ERMA New Zealand Evaluation and Review Report

Application for approval to import or manufacture ParaMite Selective Miticide for release

Application Number: ERMA200695

Executive Summary Background information

Sumitomo Chemical Australia Pty Ltd is seeking approval to import or manufacture ParaMite Selective Miticide for release.

ParaMite Selective Miticide is a soluble concentrate containing 110 g/litre etoxazole and other ingredients.

ParaMite Selective Miticide is intended for the control of Six-Spotted Mites in avocados.

ParaMite Selective Miticide will be applied by ground-based methods only, at a maximum application rate of 1.05 L/ha (121.6 g ai/ha), 1 time per year.

Etoxazole is a new active ingredient to New Zealand.

Classification The Agency has classified ParaMite Selective Miticide based on the composition of ParaMite Selective Miticide and the effects of its components.

Hazardous Property Assessment Target Organ Toxicity 6.9A Aquatic Ecotoxicity 9.1A

Risk Assessment The Agency‘s assessment of the risks posed by ParaMite Selective Miticide to the environment and to human health, during the substance‘s lifecycle, is based on qualitative assessment and quantitative modelling using the GENEEC2 and German BBA models. The Agency considers that the risk assessments indicate that the risks to human health and the environment posed by ParaMite Selective Miticide are negligible with the proposed controls in place. The Agency has evaluated information supplied by the applicant about the benefits of ParaMite Selective Miticide and considers that benefits are likely to be realised through the release of this substance.

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Controls The Agency has proposed that the default controls for ParaMite Selective Miticide be modified such that: - no Tolerable Exposure Limits (T1), Workplace Exposure Standards (T2) or Environmental Exposure Limits (E1) are set at the present time and any default values are deleted; - Acceptable Daily Exposure (ADE) and Potential Daily Exposure (PDE) values are set for etoxazole; - the maximum application rate for ParaMite Selective Miticide shall be 1.05 L/ha (121.6 g ai/ha), with a maximum application frequency of 1 application per year; - further controls regarding stationary containment systems are added; - a control which prohibits application of ParaMite Selective Miticide onto or into water is added; and - a control which restricts the application of ParaMite Selective Miticide to ground-based application methods only is added.

The Agency considers that it is appropriate for certain other variations to be made to the default controls. These variations are discussed in Section 4 of this E&R Report and further in Appendix 3.

Conclusion The Agency considers that there are negligible risks to human health and to the environment with the proposed controls in place and potentially significant benefits associated with the release of ParaMite Selective Miticide. Therefore, the Agency considers that it is evident that the benefits of releasing ParaMite Selective Miticide outweigh the costs and the application may be approved in accordance with clause 26.

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Table of Contents 1. The Application ...... 5 2. The substance, its lifecycle and its hazardous properties ...... 6 3. Identification and assessment of risks, costs and benefits ...... 8 4. Setting controls ...... 11 5. Overall evaluation and recommendation ...... 14 Appendix 1: Classification of ParaMite Selective Miticide ...... 15 Appendix 2: Risk Assessment ...... 73 Appendix 3: Default controls for ParaMite Selective Miticide...... 100 Appendix 4: Proposed controls for ParaMite Selective Miticide ...... 105 Appendix 5: Parties notified ...... 110 Appendix 6: References ...... 112 Appendix 7: Confidential material ...... 113 Supplementary Information ...... 114 1. Regulatory basis for assessing the application ...... 114 2. Legislation that will affect the use of hazardous substances within New Zealand 115 3. Risk assessment ...... 119 4. Qualitative descriptors for risk/benefit assessment ...... 121 5. Decision Path ...... 125

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1. The Application

1.1. The application details are summarised in Table 1. Table 1 Details of the application Application Code ERMA200695 Application Type To import or manufacture for release any hazardous substance under Section 28 of the Hazardous Substances and New Organisms Act 1996 (―the Act‖) Application Sub-Type Notified - Category C Applicant Sumitomo Chemical Australia Pty Ltd Date Application Received 2 December 2010 Submission Period 13 December 2010 – 18 February 2011 Consideration Further information was requested from the applicant during the evaluation and review of the application in accordance with section 58 and consequently the consideration was postponed for 5 working days. Due to additional delays in the perparation of this E&R Report the Authority has delayed the consideration of this application until xxxxxxx. Purpose of the Application To import or manufacture ParaMite Selective Miticide (110g/kg etoxazole) for control of Six- Spotted Mite (Eotetranychus sexmaculatus) in avocados.

Parties Notified On 13 December 2010 the following were notified the Minister for the Environment, the Department of Labour and the New Zealand Food Safety Authority (ACVM Group); interested parties listed in Appendix 5; and the public1. Submissions received One submission was received. The submitter did not request to be heard in support of their submission. ERMA staff involved in Haydn Murdoch – Advisor (Hazardous Substances) the assessment Johanna Prankerd – Advisor (Hazardous Substances) Apostolos Koutsaftis – Advisor (Hazardous Substances) Rhian Cope – Senior advisor (Hazardous Substances) Patrick Gemmell – Programme Manager (Kaupapa Kura Taiao). ERMA staff members Jim Waters – Senior Advisor (Hazardous Substances) responsible for review Noel McCardle – Programme Manager (Hazardous

1 The application was advertised in the Dominion Post, the New Zealand Herald, The Christchurch Press and the Otago Daily times and placed on the ERMA New Zealand website.

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Substances) Information assessed The application Confidential appendices

1.2. This report should be read in conjunction with the attached Supplementary Information which contains information on:

The legislative criteria. Approach to risk assessment. Decision pathway used in the decision process. 1.3. The Agency considers that it accessed sufficient information to undertake a full assessment of the substance from a scientific and technical perspective and that there are no other significant uncertainties that need to be considered by the Authority. 2. The substance, its lifecycle and its hazardous properties

The substance and its lifecycle

2.1. ParaMite Selective Miticide is a soluble concentrate containing 110 g/litre etoxazole and other ingredients. ParaMite Selective Miticide is intended for the control of Six-Spotted Mites in avocados.

2.2. The applicant has provided the following details about the lifecycle of ParaMite Selective Miticide.

2.2.1. Importation/Manufacture and Packaging. ParaMite Selective Miticide will be imported fully formulated, packed and labelled. The product will be shipped stacked and secured on pallets. Import will be once a year. The possibility exists for re-labelling the imported containers. The substance may be imported in bulk 200 L drums and decanted into 5 L containers and labelled after re-packaging.

2.2.2. ParaMite Selective Miticide will be packaged in 5 L HDPE containers with a plastic screw top. The label will be attached with glue.

2.2.3. Transport. Transportation of ParaMite Selective Miticide will conform to domestic requirements for transportation and will occur by road, rail and sea.

2.2.4. Storage. ParaMite Selective Miticide will be stored on arrival at Gro- Chem Agrinova premises. These premises will have storage areas in the warehouse that have prominent signage to denote the substances being held. Product will be dispatched to retail outlets to be stored on shelves for sale to the commercial end user.

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2.2.5. Use. ParaMite Selective Miticide will be applied to avocados by ground- based methods only, at a maximum application rate of 1.05 L/ha (121.6 g ai/ha), 1 time per year. Application will occur at first signs of mite crawlers.

2.2.6. Disposal. The preferable route of disposal is by use. Unused product can be stored until use in a following season, since the product is stable. If the above disposal is not possible, ParaMite Selective Miticide may be disposed of in a landfill, or in a pit especially dug for such a purpose on the farm, at least 50 cm deep and well away from any body of water.

Classification of the substance 2.3. The Agency has classified ParaMite Selective Miticide based on the composition of ParaMite Selective Miticide and the effects of its components. These assessments are attached as Appendix 1.

2.4. The applicant‘s and the Agency‘s classification of the hazard profiles of ParaMite Selective Miticide are listed in Table 2.

Table 2: Summary of the applicant’s and Agency’s classifications of ParaMite Selective Miticide

Hazardous Property Applicant’s Agency’s Assessment Assessment Target Organ Toxicity ─ 6.9A Aquatic Ecotoxicity 9.1A 9.1A

2.5. The applicant has not assigned a 6.9A classification to the proposed substance. However, the Agency has reviewed the test data and considers that chronic toxicity studies in a number of animals indicate that the test compound is a target organ toxicant, particularly affecting the liver and, therefore, a 6.9A classification is appropriate.

2.6. The risk assessment in section 3 of this report is based on the Agency‘s classification of ParaMite Selective Miticide.

Regulatory context

2.7. Before the substance can be released for sale and use in New Zealand, it must be registered under the Agricultural Compounds and Veterinary Medicines (ACVM) Act 1997. This process will assess the substance for food residue implications and potentially set withholding periods and residue limits.

2.8. The Agency notes that the importation, manufacture, transport, use and disposal of the substances will be subject to other legislation such as the Health and Safety in Employment Act 1992, the Resource Management Act 1991 and the Land Transport Act 1998 (see Supplementary Information, Section 2).

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Default controls 2.9. The HSNO Regulations specify a number of controls based on the classification of the substance. These default controls are designed to mitigate the potential risks associated with each of the hazardous properties and are listed in Appendix 3. The Authority is able to vary the default controls and impose controls under sections 77 and 77A to produce a set of controls relevant to ParaMite Selective Miticide. Variations and additional controls are considered in section 4 of this report.

2.10. The analysis of risk takes into account the controls that derive from the HSNO Regulations (in particular the default controls identified in Appendix 3) and from other legislation. The identification and assessment of effects assumes the controls are in place. 3. Identification and assessment of risks, costs and benefits

3.1. The Agency‘s identification and assessment of risks and costs (adverse effects) and benefits (positive effects) is set out in this section and supported by information in Appendix 2 and the Supplementary Information (sections 3 and 4).

Risks and costs

Human health 3.2. The Agency has evaluated the potential of ParaMite Selective Miticide to cause adverse effects to the health and safety of humans during all stages of the substance‘s lifecycle using qualitative and quantitative risk assessment methodologies.

3.3. The Agency has classified ParaMite Selective Miticide as harmful to target organs (6.9A).

3.4. In the Agency‘s opinion, chronic hazards normally require repeated exposure to the substance for the adverse effects to occur and are therefore most relevant to the end-users.

3.5. The risks of ParaMite Selective Miticide to human health and safety (with controls in place) at various stages of the lifecycle are summarised in Table 3.1.

Environmental 3.6. The Agency has evaluated the potential of ParaMite Selective Miticide to cause adverse effects to the environment (non-target organisms) during all stages of the substance‘s lifecycle using qualitative and quantitative risk assessment methodologies.

3.7. The Agency has classified ParaMite Selective Miticide as being very toxic in the aquatic environment (9.1A).

3.8. The risks of ParaMite Selective Miticide to the environment (with controls in place) at various stages of its lifecycle are summarised in Table 3.2.

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Table 3.1. Level of risk of ParaMite Selective Miticide to human health and safety.

Lifecycle stage Potential Likelihood of Magnitude of Adverse Matrix Comments Level of Risk Adverse Effect Adverse Effect Effect Occurring Manufacture/ Target organ Highly Major Low While the qualitative descriptors indicate a low level of risk Negligible packaging* toxicity improbable driven by the major chronic effects, the Agency notes that these processes will be required to meet the HSNO requirements for equipment, emergency management and provision of information as well as Health and Safety regulations. The Agency considers that these requirements will make the likelihood of exposure that would lead to a chronic effect so highly improbable that the level of risk for the chronic toxic adverse effects is negligible. Importation, Target organ The Agency considers that the risk of target organ toxicity effects from ParaMite Selective Miticide during importation, Negligible transport or toxicity transport or storage are sufficient remote that it is not necessary to address, given that exposure could only occur in storage isolated spillage incidents. Use Chronic effects: operators (quantitative assessment) Target organ toxicity Quantitative assessment indicates that the chronic risk to the health and safety of operators are acceptable even if PPE is not worn during mixing, loading and application. The use of PPE reduces the level of risk to negligible. Chronic effects: bystanders (quantitative assessment) Target organ toxicity Quantitative assessment indicated that the chronic risks to bystander health and safety are acceptable with the proposed controls in place and the level of risk is considered negligible. Disposal Target organ Highly Major Low The Agency considers that whilst the chronic toxic Negligible toxicity improbable properties of this substance could cause major adverse effects, the people disposing of the substance will have the necessary skills and knowledge (e.g. via information provided on the label) to reduce the level risk from low to negligible. *The applicant has only provided information relating to the importation of ParaMite Selective Miticide into New Zealand and that manufacture is unlikely. However, it is possible that the substance could be manufactured in New Zealand in the future. Consequently, the risks associated with the manufacture of ParaMite Selective Miticide have been evaluated so that approval of this substance will be applicable to both the import and manufacture of ParaMite Selective Miticide.

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Table 3.2. Level of risk of ParaMite Selective Miticide to the environment. Lifecycle stage Potential Adverse Effect Likelihood Magnitude Matrix Comments Level of Risk of Adverse of Adverse Effect Effect Occurring Manufacture, Spillage resulting in death Highly Moderate Negligible The Agency considers that given adherence to the HSNO Negligible importation, or adverse effects to improbable controls (e.g. packaging, identification and emergency transport and organisms in the management) and the Land Transport Rule 45001, Civil storage environment. Aviation Act 1990 and Maritime Transport Act 1994 (as applicable) any spill would involve small quantities which would lead to localised effects only. Use Use resulting in death or Quantitative assessment indicates that there is a high acute and chronic risk to crustacea. The Agency considers that the adverse effects to application of controls, such as the requirements for approved handlers and a prohibition on application of the substance onto or organisms in the aquatic into water, will ensure that these risks are negligible. environment. Use resulting in death or The Agency considers that the risks to earthworms and soil microbes from the use of ParaMite Selective Miticide are so low adverse effects to soil that quantitative assessment is unnecessary organisms. Use resulting in death or Quantitative assessment indicates that there is a low risk to birds. The Agency considers that the application of controls will adverse effects to birds. ensure that these risks are negligible. Use resulting in death or Quantitative assessment indicates that there is a low acute risk to bees. There may, however, be a risk to non-target arthropods. adverse effects to bees. The Agency considers that the application of controls, including a warning statement on the label, will ensure that these risks are negligible. Disposal Disposal resulting in death Highly Minor Negligible The applicant indicates that all attempts should be made to Negligible or adverse effects to improbable utilise the substance completely in accordance with its organisms in the registered use. In all cases of disposal, the substance will be environment disposed of in accordance with the requirements of the Hazardous Substances (Disposal) Regulations 2001 and the Resource Management Act 1991.

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Benefits 3.9. The applicant considers that there are benefits to avocado growers from the control of Six-Spotted Mite which would result in a reduction in the damage to avocados, thereby increasing economic returns to the growers.

3.10. The Agency notes that benefits may be derived for New Zealand by allowing the use of ParaMite Selective Miticide.

Likely effects of the substance being unavailable 3.11. The Agency notes that the likely effects of ParaMite Selective Miticide being unavailable be a reduction in the quality of avocados produced in New Zealand.

Submission 3.12. A submission on the application to import or manufacture ParaMite Selective Miticide was received from the Canterbury Branch of the National Beekeepers‘ Association. The submitter indicated that they opposed the application on the basis that:

The applicant has provided insufficient information about ‗bee safety‘, given that the substance is designed to kill (terrestrial invertebrates) mites; and

The operator risk assessment provided by the applicant is inadequate.

3.13. The submitter requested that the Authority:

Seeks additional information on bee safety;

Includes a requirement that there are sufficient warnings, on the label to advise the users of the dangers (to bees) and that there are conditions of use prohibiting the use of the product on plants in flower likely to be visited by bees; and

Restricts the use of the substance to use on avocados.

3.14. The Agency has undertaken a risk assessment of the risks to terrestrial invertebrates. This risk assessment concluded that there was no risk to bees from the use of the substance and therefore no specific controls to address ―bee safety‖ are necessary. However, the Agency does consider that there may be a risk to other non target beneficial insects and on this basis, is recommending that the substance label include a warning statement that ‗The substance may be harmful to non-target arthropods‖.

3.15. In regards to the operator risk, the Agency‘s risk assessment concluded that there was a low risk to operators even if PPE was not worn and considers that the use of PPE will reduce this risk to negligible.

3.16. The Agency considers that concerns raised by the submitter will be addressed by the proposed controls for the substance.

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4. Setting controls Variations to Default Controls 4.1. As a result of the risk assessments, the Agency considers that the following variations should be made to the default controls. These variations are summarised in Table 4 below. A full description of the rationale for these variations is documented in Appendix 3.

Table 4 Variations to the default controls for ParaMite Selective Miticide. Control Subject Matter Variation Comment Code T1 Limiting Etoxazole: The Agency proposes that ADEs exposure to ADE = 0.15 mg/kg bw/day and PDEs are set for etoxazole, as toxic these may be required by the New PDE = 0.105 mg/kg bw/day substances food Zealand Food Safety Authority for through the PDEdrinking water = 0.03 mg/kg bw/day the setting of maximum residue setting of TELs PDEother = 0.015 mg/kg bw/day levels and by the Ministry of Health for setting drinking water standards. No TEL values are set at this time. T2 Controlling No WES values are set at this time. The Agency notes that no WES exposure to in values have been set by the places of work Department of Labour for any through the components of ParaMite Selective setting of Miticide. WESs E1 Limiting No EEL values are set at this time and the Until the Agency has developed exposure to default EELs are deleted. formal policy on the ecotoxic implementation of section 77B, it substances proposes not to set any EEL values though the for components of ParaMite setting of EELs Selective Miticide and the default EEL water and soil values are deleted. E2 Restriction on A maximum application rate has been set As no EEL has been proposed for the use of under section 77A. ParaMite Selective Miticide, the substances in Agency is not able to propose the application setting of a maximum application areas rate under this regulation. However, the Agency notes that the environmental exposure modelling indicates there may be a risk where the substance is used outside the specific parameters of the risk assessment. The Agency, therefore, considers it appropriate to set a maximum application rate under section 77A. E7/AH1 Approved The following control is substituted for The Agency considers that this handler Regulation 9(1) of the Hazardous control should be modified for requirements Substances (Classes 6, 8, and 9 Controls) ParaMite Selective Miticide so as for ecotoxic Regulations 2001: to apply only during use. substances ―(1). ParaMite Selective Miticide must be under the personal control of an

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approved handler when the substance is – (a) applied in a wide dispersive manner; or (b) used by a commercial contractor. I11 Secondary The substance label shall contain the The Agency considers that while identifiers for following additional warning statement: there is a negligible risk to bees ecotoxic ―The substance may be harmful to non- from the use of ParaMite Selective substances target arthropods‖ Miticide, the substance may be harmful to non-target arthropods and therefore an appropriate warning statement should be included on the substance label. TR1 Tracking Deleted. It is considered that the risks that requirement may arise during the substance‘s during use of lifecycle will adequately be the substance managed by other controls such as packaging, labelling and emergency management requirements and therefore the tracking requirements can be deleted.

4.2. The Agency notes that similar variations were made to pesticides on their transfer to the HSNO regime.

Proposed additional controls 4.3. As a result of its assessment of the environmental risks associated with the use of ParaMite Selective Miticide, the Agency considers that the following additional controls should be added:

The maximum application rate for ParaMite Selective Miticide shall be 1.05 L/ha (121.6 g ai/ha), with a maximum application frequency of 1 application per year; ParaMite Selective Miticide shall not be applied onto or into water; and ParaMite Selective Miticide shall be applied via ground-based methods only.

4.4. The Agency notes that the specified controls for ParaMite Selective Miticide do not address the risks associated with stationary container systems, nor do they allow for dispensation where it is unnecessary for any associated pipework to have secondary containment. Accordingly, the Agency considers that the application of controls addressing these risks will be more effective than the specified (default) controls in terms of their effect on the management, use and risks of the substance2. The proposed controls are shown in Table A4.1 of Appendix 4.

2 section 77A(4)(a)

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4.5. Control EM12 relates to the requirements for secondary containment of pooling substances3. The EM12 secondary containment requirements have been triggered for ParaMite Selective Miticide as a result of its 9.1A classification. The Agency considers that the risks associated with the containment of substances which are not class 1 to 5 substances (i.e. do not ignite or explode) are different to those associated with class 1 to 5 substances. Consequently the Agency considers that the secondary containment requirements can be reduced. The Agency considers that these reduced secondary containment measures are adequate to manage the risks of a spillage of ParaMite Selective Miticide. Therefore, the proposed additional control, which varies the EM12 control, is more cost-effective in terms of managing the risks of the substance. The proposed controls are shown in Table A4.1 of Appendix 4.

4.6. The final proposed controls for ParaMite Selective Miticide are listed in Appendix 4. 5. Overall evaluation and recommendation

5.1. The Agency considers that there are negligible risks to human health and to the environment with the proposed controls in place and there are no potentially significant costs associated with the release of ParaMite Selective Miticide. Therefore, the Agency considers that it is evident that the benefits of releasing ParaMite Selective Miticide outweigh the costs and the application may be approved in accordance with clause 26, with the controls documented in Appendix 4.

3 Regulations 35 – 41 of the Hazardous Substances (Emergency Management) Regulations 2001

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Appendix 1: Classification of ParaMite Selective Miticide Classification of ParaMite Selective Miticide

Formulation test data was not provided for ParaMite Selective Miticide. Classification was estimated using information on the effects of the components and mixture rules. Details of the key substance components and the methods used to derive the classifications are presented in Table A1.1. The relevant sections of the User Guide to Thresholds and Classifications under the HSNO Act (ERMA 2008a) that describe the mixture rules are listed in Table A1.2.

The active ingredient, etoxazole, is a new pesticide active ingredient to New Zealand.

The Agency has provided a summary of the toxicity, ecotoxicity and environmental fate data in Tables A1.5 to A1.11.

Data quality – overall evaluation

The Agency has adopted the Klimisch et al (1997) data reliability scoring system for evaluating data used in the hazard classification and risk assessment of chemicals (section 1.2.4 in ERMA 2008a). As discussed above, the Agency has classified ParaMite Selective Miticide based on mixture rules. Classifications derived using mixture rules were determined from the classifications which were officially gazetted during the transfer process and are publicly available through the HSNO Chemical Classification Information Database (CCID) (ERMA 2008b). Where additional data has been provided by the applicant, The Agency has assigned Klimisch data reliability scores to that information and these are included in tables from A1.5 to A1.11. Generally these data are high quality by current international standards.

The Agency acknowledges that there are frequently data gaps in the hazard classification for chemicals which have been in use internationally for a long time. International programmes such as the OECD High Production Volume programme (OECD 1990) and REACH (EU 2006) are progressively working towards filling these data gaps. As new information becomes available, and resources permit the Agency will endeavour to update the HSNO classifications for those substances.

Table A1.0: Physical and chemical properties of ParaMite Selective Miticide. Test ParaMite® Selective Miticide Method Reference

Appearance Grey-white opaque liquid No data Applicant

Odour No data No data -

Density at 20°C 1.05 No data Applicant

Surface tension No data No data -

pH 7.4 (1% in water) No data Applicant

Dynamic viscosity 24 mPa.s at 23oC No data Applicant

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Flash point No data No data -

Auto flammability Autoflammable under the conditions No data Applicant of the test with a self ignition temperature of 504oC

Explosive properties No explosive behaviour observed No data Applicant

Table A1.1: Summary of the toxicity and ecotoxicity hazard classifications of ParaMite Selective Miticide. Hazardous Property Agency’s Classification Classification Component(s) driving Method classification 6.9 Target organ 6.9A Mixture rules Etoxazole systemic toxicity 9.1 Aquatic ecotoxicity 9.1A Mixture rules Etoxazole Aquatic Persistence Yes Mixture rules Etoxazole Bioaccumulative Yes Mixture rules Etoxazole Soil Persistence ND - - ND: no data

Table A1.2: Location of mixture rules within the HSNO Thresholds and Classifications User Guide (V2.0. March 2008). Hazard User Guide to HSNO Thresholds and Classifications Reference Subclass 6.1 Acute Toxicity Part V, Chapter 10, Page 12 Subclass 6.3/8.2 Skin Irritancy/Corrosivity Part V, Chapter 11, Page 7 Subclass 6.4/8.3 Eye Irritancy/Corrosivity Part V, Chapter 12, Page 9 Subclass 6.5 Contact and Respiratory Sensitisation Part V, Chapter 13, Page 8 Subclass 6.6 Mutagenicity Part V, Chapter 14, Page 5 Subclass 6.7 Carcinogenicity Part V, Chapter 15, Page 8 Subclass 6.8 Reproductive Developmental Toxicity Part V, Chapter 16, Page 11 Subclass 6.9 Target Organ Systemic Toxicity Part V, Chapter 17, Page 10 Subclass 9.1 Aquatic Ecotoxicity Part VI, Chapter 19, Page 18 Subclass 9.2 Soil Ecotoxicity Part VI, Chapter 20, Page 8 Subclass 9.3 Terrestrial Vertebrate Ecotoxicity Part VI, Chapter 21, Page 7 Subclass 9.4 Terrestrial Invertebrate Ecotoxicity Part VI, Chapter 22, Page 5

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Identity of the Active Ingredient

As this is the first HSNO application considered for this active ingredient, general data about etoxazole are provided in the Tables A1.3 and A1.4.

Table A1.3: Identification of etoxazole.

CAS number 153233-91-1 IUPAC name (RS)-5-tert-butyl-2-[2-(2,6-difluorophenyl)-4,5-dihydro-1,3- oxazol-4-yl]phenetole Common name Etoxazole

Molecular formula C21H23F2N2 Molecular weight 359.42 Structural formula Figure 1 Purity 93% minimum Significant impurities/additives -(RS)-5-tert-butyl-2-[2-(2,6-difluorophenyl)-4,5-dihydro-1,3- (% concentration) oxazol-5-yl]phenetole max 3% -3-tert-butyl-phenetole max 1% -(RS)-4-tert-butyl-2-[2-(2,6-difluorophenyl)-4,5-dihydro-1,3- oxazol-4-yl]phenetole max 0.8% and six other impurities 0.2-0.7% Known uses Acaricide HSNO classification 6.9A, 9.1A Other classification & labelling Risk phrases: R50/53, Safety phrases: S23, S25

Figure 1: Structural formula of etoxazole

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Physical and chemical properties of etoxazole submitted with the application are summarized in Table A1.4.

Table A1.4: Physical and chemical properties of etoxazole. Property Etoxazole Test Reference method Colour White No data PPDB, 2009 Physical state Crystaline powder No data PPDB, 2009 Odour No data - - Vapour pressure 7.0 x 10-6 Pascals at No data European Commission, 25oC 2004 Henry‘s Law constant 3.60 x 10-02 Pa m3 mol-1 No data PPDB, 2009 at 25oC Melting range 101.5-102.5oC No data European Commission, 2004 Relative Density 1.2389 g/cm3 at 20oC No data European Commission, 2004 Water Solubility 7.04 x 10-5 g/L at 20oC No data European Commission, 2004 Solvent Solubility (20°C) Acetone: 309 g/L No data European Commission, 1,2-dichloromethane: 2004 402 g/L Ethyl acetate 249 g/L n-heptane 18.7 g/L methanol 104 g/L xylene 252 g/L pH No data - - Log Kow 5.52 at 20oC No data PPDB, 2009 and European Commission, 2004 Flammability Not flammable No data European Commission, 2004 Autoflammability No data - - Explosive properties Not explosive No data European Commission, 2004 Surface Tension No data - - Oxidizing properties No data - -

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Biological Hazards: Class 6 Toxicity

Etoxazole is a miticide that is new to New Zealand. In addition to toxicity studies on etoxazole, the applicant has provided toxicity studies on etoxazole and its metabolites (Table A1.5).

Table A1.5: Summary of toxicity data on etoxazole and its metabolites.

The following assessments are of YI-5301 (alternatively identified as S-1283 and Etoxazole)

ACUTE TOXICITY Acute Oral Toxicity SPECIES: Mouse

ENDPOINT: LD50

VALUE: >5 g/kg

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: OECD 401 (1987), EPA FIFRA 81-1 (1984), JMAFF (1985)

REFERENCE: Allan S.A., YI-5301 Acute oral toxicity to the mouse, report number 920145D/YMA 2/AC, HRC Ltd., England, 1992

STRAIN: Hsd/Ola:ICR

NO/SEX/GROUP: 5M & 5F

TEST SUBSTANCE: YI-5301

DOSE LEVEL: 5000 mg/kg by oral gavage

STUDY SUMMARY: There were no deaths. Clinical signs consisting of piloerection, abnormal body carriage and abnormal gait were seen on Day 1 and resolved by Day2. There was no effect on bodyweight gain and no macroscopic changes evident at necropsy.

SPECIES: Mouse

ENDPOINT: LD50

VALUE: >5g/kg

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: 92/69/EEC (1992), EPA FIFRA 81-1 (1984), JMAFF (1985)

REFERENCE: McRae, L.A., YI-5301 10%SC Acute oral toxicity to the mouse, report number YMA 18/940781/AC, HRC Ltd., England, 1995

STRAIN: Hsd/Ola:ICR

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NO/SEX/GROUP: 5M & 5F

TEST SUBSTANCE: YI-5301

DOSE LEVEL: 5000 mg/kg by oral gavage

STUDY SUMMARY: There were no deaths. Clinical signs consisting of piloerection with one male and one female also showing abnormal body carriage and lethargy were seen on Day 1 and resolved by Day 2. There was no effect on bodyweight gain and no macroscopic changes evident at necropsy.

SPECIES: Rat

ENDPOINT: LD50

VALUE: >5g/kg

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: OECD 401 (1987), EPA FIFRA 81-1 (1984), JMAFF (1985)

REFERENCE: Allan S.A., YI-5301 Acute oral toxicity to the rat, report number 920136D/YMA 1/AC, HRC Ltd., England, 1992

STRAIN: Hsd/Ola:Sprague Dawley

NO/SEX/GROUP: 5M & 5F

TEST SUBSTANCE: YI-5301

DOSE LEVEL: 5000 mg/kg by oral gavage

STUDY SUMMARY: There were no deaths. Clinical signs including piloerection abnormal body carriage, abnormal gait, lethargy and decreased respiratory weight were seen on Day 1 and resolved by Day 2. Marginally lower weight gains were seen in three females and one male. There were no macroscopic changes evident at necropsy.

SPECIES: Rat

ENDPOINT: LD50

VALUE: > 5g/kg

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: 92/69/EEC (1992) EPA FIFRA 81-1 (1984), JMAFF (1985)

REFERENCE: Allan S.A., YI-5301 10%SC Acute oral toxicity to the rat, report number YMA 17/940780/AC, HRC Ltd., England, 1995

STRAIN: Hsd/Ola:Sprague Dawley

NO/SEX/GROUP: 5M & 5F

TEST SUBSTANCE: YI-5301 10%SC

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DOSE LEVEL: 5000 mg/kg by oral gavage

STUDY SUMMARY: There were no deaths. Clinical signs were limited to piloerection seen on Day 1 only. Marginally lower weight gains was seen in four females on Day 8 regaining parity by Day 15 and one male on Day 15.There were no macroscopic changes evident at necropsy. Conclusion on classification: Not classified

Acute Dermal Toxicity SPECIES: Rat

ENDPOINT: LD50

VALUE: >2g/kg

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES:

REFERENCE: Allan, S.A., YI-5301 Acute dermal toxicity to the rat, report number 920157D/YMA 3/AC, HRC Ltd., England 1992

STRAIN: OECD 402 (1987), US EPA FIFRA 81-2 (1984), JMAFF (1985)

NO/SEX/GROUP: 5M & 5F

TEST SUBSTANCE: YI-5301

EXPOSURE TYPE: Dermal

DOSE LEVEL: 2000 mg/kg occluded for 24 hours

STUDY SUMMARY: There were no deaths or systemic signs of reaction or of local reaction at the site of application. Marginally lower weight gain was noted in one male and three females on Day 8 recovering by termination and one further male on Day 15. There were no macroscopic changes evident at necropsy.

SPECIES: Rat

ENDPOINT: LD50

VALUE: >2g/kg

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES:

REFERENCE: McCrae, L.A., YI-5301 10%SC Acute dermal toxicity to the rat, report number YMA 19/940782/AC, HRC Ltd., England 1995

STRAIN: EEC 92/69/EEC, EPA FIFRA 81-2 (1984), JMAFF (1985)

NO/SEX/GROUP: 5M & 5F

TEST SUBSTANCE: YI-5301 10%SC

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EXPOSURE TYPE: Dermal

DOSE LEVEL: 2000 mg/kg occluded for 24 hours

STUDY SUMMARY: There were no deaths or systemic signs of reaction or of local reaction at the site of application. Marginally lower weight gain was noted in three males and four females on Day 8 and two males on Day 15. There were no macroscopic changes evident at necropsy.

Conclusion on Classification: Not classified Remarks on Classification: No evidence of adverse effects at doses to 6.1D levels, other than short-term marginal weight loss, thus classification as 6.1E on the basis of expert judgment is not justified.

Acute Inhalation Toxicity SPECIES: Rat

ENDPOINT: LC50

VALUE: >1.09 mg/l

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: EPA FIFRA 81-3 (1984), OECD 403 (1981), JMAFF (1985)

REFERENCE: Ebino, K., YI-5301: Acute inhalation toxicity study in rats, report number IET 93-0112, The Institute of Environmental Toxicology, Japan, 1994

STRAIN: Fischer (F344/DuCrj)

NO/SEX/GROUP: 5M & 5F

TEST SUBSTANCE: YI-5301

TYPE OF EXPOSURE: single whole body exposure for 4 hours

MMAD OF DUST: 3.6 µm

STUDY SUMMARY: There were no deaths. Reddish material adhered in the nasorostral region was noted in 4 males and all females at the end of the exposure resolving by the end of Day 1 in the males and Day 4 in the females. There were no adverse effects on weight gain or any macroscopic changes evident at necropsy.

SPECIES: Rat

ENDPOINT: LC50

VALUE: >1.09 mg/l

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: EPA FIFRA 81-3 (1984), OECD 403 (1981), JMAFF (1985)

REFERENCE: Ebino, K., YI-5301 10%SC: Acute inhalation toxicity study in rats, report number IET 94-0093, The Institute of Environmental Toxicology, Japan, 1995

STRAIN: Fischer (F344/DuCrj)

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NO/SEX/GROUP: 5M & 5F

TEST SUBSTANCE: YI-5301 10%SC

TYPE OF EXPOSURE: single whole body exposure for 4 hours

MMAD OF PARTICLE: 3.9 µm

STUDY SUMMARY: There were no deaths. Reddish material adhered in the nasorostral region was noted in 1 male and soiled fur in the abdominal region of another male resolving by the end of Day 1. There was no effect on weight gain or any macroscopic changes evident at necropsy.

Conclusion on Classification: Not classified Remarks on Classification: JMPR evaluation lists > 1.09 mg/L air, highest attainable concentration based on the IET 94-0093 study (see: http://www.fao.org/fileadmin/templates/agphome/documents/Pests_Pesticides/JMPR/Report10/Etoxazole.pdf)

Eye Irritation SPECIES: Rabbit

ENDPOINT: Irritancy

MEAN DRAIZE SCORE: Chemosis 0, iris lesions 0, corneal opacity 0, conjunctival redness 0 – non irritant

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: EPA FIFRA 81-4 (1984), OECD 405 (1987), JMAFF (1985)

REFERENCE: Liggett, M.P., YI-5301 Eye irritation to the rabbit, report number 920100D/YMA 5/SE, HRC Ltd., England, 1992

STRAIN: New Zealand White

NO/GROUP: 6

TEST SUBSTANCE: YI-5301

DOSE: 53 mg (volume of 0.1 ml) to one eye

STUDY SUMMARY: Treatment elicited mild conjunctival irritation resolving the day after instillation.

SPECIES: Rabbit

ENDPOINT: Irritancy

MEAN DRAIZE SCORE: Chemosis 0, iris lesions 0, corneal opacity 0, conjunctival redness 0.2 – non irritant

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: EPA FIFRA 81-4 (1984), 92/69/EEC (1992), JMAFF (1985)

REFERENCE: Parcell, B.I., YI-5301 10%SC Eye irritation to the rabbit, report number YMA 21/951322/SE, HRC Ltd., England, 1995

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STRAIN: New Zealand White

NO/GROUP: 7M

TEST SUBSTANCE: YI-5301 10%SC

DOSE: 0.1 ml to one eye

STUDY SUMMARY: Treatment elicited mild conjunctival irritation resolving on Days 2, 3 or 4 after instillation.

Conclusion on Classification: Not classified

Skin Irritation SPECIES: Rabbit

ENDPOINT: Irritancy

MEAN DRAIZE SCORE: Erythema 0, Oedema 0 – non irritant

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: EPA FIFRA 81-5 (1984), OECD 404 (1981), JMAFF (1985)

REFERENCE: Liggett, M.P., YI-5301 Skin irritation to the rabbit, report number 920099D/YMA 4/SE, HRC Ltd., England, 1992

STRAIN: New Zealand White

NO/GROUP: 6

TEST SUBSTANCE: YI-5301

TYPE OF EXPOSURE: Dermal, semi-occlusive for 4 hours

DOSE: 0.5g

STUDY SUMMARY: There were no signs of reaction.

SPECIES: Rabbit

ENDPOINT: Irritancy

MEAN DRAIZE SCORE: Erythema 0, Oedema 0 – non irritant

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: EPA FIFRA 81-5 (1984), 92/69/EEC !992), JMAFF (1985)

REFERENCE: Parcell, B.I., YI-5301 10%SC Skin irritation to the rabbit, report number YMA 20/951321/SE, HRC Ltd., England, 1995

STRAIN: New Zealand White

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NO/GROUP: 6 M

TEST SUBSTANCE: YI-5301 10%SC

TYPE OF EXPOSURE: Dermal, semi-occlusive for 4 hours

DOSE: 0.5 ml

STUDY SUMMARY: There were no signs of reaction.

Conclusion on Classification: Not classified

Contact Sensitization SPECIES: Guinea pig

ENDPOINT: Sensitisation

VALUE: Non sensitiser

KLIMISCH SCORE: I (reliable without restriction)

GLP: Y

TEST GUIDELINES: EPA FIFRA 81-6 (1984), 92/69/EEC (1992), JMAFF (1985)

REFERENCE: Allan, S.A., YI-5301 10%SC Skin sensitization in the guinea pig (incorporating a positive control using formalin), report number YMA 22/940694/SS, HRC Ltd., England, 1995

STRAIN: Dunkin/Hartley

NO/SEX/GROUP: 20 F and 10 F control and test group respectively

TEST SUBSTANCE: YI-5301 10%SC Positive control: Formalin

TYPE OF EXPOSURE: 3 pairs of intra dermal injections in a shaved area consisting of Freunds complete adjuvant, YI-5301 10%SC 2.5% w/v in water, YI-5301 10%SC in 50:50 mixture with Freunds adjuvant. Topical application 0.4 ml YI-5301 10%SC occluded for 48 hours. Challenge after 2 weeks with YI-5301 10%SC as supplied and 50% v/v water

STUDY SUMMARY: There were no signs of reaction (delayed contact hypersensitivity) in any of the test animals

SPECIES: Guinea pig

ENDPOINT: Sensitisation

VALUE: Non sensitiser

KLIMISCH SCORE: I (reliable without restriction)

GLP: Y

TEST GUIDELINES: EPA FIFRA 81-6 (1984), 92/69/EEC (1992), JMAFF (1985)

REFERENCE: Allan, S.A., YI-5301 Skin sensitization in the guinea pig (incorporating a positive control using formalin), report number YMA 23/940748/SS, HRC Ltd., England, 1995

STRAIN: Dunkin/Hartley

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NO/SEX/GROUP: 20 F

TEST SUBSTANCE: YI-5301 Positive control: Formalin

TYPE OF EXPOSURE: 3 pairs of intra dermal injections in a shaved area consisting of Freunds complete adjuvant, YI-5301 0.25% w/v in acetone in Alembicol D, YI-5301 0.25% in 50:50 mixture with Freunds adjuvant and 5% acetone in Alembicol D. Topical application 0.4 ml YI-5301 80% w/v in acetone occluded for 48 hours. Challenge after 2 weeks with YI-5301 80 an 40% v/v in acetone

STUDY SUMMARY: There were no signs of reaction (delayed contact hypersensitivity) in any of the test animals

Conclusion on Classification: Not classified

GENOTOXICITY In Vitro Study STUDY TYPE: Reverse mutation (Ames)

CELL TYPES: Salmonella typhimurium strains TA100, TA135, TA98, TA1537 Escherichia coli strain WP2 uvrA

TEST SUBSTANCE: YI-5301 Positive controls: 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide, 2-aminoanthracene, 9-amino acridine, sodium azide

DOSE RATE OF TEST SUBSTANCE: Preliminary study – 100, 200, 500, 1000, 2000, 5000 µg/plate with and without S-9 mix Main study – 313, 625, 1250, 2500, 5000 µg/plate with and without S-9 mix

RESPONSE: There was no indication of the test substance having any mutagenic activity

GLP: Y

TEST GUIDELINES: JMAFF (1985), EPA 84-2 (1984), OECD (1983)

REFERENCE SOURCE: Watanabe K., YI-5301: Reverse mutation test, report number IET 92-0017, The Institute of Environmental Toxicology, Japan, 1992

RELIABILITY (KLIMISCH SCORE): 1 (reliable without restriction)

STUDY TYPE: Reverse mutation (Ames)

CELL TYPE: Salmonella Typhimurium TA102

TEST SUBSTANCE: S-1283 (etoxazole) Positive controls – Mitomycin C, 2-aminoacridene

DOSE RATE OF TEST SUBSTANCE: Preliminary study – 4.88, 19.5, 78.1, 313, 1250, 5000 µg/plate with and without S-9 mix Main study – 313, 625, 1250, 1500, 5000 µg/plate with and without S-9 mix

RESPONSE: Precipitation of the test material was seen 1250 µg/plate and above however there was no cytotoxicity observed.. The test substance did not result in any increase in mutagenic activity in this assay.

GLP: Y

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TEST GUIDELINES: US EPA FIFRA § 870.5100, OECD 471 (1997), JMAFF (1985)

REFERENCE SOURCE: Ota, M., Reverse mutation test of S-1283 in Salmonella typhimurium strain TA102, report number 3397, Environmental Health Science Laboratory, Japan, 1999

RELIABILITY (KLIMISCH SCORE): 1 (reliable without restriction)

STUDY TYPE: Mammalian cell mutation assay

CELL TYPE: Mouse lymphoma L5178Y

TEST SUBSTANCE: S-1283 Positive controls: methyl methanesulphonate, 20-Methylcholanthrene

DOSE RATE OF TEST SUBSTANCE: Preliminary study – 1, 5, 10, 25, 50, 100, 200, 350 µg/ml without S-9 mix Main study – 0, 1, 10, 15, 25, 35, 40, 45, 50, 55, 60, 70, 80, 100 µg/ml without S-9 mix 0, 0.5, 1, 2.5, 3, 4, 5, 7.5, 10, 15, 20, 25 µ/ml with S-9 mix

RESPONSE: Toxicity was evident after treatment in all tests with and without S-9 mix. Increases in mutant frequency were observed in both tests in the absence of S-9 mix albeit at highly toxic concentrations. Further, little or no increases in absolute mutant colony numbers were seen. In both tests with S-9 mix increases in mutant frequency indicative of a positive response were seen. Thus the test substance did demonstrate mutagenic potential in this assay in the presence of S-9 mix. No definitive conclusion on mutagenic potential could be made for the result in the absence of S-9 mix.

GLP: Y

TEST GUIDELINES: OECD 476 (1984), EPA (1983), 87/302/EEC (1988)

REFERENCE SOURCE: Adams, K., S-1283 Mammalian cell mutation assay, report number SMO 519/952604, HLS Ltd., England, 1996

RELIABILITY (KLIMISCH SCORE): 1 (reliable without restriction)

STUDY TYPE: Mammalian cell gene mutation

CELL TYPE: Chinese Hamster lung cell CHL

TEST SUBSTANCE: YI-5301 Positive controls: benzo(a)pyrene, mitomycin C

DOSE RATE OF TEST SUBSTANCE: Preliminary study – 3.9, 7.8, 15.6, 31.3, 62.5, 125, 250 µg/ml with and without S-9 mix Main study – 15.6, 31.3, 62.5, 125 µg/ml for 24 hours, 12.5, 25, 50, 100 µg/ml for 24 hours all without S-9 mix 22.5, 45, 90, 180 µg/ml for 6 hours with S-9 mix

RESPONSE: There were no significant increases in the frequencies of structurally aberrant metaphases or polyploid cells with or without S-9 mix, thus the test substance did not induce either structural or numerical chromosome aberrations in this assay.

GLP: Y

TEST GUIDELINE: US EPA FIFRA (1989), JMAFF (1985), OECD 473 (1983), 92/69/EEC (1992)

REFERENCE SOURCE: Matsumoto K., YI-5301: In vitro cytogenetics test, report number IET 93-0116, The

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Institute of Environmental Toxicology, Japan, 1994

RELIABILITY (KLIMISCH SCORE): 1 (reliable without restriction)

In Vivo Study STUDY TYPE: Unscheduled DNA synthesis

SPECIES/CELL TYPE: Rat hepatocyte

SEX: 5M

TEST SUBSTANCE: S-1283 Positive controls: 2-acetomidofluorene, dimethylnitrosamine

DOSE RATE OF TEST SUBSTANCE: Preliminary study – 5000 mg/kg single dose by oral gavage Main study – 2500, 5000 mg/kg single dose by oral gavage

RESPONSE: The net grain count for animals receiving the test substance was not increased and the number of cells found in repair was not more than 0.7%. Thus it was concluded that the test substance did not induce unscheduled DNA synthesis in this assay

GLP: Y

TEST GUIDELINE: US EPA 84-2

REFERENCE SOURCE: Clare, C., S-1283: Measurement of unscheduled DNA synthesis in rat liver using an In vivo/In vitro procedure, report number 333/72, Corning Hazelton (Europe), England, 1997

RELIABILITY (KLIMISCH SCORE): 1 (reliable without restriction)

STUDY TYPE: Micronucleus test

SPECIES: Mouse CD-1

SEX: 5M &5F

TEST SUBSTANCE: S-1283 Positive control: cyclophosphamide

DOSE RATE OF TEST SUBSTANCE: 1250, 2500, 5000 mg/kg single dose by oral gavage

RESPONSE: The test substance did not induce any significant increase in the incidence of micronucleated polychromatic erythrocytes. Thus, it was concluded that the test substance had no potential to induce micronuclei in mouse bone marrow cells this assay.

GLP: Y

TEST GUIDELINE: US EPA FIFRA 84-2, 92/69/EEC

REFERENCE SOURCE: Odawara, K., Micronucleus test on S-1283 in CD-1 mice, report number 3171, Environmental Health Science Laboratory, Japan, 1996

RELIABILITY (KLIMISCH SCORE): 1 (reliable without restriction)

Conclusion on Classification:Not classified

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REPRODUCTIVE AND DEVELOPMENTAL TOXICITY Developmental Studies SPECIES: Rat

ENDPOINT: Embryofoetal toxicity

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: US EPA FIFRA 83-3 (1984), OECD 414 (1981), JMAFF ( 1985)

REFERENCE: Hatakenaka N., YI-5301: Teratogenicity study in rats, report number IET 93-0007, The Institute of Environmental Toxicology, Japan, 1994

TYPE OF STUDY: Teratology

STRAIN: Crj:CD (SD)

NO/GROUP: 24F

DOSE: 0, 40, 200, 1000 mg/kg/day (Days 6 to 15 of gestation inclusive) by oral gavage

Dose selection was based on the results from a preliminary study investigating doses of 0, 10, 100, 300 and 1000 mg/kg/day in pregnant rats which resulted in a slight but equivocal increase in the incidence of resorptions and foetal deaths at 1000 mg/kg/day.

TEST SUBSTANCE: YI-5301

STUDY SUMMARY: Food intake was slightly decreased during the treatment period for females receiving 1000 mg/kg/day. There were no other maternal signs. There were no adverse effects on embryofoetal development at any dosage.

MATERNAL TOXICITY NOAEL: 200 mg/kg/day LOAEL: 1000 mg/kg/day

FOETAL TOXICITY NOAEL: 1000 mg/kg/day LOAEL: >1000 mg/kg/day

SPECIES: Rabbit

ENDPOINT: Embryofoetal toxicity

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: US EPA FIFRA 83-3 (1984), OECD 414 (1981), JMAFF ( 1985)

REFERENCE: Hitoshi H., YI-5301: Teratogenicity study in rabbits, report number IET 93-0049, The Institute of Environmental Toxicology, Japan, 1994

TYPE OF STUDY: Teratology

STRAIN: Japanese White

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NO/GROUP: 18F

DOSE: 0, 40, 200, 1000 mg/kg/day (Days 6 to 18 of gestation inclusive) by oral gavage

Dose selection was based on the results from a preliminary study investigating doses of 0, 10, 100, 300 and 1000 mg/kg/day in pregnant rabbits which resulted in enlargement of the liver in 3/5 adults receiving 1000 mg/kg/day.

TEST SUBSTANCE: YI-5301

STUDY SUMMARY: A single animal receiving 1000 mg/kg/day died on Day 15 however an association with treatment was not clear. Treatment at 1000 mg/kg/day resulted in lower mean weight and weight gain in the later stages of gestation. Lower food intake was also noted amongst animals of this group. Necropsy revealed 2 adults at 1000 mg/kg/day to have an enlarged liver. There were no adverse maternal effects seen at 40 or 200 mg/kg/day. Foetal examinations revealed a significantly higher incidence of extra (13) ribs at 1000 mg/kg/day.

MATERNAL TOXICITY

NOAEL: 200 mg/kg/day LOAEL: 1000 mg/kg/day

FOETAL TOXICITY NOAEL: 200 mg/kg/day LOAEL: 1000 mg/kg/day

Conclusion On Classification: Not classified

Teratological effects only seen in the presence of doses well above the maternal NOAEL.

Reproductive Studies SPECIES: Rat

ENDPOINT: Reproductive capacity

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: US EPA FIFRA 83-4 (1984), JMAFF, (1985), OECD 416 (1983)

REFERENCE: Hatakenaka, N., YI-5301: Two generation reproduction study in rats, report number IET 93- 0047, The Institute of Environmental Toxicology, Japan, 1996

TYPE OF STUDY: 2 generation study

STRAIN: Crj:CD (SD)

NO/GROUP: 24M & 24F per generation

DOSE: 0, 80, 400, 2000 ppm in diet equivalent to 0, 5.6, 28.2, 139.1 and 0, 6.3, 31.7, 156.8 mg/kg/day for males and females FO generation respectively and 0, 6.6, 33.4, 158.7 and 0, 6.8, 35.6, 171.9 mg/kg/day males and females respectively F1 generation

Dose selection was based on the results from a preliminary study investigating doses of 0, 100, 300, 1000 or 3000 ppm in rats for three weeks prior to mating through to weaning of F1 offspring. Liver weight of adults was increased at 300, 1000 and 3000 ppm, appearing macroscopically enlarged in 4/8 males and 2/8 females at 3000 ppm. Lower weight gain was evident in offspring of both sexes at 3000 ppm

TEST SUBSTANCE: YI-5301

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STUDY SUMMARY: The only treatment related sign evident in F0 and F1 adults was increased liver weight at 2000 mg/kg/day in F0 males, increased relative adrenal gland weight in F0 females, and evidence of hepatotoxicity in F1 males. There were no adverse effects on reproductive performance at any of the dosages investigated in either generation. There was higher F1 pup mortality at 2000 mg/kg/day during the first 4 days post partum with subsequent lower weight gain in the later stages of the weaning period. The viability index on lactation day 4 was below historical control values. This lower growth was also evident to Day 21 post partum in F2 offspring receiving 2000 ppm. There were no adverse effects seen at 80 or 400 ppm amongst offspring of either generation.

PARENTAL TOXICITY

NOAEL: 400 ppm (28.2/31/7 mg/kg/day males/ females F0 generation, 33.4/35.6 mg/kg/day males/females F1 generation) LOAEL: 2000 ppm (139.1/156.8 mg/kg/day males/females F0 generation, 158.7/171.9 mg/kg/day males/females F1 generation)

REPRODUCTIVE EFFECTS

NOAEL: 2000 ppm (139.1/156.8 mg/kg/day males/females F0 generation, 158.7/171.9 mg/kg/day males/females F1 generation) LOAEL: > 2000 ppm (139.1/156.8 mg/kg/day males/females F0 generation, 158.7/171.9 mg/kg/day males/females F1 generation)

DEVELOPMENTAL TOXICITY

NOAEL: 400 ppm (28.2/31/7 mg/kg/day males/ females F0 generation, 33.4/35.6 mg/kg/day males/females F1 generation) LOAEL: 2000 ppm (139.1/156.8 mg/kg/day males/females F0 generation, 158.7/171.9 mg/kg/day males/females F1 generation)

Conclusion on Classification: Not classified

TARGET ORGAN SYSTEMIC TOXICITY Subacute Toxicity SPECIES: Rat

ENDPOINT: Dermal toxicity

VALUE: LOAEL >1000 mg/kg/day NOAEL 1000 mg/kg/day

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: OECD 410 (1981), EPA FIFRA OPPTS 870.3200 (1998), JMAFF (1985)

REFERENCE: Ichiki, T., 28 day repeated dose dermal toxicity study of S-1283TG in rats, report number 29830, Panapharm Laboratories Co., Ltd., Japan, 1999

ROUTE OF EXPOSURE: Dermal

STRAIN: Crj:CD (SD)

NO/GROUP: 10M &10F

DOSE: 0, 20, 100, 1000 mg/kg/day occlusive 6 hours per day

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TEST SUBSTANCE: S-1282 TG

STUDY SUMMARY: There were no adverse treatment related effects at any dosage on any of the parameters investigated. These consisted of clinical observations, functional observations, dermal reaction, body weight and food intake, ophthalmology, haematological and biochemical investigations, necropsy, organ weights and histopathological examinations.

Reviewer comment: These was a slight but statistically significant increase in liver weight relative to body weight for males receiving 1000 mg/kg/day, however the difference was slight and in the absence of any other corroborative data was considered not to be an adverse effect.

Conclusion on Classification: Not classified

Subchronic Toxicity SPECIES: Mouse

ENDPOINT: Toxicity

VALUE: LOAEL 1600 ppm (213.6 mg/kg/day) for males, 6400 ppm (994.5 mg/kg/day) for females NOAEL 400 ppm (55.13 mg/kg/day) for males, 1600 ppm (250.5 mg/kg/day) for females

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: EPA FIFRA 82-1 (1984), OECD 408 (1981), JMAFF (1985)

REFERENCE: Inui, K., YI-5301: 13 week oral subchronic toxicity study in mice, report number IET 92-0111, The Institute of Environmental Toxicology, Japan, 1994

TYPE OF STUDY: subchronic toxicity

STRAIN: Crj:CD-1 ICR

NO/GROUP: 12M & 12F

DOSE: 0, 100, 400, 1600, 6400 ppm in the diet equivalent to 0, 13.42, 55.13, 213.6, 878.4 and 0, 15.15, 62.00, 250.5, 994.5 mg/kg/day for males and females respectively

Dose selection was based on the results from a4 week preliminary study investigating doses of 0, 80, 400, 2000 and 10000 ppm. A trend for increased liver weight was evident from 400 ppm upwards, with increased relative liver weight evident in both sexes at 2000 and 10000 ppm. 10000 ppm also resulted in slight decreases in bodyweight and food utilization efficiency in males, increased plasma alkaline phosphatase in males and increased plasma glutamic oxaloacetic transaminase and glutamic pyruvic transaminase in both sexes and increased triglycerides in females. Dark coloured liver was noted frequently at 10000 ppm in both sexes at necropsy.

TEST SUBSTANCE: YI-5301

STUDY SUMMARY:

At 6400 ppm increased plasma alkaline phosphatase was evident in both sexes. At necropsy both sexes revealed increased liver weight with enlarged liver seen in 6 females. Histopathological examination revealed centrilobular hepatocellular swelling in the liver in 10/12 males and all females amongst which 4 males and 6 also females showed periportal hepatocellular necrosis.

1600 ppm resulted in increased liver weight in males five of which showed centrilobular hepatocellular swelling.

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There were no adverse effects seen in either sex at 100 and 400 ppm.

SPECIES: Rat

ENDPOINT: Toxicity

VALUE: LOAEL 300 ppm (18.28 mg/kg/day) for males, 1000 ppm (69.0 mg/kg/day) for females NOAEL 100 ppm (6.12 mg/kg/day) for males, 300 ppm (20.50 mg/kg/day) for females

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: EPA FIFRA 82-1 (1984), OECD 408 (1981), JMAFF (1985)

REFERENCE: Nakashima, N., YI-5301: 13 week oral subchronic toxicity study in rats, report number IET 92- 0078, The Institute of Environmental Toxicology, Japan, 1994

TYPE OF STUDY: subchronic toxicity

STRAIN: Crj:CD (SD) (SPF)

NO/GROUP: 12M & 12F

DOSE: 0, 100, 300, 1000, 3000 ppm in the diet equivalent to 0, 6.12, 18.28, 61.8, 183.7 and 0, 6.74, 20.50, 69.0, 204.8 mg/kg/day males and females respectively

Dose selection was based on the results from a 4 week preliminary study investigating doses of 0, 80, 400, 2000 and 10000 ppm in F344 rats. 10000 ppm resulted in slightly lower weight gain and food intake in females. Haematological disturbances of lower heamatocrit, haemoglobin concentration and erythrocyte count and increase in platelets was seen in both sexes. Biochemical disturbances of increased protein and globulin were seen in both sexes, males also showed increased albumin, calcium, blood urea nitrogen and females showed increased cholesterol, triglyceride and γ-glutamyl transpeptidase. Increased liver weight with a macroscopically enlarged appearance was evident in both sexes. Adrenal weight was increased in both sexes. 2000 ppm resulted in a slight increase in platelets in males and lower heamatocrit in females, increased plasma total protein and globulin in both sexes with increased albumin and blood urea nitrogen in males, increased cholesterol, total protein and γ-glutamyl transpeptidase in females. Increased liver weight and macroscopically enlarged liver was seen in 5/6 males and 3/6 females. 400 ppm resulted in lower haematocrit in females and increased liver weight. Males also showed increased adrenal weight.

TEST SUBSTANCE: YI-5301

STUDY SUMMARY:

At 3000 ppm there was lower haematocrit and haemoglobin concentration and increases in plasma glutamic oxaloacetic transaminase, γ-glutamyl transpeptidase, total cholesterol, creatinine phosphokinase and potassium in males. Females showed increases in γ-glutamyl transpeptidase, glutamic oxaloacetic transaminase and creatinine phosphokinase. Liver weight was increased in both sexes and necropsy revealed macroscopically enlarged livers for 3 males and 4 females. Histopathological examination showed centrilobular heptocellular swelling in the liver of 11 males and 9 females.

At 1000 ppm males showed decreased heamatocrit and haemoglobin levels. Increased liver weight was evident in both sexes appearing enlarged in 2 females macroscopically. Histopathological examination revealed centrilobular hepatocellular swelling in 5 males.

At 300 ppm the only treatment related change was increased liver weights in males.

100 ppm did not result in any treatment related effects in either sex

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SPECIES: Rat

ENDPOINT: Toxicity

VALUE: LOAEL 5000 ppm , 300.4 mg/kg/day for males, 336.6 mg/kg/day for females NOAEL >5000 ppm, 300.4 mg/kg/day for males, 336.6 mg/kg/day for females

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: US EPA FIFRA 82-1(1984), OECD 408 (1981), JMAFF (1985)

REFERENCE: Nakashima, N., S-1283: 90 day subchronic oral toxicity study in rats, report number IET 97- 0027, The Institute of Environmental Toxicology, Japan, 1998

TYPE OF STUDY: Dose range finder for longer term studies

STRAIN: Crj:CD (SPF)

NO/GROUP: 12M & 12F

DOSE: 0, 5000, 10000 ppm in the diet, equivalent to 0, 300.4, 610 and 0, 336.6, 692 mg/kg/day for males and females respectively

TEST SUBSTANCE: S-1283

STUDY SUMMARY:

10000 ppm resulted in decreased haematocrit and haemoglobin concentration and increased platelet count for both sexes. Increased plasma globulin, total protein, creatinine phosphokinase and total cholesterol were evident in males. Necropsy revealed increased liver weight in both sexes, increased thyroid weight in males and increased kidney weight in females. Histopathological examination revealed centrilobular hepatocellular hypertrophy in the liver of all animals. Elongated upper incisors had been noted in both sexes however no histopathological changes were evident to account for this.

5000 ppm resulted in decreased haematocrit in both sexes and increased platlets for females. Increased plasma globulin was seen in both sexes with increased total protein for males. Necropsy revealed increased liver weight in both sexes. Histopathology revealed centrilobular hepatocellular hypertrophy in 11 males and all females.

SPECIES: Dog

ENDPOINT: Toxicity

VALUE: LOAEL 2000 ppm equivalent to 53.7 and 55.9 mg/kg/day for males and females respectively NOAEL 200 ppm equivalent to 5.33 and 5.42 mg/kg/day for males and females respectively

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: US EPA FIFRA 82-1 (1984), OECD 409 (1981), JMAFF (1985)

REFERENCE: Kitazawa, T., YI-5301: 13 week oral subchronic toxicity study in dogs, report number IET 93- 0113, The Institute of Environmental Toxicology, Japan, 1995

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TYPE OF STUDY: subchronic toxicity

STRAIN: Beagle

NO/GROUP: 4M & 4F

DOSE: 0, 200, 2000, 10000 ppm in the diet, equivalent to 0, 5.33, 53.7, 268 and 0, 5.42, 55.9, 277 mg/kg/day for males and females respectively Dose selection was based on the results from a 4 week preliminary study investigating doses of 0, 1000, 3000, 10000 and 30000 ppm in 1 male and 1 females. 30000 ppm (968/594 mg/kg/day male/female respectively) resulted in vomiting of the feed in the female with bodyweight loss and decreased food intake. Lower weight gain was also seen in the male. Plasma biochemistry revealed increased alkaline phosphatase in both sexes with increased glutamic oxaloacetic and pyruvic transaminases in the female. Liver weight was increased for both animals and both showed centrilobular hepatocellular swelling in the liver, the male also with bile duct proliferation. 10000 and 3000 ppm (321/340 mg/kg/day and 99.7/102 mg/kg/day male/female respectively) resulted in low weight gain of animals, increased alkaline phosphatase, increased liver weight and centrilobular hepatocellular swelling. 1000 ppm (30.5/35.7 mg/kg/day male/female respectively) resulted in increased alkaline phosphatase activity, increased liver weight and centrilobular hepatocellular swelling.

TEST SUBSTANCE: YI-5301

STUDY SUMMARY:

10000 ppm resulted in 2 males showing mucous in faeces. Increased alkaline phosphatase and decreased albumin was evident in all animals at 7 and 13 weeks of treatment. Females also showed increased triglyceride and globulin with a concomitant lower albumin/globulin ratio at Weeks 7 and 13 and lower glucose at Week 13. Necropsy revealed increased liver weight in both sexes. Males also showed lower prostate weights. Histopathological examination revealed centrilobular hepatocellular swelling in the liver of all animals with inflammatory cell infiltration in the centrilobular area for 2 females. Acinar cell atrophy was seen in the prostate of 3/4 males. Moderate enteritis in the colon and rectum with inflammation of the neighbouring lymph nodes was evident in 1 male previously exhibiting mucous in its faeces.

2000 ppm resulted in 1 male with mucous in its faeces. Increased liver weight was evident in both sexes with centrilobular hepatocellular swelling seen in all animals with inflammatory cell infiltration in the centrilobular area evident in 1 male. A single male with low prostate weight revealed acinar cell atrophy.

200 ppm did not result in any treatment related changes in either sex.

SUPPLEMENTARY STUDY

SPECIES: Rat

ENDPOINT: P450 induction

VALUE: Not an inducer of drug metabolizing enzyme activity

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: None specified

REFERENCE: Inui, K., YI-5301:13 week oral subchronic toxicity study in rats biochemical and pathological analyses for hepatomegaly, report number IET 94-0095, The Institute of Environmental Toxicology, Japan, 1995

TYPE OF STUDY: enzyme induction

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STRAIN: Crj:CD

NO/GROUP: 12M & 12F with 6 per sex sacrificed at Week 4

DOSE: 0, 1000, 2000 ppm equivalent to 0, 59.6, 119.5 and 0, 66.7, 133.5 mg/kg/day for males and females respectively

TEST SUBSTANCE: YI-5301

STUDY SUMMARY:

2000 ppm showed increased liver weight in males at Weeks 4 and 13 and in females at Week 4 only. Histopathological investigations revealed centrilobular hepatocellular swelling in the liver of all males at Week 4. There was a significant increase in microsomal protein content in males at Week 13 however, there were no differences in cytochrome P-450 and drug metabolizing activity in either sex compared with control.

1000 ppm resulted only in increased liver weight in females at Week 4. There were no histopathological changes or changes in biochemical parameters in either sex.

Thus hepatomegaly attributed to treatment with YI-5301 was evident in both sexes with a slight disposition towards females however there were no significant increases in drug metabolizing enzyme activity in the liver. Conclusion on Classification: 6.9A

KEY TARGET ORGAN/SYSTEM: Liver, haematopoetic, adrenal

SEVERITY OF EFFECT: Liver & haematopoeitic

MODE OF ACTION (HUMAN RELVANCE): No data to suggest MOA is not human relevant. Haematopoeitic effects confined to rodents and not observed in the dog study. However, effects are still considered human relevant because of lack of a demonstrated MOA for this effect. Hepatic effects observed in 2 rodent species and in the dog study.

Chronic Toxicity SPECIES: Dog

ENDPOINT: Toxicity

VALUE: LOAEL 1000 ppm equivalent to 23.5 and 23.8 mg/kg/day for males and females respectively NOAEL 200 ppm equivalent to 4.62 and 4.79 mg/kg/day for males and females respectively

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: US EPA FIFRA 83-1 (1984), OECD 452 (1981), JMAFF (1985),

REFERENCE: Kitazawa, T., YI-5301: 12 month oral chronic toxicity study in dogs, report number IET 94- 0005, The Institute of Environmental Toxicology, Japan, 1996

TYPE OF STUDY: chronic toxicity

STRAIN: Beagle

NO/GROUP: 4M & 4F

DOSE: 0, 200, 1000, 5000 ppm in the diet, equivalent to 0, 4.62, 23.5, 116 and 0, 4.79, 23.8, 117 mg/kg/day for males and females respectively

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TEST SUBSTANCE: YI-5301

STUDY SUMMARY:

5000 ppm resulted in sporadic, transient episodes of mucous in the faeces of 3 males. Lower haemoglobin concentration and erythrocyte count was seen males at Week13 and lower haemoglobin concentration in females at Week 26. Marginally lower values for these parameters were also evident in both sexes at all other investigations including at Week 52. Increased plasma alkaline phosphatase and triglyceride was evident in both sexes at all investigations (Weeks, 13, 26 and 52). Necropsy revealed macroscopically enlarged liver in all animals with increased liver weight in both sexes, being 67% and 71% greater for males and females respectively compared with their concurrent control counterparts. Histopathological examination revealed centrilobular hepatocellular swelling in the liver of all animals and atrophy of the glandular epithelium of the prostate of 1 male.

1000ppm revealed a slightly higher alkaline phosphatase levels in both sexes throughout the study. Necropsy revealed increased liver weight for both sexes being 26% and 29% higher for males and females respectively compared with controls. Centrilobular hepatocellular swelling was evident in all animals.

200 ppm did not result in any treatment related changes in either sex.

SPECIES: Mouse

ENDPOINT: carcinogenicity

VALUE:

LOAEL 241/243 mg/kg/day males/females respectively for toxicity NOAEL 60.1/60.5 mg/kg/day males/females respectively for toxicity There was no oncogenic potential demonstrated in either sex at the dosages investigated

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: US EPA FIFRA 83-2 (1984), OECD 451 (1981), JMAFF (1985),

REFERENCE: Kitazawa, T., YI-5301 18 month oral oncogenicity study in mice, report number IET 93-0023, The Institute of Environmental Toxicology, Japan, 1996

TYPE OF STUDY: oncogenicity/chronic toxicity

STRAIN: Crj:CD-1

NO/GROUP: 52M & 52F main study (oncogenicity and toxicity), 12M & 12F toxicity with interim sacrifice at Week 52

DOSE: 0, 15, 60, 240 mg/kg/day in the diet. As the concentration in diets was adjusted during the course of the study the overall doses average to 0, 15.1, 60.1, 241 and 0, 15.1, 60.5, 243 mg/kg/day for males and females respectively

TEST SUBSTANCE: YI-5301

STUDY SUMMARY:

240 mg/kg/day resulted in lower weight gain evident amongst males and to a lesser extent females during the first 52 weeks of treatment. There were an increased number of males with centrilobular hepatocellular fatty change in the liver after 52 weeks of treatment. Female liver weight was higher than controls at Week 52

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15 and 60 mg/kg/day did not result in any treatment related change in either sex at either dose.

The test substance did not exhibit any oncogenic potential in either sex

SPECIES: Mouse

ENDPOINT:Carcinogenicity/toxicity

VALUE: LOAEL 4500 ppm equivalent to 484/482 mg/kg/day for males/females respectively for toxicity NOAEL 2250 ppm equivalent to 242/243 mg/kg/day for males/females respectively for toxicity No oncogenic potential was demonstrated in either sex at the dosages investigated

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: US EPA FIFRA 83-2 (1984) and OPPTS 870.4200 (1998), OECD 451 (1981), JMAFF (1985),

REFERENCE: Nakashima, N., S-1283: 18 month oral oncogenicity study in mice, report number IET 98-0045, The Institute of Environmental Toxicology, Japan, 2001

TYPE OF STUDY: oncogenicity/chronic toxicity

STRAIN: Crj:CD-1 (SPF) (ICR)

NO/GROUP: 50M & 50F main study (oncogenicity and toxicity), 12M & 12F toxicity with interim sacrifice at Week 52

DOSE: 0, 2250, 4500 ppm in the diet, equivalent to 0, 242, 484 and 0, 243, 482 mg/kg/day for males and females respectively

TEST SUBSTANCE: S-1283

STUDY SUMMARY:

4500 ppm resulted in increased liver weight in females after 52 weeks. After 78 weeks of treatment males showed an increased incidence of centrilobular hepatocellular fatty change in the liver. There were no treatment related changes in either sex at 2250 ppm

No oncogenic potential was demonstrated in either sex at the doses investigated.

Reviewers note: there was a marginally higher incidence of centrilobular hepatocellular fatty change in the liver of males receiving 2250 ppm which statistically created a trend however the difference from controls (8 versus 5 males) is only slight and not clearly indicative of a real effect

SPECIES: Rat

ENDPOINT: Carcinogenicity/toxicity

VALUE: LOAEL 16/64 mg/kg/day males/females respectively NOAEL 4/16 mg/kg/day males/females respectively There was no oncogenic potential considered demonstrated in either sex at the dosages investigated

KLIMISCH SCORE: 1 (reliable without restriction)

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GLP: Y

TEST GUIDELINES: US EPA FIFRA 83-5 (1984), OECD 453 (1981), JMAFF (1985),

REFERENCE: Nakashima, N., YI-5301: 24 month oral chronic toxicity and oncogenicity study in rats, report number IET 92-0148, The Institute of Environmental Toxicology, Japan, 1996

TYPE OF STUDY: oncogenicity/chronic toxicity

STRAIN: Crj:CD (SD)

NO/GROUP: 50M & 50F main study (oncogenicity and toxicity), 35M & 35F toxicity with interim sacrifices at Week 13, 52 and 78 (10 per sex per group per occasion)

DOSE: 0, 4, 16, 64 mg/kg/day in the diet. As the concentration in diets was adjusted during the course of the study the overall doses average to 0, 4.01, 16.1, 64.4 and 0, 4.03, 16.1, 64.5 mg/kg/day for males and females respectively.

TEST SUBSTANCE: YI-5301

STUDY SUMMARY:

64 mg/kg/day resulted in lower weight gain amongst males in the latter half of the study. Elevated plasma total cholesterol and total bilirubin at Week 26 and lower heamaglobin concentration at Week 78 was evident in males. Increased lactate dehydrogenase was evident in females at Week 26. Increased liver weight was seen in males at Week 26 with histopathology revealing centrilobular hepatocellular swelling in 6/10 males.

16 mg/kg/day treatment related changes were confined to elevated plasma total cholesterol, increased liver weight and liver size in males only

4 mg/kg/day did not result in any treatment related changes in either sex.

No oncogenic potential was demonstrated in either sex at the dosages investigated. The overall incidence of testicular interstitial cell tumour was significantly increased in all groups compared with controls (1/80, 10/80, 10/80, 11/78 at 0, 4, 16, 64 mg/kg/day respectively). All of the tumors were benign, there was no indication of earlier onset, the incidence of bilateral occurrence was similar across the groups and there was no concomitant increase in the incidence of testicular interstitial cell hyperplasia. Also the control incidence was also almost at the bottom of the range for background control data for this strain and source of animal. Thus the finding was considered to be coincidental.

SPECIES: Rat

ENDPOINT: Carcinogenicity/toxicity

VALUE: LOAEL 5000 ppm equivalent to 187/216 mg/kg/day males/females respectively NOAEL 50 ppm equivalent to 1.83/2.07 mg/kg/day males/females respectively There was no oncogenic potential considered demonstrated in either sex at the dosages investigated

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: US EPA FIFRA 83-5 (1984) and OPPTS 870.4300 (1998), OECD 453 (1981), JMAFF (1985),

REFERENCE: Nakashima, N., S-1283: 24 month oral chronic toxicity and oncogenicity study in rats, report number IET 97-0028, The Institute of Environmental Toxicology, Japan, 2001

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TYPE OF STUDY: oncogenicity/chronic toxicity

STRAIN: Crj:CD (SD)

NO/GROUP: 50M & 50F main study (oncogenicity and toxicity), 15M & 15F toxicity with interim sacrifice at Week 52

DOSE: 0, 50, 5000, 10000 ppm in the diet equivalent to 0, 1.83, 187, 386 and 0, 2.07, 216, 445 mg/kg/day for males and females respectively.

TEST SUBSTANCE: S-1283

STUDY SUMMARY:

10000 ppm resulted in lower weight gain amongst males and to a greater degree females throughout the treatment period with a concomitant lower food intake, and food utilisation efficiency, an increase in the number of thin females and higher survival rate. Lower heamatocrit and haemoglobin concentration and marginally lower mean corpuscular volume was seen in both sexes. Increased platelet count was seen in females at Week 13 whilst males showed an elongated activated partial thromboplastin time at Week 104. Increases in albumin, globulin and thus total protein and γ-glutamyl transpeptidase were evident in both sexes during the treatment period. Higher total cholesterol was noted in females in the first half of the study. Higher thyroid weight was noted in males at Weeks 52 and 104. Increased liver weight was evident in both sexes at Week 52 and males at Week 104 with all animals showing centrilobular hepatocellular hypertrophy at Week 52 and Week 104. An increased incidence of thickening of bone in the parietal region was noted at week 104 in both sexes, histology revealing inward hyperplasia of the bone tissue. In life observations of high incidences of incisor changes (whitening, elongation and partial abrasion of upper and lower incisors) seen in both sexes from Week 8 were complemented by histological changes showing abnormal amelogenesis.

5000 ppm resulted in slightly lower food intake and weight gain and concomitant increase in thin females during the treatment period. Females showed a lower platelet count at Week 13 with lower haematocrit and haemoglobin concentration with a lower mean corpuscular volume seen at Week 26. Males showed a longer activated partial thromboplastin time at Week 104. Instances of increased total plasma protein through either increased albumin or globulin were noted on occasions throughout the treatment period in both sexes. Higher γ- glutamyl transpeptidase was also evident in both sexes. Higher thyroid weight in males and increased liver weight in both sexes was evident at Week 52. One male and one female revealed inward hyperplasia of bone tissue in the parietal region. In life incisor changes as seen at 10000 ppm were also evident in both sexes at 5000 ppm evident from Week 12 with similar abnormal amelogenesis seen histologically.

50 ppm did not result in any treatment related changes in either sex.

There was no oncogenic potential demonstrated in either sex at the dosages investigated.

SUPPLEMENTARY STUDIES

SPECIES: Rat

ENDPOINT: Investigating potential effects of YI-5301 on proliferative activity of testicular interstitial cells, spermatogenesis and related serum hormone levels

VALUE: The test substance did not exert any effect on proliferative activity of testicular interstitial cells, spermatogenesis and related serum hormone levels

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: None specified

REFERENCE: Yoshida, A., YI-5301: 4 week supplementary study in rats, report number IET 95-0164, The Institute of Environmental Toxicology, Japan, 1996

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TYPE OF STUDY: investigatory

STRAIN: Crj:CD (SD) (SPF)

NO/GROUP: 14M

DOSE: 0, 4, 16, 64 mg/kg/day in the diet. As the concentration in diets was adjusted during the course of the study the overall doses average to 0, 3.90, 16.0, 64.1mg/kg/day

TEST SUBSTANCE: YI-5301

STUDY SUMMARY: There were no treatment related effects on bodyweight, food intake, serum levels of oestradiol, luteinising hormone, prolactin or testosterone, organ weights or any histopathological changes in the testes or epididymides. There no differences in germ cell indices representing spermatogonia, prereptotene spermatocyte, pachytene spermatocyte and round spermatid in stage VII seminiferous tubules. Brdu labeling did not show any increase in cell proliferation in treated groups. Thus YI-5301 did not demonstrate any effect on serum hormones reflecting testicular function, proliferative activity of testicular interstitial cells and spermatogenesis.

SPECIES: Rat

ENDPOINT: Investigating potential effects of YI-5301 on proliferative activity of testicular interstitial cells

VALUE: The test substance did not exert any effect on proliferative activity of testicular interstitial cells

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: None specified

REFERENCE: Nakashima, N., YI-5301: 13 week oral subchronic toxicity study in rats additional study of effect on proliferative activity of testicular interstitial cells, report number IET 95-0182, The Institute of Environmental Toxicology, Japan, 1996

TYPE OF STUDY: investigatory

STRAIN: Crj:CD (SD) (SPF)

NO/GROUP: 8M

DOSE: 0, 3000 ppm in the diet equivalent to 183.7 mg/kg/day

TEST SUBSTANCE: YI-5301

STUDY SUMMARY: The tissues examined in this study were derived from the previously reported 13 week subchronic study. Sections from the testes were immunohistochemically stained for proliferating cell nuclear antigen (PCNA) and the number of PCNA- positive cells per about 1000 interstitial cells was counted and the PCNA labeling index calculated. The mean percentage and standard deviation was 0.16 ± 0.12 and 0.19 ± 0.16 in controls and treated animals respectively. Thus, there was no difference in the proliferative activity of interstitial cells of both groups.

Conclusion on Classification: 6.9A

KEY TARGET ORGAN/SYSTEM: Liver Remarks on Classification:

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Metabolism SPECIES: Rat

ENDPOINT: ADME

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: JMAFF (1985)

REFERENCE: Elsom L.F., 14C-YI-5301 Metabolism in the rat, report number YMA 15/950478, HLS Ltd., England, 1996

STRAIN: Hsd/Ola:CD® SD

NO/SEX/GROUP: 5M & 5F for excretion studies, 9M & 9F for plasma radioactivity kinetics, 3M & 3F for biliary excretion, 12M & 12F for tissue distribution/accumulation

TEST SUBSTANCES: [ 14C-t-butylphenyl1]YI-5301 and [14C-oxazole]YI-5301

DOSE LEVELS: 5, 500 mg/kg by oral gavage, single dose. Repeat dose oral gavage studies for 14 days were equimolar dose of the two labeled forms

STUDY SUMMARY:

Excretion studies After a single dose of [ 14C-t-butylphenyl1]YI-5301 5 mg/kg total radioactivity recoveries during 7 days were 95.0- 99.6% and 93.0 – 96.6% for males and females respectively. Means of 8.49% and 7.55% of the dose was excreted in the urine of males and females respectively with the corresponding faecal excretion being 88.3% and 86.8% of the dose respectively. Most of the radioactivity was eliminated during 0 – 48 hours. No radioactivity was recovered in the expired air. After sacrifice on Day 7 post dose means of 0.13%, 0.05%, 0.47% and 0.09, 0.03, 0.12% of dose was recovered in the carcasses, gastrointestinal tracts and liver respectively for male and female rats. Only the liver had any significant radioactivity after 7 days, 0.491 and 0.143 µg/g in males and females respectively.

After a single dose of [14C-oxazole]YI-5301 5 mg/kg total radioactivity recoveries during 7 days was 90.5 – 94.5% and 90.2 – 106% for males and females respectively. Means of 14.2% and 16.6% of the dose were excreted in the urine of males and females respectively. Faecal excretion over the same period was 77.1% and 77.6% in males and females respectively. Only low levels (0.05% of dose) were found excreted in expired air between 0 – 48 hours. At sacrifice after 7 days means of 0.18%, 0.05%, 0.42% and 0.10%, 0.03%, 0.12% of dose was found in the carcass, gastrointestinal tract and liver of male and female s respectively. The highest concentrations after 7 days were in the liver (0.0320 µg/g and 0.134 µg/g males and females respectively) and thyroids (0.157 µg/g and 0.120 µg/g males and females respectively)

After a single 500 mg/kg dose of [14C-t-butylphenyl1]YI-5301 or [14C-oxazole]YI-5301 a larger proportion of the radioactivity was excreted in the faeces indicating much lower absorption of the test compound. Faecal excretion was greater than 90% of both labeled forms in males and females. Urinary excretion accounted for 1.55% and 1.65% of the dose in males and females respectively receiving [14C-t-butylphenyl1]YI-5301 and 3.23% and 1.94% of dose respectively receiving [14C-oxazole]YI-5301. Concentration of radioactivity after 7 days was highest in the liver with 3.76 µg/g and 1.84 µg/g in males and females respectively receiving [14C-t- butylphenyl1]YI-5301 and 4.96 and 1.36 µg/g respectively receiving [14C-oxazole]YI-5301. Total recoveries of radioactivity during 7 days post dose were 91.1 – 100.7% for [14C-t-butylphenyl1]YI-5301 and 90.6 – 100% for rats dosed with [14C-oxazole]YI-5301.

Plasma concentrations

After a single 5 mg/kg dose of [14C-t-butylphenyl1]YI-5301 or [14C-oxazole]YI-5301 mean maximum plasma concentrations of radioactivity (Cmax) were 1.51and 0.961 µg/g for males and 0.631 and 0.646 µg/g for females

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with peak plasma concentrations occurring between 2 – 4 hours. Concentrations declined with terminal half lives of 52.9 and 61.3 hours for males and females respectively receiving [14C-t-butylphenyl1]YI-5301 and 71.4 and 88.8 hours for males and females respectively receiving [14C-oxazole]YI-5301. After a single 500 mg/kg 14 14 dose of [ C-t-butylphenyl1]YI-5301 or [ C-oxazole]YI-5301Cmax was respectively 16.4 and 5.3 µg/g for males and females and 15.8 and 5.6 µg/g for males and females respectively. Terminal half lives were 44.4 and 28.2 hours for males and females respectively receiving [14C-t-butylphenyl1]YI-5301 and 101.9 and 7.1 hours for males and females respectively receiving [14C-oxazole]YI-5301.

Comparison of the area under the curve (AUC) at the high and low dose indicated reduced absorption at 500 mg/kg which concurs with the excretion data. Comparison of the pharmacokinetic parameters showed a marked difference between the sexes in terms of Cmax and AUC with females exhibiting values approximately half those observed in male rats.

After 14 daily doses at 5 mg/kg/day of an equimolar mixture of [14C-t-butylphenyl1]YI-5301 and [14C- oxazole]YI-5301 Cmax on day 14 was 3.46 and 1.02 µg/g for males and females respectively. Maximum values occurred at 2 and 3 hours for males and females respectively. The accumulation rate after multiple dosing compared with a single dose was 2.6 for males and 1.6 for females based on the respective AUC24 values on Days 1 and 14.

Thus, results show that oral doses of 14C-YI-5301 are quickly eliminated at low and high doses

Bile excretion

After a single 5 mg/kg dose of [ 14C-t-butylphenyl1]YI-5301 40.25% and 53.95% of the dose was excreted in the bile during 0 – 48 hours in males and females respectively. During the same period urinary excretion accounted for 12.13% and 13.53% respectively and faecal excretion for 46.55% and 33.99% respectively.

After a single 5 mg/kg dose of [14C-oxazole]YI-5301 29.89% and 36.80% of the dose was excreted in the bile during 0 – 48 hours in males and females respectively. Urinary excretion accounted for 18.37% and 24.11% and faecal excretion for 50.46% and 39.14% in males and females respectively. After a single 500 mg/kg dose of [ 14C-t-butylphenyl1]YI-5301 biliary excretion was lower than at the low dose with proportions of 12.54% and 11.87% of the dose in males and females respectively. Urinary excretion accounted for 4.29% and 6.02% and faecal excretion for 80.32% and 70.97% of the dose respectively.

After a single 500 mg/kg dose of [14C-oxazole]YI-5301biliary excretion was similarly lower than the low dose with proportions of 9.77% and 10.91% of the dose excreted during 0 – 48 hours in males and females respectively. Urinary and faecal excretion accounted for 5.38% and 79.35% and 8.17% and 74.32% of the dose in males and females respectively.

Thus, 50% to 60% of dose at 5 mg/kg was absorbed but only 16% to 19% at 500 mg/kg. Bile is a principal route of excretion with 30% to 50% of dose excreted during 0-48 hours after a dose of 5 mg/kg. Results indicate that most of the biliary radioactivity was finally eliminated in the faeces rather than urine and that reabsorption had occurred of the radioactivity excreted via the bile.

Tissue distribution

After a single dose of 5 mg/kg of [14C-t-butylphenyl1]YI-5301 or [14C-oxazole]YI-5301 concentrations of radioactivity were significantly higher in the tissues of males compared with females at all sacrifice times. The highest concentrations were found at 3 hours (Cmax) and were greatest in the gastrointestinal tract and tissues such as liver and kidneys which are responsible for metabolism and excretion. By 168 hours the concentrations in most tissues were below the corresponding plasma with only the liver recording significant levels of radioactivity.

After a single dose at 500 mg/kg (with Cmax at 6 hours) )the pattern of distribution in the tissues was proportionally similar to those found at the low dose.

After 14 daily doses at 5 mg/kg/day of an equimolar mixture of [14C-t-butylphenyl1]YI-5301 and [14C- oxazole]YI-5301peak concentrations of radioactivity in tissues occurred at 2 hours (Cmax) and then declined. The distribution of radioactivity after single doses of 14C-YI-3501 showed a similar profile but was significantly higher indicating some accumulation of radioactivity, which was also observed in the plasma kinetic studies.

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Thus, concentrations of radioactivity were highest in the gastrointestinal tract and livers at most sacrifice times with significantly higher concentrations in males compared with females often being 2 fold higher in tissues with significant concentrations.

Metabolism

Metabolite profiles were determined in urine, bile and faecal extracts.

A single metabolite in the urine from rats dosed with [14C-oxazole]YI-5301 was identified as 2,6- difluorobenzoic acid. There were two major components from rats dosed with [14C-t-butylphenyl1]YI-5301. Of these the major metabolite in male urine was identified as 2-amino-2-(2-ethoxy-4-(1‘hydroxycarbonyl-1‘- methylethyl)phenyl)ethanol and accounted for up to 70% of the urinary radioactivity. It was also present at lower levels in the urine of females. The major female urinary metabolite was identified as 2-amino-2-(2- ethoxy-4-(1‘-hydroxymethyl-1‘-methylethyl)phenyl)ethanol.

The bile metabolite profiles from rats dosed with either radioactive form of YI-3501 were almost identical indicating that no cleavage of the molecule had occurred in the bile metabolite. At least 10 metabolites were resolved of which 3 were major components analysis of which revealed that one was formed by hydroxylation of the 4,5-dihydrooxazole ring.

The major component from faecal extract was unchanged parent compound at the low and high dose. At the low dose at least 14 other components from both labeled forms of YI-5301 were observed but none accounted for more than 6.3% of the dose and most accounted for less than 5%. One of these components (maximum of 6.1% of the dose) was shown to be identical to a reference standard supplied by the Sponsor – 2-amino-2-(4- tert-butyl-2-ethoxyphenyl)ethyl-2‘,6‘-difluorobenzoate hydrochloride.

Radioactivity extracted from plasma and livers from rats sacrificed at Cmax and C1/2max showed low levels of unchanged parent compound. Metabolite profiles in the plasma from either radiolabelled form were very similar showing that no cleavage on the molecule had occurred in the plasma metabolites. There was however a significant difference between male and female rats with one component being a major component in the plasma of males but not females however the component did not identify with any of the reference compounds supplied by the Sponsor.

Analysis of liver extracts showed some significant differences between the two radiolabelled forms. The common metabolites to both forms had similar chromatographic properties to the major bile metabolites. The two metabolites unique to [14C-t-butylphenyl1]YI-5301 derived samples had similar properties to the corresponding urinary metabolites.

Thus, there was a significant difference in the proportions of metabolites excreted in the urine of male and female rats and a difference in the major component in the urine.

SPECIES: Goat

ENDPOINT: ADME

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: US EPA 171-4 (Residual Chemistry Section)

REFERENCE: Langford-Pollard, A. D., S-1283 Metabolism in the lactating goat, report number SMO 510/970907, HRC Ltd., England, 1997

STRAIN: British Sannen

NO/SEX/GROUP: 3F (lactating)

TEST SUBSTANCES: [t-butylphenyl-14C]S-1283 and [difluorophenyl-14C]S-1283

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DOSE LEVEL: oral capsule, nominal dose of 21 mg S-1283 per day for 4 days after milking

STUDY SUMMARY:

Recovery of radioactivity in the urine and faeces after dosing with [t-butylphenyl-14C]S-1283 was 1.9% and 17% of dose respectively with a further 80% recovered in the gastrointestinal tract. For [difluorophenyl-14C]S- 1283 recovery in the urine and faeces was 1.5% and 54% of the dose with 29% recovered from the gastrointestinal tract. Overall recoveries were 99% and 85% for [t-butylphenyl-14C]S-1283 and [difluorophenyl-14C]S-1283 respectively.

Unmetabolised S-1283 accounted for 63% - 65% of dose in the faeces and gastrointestinal tract. The major urinary metabolite [t-butylphenyl-14C]S-1283 accounted for 1.4% of the dose and was identified as 2-amino-2- (2-ethoxy-4-(1‘-hydroxycarbonyl-1‘-methylethyl)ethanol. The major metabolites in the urine after dosing with [difluorophenyl-14C]S-1283were 2,6 difluorobenzoic acid (0.5% of dose) and N-(2,6-difluorobenzoylglycine – 0.8% of dose) both of which corresponded with reference compounds supplied by the Sponsor.

During administration of [t-butylphenyl-14C]S-1283 daily milk concentrations increased from 0.001 ppm during Day 1 to 0.004 ppm on Day 4. During administration of [difluorophenyl-14C]S-1283 mean daily milk concentrations increased to a plateau of 0.002 ppm during Days 2 to 4. There was no inhibition of milk yield. Residues in the liver were 0.230 and 0.063 µg/g for [t-butylphenyl-14C]S-1283 and [difluorophenyl-14C]S-1283 respectively and 0.938 µg/g in the kidney after dosing with [t-butylphenyl-14C]S-1283.

The major tissue metabolites corresponded to the major urinary metabolite 2-amino-2-(2-ethoxy-4- (1‘hydroxycarbonyl-1‘-methylethyl)phenyl)ethanol. Another liver metabolite also degraded to this compound on storage. A third liver metabolite was identified as hydroxymethyl benzoic acid (a reference compound supplied by the Sponsor) whilst a fourth was characterized as a polar component. Concentrations of radioactivity after dosing with [difluorophenyl-14C]S-1283 were 0.007 ppm. Concentrations in fat and liver after administration of both radiolabelled forms were ≤0.001 – 0.008 ppm. Concentrations of radioactivity in the heart after [t-butylphenyl-14C]S-1283 were 0.011 ppm.

The results indicate very low potential for the transfer of residues of S-1283 and/or its metabolites to meat, milk or meat by-products in ruminants after dietary exposure to S-1283

SPECIES: Hen

ENDPOINT: Residues

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: US EPA FIFRA § 860.1300

REFERENCE: Jalal, M.A.F., Lee, T.G., Maurer, J.J., Nature or residues: Metabolism of: [t-butylphenyl-14C] and [difluorophenyl-14C]S-1283 in laying hens , report number VP-11888, Valen Technical Center, USA, 1999

STRAIN: White Leghorn

NO/SEX/GROUP: 3 F Control group,5F per treated group. Egg laying, eggs collected twice daily prior to each dose

TEST SUBSTANCES: S-1283, [t-butylphenyl-14C]S-1283 and [difluorophenyl-14C]S-1283

DOSE LEVEL: 0, 12 ppm and 11 ppm average daily dose for [t-butylphenyl-14C] and [difluorophenyl-14C]S- 1283 respectively for 4.5 days

STUDY SUMMARY:

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The total radioactivity residues in egg yolks and whites increased gradually with time to a maximum of 0.23 – 0.27 ppm and 0.008 – 0.013 ppm respectively. The total tissue residue levels were similar for both treated groups varying from a high of around 2.4 ppm in the liver to 0.015ppm in breast muscle.

The majority (84.4 – 99.8%) of the radioactivity in egg yolk, egg white, abdominal and skin fat, thigh muscle, breast muscle and liver was extractable. The bound residue in the post extraction solids of the liver was about 0.29 ppm. The amount of unextractable residue in all other samples was less than 0.03 ppm.

Unmetabolised parent compound was the major radiolabelled residue in egg yolk, abdominal and skin fat, thigh and breast muscle. Its concentration in isolated egg yolk was about 0.1 ppm. However, the whole egg with a yolk to white ratio of 31:69 w/w contained S-1283 at a much lower concentration (<0.036 ppm). S-1283 accounted for about 3% (0.057 – 0.078 ppm) of radioactivity in the liver but 90 – 92% (0.55 – 0.69 ppm) in the composite fat.

Most of the 14C residue in the liver was the metabolite 2-Methyl-2-{3-ethoxy-4-[2-(2,6-difluoropehenyl)-4,5- dihydro-1,3-oxazol-4-yl]phenyl}propionic acid also observed in minor quantities in all tissues except egg white. The metabolite 2-Methyl-2-{3-ethoxy-4-[2-(2,6-difluorophenyl)-4,5-dihydro-1,3-oxazol-4-yl]phenyl}propanol was present in trace amounts in eggs and tissues. 2-Amino-2-(4-tert-butyl-2-ehoxyphenyl)ethyl 2,6- difluorobenzoate was present in small quantities in a number of tissues whilst the -7-CO2H form was observed in the liver only. The metabolite 5-ter-Butyl-2-[2-(2,6-difluorphenyl)-1,3-oxazol-4-yl]phentole was observed in egg yolk, fat and muscle. Other minor metabolites were observed in the liver.

The liver contained unextractable bound 14C residues with both labels (about 0.29 ppm or 12 – 15% of total radioactivity). The majority (80%) was protein bound. Minor amounts of metabolites were detected from the bound residues. All the metabolites specified corresponded with reference compounds supplied by the Sponsor.

Thus S-1283 was extensively metabolized by the laying hen. Around ten metabolites were identified from eggs and various tissues. The major metabolic processes were oxidation of the tert-butyl moiety and hydrolysis of the dihydrooxazole ring. Based on the findings a metabolic pathway of S-1283 could be postulated. The metabolic routes in the hen were similar to those observed in the rat and goat.

. Conclusion on classification: Remarks on Classification:

The following assessments are of a metabolite of YI-5301 designated 2,5-YI

ACUTE TOXICITY Acute Oral Toxicity SPECIES: Rat

ENDPOINT: LD50

VALUE: >5g/kg

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: JMAFF (1985)

REFERENCE: McCrae, L.A., 2,5-YI Acute oral toxicity to the rat, report number YMA 28c/952619/AC, HLS Ltd., England, 1996

STRAIN: Hsd/Ola:Sprague Dawley (CD)

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NO/SEX/GROUP: 5m & 5F

TEST SUBSTANCE: 2,5-YI 5-(4-Tert-butyl-2-ethoxyphenyl)-2-(2,6-difluorophenyl)-4,5-dihydrooxazole

DOSE LEVEL: 5000 mg/kg single oral dose by gavage

STUDY SUMMARY: There were no deaths. Clinical signs of reaction to treatment included piloerection, soft to liquid faeces and gasping/noisy respiration seen in all or the majority of rats. Less frequent signs were hunched posture, waddling gait, lethargy, decreased respiratory rate, pallor of the extremities, increased urine production, increased salivation, walking on toes, unsteadiness, hair loss and brown staining around the nose and mouth. All signs had resolved by Day 12 post dose. Slightly lower weight gain was seen in 1 male and 1 female to Day 8 but had regained parity with their counterparts by termination. There were no treatment related macroscopic changes evident at necropsy

GENOTOXICITY In Vitro Study STUDY TYPE: Ames test

CELL TYPES: Salmonella typhimurium (strainsTA1535, TA 1537, TA 98, TA 100), Escherichia coli (WPS uvrA)

TEST SUBSTANCE: 2,5-YI 5-(4-Tert-butyl-2-ethoxyphenyl)-2-(2,6-difluorophenyl)-4,5-dihydrooxazole Positive controls: N-Ethyl-N’-nitro-N-nitrosoguanidine, 9-Aminoacridine, 2-Nitrofluorene, 2-Aminoanthracene

DOSE RATE OF TEST SUBSTANCE: Preliminary study – 5, 50, 500, 5000 µg/plate with and without S-9 mix Main study – 0, 312.5, 625, 1250, 2500, 5000 µg/plate with and without S-9 mix RESPONSE: No toxicity was observed in the preliminary study. No evidence of mutagenic activity was seen at any dose level in the main study

GLP: Y

TEST GUIDELINE: OECD 471 and 472 (1983), 92/69/EEC, US EPA (1984), JMAFF (1985), JMOHW (1989), Japan Ministry of International Trade & Industry (1987), Japan Ministry of Labour (1987)

REFERENCE SOURCE: Jones, E., 2,5-YI Bacterial mutation assay, report number YMA 29C/952787, HLS Ltd., England, 1996

RELIABILITY (KLIMISCH SCORE): 1 (reliable without restriction)

The following assessments are of a metabolite of YI-5301 designated R-3

ACUTE TOXICITY Acute Oral Toxicity SPECIES: Rat

ENDPOINT: LD50

VALUE: >5g/kg

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

TEST GUIDELINES: JMAFF (1985)

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REFERENCE: McCrae, L.A., R-3 Acute oral toxicity to the rat, report number YMA 28a/952617/AC, HLS, Ltd., England, 1996

STRAIN: Hsd/Ola:Sprague Dawley (CD)

NO/SEX/GROUP: 5m & 5F

TEST SUBSTANCE: R-3 N-(2,6-difluorobenzoyl)-4-tert-2-ethoxybenzamide

DOSE LEVEL: 5000 mg/kg single dose by oral gavage

STUDY SUMMARY: There were no deaths or adverse effect on bodyweight. Signs of reaction to treatment were confined to piloerection and hunched posture, seen in all rats. The signs were resolved by Day 5. There were no treatment related macroscopic changes seen at necropsy.

GENOTOXICITY In Vitro Study STUDY TYPE: Ames test

CELL TYPES: Salmonella typhimurium (strains TA 1535, TA 1537, TA 98, TA 100), Escherichia coli (WPS uvrA)

TEST SUBSTANCE: R-3 N-(2,6-difluorobenzoyl)-4-tert-2-ethoxybenzamide Positive controls: N-Ethyl-N’-nitro-N-nitrosoguanidine, 9-Aminoacridine, 2-Nitrofluorene, 2-Aminoanthracene

DOSE RATE OF TEST SUBSTANCE: Preliminary study – 550, 500, 5000 µg/plate with and without S-9 mix Main study – 0, 312.5, 625, 1250, 2500, 5000 µg/plate with and without S-9 mix

RESPONSE: No toxicity was observed in the preliminary study. No evidence of mutagenic activity was seen at any dose level in the main study

GLP: Y

TEST GUIDELINE: OECD 471 and 472 (1983), 92/69/EEC, US EPA (1984), JMAFF (1985), JMOHW (1989), Japan Ministry of International Trade & Industry (1987), Japan Ministry of Labour (1987)

REFERENCE SOURCE: Jones, E., R-3 Bacterial mutation assay, report number YMA 29A/952785, HLS Ltd., England, 1996

RELIABILITY (KLIMISCH SCORE): 1 (reliable without restriction)

The following assessments are of a metabolite of YI-5301 designated R-7 HCl salt

ACUTE TOXICITY Acute Oral Toxicity SPECIES: Rat

ENDPOINT: LD50

VALUE: >5g/kg

KLIMISCH SCORE: 1 (reliable without restriction)

GLP: Y

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TEST GUIDELINES: JMAFF (1985)

REFERENCE: McCrae, L.A., R-7 HCl salt Acute oral toxicity to the rat, report number YMA 28b/952618/AC, HLS, Ltd., England, 1996

STRAIN: Hsd/Ola:Sprague Dawley (CD)

NO/SEX/GROUP: 5m & 5F

TEST SUBSTANCE: R-7 HCl salt 2-Amino-2-(4-tert-butyl-2-ethoxyphenyl)ethyl-2‘,6‘-difluorobenzoate hydrochloride

DOSE LEVEL: 5000 mg/kg

STUDY SUMMARY: There were no deaths. Clinical signs of reaction included piloerection, hunched posture, waddling gait, pallor of the extremities, walking on toes, unsteadiness, protruding eyes, hair loss and red/brown staining around the nose and mouth, seen in all or the majority of rats. Less commonly observed were lethargy, decreased respiratory rate, increased urine production, faecal disturbances, gasping, body tremors, increased respiratory rate and excitability. Signs were all resolved by Day 12. Slightly lower weight in all males and 4 females was noted to Day 8 but parity with their counterparts was regained by Day 15. There were no treatment related macroscopic changes evident at necropsy.

GENOTOXICITY In Vitro Study STUDY TYPE: Ames test

CELL TYPES: Salmonella typhimurium (strains TA 1535, TA 1537, TA 98, TA 100), Escherichia coli (WPS uvrA)

TEST SUBSTANCE: R-7 HCl salt 2-Amino-2-(4-tert-butyl-2-ethoxyphenyl)ethyl-2‘,6‘-difluorobenzoate hydrochloride Positive controls: N-Ethyl-N’-nitro-N-nitrosoguanidine, 9-Aminoacridine, 2-Nitrofluorene, 2-Aminoanthracene

DOSE RATE OF TEST SUBSTANCE: Preliminary study – 5, 50, 500, 5000 µg/plate with and without S-9 mix Main study – 0, 78.13, 156.25, 312.5, 625, 1250, 2500, 5000 µg/plate with and without S-9 mix RESPONSE: Toxicity was observed in the preliminary study at 5000 µg/plate. No evidence of mutagenic activity was seen at any dose level investigated in the main study.

GLP: Y

TEST GUIDELINE: OECD 471 and 472 (1983), 92/69/EEC, US EPA (1984), JMAFF (1985), JMOHW (1989), Japan Ministry of International Trade & Industry (1987), Japan Ministry of Labour (1987)

REFERENCE SOURCE: Jones, E., R-7 HCl salt Bacterial mutation assay, report number YMA 29B/952786, HLS Ltd., England, 1996

RELIABILITY (KLIMISCH SCORE): 1 (reliable without restriction)

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Class 9 Ecotoxicity and environmental fate

The active ingredient etoxazole is also stated as YI-5301 or S-1283 in the following tables.

Classification under this sub-class requires consideration of the acute and chronic aquatic toxicity of the substance and the bioaccumulation and persistence properties of the components of the substance.

Aquatic fate and degradation of etoxazole and its metabolites Information on aquatic fate and degradation is summarised in the next table.

Table A1.6: Summary of aquatic fate and degradation data on etoxazole and its metabolites.

Test results Test method Study type [reference Active number]

Abiotic degradation

Hydrolysis The hydrolysis in aqueous buffer solutions (pH 1.2, 5, 7, and 9) was Equivalent to investigated: OECD 111 pH/incubation temperature Half life (hours or days) [Elsom, 1996- 1.2/37oC 0.734 hours SKM-0014] 5/20oC 9.57 days

7/20oC 161 days 7/50oC 7.96 days GLP 7/60oC 3.15 days 7/70 oC 1.48 days No deviations o 9/20 C 165 days Klimisch 2b 9/50oC 9.49 days 9/60oC 3.9 days 9/70oC 1.61 days Conclusion: According to OECD 111 criteria, at environmental pH, Etoxazole is considered as hydrolytically stable. At 20°C the hydrolytic stability of YI-5301 in aqueous buffer is of the order pH 9 > pH 7 > pH 5. In buffers of acidic pH, YI-5301 is hydrolysed to R-7, (2-amino-2-14-ternbutyl-2-ethoxyphenyl)ethyl 2,6- dtfluorobenzoate) and m neutral or basic pl-I to R-4 (N-(2,6- difluorobenzoyl)-2-anuno-2-(4-tem 1 U butyl-2-ethoxyphenyl)ethanol.

Photolysis The photolysis of YI-5301, (RS)-5-tert-butyl-2-[2-(2,6- USEPA 161-2 difluorophenyl)-4,5-dihydr0-1,3-oxazol—4-yl]phenetole in pH 9 aqueous buffer solution has been investigated. [Elsom, 1997- SKM-0032] Two radiolabelled fomts, [14C-oxazole] and [14C—t-butylphenyl] of YI-5301 were used in the study. GLP 14C -YI-5301 was added to pH 9 buffer containing 10% acetonitrile at Klimisch 1 a rate of 5 μg/L (5 ppb). The high concentration of co-solvent and low concentration of test substance were required for reasons of solubility.

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Test results Test method Study type [reference Active number] Test solutions were irradiated continuously using a xenon arc simulated sunlight source for periods of up to 361.61 hours (ca 47 days equivalent summer sunlight at latitude 40°N). Further test solutions were incubated in the dark and acted as controls. All test solutions were maintained at 20° ± 1°C during the study. Recovery of radioactivity from test solutions was determined by liquid scintillation counting and proportions of radioactive components in test solutions at each analysis time were detennined by HPLC. The photolytic half-life of YI-5301 in pH 9 buffer was found to be 15.9 days summer sunlight equivalents at latitude 40°N (oxazole label) and 17.4 days summer sunlight equivalents at latitude 40°N (t- butylphenyl label). Major photodegradates were identified as R-11, R-12 and R-15. No significant degradation of YI-5301 was found in dark control samples. A pilot study showed that photodegradates were not volatile. The quantum yield of YI-5301 was found to be 0.026. The theoretical lifetimes obtained using the GCSOLAR modelling progra.rnme were 5.56 and 6.17 days at latitudes of 40°N and 50°N (0° longitude) respectively in the summer at a depth of 30 cm. The corresponding lifetimes in the spring were 7.19 and 9.09 days respectively. The photolytic half-life of YI-5301 at pH 9 was 16.7 days stmamer sunlight equivalents at 40°N. From the quantum yield of 0.026, the photolytic lifetime of YI-5301 has been obtained using the computer modelling programme GCSOLAR and was 5.56 days at 40°N in summer at a depth of~ 30 cm. This value is lower than would be expected from the UV spectrum of YI-5301 and indicates that the photolysis is indirect rather than direct. lt has been shown that oxazoles undergo photolytic rearrangement following reaction with singlet state oxygen (reference 3). This would give a higher quantum yield than expected and hence a lower enviromnental lifetime.

Biodegradation (laboratory) BIOWIN (v4.10) Program Results: Ready ======Modelling biodegradation SMILES : Fc1cccc(F)c1C2=NC(c3ccc(C(C)(C)C)cc3OCC)CO2 (BIOWIN) CHEM : Etoxazole [ERMA, 2001] MOL FOR: C21 H23 F2 N1 O2 MOL WT : 359.42 Not GLP ------BIOWIN v4.10 Results ------Klimisch 2f

Biowin1 (Linear Model Prediction) : Does Not Biodegrade Fast Biowin2 (Non-Linear Model Prediction): Does Not Biodegrade Fast Biowin3 (Ultimate Biodegradation Timeframe): Recalcitrant Biowin4 (Primary Biodegradation Timeframe): Days-Weeks Biowin5 (MITI Linear Model Prediction) : Does Not Biodegrade Fast Biowin6 (MITI Non-Linear Model Prediction): Does Not Biodegrade

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Test results Test method Study type [reference Active number] Fast Biowin7 (Anaerobic Model Prediction): Does Not Biodegrade Fast Ready Biodegradability Prediction: NO According to BIOWIN, Etoxazole is not considered as a ready biodegradable substance. This conclusion is also indicated in the Draft Asssessment Report published by the European Commission in 2004.

Biodegradation (laboratory)

Water/sediment Two aquatic systems under aerobic conditions at 200C for up to 100 Equivalent to (pond) aerobic days were used to study the metabolism and degradation of the test OECD 308 item, Bury pond water/sediment and Houghton Meadow water sediment. [Elsom, 1997- SKM-0021] In the Buty Pond water sediment the DT50 values were 0.4-3 days for the water and 59.7 for the whole system. The corresponding values in GLP Houghton Meadow were 0.4-2 days and 98.8-107 days respectively. Klimisch 2b Conclusion: 14C—S-1283 was degraded in the Bury Pond water/sediment system with DTN values of 0.4 days and 59.7 days for the water and water/sediment respectively for the 14C-r-butylphenyl and 3.0 days and 52.1 days for the water and water and sediment respectively for the 14C-difluorophenyl label. In the Houghton Meadow water/sediment system 14C-S-1283 was degraded with DT50 values of 2.0 days and 98.8 days for the water and water and sediment respectively for the "C-t-butylphenyl label and 0.4 days and 107 days for the water and water and sediment respectively for the 14C-difluorophenyl label. For both water/sediment types and both radiolabels the major degradate was R13 which has been identitied by TLC and HPLC co- chromatograph. R13 was mostly formed in the sediments during the course of study. Minor degradates for the 14C-t-butylphenyl label were R12, R15, R4, R17, R16, R2, R7, R9 and R3. For the 14C- difluorophenyl label minor degradates were R3, R17, R11, R7 and R4. 14 14 In the [difluorophenyl- C]-S-1283 samples mineralisation to CO2 was signiticantly higher (11.9 - 13.0% AR at 100 days) than the corresponding samples which had been treated with [t-butylphenyl- 14C]-S-1283.

Anaerobic Etoxazole dissipates under anaerobic aquatic conditions with a half- Equivalent to (pond sediment life of 133 to 142 days. Most of the Etoxazole and its degradates are OECD 308 and pond found in the soil. Only degradates R-4 and R-1 1 exceeds 10% of water) applied radioactivity. Degradates R-7, R-8, R-12, and R-13 are found USEPA 162-3 at smaller amounts ranging from 0.08 to 6.05% of applied [Assaf, 2001- radioactivity or 5 0.01 ppm in Etoxazole equivalents. Four unknowns SKM-0046] were observed at trace concentrations between 0.001 and 0.009 ppm in etoxazole equivalents. The significant microbial-mediated reactions GLP were hydrolysis and oxidation. Terminal residues from the 14 14 Klimisch 2b ditluorophenyl label were CO2, CH4, and soil-bound residues. The majority of the soil-bound residues were associated with the insoluble htunin fraction.

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Test results Test method Study type [reference Active number]

Bioaccumulation

Rainbow trout The bioaccumulation of radioactivity by rainbow trout was studied OECD 305E during 30 exposure to S-1283 under dynamic conditions at two different concentrations of 0.5 and 5 μg/L. Eimination of radioactivity [McEwen, 1997- was also studied during a depuaration period of 20 days. SKM-0037] GLP Klimisch 1

Conclusion: Concentrations of total radioactivity in whole fish, edible and non- edible tissues after exposure in the high level tank water were generally 8 - 14 times higher than in the same portions after the low level exposure. The concentrations of "C-S-1283 in whole fish, edible and non-edible tissues after exposure in the high level tank water were generally 8 - 19 times higher than in the same portions aher the low level exposure. Elimination was relatively rapid with around 70 - 80% radioactivity eliminated after S days and 94 - 96% after 20 days. The concentration data was modelled using a SIPI-IAR computer programme. Bioconcentration factors, calculated using total radioactivity concentrations (BCF,,,), were similar for whole fish of both high level (BCFM 3000) and low level (BCFW, 2700) exposure groups. Values calculated for edible tissues were lower at 1300 (low level exposure) and 1500 (high level exposure), whilst values for non- edible tissues were higher at 3900 (low level) and 4600 (high level). Similar values were obtained for bioconcentration factors calculated using concentrations of "C-S-1283 (BCF,_,,,,,). The values obtained using this model were similar to those obtained directly from the experimental data. Elimination half·lives were similar for fish portions from both high and low level exposure groups, and were in the range 3.3 - 6.4 days. The major radioactive component detected in all fish portions, was identified as S-1283 by co-chromatography with authentic S-1283 reference standard using reverse phase HPLC and normal phase TLC. Eleven further radioactive components were detected in fish portions, each component was present at $4.4% tissue radioactivity. One of these components was identified as the oxazole degradate (R13). Therefore on Etoxazole is considered as a bioaccumulative substance.

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Conclusion Etoxazole is considered bioaccumulative based on the results of an OECD 305E guideline study which indicate fish BCF ranging from 2600 (whole fish) to 3500 (non-edible parts) at the highest concentration tested (5µg/L). Etoxazole is considered as persistent based on the outcome of modelling (BIOWIN) and aerobic biodegradation (laboratory) whole system (water/sediment) DT50 values. Moreover etoxazole is hydrolytically stable at environmental pH.

Aquatic Toxicity

The toxicity of etoxazole to aquatic organisms is summarized in the next table.

Table A1.7: Summary of aquatic toxicity data for etoxazole a, b, c Test type Test results d Test species & Test method [reference number] duration Active and/or metabolites

Fish

Rainbow 96 h semi- LC50 2.8 mg/L (95% C.I. 2.1-3.6 mg/L) OECD 203;EEC trout, static Methods for NOEC 0.22 mg/L determination of Oncorhynchus Based on actual concentrations ecotoxicity Annex to mykiss 92/69/EEC (O.J. No. Mean measured concentrations 66-106% of L383A, 1992) Part c, nominal method 1 Conclusion: [Bell, Groom and Smith, 1996- SKW- The substance is classified as 9.1B 0039]

GLP Purity of the tested substance 95.4% No significant deviation from the standard guidelines. Klimisch 1

Bluegill 96 h semi- LC 50 1.4 mg/L (95% C.I. 0.95-1.9 mg/L) OECD 203 ; EEC sunfish, static Methods for NOEC 0.73 mg/L determination of Lepomis Based on actual concentrations ecotoxicity Annex to macrochirus 92/69/EEC (O.J. No. Mean measured concentrations 65-106% of L383A, 1992) Part c, nominal (in 5 highest concentrations tested) method 1 Conclusion: [Bell, Groomand Smith, 1996- SKW- The substance is classified as 9.1B 0040]

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a, b, c Test type Test results d Test species & Test method [reference number] duration Active and/or metabolites GLP Purity of the tested substance 95.4% No significant deviation from the standard guidelines.

Klimisch 1

Sheepshead 96 h flow- LC50 was empirically estimated to be > 0.16 mg/L OPPTS 830.1075 minnow, through (the highest mean measured concentration tested) FIFRA 72-3 no mortality observed at any concentration Cyprinodon [Dionne, 2000-SKW- varigatus NOEC ≥0.16 mg/L 0083] Conclusion: GLP The substance is classified as 9.1A Purity of the tested substance 98.3% Klimisch 2b

Bluegill 96 h semi Five metabolites of active ingredient tested: R-3, OECD 203;EC sunfish, static R-4, R-7, R-8, R-13 Guideline number L383A-C.1 Lepomis Limit test, nominal concentrations tested 1, 0.99, macrochirus 0.99, 0.99, 1 mg/L respectively [Collins, 1998-SKM- 0065] No mortality or other adverse effects were observed GLP Conclusion: Minimum purity of 95.7% Comparison of the data generated during these toxicity tests Deviations with no indicates that R-3, R-4, R-7, R-8 and R-13 elicited impact on study no adverse relevancy. response by exposed organisms, and that each of these materials Klimisch 2b is not considered toxic to L. macrochirus at nominal concentrations of approximately 1.0 mg a.i./L. Rainbow 89 day ELS Nominal concentrations tested: 0.019, 0.038, OECD 210 trout, (60 day 0.075, 0.15 and 0.3 mg/L (mean measured: 0.015, post-hatch) 0.033, 0.064, 0.13 and 0.26 mg/L) [Sousa, 1996-SKM- Oncorhynchus flow 0032] mykiss through Embryo viability, survival at hatch, survival and growth were observed. GLP Growth (length) was the most sensitive parameter Purity of the tested monitored with a NOEC value of 0.015 mg/L substance 95.3% (measured concentration) and a LOEC value of Deviations with no 0.033 mg/L (measured concentration). impact on study relevancy.

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a, b, c Test type Test results d Test species & Test method [reference number] duration Active and/or metabolites Klimisch 1

Invertebrates

Daphnids, 48 h flow Nominal concentrations tested: 3.9, 7.7, 15, 31 and OECD 202 ; EC through 62 μg/L (mean measured: 2.9, 6.1, 10, 22 and 36 Guideline number Daphnia μg/L) L383A-C.2 magna EC50 7.1 μg/L (95% C.I. 9-8.5 μg/L) [Putt, 1996-SKW- 0036] NOEC 2.9 μg/L GLP Lowest concentration causing 100% immobilization: 22 μg/L Purity of the tested substance 95.4% (all above results are based on actual concentrations) Klimisch 1 Conclusion: The substance is classified as 9.1A

Daphnids, 48 h static Five metabolites of active ingredient tested: R-3, OECD 202 ; EC R-4, R-7, R-8, R-13 Guideline number Daphnia L383A-C.2 Limit test, nominal concentrations tested: 1, 0.99, magna 0.99, 0.99, 1 mg/L respectively [Collins, 1998-SKW- 0066] No mortality or other adverse effects were observed except 20% immobilization for R-13 GLP treatment Minimum purity of Conclusion: 95.7% Comparison of the data generated during these Deviations with no toxicity tests impact on study indicates that R-3, R-4, R-7 and R-8 elicited no relevancy. adverse response by exposed organisms, and that each of these materials is not Klimisch 2b considered toxic to D. magna at nominal concentrations of approximately 1.0 mg a.i./L. Exposure to approximately 1.0 mg a.i./L of metabolite R-13 elicited a response among test organisms that was statistically different from control organisms (20% immobilization). Daphnids, 21 day-full Nominal concentrations tested: 0.063, 0.13, 0.25, OECD 202 life cycle 0.5 and 1 μg/L (mean measured: 0.053, 0.11, 0.2, [Putt, 1997-SKW- Daphnia toxicity 0.48 and 1.1 μg/L) under flow- 0041] magna EC 0.62μg/L (95% C.I. 0.48-1.1 μg/L) through 50 GLP conditions (immobilization) Organism reproduction was not adversely affected Purity of the tested by exposure to concentrations less than those substance 95.4% affecting daphnid survival NOEC 0.20 μg/L Klimisch 1

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a, b, c Test type Test results d Test species & Test method [reference number] duration Active and/or metabolites LOEC 0.48 μg/L (all above results are based on actual concentrations)

Daphnids, 48 days- Treatments: 1.4, 2.8, and 4.2 μg/L No guideline indicated Indoor Assessment of ecological [Schanne, 2001-SKW- Daphnia aquatic microcosm acceptability of effects 0087] magna Control - study GLP 1.4 μg a.i./L • LOEC for acute effects (transient) Purity of the tested • NOEC for maximum substance 99.86% population abundance • NOAEC for time to population peak. Recovery Klimisch 2e within 3 weeks time in comparison with the controls is not considered to adversely impact on field populations of Daphnia. 2.8 μg a.i./L • EC for acute effects • LOEC for maximum population abundance • LOAEC for time to • •uIation eak 4.2 μg a.i./L • EC for acute effects • EC for maximum population abundance • EC for time to o ulation eak NOEC: No Observed Effect Concentration LOEC: Lowest Observed Effect Concentration EC: Effect Concentration NOAEC: No Obsenred Adverse Ecological Effect Concentration LOAEC: Lowest Observed Adverse Ecological Effect Concentration Conclusion: The resuls of the definitive test indicate that the initial acute effect on Daphnia magna mixed population at test level 1.4 μg/L is not considered to adversely impact on field populations of Daphnia. The effect was transient due to rapid population recovery within 3 weeks lag time in comparison with the controls.

Mysids, 96 h flow- Nominal concentrations tested: 1.4, 2.4, 4, 6.6 and OPPTS 850.1035 through 11 μg/L (mean measured: 1.2, 1.8, 3.3, 5 and 8.4 Mysidopsis μg/L) [Lima, 2000 SKW- bahia 0084] LC 4.4 μg/L (95% C.I. 4-5 μg/L) 50 GLP NOEC 1.8 μg/L Purity of the tested (all above results are based on actual substance 98.3%

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a, b, c Test type Test results d Test species & Test method [reference number] duration Active and/or metabolites concentrations) Klimisch 1

Conclusion: The substance is classified as 9.1A

Eastern 96 h flow- Nominal concentrations tested: 0.38, 0.75, 1.5, 3 OPPTS 850.1025 oysters, through and 6 μg/L (mean measured: 0.37, 0.59, 1.3, 2.1 and 4.3 μg/L) [Dionne, 2000-SKW- Crassostrea 0085] virginica EC 1.2 μg/L (95% C.I. 0.24-5.3 μg/L) 50 GLP NOEC 0.37 μg/L Purity of the tested (all above results are based on actual substance 98.3% concentrations) Deviations with no Conclusion: impact on study relevancy. The substance is classified as 9.1A Klimisch 1

Mysids, 28 day-full Nominal concentrations tested: 0.12, 0.25, 0.5, 1 EPA 72-4 life cycle and 2 μg/L (mean measured: 0.1, 0.17, 0.32, 0.71 Americamysis toxicity and 1.3 μg/L) [Lima, 2002-SKM- bahia under flow- 0088] (Based on reproduction which was the most through GLP conditions sensitive performance criterion) NOEC 0.32 μg/L Purity of the tested substance 98.3% LOEC 0.71 μg/L Klimisch 1 Conclusion: The substance is classified as 9.1A

Midge, 10 day Nominal sediment concentrations: 3.8, 7.5, 15, 30 ASTM Guideline sediment and 6O mg a.i./kg E1706-95b 1997 Chironomus exposure Mean measured concentrations: 3.5, 6,2, 14, 25 [Putt, 1998-SKW- riparius under static- renewal and 56 mg/kg 0067] conditions Results: GLP The data generated during this study established Purity of the tested that midge substance 97.2% survival was the most sensitive endpoint measured. Klimisch 1 The Lowest-Observed-Effect Concentration (LOEC) for S-1283 was 56 mg/kg and the No—Observed-Effect Concentration (NOEC) established forthis study was 25 mg/kg. The 10- day LC5O value

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a, b, c Test type Test results d Test species & Test method [reference number] duration Active and/or metabolites was estimated to be >56 mg/kg (the highest concentration tested).

Algae/Aquatic plants

Green alga, 72 h Limit test at a nominal concentration of 10 mg/L OECD 201 ; EC (due to maximum solubility) Guideline number Selenastrum L383A-C.3 capricornutum No inihibitory effects on growth were observed [Bell Groom, Smith, EbC50 (72 hr) > 10 mg/L 1996-SKW-0037] ErC50 (0-72 hr) > 10 mg/L GLP NOEC ≥ 10 mg/L Purity of the tested Measured concentrations 105% and 94% of substance 95.4% nominal at 0 and 72 hr respectively. Klimisch 1 Conclusion: The substance is classified as 9.1D

72 h Test item: R3 metabolite of the active ingredient OPPTS 850.5400; OECD 201; EC Nominal concentrations: tested: 0.1, 0.22, 0.36, Guideline number 0.6 and 1 mg/L (mean measured: 0.085, 0.17, 0.29, L383A-C.3 0.46 and 0.84 mg/L) [Hoberg, 1998-SKW- EbC50 (72 hr) > 0.84 mg/L 0064] ErC50 (0-72 hr) > 0.84 mg/L GLP Percent inhibition at the 0.84 mg/L for 72 hr Purity of the tested biomass and growth rate was 34 and 7.1%, substance 98.2% respectively. Klimisch 1 NOEC 0.085 mg/L (biomass) NOEC < 0.085 mg/L (growth rate)

Conclusion: The R3 metabolite is classified as 9.1A

72 h Test item: R7 metabolite of the active ingredient OPPTS 850.5400; OECD 201; EC Nominal concentrations: tested: 0.1, 0.22, 0.36, Guideline number 0.6 and 1 mg/L (mean measured: 0.07, 0.18, 0.30, L383A-C.3 0.51 and 0.99 mg/L) [Hoberg, 1998-SKW- EbC50 (72 hr) > 0.99 mg/L 0069] ErC50 (0-72 hr) > 0.99 mg/L GLP Percent inhibition at the 0.99 mg/L for 72 hr Purity of the tested biomass and growth rate was 27 and 8.5%, substance 95.7%

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a, b, c Test type Test results d Test species & Test method [reference number] duration Active and/or metabolites respectively. Klimisch 1 NOEC 0.07 mg/L (biomass and growth rate) Conclusion: The R7 metabolite is classified as 9.1A

72 h Test item: R13 metabolite of the active ingredient OPPTS 850.5400; OECD 201; EC Nominal concentrations: tested: 0.1, 0.22, 0.36, Guideline number 0.6 and 1 mg/L (mean measured: 0.056, 0.14, 0.23, L383A-C.3 0.4 and 0.81 mg/L) [Hoberg, 1998-SKW- EbC50 (72 hr) > 0.81 mg/L 0068] ErC50 (0-72 hr) > 0.81 mg/L GLP Percent inhibition at the 0.84 mg/L for 72 hr Klimisch 1 biomass and growth rate was 38 and 7.6%, respectively. NOEC 0.056 mg/L (biomass and growth rate) Conclusion: The R13 metabolite is classified as 9.1A a Results are reported on the basis of nominal concentrations except where otherwise stated, Standard test guidelines provide for reporting of results on a nominal basis where measurements indicate the test substance remains within 20% of nominal. b [measured] range X - Y% of [nominal] – the measured concentration range as a percentage of the nominal concentration. c 95% confidence intervals are stated where available d Unless otherwise stated, the tests were conducted according to the test method identified

Conclusion The toxicity of etoxazole and its main metabolites has been assessed in the frame of standardized tests. Based on the available results it can be concluded that etoxazole and its metabolites are acutely toxic to fish, invertebrates and algae. Therefore etoxazole is classified as 9.1A.

Soil ecotoxicity and terrestrial fate Classification under this sub-class requires consideration of the persistence of the components of the ParaMite® Selective Miticide in soil, and the toxicity of the ParaMite® Selective Miticide to soil-dwelling invertebrates (e.g. earthworm), soil microbial function and terrestrial plants resulting from soil-based exposure.

Data on the adsorption, mobility and field dissipation of the active ingredient is used in the ecological risk assessment for the substance.

Terrestrial fate and degradation of etoxazole (and its metabolites) Information of terrestrial fate and degradation is summarised in the next table.

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Table A1.8 Terrestrial fate and degradation of etoxazole and its metabolites R-7, R-8, R-13.

Test results a Test type Test method [reference number] Active

Abiotic Photodegradation in soil of S-1283 Elsom, 1996-SKM- degradation 0018] The photolysis ofthe insecticide and acaricide S-1283, (RS)-5-tert- butyl-2-[2-(2,6·difluorophenyl)4,5-dihydro-1,3-oxazol-4- GLP yl]phenetole, on soil has been studied. S-1283 was labelled with carbon-14 in the tert-butylphenyl and difluorophenyl ring. The study Radiochemical purity was conducted on ca 2 mm-thin layers of a clay loam soil to which > 97% S-1283 was applied at a concentration equivalent to a field Klimisch 2 concentration of 150 g ai/ha. The water content of the soil layers

were maintained at 40% of the maximum water holding capacity throughout the study. A xenon—arc-simulated sunlight source was used and irradiation was continuous with time. Irradiated and non- irradiated control soil plates were maintained at ca 20°C.

14 DT50 and DT90 9.7 and 32.2 days respectively [ C-t-butylphenyl]S- 1283, equivalent to 24.3 and 80.9 days of summer sunlight at latitude 40oN.

14 DT50 and DT90 9.5 and 73.2 days respectively [ C-difluorophenyl]S- 1283, equivalent to 22 and 73.2 days of summer sunlight at latitude 40oN.

In non irradiated soil DT50 and DT90 values were 118 and 392 respectively for [14C-t-butylphenyl]S-1283 and 62.1 and 206.1 days respectively for [14C-t-butylphenyl]S-1283. The degradation products found in the non-irradiated soil were the same as those found in the irradiated samples but at much lower level. Conclusion:

S-1283 was rapidly degraded photolytically on soil with mean DT50 and DT90 values of 9.6 and 32 days respectively. Degradation also occurred in non-irradiated soil but the DT50 and DT90 values were much larger at 62 - 118 and 206 - 392 days respectively. In terms of summer sunlight equivalems at 40°N, the DT50 and DT90 for S-1283 were 23 and 77 days respectively. The major photolytic degradates 14 of S-1283 were R3, R4, R7, R8, R11, R12, R13, R15 and CO2. The proposed photolytic degradation pathway in soil is shown in Figure 34. In the non-irradiated soil, much lower level of degradates R3, 14 R4, R7, R8 and R11 were detected and only trace levels of CO2 (≤0.7%). ,

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Route and Aerobic conditions in the dark at 25±1oC. Sampling conducted up to USEPA Subdivision rate of 272 days following application. N Chemistry: degradation 14 14 Environmnental Fate DT50 19 and 24 days for [ C-difluorophenyl]S-1283 and [ C-t- Series 162-1 (Laboratory) butylphenyl]S-1283 respectively. [Assaf, 1999-SKM- 0042] GLP Klimisch 1

Aerobic conditions in the dark at 20oC in a sand loam soil for 269 Hawkins, Elsom, days. Girkin, 1997 SKM-

14 0027 DT50 and DT90 10.6 and 35.2 days respectively for [ C- difluorophenyl]S-1283 and DT50 and DT90 9.9 and 33 days German BBA respectively for [14C-t-butylphenyl]S-1283 Guidelines for the Official Testing of Plant Protection Products; Part IV, 4-1, Stage Iand Draft Annex II Guidelines Concerning the Inclusion of active substances in Annex I to Council Directive 91/414/EEC GLP Klimisch 1

Anaerobic conditions in the dark at 20oC in a sand loam soil for 120 Hawkins, Elsom, days. Girkin, 1997 SKM-

14 0023 DT50 and DT90 102.2 and 339.4 days respectively for [ C-t- butylphenyl]S-1283 and DT50 and DT90 111.9 and 371.7 days German BBA respectively for [14C-difluorophenyl]S-1283 Guidelines for the Official Testing of Plant Protection Products; Part IV, 4-1, Stage Iand Draft Annex II Guidelines

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Concerning the Inclusion of active substances in Annex I to Council Directive 91/414/EEC GLP Klimisch 1

Adsorption/ desorption Soil Adsorption 2nd desorption Elsom, Winwick, Nicoll, 1996 SKM- Ka Koc Kd Koc 0019 Aldhams Farm 131 5460 978 40750 USEPA Subdivision (sandy loam) 163-1; OECD 106; Evesham 3 (clay 68 5230 154 11850 91/414/EEC Section loam) 7.1.2 (1995); SETAC Speyer 2.1 (sand) 66 11000 141 23500 1995 Speyer 2.2 103 4910 419 19950 GLP (loamy sand) Klimisch 1 Soil (all sandy Etoxazole (S-1283) Metabolite R-13 loam) degraded Jalal, 2000 SKM-0043 significantly in all Sorption Koc USEPA Subdivision four soils and was 163-1 coefficient not amenable to K Freudlih isotherm GLP San Joaquin 156 18000 experiments. Its Klimisch 1 average adsorption Elder 335 23100 coefficient (K) and Koc based on screening tests were Bosket 193 55300 1320 and 146600 respectively. Timmerman 156 14200 Soil Metabolite R-7 Hawkins, Elsom, Adsorption 2nd desorption Winwick, Nicoll, 1997 SKM-0028 Ka Koc Kd Koc USEPA Subdivision Aldhams Farm 27 1125 84 3500 163-1; OECD 106; (sandy loam) 91/414/EEC Section 7.1.2 (1995); SETAC Evesham 3 (clay 98 7540 286 22000 1995 loam) GLP

Speyer 2.1 (sand) 14 2330 79 13170 Klimisch 1

Soil Metabolite R-8 nd Hawkins, Elsom, Adsorption 2 desorption Winwick, Nicoll, 1997 SKM-0026 Ka Koc Kd Koc Aldhams Farm 2.48 103 0.9 38 USEPA Subdivision (sandy loam) 163-1; OECD 106; 91/414/EEC Section 7.1.2 (1995); SETAC

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Evesham 3 (clay 4.56 351 4.89 376 1995 loam) Speyer 2.1 (sand) 1.24 207 No No GLP values values Klimisch 1 available available Soil Metabolite R-13 nd Hawkins, Elsom, Adsorption 2 desorption Winwick, Nicoll, Ka Koc Kd Koc 1996 SKM-0020 Aldhams Farm 877 36540 619 25790 USEPA Subdivision (sandy loam) 163-1; OECD 106; 91/414/EEC Section Evesham 3 (clay 1082 83230 3534 271850 7.1.2 (1995); SETAC loam) 1995 GLP Speyer 2.1 (sand) 82 13670 154 25670 Klimisch 1

Metabolites R-3, R-4, R-7 Koc determined by HPLC Howes, Betteley, Metabolite Koc Young, Bracey- Wright, 1997 SKM- R-3 5130 0022 R-4 759 OECD TPG/94.75 R-7 79400 (draft document, April 1994) GLP Klimisch 1 Terrestrial Bare soil in Idaho; the test plot was located within an apple orchard. Schreier, 2002 SKR- field Two applications of S-1283 72 WDG with a 21 days interval 0092 dissipation between applications (0.151 kg/ha). USEPA 164-1 Etoxazole (S-1283) DT 11.4 days (1st order exponential decay) 50 GLP DT50 11.7 days (log-linear regression analysis) Klimisch 1 Metabolite R-7 DT50 56.6 days (1st order exponential decay)

DT50 63.5 days (log-linear regression analysis) The degradate R-3 never exceeded the analytical method limit of quantitation No detectable residues of etoxazole or its degradates were found below 7.5 cm horizon layer Bare soil in Mississipi; the test plot was located in an area suitable to Schreier, 2002 SKR- growing row crops such as cotton. Two applications of S-1283 72 0093 WDG with a 21 days interval between applications (0.151 kg/ha). USEPA 164-1 Etoxazole (S-1283) DT 0.8 days (1st order exponential decay) 50 GLP DT50 8.25 days (log-linear regression analysis) Klimisch 1 Metabolite R-7 DT50 3.3 days (1st order exponential decay)

DT50 7.74 days (log-linear regression analysis) No detectable residues of etoxazole or its degradates were found below 7.5 cm horizon layer Dissipation of S-1283 (first order kinetics) under field conditions in Burden, 1997 SKR- France. S-1283, as a 10.7% (w/w) FL formulation was applied at 275 0036 g a.i./ha to bare soil. GLP Soil DT50 (days) DT90 (days) Klimisch 2

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Site 1: St Martin des Bois, Tours 8 28 No guideline (silty clay loam) mentioned Montech, Montauban (clay loam) 8 27 Senas, Provence (clay loam) 4 13 Schleithal, Alsace (silt loam) 9 31

a unless otherwise stated, the tests were conducted in accordance with the named test guideline

Conclusion Based on these data etoxazole is considered to meet the HSNO criteria for degradability in soil <30 days.

Based on the minimum Koc value (5230) measured for a non sand soil (clay loam), etoxazole can be classified, according to McCall et al (1981), as immobile. All etoxazole‘s metabolites (based on lowest Koc values for non sand soils) can be classified low, slight or immobile except for metabolite R-8 which had one Koc value (desorption, for a sandy loam soil) between 0-50 which indicates very high mobility.

Soil Toxicity

A summary of the toxicity of etoxazole to soil dwelling macro-organisms, soil microbial function and terrestrial plants is provided in the next table.

Table A1.9 Summary of terrestrial toxicity data for etoxazole Test species Test type & Test resultsa, b Test methodc duration [reference number] Active Soil-dwelling invertebrates

Earthworm 14 days acute Soil containing 0, 95, 171, 309, 556 and Rodgers, Mansell, Eisenia foetida toxicity 1000 ppm. Cameron, 1996- One mortality observed in 556 ppm SKM-0070] treatment GLP LC50 > 1000 ppm NOEC 1000 ppm Klimisch 1 Weight changes were variable in all groups with no treatment related effects evident Terrestrial plants

Soybean, lettuce, Tier I Seedling Application rate of 0.06 lb s.i./A or 67.26 g FIFRA Subdivision J, radish, tomato, emergence (21 a.i./ha 122-1 (a) cucumber, oat, days) Test endpoints were: ryegrass, corn, onion [Chetram, 1998- 1) % emergence after 10 and 14 days 9800172] 2) % survival after 21 days 3) phytotoxicity (visual rating scale) after GLP 21 days Klimisch 1 4) plant height after 21 days 5) plant dry weight (aerial portion only) after 21 days. No single endpoint was a sensitive indicator of adverse effects for all test species. The detrimental effect of Etoxazole was <24%

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on all endpoints therefore, e?? Tier II test was not required.

Tier I Application rate of 0.06 lb s.i./A or 67.26 g FIFRA Subdivision J, Vegetative a.i./ha 122-1 (b) vigour (21 Test endpoints were: days) [Chetram, 1998- 1) phytotoxicity (visual rating scale) after 9800172] 21 days 2) % survival after 21 days 3) plant height after 21 days GLP 4) plant dry weight (aerial portion only) Klimisch 1 after 21 days. No single endpoint was a sensitive indicator of adverse effects for all test species. The detrimental effect of Etoxazole was <24% on all endpoints therefore, e Tier II test was not required. Soil microbial function

28 days Application of S-1283 as a foliage-directed spray at 50 g/ha SETAC 1995; once per year. The tet soil was a common sandy agricultural 91/414/EEC Annex soil (sandy loam) obtained from Clifton, UK. II, 8.5 The results demonstrated that the nitrogen transformation and carbon mineralization in treated soil were comparable to [Carter, Thomas, the results obtained from control soil. The deviations in Jackson, 1996-SKM- measured activity at the end of the study period being less 0027] than 25% for nitrate formation and carbon mineralization GLP and were considered not to be significantly different for transformation of ammonium. Klimisch 1 a Results are reported on the basis of nominal concentrations except where otherwise stated, Standard test guidelines provide for reporting of results on a nominal basis where measurements indicate the test substance remains within 20% of nominal. b 95% confidence intervals are stated where available cUnless otherwise stated, the tests were conducted according to the test method identified NA= Not applicable ND= No data provided

Conclusion Based on the information above, etoxazole does not trigger the threshold for toxicity to the soil environment.

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Terrestrial vertebrate ecotoxicity The mammalian toxicity of both etoxazole and the formulation has been addressed under sub- class 6. Key endpoints for both mammalian and avian toxicity are summarized in the following table.

Table A1.10 Summary of terrestrial vertebrate toxicity data for etoxazole and the formulation (only for mammals)

a, b Test type Test results c Test species & Test method [reference number] duration Active

Mammals

Rat Acute oral Etoxazole and metabolites 2,5-YI, R-3, R-7 did Refer to studies in and dermal not cause mortalities up to 5000 mg/kg with oral mammalian administration. Etoxzole did not cause mortality toxicology section to rats in a dermal exposure study up to 2000 mg/kg

Birds

Mallard duck Single oral S-1283 was administered orally to 10 birds (5 Rodgers, 1996 SKW- Anas dose male and 5 female) at 500, 1000 and 2000 0028 platyrhynchos mg/kg bodyweight. USEPA Pesticide After 14 days there were no mortalities and all Assessment birds remained in good health throughout the Guidelines, study period. Bodyweights and food Subdivision E, 71-1 consumption were unaffected by treatment with GLP the test item. Klimisch 1 Under the conditions the acute oral LD50 was found to be > 2000 mg/lg and the NOEL was considered to be 2000 mg/kg.

Mallard duck Dietary S-1283 was offered in diet to 10 young chicks at Rodgers, 1998 SKW- Anas toxicity 163, 325, 650, 1300, 2600 and 5200 ppm.Two 0074 platyrhynchos similar sized control groups were offered basal USEPA Pesticide diet alone. Test diets were introduced when the Assessment birds were 10 days old and were offered to the Guidelines, birds for 5 days. Test diets were then replaced Subdivision E, 71-2 with basal diet and the birds observed for a further 3 days. Observations, including GLP mortality, clinical signs, bodyweight and food Klimisch 1 consumption made during the study. There were no mortalities and no signs of clinical toxicity were observed. Bodyweight or food consumption remained unaffected by treatment with S-1283.

The LC50 was in excess of 5200 ppm and the NOEC (in the absence of any effects) was 5200 ppm.

Mallard duck Effects on 18 replicates of one male and one female per Rodgers, 1997 SM- Anas reproduction replicate were offered test diet containing 100, 0075 platyrhynchos 23weeks 300 and 1000 ppm S-1283 over 23 weeks. USEPA Subdivision Number of eggs laid, number of eggs damaged. E, 71-4 egg shell thickness, embryonic viability and

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chick survival were examined. GLP No treatment related effects were observed in all Klimisch 1 parameters. The NOEC in this study (health, growth and reproductive performance of adult birds or on their chicks) was considered to be 1000 ppm.

Bobwhite quail Subacute YI-5301 was offered in diet to 10 young chicks Rodgers, 1996 SKW- Colinus dietary at 163, 325, 650, 1300, 2600 and 5200 ppm. 0029 virginianus toxicity Two similar sized control groups were offered USEPA Pesticide basal diet alone. Test diets were introduced Assessment when the birds were 10 days old and were Guidelines, offered to the birds for 5 days. Test diets were Subdivision E, 71-2 then replaced with basal diet and the birds GLP observed for a further 3 days. Observations, including mortality, clinical signs, bodyweight Klimisch 1 and food consumption made during the study. There were no mortalities and no signsof clinical toxicity were observed. There was no effect of any treatment related effect on bodyweight or food consumption.

The LC50 was in excess of 5200 ppm and the NOEC (in the absence of any effects) was 5200 ppm.

Bobwhite quail Effects on 20 replicates of one male and one female per Rodgers, 1997 SM- Colinus reproduction replicate were offered test diet containing 100, 0043 virginianus 20 weeks 300 and 1000 ppm S-1283 over 20 weeks. OECD 206 Number of eggs laid, number of eggs damaged. egg shell thickness, embryonic viability and GLP chick survival were examined. Klimisch 1 No treatment related effects were observed in all parameters. The NOEC in this study (health, growth and reproductive performance of adult birds or on their chicks) was considered to be 1000 ppm. a Results are reported on the basis of nominal concentrations except where otherwise stated, Standard test guidelines provide for reporting of results on a nominal basis where measurements indicate the test substance remains within 20% of nominal. b 95% confidence intervals are stated where available cUnless otherwise stated, the tests were conducted according to the test method identified NA= Not applicable ND= No data provided

Conclusion Based on the information above, etoxazole does not trigger the threshold for toxicity to terrestrial vertebrates.

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Sub-class 9.4 Terrestrial invertebrate ecotoxicity A summary of the data on the toxicity of Etoxazole to honeybees and the toxicity of the formulation PHF 9502 (110 g etoxazole/L) to other non-target terrestrial invertebrates is provided in the next table.

Table A1.11 Summary of terrestrial invertebrate toxicity data for etoxazole and PHF 9502

a, b Test Test type & Test results Test methodc species duration [Reference number] Active

Honey 48 hour oral and Oral LD50 > 200 μg/L Wiles, 1996 SKW-0035 bees contact Contact LD50 > 200 μg/L UK Control of Pesticide Apis Regulations 1986 (working mellifera document 7/3); USEPA Subdivision L, 141-1; EPPO 1992 guideline no. 170 GLP Klimisch 1

Honey Honeybee brood Three doses of S-1283 at 5.5, 55, 110 mg/L were Hughes, 1996 SKW-0038 bee Apis feeding study fed in sugar syrup to each of 3 standardised bee EPPO 1992 bulletin 22, mellifera colonies per dose. 613-616. L. Control colonies gave a mean mortality of 10/6% GLP by the expected time of adult emergence. Compared to that no significant brood mortality Klimisch 1 occurred following application of S-1283 to test colonies at any dose. However, at the highest dose of S-1283 significantly more adult bees died than the control It is concluded that S-1283 is not toxic to uncapped honey bee brood when fed to colonies, however, under the conditions of this test S-1283 appears to show some toxicity to adult bees.

Test Test type & Formulation Test methodc species duration [Reference number]

Heteropte 9 days treatment PHF 9502 containing 110 g/L etoxazole (S-1283) Tessier, Austin, 1997 ran bug (sprayed and applied at 55 g a.i./ha on second instar nymphs of SKW-0058 Orius dried cells) Orius laevigatus. Bakker et al (1992): Side laevigatu After 9 days mortality in treated cells was 82.7% effects for phytoseiids and s compared with 14% mortality in the control. their rearing methods Bull The formulation can be classified as harmful to IOBC/WPRS 1992/XV/3 Orius laevigatus nymphs, class 4 of the IOBC pp 61-82; Van de Viere categorisation when applied ata a rate of 55 g (1992) Laboratory methods a.i./ha. for testing side-effects of pesticides on the predatory bug Orius niger Wolff. Bull IOBC/WPRS 1992/XV/3 pp 89-95 GLP

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Lacewig Spray PHF 9502 containing 110 g/L etoxazole (S-1283) Thompson, 1997 SKW- Chrysope application on applied at 55 g a.i./ha on larvae of the lacewig 0060 rla glass plates Chrysoperla carnea. IOBC Bigler, 1988 in line carnea Mortality of 85% was observed before pupation with ESCORT, 1994 while all larvae in the tap water control \treatment GLP pupated. Klimisch 1 The formulation was harmful to Chrysoperla carnea when applied to glass plates at its recommended field rate 0.5 L/ha.

Staphylin 28 days PHF 9502 containing 110 g/L etoxazole (S-1283) Beech, 1997 SKW-0061 id beetle applied at 55 g a.i./ha on the beetle Aleochara IOBC Bigler, 1988 in line Aleochar bilineata Gyll. with ESCORT, 1994 a 75% of the beetles were recovered alive after 28 GLP bilineata days compared with 83.3% in the water control. A 14.2% reduction in new adult emergence was Klimisch 1 observed compared to water control. The author concluded that according to the results the formulation did not cause any harmful effects on populations of Aleochara bilineata under the conditions of the study.

Paracitic Glass plates PHF 9502 containing 110 g/L etoxazole (S-1283) Nickless, 1997 SKW-0059 wasp spray applied at 55 g a.i./ha on the reared adult Barrett et al 1994 Aphidius application-48 hr parasitoids over 48 hours. Mortality was assessed (ESCORT); Mead-Briggs rhopalosi mortality and the fecundity of 10 surviving females per (1992) treatment was evaluated. phi and GLP The adult test resulted in 15% mortality in test juvenile life Klimisch 1 stage units treated with PHF 9502compared with 13% mortality in water control units. Surviving females from the control treatment produced a mean of 1 mummy/female, while females from the PHF 9502 treatment produced a mean of 0.5 mummies/female. Five days after application in the juvenile life stage there was a 100% emergence in the control units and 96% from the PHF 9502 treated mummies. The mortality of emerged wasps was 33% in PHF 9502 and 21% in treated controls. Surviving females from the control treatment produced a mean 5.6 mummies per female compared with 9.1 mummies/female in the PHF 9502 treatment.

Predators Field study in PHF 9502 at a dose of 0.05 L/hectolitre, Reboulet, 1997 SKW-0071 of the red apple orchard in observations before treatment and up to 35 days ACTA Publication – mite production with after treatment vol.no. 1, 1994, pp 30-38 (P.ulmi) infestation by red Under the conditions of the test, the product has Klimisch 2 in apple mite been found to be inhibiting for the red mite orchards: P.Ulmi No GLP Predatory mite N. Neutral for the neoptera and for the parasitoid Californi hymenoptera cus, Neutral to slightly toxic for N. Californicus and predatory the ladybird genus Stethorus acaropha

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ge Slightly toxic for predatory hymenoprera insects: (Mirides and Anthocorides of genus Orius) ladybird Stethorus spp., heteropte ra (Anthoco rides+Mir ides), neuropter an (Chrysop ae, Hemerob ae and Coniopter ygidae)

Predatory Field trial (vine), PHF 9502 at a dose of 0.5 L/ha, observations Lacote, 1996 SKW-0044 mite non target effects before treatment and up to 42 days after Commission of Biological Typhlodr on T. pyri treatment. Trials of the French Plant omus pyri The calculation of the residual population 21 days Protection Association, after treatment leads to a classification in the method no. 107 category moderately harmful (30%

Predatory 15 days PHF 9502 at a dose of 0.5 L/ha, caused no Auger, 1996 SKW-0052 mite laboratory test on mortality to adult females, the fertility of Commission of Biological Typhlodr two different remained relatively high but the viability of the Trials of the French Plant omus pyri (sensitive and offspring was zero for the sensitive population Protection Association resistant) and just 8% for the resistant population. The document, method no. 167, populations overall effect was therefore 100% for the 1993 sensitive population and 94.72% for the resistant population which indicates that PHF 9502 at Klimisch 2 0.5L/ha is highly toxic in the laboratory and No GLP several field tests are required.

Predatory Field trial PHF 9502 at a dose of 0.5 L/ha, one single Lacote, 1997 SKW-0072 mite (vines), natural application at the stage of ―closure of the bunch‖ Commission of Biological Typhlodr presence of the and at BBCH 79. Trials of the French Plant omus pyri predatory mite The calculation of the residual population, 83.5% Protection Association (21 days after treatment) allows this product to be document, method no. 167, classified as neautral to weakly toxic under the 1993 conditions of the test. Neverthelss it can be stated Klimisch 2 that this residual population decreases gradually during the observation period and reached 64% No GLP 43 days after treatment. a Results are reported on the basis of nominal concentrations except where otherwise stated, Standard test guidelines provide for reporting of results on a nominal basis where measurements indicate the test substance remains within 20% of nominal. b 95% confidence intervals are stated where available cUnless otherwise stated, the tests were conducted according to the test method identified NA= Not applicable ND= No data provided

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Conclusion Based on the information above etoxazole does not trigger the threshold for toxicity to terrestrial invertebrates (based on bee study). However, laboratory tests and field trials show that the formulated product can be harmful to beneficial non target terrestrial invertebrates.

Table A1.12 Summary of ecotoxicity classifications for etoxazole and ParaMite® Selective Miticide Sub-class Etoxazole ParaMite® Selective Miticide 9.1 Aquatic ecotoxicity 9.1A highly ecotoxic to the No formulation data available aquatic environment 9.2 Soil ecotoxicity Not triggered No formulation data available 9.3 Terrestrial vertebrate ecotoxicity Not triggered No formulation data available 9.4 Terrestrial invertebrate Not triggered No formulation data available ecotoxicity

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Appendix 2: Risk Assessment

The methodology involved in assessing risk is outlined in the Supplementary Information section.

Quantitative assessments have been undertaken for the use phase of the substance‘s lifecycle using the GENEEC2 and German BBA models.

Qualitative assessments have been undertaken for all other stages of the lifecycle. In these cases, the level of risk has been evaluated on the basis of the magnitude and likelihood of adverse effects occurring to people or the environment.

The Agency did not identify any risks associated with society and the community, the market economy or New Zealand‘s international obligations.

Relationship of Māori to the environment The Agency notes that the substance triggers a number of hazardous properties giving rise to the potential for cultural risk. However, based on the information provided, the Agency considers that the risks will be negligible. The rationale for this approach is outlined in the Supplementary Information (section 3).

Human health risk assessment

Worker (operator) risk assessment

Selection of the key study and key/critical effects

The Agency typically uses 90 day studies for the derivation of AOELs. The available data is summarized as follows:

Reference Species Duration Key/critical effect(s) IET 92- Mouse 13 week Hepatotoxicity 0111 IET 92- Rat 13 week Hepatotoxicity 0078 IET 93- Dog 13 week Hepatotoxicity 0113

The Agency notes that the dog and the rat are the most sensitive of the species examined and the males of these species are approximately equally sensitive to the effects of etoxazole. It should be noted that female dogs appear more sensitive to the hepatotoxic effects of etoxazole than either female rats or mice. Within the dog study, the females displayed a greater percent increase in relative liver weight relative to the controls at the highest level of exposure (53% compared with 30% in the males)

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Derivation of an AOEL using the Benchmark Dose Low + Uncertainty Factor (BMDL + UF) Method

The Agency has selected the dog study for dose modeling and an increase in relative liver weight of 10% relative to the controls (i.e. 0 mg/kg bw/d or zero risk) as the most sensitive precursor key event given that the critical effect is hepatotoxicity. A benchmark response of a 10% increase in relative liver weight is regarded as adverse based upon the relevant UK PSD guidance document.4

Modeling of dose responses was performed using the US EPA BMDS software (Ver. 2.1.2, Lockheed Martin). The following continuous dose, constant variance response data models were examined for each critical effect: exponential (2-5 parameters), Hill, linear, polynomial and power. All models were restricted in terms of the number of parameters as per the US EPA draft guidance requirements.5 The assumption of constant variance of the response data was subsequently validated by the modeling. The criteria for selection of the most appropriate model were as follows:

Test 1 (tests the hypothesis that response and variance don't differ among dose levels. If this test accepts, there may not be a dose-response) : p < 0.05 is regarded as acceptable; Test 2 (tests the hypothesis that variances are homogeneous. If this test accepts, the simpler constant variance model may be appropriate.): p > 0.1 is regarded as acceptable, however the closer this value is to 1, the better; Test 3 (tests the hypothesis that the model for the mean fits the data. If this tests accepts, the user has support for the selected model): p > 0.1 is regarded as as acceptable, however the closer this value is to 1, the better; Test 4 (tests the hypothesis that the variances are adequately modeled i.e. global fit of the curve to the data. If this test accepts, it may be appropriate to conclude that the variances have been modeled appropriately.): p > 0.1 is regarded as as acceptable, however the closer this value is to 1, the better; Scaled residuals (test the fit of individual points on the dose response curve): < 2 is regarded as acceptable, but the smaller the better; Provided other parameters are acceptable, the model with the lowest number of model parameters is more desirable; Akaike‘s Information Criterion (AIC): For comparison of models and selection of the model to use for BMDL, the model with the lowest AIC is recommended assuming all other parameters are met; If necessary, the upper most dose of the dose response can be dropped from the analysis in order to facilitate better curve fitting to the area of interest (i.e. the shape of the does response curve at low doses); Visual inspection of curve fit.

4 http://www.pesticides.gov.uk/uploadedfiles/Web_Assets/ACP/ACP_Paper_on_the_interpretation_of_Liver_Enlargement.pdf 5 Risk Assessment Forum, U.S. Environmental Protection Agency (2000) External Review Draft Benchmark Dose Technical Guidance Document. EPA/630/R-00/001, Washington, DC. http://www.epa.gov/ncea/pdfs/bmds/BMD-External_10_13_2000.pdf

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Derivation of BMDL for increased relative liver weight:

The following data was modeled:

Female Dogs (Study IET 93-0113) Animal dose Animal dose N Mean Relative SD (ppm) mg/kg bw/d Liver Weight 0 0 4 2.53 0.17 200 5.42 4 2.55 0.27 2000 55.9 4 3.19 0.36 10000 277 4 3.86 0.37

The results of the Continuous Hill model selection criteria for the female data was as follows:

Hill Model with 0.95 Confidence Level

Hill 4.5

4

3.5 Mean Response Mean

3

2.5

2 BMDL BMD

0 50 100 150 200 250 dose 10:48 02/22 2011

Model Selection Criteria Result Test 1 p < 0.0001 Test 2 p = 0.4548 Test 3 p =0.4548 Test 4 Not Applicable Scaled residuals of interest Point 1 = 3.29x10-9 Point 2 = 1.02x10-8 Point 3 = 2.02 x 10-8 Point 4 = 1.58 x 10-7 AIC A1 = -16.765342 A2 = -13.380463 A3 = -16.765342 Fitted = -16.765342 R = 3.995457

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AICs were best of all models examined

Accordingly, the BMD and BMDL for females for this endpoint were as follows:

Parameter +10% increase of relative liver + 1 standard deviation increase weight relative to the controls of relative liver weight relative to the controls for comparison BMD 25.4 mg/kg bw/d (animal dose) 26.1 mg/kg bw/d (animal dose) BMDL 6.5 mg/kg bw/d (animal dose) 7.5 mg/kg bw/d (animal dose)

Allometric Scalling of the BMDL Value

Allometric scalling is regarded as relvant to the liver relative weight key effect.

Accordingly the following human equivalent dose calculation was applied to both animal BMDL values:

1 AbsH BWA 4 BMDL HED BMDL Animal x x AbsA BWH

Where human body weight (BWH) = 70 kg, and the weight of the female dogs was 9.8 kg (mean from IET 93-0113 study, week 13 control animals). Because of lack of information on human oral absorption of the etoxazole, the human: animal oral absorption ratio is assumed to be 1. Accordingly the BMDL HED for the critical/key endpoints are:

Key Effect BMDL HED 10% increase in relative liver weight 6.5 x 1 x (70/9.8)0.25 = 10.6 mg/kg BW/day

Uncertainty Factors

The Agency notes that etoxazole is extensively metabolized and the toxicologically important moieties are include both the parent compound and its metabolites. Given that metabolic activation seems to be part of the mammalian toxicological mode of action for etoxazole and that there was no toxicokinetic/toxicodynamic information supplied regarding the putative toxicologically active moiety(ies), insufficient information was available to allow for the development of chemical specific adjustment factors. For the chosen key effect, the BMR of 10% is regarded as being equivalent to a conservative LOAEL since it is on the nexus between adaptive and adverse effects in the liver.6 Accordingly the following default uncertainty factors were applied:

Uncertainty Factor Type Value Interspecies 37

6 http://www.pesticides.gov.uk/uploadedfiles/Web_Assets/ACP/ACP_Paper_on_the_interpretation_of_Liver_Enlargement.pdf 7 Note: allometric scalling was applied, so this uncertainty factor is applied to account for any remaining interspecies differences. See US EPA (2006) Harmonization in Interspecies Extrapolation: Use of BW 3/4 as Default Method in Derivation of the Oral

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IntraspeciesToxicokinetic + 10 Toxicodynamic LOAEL to NOAEL 2 extrapolation

Oral absorption

The Agency notes that the degree of oral absorption of etoxazole is sex-dependent at the low doses: the degree of absorption in males (50–54%) is less than that in females (63–70%). However since the BMDL was derived from female data, an oral absorption factor of 0.6 (the most conservative8) has been applied in the AOEL derivation.

Derivation of the AOELs for Critical/Key Effects

BMDL HED 10.6 AOELIncreased Relative Liver Weight x Oral Absorption Factor x 0.6 0.11 mg/kg bw/day (human) UF 60

It should be noted that this AOEL is approximately the same as the EFSA value for etoxazole.6

Derivation of the AOEL using the NOAEL/LOAEL + UF method

The NOAEL for the critical/key effects from the selected study are as follows:

Critical/Key Effect NOAEL Increased relative liver weight in females 5.42 mg/kg/day females

Allometric scalling of NOAEL values:

Critical/Key Effect NOAEL HED Increased relative liver weight in females 5.42 x 1 x (70/9.8)0.25 = 8.9 mg/kg BW/day

Uncertainty factors:

Uncertainty Factor Type Value Interspecies 39 IntraspeciesToxicokinetic + 10 Toxicodynamic

RfD (External Review Draft). U.S. EPA, Washington, D.C., EPA/630/R-06/001, 2006 8 http://ec.europa.eu/food/plant/protection/evaluation/newactive/etoxazole_draft_review_report_.pdf 9 Note: allometric scalling was applied, so this uncertainty factor is applied to account for any remaining interspecies differences. See US EPA (2006) Harmonization in Interspecies Extrapolation: Use of BW 3/4 as Default Method in Derivation of the Oral RfD (External Review Draft). U.S. EPA, Washington, D.C., EPA/630/R-06/001, 2006

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AOEL calculations:

NOAEL HED 8.9 AOELIncreased Relative Liver Weight x Oral Absorption Factor x 0.7 0.21 mg/kg bw/day UF 30

Comparison of Results of the BMD + UF and the NOAEL + UF Methods

Method AOELIncreased Relative Liver Weight BMDL + UF 0.11 mg/kg BW/day NOAEL + UF 0.21 mg/kg BW/day

It is notable that all calculated AOELs in this case are within a factor of about 2 of each other, which is consistent with the known accuracy of both methodologies (AOELs and RfDs are estimates with uncertainty spanning perhaps an order of magnitude).

Given that the BMDL + UF methodology is currently considered to have substantial advantages over the NOAEL + UF methodology, the Agency has used the AOELIncreased Liver Relative Weight of 0.11 mg/kg BW/day for risk assessment purposes.

Dermal Absorption Factors for Etoxazole

Due to a lack of available data, the Agency has adopted the EFSA default value of 10% for both concentrates and aqueous dilutions.10

Maximum Application Rates for Modelling Purposes

ParaMite® concentrate is diluted at a rate of 35 mL per 100L and the diluent is applied at a maximum rate of 3000 L/Ha. Etoxazole is present in the concentrate at 110 g/L.

The maximum application rate of etoxazole is therefore:

0.035L concentrate 110g Etoxazole 3000L dilutent x x 115.5g A.I./Ha 0.116 kg A.I./Ha 100L dilutent 1L concentrate 1Ha

Although the minimum application interval is not specified on the product label, the Agency has assumed a minimum application interval of ≥ 14 days for modeling purposes.

10 http://ec.europa.eu/food/plant/protection/evaluation/newactive/etoxazole_draft_review_report_.pdf

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OUTPUT OF HUMAN WORKER (OPERATOR) MIXING, LOADING AND APPLICATION EXPOSURE MODELING Boom Exposure Scenario Estimated Operator Risk Quotient Exposure (mg/kg bw/day) No PPE11 during mixing, loading and application 0.0147 0.13 Gloves only during mixing and loading 0.0069 0.06 Gloves only during application 0.0135 0.12 Full PPE during mixing, loading and application 0.0004 0.00 (excluding respirator) Full PPE during mixing, loading and application 0.0004 0.00 (including respirator)

Airblast Exposure Scenario Estimated Operator Risk Quotient Exposure (mg/kg bw/day) No PPE during mixing, loading and application 0.0186 0.17 Gloves only during mixing and loading 0.0155 0.14 Gloves only during application 0.0177 0.16 Full PPE during mixing, loading and application 0.0010 0.01 (excluding respirator) Full PPE during mixing, loading and application 0.0007 0.01 (including respirator)

Backpack - High Level Target Exposure Scenario Estimated Operator Risk Quotient Exposure (mg/kg bw/day) No PPE during mixing, loading and application 0.0411 0.37 Gloves only during mixing and loading 0.0076 0.07 Gloves only during application 0.0393 0.36 Full PPE during mixing, loading and application 0.0012 0.01 (excluding respirator) Full PPE during mixing, loading and application 0.000605 0.01 (including respirator)

Re-entry Risk Assessment:

The formula applied is:

D = DFR x TC x WR x AR x P

Where:

D = Dermal exposure [µg a.s./person/day] (a.s. represents the ―active substance‖ in this case, etoxazole) DFR = Dislodgeable Foliar Residue per kg a.s./ha TC = Transfer coefficient [cm2/hour] WR = Work rate [8 hours/day]

11 Full‖ PPE includes: gloves, hood/visor, coveralls, and heavy boots during application. The model only provides for use of gloves at mixing loading.

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AR = Application rate [kg a.s./ha] P = Protection factor (for use of clothing) [A value of 1 is used assuming no clothing such as a long sleeved shirt is worn to protect the skin from exposure.]

In the case of etoxazole, the TC value of 2,500 cm2/hr for vegetables ―reach and pick‖ has been used from the Guidance document. This is a conservative assumption given the proposed use pattern of ParaMite Selective Miticide.

Taking the application rates for lettuce as the highest value the input values are:

DFR = the default value has been applied, 3 µg of a.s./square cm of foliage/kg a.s per hectare. TC = 2500 cm2/h WR = 8 hours per day AR = Application rate [0.116 kg a.s./ha] P = 1

So D = DFR x TC x WR x AR x P = 3 x 2,500 x 8 x 0.116 x 1 = 6960 µg a.i. per person per day (as a dermal exposure) ≈ 0.7 mg a.i. per person per day (as dermal exposure)

Given that the dermal absorption factor of 0.1 for etoxazole (as previously), the intake for the re-entry worker from this estimate on a per kg bw basis assuming a 70 kg body weight :

[0.7 x 0.1]/[70] ≈ 0.001 mg/kg bw/day

The AOEL for etoxazole is 0.11 mg/kg bw/day, as above, so the above estimate suggests that the intake for the re-entry worker may be associated with an RQ value ≈ 0.009.

Outcomes of the worker (operator) exposure assessment:

No PPE is recommended to reduce the risk to an acceptable level during mixing, loading, and application for boom and airblast spraying. 12 A re-entry period is not required.

12 The Agency considers that, while the ‗no PPE‘ exposure model leads to an acceptable level of risk, it is appropriate to retain requirements for PPE since the use of PPE when handling agrichemicals is good practice. The Agency notes that the HSNO PPE requirements are not prescriptive allowing users to select an appropriate level of PPE.

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QUANTITATIVE BYSTANDER RISK ASSESSMENT13

Selection of the key studies for derivation of the chronic reference dose (CRfD)

The following studies were available:

Study Species Duration LOAEL NOAEL Key/Critical Effects (Animal) (Animal) IET 94- Dog 1 year 23.5 mg/kg bw/d 4.62 mg/kg Hepatotoxicity 0005 ♂ bw/d ♂ 23.8 mg/kg bw/d 4.79 mg/kg ♀ bw/d ♀ IET 93- Mouse Near life- 241 mg/kg bw/d 60.1 mg/kg Reduced weight gain 0023 time ♂ bw/d ♂ Hepatotoxicity 243 mg/kg bw/d 60.5 mg/kg ♀ bw/d ♀ IET 98- Mouse Near life- 484 mg/kg bw/d 242 mg/kg bw/d Hepatotoxicity 0045 time ♂ ♂ 482 mg/kg bw/d 243 mg/kg bw/d ♀ ♀ IET 92- Rat Near life- 16 mg/kg bw/d ♂ 4 mg/kg bw/d ♂ Reduced weight gain 0148 time 64 mg/kg bw/d ♀ 16 mg/kg bw/d Hepatotoxicity in ♂ ♀

Of the available studies, IET 94-0005 was selected because:

Both sexes had equivalent NOAELs and LOAELs; The increase in relative liver weights observed in the males and females had the largest % increase relative to control values of any other endpoint in any of the other studies (67% for males, 71% for females); An acceptable range of doses of the test article were tested.

13 The Agency considers that the main potential source of exposure to the general public for substances of this type (other than via food residues which will be considered as part of the registration of this substance under the Agricultural Compounds and Veterinary Medicines (ACVM) Act 1997) is via spray drift. In terms of bystander exposure, toddlers are regarded as the most sensitive sub-population and are regarded as having the greatest exposures. For these reasons, the risk of bystander exposure is assessed in this sub- population. The oral chronic reference dose (CRfD), or an equivalent threshed such as an ADE, ADI or a general population DN(M)EL is selected because these are an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. Thus, the bystander exposure risk assessment estimates the life-time risk associated with repeated daily exposure of the most sensitive human sub-population over their lifespan;

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Derivation of a Chronic Reference Dose (CRfD) using the Benchmark Dose Low + Uncertainty Factor (BMDL + UF) Method

The Agency has selected the dog study for dose modeling and an increase in relative liver weight of 10% as the most sensitive precursor key event given that the critical effect is hepatotoxicity. A benchmark response of a 10% increase in relative liver weight is regarded as adverse based upon the relevant UK PSD guidance document.14 Modeling of dose responses was performed using the US EPA BMDS software (Ver. 2.1.2, Lockheed Martin). The following continuous dose, constant variance response data models were examined for each critical effect: exponential (2-5 parameters), Hill, linear, polynomial and power. All models were restricted in terms of the number of parameters as per the US EPA draft guidance requirements.15 The assumption of constant variance of the response data was subsequently validated by the modeling.

Derivation of BMDL for increased relative liver weight:

Given that the female animals displayed the greatest increase in relative liver mass compared with the controls, the following data were modeled:

Female Dogs (Study IET 94-0005) Animal dose Animal dose N Mean Relative SD (ppm) mg/kg bw/d Liver Weight 0 0 4 2.13 0.14 200 4.79 4 2.44 0.21 500 23.8 4 2.74 0.34 1000 117 4 3.65 0.25

The results of the Continuous polynomial model selection criteria for the female data was as follows:

Polynomial Model with 0.95 Confidence Level

Polynomial

4

3.5

3 Mean Response Mean

2.5

2

BMDL BMD

0 20 40 60 80 100 120 dose 15:02 02/22 2011

14 http://www.pesticides.gov.uk/uploadedfiles/Web_Assets/ACP/ACP_Paper_on_the_interpretation_of_Liver_Enlargement.pdf 15 Risk Assessment Forum, U.S. Environmental Protection Agency (2000) External Review Draft Benchmark Dose Technical Guidance Document. EPA/630/R-00/001, Washington, DC. http://www.epa.gov/ncea/pdfs/bmds/BMD-External_10_13_2000.pdf

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Model Selection Criteria Result Test 1 p < 0.0001 Test 2 p = 0.3855 Test 3 p =0.3855 Test 4 P = 0.2115 Scaled residuals of interest Point 1 = -0.728 Point 2 = 0.951 Point 3 = -0.23 Point 4 = 0.00794 AIC A1 = -23.497932 A2 = -20.537830 A3 = -23.497932 Fitted = -23.936893 R = 4.000350

AICs were best of all models examined

Accordingly, the BMD and BMDL for females for this endpoint were as follows:

Parameter +10% increase of relative liver + 1 standard deviation increase weight relative to the controls of relative liver weight relative to the controls for comparison BMD 8.8 mg/kg bw/d (animal dose) 8.9 mg/kg bw/d (animal dose) BMDL 5.5 mg/kg bw/d (animal dose) 5.6 mg/kg bw/d (animal dose)

Allometric Scalling of the BMDL Value

Allometric scalling is regarded as relevant to the liver relative weight key effect.

Accordingly the following human equivalent dose calculation was applied to both animal BMDL values:

1 AbsH BWA 4 BMDL HED BMDL Animal x x AbsA BWH

Where human body weight (BWH) = 70 kg, and the weight of the female dogs was 9.6 kg (mean from IET 93-0113 study, week 13 control animals). Because of lack of information on human oral absorption of the etoxazole, the human: animal oral absorption ratio is assumed to be 1. Accordingly the BMDL HED for the critical/key endpoints are:

Key Effect BMDL HED 10% increase in relative liver weight 5.6 x 1 x (70/9.6)0.25 = 9.2 mg/kg BW/day

Uncertainty Factors

The Agency notes that etoxazole is extensively metabolized and the toxicologically important moieties are include both the parent compound and its metabolites. Given that metabolic activation seems to be part of the mammalian toxicological mode of action for etoxazole and that there was no toxicokinetic/toxicodynamic information supplied regarding the putative

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toxicologically active moiety(ies), insufficient information was available to allow for the development of chemical specific adjustment factors. For the chosen key effect, the BMR of 10% is regarded as being equivalent to a conservative LOAEL since it is on the nexus between adaptive and adverse effects in the liver.16 Accordingly the following default uncertainty factors were applied:

Uncertainty Factor Type Value Interspecies 317 IntraspeciesToxicokinetic + 10 Toxicodynamic LOAEL to NOAEL 2 extrapolation

Derivation of the CRfD for the Key Effect

BMDL HED 9.2 CRfD Increased Relative Liver Weight 0.15 mg/kg bw/day (human) UF 60

It should be noted that this CRfD is approximately the same as that used by EFSA for etoxazole.6

Derivation of the CRfD using the NOAEL/LOAEL + UF method

The NOAEL for the critical/key effects from the selected study are as follows:

Critical/Key Effect NOAEL Increased relative liver weight in females 4.79 mg/kg/day females

Allometric scalling of NOAEL values:

Critical/Key Effect NOAEL HED Increased relative liver weight in females 4.79 x 1 x (70/9.6)0.25 = 7.9 mg/kg BW/day

Uncertainty factors:

Uncertainty Factor Type Value Interspecies 318 IntraspeciesToxicokinetic + 10 Toxicodynamic

16 http://www.pesticides.gov.uk/uploadedfiles/Web_Assets/ACP/ACP_Paper_on_the_interpretation_of_Liver_Enlargement.pdf 17 Note: allometric scalling was applied, so this uncertainty factor is applied to account for any remaining interspecies differences. See US EPA (2006) Harmonization in Interspecies Extrapolation: Use of BW 3/4 as Default Method in Derivation of the Oral RfD (External Review Draft). U.S. EPA, Washington, D.C., EPA/630/R-06/001, 2006 18 Note: allometric scalling was applied, so this uncertainty factor is applied to account for any remaining interspecies differences. See US EPA (2006) Harmonization in Interspecies Extrapolation: Use of BW 3/4 as Default Method in Derivation of the Oral RfD (External Review Draft). U.S. EPA, Washington, D.C., EPA/630/R-06/001, 2006

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CRfD calculations:

NOAEL HED 7.9 CRfDIncreased Relative Liver Weight 0.26 mg/kg bw/day UF 30

Comparison of Results of the BMD + UF and the NOAEL + UF Methods

Method AOELIncreased Relative Liver Weight BMDL + UF 0.15 mg/kg BW/day NOAEL + UF 0.26 mg/kg BW/day

It is notable that all calculated AOELs in this case are within a factor of 2 of each other, which is consistent with the known accuracy of both methodologies (AOELs and RfDs are estimates with uncertainty spanning perhaps an order of magnitude).

Given that the BMDL + UF methodology is currently considered to have substantial advantages over the NOAEL + UF methodology, the Agency has used the CRfCIncreased Liver Relative Weight of 0.15 mg/kg BW/day for risk assessment purposes.

OUTPUT OF HUMAN BYSTANDER MIXING, LOADING AND APPLICATION EXPOSURE MODELING19 Boom Exposure Scenario Estimated Exposure of 15 Risk Quotient kg Toddler Exposed Through Contact to Surfaces 8 m From an Application Area High boom, fine droplets 0.80 0.0053 High boom, coarse droplets 0.13 0.0008 Low boom, fine droplets 0.27 0.0018 Low boom, coarse droplets 0.06 0.0004

Airblast Exposure Scenario Estimated Exposure of 15 Risk Quotient kg Toddler Exposed Through Contact to Surfaces 8 m From an Application Area Airblast normal orchard 0.05 0.0004

19 Exposure is estimated using the equations from the UK Heath & Safety Chemical Regulation Directorate which account for dermal exposure, hand-to-mouth exposure and object-to-mouth exposure (http://www.pesticides.gov.uk/uploadedfiles/Web_Assets/PSD/Bystander%20exposure%20guidance_final%20version. pdf Accessed 27/01/2010a). In addition, incidental ingestion of soil is taken into account using a modified exposure equation from the United States Environmental Protection Agency (USEPA, 2007, Standard Operating Procedures (SOPs) for Residential Exposure Assessments, Contract No. 68-W6-0030, Work Assignment No. 3385.102). Spray drift is estimated using models specific to the type of application equipment. For pesticides applied by ground boom or air blast sprayer, the AgDrift model is used. Spray drift deposition from aerial application is estimated using the AGDISP model along with appropriate New Zealand input parameters

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Airblast sparse orchard 2.30 0.0154 Airblast dense orchard 0.77 0.0051 Airblast vineyard 0.11 0.0007

The risks to the bystanders are considered acceptable.

Environmental exposure and risk assessment

For Class 9 substances, irrespective of the intrinsic hazard classification, the ecological risk can be assessed for a substance by calculating a risk quotient based on an estimated exposure concentration. Such calculations incorporate toxicity values, exposure scenarios (including spray drift, application rates and frequencies), and the half lives of the component(s) in soil and water. For the aquatic environment, the calculations provide an Estimated Environmental Concentration (EEC) which, when divided by the LC50 or EC50, gives a risk quotient (RQ).

Acute RQ = EECshort term Chronic RQ = EEClong term LC50 or EC50NOEC

If the RQ exceeds a predefined level of concern, this suggests that it may be appropriate to refine the assessment or to apply the approved handler (AH) control and/or other controls to ensure that appropriate matters are taken into account to minimize off-site movement of the substance. Conversely, if a worst-case scenario is used, and the level of concern is not exceeded, then in terms of the environment, there is a presumption of low risk which is able to be adequately managed by such things as label statements (warnings, disposal). The AH control can then be removed on a selective basis.

Levels of concern (LOC) developed by the USEPA (Urban and Cook 1986) and adopted by the Agency, to determine whether a substance poses an environmental risk are provided in the table below.

Levels of concern as adopted by the Agency. Endpoint LOC Presumption Aquatic (fish, invertebrates) Acute RQ≥ 0.5 High acute risk Acute RQ 0.1-0.5 Risk can be mitigated through restricted use Acute RQ< 0.1 Low risk Chronic RQ≥ 1 High chronic risk

Plants (aquatic and terrestrial) Acute RQ≥ 1 High acute risk

For terrestrial organisms toxicity-exposure ratios (TER) are used for terrestrial vertebrates and earthworms and hazard quotient (HQ) values for terrestrial invertebrates. This convention results in concern arising if a risk quotient is less than the trigger value for birds and earthworms and more than a trigger value for terrestrial invertebrates. The levels of concerns are shown in the table below.

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TER= LD50 / estimated environmental concentration

HQ bees= application rate/ LD50

HQ invertebrates= exposure/ LR50

Levels of concern in environmental risk assessment for terrestrial organisms

Level of Concern (LOC) Presumption Bird/ earthworm Acute TER <10 High risk

Chronic TER <5 high risk Bees HQ < 50 Low risk HQ >50 Higher tier testing required Terrestrial invertebrates HQ < 2 Low risk

HQ Higher tier testing< required ≥2

Aquatic risk

Assessment of Expected Environmental Concentration The Agency has used the Generic Estimated Environmental Concentration Model v2 (GENEEC2) surface water exposure model (USEPA 2001) to estimate the EEC of etoxazole in surface water. Environmental concentration may arise as a result of spray drift and surface runoff from the applicant‘s proposed New Zealand use pattern.

The parameters used in the GENEEC2 modeling are listed in the table below and represent the recommended use on avocado (highest rate) as a conservative estimate.

Input parameters for GENEEC2 analysis. etoxazole Reference Application rate 121.59 g/ha Label Application frequency 1 Label Application interval NA -

Koc 5230 Elsom, Winwick, Nicoll, 1996

Aerobic soil DT50 24 Assaf, 1999 Pesticide wetted in? No Label Methods of application Airblast Label

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‗No spray‘ zone 0 Assumption Water solubility 0.07 European Comission, 2004

Aerobic aquatic DT50 107 Elsom, 1997 Aqueous photolysis 17.4 Elsom, 1997 DT50

Output from the GENEEC2 model. RUN No. 1 FOR Etoxazole ON Avocado * INPUT VALUES * ------RATE (#/AC) No.APPS & SOIL SOLUBIL APPL TYPE NO-SPRAY INCORP ONE(MULT) INTERVAL Koc (PPB ) (%DRIFT) (FT) (IN) ------.108( .108) 1 1 5230.0 70.0 ORCHAR( 9.7) .0 .0

FIELD AND STANDARD POND HALFLIFE VALUES (DAYS) ------METABOLIC DAYS UNTIL HYDROLYSIS PHOTOLYSIS METABOLIC COMBINED (FIELD) RAIN/RUNOFF (POND) (POND-EFF) (POND) (POND) ------24.00 2 N/A 17.40- 2157.60 107.00 101.94

GENERIC EECs (IN MICROGRAMS/LITER (PPB)) Version 2.0 Aug 1, 2001 ------PEAK MAX 4 DAY MAX 21 DAY MAX 60 DAY MAX 90 DAY GEEC AVG GEEC AVG GEEC AVG GEEC AVG GEEC ------1.01 .99 .87 .66 .55

The Estimated Environmental Concentration (EEC) for etoxazole as estimated by GENEEC2 are: Peak EEC 0.7617 μg/L Chronic EEC (21 days) 0.57821 μg/L

Assessment of acute risk Aquatic Ecotoxicity endpoints to be used in risk assessment. Acute risk Chronic risk Species LC/EC50 (μg/L) Species NOEC (μg/L) Fish 14000 Fish 15 Crustacea 1.2 (marine Crustacea 0.32 (marine species) / 7.1 species)/0.20 (freshwater (freshwater species) species) Algae >70.4* Algae 70.4* *in the frame of an OECD201 test, etoxazole acute toxicity to algae has been determined to be above the water solubility limit. For risk assessment purpose, water solubility is therefore used as cut-off criteria

The Estimated Environmental Concentration (EEC) for etoxazole as estimated by GENEEC2 are shown in the table below, along with the aquatic data for etoxazole for the most sensitive species tested.

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Acute risk quotients derived from the GENEEC2 model and toxicity data.

Peak EEC from LC50 or EC50 RQ (Acute) GENEEC2 (μg/L) (μg/L) EEC/ LC50 or EC50 Fish 14000 0.000072 Crustacea 1.2 (marine species) 0.91 (marine / 7.1 (freshwater species) / 0.14 1.01 species) (freshwater species) Algae >70.4 <0.014

When compared against the relevant acute levels of concern, the acute RQs derived from the GENEEC2 modeling for etoxazole indicate the following:

For fish: the acute risk is low For marine crustacean: the acute risk is high For freshwater crustacean: the acute risk can be mitigated through restricted use For algae: the acute risk is low

Assessment of chronic risk Chronic risk quotients derived from the GENEEC2 model and chronic aquatic toxicity data.

21-day EEC from NOEC RQ (Chronic) GENEEC2 (μg/L) (μg/L) EEC/ NOEC Fish 15 0.058 Crustacea 0.32 (marine 2.71 (marine 0.87 species) / 0.20 species) / 4.35 (freshwater species) (freshwater species)

When compared against the relevant chronic levels of concern, the chronic RQs derived from the GENEEC2 modeling for etoxazole indicate the following:

For fish: the chronic risk is low For marine crustacean: the chronic risk is high For freshwater crustacean: the chronic risk is high For algae: the levels of concern to estimate chronic risks to algae are not currently defined

Based on the acute and chronic RQs for crustacean, the Agency considers it is appropriate to retain the approved handler controls for ParaMite® Selective Miticide when it is used in a wide dispersive manner, or by a commercial contractor. Further, the Agency considers that the application rate proposed by the applicant and used in the modeling should be set as a maximum application rate.

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Buffer zones

To examine how buffer zones would reduce the etoxazole concentrations in receiving waters, the Agency used the AgDrift model. Calculations were made assuming the receiving water is a 30 cm deep pond.

The model is used to estimate the buffer zone that would reduce exposure through spray drift to such a concentration that an acute risk quotient of 0.1 cannot be calculated. It is noted that unlike GENEEC2 the AgDrift model only considers transport by spraydrift, input through runoff, volatilisation etc will pose additional risks. The following buffer zones were calculated based on the assumption that the orchard were ParaMite® is applied is dense.

Buffer zone to protect Daphnia magna 2 m Buffer zone to protect eastern oysters Crassostrea 38 m virginica Buffer zone to protect mysids Mysidopsis bahia 16 m

The calculated buffer zone to prevent risk from spray drift for Daphnia magna is not wide enough . The product should be used according to good agricultural practice and any measures to prevent spray drift should be considered by the user. The calculated buffer zones to prevent risk from spray drift for mysids and eastern oysters are wider. It can be safely assumed that the edge of agricultural farms from estuaries or coastal zones are at least in such distances (i.e. 16 and 38 m respectively for Mysidopsis bahia and Crassostrea virginica).

Tier 2 assessment

The applicant has submitted a microcosm study where it was shown that up to a level of exposure of 1.4 μg formulated etoxazole/L (SC, 110 g a.i./L), Daphnia magna populations could recover with a 3 week delay for growth parameters. ,. All the size-class of daphnids are present during the recovery phase and no detrimental sign of treatment related effects remains by day 32. The Dutch authority CTGB was of the opinion that the risk assessment for the formulated product cannot be based on the endpoint from the microcosm study, since the endpoint is based on recovery in a single species test. A NOEC is considered necessary for this type of study. Therefore, a higher tier risk assessment is required to address the risk to aquatic invertebrates (e.g. a multi-species micro/mesocosm study or a single species microcosm from which a valid NOEC can be estimated).

According to the report prepared by the Dutch authority CTGB http://www.ctb.agro.nl/ctb_files/13227_01.html there was an outdoor semi-field test on another formulated product containing 110 g etoxazole/L that can be used to evaluate the effects of a short-term etoxazole exposure on phyto- and zooplankton. The study was performed in isolated standing water systems, representing shallow freshwater ecosystems under Mediterranean conditions. In this study relatively worst-case exposure conditions were simulated due to the mixing of the test compound in the water column immediately after application. It was concluded that: - Due to the short DT50 in water, chronic toxicity in the water compartment will not develop.

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- On basis of the most sensitive endpoints studied, a NOECpopulation of <0.20 µg/L and a NOECcommunity of ≥1.54 µg/L could be derived from this study. - Under the assumption that short-term effects on a few populations of sensitive short- cyclic arthropods are acceptable, a NOEC of 1.54 µg a.i./L (based on nominal initial concentration) can be derived from this semi-field experiment, which evaluated effects on plankton communities (recovery within one week). - No algal blooms were induced at the 1.54 µg a.i./L treatment level. - This study provides no information on potential risks for macroinvertebrates in general, and more specifically for macrocrustaceans (e.g. asellids and gammarids).

According to the Dutch authority (CTGB): Due to the fact that the indoor microcosm study provides no information on potential risks for macroinvertebrates in general, and more specifically for macrocrustaceans (e.g. asellids and gammarids), the study cannot be used for risk assessment without additional data which shows that the relevant endpoint also covers the risk for macroinvertebrates. Laboratory studies with macroinvertebrates may be performed or it can be shown that for compounds with the same mode of action macroinvertebrates are less sensitive. If it appears from additional data that macroinvertebrates are in the same range of sensitivity as the microinvertebrates, the NOEC of 1.54 µg a.i./L, which is based on recovery, cannot be used for these organisms. The reason is that the tested microinvertebrates are short-cyclic and the macroinvertebrates in general longer-cyclic. It must be shown then that longer-cyclic organisms also recover within 8 weeks after the first application. The applicants submitted additional data to the European authorities: short term non-GLP tests (screening studies) with a number of aquatic invertebrates. Information was available for one representant of the macrocrustaceans (Asellus aquaticus). This species does not seem to be more sensitive than the cladocerans. Based on this information it can be concluded that the cladocerans are representants of sensitive groups. Hence, the microcosm study could be used for risk assessment. However, the NOEC cannot be used as an endpoint, because it is not clear from the information if macrocrustaceans will recover at this concentration. In this case a NOEC value could be used. However, the NOEC is < 0.20 μg/L. Looking closer to this endpoint it appears that these were class 2 effects (small effects) which were only present for a very short time. So, this level is considered to be close to the threshold level. Macrorustaceans are considered to be able to recover also at this concentration. Because it is not a real NOEC value and because no insect species were tested (apart from Chironomus riparius, but this was a sediment spiked test and difficult to compare with the water-only tests), a safety factor of 3 was considered necessary on the value of 0.20 μg/L. Hence, the value to be used in the chronic risk assessment was 0.067 μg/L.

If this value is compared with maximum predicted environmental concentration (PECmax) calculated by the Dutch authority then the risk can be considered low. However, the lowest chronic (90 days) EEC calculated by GENEEC is 0.275 μg/L and it is 4 times higher than the 0.067 μg/L value which indicates a high chronic risk.

Sediment organisms

Given the low NOEC reproduction value for the midge Chironomous riparius (0.32 μg/L) and the fact that etoxazole has low DT50 values in water but high DT50 values in the whole system (water/sediment) it seems that there is a potential for high risk to sediment organisms. However, as currently the Agency does not model and calculate expected values in the sediment, a quantitative risk assessment cannot be performed.

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Moreover based on the existing data concerning aquatoxicity profile of the main metabolites, it can also be assumed that they represent a potential risk to sediment organisms.

Birds

Exposure The exposure of birds to Etoxazole is shown in the following tables.

Exposure of birds for acute assessment th Crop & BBCH Indicator/generic 90 Application MAF DDDsingleapplication class (where Species2 percentile rate (90th appropriate)1 short- (kg/ha) %)4 cut value3 Avocado/orchards Small 46.8 0.121 - 5.66 insectivorous birds 1 Crop type (EFSA, 2008, Table I.1 & I.3) 2 Indicator species (EFSA, 2008, Table I.1 & I.3) 3 Short-cut value(EFSA, 2008, Table I.1 & I.3) 4 Multiple application factor (90th percentile) (EFSA, 2008, Table 11)

Exposure of birds for reproduction assessment

Crop + BBCH Generic focal Mean Application MAF TWA DDDsingle 2 4 code where species short- rate (mean) application appropriate1 cut (kg/ha) value3

Avocado/orchards Small 18.2 0.121 - 0.53 1.17 insectivorous birds 1 Crop type (EFSA, 2008, Tables I.1 & I.3) 2 Generic focal species (EFSA, 2008, Tables I.1 & I.3) 3 Short-cut value(EFSA, 2008, Tables I.1 & I.3) 4 Multiple application factor (mean) (EFSA, 2008, Table 14)

Toxicity The toxicity values used in the risk assessment of etoxazole are shown in the following table. Toxicity values used in risk assessment Endpoint Value Study Reference (mg/kg bw/d) LD50 >2,000 USEPA Rodgers, Pesticide 1996 Assessment Guidelines, Subdivision E, 71-1

NOEC* Males: 132.84 USEPA Rodgers, Females: Pesticide 1997 Assessment 150.15 Guidelines, Subdivision E,

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71-4 * Daily dose (mg/kg/d) = [Concentration in food (mg/kg) * Daily food consumption (g/bird/day)] / body weight (g) (over the entire exposure period). In this case: Daily dose (mg/kg/d) males = [1000*145] / 1091.5 = 132.84 mg/kg/d Daily dose (mg/kg/d) females = [1000*145] / 965.7 = 150.15 mg/kg/d

Risk Assessment Birds type DDD Toxicity TER ratio Trigger Acceptable single endpoint value value risk (Y/N) application (mg/kg bw/d) Acute Insectivorous 5.66 >2000 2000/5.66 = 10 Y birds 371 Long- 1.17 Males: 132.84 132.84/1.17 Y term Females:150.15 = 119.7 Y 5 150.15/1.17 = 136.5

Conclusion: Since no treatment related effects were identified during the acute, subacute and chronic toxicity studies with birds, acute and chronic risks are expected to be low. The risk assessments carried out confirm that birds are out of concern when the formulated product is applied according to the good agricultural practices.

Secondary poisoning Bioconcentration is defined as the net result of the uptake, distribution and elimination of a substance in an organism due to waterborne exposure, whereas bioaccumulation includes all routes, i.e. air, water, soil and food (EC, 2003). Bioaccumulation often correlates with lipophilicity, thus, for organic chemicals, a log Kow ≥ 3 indicates a potential for bioaccumulation. If this condition is met, secondary poisoning and biomagnification issues should be considered.

Food chain from earthworm to earthworm-eating birds EFSA concluded in 2009 that for soft bodied soil organisms (earthworms, enchytraeids, nematodes) and plants in close contact with the soil solution, pore water mediated uptake of pesticides seems mainly responsible for the effects caused, and would therefore be the relevant metric for effects assessment, and consequently also for exposure assessment (EFSA, 2009). The approach is based on pore water concentrations and includes the gut content of the earthworms. The inclusion of the gut content of worms is particularly of importance for soils with > 1 % organic matter. This approach is equivalent to the approach taken in the Technical GD for existing chemicals (EC, 2003).

Pore water approach Step 1 A pore water concentration (Cporewater with an appropriate TWA according to the reproductive assessment) must be selected.

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In the present case, the selected pore water concentration is based on GEENEC2 model output at 90 days.

Cporewater = 0.0002756 mg/L

Step 2 The bioconcentration factor for the earthworm (BCFearthworm) related to porewater has been calculated as follows:

Where for RHOearthworm by default a value of 1 [kgwwt × L-1] can be assumed (Jager, 1998).

BCFearthworm = (0.84 + 0.012 X 331131) / 1 = 3974

Step 3 The concentration in earthworms has been calculated as follows:

Where

With: CONVsoil conversion factor for soil concentration wet-dry weight soil [kgwwt kgdwt-1] = 1.13 Fsolid volume fraction of solids in soil [m3 m-3] = 0.6 Fgut fraction of gut loading in worm [kgdwt kgwwt-1] = 0.1 RHOsoil bulk density of wet soil [kgwwt m-3] = 1700 RHOsolid density of solid phase [kgdwt m-3] = 2500 Csoil in-field for etoxazole following the good agricultural practices = 0.16 mg/kg soil

Cearthworm = (3974 X 0.0002756 + 0.16 X 0.1 X 1.13) / (1 + 0.1 X 1.13) = 1.00 mg/kg earthworm

Step 4 Cearthworm is converted to daily dose by multiplying with 1.05 (birds), and is compared with relevant long-term NOAEL. Multiplicators are based on a 100-g bird, eating 104.6 g per day, according to Smit (2005).

Cearthworm = 1.00 X 1.05 = 1.05 mg/kg earthworm

Step 5 The toxicity-exposure ratio is compared to the respective trigger value: TER > 5 No further refinement required. TER < 5 Further refinement required.

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The relevant NOEC used is 132.84 mg/kg bw/d based on bird reproduction test.

TER = 132.84/1.05 = 126.5

The calculated TER is above the trigger value of 5 and therefore the risk is considered as acceptable for earthworm-eating birds.

Food chain from fish to fish-eating birds A simple worst-case assessment is conducted according to the following steps:

Step 1 The fish bioconcentration test has been performed following a 30-days exposure period. Therefore the PECwater considered as conservative enough and used for assessing the secondary poisoning risk for fish-eating birds is derived from GEENEC2 model at 21 days.

PECwater = 0.0005782 mg/L

This PECwater based on the regulatory acceptable concentration from the environmental fate section is multiplied this value with an appropriate TWA value according to the reproductive assessment.

Step 2 The whole-body BCFfish selected for risk assessment purpose is:

BCF = 2600 (McEwen, 1997)

Step 3 The estimated residues in fish is:

PECfish = 0.0005782 X 0.53 X 2600 = 0.79 mg/kg

Step 4 The PECfish is convertedto daily dose by multiplying with 0.159, and is compared with the relevant long-term NOAEL. Multiplicators is based on a 1000-g bird, eating 159 g per day, according to Smit (2005).

PECfish = 0.79 X 0.159 = 0.13 mg/kg

Step 5 Compare the toxicity-exposure ratio to the respective trigger value: TER > 5 No further refinement required. TER < 5 Further refinement required.

The relevant NOEC used is 132.84 mg/kg bw/d based on bird reproduction test.

TER = 132.84/0.13 = 1048

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The calculated TER is above the trigger value of 5 and therefore the risk is considered as acceptable for fish-eating birds.

Exposure via drinking water Exposure of birds via drinking water is not explicitly included in the DDD calculations of the dietary risk assessment. Therefore, an approach is presented that allows estimating the possible risk arising from uptake of contaminated drinking water.

Most birds can in principle satisfy (at least parts of) their daily water demand via uptake of food. However, this potential depends on the water content of the diet items, which is lowest for seeds. Therefore, the assessment methodology for the risk to birds of pesticides in drinking water as provided below uses small granivorous animals as indicator species at Tier 1.

The scenario covered by the assessment refers to smallest water reservoirs, namely puddles on soil. Experience has shown that uptake of drinking water from larger water bodies is unlikely to pose a relevant risk. Uptake of drinking water by animals is estimated using allometric equations.

A puddle scenario is relevant for all types of application that may cause contamination of soil. This also includes non-foliar applications of pesticides. If necessary, a puddle scenario may further be applied for a risk assessment for metabolites and degradation products, according to their toxic potential.

Calculation of exposure concentrations for a puddle scenario. To obtain an estimate for pesticide concentrations in puddles formed on a field after rainfall (predicted environmental concentration, PECpuddle), it may be assumed that this concentration would be the same as the concentration in runoff water as calculated for the assessment of surface water exposure. A simplified model can be proposed to calculate PECpuddle in mg/L as a function of application rate and the organic carbon adsorption coefficient (KOC) of a substance. Provided that the full application rate is considered, this approach assumes application to bare soil without degradation and thus reflects a worst case for crop directed applications. Where appropriate, crop interception may be considered in the same way as for calculation of PECsoil, PECgw and PECsw, in order to increase realism.

With: AR = application rate [g/ha]; divisor of 10 to achieve rate in mg/m2 w = 0.02 (pore water term: volume) s = 0.0015 (soil term: volume, density, organic carbon content)

PECpuddle = (121.6/10)/(1000(0.02 + 11850*0.0015)) = 0.00068 mg/L

When multiple spray applications are considered, a MAF based on the DT50 in soil (single first order

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kinetics, geometric mean as used for PECgw and PECsw) may be applied to achieve the effective application rate AReff. With:

k = ln(2)/DT50 (rate constant) n = number of applications i = application interval (d)

Due to the characteristics of the exposure scenario in connection with the standard assumptions for water uptake by animals , no specific calculations of exposure and TER are necessary when the ratio of effective application rate (in g/ha) to relevant endpoint (in mg/kg bw/d) does not exceed 50 in the case of less sorptive substances (Koc < 500 L/kg) or 3000 in the case of more sorptive substances (Koc ≥ 500 L/kg).

Drinking water uptake by birds and calculation of TER values. The calculation for birds is performed on a level of generic focal species, i.e. basic ecological traits already form part of the considerations. According to the relatively low water content of their diet, granivorous species will face the greatest necessity to satisfy their daily water demand by additional uptake of drinking water. In line with the proposals made for dietary exposure, the following generic species should be considered for estimating the uptake of drinking water:

Small granivorous bird (bw = 15.3 g) Drinking water rates (DWR) as published by DEFRA (2007) should be used. They are based an allometric equations for total water flux (WF) in different categories of birds and on data on the contribution of other sources on birds‘ water balance.

• Small granivorous bird log10(WF) = -0.195 + 1.003 × log10(bw) for passerines linnet: WF = 9.8 mL/d; DWR = WF – (food water + metabolic water) = 7.0 mL/d, equivalent to 0.46 L/kg bw/d

TER values are calculated by division of the relevant ecotoxicological endpoint (leaf scenario: acute; puddle scenario: acute and reproduction) by the product of PECpool or PECpuddle, in summary termed PECdw and the DWR related to bodyweight. It is suggested that the same acceptability criteria should apply as for the dietary risk assessment.

The toxicity figures used for risk assessment purpose are:

LD50 > 2000 mg/kg bw/d NOEC Males: 132.84 mg/kg bw/d Females: 150.15 mg/kg bw/d

The ratios of effective concentration to relevant endpoint do not exceed 3000. 2000/(0.00068 x 0.46) = 6393861 132.84/(0.00068 X 0.46) = 424680

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Therefore no acute or chronic poisoning through drinking water is foreseen.

Biomagnification in terrestrial food chains Substances that have a potential for biomagnification, i.e. the whole-body residue in an animal at steady state is higher than the residue in its food (biomagnification factor BAF > 1), are of concern for terrestrial food chains. Etoxazole bioconcentration factor determined in the frame of a fish study confirms this point with a bioconcentration factor of 2600 (whole fish). In Annex VI of the European Directive 91/414/EEC a trigger value of 1 is provided for the BAF (not quite correctly termed ‗BCF‘) which is specified as related to fat tissue. This trigger implies some degree of precaution since, when exposed to lipophilic organic chemicals the whole body residue is lower than the residue in fat tissue. The following step- wise approach is proposed:

Step 1 Obtain the information from the toxicology section on the ADME studies and from the residue section on the metabolism studies with livestock. A brief conclusion from these assessments with regard to bioaccumulation is reported in the list of endpoints. If the bioaccumulation potential is stated as being low then, no further assessment is required. If this is not the case, Step 2 has to be followed.

The conclusion of the assessment for the mammalian toxicity concerning adsorption, desorption, metabolism and excretion is that etoxazole is extensively metabolized and that there is no potential for accumulation (European Commission, 2004).

General conclusion about secondary poisoning Since the logkow of etoxazole is 5.52 and the bioconcentration factors were found high, secondary poisoning through contaminated fish can be considered a relevant and possible exposure route. The risk as a result of secondary poisoning is assessed based on bioconcentration in fish and PEC values modelled through GEENEC2 model.

Concerning food chain from earthworm to earthworm-eating birds, the risk is considered as acceptable:

Concerning food chain from fish to fish-eating birds, the risk is considered as acceptable.

No biomagnifications in terrestrial food chains is foreseen.

With regard to the acute exposure of birds to etoxazole via drinking water, considering a very worst-case evaluation with surface water contaminated by overspray, no risk is foreseen.

Terrestrial invertebrates ERMA New Zealand uses the Guidance from ESCORT Workshop 2 to estimate the in-field and off-field exposure (Barett et al 2000). However, for in-field and off-field exposure the risk quotients cannot be calculated this time due to the lack of acute LR50 values. The formulation was found harmful to Orius laevigatus nymphs and to the lacewig Chrysoperla carnea when applied at 55 g etoxazole/ha (lower than the proposed application rate by the applicant). At 0.5L/ha the formulation was found very toxic to predatory mites

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Typhlodromus pyri causing approximately zero viability to the offspring in a laboratory experiment with a sensitive and a resistant population. The applicant has provided field trials studies. In a field trial in an apple orchard the formulation was found to inhibit the target organism (red mite) but it was also neutral to slightly toxic for N.Californicus and the ladybird genus Stethorus and slightly toxic for predatory hymenoptera. In a field trial in a vineyard the formulated product was applied at 0.5L/ha and based on the calculation of the residual population 21 days after treatment it was categorised as moderately harmful to Typhlodromus pyri.

Even if the field trials can be considered not relevant to the proposed use in avocados the Agency considers that there are uncertainties regarding the potential risks to non target beneficial terrestrial invertebrates and therefore the following warning sentence must be placed on the label/instructions for use:

―The substance may be harmful to non target arthropods.‖

Summary and conclusions of the ecological risk assessment Based on the risk assessment for the aquatic and terrestrial environment as set out above, high acute and chronic risks to aquatic invertebrates groups have been identified.

An approved handler control should be assigned.

The buffer zones calculated are not deemed to be required for the protection of the aquatic environment, however, the users should be applying the product considering minimizing spray drift as much as possible.

Even though the product is not classified 9.4, due to the fact that it is not toxic to bees, there are clear indications that it can be harmful to other terrestrial beneficial invertebrates even at rates lower than the one proposed by the applicant. Therefore, a label statement such as: ―The substance may be harmful to non target arthropods‖ must be placed.

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Appendix 3: Default controls for ParaMite Selective Miticide and their variations.

Based on the hazard classification as shown in Table A3.1, the set of associated controls has been identified. These default controls, expressed as control codes are listed in Table A3.1. Table A3.1: List of default controls for ParaMite Selective Miticide Hazardous Substances (Classes 6, 8, and 9 Controls) Regulations 2001 Code Regulation Description T1 11 – 27 Limiting exposure to toxic substances through the setting of TELs T2 29, 30 Controlling exposure in places of work through the setting of WESs. T3 5(1), 6 Requirements for keeping records of use T4 7 Requirements for equipment used to handle substances T5 8 Requirements for protective clothing and equipment

E1 32 – 45 Limiting exposure to ecotoxic substances through the setting of EELs E2 46 – 48 Restrictions on use of substances in application areas E5 5(2), 6 Requirements for keeping records of use E6 7 Requirements for equipment used to handle substances E7 9 Approved handler/security requirements for certain ecotoxic substances

Hazardous Substances (Identification) Regulations 2001 Code Regulation Description 6, 7, 32 – Identification requirements, duties of persons in charge, accessibility, I1 35, 36(1) – comprehensibility, clarity and durability (7) I3 9 Priority identifiers for ecotoxic substances I9 18 Secondary identifiers for all hazardous substances I11 20 Secondary identifiers for ecotoxic substances I16 25 Secondary identifiers for toxic substances I17 26 Use of generic names I18 27 Requirements for using concentration ranges Additional information requirements, including situations where substances I19 29 – 31 are in multiple packaging 37 – 39, 47 I21 General documentation requirements – 50 I23 41 Specific documentation requirements for ecotoxic substances I28 46 Specific documentation requirements for toxic substances I29 51, 52 Signage requirements

Hazardous Substances (Packaging) Regulations 2001 Code Regulation Description P1 5, 6, 7(1), 8 General packaging requirements Criteria that allow substances to be packaged to a standard not meeting P3 9 Packing Group I, II or III criteria P13 19 Packaging requirements for toxic substances P15 21 Packaging requirements for ecotoxic substances PG3 Schedule 3 Packaging requirements equivalent to UN Packing Group III PS4 Schedule 4 Packaging requirements as specified in Schedule 4

Hazardous Substances (Disposal) Regulations 2001 Code Regulation Description D4 8 Disposal requirements for toxic and corrosive substances D5 9 Disposal requirements for ecotoxic substances D6 10 Disposal requirements for packages

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Information requirements for manufacturers, importers and suppliers, and D7 11, 12 persons in charge Documentation requirements for manufacturers, importers and suppliers, D8 13, 14 and persons in charge

Hazardous Substances (Emergency Management) Regulations 2001 Code Regulation Description EM1 6, 7, 9 – 11 Level 1 information requirements for suppliers and persons in charge EM7 8(f) Information requirements for ecotoxic substances 12 – 16, 18 EM8 Level 2 information requirements for suppliers and persons in charge – 20 Level 3 emergency management requirements: duties of person in charge, EM11 25 – 34 emergency response plans EM12 35 – 41 Level 3 emergency management requirements: secondary containment EM13 42 Level 3 emergency management requirements: signage

Hazardous Substances (Personnel Qualifications) Regulations 2001 Code Regulation Description Approved Handler requirements (including test certificate and qualification AH 1 4 – 6 requirements)

Hazardous Substances (Tracking) Regulations 2001 Code Regulation Description TR1 4(1), 5, 6 General tracking requirements

Hazardous Substances (Tank Wagon and Transportable Containers) Regulations 2004 Code Regulation Description 4 to 43 as Tank Wagon Controls relating to tank wagons and transportable containers. applicable

The Authority is able to vary the default controls and impose controls under sections 77 and 77A to produce a set of controls relevant to substance under assessment. Those controls which require calculations, derivations or extended discussion are considered in the following sections.

Toxicity Controls

Setting of TELs (Control Code T1)

Tolerable Exposure Limits (TELs) are designed to limit the extent to which the general public is exposed to hazardous (toxic) substances. A TEL represents the maximum concentration of a substance legally allowable in a particular medium, and can be set as either a guideline value or an action level that should not be exceeded. For the purposes of setting TELs, an environmental medium is defined as air, water, soil or a surface that a hazardous substance may be deposited onto.

TELs are established from PDE (Potential Daily Exposure) values, which are themselves established from ADE (Acceptable Daily Exposure) values or reference doses (RfD) which are similar to ADE but are used to protect against a specific toxic effect of concern.

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Human exposure may also occur through food or drinking water. Exposure through food is managed via the establishment of Maximum Residue Limits (MRLs) as set by the Minister of Food Safety on the advice of the New Zealand Food Safety Authority (NZFSA). Exposure through drinking water is managed via the establishment of Maximum Acceptable Values (MAVs) as set by the Ministry of Health. MRLs and MAVs are also established from ADE values.

Setting of PDEs

If an ADE or RfD value is set for a substance, or component of a substance, a PDE value for each relevant exposure route must also be set. A PDE is an amount of substance (mg/kg bodyweight/day), calculated in accordance with Regulation 23, that estimates the relative likelihood of particular exposures. A PDE for any single exposure route is a fraction of the ADE or RfD, and the sum of all PDE values from all possible exposures must be less than or equal to the ADE or RfD.

The main routes of exposure considered are ingestion (food, water, air, soil), inhalation (air) and skin contact (surface deposition, water, soil).

Setting of ADEs

An ADE is an amount of a hazardous substance (mg/kg bodyweight/day), that, given a lifetime of daily exposure, would be unlikely to result in adverse human health effects. An RfD (reference dose) is a similar measure that can be used to protect against a specific toxic effect of concern.

Regulation 11(1) of the Hazardous Substances (Classes 6, 8, and 9 Controls) Regulations 2001 determines when an ADE/RfD is required to be set:

(1) This regulation applies to a class 6 substance if- (a) it is likely to be present in- (i) 1 or more environmental media; or (ii) food; or (iii) other matter that might be ingested; AND (b) it is a substance to which a person is likely to be exposed on 1 or more occasions during the lifetime of the person; AND (c) exposure to the substance is likely to result in an appreciable toxic effect.

If all three requirements of regulation 11(1) are met, then an ADE/RfD should be set for the relevant component(s), and PDE and TEL values subsequently established for each relevant exposure route.

The toxicity (Class 6) classification of ParaMite Selective Miticide that triggers the need to consider setting a TEL is 6.9A.

The Agency considers that etoxazole meets the requirements of Regulation 11(1)(a), (b) and (c), and therefore notes that an ADE, and subsequently PDEs and TELs are required to be set for this component.

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However, the Agency is intending to review the setting of ADEs, PDEs and TELs under section 77B of the Act, and until this review is complete, the Agency proposes not to set TELs for etoxazole. Noting that ParaMite Selective Miticide is intended for use on food crops and contains etoxazole, a new active ingredient to New Zealand, an ADE and PDEfood value are calculated for this component which will enable the NZFSA to set MRLs as needed.

The Agency considers that the ADE of 0.15 mg/kg bw/day should be adopted for etoxazole. Based on this value, and considering the main ingestion exposure to etoxazole would be via food stuff (70%), drinking water (20%) and other non-foodstuffs (10%), the Agency proposes that PDEfood = 0.105 mg/kg bw/day, PDEdrinking water = 0.03 mg/kg bw/day and PDEother = 0.015 mg/kg bw/day should be set for etoxazole.

Setting of WES (Control Code T2)

Workplace Exposure Standards (WES) are designed to protect persons in the workplace from the adverse effects of toxic substances. A WES is an airborne concentration of a substance (expressed as mg substance/m3 of air, or ppm in air), which must not be exceeded in a workplace and only applies to places of work (Regulation 29(2), Hazardous substances (Classes 6, 8 and 9 Controls) Regulations 2001).

Regulation 29(1) of the Hazardous Substances (Classes 6, 8, and 9 Controls) Regulations 2001 determines when a WES is required to be set. If all three of the requirements of this regulation are met then a WES is required to be set.

Regulation 29 states: (1) This regulation and regulation 30 apply to a class 6 substance if,- (a) under the temperature and pressure the substance is to be used in, it can become airborne and disperse in air in the form of inspirable or respirable dust, mists, fumes, gases or vapours; AND (b) human exposure to the substance is primarily through the inhalation or dermal exposure routes; AND (c) the toxicological and industrial hygiene data available for the substance is sufficient to enable a standard to be set.

\When setting WES, the Authority must either adopt a value already proposed by the Department of Labour or already set under HSNO or derive a value by taking into account the matters described in Regulation 30(2) of the Hazardous Substances (Classes 6, 8, and 9 Controls) Regulations 2001.

The Agency typically adopts WES values listed in the Workplace Exposure Standards (Effective from 2010) document (refer to the link below). http://www.osh.govt.nz/publications/booklets/wes-dec-2010/wes-dec-2010.pdf

The Agency notes that at this time no Department of Labour WES values have been set for any component in ParaMite Selective Miticide. Also, no values have been found to have been set for any of the remaining components of ParaMite Selective Miticide. Therefore, it is proposed that no WES values are set for the proposed substance at this time.

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Ecotoxicity Controls

Setting of EELs (Control code E1)

Regulation 33 of the Hazardous Substances (Classes 6, 8, and 9 Controls) Regulations 2001 specify that an environmental exposure limit (EEL) may be set for a class 9 substance for one or more environmental media if organisms that live in that environment may be exposed to the substance. An EEL is the (maximum) concentration of a substance in an environmental medium that will present a negligible risk of adverse environmental effects to organisms (excluding humans) in non-target areas.

As specified by regulation 32, a default EEL of 0.1 µg/L water is set for any class 9.1 substance, and 1 µg/kg soil (dry weight) for any class 9.2 substance.

For the purposes of setting EELs, an environmental medium is defined as water, soil or sediment where these are in the natural environment, or a surface onto which a hazardous substance may be deposited.

An EEL can be established by one of three means: Applying the default EELs specified in regulation 32 Adopting an established EEL as provided by regulation 35(a) Calculating an EEL from an assessment of available ecotoxicological data as provided by regulation 35(b).

The Hazardous Substances and New Organisms (Approvals and Enforcement) Act 2005 added a new section (s77B) to the HSNO Act, which, amongst other things provided the Authority with the ability to set EELs as guideline values, rather than the previous pass/fail values.

However, until the Agency has developed formal policy on the implementation of s77B, it proposes not to set EELs for any components of ParaMite Selective Miticide at this time. It is also proposed that the default EEL water and soil values be deleted until the policy has been established.

Setting of Application Rate (Control Code E2) These regulations relate to the requirement to set an application rate for a class 9 substance that is to be sprayed or applied to an area of land (or air or water) and for which an EEL has been set.

Although no EEL has been set for ParaMite Selective Miticide, the Agency proposes setting the application rate of 1.05 L/ha (121.6 g ai/ha), 1 time a season as the application rate for ParaMite Selective Miticide. This rate was used in the ecological risk assessment.

Other controls required as a result of the ecological risk assessment. The applicant restricted the application method to ground based mechanical spraying equipment. Therefore the Agency added this control.

This substance is to be applied via ground based methods only. This substance is not to be applied onto or into water.

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Appendix 4: Proposed controls for ParaMite Selective Miticide Table A4.1: Proposed controls for ParaMite Selective Miticide codes, regulations and variations. Hazardous Substances (Classes 6, 8, and 9 Controls) Regulations 2001 Code Regulation Description Variation T1 11 – 27 Limiting exposure to toxic The following ADE and PDE values are set for substances through the setting of Etoxazole: TELs ADE = 0.15 mg/kg bw/day

PDEfood = 0.105 mg/kg bw/day

PDEdrinking water = 0.03 mg/kg bw/day

PDEother = 0.015 mg/kg bw/day No TEL values are set for any components of ParaMite Selective Miticide at this time.

T2 29, 30 Controlling exposure in places No WES values are set at this time. of work through the setting of WESs. T3 5(1), 6 Requirements for keeping records of use T4 7 Requirements for equipment used to handle substances T5 8 Requirements for protective clothing and equipment

E1 32 – 45 Limiting exposure to ecotoxic No EEL values are set at this time and the default substances through the setting of EELs are deleted. EELs E2 46 – 48 Restrictions on use of substances A maximum application rate has been set under in application areas section 77A. E5 5(2), 6 Requirements for keeping records of use E6 7 Requirements for equipment used to handle substances E7 9 Approved handler/security The following control is substituted for Regulation requirements for certain ecotoxic 9(1) of the Hazardous Substances (Classes 6, 8, and substances 9 Controls) Regulations 2001: ―(1). ParaMite Selective Miticide must be under the personal control of an approved handler when the substance is – (a) applied in a wide dispersive manner; or (b) used by a commercial contractor.

Hazardous Substances (Identification) Regulations 2001 Code Regulation Description Variation I1 6, 7, 32 – 35, Identification requirements, 36(1) – (7) duties of persons in charge,

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accessibility, comprehensibility, clarity and durability I3 9 Priority identifiers for ecotoxic substances I9 18 Secondary identifiers for all hazardous substances I11 20 Secondary identifiers for The substance label shall contain the following ecotoxic substances additional warning statement: ―The substance may be harmful to non-target arthropods‖ I16 25 Secondary identifiers for toxic substances I17 26 Use of generic names I18 27 Requirements for using concentration ranges I19 29 – 31 Additional information requirements, including situations where substances are in multiple packaging I21 37 – 39, 47 – General documentation 50 requirements I23 41 Specific documentation requirements for ecotoxic substances I28 46 Specific documentation requirements for toxic substances I29 51, 52 Signage requirements

Hazardous Substances (Packaging) Regulations 2001 Code Regulation Description Variation P1 5, 6, 7(1), 8 General packaging requirements P3 9 Criteria that allow substances to be packaged to a standard not meeting Packing Group I, II or III criteria P13 19 Packaging requirements for toxic substances P15 21 Packaging requirements for ecotoxic substances

PG3 Schedule 3 Packaging requirements equivalent to UN Packing Group III PS4 Schedule 4 Packaging requirements as specified in Schedule 4

Hazardous Substances (Disposal) Regulations 2001 Code Regulation Description Variation D4 8 Disposal requirements for toxic and corrosive substances

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D5 9 Disposal requirements for ecotoxic substances D6 10 Disposal requirements for packages D7 11, 12 Information requirements for manufacturers, importers and suppliers, and persons in charge D8 13, 14 Documentation requirements for manufacturers, importers and suppliers, and persons in charge

Hazardous Substances (Emergency Management) Regulations 2001 Code Regulation Description Variation EM1 6, 7, 9 – 11 Level 1 information requirements for suppliers and persons in charge EM7 8(f) Information requirements for ecotoxic substances EM8 12 – 16, 18 – 20 Level 2 information requirements for suppliers and persons in charge EM11 25 – 34 Level 3 emergency management requirements: duties of person in charge, emergency response plans EM12 35 – 41 Level 3 emergency management The following subclauses are added after subclause requirements: secondary (3) of regulation 36: containment (4) For the purposes of this regulation, and regulations 37 to 40, where this substance is contained in pipework that is installed and operated so as to manage any loss of containment in the pipework it— (a) is not to be taken into account in determining whether a place is required to have a secondary containment system; and (b) is not required to be located in a secondary containment system. (5) In this clause, pipework— (a) means piping that— (i) is connected to a stationary container; and (ii) is used to transfer a hazardous substance into or out of the stationary container; and (b) includes a process pipeline or a transfer line.

The following subclauses are added at the end of regulation 37: (2) If pooling substances which do not have class 1 to 5 hazard classifications are held in a place above ground in containers each of which has a capacity of 60 litres or less—

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(a if the place’s total pooling potential is less than 20,000 litres, the secondary containment system must have a capacity of at least 25% of that total pooling potential: (b) if the place’s total pooling potential is 20,000 litres or more, the secondary containment system must have a capacity of the greater of— (i) 5% of the total pooling potential; or (ii) 5,000 litres. (3) Pooling substances to which subclause (2) applies must be segregated where appropriate to ensure that leakage of one substance may not adversely affect the container of another substance.

The following subclauses are added at the end of regulation 38: (2) If pooling substances which do not have class 1 to 5 hazard classifications are held in a place above ground in containers 1 or more of which have a capacity of more than 60 litres but none of which have a capacity of more than 450 litres— (a) if the place’s total pooling potential is less than 20,000 litres, the secondary containment system must have a capacity of either 25% of that total pooling potential or 110% of the capacity of the largest container, whichever is the greater: (b) if the place’s total pooling potential is 20,000 litres or more, the secondary containment system must have a capacity of the greater of— (i) 5% of the total pooling potential; or (ii) 5,000 litres (3) Pooling substances to which subclause (2) applies must be segregated where appropriate to ensure that the leakage of one substance may not adversely affect the container of another substance. EM13 42 Level 3 emergency management requirements: signage

Hazardous Substances (Personnel Qualifications) Regulations 2001 Code Regulation Description Variation AH 1 Regs 4 – 6 Approved Handler requirements (including test certificate and qualification requirements)

Hazardous Substances (Tank Wagon and Transportable Containers) Regulations 2004 Code Regulation Description Variation Tank 4 to 43 as Controls relating to tank wagons Wagon applicable and transportable containers.

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Additional Controls

Code Regulation Description Variation Sch 8 Schedule 8 This schedule prescribes the controls for stationary container systems. The requirements of this schedule are detailed in the consolidated version of the Hazardous Substances (Dangerous Goods and Schedule Toxic Substances) Transfer Notice 2004

Water 77A The substance shall not be applied onto or into water. App Rate 77A A maximum application rate is The maximum application rate for ParaMite set for this substance. Selective Miticide shall be 1.05 L/ha (121.6 g ai/ha), with a maximum application frequency of 1 application per year. App 77A A restriction has been placed on This substance shall be applied via ground based method the application method for this application methods only substance.

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Appendix 5: Parties notified

Aakland Chemicals (1997) Limited AgBio Research Limited Agcarm Incorporated AgResearch Limited Agronica New Zealand Limited AR and JA Drysdale Limited ARPPA BALDWINS BASF New Zealand Limited Bayer New Zealand Limited BOC Limited Chancery Green Chemagro New Zealand Limited Chemsafety Limited Crown Public Health CSD Consultancy Ltd DuPont (New Zealand) Limited Far North District Council Federated Farmers of New Zealand (Incorporated) Fish and Game Eastern Region Fruitfed Supplies Limited (PGG Wrightson Ltd) Grayson Wagner Company Ltd Greater Wellington - The Regional Council Green Party of Aotearoa New Zealand Hawkes Bay Regional Council IMCD New Zealand Limited IPM Research Ltd Kaipara District Council Kawerau District Council Landcorp Farming Limited Lowndes Associates MAF Biosecurity New Zealand (MAFBNZ) Ministry of Research Science and Technology (MoRST) Napier Health Centre - Public Health Unit New Zealand Bee Industry Group - Federated Farmers New Zealand Chemical Industry Council Inc New Zealand Customs Service New Zealand Meatworkers Union New Zealand Press Association New Zealand Society of Gunsmiths Inc Ngati Kahungunu Iwi Incorporated Northland Health Northland Regional Council Nufarm New Zealand Limited Pacific Building Steel Group Pacific Growers Supplies Limited Pesticide Action Network Aotearoa New Zealand

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PharmVet Solutions Physicians and Scientists for Global Responsibility (PSGR) Rangitikei District Council Reckitt Benckiser Selleys Pty Ltd (ORICA) South Taranaki District Council Sustainability Council of New Zealand Syngenta Crop Protection Limited Taranaki Regional Council Tasman District Council Taupo District Council Technical Strategy Group Limited Television New Zealand The National Beekeepers Association of New Zealand The New Zealand Institute for Plant and Food Research Limited (Auckland) The New Zealand Institute for Plant and Food Research Limited (Motueka) TMP Consultancy Wellington City Council Zelam Limited

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Appendix 6: References

CTGB http://www.ctb.agro.nl/ctb_files/13227_01.html

EPPO(2001) Guideline on the test methods for evaluating the side-effects of plant protection products. No PP 1/170(3)

EPPO (2002) Environmental risk assessment scheme for plant protection products. Chapter 10 honeybees. EPPO Bulletin 33 http://archives.eppo.org/EPPOStandards/PP3_ERA/pp3-10(2).pdf

ERMA New Zealand (2008a) User Guide to HSNO Thresholds and Classifications. ERMA New Zealand, Wellington.

European Commission, Guidance Document on terrestrial ecotoxicology under Council Directive 91/414/EEC, SANCO/ 10329/2002 rev. 2 final, 17 October 2002. http://ec.europa.eu/food/plant/protection/evaluation/guidance/wrkdoc09_en.pdf

European Commission (2000) Guidance Document on terrestrial ecotoxicology under Council Directive 91/414/EEC(9188/VI/97 rev8)

European Union (2006). Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), establishing a European Chemicals Agency, amending Directive 1999/45/EC and repealing Council Regulation (EEC) No 793/93 and Commission Regulation (EC) No 1488/94 as well as Council Directive 76/769/EEC and Commission Directives 91/155/EEC, 93/67/EEC, 93/105/EC and 2000/21/EC. http://reach.jrc.it/

Klimisch, HJ, Andreae, E, Tillman, U (1997). A systematic approach for evaluating the quality of experimental and ecotoxicological data. Regulatory Toxicology and Pharmacology 25: 1–5.

OECD (1990). Manual for Investigation of HPV Chemicals. http://www.oecd.org/document/21/0,3343,en_2649_34379_1939669_1_1_1_1,00.html Retrieved 23 January 2008.

Urban DJ, Cook, NJ (1986) Hazard Evaluation Division Standard Evaluation Procedure: Ecological Risk Assessment. EPA 540/9-85-001. United States Environmental Protection Agency Office of Pesticide Programs, Washington DC, USA.

USEPA (2001) Generic Estimated Environmental Concentration Model v2 (GENEEC2). United States Environmental Protection Agency Office of Pesticide Programs, Washington DC, USA http://www.epa.gov/oppefed1/models/water/index.htm#geneec2

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Appendix 7: Confidential material

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Supplementary Information

This document has been prepared to support the Agency‘s Hazardous Substances Evaluation and Review reports. It contains background information on five areas and has been divided into the following sections:

1) The regulatory basis for assessing the application.

2) Legislation that will affect the use of hazardous substances within New Zealand. This section covers the range of default controls available for use by the Agency and lists other legislation that will affect the use of hazardous substances.

3) Risk Assessment - The steps and methodology involved in assessment of effects.

4) Qualitative Descriptors for Risk/Benefit Assessment - the descriptors used to assess the level of each risk or benefit to determine their level of significance.

5) Decision Pathway - to be used when assessing an application for the release of hazardous substances. 1. Regulatory basis for assessing the application

1.1. The application was lodged pursuant to section 28 of the Hazardous Substances and New Organisms Act 1996 (―the Act‖).

1.2. The Evaluation and Review report (―the E&R report‖) takes into account matters to be considered in section 29; matters specified under Part 2 of the Act; and the relevant provisions of the Hazardous Substances and New Organisms (Methodology) Order 1998 (―the Methodology‖). Unless otherwise stated, references to section numbers in the report refer to sections of the Act and clauses to clauses of the Methodology.

1.3. The Minister for the Environment was advised of the application under section 53(4) (a) and given the opportunity to ―call-in‖ the application under section 68. This action was not initiated.

1.4. The Authority is able to vary the default controls and impose controls under sections 77 and 77A to produce a set of controls relevant to the substance. Variations and additional controls for the substance are considered in Section 5 of the E&R report.

1.5. In undertaking this assessment the Agency has considered the Authority‘s approvals given to substances under Part 5 of the Act as well as those transferred to the Act under the Hazardous Substances (Pesticides) Transfer Notice 2004.

1.6. Section 96 provides that the Authority may identify and report to the Minister where it considers that a reduction in the likely occurrence of adverse effects similar to that achieved by the controls attached to any substance could be achieved by any environmental user charge, or a combination of an environmental user charge and controls.

1.7. The Agency considers that use of controls is the most effective means of managing the risks throughout the lifecycle of the substance being assessed. The imposition of

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an environmental user charge instead of, or in combination with controls, is therefore not recommended under this approval. 2. Legislation that will affect the use of hazardous substances within New Zealand

2.1. The HSNO legislation and other legislation, such as the Resource Management Act 1992 (―the RMA‖) and the Health and Safety in Employment Act (―the HSE Act‖) provide for a number of controls that are aimed at preventing exposure to hazardous substances, and/or mitigating any adverse effects caused by such substances in the event of an accident, or a breach of controls. The key controls that relate to the protection of human health and the environment during the various stages of the lifecycle of hazardous substances are outlined in the sections below.

HSNO Legislation 2.2. The controls available to control a substances use under the HSNO legislation are determined by the substances hazard classification and are comprehensively described in ERMA New Zealand‘s User Guide to the Threshold and Classifications under the Hazardous Substances and New Organisms Act 1996. The following paragraphs describe the sorts of controls available and list those that are available for use.

2.3. The Hazardous Substances (Identification) Regulations 2001 require that the hazardous properties of substances be clearly identified on the label, as well as described in any documentation (Safety Data Sheet) supplied with the substance. While the substance is being transported (including importation), the regulations provide for bulk transport containers and/or any outer packaging to be labelled or marked in compliance with either the Land Transport Rule 45001, Civil Aviation Act 1990 or the Maritime Safety Act 1994 as relevant (control code I19).

Identification Controls I1 Identification requirements, duties of persons in charge, accessibility, comprehensibility, clarity and durability I2 Priority identifiers for corrosive substances I3 Priority identifiers for ecotoxic substances I4 Priority identifiers for explosive substances I5 Priority identifiers for flammable substances I6 Priority identifiers for organic peroxides I7 Priority identifiers for oxidising substances I8 Priority identifiers for toxic substances I9 Secondary identifiers for all hazardous substances I10 Secondary identifiers for corrosive substances I11 Secondary identifiers for ecotoxic substances I12 Secondary identifiers for explosive substances I13 Secondary identifiers for flammable substances I14 Secondary identifiers for organic peroxides I15 Secondary identifiers for oxidising substances

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I16 Secondary identifiers for toxic substances I17 Use of generic names I18 Requirements for using concentration ranges I19 Additional information requirements, including situations where substances are in multiple packaging I20 Durability of information for class 6.1 substances I21 General documentation requirements I22 Specific documentation requirements for corrosive substances I23 Specific documentation requirements for ecotoxic substances I24 Specific documentation requirements for explosive substances I25 Specific documentation requirements for flammable substances I26 Specific documentation requirements for organic peroxides I27 Specific documentation requirements for oxidising substances I28 Specific documentation requirements for toxic substances I29 Signage requirements I30 Advertising corrosive and toxic substances

2.4. The Hazardous Substances (Emergency Management) Regulations 2001 prescribe controls that must be complied with if the levels of substance held are above the trigger quantities specified. These controls are aimed at mitigating adverse effects in the event of a spill and prescribe specific requirements with respect to emergency management information, emergency response plans, secondary containment facilities and signage.

Emergency Management Controls EM1 Level 1 information requirements for suppliers and persons in charge EM2 Information requirements for corrosive substances EM3 Information requirements for explosive substances EM4 Information requirements for flammable substances EM5 Information requirements for oxidising substances and organic peroxides EM6 Information requirements for toxic substances EM7 Information requirements for ecotoxic substances EM8 Level 2 information requirements for suppliers and persons in charge EM9 Additional information requirements for flammable and oxidising substances and organic peroxides EM10 Fire extinguisher requirements EM11 Level 3 emergency management requirements: duties of person in charge, emergency response plans EM12 Level 3 emergency management requirements: secondary containment EM13 Level 3 emergency management requirements: signage

2.5. The Hazardous Substances (Packaging) Regulations 2001 prescribe a number of controls aimed at ensuring hazardous substances are adequately and appropriately packaged.

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Packaging Controls P1 General packaging requirements P2 Specific criteria for class 4.1.2 and 5.2 substances P3 Criteria that allow substances to be packaged to a standard not meeting Packing Group I, II or III criteria P4 Packaging requirements for explosive substances P5 Packaging requirements for flammable liquids P6 Packaging requirements for liquid desensitised explosives P7 Packaging requirements for flammable solids P8 Packaging requirements for self-reactive flammable substances P9 Packaging requirements for substances liable to spontaneous combustion P10 Packaging requirements for substances that emit flammable gases when in contact with water P11 Packaging requirements for oxidising substances P12 Packaging requirements for organic peroxides P13 Packaging requirements for toxic substances P14 Packaging requirements for corrosive substances P15 Packaging requirements for ecotoxic substances PG1 Packaging requirements equivalent to UN Packing Group I PG2 Packaging requirements equivalent to UN Packing Group II PG3 Packaging requirements equivalent to UN Packing Group III PS4 Packaging requirements as specified in Schedule 4

2.6. The Hazardous Substances (Classes 6, 8 and 9 Controls) Regulations 2001 prescribe a number of controls aimed at ensuring hazardous substances handled in a manner appropriate to their toxicity.

Toxicity Controls T1 Limiting exposure to toxic substances through the setting of TELs T2 Controlling exposure in places of work through the setting of WESs. T3 Requirements for keeping records of use T4 Requirements for equipment used to handle substances T5 Requirements for protective clothing and equipment T6 Approved handler/security requirements for certain toxic substances T7 Restrictions on the carriage of toxic or corrosive substances on passenger service vehicles T8 Controls for vertebrate poisons

2.7. The Hazardous Substances (Classes 6, 8 and 9 Controls) Regulations 2001 specify a number of controls primarily aimed at limiting the extent to which the environment are exposed to hazardous substances with ecotoxic properties.

Ecotoxicity Controls E1 Limiting exposure to ecotoxic substances through the setting of EELs E2 Restrictions on use of substances in application areas

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E3 Controls relating to protection of terrestrial invertebrates eg beneficial insects E4 Controls relating to protection of terrestrial vertebrates E5 Requirements for keeping records of use E6 Requirements for equipment used to handle substances E7 Approved handler/security requirements for certain ecotoxic substances

2.8. The Hazardous Substances (Disposal) Regulations 2001 specify controls on the disposal of substances and their containers.

Disposal Controls D1 Disposal requirements for explosive substances D2 Disposal requirements for flammable substances D3 Disposal requirements for oxidising substances and organic peroxides D4 Disposal requirements for toxic and corrosive substances D5 Disposal requirements for ecotoxic substances D6 Disposal requirements for packages D7 Information requirements for manufacturers, importers and suppliers, and persons in charge D8 Documentation requirements for manufacturers, importers and suppliers, and persons in charge

2.9. The Hazardous Substances (Tracking) Regulations 2001 specify controls for the tracking of substances.

Tracking Controls TR1 General tracking requirements

2.10. The Hazardous Substances (Personnel Qualifications) Regulations 2001 specify the qualifications required of an approved handler.

Approved handler Controls AH1 Approved Handler requirements (including test certificate and qualification requirements)

2.11. The Hazardous Substances (Tank Wagon and Transportable Container) Regulations 2001 prescribe a number of controls relating to tank wagons and transportable containers.

Tank Wagon and Transportable Containers Controls The Hazardous Substance (Tank Wagons and Transportable Containers) Regulations 2004 prescribe a number of controls relating to tank wagons and transportable containers.

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Other legislation

2.12. For internal land transport within New Zealand, the Land Transport Rule: Dangerous Goods 2005 will govern the type of transport, the qualifications of the driver and carrier, and the information requirements for transportation including packaging. Drivers are required to carry emergency management instructions for the substance they are carrying. For internal sea transport within New Zealand (e.g. across the Cook Strait), packages will have to meet the labelling requirements of the IMDG Code for the transport of dangerous goods by sea.

2.13. Under the HSE Act, employers and workers are required to be aware of all hazards.

2.14. The RMA prohibits discharge of contaminants into the environment unless it has been expressly allowed for in a Regional Plan, resource consent or by regulation. This is relevant to all stages of the substance‘s lifecycle, with specific relevance to the substance during its manufacturing, storage, use and disposal. 3. Risk assessment

3.1. The process by which the risk assessment of substances should be undertaken is specified in the Methodology. The process requires that the risks and benefits of a substance be identified and then assessed for their level of significance.

3.2. Potentially non-negligible risks must first be identified for evaluation following clauses 9 and 11, (which incorporate sections 5, 6 and 8) of the Methodology. These risks must then be assessed in accordance with sections 5 and 6 and clauses 9 and 12. The assessment must be undertaken with regard to:

the environment, human health and safety, the relationship of Māori to the environment, society and the community, the market economy, and New Zealand‘s international obligations.

3.3. For the purposes of the assessment the following definitions are made in Regulation 2 of the Methodology.

A ―cost‖ is ―the value of a particular adverse effect expressed in monetary or non- monetary terms‖. Thus, these should be assessed in an integrated fashion together with the risks of the adverse effects in the following assessment. A ―benefit‖ is ―the value of a particular positive effect expressed in monetary or non- monetary terms‖. Benefits that may arise from any of the matters set out in clauses 9 and 11 were considered in terms of clause 13.

3.4. To facilitate the assessment of risks the applicant and the Agency have identified the most common potential sources of risk to the environment and to human health and safety through release, spillage or exposure throughout the lifecycle of the substance. These are tabulated in Table S3.1 and are used as the basis for the risk assessment in the ―Identification and Assessment of effects‖ section of the E&R report.

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Table S3.1: Potential sources of risks associated with hazardous substances Lifecycle Activity Associated Source of Risk Manufacture / An incident during the manufacture or importation of the substance resulting in Import spillage and subsequent exposure of people or the environment to the substance. Packing An incident during the packing of the substance resulting in spillage and subsequent exposure of people or the environment to the substance. Transport or An incident during the transport or storage of the substance resulting in spillage storage and subsequent exposure of people or the environment to the substance. Use Application of the substance resulting in exposure of users or bystanders or the environment; or an incident during use resulting in spillage and subsequent exposure of users or the environment to the substance. Disposal Disposal of the substance or packaging resulting in exposure of people or the environment to the substance.

3.5. In undertaking the assessment the Agency notes that the evidence provided by the applicant and additional evidence found by the Agency, relating to the hazardous properties of the substances is largely scientific in nature (clause 25(1)). However, as some of the evaluation of risks, costs and benefits has been carried out on a qualitative basis, it is recognised that there is a degree of uncertainty in the risk analysis.

3.6. Where qualitative assessment is used at any stages of the lifecycle the level of risk has been evaluated on the basis of the magnitude and likelihood of adverse effects occurring to people or the environment.

3.7. In accordance with section 29, consideration is given to the likely effects of the substances being unavailable.

3.8. As in 3.2 above outlining the aspects in which the risk assessment is undertaken in relation with, the Agency assesses each application for any effects associated with the relationship of Māori to the environment. In most cases the substance will trigger a number of hazardous properties giving rise to the potential for cultural risk including the deterioration of the mauri of taonga flora and fauna species, the environment and the general health and well-being of individuals and the community.

3.9. In addition, the introduction and use of hazardous substances have the potential to inhibit the ability of iwi/Māori to fulfill their role as kaitiaki, particularly in relation to the guardianship of waterways given the highly ecotoxic nature of the substance to aquatic species, and potential risks to the mauri ora of human health under prolonged exposure to this substance.

3.10. Where significant effects on the relationship of Māori to the environment are identified during the Agency‘s risk assessment these will be fully discussed in the body of the E&R report. Where effects are identified which will have a negligible impact the following process will be undertaken to ensure that significant effects are not overlooked.

3.11. The Agency will consider the information outlined in the report, to determine that there is a minimal impact from the substance on the relationship of Māori and their

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culture and traditions with their ancestral lands, water, sites, wāhi tapu, valued flora and fauna and other taonga to ensure that any impacts are highly improbable.

3.12. If this is determined the overall level of risk will therefore be considered to be negligible assuming that the substance will be handled, stored, transported, used, and disposed of, in accordance with the explicitly stated default and additional controls proposed in the report, and any other controls required by other legislation.

3.13. However, the Agency will propose that should inappropriate use, or accident, result in the contamination of waterways or the environment generally, that users will be required to notify the appropriate authorities including the relevant iwi authorities in that region. This action should include advising them of the contamination and the measures taken to contain and remediate. 4. Qualitative descriptors for risk/benefit assessment

4.1. This section describes how the Agency staff and the Authority address the qualitative assessment of risks, costs and benefits. Risks and benefits are assessed by estimating the magnitude and nature of the possible effects and the likelihood of their occurrence. For each effect, the combination of these two components determines the level of the risk associated with that effect, which is a two dimensional concept. Because of lack of data, risks are often presented as singular results. In reality, they are better represented by ‗families‘ of data which link probability with different levels of outcome (magnitude).

4.2. The magnitude of effect is described in terms of the element that might be affected. The qualitative descriptors for magnitude of effect are surrogate measures that should be used to gauge the end effect or the ‗what if‘ element. Tables S4.1 and S4.2 contain generic descriptors for magnitude of adverse and beneficial effect. These descriptors are examples only, and their generic nature means that it may be difficult to use them in some particular circumstances. They are included here to illustrate how qualitative tables may be used to represent levels of adverse and beneficial effect.

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Table S4.1 Magnitude of adverse effect (risks and costs) Descriptor Examples of descriptions - Adverse Minimal Mild reversible short term adverse health effects to individuals in highly localised area Highly localised and contained environmental impact, affecting a few (less than ten) individuals members of communities of flora or fauna, no discernible ecosystem impact Local/regional short-term adverse economic effects on small organisations (businesses, individuals), temporary job losses No social disruption Minor Mild reversible short term adverse health effects to identified and isolated groups Localised and contained reversible environmental impact, some local plant or animal communities temporarily damaged, no discernible ecosystem impact or species damage Regional adverse economic effects on small organisations (businesses, individuals) lasting less than six months, temporary job losses Potential social disruption (community placed on alert) Moderate Minor irreversible health effects to individuals and/or reversible medium term adverse health effects to larger (but surrounding) community (requiring hospitalisation) Measurable long term damage to local plant and animal communities, but no obvious spread beyond defined boundaries, medium term individual ecosystem damage, no species damage Medium term (one to five years) regional adverse economic effects with some national implications, medium term job losses Some social disruption (e.g. people delayed) Major Significant irreversible adverse health effects affecting individuals and requiring hospitalisation and/or reversible adverse health effects reaching beyond the immediate community Long term/irreversible damage to localised ecosystem but no species loss Measurable adverse effect on GDP, some long term (more than five years) job losses Social disruption to surrounding community, including some evacuations Massive Significant irreversible adverse health effects reaching beyond the immediate community and/or deaths Extensive irreversible ecosystem damage, including species loss Significant on-going adverse effect on GDP, long term job losses on a national basis Major social disruption with entire surrounding area evacuated and impacts on wider community

Table S4.2 Magnitude of beneficial effect (benefits) Descriptor Examples of descriptions - Beneficial Minimal Mild short term positive health effects to individuals in highly localised area Highly localised and contained environmental impact, affecting a few (less than ten) individuals members of communities of flora or fauna, no discernible ecosystem impact Local/regional short-term beneficial economic effects on small organisations (businesses, individuals), temporary job creation No social effect Minor Mild short term beneficial health effects to identified and isolated groups Localised and contained beneficial environmental impact, no discernible ecosystem impact Regional beneficial economic effects on small organisations (businesses, individuals)

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lasting less than six months, temporary job creation Minor localised community benefit Moderate Minor health benefits to individuals and/or medium term health impacts on larger (but surrounding) community and health status groups Measurable benefit to localised plant and animal communities expected to pertain to medium term Medium term (one to five years) regional beneficial economic effects with some national implications, medium term job creation Local community and some individuals beyond immediate community receive social benefit. Major Significant beneficial health effects to localised community and specific groups in wider community Long term benefit to localised ecosystem(s) Measurable beneficial effect on GDP, some long term (more than five years) job creation Substantial social benefit to surrounding community, and individuals in wider community. Massive Significant long term beneficial health effects to the wider community Long term, wide spread benefits to species and/or ecosystems Significant on-going effect beneficial on GDP, long term job creation on a national basis Major social benefit affecting wider community

4.3. The likelihood applies to the composite likelihood of the end effect, and not either to the initiating event, or any one of the intermediary events. It includes:

the concept of an initiating event (triggering the hazard), and the exposure pathway that links the source (hazard) and the area of impact (public health, environment, economy, or community).

4.4. Thus, the likelihood is not the likelihood of an organism escaping, or the frequency of accidents for trucks containing hazardous substances, but the likelihood of the specified adverse effect20 resulting from that initiating event. It will be a combination of the likelihood of the initiating event and several intermediary likelihoods21. The best way to determine the likelihood is to specify and analyse the complete pathway from source to impact.

4.5. Likelihood may be expressed as a frequency or a probability. While frequency is often expressed as a number of events within a given time period, it may also be expressed as the number of events per head of (exposed) population. As a probability, the likelihood is dimensionless and refers to the number of events of interest divided by the total number of events (range 0-1).

20 The specified effect refers to scenarios established in order to establish the representative risk, and may be as specific as x people suffering adverse health effects, or y% of a bird population being adversely affected. The risks included in the analysis may be those related to a single scenario, or may be defined as a combination of several scenarios. 21 Qualitative event tree analysis may be a useful way of ensuring that all aspects are included.

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Table S4.3 Likelihood Descriptor Description Highly improbable Almost certainly not occurring but cannot be totally ruled out Very unlikely Considered only to occur in very unusual circumstances Unlikely Could occur, but is not expected to occur under normal operating conditions (occasional) Likely A good chance that it may occur under normal operating conditions Highly likely Almost certain, or expected to occur if all conditions met

4.6. Using the magnitude and likelihood tables a matrix representing a level of risk/benefit can be constructed.

4.7. In the example shown in Table S4.4, four levels of risk/benefit are allocated: A (negligible), B (low), C (medium), and D (high). These terms have been used to avoid confusion with the descriptions used for likelihood and magnitude, and to emphasise that the matrix is a tool to help decide which risks/benefits require further analysis to determine their significance in the decision making process.

4.8. For negative effects, the levels are used to show how risks can be reduced by the application of additional controls. Where the table is used for positive effects it may also be possible for controls to be applied to ensure that a particular level of benefit is achieved, but this is not a common approach. The purpose of developing the tables for both risk and benefit is so that the risks and benefits can be compared.

Table S4.4 Level of risk Magnitude of effect Likelihood Minimal Minor Moderate Major Massive Highly improbable A A A B B Very unlikely A A B B C Unlikely A B B C C Likely B B C C D Highly likely B C C D D

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5. Decision Path 1 Review the content of the application and all relevant information

2 3 4 Is this information sufficient No Seek additional Sufficient? to proceed? information

Yes No 5 Identify the composition of the substance, Yes classify the hazardous properties of the substance, and determine default controls

6 Identify all risks, costs and benefits that are Decline potentially non-negligible (section 29(1)(c))

7 Assess each risk assuming controls in place. Add, substitute or delete controls in accordance with clause 35 and sections77, 77A, 77B

8 Undertake combined consideration of all risks and costs, cognisant of proposed controls

9 Clause 27 12 Are all risks with controls in place No Establish position on risk averseness negligible? and appropriate level of caution

Clause 26 Yes 10 13 Review controls for cost-effectiveness in Review controls for cost-effectiveness accordance with clause 35 and sections 77, in accordance with clause 35 and 77A, 77B sections 77, 77A, 77B

11 14 Is it evident that benefits outweigh No Assess benefits costs?

15 Yes Taking into account controls, Yes do positive effects outweigh adverse effects? 16 Confirm and set controls No

Approve Decline (section 29(1)(a)) (section 29(1)(b))

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