2.1. Carbetamide

2 Interim decisions on proposed amendments referred to the Advisory Committee on Chemicals Scheduling (ACCS #7, March 2020)

2.1. Interim decision in relation to carbetamide

Interim decision

Pursuant to regulation 42ZCZN of the Regulations, a Delegate of the Secretary has, in relation to the proposed amendment, made an interim decision to amend the current Poisons Standard in relation to carbetamide as follows:

Proposed date of effect of the proposed amendment

1 October 2020

Reasons for the interim decision (including findings on material questions of fact)

In making this interim decision, the Delegate considered the following material:

• The application to amend the current Poisons Standard with respect to carbetamide;
• Advisory Committee on Chemicals Scheduling's advice;
• Section 52E of the Therapeutic Goods Act 1989, in particular (a) the risks and benefits of the use of a substance; (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;
• Scheduling handbook: Guidance for amending the Poisons Standard; and
• Scheduling Policy Framework (SPF 2018).

Pre-meeting public submissions

In response to the notice published under regulation 42ZCZK advising of the proposed amendment no public submissions were received.

Summary of ACCS advice/recommendations to the Delegate

The Advisory Committee on Chemicals Scheduling recommended that the scheduling of carbetamide be rescheduled from Appendix B to Schedule 6 in the Poisons Standard as follows:

The reasons for the advice included:

1. risks and benefits of the use of a substance
   • Benefits
     • Herbicide used for human and animal food production.
2. the purpose for which a substance is to be used and the extent of use
   • Carbetamide is a herbicide for grass weed control used at the time of sowing or immediately post-sowing.
   • The product is intended only for professional use, and will not be available to the general public.
   • No uses in the home garden are proposed.
   • Intended for use as a pre-emergent herbicide for weed grass control.
3. the toxicity of a substance
   • Low acute toxicity but moderate risk of producing irreversible toxicity.
   • Non-genotoxic carcinogen.
   • Category 1B developmental toxicant (according to Annex III inventory of ECHA) - may damage unborn child, toxic to aquatic life with long lasting effects, is harmful if swallowed and suspected of causing cancer.
   • Dose related carcinogenicity and reproductive toxicity at high animal test doses.
4. the dosage, formulation, labelling, packaging and presentation of a substance
   • NIL
5. the potential for abuse of a substance
   • NIL
6. any other matters that the Secretary considers necessary to protect public health
   • APVMA has controls in place over environmental concerns regarding toxicity.

Reasons for the interim decision

I agree with the Committee's finding that the relevant provisions of section 52E of the Therapeutic Goods Act 1989 are (a) the risks and benefits of the use of a substance; (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.

In my view, the relevant parts of the SPF 2018 are the Scheduling Factors for Schedule 6 and Schedule 7 and the considerations for inclusion of a substance in Appendix B.

I have made a decision to amend the entry of carbetamide in the Poisons Standard, removing it from Appendix B and adding it to Schedule 6. In making my decision, I have taken into consideration new toxicological data that identifies hazards related to carcinogenicity and developmental toxicity that are consistent with its inclusion in Schedule 6.

Carbetamide is an approved active constituent available for use as an agricultural and veterinary (Agvet) chemical. The substance was included under Appendix B, Part 3 of the Poisons Standard in August 1991 as it did not meet the factors for inclusion in the Schedules based on the information available at that time. While there are currently no registered products containing carbetamide in Australia, the re-scheduling proposal has been submitted in support of a new herbicide product being assessed by the APVMA. Information presented with this current application supports that carbetamide presents a moderate to high health hazard, inconsistent with its current Appendix B entry.

I gave consideration to inclusion of carbetamide in Schedule 7 based on the adverse effects observed in carcinogenicity and developmental toxicity studies. Inclusion in Schedule 7 requires that a substance has high to extremely high toxicity and presents a severe hazard from repeated use that would result in a significant risk of producing irreversible toxicity. While the data were limited, both the European Chemicals Agency (ECHA) and the European Food Safety Authority (EFSA) have determined that carbetamide should be regarded as possibly carcinogenic and a potential developmental toxicant in humans. Concordant with these findings and that of the risk assessment undertaken by the applicant (APVMA), I agree with the Committee that these adverse effects occurred at high animal test doses and do not warrant a Schedule 7 listing. In coming to this conclusion, I have noted that:

• Carbetamide has been tested in a range of in vitro and in vivo genotoxicity assays, and found overall to be non-genotoxic.
• In the carcinogenicity studies in rats and mice, there were positive tumour responses in various tissues with an increased incidence of neoplastic lesions in both species. Several rare tumours were observed, including carcinomas, which occurred in different tissues (brain astrocytoma, liver cholangiocarcinoma and adrenal phaeochromocytoma). The tumour incidences were all above the available historical control ranges. However, there was neither an effect on morbidity or mortality relative to concurrent controls nor was there any difference in tumour latency. The observation of rare tumours was restricted to high dose animals, and in the case of astrocytoma it was only observed among female rats. Moreover, carbetamide is considered to be a non-genotoxic carcinogen.
• In the 2-generation study in rats, no adverse effects on fertility or reproductive parameters were observed. In developmental toxicity studies in rats and rabbits, skeletal and visceral abnormalities (severe in the rat), delayed ossifications and post-implantations losses were observed at doses associated with minimal maternal toxicity e.g. slight reduction in material body weight gain. The maternal and developmental no-observed-adverse-effect-levels (NOAELs) in rat and rabbit were 450 and 40 mg/kg bw/day, respectively. These developmental effects were seen only at doses higher than those producing other effects noted in both short and long-term studies in the rat. Based on this information, I am satisfied that while carbetamide is of low acute toxicity, it presents a moderate risk of producing irreversible toxicity that is consistent with a Schedule 6 entry.

On balance, I am satisfied that the weight of evidence supports that carbetamide meets the scheduling Factors for Schedule 6. While the acute oral and dermal toxicity in rats (> 2000 mg/kg bw and LD₅₀ >2000 mg/kg bw, respectively) is low and consistent with Schedule 5, the acute oral toxicity in mice (1718 mg/kg bw combined sex) is consistent with Schedule 6. I note that the acute inhalation toxicity LC₅₀ >380 mg/m³/4 hours) is consistent with Schedule. However, given there were no deaths and no clinical signs of toxicity at the maximum attainable concentration, I consider it is unlikely that the substance poses an inhalation risk.

In determining that carbetamide meets the requirements for listing under Schedule 6, I have also taken into account that this scheduling proposal is in support of a new Agvet product containing 900 g/kg carbetamide (as a water dispersible granule) that is intended for professional use only. The toxicological data for the formulated product, demonstrated that it has low acute toxicity via the oral, dermal and inhalation routes, is a slight eye irritant but not a skin irritant or skin sensitiser. Given the proposed use on broad care crops and the application methods (either by incorporation at sowing or post-sowing pre-emergence, using ground boom or aerial application methods), access to the formulated product by the general public for non-commercial use is highly unlikely. I am satisfied therefore that potential and reasonably foreseeable harm to professional users can be effectively addressed through the use of packaging and strong warning statements, as well as adherence to the conditions of use as recommended by the APVMA for inclusion on the product label. This is consistent with the requirements for inclusion in Schedule 6 and with controls on use of carbetamide products in other jurisdictions, particularly in the UK and Europe.

Implementation date

I have decided on an implementation date of 1 October 2020.