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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, March 2016
Scheduling medicines and poisons
Part A - Interim decisions on scheduling proposals referred to an advisory committee (March 2016)
1. Advisory Committee on Chemicals Scheduling (ACCS#16)
Referred scheduling proposal
- To delete the current Schedule 5 entry and create a new entry in Appendix B.
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.
Specific issues/questions raised by the delegate
The Delegate's reasons for referring this to the Committee were as follows: While the toxicological profile of propamocarb is reasonably straightforward, and could be considered for a scheduling decision to be made by the delegate, ACCS advice is sought on whether the newly submitted data is sufficient to justify deletion of propamocarb from Schedule 5, and listing in Appendix B.
The Delegate sought advice from the Committee on the following questions:
- Does the ACCS support the proposal that propamocarb has sufficiently low toxicity that it does not meet any of the SPF criteria for scheduling and, consequently, that its current listing in Schedule 5 could be deleted?
Figure 8. Structure of propamocarb (HCl salt)
The acute toxicity end-points for propamocarb are listed in the below table.
|Acute oral toxicity LD50 (mg/kg bw)||SD Rat||> 2000||Low toxicity|
|Wistar Rat||> 5000|
|Acute dermal toxicity LD50 (mg/kg bw)||Rat||> 5000||Low toxicity|
|Acute inhalational toxicity LC50 (mg/m3/4h)||Rat||5540||Low toxicity|
|Skin sensitisation (LLNA and maximisation)||Guinea pig||Sensitiser||Sensitiser|
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
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.
Propamocarb was not genotoxic in the battery of in vivo and in vitro genotoxicity studies.
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.
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.
Not explored by the APVMA in this report. Propamocarb is been registered for use in the USA and European Union.
Current scheduling status
Propamocarb is currently listed in Schedule 5.
Relevant 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.
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.
The delegate considered the following in regards to this proposal:
- Scheduling proposal;
- APVMA Human Health Risk Assessment Report;
- 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.