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Publication of interim decisions proposing to amend, or not amend, the current Poisons Standard, September 2018

Scheduling medicines and poisons

10 September 2018

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2.1 2-Butoxyethanol

2. Joint Advisory Committee on Medicines and Chemicals Scheduling (Joint ACMS-ACCS #19)

Delegate's interim decision

The delegate's interim decision under regulation 42ZCZN of the Therapeutic Goods Regulations 1990 (the Regulations) is to amend the current Poisons Standard in relation to 2-butoxyethanol as follows:

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Schedule 6 - Amend Entry

2-BUTOXYETHANOL and its ACETATES except:

  1. in plant growth regulator preparations containing 20 percent or less of such substances; or
  2. in other preparations containing 10 percent or less of such substances.

Proposed implementation date: 1 February 2019

Reasons

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate for the decision include:

  1. the risks and benefits of the use of a substance:
    • Benefits:
      • 2-Butoxyethanol is a useful solvent in a range of applications, including agricultural and domestic products, medicines and cosmetics.
    • Risks:
      • The most sensitive toxicological end point is the destruction of red blood cells (haemolysis). Additional toxicities include neurotoxicity (loss of coordination, sluggishness and narcosis) and nephrotoxicity.
      • 2-butoxyethanol has low to moderate acute toxicity via oral, dermal and inhalation routes, and severe skin and eye irritancy.
  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • 2-Butoxyethanol is used as a solvent in a range of applications.
    • 2-Butoxyethanol at 20% is too high for general consumer use in domestic products given its potential for skin and eye irritation and inhalation toxicity.
  3. the toxicity of a substance:
    • 2-butoxyethanol has adverse effects on the CNS (e.g. loss of coordination, sluggishness and narcosis).
    • 2-Butoxyethanol has haemolytic effects. Studies suggest that rats are more susceptible to haemolytic effects than humans and that rats exposed to 2-butoxyethanol develop tolerance and show reduced haemolytic effects over time, or on future exposure.
    • 2-Butoxyethanol is readily absorbed via all routes of exposure (inhalation, dermal, ingestion) with low to moderate acute toxicity via oral, dermal and inhalation routes.
    • 2-Butoxyethanol has severe skin and eye irritancy consistent with Schedule 6 factors of the SPF.
    • Respiratory irritant consistent with Schedule 6 factors of the SPF.
    • In-vitro studies show no mutagenicity or genotoxicity.
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • Toxicity of 2-butoxyethanol is mitigated when formulated as a plant grown regulator, allowing a higher percentage cut off.
    • Although the inhalation and skin and eye irritation data of a 20% 2-butoxyethanol preparation aligns with the Schedule 5 SPF factors, mandatory GHS labelling of plant growth regulator preparations as regulated by the APVMA should be sufficient.

Delegate's considerations

The delegate considered the following in regards to this interim decision:

  • The application to amend the current Poisons Standard with respect to 2-butoxyethanol;
  • The advice received from the Joint Advisory Committees on Medicines and Chemicals Scheduling (Joint ACMS-ACCS #19);
  • The Australian Health Ministers' Advisory Council's Scheduling Policy Framework (SPF 2018); and
  • Section 52E of the Therapeutic Goods Act 1989, in particular (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.

Scheduling proposal

The pre-meeting scheduling proposal was published on the TGA website on 12 April 2018 at Consultation: Proposed amendments to the Poisons Standard being referred to the June 2018 meetings of the ACCS, ACMS and Joint ACCS/ACMS.

Background information for 2-butoxyethanol

Delegate's referral to ACCS/ACMS

An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to amend the Poisons Standard with respect to 2-butoxyethanol. The application proposes to amend the Schedule 6 entry for 2-butoxyethanol in the Poisons Standard to increase the exemption concentration from 10 per cent to 20 per cent.

Applicant's scheduling proposal and reasons

The application proposed the following amendments to the Poisons Standard:

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Deleted text is shown as red, smaller font, with a strikethrough.

Schedule 6 - Amend Entry

2-BUTOXYETHANOL and its ACETATES except in preparations containing 1020 per cent or less of such substances.

The applicant's reasons for the proposal were:

  • The APVMA recently evaluated acute toxicity data for a product containing approximately 20% 2-butoxyethanol (final concentration was 175 g/L). The formulated product had low toxicity via the oral, dermal and inhalation routes of exposure as follows:
    • Oral LD50 in rats was 3129 mg/kg;
    • Dermal LD50 in rats was >5000 mg/kg; and
    • Inhalation LC50 in rats was >2120 mg/m3 (nose-only; maximum attainable concentration).
  • The primary eye irritation study with the formulated product revealed slight irritation that resolved completely by 48 hours following administration of the test material.
  • The primary skin irritation study with the formulated product revealed slight irritation that resolved completely by 72 hours following administration of the test material.
  • The first aid instructions in the Poisons Standard (Appendix E, Standard Statements A, E2 and S1) for 2-butoxyethanol are inconsistent with the eye and skin irritation.

Current scheduling status

2-Butoxyethanol is in Schedule 6, Appendix E and Appendix F of the Poisons Standard as follows:

Schedule 6

2-BUTOXYETHANOL and its ACETATES except in preparations containing 10 per cent or less of such substances.

Appendix E, Part 2

2-BUTOXYETHANOL and its acetates

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

Appendix F, Part 3

2-BUTOXYETHANOL and its acetates

Safety Directions: 1 (Avoid contact with eyes), 4 (Avoid contact with skin), 8 (Avoid breathing dust (or) vapour (or) spray mist).

Scheduling history

August 1995 meeting of the National Drugs and Poisons Schedule Committee (NDPSC)

In August 1995, the NDPSC considered a proposal to either exempt 2-butoxyethanol from scheduling or create a separate entry for 2-butoxyethanol in Schedule 5. At this time, 2-butoxyethanol was captured by the generic entry in Schedule 6 for ethylene glycol monoalkyl ethers and their acetates except those containing 10% or less. The committee considered that the acute toxicological profile, particularly in regard to eye and skin irritancy and the ready absorption by the dermal route, indicated that Schedule 6 remained appropriate for this compound and did not support the proposal for rescheduling.

August 1998 meeting of the National Drugs and Poisons Schedule Committee (NDPSC)

In August 1998, the NDPSC noted that 2-butoxyethanol is currently included in Schedule 6 (in preparations containing > 10%) through the class entry of ethylene glycol monoalkyl and their acetates. However, the committee agreed to create a new separate entry in Schedule 6 for 2-butoxyethanol and its acetates with an exception for preparations containing 10 per cent or less. It was agreed that Schedule 6 was appropriate due to the formulation, handling and use of cleaning products containing 2-butoxyethanol which may give rise to a risk of adverse health effects and that 2-butoxyethanol is considered acutely more toxic that most glycol ethers. The Schedule 6 entry for ethylene glycol monoalkyl ethers and their acetates was also amended at this time to add the exception 'when separately specified in these Schedules'.

November 2014 meeting of the Advisory Committee on Chemicals Scheduling (ACCS #12)

In November 2014, the ACCS considered a proposal to create separate entries for a number of ethylene glycol monoalkyl ethers and their acetates, including 2-butoxyethanol. The National Industrial Chemicals Notification and Assessment Scheme (NICNAS) Inventory Multi-tiered Assessment and Prioritisation (IMAP) programme had reviewed a number of chemicals in this class and recommended that separate entries be created for selected chemicals (see Human health tier II assessment for Ethanol, 2-butoxy acetate). The advice from the ACCS was that the toxicity profile of 2-butoxyethanol is consistent with Schedule 6 criteria and that it was adequately captured by the current generic entry for ethylene glycol monoalkyl ethers and their acetates, and the specific 2-butoxyethanol and its acetates Schedule 6 entry. Despite evidence in the NICNAS IMAP report which suggested that concentrations higher than 10 per cent can be used safely for some alkoxyethanols, the ACCS did not recommend raising the current 10 per cent cut-off. The delegate accepted the ACCS advice that the current scheduling of 2-butoxyethanol remained appropriate.

Scheduling history of ethylene glycol monoalkyl ethers and their acetates

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

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

In November 2013, based on the ACCS advice, the delegate created a separate schedule entry for hexyloxyethanol with a cut-off level to exempt from scheduling for preparations containing 10 per cent of less of hexyloxyethanol. The delegate also decided to create new Appendices E, F and I entries specifically for hexyloxyethanol. The delegate's decision was based on the fact that hexyloxyethanol's toxicity profile was different from the chemical class ethylene glycol monoalkyl ethers.

Australian regulations

2-Butoxyethanol is listed on the Australian Inventory of Chemical Substances (AICS). An assessment of its uses in cleaning products was completed in 1996. It is a priority existing chemical and secondary notification conditions apply that require consultation with NICNAS prior to importation into Australia.

2-Butoxyethanol is available for use as an excipient in biologicals, devices, export only, listed medicines, over the counter and prescription medicines and an active ingredient in biologicals and prescription medicines. Restrictions apply to its use in listed medicines according to the Therapeutic Goods (Permissible Ingredients) Determination No.2 of 2018:

Column 1

Column 2

Ingredient Name

Column 3

Purpose of the ingredient in the medicine

Column 4

Specific requirement(s) applying to the ingredient in Column 2

968 BUTOXYETHANOL E

Only for use in topical medicines for dermal application and not to be included in medicines intended for use in the eye.

The concentration in the medicine must be no more than 0.1%.

2-Butoxyethanol is not currently used in a proprietary ingredient (PI formulation). Butoxyethanol is an excipient ingredient in 5 products on the Australian Register of Therapeutic Goods (ARTG). Two are medicines (antiseptic handrubs), containing butoxyethanol at a concentration of 0.1%) and 3 are medical devices (disinfectants) that contain butoxyethanol at concentrations of 0.25-9 % w/w.

International regulations

Canada

Canada completed its assessment of 2-butoxyethanol in 2002 and as a result developed regulations to limit its concentration in a variety of consumer products intended for indoor use: 2-Butoxyethanol Regulations (SOR/2006-347).

United States

2-Butoxyethanol appears in the Appendix A to section 1926.55-1970 American Conference of Governmental Industrial Hygienist's threshold limit values of airborne contaminants of the Electronic Code of Federal Regulations as follows:

Substance CAS No. ppm mg/m3 Skin Designation
2-Butoxyethanol 111-76-2 50 240 X
European Union

Butoxyethanol in is Annex III to Regulation (EC) No 1223/2009 and is permitted for use as a solvent in oxidative hair dye products at 4% and in non-oxidative hair dye products at 2%. Butoxyethanol is not permitted for use in aerosol dispenser (sprays).

Substance summary

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2-Butoxyethanol is very widely used in industrial, trade and domestic cleaning applications. Common formulations which include 2-butoxyethanol are surface cleaners, floor strippers, paints, laundry detergents, rust removers, oven and carpet cleaners. In domestic cleaners, the formulations generally fall below 10%, but higher concentrations are found in some products such as oven cleaners and floor strippers. Some industrial cleaners contain greater than 90% 2-butoxyethanol. 2-Butoxyethanol is also used in medicines and medical devices currently registered on the ARTG.

The source of the below information on the toxicological profile for 2-butoxyethanol is from the Concise International Chemical Assessment (CICAD), Document 10 (pdf,164kb).

Table 2.1A: Chemical information for 2-butoxyethanol
Property 2-Butoxyethanol
CAS number 111-76-2
IUPAC and/or common and/or other names Ethylene glycol mono-n-butyl ether; butyl cellosolve; 2-butoxy-1-ethanol; 2-n-butoxyethanol; butyl glycol; butyl monoether glycol
Chemical structure Chemical structure of 2-butoxyethanol
Molecular formula C6H14O2
Molecular weight 118.2 g/mol
Table 2.1B: Acute toxicity end-points for 2-butoxyethanol
Toxicity Species 2-butoxyethanol SPF (2018) Classification
Acute oral toxicity LD50 (mg/kg) Rat 2500 mg/kg 5
Mouse 1400 mg/kg 6
Guinea pig 1200 mg/kg 6
Rabbit 320 mg/kg 6
Acute dermal toxicity LD50 (mg/kg) Guinea pig 2000 mg/kg 5/6
Rabbit 404-502 mg/kg 6
Acute inhalational toxicity LC50 (mg/m3/4h) Rat (male, 4h) 2347 mg/m3 6
Rat (female, 4h) 2174 mg/m3 6
Mouse (7h) 3381 mg/m3 5
Guinea pig (1h) 3140 mg/m3 5
Skin irritation Rabbit Severe irritant 6
Eye irritation Rabbit Severe irritant 6
Skin sensitisation Guinea pig Non-sensitiser -
Acute toxicity

2-Butoxyethanol is moderately toxic via the oral and dermal routes of exposure and it is of low toxicity via the inhalation route of exposure.

Skin irritation

When tested undiluted, 2-butoxyethanol is a severe skin irritant.

Eye irritation

When tested undiluted, 2-butoxyethanol is a severe eye irritant (CICAD 1998). A study conducted in 1989 tested a series of 2-butoxyethanol concentrations (10, 20, 30, 70 and 100%) for eye irritation. The results showed that 100% was severely irritating, at 30 and 70%, 2-butoxyethanol was moderately irritating, and at 10 and 20%, 2-butoxyethanol was reported in the study as mildly irritating. However, the Draize scores indicate that at those concentrations, it is practically non-irritating (scores of 1/110 and 2/110 at 10% and 20%, respectively) (Kennah et al., 1989).

Sensitization

2-butoxyethanol is not considered to be a skin sensitiser.

Repeat-dose toxicity

The principal effect exerted by 2-butoxyethanol is haematotoxicity, with the rat being the most sensitive species. The results of in vitro studies indicate that human red blood cells are not as sensitive as rat red blood cells to the haemolytic effects of 2-butoxyethanol and 2-butoxyacetic acid and also that red blood cells are more sensitive to haemolysis by 2-butoxyacetic acid than to haemolysis by 2-butoxyethanol. In rats, adverse effects on the central nervous system, kidneys, and liver occur at higher exposure concentrations than do haemolytic effects.

Genotoxicity

2-Butoxyethanol is not considered to be genotoxic.

Carcinogenicity

2-Butoxyethanol is not classified with respect to carcinogenicity. No studies are available.

Reproduction and developmental toxicity

In animals, adverse effects on reproduction and fetal development have not been observed below maternally toxic doses.

Observation in humans

Based on limited data from case reports and one laboratory study, similar acute effects, including haemolytic and CNS effects are observed in humans and rats exposed to 2-butoxyethanol, although the effects are observed at much higher exposure concentrations in humans than in rats.

Pre-meeting public submissions

No public submissions were received before the first closing date in response to an invitation published on 12 April 2018 under regulation 42ZCZK of the Regulations.

Joint ACMS-ACCS advice

The committee recommended that the Schedule 6 entry for 2-butoxyethanol in the Poisons Standard be amended as follows:

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New text is shown as green, larger font, with a horizontal line above it.

Schedule 6 - Amend Entry

2-BUTOXYETHANOL and its ACETATES except:

  1. in plant growth regulator preparations containing 20 percent or less of such substances; or
  2. in other preparations containing 10 percent or less of such substances.

The committee also recommended an implementation date of 1 February 2019.

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 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 included:

  1. the risks and benefits of the use of a substance:
    • Benefits: 2-Butoxyethanol is a useful solvent in a range of applications.
    • Risk: 2-Butoxyethanol has haemolytic and Central Nervous System (CNS) effects, low to moderate acute toxicity via oral, dermal and inhalation routes, and severe skin and eye irritancy.
  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • 2-Butoxyethanol is used as a solvent in a range of applications.
  3. the toxicity of a substance:
    • 2-Butoxyethanol has haemolytic and Central Nervous System (CNS) effects, low to moderate acute toxicity via oral, dermal and inhalation routes, and severe skin and eye irritancy.
    • Exposed test subjects (rats) developed tolerance to 2-butoxyethanol (haemolytic effects).
    • Skin and eye irritation consistent with Schedule 6.
    • Respiratory irritant consistent with Schedule 6.
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • Toxicity of 2-butoxyethanol is mitigated when formulated as a plant grown regulator, allowing a higher percentage cut off.

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