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Scheduling delegate's final decisions, March 2016
Scheduling medicines and poisons
Part A - Final decisions on matters referred to an expert advisory committee
1. Scheduling proposals referred to the November 2015 meeting of the Advisory Committee on Chemicals Scheduling (ACCS#15)
The chemicals scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS):
- In September 2015, the Office of Chemical Safety (OCS), based on an application made to the Australian Pesticides and Veterinary Medicines Authority (APVMA) to approve a new active constituent, recommends that the Delegate consider creating a new entry for topramezone in Schedule 6 of the SUSMP.
The reasons for the request were:
- The applicant submitted a data package seeking approval of the new active constituent topramezone, an inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase (4 HPPD), the second enzyme in the tyrosine catabolic pathway. As a new chemical for AgVet use, it will require consideration by the Delegate/ACCS for SUSMP listing prior to final registration of products containing this active constituent.
- There is currently no proposed product attached to this application however, there are indications that topramezone will be incorporated into herbicidal products to be used on food-producing crops (EFSA, 2014).
Specific issues/questions raised by the delegate
The delegate asked the committee the following questions:
- The delegate notes that much of the toxicity profile of topramezone (acute toxicity, skin/eye irritancy and sensitisation potential) is consistent with listing in Schedule 5 or exempt from scheduling. However, the OCS recommendation for listing in Schedule 6 is based primarily on findings of a low incidence of developmental toxicity in a rabbit study, in the absence of any apparent maternal toxicity. Does the ACCS support this as a basis for listing in Schedule 6?
- The OCS evaluation of the observed thyroid carcinogenicity and corneal opacities in rats suggests that these findings are not of significance for scheduling purposes. Does the ACCS agree with this evaluation?
To what extent is the toxicity of topramezone consistent with that of other HPPD inhibitors (e.g. mesotrione - listed in Schedule 5 in 2011)?
Figure 1. Chemical structure of topramezone (BAS 670 H)
The acute toxicity end-points for topramezone are listed in the below table.
|Acute oral toxicity LD50 (mg/kg bw)||Wistar Rat||>2000 (no deaths)||Appendix B|
|Acute dermal toxicity LD50 (mg/kg bw)||Wistar Rat||>2000 (no deaths)||Appendix B|
|Acute inhalational toxicity LC50 (mg/m3/4h)||Wistar Rat||>5050 (no deaths)||Appendix B|
|Skin irritation||NZW rabbit||Slight irritant||Schedule 5|
|Eye irritation||NZW rabbit||Slight irritant||Schedule 5|
|Skin sensitisation (GPMT)||Guinea pig||Non-sensitising||Appendix B|
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
For full summaries and discussion of other endpoints, please see the OCS evaluation report for topramezone. An abridged overview is included below.
In repeat-dose toxicity studies, the rat appeared to be the most sensitive species, with the thyroid gland (increased incidence and/or severity of flaky colloid, follicular cell hypertrophy and follicular cell hyperplasia), pancreas (diffuse degeneration) and eyes (corneal opacity) as target organs for toxicity in this species, but not mice or dogs. Increased kidney and/or liver weights, generally in the absence of histopathological lesions, was evident in mice and/or dogs. Serum chemistry (all species) and urinalysis findings (rats and dogs; not assessed in mice) consistent with the pharmacological action of topramezone (4-HPPD inhibition) included elevated serum tyrosine levels and increased urinary ketone levels. While reversibility of effects was not always assessed, the nature of the toxicity findings indicates reversibility is possible. Overall, the repeat-dose toxicity profile of topramezone is very similar to other 4-HPPD inhibitors, such as mesotrione.
There was no evidence of a mutagenic/genotoxic potential of topramezone in vitro with and without metabolic activation, or a genotoxic potential in vivo.
There was no evidence of a carcinogenic potential in an 18-month carcinogenicity study in mice by dietary administration up to and including the highest dose tested of 1903/2467 mg/kg bw/day (8000 ppm) for males/females, respectively.
In a rat dietary oral carcinogenicity study, an increased incidence of thyroid gland tumours (follicular cell adenoma and carcinoma; both sexes) with an increased incidence of follicular cell hyperplasia was observed in females only. The Mode of Action data did indicate that topramezone treatment causes a perturbation of thyroid-pituitary hormone homeostasis, which is a potentially underlying cause for thyroid tumour formation in rats. Thyroid tumours in rodents that occur as a result of alterations to thyroid hormone levels are generally not considered to be relevant to human subjects. Therefore, topramezone is unlikely to pose a carcinogenic risk to human subjects.
Reproductive and developmental toxicity potential
Fertility was unaffected in mice and rats in three and two generation reproduction studies, respectively.
Topramezone crossed the placenta in rabbits and elevated foetal serum levels of tyrosine were observed. There were no adverse embryofoetal developmental effects observed in mice. Similar foetal skeletal variations (delayed ossification and supernumerary ribs and/or vertebrae) were seen in rats and rabbits. These variations occurred in the absence of maternotoxicity and are considered to be secondary to the pharmacological effects of topramezone. Similar foetal skeletal effects were observed with other 4-HPPD inhibitors, such as mesotrione. These effects alone were not considered sufficient to warrant labelling of mesotrione as a developmental toxicant.
However, in both rats and rabbits, topramezone appeared to have adverse effects on kidney genesis and development in foetuses/pups following maternal exposure. Foetuses lacking a kidney/ureter were seen in developmental studies with rabbits, while F1 pups adults and with renal pelvic dilation (a malformation) were seen in a reproductive study in rats; kidney anatomical maturation occurs postnatally in rodents.
The data from two species (rats and rabbits) suggests topramezone treatment has an irreversible effect on the developing kidney. Irreversible foetal kidney lesions have not been reported in developmental/reproductive studies with other 4-HPPD inhibitors. With the available data, this effect cannot be ruled out as not being relevant to humans. Unlike other members of the 4-HPPD inhibitor class, topramezone should be considered as a developmental toxicant.
Other toxicology endpoints
No evidence of neurotoxicity was seen in an acute and repeat dose developmental neurotoxicity study.
Topramezone was not investigated for immunotoxic potential.
Observation in humans
No information was provided.
At this time, no agricultural use product containing topramezone has been proposed.
Topramezone as an active constituent as well as a SC herbicidal product containing topramezone have been approved/registered by the US EPA (2005, conditional approval), EFSA (2014) and Health Canada (2006, as a temporary approval).
Topramezone is not specifically scheduled.
Topramezone has not been previously considered for scheduling; therefore, scheduling history is not available.
Pre-meeting public submissions
One public submission was received. The submission was a comment on the OCS Technical Report. The submission refers to the dilated renal pelvis findings stating that these occur at maternal toxic concentrations and should be considered a variation, rather than a malformation, and are secondary to tyrosinemia. The dilated renal pelvis findings are proposed not to be human-relevant and should not be used for the derivation of reference values. The NOAEL from the developmental rabbit studies should be used instead.
The public submission is available at Public submissions on scheduling matters.
ACCS advice to the delegate
The committee recommended that a new Schedule 5 entry be created for topramezone as follows:
Schedule 5 - New Entry
The Committee recommended an implementation date of 1 June 2016.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance.
The reasons for the recommendations comprised of the following:
- active constituent for use in AgVet chemicals
- the toxicological profile of topramezone fit that of other HDDP inhibitors
- inconsistent findings on developmental effects in kidneys and maternotoxicity were observed in the animal studies but the skeletal findings should constitute a hazard
- the substance meets the criteria for inclusion in Schedule 5
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 factors15;
- Other relevant information.
Delegate's interim decision
The delegate notes, and accepts, ACCS advice that topramezone be listed in Schedule 5, with no cut-off to exempt at this time in light of there being no product information. The delegate agrees that the overall toxicological profile of topramezone is consistent with SPF criteria for listing in Schedule 5. The equivocal nature of the foetal developmental effects, including the apparently flat dose-response relationship and their possible relationship to the elevated tyrosine levels associated with treatment with this HPPD inhibitor, were considered insufficient to require listing in Schedule 6.
The earliest practicable implementation of the scheduling decision will facilitate approval of the substance by the APVMA.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: c) the toxicity of the substance.
Schedule 5 - New Entry
Public submissions on the interim decision
No public 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 reasons for the final decision are in keeping with those for the interim decision.
Schedule 5 - New Entry
The proposed implementation date is 1 June 2016.