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Scheduling delegate's final decisions, July 2016

Scheduling medicines and poisons

27 October 2016

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3.1 Geraniol and related compounds

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

3. Scheduling proposals referred to the July 2016 meeting of the Joint Advisory Committees on Chemicals and Medicines Scheduling (ACCS/ACMS#13)

3.1 Geraniol and related compounds

Note

  • Red strikethrough text indicates text that has been deleted.
  • Green italicised text indicates text that has been added.
Referred scheduling proposal

An application was submitted to create a new Schedule 5 or Schedule 6 entry for geraniol and related compounds and to investigate whether an appropriate exemption cut-off is required.

Scheduling history

Geraniol has not been previously considered for scheduling; therefore no scheduling history is available.

Other restrictions for use
Geraniol

Geraniol is a permissible excipient ingredient under subsection 26BB(1) of the Therapeutic Goods Act 1989 when in topical medicines for dermal application.

This group of chemicals includes geraniol, nerol and citrol. Geraniol (not to be confused with geranial) and nerol are trans and cis isomers respectively of 3,7-dimethyl-2,6-octadien-1-ol. Citrol (not to be confused with citral) is a 1:1 mixture of geraniol and nerol. They are grouped together here because of their similarity of end use and chemical structures.

The current usage of geraniol and related compound in Australia, outside of cosmetics and OTC medicines, is unclear. Overseas however, these compounds are used as fragrances in cosmetic, domestic, commercial and non-commercial products, including pharmaceuticals. Some restrictions apply to these products.

In EU and New Zealand the use of geraniol and related compounds in cosmetics requires label declaration for levels >0.001% in leave-on products and >0.01% in rinse-off products. In toys, geraniol and related compounds is permitted in EU when 'technically unavoidable' up to 100 mg/kg. In Australia, geraniol is listed as a permitted excipient for topical products for dermal application under the Therapeutic Goods Act and a number of complementary medicines that contain it are listed in the ARTG. In USA, geraniol and nerol are listed as safe for human consumption.

Geranial

Geranial (an oxidised form of geraniol) and related compounds were considered for scheduling by a joint meeting of the ACCS and ACMS in July 2014. At that meeting, the committee advised that cosmetic and household cleaning preparations containing more than 5% of citral be listed in Schedule 5.

The delegates' final decision on geranial was to create a new Schedule 5 entry as follows:

3,7-DIMETHYL-2,6-OCTADIENAL and its isomers in cosmetic and household cleaning preparations except in preparations containing 5 per cent or less of 3,7-DIMETHYL-2,6-OCTADIENAL isomers.

Other relevant considerations
Public exposure

Although the extent of use in cosmetic and domestic products in Australia is not well known, geraniol is contained within formulations of cosmetic and domestic products (at unspecified concentrations in aerosol/pump spray, liquid, cream and gel personal care products).

The main route of exposure for these products is through skin and eye contact.

Geraniol is listed on the following:

  • EU Cosmetics Regulation 1223/2009 Annex III - List of substances which cosmetic products must not contain except subject to the restrictions laid down. 'The presence of the substance must be indicated in the list of ingredients referred to in Article 19(1)g when its concentration exceeds:
    • 0.001% in leave-on products; and
    • 0.01% in rinse-off products.
  • New Zealand Cosmetic Products Group Standard - Schedule 5: Components cosmetic products Must not contain except subject to the restrictions listed above.
  • Directive 2009/48/EC of the European parliament and of the Council on the safety of toys - Annex II lists allergenic fragrances toys shall not contain, stating 'however, the presence of traces of these fragrances shall be allowed provided that such presence is technically unavoidable under good manufacturing practice and does not exceed 100 mg/kg.
Scheduling application

General application.

The applicant's proposed amendments to the SUSMP are as follows:

Schedule 6 - New Entry

GERANIOL AND RELATED COMPOUNDS.

The applicant's reasons for the request are:

  • Currently, there are no restrictions on introducing or using these chemicals in Australia. In the absence of any regulatory controls, the characterised critical health effects (particularly skin and eye irritation and skin sensitisation) have the potential to pose an unreasonable risk if used in cosmetic products. Whilst domestic use of the chemicals will result in lower levels of exposure, there is sufficient uncertainty regarding the safety of such products to warrant some restriction;
  • Although use in cosmetic and/or domestic products in Australia is not known, the chemicals are reported to be used (at unspecified concentrations) in cosmetic and/or domestic products overseas, such as perfumes, hair conditioners and colourants that could result in exposure of the general population;
  • The presence of the chemicals in essential oils, the use of which is not subject to existing controls;
  • Geraniol, has a labelling restriction under international jurisdictions European Union (EU) Cosmetics Regulation 1223/2009 Annex III - List of substances which cosmetic products must not contain except subject to the restrictions laid down;
  • The chemicals have been shown to cause local effects (skin and eye irritation and particularly skin sensitisation) which may occur following exposure to the chemicals;
  • Exemptions to scheduling might be applicable at low concentrations;
  • Acute oral and dermal toxicity - LD50 >2000 (for geraniol and nerol);
  • No information on inhalational toxicity. It is a moderate skin irritant in rabbits and a severe irritant in humans. It is a severe eye irritant in rabbits. It is a skin sensitizer in mice (LLNA); and
  • Repeat dose toxicity is likely to be associated with local effects (corrosion/irritation). It is not considered to be genotoxic. No data on carcinogenicity. Not considered to be specific reproductive or developmental toxins.
Substance summary

Please refer to the publically available NICNAS IMAP Human Health Tier II group assessment report for geraniol and related compounds.

Grouping rationale

The chemicals in this group (geraniol and related compounds) are the (E)- (geraniol, Figure 3.1A) and (Z)- (nerol, Figure 3.1B) isomers of 3,7-dimethyl-2,6-octadien-1-ol (other names include: i) 2,6-octadien-1-ol, 3,7-dimethyl-; ii) 3,7-dimethyl-2,6,-octadienol and iii) citrol. Citrol (CAS No. 624-15-7) is an approximate 50:50 mixture of the two isomers. The chemicals have been grouped due to their related end-uses and their close chemical relationship based on:

  • Structural similarity, where orientation of the substituents differs only around the double bond at C2; and
  • Similarity of the physico-chemical properties including melting points, boiling points and water solubility.

Figure 3.1: Geraniol (CAS No. 106-24-1) (A) and nerol (CAS No. 106-25-2) (B)

Figure 3.1: Geraniol (CAS No. 106-24-1) (A) and nerol (CAS No. 106-25-2) (B)

Acute toxicity

The acute toxicity endpoints for these chemicals are listed in Table 3.1. Briefly, geraniol and nerol have low oral (LD50 >2000 mg/kg bw) and dermal toxicity (LD50 >2000 mg/kg bw). Based on the available animal data for geraniol and nerol and observations in humans, the chemicals in this group are considered to be moderate to severe skin irritants, severe eye irritants and skin sensitisers (LLNA, EC = 11.4-23%). Geraniol and nerol are not considered to be genotoxic nor a reproductive or developmental toxin. No animal toxicity data are available on the carcinogenicity of the chemicals in this group; however the chemicals in this group present no alerts for mutagenicity or carcinogenicity based on molecular structure as profiled by the OECD Quantitative Structure-Activity Relationship (QSAR) Toolbox v3.2.

Table 3.1: Acute toxicity end-points for geraniol and related compounds
Toxicity Species Geraniol and nerol SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bw) N/A > 2000 (for geraniol and nerol) Schedule 5
Acute dermal toxicity LD50 (mg/kg bw) N/A > 2000 (for geraniol and nerol) Appendix B or Schedule 5
Acute inhalational toxicity LC50 (mg/m3/4h) N/A No data N/A
Skin irritation Rabbit Moderate irritant (geraniol of 90.7 % purity and nerol of unspecified purity) Schedule 5
Humans Severe irritant (conc. 32%) (geraniol of unspecified purity), occlusive patch test (see below) Schedule 6
Eye irritation Rabbit Severe irritant (geraniol and nerol of unspecified purity); irreversible symptoms evident after 7 days post-treatment in all animals Schedule 6
Skin sensitisation (LLNA) Mice Moderate sensitiser with (EC = 11.4-23%) (geraniol of 98.5 % purity and nerol of unspecified purity) Schedule 6
Genotoxicity Various Not genotoxic*
Carcinogenicity -

No animal data

Not considered to be carcinogenic based on QSAR*

Reproduction and developmental toxicity Rats Nerol is negative*; limited data available for other chemicals

* See the NICNAS IMAP Human Health Tier II group assessment report for geraniol and related compounds for more information.

Skin irritation
  • Geraniol was applied (0.2 mL) in a closed patch test conducted on the upper outer arm of 25 subjects (male and female) between the ages of 18 and 65 years old over four hours (at 15 and 30 minute intervals and also after 1, 2, 3 and 4 hours). Reactions were assessed at 24, 48 and 72 hours after patch removal. Dermal exposure to the substance in humans resulted in irritant effects in 2 out of 25 subjects.
  • In another test, 0.05 g of a solution containing 32 % geraniol was applied to the back of each subject for 48 hours. The reactions were read 30 minutes after patch removal and if necessary at 72, 96 and 120 hours after patch removal. The substance was determined to be a severe irritant at 32 % concentration and given an irritation score of 3.
Eye irritation

Based on the available animal data for geraniol and nerol, the chemicals in this group are considered to be severe eye irritants.

  • In an acute eye irritation and corrosion study, 0.1 mL of geraniol (purity unspecified) was instilled into the eyes of four female Specific Pathogen Free (SPF) white rabbits which were observed for 21 days (at 1, 24, 48 and 72-hours as well as after 7, 14 and 21 days). Well defined signs of eye irritation reported 24 hours after exposure included corneal opacity, iris lesion, swelling and crimson red colouration of the conjunctivae. No Draize scores were available. Irreversible symptoms in two out of the four animals were reported after the 21 day observation period.
  • In a similar study, 0.1 mL of undiluted nerol was instilled into the eyes of six female New Zealand White rabbits and observed for a period of 7 days (at 24, 48 and 72-hour intervals and then after 4 and 7 days). Nerol was reported to be irritating to the eyes of rabbits, with Draize scores for days 1, 2, 3, 4 and 7 of 31, 21, 15, 5 and 1 (out of a maximum score of 110), respectively. Irreversible effects were reported after the seven day observation period.
Skin sensitisation

Based on the available animal data for geraniol and nerol, the chemicals in this group are considered to be skin sensitisers.

  • In a study (OECD TG 429), geraniol (98.5 % purity) was reported to be positive for skin sensitisation in a mouse local lymph node assay (LLNA). Female CBA mice (4/dose) were administered daily applications of 2.5 %, 5 %, 10 %, 25 % or 50 % (w/v) of geraniol in ethanol:diethyl phthalate (ratio of 1:3) for three consecutive days. Stimulation indices of 1.7, 2.4, 2.8, 4.8 and 6.0 were reported, respectively. The estimated concentration needed to produce a three-fold increase in lymphocyte proliferation (EC3) was reported to be 11.4 %.
  • In an additional skin sensitisation study using geraniol (purity unspecified), positive results for skin sensitisation in a CBA mouse LLNA were reported. Mice (3/dose) were administered daily applications of 0 %, 12.5 %, 25 % (w/v) of geraniol in acetone:olive oil (4:1 v/v) for three consecutive days (after being pre-exposed with 50 % of geraniol). No stimulation indices or EC3 values were provided. However, increases of lymph node cell proliferation and lymph node weights were reported at the highest dose.
  • Positive results for skin sensitisation were reported for nerol (98.5 % purity) in a mouse local lymph node assay (LLNA). Female CBA/J mice (4/dose) were administered daily applications of 5 %, 10 %, 25 %, 50 % and 100% (w/v) of nerol in acetone/olive oil (4/1; v/v) to the dorsal surface of both ears for three consecutive days. Stimulation indices of 1.10, 1.77, 3.16, 5.12 and 2.47 were reported, respectively. The EC3 value was reported to be 23 %.
  • There are limited human data available for the chemicals in this group. Geraniol was reported to cause skin sensitisation in 1 out of 35 subjects (13 male, 22 female) in a human patch test study (where 8 subjects had previous history of eczematous skin and 12 subjects had cosmetic sensitivity). Subjects were dermally exposed under occlusive conditions to geraniol at 5 % over a 48 hour period. Reactions were recorded at 48 and 96 hours post-exposure. However, it was reported that the positive subject had previous signs of eczematous skin (redness, itching and inflammation).
Repeat-dose toxicity

Based on the available animal data for geraniol, repeated oral exposure to the chemicals in this group is not expected to cause adverse systemic toxic effects, but repeated dermal exposure with local effects have been noted.

No information was available for repeated dose toxicity by inhalation route.

Pre-meeting public submissions

One (1) public submission was received that opposed the scheduling on the basis that all companies comply with the International Fragrance Association standard of 0.3-8.6% geraniol, depending on usage. However, if scheduling is deemed necessary, the submission suggests a reverse scheduling entry to include geraniol (excluding salts and derivatives) in Schedule 6 for leave-on products containing >0.0001% and rinse-off products containing >0.001% unless the products are listed on the label. They also request a long lead time to permit label changes.

The public submission is available on the TGA website.

Summary of Joint ACMS/ACCS advice to the delegates

The committee advised that a new Schedule 6 entry for geraniol and its isomers be created in the SUSMP as follows:

Schedule 6 - New Entry

3,7-DIMETHYL-2,6-OCTADIEN-1-OL and its isomers except in products containing 5 per cent or less 3,7-dimethyl-2,6-octadien-1-ol and its isomers.

The committee advised that a cross reference to geraniol, nerol and citrol be created as follow:

3,7-DIMETHYL-2,6-OCTADIEN-1-OL

cross reference: GERANIOL, NEROL, CITROL

Schedule 6

The committee advised Appendix E and F entries be created as follows:

Appendix E - 3,7-DIMETHYL-2,6-OCTADIEN-1-OL

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), E1 (if in eyes wash out immediately with water), S1 (if skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water).

Appendix F - 3,7-DIMETHYL-2,6-OCTADIEN-1-OL

Warning Statement: 5 (irritant).

Safety Directions: 1 (avoid contact with eyes), 4 (avoid contact with skin).

To allow sufficient time for implementation the committee advised an implementation date of 1 June 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 extent of use; and (c) the toxicity of a substance.

The reasons for the advice included:

  • Geraniol and nerol are moderate skin irritants and severe eye irritants (consistent with Schedule 6 criteria). Furthermore, there is a risk of skin sensitisation at concentrations greater than 5 per cent;
  • There are currently no restrictions on the use of geraniol and related compounds in Australia; and
  • Overseas these substances are used in consumer products including cosmetics and household cleaning products. There is the potential for skin and eye contact with these types of products. The extent of use in Australia is not known.
Delegates' considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • ACCS/ACMS advice;
  • Public submissions received;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling Policy Framework (SPF 2015); and
  • Other relevant information.
Delegates' interim decision

The delegates note and accept the ACMS-ACCS advice to create a new Schedule 6 entry for 3,7-dimethyl-2,6-octadien-1-ol and its isomers with a cross reference to geraniol, nerol and citrol in the index. The skin and eye irritation data for geraniol and nerol (moderate skin irritant and severe eye irritant) are consistent with the SPF criteria for Schedule 6. Furthermore, there is a risk of skin sensitisation at concentrations greater than 5 per cent. Whilst the extent of use of geraniol and related compounds is not known in Australia, internationally these substances are common in cosmetics and household cleaning consumer products. With products such as these, there is potential for skin and eye contact.

The proposed implementation date is 1 June 2017. A later implementation date is proposed, in line with the request included in the submission from industry, to allow sufficient time for implementation.

The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (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; and (c) the toxicity of a substance.

Schedule 6 - New Entry

3,7-DIMETHYL-2,6-OCTADIEN-1-OL and its isomers except in products containing 5 per cent or less 3,7-dimethyl-2,6-octadien-1-ol and its isomers.

Index - New Entry

3,7-DIMETHYL-2,6-OCTADIEN-1-OL

cross reference: GERANIOL, NEROL, CITROL

Schedule 6

Appendix E, Part 2

Appendix F, Part 3

Appendix E - 3,7-DIMETHYL-2,6-OCTADIEN-1-OL

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)], E1 (if in eyes wash out immediately with water), S1 (if skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water).

Appendix F - 3,7-DIMETHYL-2,6-OCTADIEN-1-OL Warning statement: 5 (irritant).

Safety directions: 1 (avoid contact with eyes), 4 (avoid contact with skin).

Public submissions on the interim decision

One (1) public submission was received that opposed the interim decision on the basis that the scheduling decision should be in line with the IFRA Standard determined by Quantitative Risk Assessment. The main points were related to adverse reactions and consistency with the Poisons Standard and with comparable EU and US regulations. A longer implementation timeframe was proposed.

Delegates' final decision

The delegates note the submission; however as no new evidence has been received to alter the interim decision, the delegates have confirmed that the final decision and reasons for the final decision are in keeping with those for the interim decision.

The implementation date is 1 October 2017.

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