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Scheduling delegate's final decisions, June 2016

Scheduling of medicines and poisons

23 June 2016

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1.9 Propamocarb

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)

1.9 Propamocarb

Referred Delegate's scheduling proposal
  • To delete the current Schedule 5 entry and create a new entry in Appendix B.
Applicant's application and scheduling proposal

In December 2015, the Australian Pesticides and Veterinary Medicines Authority (APVMA) referred the following proposal to be considered by the delegate:

  • A proposal to reschedule propamocarb and remove it from Schedule 5 to be included in Appendix B.

The reasons for the request are:

  • Propamocarb has low acute oral, dermal and inhalational toxicity;
  • Propamocarb is not irritant to eyes or skin, but is a mild skin sensitiser;
  • Propamocarb is not a teratogen, genotoxin or carcinogen;
  • It belongs to the carbamate class of chemicals. However, unlike some other carbamates, acetylcholinesterase inhibition by propamocarb is seen only at very high dose levels, which are not achievable through dermal absorption and therefore this is considered not relevant to human risk assessment; and
  • Decreased sperm count and motility observed in reproductive study were seen at dose levels which are unlikely to be achieved through dermal absorption or by inhalation in humans when the product is used in accordance with directions.

New data provided by the applicant includes:

  • Acute toxicity studies;
  • Skin irritation and sensitisation and eye irritation studies;
  • Repeated dose toxicity studies in rats, rabbits and dogs;
  • Reproduction and developmental toxicity studies in rats and rabbits;
  • A comprehensive data package on in vivo and in vitro genotoxicity studies; and
  • Neurotoxicity studies.

The majority of these studies were conducted after the ADI for propamocarb was set in 1987. The analysis of these new data supports the removal of propamocarb from Schedule 5 to an Appendix B listing in the Poisons Standard.

Substance summary

Figure 8. Structure of propamocarb (HCl salt)
Figure 8. Structure of propamocarb (HCl salt)

Acute toxicity

The acute toxicity end-points for propamocarb are listed in the below table.

Toxicity Species Result SPF* Classification
Acute oral toxicity LD50 (mg/kg bw)

SD Rat

Wistar Rat

> 2000

> 5000

Low toxicity
Acute dermal toxicity LD50 (mg/kg bw) Rat > 5000 Low toxicity
Acute inhalational toxicity LC50 (mg/m3/4h) Rat 5540 Low toxicity
Skin irritation Rat Non-irritant Non-irritant
Eye irritation Rabbit Non-irritant Non-irritant
Skin sensitisation (LLNA and maximisation) Guinea pig Sensitiser Sensitiser

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

Repeat-dose toxicity

In the short-term toxicity studies, the critical effect was vacuolation of the choroid plexus in the brain and other tissues/glands, which was observed in a 28-day mouse dietary study at 172 mg/kg bw/d. The relevant short-term toxicity NOEL was set at the next lowest dose at 100 mg/kg bw/d.

In the sub-chronic toxicity studies, the critical effects observed were consistent with the effects found in the short-term studies. In rats reduced body weight gain and vacuolar changes in the choroid plexus and the lacrimal glands were observed. In dog dietary studies, wide spread vacuolation in secretary glands was observed and the sub-chronic NOEL was set at 131 mg/kg bw/d.

Consistent with the critical effects found in short-term and sub-chronic toxicity studies, vacuolation of multiple tissues was observed in 52-week dog dietary study. While vacuolation was seen at every dose level, there was a dose-related response in the severity of vacuolation. The NOEL for chronic toxicity was 39 mg/kg bw/d.

Genotoxicity

Propamocarb was not genotoxic in the battery of in vivo and in vitro genotoxicity studies.

Carcinogenicity

Propamocarb was not carcinogenic.

Reproduction and developmental toxicity

In the 2-generation reproductive toxicity study in rats, female survival was decreased in both generations, female fertility index was slightly lowered and in males, a decreased sperm motility and count was observed at the highest dose level tested (1000 mg/kg bw/d). Consistent with the findings in other rat toxicity studies, vacuolation of tissues was also observed at the higher dose levels. The NOEL for parental toxicity was set at 50 mg/kg bw/d. The NOEL of 200 mg/kg bw/d was set for pup development based on decreased pup viability at the highest dose. The overall NOEL for reproduction toxicity was set at 200 mg/kg bw/d based on the adverse effects on sperm parameters.

Propamocarb was not a teratogen in the tested animals. In rats, a reduced body weight gain and increased mortality of dams were the basis for a NOEL of 680 mg/kg bw/d for maternal toxicity. The NOEL for foetal toxicity was set at 204 mg/kg bw/d based on slightly increased number in foetal deaths and retarded ossification.

Neurotoxicity

Propamocarb was not acutely neurotoxic. In a sub-chronic study a vacuolation of choroid plexus in the ventricles of cerebrum and cerebellum was observed but these studies did not show any functional deficits in the tested animals and therefore the biological significance of vacuolation is unknown.

International regulations

Not explored by the APVMA in this report. Propamocarb is been registered for use in the USA and European Union.

Public exposure

No information was provided.

Current scheduling status

Propamocarb is currently listed in Schedule 5.

Scheduling history

Propamocarb has been considered for scheduling in May 1979 and July 1987. In the 1979 meeting the committee noted the limited toxicological data that were available but agreed to include the substance in Schedule 5 for the proposed, limited use (soil fungicide in ornamental plants).

In the 1987 meeting the committee considered additional studies and noted the low acute toxicity of the substance, that it was slightly irritating to the eye (rabbit) but non-irritating to the skin (rabbit). It did not cause skin sensitization (guinea pig), showed negative genotoxic, carcinogenic or teratogenic potential but was embryotoxic at maternotoxic doses. A schedule 5 entry was deemed appropriate.

Pre-meeting public submissions

No public submissions were received.

Summary of ACCS advice to the delegate

In response to the Delegate's questions the Committee advised that it was appropriate to retain the current listing for propamocarb in Schedule 5 due to concerns with the neurotoxicity in dogs and skin sensitisation potential, and therefore an Appendix B entry was not supported.

The committee advised that the current scheduling of propamocarb remains appropriate.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: c) toxicity of the substance: Acute oral toxicity (effects in dogs), skin sensitisation.

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 factors9;
  • Other relevant information.
Delegate's interim decision

The delegate notes, and accepts, ACCS advice that the current listing of propamocarb in Schedule 5 remains appropriate. The extension of the toxicological database provided in newly submitted studies confirms the relatively low toxicity of this fungicide, but the findings of slight skin sensitisation, neurotoxicity and lethality observed with acute oral dosing in dogs, and vacuolations observed in the brain and other tissues in chronic and repeat-dosing studies, albeit observed only at quite high dosing rates, nevertheless suggest that retaining the current listing in Schedule 5 is suitably precautionary.

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

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.


Footnote

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

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