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Application Form: Import or Manufacture any Hazardous Substance in Containment (Submitted by ORILLION, 14 January 2020)

Important

1. You can talk to an applications advisor at the EPA, who can help you scope and prepare your application. We need all relevant information early on in the application process. Quality information up front will speed up the process.

2. This application form may be used to seek approvals for more than one hazardous substance where the substances are related – for example, a concentrated compound (active ingredient) and its related formulations, or a range of substances for similar purposes to be tested in a field trial.

3. Any extra material that does not fit in the application form must be clearly labelled, cross-referenced, and included in an appendix to the application form.

4. Commercially sensitive information must be collated in a separate appendix.

5. Unless otherwise indicated, all sections of this form must be completed for the application to be progressed.

6. You can get more information at any time by contacting us. One of our staff members will be able to help you.

Environmental Protection Authority Private Bag 63002 Wellington New Zealand Telephone: 64 4 916 2426 Facsimile: 64 4 914 0433 Email: [email protected] http://www.epa.govt.nz

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Application Form: Import or Manufacture any Hazardous Substance in Containment (Submitted by ORILLION, 14 January 2020)

Baits containing anticoagulant toxicants are widely used to control rats. While cholecalciferol baits are also used, being the only real alternative to anticoagulant baits in New Zealand, they are not in widespread use due to their cost, the risk of fatality they pose to dogs and the need for pre-feeding to optimise bait consumption before the stop-feed effect caused by Vitamin D3 occurs. (Note that 1080 use against rats is usually limited to broadscale Rattus rattus control over mainland forests to protect biodiversity). As summarised by Eason & Wickstrom (2001), anticoagulant toxicants have a number of disadvantages:

 secondary-poisoning risk

 accumulation in the food chain

 no effective antidote other than expensive and lengthy treatment with Vitamin K

 expensive due to long or frequent baiting periods

 inhumane relative to acute toxicants

 the development of physiological resistance by pests to some anticoagulants esp. 1st generation.

Rodenticides that overcome these disadvantages are needed and are vital. This need is likely to increase globally in the foreseeable future, driven mainly by increasing population, urbanisation and pressure on world food resources (due to both population increase and climate change impacts on food security). Also, increasing restrictions, particularly on 2nd generation anticoagulants, have been signalled during reviews by New Zealand regulatory authorities. Significant restrictions have been imposed in the USA and the EU, also with a strong focus on the second-generation compounds e.g. difenacoum, bromadiolone, flocoumafen and brodifacoum. The demand for continued access to efficacious rodenticide compounds drives the need for the development of novel and improved rodenticides. In New Zealand, improved rodenticide baits are also needed to support the aims of the government-initiated Predator Free 2050 program, which includes nationwide eradication of rats.

In early 2020, Orillion applied for Research Approval from MPI and a Containment Approval from EPA, APP203980 & HSC100228, for a field trial on private property at Banks Peninsula to determine the efficacy on Ship rats (Rattus rattus) of ”DR8 Rodenticide” containing 1% w/w of the norbormide pro-drug DR8, was carried out in winter 2020 in a privately owned, forested area of Banks Peninsula. Despite robust laboratory data indicating that the LD50 of Ship rats consuming DR8 baits was as high as 100mg/kg of body weight (B/W), it was hoped that with a very palatable bait substrate, wild, food-stressed Ship rats would consume sufficient bait to receive a lethal dose within forty minutes of encountering bait. This is the normal lag time between ingestion of DR8 bait and the onset of sickness behaviour. The lesser toxicity of DR8 to Ship rats resulted in a moderate number of the rats being killed - below the 80% minimum required under the MPI efficacy standard for VTA’s.

Maintaining its collaboration with MWLR, Orillion now wishes to test the DR8 Rodenticide containing 1% norbormide in pro-drug form on Norway rats (Rattus norvegicus).

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Application Form: Import or Manufacture any Hazardous Substance in Containment (Submitted by ORILLION, 14 January 2020)

The Norway rat is a major pest in most developed countries. While the species is essentially a commensal rodent in contrast with the forest dwelling ship rat or the kiore (Rattus exulans), its impacts include serious damaging effects on biodiversity, food production through foraging and fouling as well as disease transmission vectors. This is summarised in Shapiro et al (2018). This paper provides a more detailed background and context for this Research Application, and is accessible via this hypertext link: Shapiro et al 2018.pdf

Laboratory studies using oral gavage and presenting 1% DR8 baits to Norway rats have shown good efficacy, with an LD50 of 20mg/kg B/W for Norway rats, successive trials by researchers have recorded 100% kills when presenting 1% DR8 rodenticide blocks to rats in ad libitum feeding episodes. This level of efficacy and the low toxicity of DR8 to species other than rats suggests that 1% DR8 rodenticide blocks would have significant appeal for Norway rat control in poultry, piggery, horticulture, and stored feed lots where Norway rats are consuming or fouling feed or produce.

The advantages of developing a rat specific rodenticide include the potential to reduce the present reliance on anticoagulant-based rodenticides, which are a cause of growing concern around residues in food and in non-target pathways (wildlife and domestic animals) through both primary and secondary exposure.

In reviewing vertebrate toxic agents in New Zealand, Eason et al (2015) stated: “Norbormide is a development showing considerable promise. It is a truly species-specific rodenticide and should be accelerated. Both norbormide and DR8 meet requirements for humaneness and specificity”.

TOXICITY OF THE ACTIVE INGREDIENT AND BAIT CONTAINING 1% DR8 TO VARIOUS SPECIES

1% DR8 bait Oral LD50 of Norbormide/DR8 Body DR8 required Species required for (mg/kg) (and source) weight for LD50 (mg) LD50 (g)

Norway rat 201 400g 8 0.8 Ship rat 1001 150g 15 1.5 Hamster 1401 400g 56 6 Mouse 22501 25g 56 6 Guinea Pig 6401 800g 512 52 Mallard Duck >30002 1kg >3000 >300 Cat >10001 4kg >4000 >400 Dog >10001 20kg >20000 >2000 Human >3001 70kg >21000 >2100

References to Oral LD50 data column 2: 1. Roszkowski AP, Nause BR, Michael EH, Jacobs L. 1965. The pharmacological properties of norbormide, a selective rat toxicant. Journal of Pharmacology and Experimental Therapeutics. 149 (2):288–299 2. Tucker RK and Crabtree DG, 1970. Handbook of toxicity of pesticides to wildlife. Denver Wildlife Research Centre, Resource Publication No. 84. 131p

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Application Form: Import or Manufacture any Hazardous Substance in Containment (Submitted by ORILLION, 14 January 2020)

While norbormide has historically been associated with low bait acceptance by rats owing to its taste and/or swift onset of symptoms, laboratory trials have shown that in vivo, the DR8 pro-drug releases the active ingredient norbormide sufficiently slowly that the inherent taste aversion which normally occurs with norbormide, is delayed due to the norbormide release occurring only when the compound reaches the stomach. This has resulted in significantly improved kill rates under controlled conditions.

To provide data to support an application for NZ registration, it is proposed that the field efficacy study will be carried out at a to determine whether rodenticide blocks containing 1% DR8 can meet the MPI/ACVM minimum efficacy standard for VTAs of 80% mortality in wild population of Norway rats. A new application for Research Approval covering this proposed Norway rat study has been forwarded concurrently to MPI.

If this is demonstrated, larger scale field studies of bait efficacy will be undertaken by MWLR to provide additional data to support a registration application. These will be detailed in later Research Applications or Provisional Registration applications as deemed appropriate. Either an EPA Containment approval or a new Hazardous Substance approval would be sought also, depending on the scale and breadth of the study.

2.3 Is the information in this application relevant to import, manufacture or both?

Import the substance(s) only? Yes No

Manufacture the substance(s) only? Yes No

Import and manufacture the substance(s)? Yes No

If import only, indicate whether or not manufacture is likely in New Zealand: Yes No

2.4 If the information in the application relates to manufacture of the substance(s) in New Zealand, provide information on the proposed manufacturing process and any alternatives.

Orillion will manufacture the ready-to-use rodenticide incorporating 1% DR8 on its standard “A Plant” production equipment using the processes it normally uses to manufacture commercial rodenticides. Details of the production process and the pre and post-manufacture decontamination procedures are contained within Confidential Appendix IV. A small quantity of the DR8 active material is currently held by MWLR, Lincoln and was manufactured by a competent off-shore company (named in Confidential Appendix VI) and according to a specification supplied by MWLR. The field trials will be carried out in containment, under the authority of an ACVM research approval and the necessary animal welfare approvals. Manufacture of the bait will be as a single batch of 30kg. Bait will be placed into 5kg plastic pails with tamper-evident lids before being delivered to a secure storage area at MWLR. A copy of the proposed label is contained in Confidential Appendix II.

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Application Form: Import or Manufacture any Hazardous Substance in Containment (Submitted by ORILLION, 14 January 2020)

 Molecular formula for norbormide C33H25N3O3 *  Structural formula for norbormide *

 Impurities There are no additives or impurities of toxicological or environmental concern *

 PLEASE REFER TO CONFIDENTIAL APPENDIX I FOR DETAILS OF THE PRODUCT FORMULATION

For mixtures, in addition to the above information being provided on the actual mixture, information is also required on the composition of the mixture – i.e., the chemical name, CAS number, function (e.g., active ingredient, emulsifier, surfactant, filler) and percentages of ALL components of the mixture (including non-hazardous components and impurities) should be provided. This information may be best expressed in tabular form. If the composition is variable, please ensure to state the limits.

If there are commercial reasons for not providing full information in the main part of the form, alternative approaches must be discussed with and agreed by the EPA. These must include the provision of a unique identifier of some kind.

3.2 Provide information on the chemical and physical properties of the substance(s).

Provide as much information as possible on the chemical and physical properties of the substance(s) [at 20°C and 1 atmosphere unless otherwise stated] – e.g.:

 Appearance (colour, odour, physical state or form) Solid, rectangular cereal bait coloured green  pH - Cannot be measured  Density – Not measured. Individual baits are heavier than water.  Vapour pressure N/A  Boiling/melting point N/A  Solubility in water - Not soluble but baits will disintegrate in water  Water/octanol partitioning co-efficient.N/A

For mixtures, information is required on the chemical and physical properties of the mixture itself. However, if this information is not available, you should provide information on the chemical and physical properties of EACH hazardous component of the mixture.

3.3 Provide information on the hazardous properties of the substance(s).

Information should be provided on the hazardous properties of the substance(s) known to the applicant. You should consider each of the six hazardous properties below and provide information on those hazardous

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Application Form: Import or Manufacture any Hazardous Substance in Containment (Submitted by ORILLION, 14 January 2020)

properties. This information is needed in order to assess risks and determine whether or not, and how, the substance can be adequately contained.

 Explosiveness: This bait does not contain properties or components classified as explosive.

 Flammability: This bait does not contain properties or components classified as flammable.

 Oxidising properties: This bait does not contain any oxidising agents or compounds.

 Corrosiveness: This bait is not corrosive and does not contain components which are corrosive.

 Toxicity: Class 6 Sub class 6.1 (Acute toxicity) Oral – 6.1B Triggered for pure DR8 but not triggered for the 1% DR8 Rodenticide (See executive summary section 8.4) Dermal – Not triggered Inhalation – Not triggered Sub Class 6.3 (Skin irritation) – Not triggered Sub Class 6.4 (Eye irritation) – Not triggered Sub Class 6.5 (Sensitisation)- Not triggered Sub Class 6.6 (Mutagenicity) - Not triggered Sub Class 6.7 (Carcinogenicity) - Not triggered Sub Class 6.8 (Reproductive/developmental toxicity) – Not triggered Sub Class 6.9 (Target organs/systems) – Not triggered

 Ecotoxicity: Class 9 Sub Class 9.1 (Aquatic) – Not triggered Sub Class 9.2 (Soil environment) – Not triggered Sub Class 9.3 (Terrestrial vertebrates) - 9.3C Triggered ** Sub Class 9.4 (Terrestrial invertebrates) – Not triggered

If your substance is a mixture and you cannot provide direct information on its hazardous properties, you can apply mixture rules to the hazardous components of the mixture. If you do this, then you will need to provide information on the hazardous properties of each hazardous component of the mixture, and show your workings.

3.4 Provide information on what will happen to the substance throughout its whole life, from its introduction into New Zealand, its uses, through to disposal.

The information provided needs to reflect the containment character of the application. It will be used in the development of exposure scenarios and the assessment of risks, and hence the specification of the containment conditions.

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Application Form: Import or Manufacture any Hazardous Substance in Containment (Submitted by ORILLION, 14 January 2020)

Manufacture of Active

The norbormide pro-drug compound DR8 which will be used in the formulation of the trial baits, has been manufactured by a competent overseas manufacturer and is held by MWLR at Lincoln. Prior to Orillion manufacturing the 30kg of DR8 Rodenticide Blocks required for the trial, this material (300grams) will be sent by MWLR to Orillion in Whanganui via “Chemcouriers” or a similar freight company authorised and competent in the transport of hazardous substances. On receipt of the 300g of DR8 compound from MWLR, Orillion will place the material into its secure dangerous goods storage facility on the Whanganui site. The dangerous goods store is an area where only approved staff members who are certified handlers for Class 6.1 substances have access, which is further restricted by key pad code entry requirements and the need for two authorised persons to be present at all times.

Manufacture of the hazardous substance under this application (DR8 rodenticide)

The 30 kg of cereal composite blocks incorporating 1% of DR8 as the active will be manufactured by Orillion on its production site at 408 Heads Road Whanganui. Orillion holds the necessary Category 8 and Category 10 approvals from MPI ACVM Group to formulate, manufacture, test and release vertebrate toxic agents without restriction, under GMP protocols. Manufacture of the 30kg of cereal bait will be according to Orillion’s manufacturing manual and protocols which establish safe and consistent operating procedures and standards for producing baits. Copies of the manufacturing process and standards are attached in confidential appendix IV..

Packaging and Labelling

The final step of manufacturing will involved placing the finished DR8 Rodenticide cereal bait into rigid plastic packaging (5kg or 10kg plastic pails) with tamper-evident lids. Each container will have a product label adhered to its exterior, indicating the identity and hazardous nature of its contents along with instructions and precautions for its handling, storage, use and disposal. Emergency and first aid response requirements, pack size, pack number, manufacture’s name and contact details will also be included on the label shown in the confidential appendices. A full Safety Data Sheet (SDS) providing detailed information relating to the rodenticide will be available in a plastic sleeve attached to the lid of each container. A copy of the updated SDS and product label are contained within the Confidential Appendices.

Delivery of the finished product to Landcare Research

The packed DR8 Rodenticide will be sent as a single consignment to the MWLR secure storage facility for dangerous goods at Lincoln, via Chemcouriers or a similar freight company approved for the carriage of hazardous goods.

Deployment of baits in the field trial

MWLR researcher Samantha Brown, who is a certified handler for Class 6.1 substances, will manage the transport, application into approximately 80 weatherproof bait stations and return of unused or spoiled bait to the MWLR secure storage at Lincoln.

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Application Form: Import or Manufacture any Hazardous Substance in Containment (Submitted by ORILLION, 14 January 2020)

The trial will be guided by the work plan contained within Confidential Appendix V and led by Samantha Brown who has prepared the work plan in consultation with Dr Brian Hopkins, the Principal Scientist for the DR8 development.

Pre-feed baiting phase

Approximately 120g of non-toxic cereal wax blocks will be placed in approximately 80 secure (lockable) Protecta Evo Ambush bait stations set along building edges at 10 metre spacings, aligned with tracking tunnel locations. Bait stations will be placed out at the same time as the tracking tunnels to allow rodents to acclimatise to their presence. Bait will be checked, weighed and refilled as required every 3rd day for 14 days or until bait uptake reaches 80%. Cameras will be redeployed from tracking tunnels to bait stations to monitor bait station visitation rates during both the pre feeding and toxic baiting phases.

Toxic baiting phase

Approximately 120g of toxic bait containing 1% w/w DR8 will be presented in the 80 bait stations for seven nights, or until bait take decreases to 20% (up to a maximum of 10 nights). Bait will be checked, weighed and refilled as required daily. The same layout will be used as for the pre-feed stage and some bait stations will also be monitored with trail cameras.

Post-control monitoring

Rodent activity will be reassessed immediately after the final deployment of toxic bait using a 1- and 7-night tracking tunnel index and a 7-night chew card index as used for the pre control monitoring. Trail cameras will also monitor a subset of tracking tunnels and chew cards for 7 nights.

Disposal

All spoiled bait found in bait stations during the trial and all uneaten bait remaining in bait stations at the conclusion of the trial will be recovered for disposal. All recovered and remaining stored bait will be disposed of at the end of the trial by burning or burying in an approved landfill facility. This will very likely be less than 10kg of bait, containing less than 100 grams of pro-drug active material.

3.5 Provide information on the quantity of the substance proposed to be imported or manufactured.

This information is used in the development of exposure scenarios and the assessment of risks.

The 300 grams of DR8 pro-drug required has been manufactured by a reputable overseas company named in Confidential Appendix VI. The DR8 active used in the 2020 ship rat trial was also from this manufacturer.

Orillion will manufacture 30kg of DR8 Rodenticide cereal bait containing 1% norbormide, for the trial. This will ensure that sufficient bait is available to conclude the trial, even in the event of a plague-level rat irruption occurring before the trial.

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Application Form: Import or Manufacture any Hazardous Substance in Containment (Submitted by ORILLION, 14 January 2020)

Baits will be transported from Orillion’s manufacturing site to MWLR and then the field trial site in sealed tamper-evident pails with a Safety Data Sheet covering emergency response, first aid and accidental release requirements All staff involved will receive instruction in containment and response measures and the numbers and qualifications of staff to be used in the trial will be checked to ensure coverage and completeness. At the conclusion of the trials all uneaten baits and rat carcasses located within the study area will be disposed of at an approved landfill.  Inspection and monitoring requirements of the containment facility.

Field trial sites will be checked daily during the toxic bait application.

A management plan may be attached as an appendix. This plan should specify the procedures for implementing the above methods for containing the substance(s), and provide details of the qualifications of the person responsible for implementing those controls.

The Trial Work Plan is included in Confidential Appendix V.

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Application Form: Import or Manufacture any Hazardous Substance in Containment (Submitted by ORILLION, 14 January 2020)

Secondary Non-target species, D, U Low Collect rodent carcasses found daily, Poisoning cats, dogs, harriers, pigs Toxicological studies indicate a low scavenge rodent secondary poisoning risk. Risk not likely to be carcasses significant compared with regular anticoagulant baiting normally undertaken. T=Transport, S=Storage, U=Use, D=Disposal

5.2 Provide an assessment of the potential risks identified in Section 5.1.

An explicit risk assessment only needs to be provided for those risks which might be significant. The assessment should consider whether the identified risks can be adequately managed by the proposed containment system, and the substance(s) itself adequately contained.

The assessment should include the nature, probability of occurrence, and magnitude of each adverse effect. The uncertainty bounds of the information contained in the assessment should also be discussed.

(Optional)

Risk assessment

Current information (see toxicity data in tables in Appendices III and VIII) indicates that the level of hazard associated with deploying DR8 Rodenticide Blocks in the field, is low to most organisms other than rats. This target animal specificity, combined with:

 the low concentration of active in the bait

 the small quantities of bait material to be used (30kg)

 the secure nature of the rigid tamper-evident packaging

 the placing of the bait into monitored secure storage facilities

 the limiting of access by certain persons to the storage

 the unitisation of the packs for freighting between secure storage locations

 the requirement for only qualified handlers to have access to the bait during the trial

 the use of secure bait stations and placement of stations to exclude non-targets otherwise at risk

 the removal of uneaten and spoiled baits from the trial area and

 the destruction by burning or burying of all bait remaining after the trial,

These factors point to a very low probability of accidental release or spillage occurring and to and a similarly low consequential hazard in the event of a spill, unexpected accident or adverse event resulting from unintended release.

Risks of DR8 to the relationship with Māori, their culture and the environment

There are increasing numbers of examples of areas where Maori are partnering or leading biodiversity programmes focusing on protecting or restoring the natural and cultural values important to Maori and embracing

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Application Form: Import or Manufacture any Hazardous Substance in Containment (Submitted by ORILLION, 14 January 2020)

landforms, forests, waters, soils, marshlands, estuaries and coastlines. Many of these programmes are supported financially or resourced by central or regional government agencies under treaty partnership programmes, Predator Free 2050 or local initiatives.

As part of these programmes, Maori are actively engaged in animal pest projects aimed at maintaining natural areas as this relates to cultural values and taonga; such as the Taranaki Maunga Project, Paraninihi/Whitecliffs on the northern Taranaki Coast, the Warawara Forest project north of Hokianga and Maungatautari fenced Sanctuary near Cambridge Numerous smaller programmes are underway.

The deployment of toxic pest baits by field teams working in these areas is accepted as a necessary component of the projects. The main toxins used are those which have been available for many years such as cyanide, 1080, cholecalciferol and anticoagulant rodenticides such as brodifacoum and diphacinone. All of these traditional toxins have the potential to adversely affect native fauna but successive improvements to bait design, bait presentation, timing of bait applications, the use of bait stations and bait application rates ensure that non-target exposure is minimal and that there is a significant net benefit to native non-target animals through less predation and competition.

The development and use of a rodenticide containing the pro-drug form of norbormide, which is toxic only to introduced rats and presents no likely risk to other species would be consistent with Maori aspirations for conducting pest programmes in a manner which has minimal impact on other values; where the main impact on cultural values comes from predation of taonga by introduced rats. Although further studies will be necessary, the risk of DR8 affecting traditional kai, water or soils is also likely to be lower than for the toxins currently used in pest programmes.

It is therefore probable that DR8 Rodenticide, if found to be effective, will positively contribute to the cultural well- being of Maori by providing an option for replacing traditional pesticides with a lower-risk alternative for controlling Norway rats affecting kai, biodiversity, community wellbeing and hygiene..

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Application Form: Import or Manufacture any Hazardous Substance in Containment (Submitted by ORILLION, 14 January 2020)

1. Function/Use category: There are 55 function/use categories.

IU 39. Non-agricultural pesticides

8.4 Executive summary:

In this section, the applicant should provide a summary of information contained in this application, including:

 the identification of the substance, its hazardous properties, intended uses and disposal  an assessment of the adverse effects of the substance  information on the proposed containment.

DR8, the pro-drug form of norbormide, is to be manufactured by an overseas company under specification provided by Manaaki Whenua Landcare Research, the inventor of the substance, whose toxicology laboratory will also take receipt of the material on arrival in New Zealand.

Orillion will manufacture cereal baits containing 1% w/w of DR8 active supplied by MWLR and will provide the finished bait product (up to 50kg) to MWLR to undertake field trials designed to assess the efficacy of the baits on a population of wild ship rats.

Both MWLR and Orillion have secure storage facilities, documented processes and qualified personnel for the secure management of deadly, dangerous and harmful substances.

We note that in the application APP203380 by Invasive Pest Control Ltd. “to manufacture norbormide and Norbormide Paste Bait in containment to undertake field trials to determine efficacy on rats”, approved on 21 November 2017 with controls, as HSC100163, the applicant proposed that the substances should be classified 6.1C and 9.3C We agree that Class 9.3 may be triggered.

The assignment of Packing Group or sub-class according to the degree of hazard, under the UN Classification system, assigns substances with an oral LD50 of 5mg/kg or less to Packing Group I (6.1A), those above 5 mg/kg and up to 50 to Packing Group II (6.1B) and those above 50 mg/kg up to 300mg/kg to Packing Group III (6.1C). The calculation of LD50 of substances containing a single active ingredient is based on the formula:

LD50 of the substance = LD50 of the active X 100/ Percentage of active in substance

The EPA uses the most sensitive mammal for classifying oral toxicity. The Norway rat is the most sensitive known mammal to norbormide and has an oral LD50 of 20mg/kg (confirmed by MWLR lab tests). Applying the UN Classification system above, pure DR8 as an analogue of norbormide, therefore has a classification of 6.1B while DR8 Rodenticide containing 1% w/w of DR8/norbormide has an LD50 of 2000 mg/kg - an oral toxicity more than six times lower than the 300mg/kg required to place the substance in Dangerous Goods Class 6.1C (300mg/kg)

Internet searches highlighted published norbormide toxicology data that included information on human health effects, range of toxicity, animal toxicity studies, pharmacokinetics, environmental fate and exposure etc. supported by cited peer reviewed publications (See Confidential Appendix VIII).

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