivatives should be captured by this entry.

The delegate has confirmed that the final decision and reasons for the final decision are in keeping with those for the interim decision.

The delegate's final decision is that the current Schedule 10 and 4 entries for ethyl hexanediol be deleted and that a new Schedule 6 entry be created. The implementation date is 1 October 2017.

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