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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, July 2016

Scheduling medicines and poisons

15 September 2016

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3.2 Aminopyralid

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 amend the Schedule 5 and Schedule 6 entries for aminopyralid to include reference to the triisopropanolamine (TIPA) salt and to investigate whether an appropriate exemption cut-off is required.

Scheduling history

Aminopyralid was first considered by the National Drugs and Poisons Schedule Committee (NDPSC) in June 2005. At that time, the committee agreed aminopyralid be included in Schedule 6 of the SUSMP based on the assessment of toxicity and having regard to severe eye irritancy.

Aminopyralid was considered again in November 2013 by the Advisory Committee on Chemicals Scheduling (ACCS) following an application for rescheduling the current Schedule 6 entry for aminopyralid to provide a cut‐off to Schedule 5 at 0.5 per cent for the product. The application sought to include aminopyralid, present as the TIPA salt, in Schedule 5.

In its deliberations, the committee noted that the Office of Chemical Safety (OCS) had recently evaluated studies that were provided to support the rescheduling application for the TIPA salt, and indicated that data provided did not use 100% aminopyralid TIPA, but rather a 459.4 g/L aqueous solution of aminopyralid TIPA. The OCS, therefore, considered there was insufficient information to provide advice on a Schedule 5 entry for aminopyralid TIPA as a separate active constituent from aminopyralid to the scheduling delegate.

The ACCS agreed that there was a lack of data to support a Schedule 5 entry for aminopyralid TIPA and that the Schedule 6 entry for aminopyralid be amended to provide a cut‐off to Schedule 5 at 0.5 per cent (as in the current entries).

Current scheduling status

The current scheduling of aminopyralid is:

Schedule 6

AMINOPYRALID except when included in Schedule 5.

Schedule 5

AMINOPYRALID in water soluble gel formulations containing 0.5 per cent or less of aminopyralid.

Scheduling application

General application.

The application's proposed amendments to the SUSMP is to amend the existing entry in Schedule 5 for aminopyralid to include the TIPA salt, in concentrations equivalent to more than 5% of aminopyralid and less than 20% aminopyralid and exempt concentrations of 5% or less from the scheduling.

The applicant's reasons for the request are:

  • The current Poisons Schedule for Foragemax Herbicide is determined by the Schedule 6 listing for aminopyralid acid which is driven primarily by severe eye irritancy;
  • The other active constituent in the product, halauxifen-methyl, is included in Appendix B of the SUSMP, based on its low toxicity profile, when used as a herbicide;
  • The APVMA has indicated that the toxicology profile of aminopyralid TIPA at 40% or less (approx. 20 % aminopyralid active ingredient or less) does not appear to be consistent with the SPF factors identified for inclusion in a schedule of the SUSMP; and
  • The delegate may wish to consider either an exemption from scheduling for aminopyralid as the TIPA salt at specified concentrations equivalent to 20 % or less of aminopyralid, OR inclusion in Schedule 5 at 20% or less, with a cut-off to exempt at 5% or less of aminopyralid, to be appropriate.
Substance summary

Aminopyralid (CAS No. 150114-71-9) (Figure 3.2) belongs to the picolinic acid family of herbicides, which also includes clopyralid, picloram and triclopyr. It is a synthetic auxin and selective herbicide used for control of broadleaf weeds, woody weeds, wild tobacco trees, rhizomatous plants, wandering jew and herbaceous weeds.

Figure 3.2: Structure of aminopyralid

Figure 3.2: Structure of aminopyralid

Acute toxicity

The acute toxicity end-points for aminopyralid are listed in Table 3.2. Aminopyralid has low acute oral toxicity in rats (LD50 >5000 mg/kg bw; 1/10 died at 5000 mg/kg bw/d), low acute dermal toxicity (LD50 >5000 mg/kg bw; no deaths) and low acute inhalation toxicity (LC50 >5500 mg/m3; no deaths) in male and female rats. Aminopyralid is non-irritating to rabbit skin and non-sensitising to guinea pig skin but a severe eye irritant in rabbits. Aminopyralid is neither, a teratogen in rats or rabbits, a reproductive toxin in rats, a genotoxin, nor a carcinogen in life time studies in rats or mice. Aminopyralid was not neurotoxic in a 1 year rat study.

Table 3.2: Acute end-points for aminopyralid
Toxicity endpoint Species Results SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bw) Rats > 5000, low toxicity Appendix B
Acute dermal toxicity LD50 (mg/kg bw) Rats > 5000, low toxicity Appendix B
Acute inhalational toxicity LC50 (mg/m3/4h) Rats > 5500, low toxicity Appendix B
Skin irritation Rabbits Non-irritant Appendix B
Eye irritation Rabbits Severe eye irritant, Moderate irritation Schedule 6
Skin sensitisation (Magnusson and Kligman) Guinea Pigs Non-sensitiser Appendix B
Neurotoxicity Rats Not neurotoxic N/A
Genotoxicity Rats Not genotoxic N/A
Reproduction and developmental toxicity Rats, Rabbits Negative N/A
Carcinogenic Rats, Mice Not carcinogenic N/A
Repeat-dose toxicity

Effects on various organs were observed in oral repeat-dose studies using aminopyralid or aminopyralid TIPA. In the case of the liver, there was an increase in hepatocyte size with altered cytoplasmic staining and decreased liver glycogen at 1000 mg/kg bw/d in mice. Higher relative liver weights, associated in some cases with very slight hypertrophy of centrilobular to midzonal hepatocytes, were observed at 967 mg/kg bw/d in male dogs and at 1038 mg/kg bw/d in females. A dermal repeat-dose study found slight chronic focal inflammation of the liver in male rats at 500 mg/kg bw/d.

The caecum was affected in a number of rat studies. Increased caecum size and/or weight was observed in four studies in rats, at dose levels between 500 mg/kg bw/d and 1000 mg/kg bw/d. In two of these studies, increased caecum weights were associated with very slight hyperplasia of the caecal mucosal epithelium of the rats at 1000 mg/kg bw/d.

In dogs, effects on the stomach included a slight, diffuse hyperplasia and hypertrophy of the mucosal epithelium of the stomach at 1070 mg/kg bw/d in males and at 929 mg/kg bw/d in females. Another study found diffuse thickening of the stomach mucosa, slight diffuse mucosal hyperplasia and hypertrophy, slight chronic mucosal inflammation and slight lymphoid hyperplasia of the stomach mucosa, in male and females at 967 mg/kg bw/d and 1038 mg/kg bw/d, respectively.

No kidney pathology was observed. However there were reductions in urine pH and decreased urine protein and ketones at 1000 mg/kg bw/d in rats. In another rat study, there was increased urine volume, with decreased urine specific gravity, pH, protein and ketones at 1000 mg/kg bw/d. A study using aminopyralid TIPA found increased urine volume and decreased urine specific gravity at 1000 mg/kg bw/d in rats.

Pre-meeting public submissions

No pre-meeting submissions were received for aminopyralid.

Summary of ACCS advice to the delegate

The committee advised the following amendments to the SUSMP:

Schedule 6 - Amend Entry

AMINOPYRALID except when included in Schedule 5 in preparations containing aminopyralid triisopropanolamine (TIPA) salt equivalent to 22 per cent or less of aminopyralid.

Schedule 5 - Delete Entry

AMINOPYRALID in water soluble gel formulations containing 0.5 per cent or less of aminopyralid.

Index - Amend Entry

AMINOPYRALID

Schedule 6

Schedule 5

The committee suggested an implementation date of 1 February 2017.

Members agreed that the relevant matters under Section 52E (1) of the Therapeutic Goods Act 1989 included: (c) the toxicity of a substance.

The reasons for the advice included:

  • Aminopyralid is a severe eye irritant; and
  • Negligible eye irritation potential of the TIPA salt at 22%.
Delegate's considerations

The delegate considered the following in regards to this proposal:

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

The delegate notes the ACCS advice and reasons to amend the Schedule 6 entry to include the aminopyralid triisopropanolamine (TIPA) salt and to delete the Schedule 5 entry for aminopyralid. However, the delegate's interim decision is that the Schedule 6 entry for aminopyralid remains appropriate and that the Schedule 5 entry for aminopyralid be amended to include preparations containing 22 per cent or less of aminopyralid. While the toxicity profile of the pure chemical is consistent with the SPF factors for listing in Schedule 6, the reduction in eye irritancy associated with the diluted preparation is consistent with the SPF factors for Schedule 5. The data for aminopyralid TIPA referred to in the JMPR report and used in the APVMA HHRA has previously been evaluated by the OCS (67378/55918 (2013)). The acute toxicity studies were performed with the formulated product GF-871 (41.3%-42% TIPA, corresponding to 21.7% aminopyralid). GF-871 has low acute oral (LD50 >5000 mg/kg), dermal (LD50 >5000 mg/kg) and inhalational toxicity (LC50 >5.79 mg/L). It is a slight skin and eye irritant and is not a skin sensitiser. The data available to the committee for aminopyralid TIPA did not use 100% aminopyralid TIPA, but rather formulated products containing 0.5-45% aminopyralid TIPA. It was therefore, considered that there was a lack of data to support a Schedule 5 entry for aminopyralid TIPA as a separate active constituent from aminopyralid (as was concluded in previous deliberations by the Advisory Committee for Chemicals Scheduling in 2013).

An early implementation date of 1 February 2017 is proposed in order to bring the regulation of this ingredient in products sold in Australia into alignment with international regulations.

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

Schedule 6 - Current Entry

AMINOPYRALID except when included in Schedule 5.

Schedule 5 - Amend Entry

AMINOPYRALID in preparations containing 22 per cent or less of aminopyralid.

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