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Scheduling delegate's final decisions, June 2016

Scheduling of medicines and poisons

23 June 2016

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1.11 Nonanoic acid

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

1. Scheduling proposals referred to the March 2016 meeting of the Advisory Committee on Chemicals Scheduling (ACCS#16)

1.11 Nonanoic acid

Referred Delegate's scheduling proposal
  • To create a new Schedule 5 entry for the use of NONANOIC ACID in agricultural preparations with a proposed exemption concentration cut-off at 3%.
Applicant's application and scheduling proposal

In December 2015 the APVMA referred the following proposal to be considered by the delegate:

  • A proposal to create a new entry for nonanoic acid (NNA) in Schedule 5 with a 5% cut-off.

The reasons for the request were:

  • NNA has low systemic toxicity and is not corrosive. The acute oral and dermal toxicity (rat) is greater than 2000 mg/kg. Acute inhalation LC50 (rat) is more than 3000 mg/m3 (4 h).
  • The human clinical data for skin irritation indicates reversible moderate irritation. Eye irritation is slight to moderate and NNA is not classifiable as a skin sensitiser. The eye irritation is considered reversible although corneal opacity has been reported in some older studies.
  • NNA did not cause marked organ toxicity in repeat dose toxicity studies, but caused gastrointestinal irritation. It is unlikely to produce significant toxicity (organ damage, respiratory sensitisation, mutagenicity, carcinogenicity, reproductive toxicity).
  • The evaluation considered whether the eye irritation observed and the uncertainty in the data available was sufficient to classify NNA as an irreversible eye irritant (Schedule 6). Recent studies for octanoic acid and decanoic acid (in vivo eye irritation GLP test according to OECD TG 403 and a Bovine Corneal Opacity and Permeability (BCOP) test respectively) showed evidence for reversible eye irritation. On this basis Schedule 5 was recommended.
  • A low level cut-off of 5% is also proposed for the schedule 5 listing given that the endpoint is a local effect. A threshold for moderate irritation (i.e. the threshold for GHS hazard classification is greater than 10%). At approximately 10% mild irritation is expected and at 3% very slight irritation has been noted in clinical patch tests. A threshold for slight to moderate irritation is interpolated as 5%.

The evaluation also considered that other medium chain fatty acids and their derivatives are not listed as scheduled poisons.

Substance summary

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Please refer to publically available reports on the NICNAS website for nonanoic acid.

Figure 10. Structure of nonanoic acid
Figure 10. Structure of nonanoic acid

Nonanoic acid (NNA; also frequently referred to as pelargonic acid) is a naturally occurring carboxylic acid with a carbon chain-length of nine, belonging to the chemical class saturated fatty acids commonly referred to as medium chain fatty acids (C8 to C12).

It is a clear, colourless liquid with a weak odour. NNA is soluble in aqueous solution however it can readily form esters and partially dissociate into the pelargonate anion (CH3(CH2)7COO-) and the hydronium cation (H3O+) in an aqueous solution (NICNAS IMAP, 2015). The molecular weight (158.24 g/mol) and octanol-water partition coefficient (3.4 logPow) of NNA suggest that dermal penetration is possible.

Oral, dermal or inhalation absorption studies are not available. The default of 100% is assumed for oral, dermal and inhalation absorption. NNA has low systemic toxicity and is not corrosive. The acute oral and dermal toxicity (rat) is greater than 2000 mg/kg. Acute inhalation median lethal concentration (LC50)(rat) is more than 3000 mg/m3 (4 h).

The human clinical data for skin irritation indicates reversible moderate irritation. Eye irritation is slight to moderate and nonanoic acid is not classifiable as a skin sensitiser. The eye irritation is considered reversible although corneal opacity has been reported in some older rabbit studies. NNA did not cause marked organ toxicity in repeat dose toxicity studies. It did cause gastrointestinal irritation. It is unlikely to produce significant toxicity (organ damage, respiratory sensitisation, mutagenicity, carcinogenicity, reproductive toxicity).

For occupational margin of exposure assessment the selected no observed adverse effect level (NOAEL) is from a 28-day oral study in male and female Wistar rats. NNA was administered by gavage at doses of 0, 50, 150 or 1000 mg/kg bw/d in concentrations of 1, 3 or 20% in propylene glycol as a vehicle. Treatment related effects were minimal except for gastrointestinal irritation. An irregular surface of the forestomach was noted in all high dose animals. In this dose group, histopathological examination showed slight to marked hyperplasia of the squamous epithelium of the forestomach. These latter effects were also noticed in 2 from 10 animals of the mid-dose group but these were considered to be without any toxicological relevance since they were minimal and occurred in the absence of (other) functional or morphological disturbances or clinical signs. Therefore a local oral (i.e. for gastric effect) NOAEL of 150 mg/kg bw/d was established (ECHA 2013). The ECHA did not establish a systemic NOAEL.

Given the effects are local and not systemic for home garden assessments the potential for skin and eye contact and the magnitude of skin and eye irritation should be the focus. The threshold for slight to moderate skin irritation is between 3 and 10% w/w NNA. At 10% skin irritation is transient and mild.

For occupational margin of exposure assessment the selected NOAEL is from a 28-day oral study in Wistar rats (ECHA 2013). A local irritation effect was noted, with an oral NOAEL of 150 mg/kg bw/d; general systemic toxicity was not observed. The NOAEL is based on slight to marked hyperplasia of the squamous epithelium of the forestomach, a local irritant effect rather than a systemic effect. In this case the presence or absence of skin and eye irritation is the primary considerations for the home garden health risk assessment but also for occupational risk assessment.

Based on skin and eye irritation the evaluation proposes that NNA be included in Schedule 5 of the SUSMP with a cut off of 3%.

Hazard characterisation summary

The following table summarises the toxicological information for nonanoic acid.

Study type Species / Test System Result Reference
Acute Oral Toxicity Wistar rat, Crl:(WI) BR (outbred, SPFQuality), 3/sex/dose LD50 >2000 mg/kg bw ECHA 2013
Acute Dermal Toxicity Wistar rat, Crl:(WI) BR (outbred, SPFQuality), 5/sex/dose LD50 >2000 mg/kg bw ECHA 2013
Acute Inhalation Toxicity Details not provided in summary LC50 (4 h) >5.3 mg/L ECHA 2013
Skin irritation Human and Rabbits (NZW) Irritating ECHA 2013
Eye irritation Human experience and Rabbits (NZW) Irritating ECHA 2013a, b, c
Skin sensitisation Albino Guinea pigs, Dunkin Hartley strain (SPF-quality), 10 females per test item group. Maximisation test. No evidence of sensitisation ECHA 2013
Respiratory sensitisation No information No evidence of sensitisation ECHA 2013
Carcinogenicity Non-standard dermal carcinogenicity study No evidence for carcinogenicity ECHA 2013
Mutagenicity – Genetic toxicity Bacterial gene mutation test, mammalian in vitro chromosomal aberration test and in vivo mouse micronucleus assay No evidence for genotoxicity or mutagenicity ECHA 2013
Toxicity to reproduction – fertility

47 week Rat, McCollum-Wisconsin. A casein diet, containing 18.5% medium chain triglyceride (MCT)

The MCT contained about 51% octanoic acid and 35% decanoic acid resulting in an octanoic acid dietary dose of about 4700 mg/kg bw/d and a decanoic acid dietary dose of about 3200 mg/kg bw/d.

No concern for reproductive toxicity.

Overall LOEL of ≥ 8000 mg/kg bw d

ECHA 2013
Toxicity to reproduction - development
Toxicity to reproduction - breastfed babies. Effects on or via lactation
Specific Target Organ Toxicity - Repeat Dose 28 day study with Wistar rat, Crl:(WI) BR (outbred, SPF-Quality), 5 males and 5 females per dose group

NOAEL - 150 mg/kg bw/d

Based on the observation of macroscopic irregular surface of the forestomach (hyperplasia of the squamous epithelium) at 1000 mg/kg bw/d

ECHA 2013
Public exposure

The technical report notes that NNA was listed on the 2007 OECD list of high production volume chemicals, meaning that the chemical was produced or imported levels greater than 1,000 tonnes per year in at least one member country/region (OECD 2007).

The principal uses for NNA are in cosmetics and conventional pesticides. NNA is used in cosmetics for skin-conditioning, fragrance, surfactant-cleansing, and surfactant-emulsifying (Johnson et al., 2011). It is an active ingredient of antimicrobial agents (e.g. surface sanitiser), blossom thinners (formulations that decrease flower load and improve fruit yields), biopesticides and conventional pesticides registered with the US Environmental Protection Agency (US EPA) (US EPA, 2010, US EPA, 2000). The US EPA-registered products contain NNA in the range 0.96-57%. It is also used in lacquers, plastics, lubricants, metalworking fluids, photographic plate development and in the manufacture of plastics and pharmaceuticals (US EPA, 2010). In Australia NNA has reported domestic use as a surface-active agent (NICNAS IMAP, 2015).

Fatty acids are a significant part of a person's normal daily diet with NNA being naturally present in fruits, vegetables, dairy products, meat and grains at levels ranging from 0.2 - 400 mg/kg (Marin Water, 2010). Natural levels of NNA include 1.4 mg/kg in dried mushrooms, 0.03-0.04 mg/kg in beer, and 2.5-20.5 mg/kg in coffee (Council of Europe, 2000).

International regulations

The APVMA report notes that no known Australian or international restrictions were identified in their review or by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS IMAP, 2015).

The FDA has approved NNA for use as a direct food additive under the synthetic flavouring substances and adjuvants category at the minimum quantity required to produce their intended effect (21CFR172, 2015), and as an indirect additive as a surface sterilant on food-processing equipment and utensils and dairy-processing equipment (21CFR178, 2015), at the amount reasonably required to accomplish its intended physical, nutritive, or other technical effect in food. FDA approval has also been reported for use in cosmetics, shampoos and other personal care products and in transdermal drug delivery systems (US EPA, 2010).

It was also noted the primary metabolite of NNA is azelaic acid, which is approved by the Therapeutic Goods Administration as an over the counter acne treatment.

Current scheduling status

Nonanoic acid is not specifically scheduled.

Scheduling history

Nonanoic acid has not been previously considered for scheduling; therefore, scheduling history is not available.

Pre-meeting public submissions

Two public submissions were received. The first submission did not support the scheduling proposal. It was claimed that at the concentration of the ready-to-use product, the pH was sufficiently low to not require scheduling. A cut off concentration of 4% was suggested. The second submission did not support the proposal. They noted the substance is listed in the ARTG ingredient list and may have a use as an excipient in fragrances. Therefore, they request that the ACCS considers exemption for the use of the substance as an excipient in therapeutic goods, with a suitable cut off concentration if appropriate.

The public submissions are available at the Public submissions on scheduling matters.

Summary of ACCS advice to the delegate

In response to the Delegate's request, the Committee have advised that the irritant properties of the substance meet the criteria for inclusion in Schedule 6 rather than Schedule 5. In relation to the Delegate's questions, the Committee noted the broad use pattern of NNA and given its irritancy, the schedule entry should not be restricted to agricultural uses only to capture other areas of potential public exposure.

The Committee advised that a 10% cut off for the substance was appropriate, below which the substance would not be scheduled. This cut off concentration was considered appropriate to avoid capturing its use in food additives and cosmetics.

The Committee recommended use of the IUPAC name of nonanoic acid for scheduling, and the following amendments to the Poisons Standard:

Schedule 6 - New Entry

NONANOIC ACID except in preparations containing 10 per cent or less of nonanoic acid.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: c) The substance has severe eye irritation potential that meet Schedule 6 criteria; f) The committee considered the eye irritancy/damage of the substance warranted schedule 6 entry. It was noted currently available products (non-agricultural) would be below 10%.

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 factors11;
  • Other relevant information.
Delegate's interim decision

Nonanoic acid was referred by the APVMA for consideration of scheduling because if its use as an adjuvant in AgVet products. This substance is a naturally occurring fatty acid and it may also be used as a food additive and in therapeutic goods. As such, it represents a challenge to devise a scheduling proposal that provides appropriate controls over uses where suitable warning statements are necessary, while exempting uses where such controls are inappropriate.

The delegate notes the advice from the ACCS, that a new Schedule 6 entry be created for nonanoic acid, with a cut-off to exempt in preparations containing 10% or less. The advice for a primary listing in Schedule 6 is based primarily on the potential for severe eye damage associated with exposure to this fatty acid, while most of the other toxicological criteria are consistent with SPF criteria for listing in Schedule 5. The delegate notes comments made by the ACCS that the evaluation of the eye irritancy studies presented lacked rigour and that there is some uncertainty about the severity and reversibility of the lesions associated with concentrated solutions of the acid. The delegate also notes submissions from industry, suggesting the lack of concern for dilute preparations and that the ACCS did not recommend any entries in Appendices E or F, to provide for any First Aid or label Warning Statements for products that would be captured by the schedule listing.

The delegate has decided to create a primary listing for nonanoic acid (the preferred IUPAC name) in Schedule 5, with an exemption for products containing 10% or less. There is sufficient evidence that, at concentrations below 10%, that should cover most uses and natural occurrences of nonanoic acid in products available to the public, the risks of eye damage are sufficiently ameliorated to warrant scheduling controls unnecessary.

The proposed implementation date is 1 February 2017. While an early implementation date would facilitate registration of new products by the APVMA, there is some doubt as to whether any existing products regulated by the APVMA could be affected and require re-labelling. Accordingly, an intermediate implementation date is proposed.

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

Schedule5 - New Entry

NONANOIC ACID except in preparations containing 10 per cent or less of nonanoic acid.

The delegate has determined that listing in Schedule 5 is more consistent with SPF criteria and provides adequate controls for any preparations in current use that would contain more than 10% of nonanoic acid.

Public submissions on the interim decision

No 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 final decision and reasons are in keeping with those for the interim decision.

The implementation date is 1 February 2017.


Footnote

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

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