application for approval to import mainman for …...6 application for approval to import mainman...

EPA STAFF EVALUATION AND REVIEW REPORT

www.epa.govt.nz

Application for approval to import Mainman for release

APP202145

9 February 2015

2

Application for approval to import Mainman for release (APP202145)

February 2015

Overview

Application Code APP202145

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 ISK New Zealand Limited

Purpose of the application

To import Mainman insecticide, which contains 500 g/kg of

flonicamid, for the control of various insect pests in potatoes and

other horticultural crops

Date Application Received 27 May 2014

Submission Period 12 June 2014 –24 July 2014

Submissions received Three submissions were received, from:

Gerry Coates on behalf of Te Rūnanga o Ngāi Tahu (“Ngāi Tahu”)

Don MacLeod on behalf of The National Beekeepers’ Association of

New Zealand (“the NBA”)

Philippa Rawlinson on behalf of Federated Farmers of New Zealand

Bee Industry Group (“Federated Farmers”)

Information requests and

time waivers

Further information was requested under section 58 of the Act.

Consequently, a time waiver was applied under section 59 of the Act

to the start of the consideration period

Hearing date 23 Feburary 2015

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February 2015

Table of Contents

1. Executive Summary .................................................................................................................... 6

2. Background .................................................................................................................................. 9

3. Process, consultation and notification ..................................................................................... 9

4. Hazardous properties ............................................................................................................... 11

5. Submissions .............................................................................................................................. 11

6. Risk and benefit assessment ................................................................................................... 16

7. Controls ...................................................................................................................................... 22

8. Overall evaluation and recommendation ................................................................................ 25

Appendix A: Submissions received .................................................................................................. 27

Appendix B: EPA standard risk descriptors ..................................................................................... 28

Appendix C: Classification of Mainman ............................................................................................ 31

Appendix D: Active ingredient and metabolites ............................................................................... 73

Appendix E: Staff’s risk identification ............................................................................................. 193

Appendix F: Qualitative risk assessment ....................................................................................... 194

Appendix G: Human health risk assessment ................................................................................. 196

Appendix H: Environmental risk assessment ................................................................................ 204

Appendix I: Controls applying to Mainman .................................................................................... 208

Appendix J: Confidential information ............................................................................................. 212

Appendix K: Standard terms and abbreviations ............................................................................ 213

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February 2015

List of tables and figures (listed in order of appearance in the document)

Table 1 Hazard classifications of Mainman as proposed by the applicant and the staff ............. 11

Table 2 Risk descriptors ..................................................................................................................... 28

Table 3 Likelihood Descriptors .......................................................................................................... 28

Table 4 Magnitude of adverse effect .................................................................................................. 29

Table 5 Magnitude of beneficial effect ............................................................................................... 30

Table 6 Applicant and staff classifications of the mixture .............................................................. 31

Table 7 Physical and chemical properties of the mixture ............................................................... 33

Table 8 Identification of flonicamid ................................................................................................... 73

Table 9 Applicant and staff classifications of the active ingredient .............................................. 74

Table 10 Physico-chemical properties of flonicamid ....................................................................... 75

Table 11 Summary of studies for the active ingredient with NOAEL and LOAEL values

and key effects. ................................................................................................................... 122

Figure 1: Proposed metabolic pathway of IKI-220 in aerobic water/sediment systems ............ 134

Figure 2: Degradation pathway of flonicamid in soils ................................................................... 139

Table 12 Potential sources of risks associated with hazardous substances ............................. 193

Table 13 Qualitative assessment of human health risks ............................................................... 194

Table 14 Qualitative assessment of risks to the environment ...................................................... 195

Table 15 Deriving an AOEL for flonicamid ...................................................................................... 196

Table 16 Derivation of dermal absorption value in humans ......................................................... 197

Table 17 Risk Quotients for Mainman: Potato – 80 g ai/ha, 2 applications at 7 days,

ground based ..................................................................................................................... 198

Table 18 Risk Quotients for Mainman: Confidential use 1 – 70 g ai/ha, 2 applications at

14 days, ground based ....................................................................................................... 198

Table 19 Risk Quotients for Mainman: Confidential use 3– 70 g ai/ha, 2 applications at

7 days, ground based ......................................................................................................... 199

Table 20 Risk Quotients for Mainman: Confidential use 5 – 70 g ai/ha, 3 applications at

21 days ................................................................................................................................. 199

Table 21 Risk Quotients for Mainman: Re-entry exposure modelling ......................................... 200

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February 2015

Table 22 Risk Quotients for Mainman: Use on Potatoes ............................................................... 201

Table 23 Risk Quotients for Mainman: Confidential uses 1 and 2 – 70 g ai/ha,

2 applications at 14 days, ground based and aerial ....................................................... 202

Table 24 Risk Quotients for Mainman: Confidential uses 3 and 4 – 70 g ai/ha,

2 applications at 7 days, ground based and aerial ........................................................ 202

Table 25 Risk Quotients for Mainman: Confidential use 5 – 70 g ai/ha,

3 applications at 21 days .................................................................................................. 203

Table 26 Summary of environmental fate data on flonicamid and its metabolites . ... 204

Table 27 Summary of ecotoxicological data on flonicamid and its metabolites – ..................... 205

Table 28: Controls for Mainman ....................................................................................................... 208

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February 2015

1. Executive Summary

ISK New Zealand has applied to import Mainman, containing 500 g/kg flonicamid, for the control of 1.1.

various insect pests in potatoes and other horticultural crops. It is intended to be applied as a dilute

spray by ground-based and aerial application methods at rates of up to 80 g flonicamid /ha, at a

maximum of three times a year.

The staff of the Environmental Protection Authority (“the staff”) have identified the hazard classifications 1.2.

of Mainman based on product data, the composition of the substance, and the properties of its

components:

Hazard Endpoint EPA classification

Eye irritant 6.4A

Vertebrate ecotoxicity 9.3C

In response to public notification, three submissions were received (Section 5 and Appendix A): One 1.3.

opposing approval of Mainman, one which neither opposed nor supported the application, and one

opposing the application in its current form.

Ngāi Tahu had concerns about the lack of information available to submitters and thought there had 1.4.

been no consideration of Māori issues. They were concerned about the effects on aquatic and

terrestrial invertebrates and wanted tests to be carried out on native species.

The National Beekeepers’ Association was concerned with the effects of Mainman on bees. They 1.5.

wanted to ensure that the EPA had access to all the information overseas regulators had. They wanted

a draft label to be publically available for submitters to comment on. They recommended that the EPA

apply a control stating that Mainman must not be applied to flowering plants within 10 days of flowering

and that the approval be limited to potatoes.

Federated Farmers Bee Interest Group had concerns about bees foraging on weeds in the crop and 1.6.

crop margins. They wanted an enforceable label, clearly listing each warning and how to avoid effects

on bees and other beneficial insects in nearby habitats. If these concerns were addressed, Federated

Farmers would consider withdrawing its opposition.

The staff conducted quantitative human health and environmental risk assessments (Section 6 and 1.7.

Appendixes E-G) based on the evaluation of toxicological and ecotoxicological data for the formulated

substance (Mainman) and the active ingredient. These assessments considered the exposure and

subsequent effects on people and the environment throughout the entire life cycle of the substance.

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February 2015

The exposure modelling indicates that risks to operators are acceptable even without the use of 1.8.

personal protective equipment (PPE) and PPE is not triggered by the hazard classifications of

Mainman. However, the staff consider it is appropriate to apply requirements for PPE as its use when

handling agrichemicals is good practice. The exposure assessment also indicates acceptable risks for

re-entry workers even without the use of PPE. However, the staff consider that in order to promote

good practice it is appropriate to include a label statement requiring the use of PPE when entering

treated areas before the spray has dried.

The risk assessment shows that low risks are expected for the environment. However, effects on bees 1.9.

could occur if the bees are directly exposed to the spray. For this reason, the staff recommend that bee

protection controls are applied to Mainman.

Based on the risk assessment, the staff have proposed controls to reduce worker exposure, prevent 1.10.

Mainman entering waterways and prohibit it from being applied to flowering plants or when bees are

present. These controls include:

a maximum application rate of 80 g ai/ha

bee protection controls are applied to Mainman, and must be mentioned on the label

Mainman must not be applied onto or into water

label statement should be added requiring the use of PPE if entering treated areas before the

spray has dried

a limit of 3 g/kg is set for the toxicologically relevant impurity toluene in the active ingredient.

With the suite of proposed controls in place the staff consider that the risks to human health and the

environment are reduced to negligible.

The staff assessed the risks posed by Mainman to the relationship of Māori to the environment and their 1.11.

culture and traditions with their ancestral lands, water, taonga and the principles of the Treaty of

Waitangi (Te Tiriti o Waitangi). The assessment identified potential cultural risks from the impacts on

taonga species, such as native pollinators, and the potential disruption to the mauri of native species

and valued ecosystems. However, given the proposed use in agricultural ecosystems and with the

proposed controls in place, the staff consider the cultural impacts of Mainman can be appropriately

managed.

The staff consider that the approval and subsequent availability of Mainman would give rise to 1.12.

significant (i.e. non-negligible) benefits. These benefits include:

improved crop health and yields

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February 2015

the availability of a new active ingredient with a new mode of action for the control of insect

pests in potatoes and other horticultural crops, which will provide a new solution for controlling

insect pests

reduced risk of pests developing resistance to insecticidal active because this will allow new

combinations of actives with different modes of action to be used; effectively managing pest

resistance also prolongs the efficacy of active ingredients

the opportunity to replace more hazardous insecticides that are currently used (e.g.

organophosphates).

With the proposed controls in place, the potential benefits of Mainman will outweigh the risks posed by 1.13.

the substance. Therefore, the staff consider that the application by ISK New Zealand to import

Mainman can be approved in accordance with clause 26 of the Hazardous Substances and New

Organisms (Methodology) Order 1998 (“the Methodology”).

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February 2015

2. Background

Mainman is a foliar applied insecticide that is intended to be used to control sucking pests in 2.1.

horticultural crops.

Mainman contains 500 g/kg of flonicamid as the active ingredient. Flonicamid is a new active ingredient 2.2.

to New Zealand, i.e. Mainman is the first product containing flonicamid to be considered for approval in

New Zealand. However, Mainman has been approved for use in other jurisdictions including: Canada,

the European Union, Japan, the United States of America, and South Korea.

The full formulation of Mainman is presented in the confidential Appendix I. 2.3.

A summary of the lifecycle of the substance is as follows: 2.4.

Mainman will be imported into New Zealand fully formulated, packaged and labelled in 500 g to

5 kg high density polyethylene plastic containers. Mainman is not expected to be imported in

bulk containers or repackaged in New Zealand; however, if re-packaging were required (e.g.

due to a damaged shipment) it would take place in facilities approved for that purpose under

the Agricultural Chemicals and Veterinary Medicines Act 1997 (ACVM Act).

Containers of Mainman will be transported by sea, road or rail throughout New Zealand. The

substance will be stored in secure chemical storage facilities.

Mainman will be used by commercial growers and contractors who are familiar with the safe

practices for storing and handling pesticides. Domestic or home-use by untrained users is not

anticipated.

Mainman will be diluted with water and applied as a foliar spray to potatoes and other crops to

treat sucking pests such as aphids and psyllids.

The applicant expects that Mainman will be disposed of by use, eliminating the need to dispose

of unused chemical. However, excess chemical can be disposed of to landfill or waste water

treatment plants according to local hazardous waste requirements. Users will be advised to

rinse the containers which can be disposed of at an approved landfill or recycled via an

appropriate recycling programme.

3. Process, consultation and notification

The application was lodged pursuant to section 28 of the Act on 5 November 2013 and formally 3.1.

received on 27 May 2014.

The Minister for the Environment was advised of the application in writing on 12 June 2014, in 3.2.

accordance with section 53(4) of the Act.

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February 2015

The Ministry for the Environment, WorkSafe New Zealand, the Ministry of Health, the Department of 3.3.

Conservation and the Agricultural Compounds and Veterinary Medicines (ACVM) group of the Ministry

for Primary Industries were notified of the application on 12 June 2014 and invited to comment. No

comments were received.

The staff advised the applicant that consultation with Māori would be beneficial for this application. A 3.4.

summary of the application was prepared and distributed on behalf of the applicant to the EPA’s Māori

advisory network, Te Herenga, in April 2014. .Although some feedback was received, it was not

applicable to the application but rather focused on the decision making process so did not alter the

application. The feedback was provided to the applicant to allow them to review the application before

it was formally received.

The application was publicly notified and opened for submissions on 12 June 2014; the submission 3.5.

period closed on 24 July 2014.

The application was publicly notified because the staff considered it to be of significant public interest in 3.6.

that Mainman contains an active ingredient that is new to New Zealand.

Three submissions were received. Te Rūnanga o Ngāi Tahu (“Ngāi Tahu”) opposed the approval of 3.7.

Mainman, the National Beekeepers’ Association (“the NBA”) did not indicate whether they opposed or

supported the application. Federated Farmers Bee Industry Group (“Federated Farmers”) opposed the

application in its current form but was not opposed to the use of Mainman by farmers to control sucking

pests on horticultural crops. The issues raised in these submissions are discussed in section 5. Ngāi

Tahu and the NBA indicated that they wished to be heard in person by the committee.

During the evaluation of the application, the staff required further information to complete the evaluation 3.8.

and risk assessment, which was requested under section 58 of the Act.

In preparing this report, the following documents were used: 3.9.

the application form and confidential material submitted by the applicant (including toxicological

and ecotoxicological studies on the product, the active ingredient and its metabolites, the full

composition of the product, chemical and physical properties of the product, and the purity of

the active ingredient)

the submissions

a report from the EPA’s Māori Advisory Committee, Ngā Kaihautū Tikanga Taiao, and

other available information.

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February 2015

4. Hazardous properties

The staff determined the hazard profile of Mainman (Table 1) as described in Appendix C. 4.1.

The classifications determined by the staff are different to those submitted by the applicant (Table 1). 4.2.

The difference in the 6.1 (oral) classification is because the applicant used the toxicity of the active

ingredient, flonicamid, to determine the classification, rather than the results of the acute oral toxicity

test performed with Mainman. The staff determined that the 6.1 classification did not apply to Mainman.

Likewise the applicant anticipated that flonicamid, and therefore Mainman would be classified 6.9B but

the staff determined that this classification should not apply to either flonicamid or Mainman. The

applicant and the study author did not consider that the formulation should be classified as an eye

irritant, based on European Union classification criteria. However the HSNO criteria for 6.4A

classification are met (mean Draize score ≥ 1, but < 3, for corneal opacity). The 9.1D classification was

applied by the applicant because Mainman is intended to be biocidal. However, given that the staff

have assigned the 9.3C classification there is no need for the 9.1D biocidal classification. The staff has

assigned the 9.3C classification based on data submitted by the applicant for flonicamid and data on

other components of Mainman.

Table 1 Hazard classifications of Mainman as proposed by the applicant and the staff

Hazard Endpoint Applicant classification EPA classification

Acute toxicity (oral) 6.1E -

Eye irritation - 6.4A

Target organ systemic toxicity 6.9B -

Aquatic ecotoxicity 9.1D -

Ecotoxic to terrestrial vertebrates - 9.3C

5. Submissions

The submissions received by the EPA are attached as Appendix A. The key points from the 5.1.

submissions have been grouped into related issues and are discussed, alongside the EPA staff

response, below. All submissions were sent to the applicant.

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February 2015

Matters related to issues broader than this application

Submissions

Ngāi Tahu expressed dissatisfaction with the level of toxicity and ecotoxicity information that is made 5.2.

publically available with applications; the lack of testing on New Zealand native species; and that the full

composition of the substance, impurities in the active ingredient and other commercially sensitive

information are not disclosed to the public.

EPA staff response to the submissions

The staff note that these matters have been raised by Ngāi Tahu in submissions to previous 5.3.

applications. The Committee has previously stated that these matters are not specific to the

consideration of individual applications but relate to the requirements of the Act itself, and the EPA’s

approach to implementing the Act1. Therefore these matters are not discussed further in this evaluation

report but can be found in the submissions attached as Appendix A. The staff also note that the EPA

has, and continues to, work with Ngāi Tahu and applicants on these issues outside the application

process.

Risks

Submissions

Ngāi Tahu commented that the applicant did not provide any evidence to support their statement that 5.4.

they were “unaware of any significant or adverse impact the importation, release and use of the

substance would have on Māori cultural spiritual, ethical and social-economic values”, and questioned if

the applicant had considered the potential cultural risks of this substance.

The NBA and Federated Farmers have both raised concerns about the potential impacts of Mainman on 5.5.

honey bees. The NBA notes that the active ingredient of Mainman, flonicamid, is systemic i.e. it is

transmitted throughout the plant, and this may result in honey bees being exposed to flonicamid via

nectar or pollen of flowering plants. They request that a control is placed on Mainman to prevent it

being applied to flowering plants or immediately before flowering. Federated Farmers had similar

concerns and note that bees could also be exposed if Mainman was applied to flowering weeds in the

crop or crop margins, even if the crop itself was not in flower. They request that an enforceable label

warning is placed on Mainman to warn users about the risks to bees.

1 Recommendations in the Decision for application APP201999 – Solvigo.

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February 2015

Ngāi Tahu have raised concerns about the risks to aquatic and terrestrial species, due to the toxicity 5.6.

values cited in the application form, specifically the ‘low concentrations’ tested (Trout LD502 >100 mg/L;

Quail LD50 >2000 mg/kg/day; bees LD50 (oral) >60 µg/bee, LD50 (contact) >100 µg/bee, soil organisms;

earthworm NOEC3 >1000 mg/kg)

4.

The NBA notes this application only includes use on potatoes (GAP table, section 5.1 of the application 5.7.

form) but that similar substances from the same company are approved for use on brassicas, pome fruit

and stone fruit overseas. The NBA notes use on potatoes is low risk to bees because potatoes are not

a significant source of pollen for bees and do not rely on bees for pollination. However, they are

concerned about market creep and off-label uses – i.e. use on other crops that may be higher risk.

Ngāi Tahu have noted that the applicant did not include information on the metabolites of flonicamid in 5.8.

the application form, and that the DT505 of flonicamid in water was presented (DT50 =34 days), but that

no values for degradation in the soil were presented. They also note that it is impossible for them to

assess the risks of the metabolites because those metabolites are not named in the application form.


The staff note that the applicant sought guidance from members of the EPA’s Te Herenga network, 5.9.

including Ngāi Tahu, to provide assistance in identifying the impact on Māori cultural spiritual, ethical

and social-economic values. The responses received best related to the decision making process,

rather than the application itself. Ngāi Tahu indicated that they preferred to contribute at the public

submissions stage rather than the consultation stage of the application process.

The staff note that the toxicity test values (LD50 and NOEL) cited in the application form are relatively 5.10.

high and that the values for aquatic and soil environments and terrestrial invertebrates (bees) are below

thresholds for the respective HSNO classifications i.e. these classifications are not triggered. The LD50

test determines the dose at which 50% of the test population would be killed. High LD50 values indicate

lower toxicity to the test organism.

The staff note that Mainman has low toxicity to adult bees, hence it does not trigger a 9.4 classification. 5.11.

However, this test for 9.4 classification is only based on the acute effect to adult bees. The EPA’s risk

2 LD50 is the statistically or experimentally determined dose at which 50% of the test population dies.

3 NOEC is the no observed effect concentration.

4 Values quoted in the submission

5DT50 is the time required for 50% of the substances to degrade.

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February 2015

assessment considers a broader range of human health and ecological outcomes than those

considered to determine the classification of a substance.

The chronic effects of a substance and effects to other life stages are considered as part of the EPA’s 5.12.

full risk assessment which considers a broader range of human health and ecological outcomes than

those required to determine the classification of a substance. The studies submitted by the applicant

(Appendix C of this report) indicate that flonicamid could affect bee larvae; therefore the staff have

proposed controls to restrict the use of Mainman on flowering plants.

Regarding the LD50 values presented in the application form, the staff note that the concentrations 5.13.

tested are high and correspond to low toxicity. The toxicity testing guidelines allow limit tests to be

conducted when a product is expected to be of low toxicity. In a limit test, a high concentration is tested

first and if the result is not observed then there is no need to repeat the test at lower concentrations.

The staff note that the LD50 values presented in the application form for trout, bees and soil organisms

are below the threshold for triggering the respective hazard classifications.

The staff have noted the broader use pattern of Mainman, and similar products overseas, and have 5.14.

included additional scenarios in their risk assessments to account for possible future uses in New

Zealand.

The staff agree that limited information on metabolites and degradation is provided in the application 5.15.

form, but acknowledge that this is probably because it is not requested in the application form. The

staff also note that sufficient information on the metabolism and environmental fate of Mainman and its

active ingredient were provided with the application to allow the risk assessment to be completed.

Benefits

Submissions

Ngāi Tahu have noted that the benefits listed by the applicant are limited to the substance containing a 5.16.

‘new active ingredient which has a different mode of chemistry’, which will ‘minimise the risk of pest

resistance developing’ and a product with a ‘lesser hazard classification’ than existing insecticides, and

that the application does not provide a persuasive case for the benefits of this substance.

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February 2015


The staff agree that limited information was provided about the benefits, but that this is consistent with 5.17.

the level of benefits information typically provided with applications. The staff consider that the benefits

mentioned are valid.

Controls

Submissions

The NBA have indicated that they would like the EPA to apply the E3 control, regulation 49 from the 5.18.

Hazardous Substances (Classes 6, 8 and 9) Regulations 2001. This control prohibits the application of

a substance to flowering plants and plants that are expected to flower within a set period (up to 10

days).

Federated Farmers have similar concerns to the NBA, and are particularly concerned that the product 5.19.

could be applied to flowering weeds in or around a crop even if the crop is not attractive to bees.

Federated farmers have indicated that they would like to see clear enforceable warning about the risks

to bees on product labels. They have suggested the following wording for warning statements that

should appear on the label.

The product should not be used on horticultural crops during daylight hours when bees are

foraging on bee attractive weeds in the crop or flowers in headlands and /or paddock margins.

The product should not be used on horticultural crops during daylight hours when bees are

foraging.

Federated Farmers were also concerned about the warnings on the product label, practically that these 5.20.

were not clear and did not adequately address the risks posed by the substance. They have suggested

that the following warning appear on the label and that each warning is presented on a separate line to

improve clarity.

Harmful – may be harmful [if] swallowed, inhaled, or absorbed through the skin

May cause damage to the hematopoietic system from prolonged or repeated exposure

Designed for biocidal action against specific insects

Avoid spray drift to reduce harmful effects on beneficial insects in nearby habitats

Mainman shall not be applied directly onto, over or into water

Avoid contamination of any water supply with product or empty container

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February 2015


The staff agreed with the submitters that the E3 control should be applied. The staff took submitters 5.21.

comments about label directions into consideration when drafting the proposed controls. The staff

consider that the controls recommended in this document will mitigate the risks to people and the

environment.

Other matters

Submissions

Ngāi Tahu also note that the application is incomplete because it is not signed and witnessed as 5.22.

required.


The statutory declaration section of the EPA application form is only required to be completed by 5.23.

applicants seeking a rapid application under section 28A of the Act. This application is a full

assessment under section 28 of the Act and the statutory declaration is not required, and the

application form is appropriately signed.

6. Risk and benefit assessment

The staff conducted a qualitative risk assessment covering all stages of Mainman’s lifecycle, and a full 6.1.

quantitative human health and ecotoxicological risk assessment for the use phase. Full details of those

assessments are shown in Appendices E to G. This section provides a summary of the staff

assessment of the risks and benefits of Mainman.

Risks during manufacture, packaging and importation

The applicant intends to import Mainman packaged for sale, and manufacturing or repackaging in New 6.2.

Zealand is not anticipated. However if manufacturing or packing were to occur in New Zealand, the

HSNO requirement’s for equipment, emergency management and personal protective equipment (PPE)

would apply as well as WorkSafe New Zealand’s health and safety requirements. Assuming

compliance with the default controls and other relevant legislation, the staff consider that the risks to

people during import, manufacture and packaging would be negligible.

Risks during transport and storage

Workers and bystanders will only be exposed to the substance during transport and storage in isolated 6.3.

incidents where spills occur. Once in New Zealand, HSNO controls (e.g. labels, SDS, packaging) and

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February 2015

adherence to the Land Transport Rule 45001, Civil Aviation Act 1990 and Maritime Transport Act 1994

(as applicable) will apply. Therefore, the likelihood of people or the environment being exposed to

Mainman while it is being transported is so low that the resulting level of risk is considered negligible.

Risks during use

In addition to the use on potatoes described in the application form, the applicant intends to develop the 6.4.

use of Mainman on other crops in future but has requested that these uses are kept confidential. These

uses have been included in the risk assessment and identified as confidential use 1 to 5.

Human health effects

The quantitative human health risk assessment, detailed in Appendix F, determined that the risks to 6.5.

operators, bystanders and re-entry workers are acceptable (i.e. below the acceptable operator

exposure level (AOEL)) for the proposed uses of Mainman.

The exposure modelling indicated that risks for operators and re-entry workers are acceptable even 6.6.

without the use of PPE, and controls requiring PPE are not triggered by the hazard classifications of

Mainman. However, it is considered good practice to use of PPE when handling agrichemicals

therefore the staff recommend applying a labelling control that states that:

“Personal protective equipment (PPE) should be worn if entering areas treated with the

substance before the spray has dried”

or words to this effect. The minimum of PPE recommended is chemical resistant gloves, long sleeved

trousers and long sleeved shirt.

Environmental effects

Due to the proposed use pattern of Mainman, target and non-target organisms in the environment are 6.7.

expected to be exposed to this substance. Therefore a quantitative risk assessment was completed for

the active ingredient in Mainman, flonicamid. The risk assessment included consideration of the

metabolites of flonicamid.

The environmental risk assessment showed that Mainman poses a low risk to the environment when 6.8.

used according to the proposed application rates and label instructions. It was considered harmful to

terrestrial vertebrates (9.3C) but did not trigger aquatic (9.1), soil (9.2) or terrestrial invertebrates (9.4)

classifications.

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February 2015

The potential effect on bees and other beneficial insects has been noted by the submitters. The 6.9.

ecological risk assessment showed Mainman posed a low risk to adult bees and non-target arthropods

(e.g. predatory mites (Typhlodromus pyri), parasitic wasp (Aphidius rhopalosiphi), lacewing

(Chrysoperla carnea), hoverfly (Episyrphus balteatus) and ladybird (Coccinella septempunctata)).

However, several studies submitted with the application reported increased mortality and behavioural 6.10.

impairments (e.g. nervousness, dis-coordinated movement and apathy). In one study the effects were

observed on the day after the substance was applied, when the application occurred during foraging but

not when the substance was applied at the end of the day after foraging had ceased.

Consequently the staff consider that the use of Mainman should be restricted to plants (including weeds 6.11.

within and around the crop) that are not in flower, to minimise the likelihood that foraging bees will be

exposed to the substance. Therefore, the E3 Control6 has been in the draft controls under section 77

(3) of the Act.

It is considered that, with the default and additional controls in place, the risks to the environment from 6.12.

the use of Mainman will mitigate the level of risk to negligible.

Risks during disposal

The applicant indicates that the substance should be disposed of via an appropriate waste facility 6.13.

according to local by-laws, and that containers can be triple rinsed and disposed of at a landfill that is

consented to receive that type of waste or recycled.

Disposal of the substance and used containers in accordance with the requirements of the Hazardous 6.14.

Substances (Disposal) Regulations 2001 will ensure individuals and the environment are not exposed

to the substance. The level of risk during the disposal stage of the lifecycle is considered negligible.

Relationship of Māori to the Environment

The potential effects on the relationship of Māori to the environment have been assessed in accordance 6.15.

with sections 6(d) and 8 of the HSNO Act. Under these sections everyone exercising functions,

powers, and duties under the Act must take into account the relationship of Māori and their ancestral

lands, their water, their taonga and the principles of the Treaty of Waitangi (te Tiriti o Waitangi).

6 Regulation 49 of the Hazardous Substances (Classes 6,8 and 9) Regulations 2001

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February 2015

In consideration of these requirements, this section provides an evaluation of impacts (positive and 6.16.

negative) to kaitiakitanga and the Treaty of Waitangi.

Kaitiakitanga

Kaitiakitanga7 is the exercise of guardianship of natural and physical resources by the tangata whenua 6.17.

of an area in accordance with tikanga Māori. A kaitiakitanga role has many functions including enabling

the protection of the life-supporting capacity of resources; maintaining the character and spiritual

integrity of those resource; as well as preserving them for future generations.

Members of the EPA’s Te Herenga network were given the opportunity to comment on this application 6.18.

prior to the public notification process. Although no specific information was provided during

consultation, the staff identified some key cultural elements that are relevant to this application.

In particular, the staff note that native pollinators are a taonga species with a critical role for kaitiaki in 6.19.

maintaining native food sources, rongoa and forest regeneration. In addition, the use of chemicals in

the environment always poses the potential for disruption to the mauri of native and valued species and

ecosystems, and consequently the ability of Māori to manage such impacts in their kaitiakitanga role.

Information relating to bees and other invertebrates is outlined elsewhere in this report. Though there is 6.20.

no specific information available on the impacts to native pollinators – including native bee species –

the staff note that Mainman is not intended for use in native ecosystems where such species are likely

to be more abundant. The use of the substance in highly modified horticultural regions also lends to a

conclusion that negative impacts on native species and ecosystems are likely to be minimal, particularly

in light of the ecotoxicology risk assessment outlined elsewhere in this report. .

In addition, with the controls proposed in this report (particularly those relating to labelling) , the likely 6.21.

use pattern, and environmental risk assessment, the staff consider that any potential impact to the

relationship of Māori to the environment will be negligible.

Treaty of Waitangi

In determining the impacts and relevance of the principles of the Treaty of Waitangi, we refer to the 6.22.

principles of partnership, participation and protection. These principles are regularly referenced by the

courts and the Waitangi Tribunal.

7 As defined in the Resource Management Act (1991); kaitiakitanga is not specifically defined in the HSNO Act.

20


February 2015

The principles of partnership and participation refer to the “shared obligation on both the Crown and 6.23.

Māori to act reasonably, honourably and in good faith towards each other to ensure the making of

informed decisions on matters affecting the interests of Māori”.

Additionally, the Waitangi tribunal has previously recommended that “environmental matters, especially 6.24.

as they may affect Māori access to traditional food resource also require consultation with Māori people

concerned.”

The EPA’s Engagement with Māori Policy requires that consultation be undertaken both prior to and 6.25.

throughout the application process where significant impacts to Māori interests are posed. Also, that

such consultation should lead to the effective exchange of information between the applicant and Māori,

as appropriate. Another purpose of consultation in this context is to provide decision-makers with

information to enable them to effectively evaluate the risks, costs and benefits of the substance, and to

make better informed decisions. This is in accordance with the decision-makers legal duty under the

HSNO Act.

In April 2014 and on behalf of the applicant, the EPA sent out summary information on the Mainman 6.26.

draft application to Te Herenga (the EPA’s national network of Māori resource managers, practitioners

and experts in the environment space) requesting enquires or feedback regarding the application. No

feedback was received that would be of benefit to this application.

In June 2014 the application was open for public submissions. Ngāi Tahu provided a submission on the 6.27.

application during this period.

Ngāi Tahu’s submission questioned whether the applicant had provided sufficient evidence to show that 6.28.

Mainman and its breakdown products pose no risks to terrestrial and aquatic environments. Ngāi Tahu

also note that the benefits of releasing further agrichemicals should be explicitly spelt out.

The Crown's settlement with Ngāi Tahu includes recognition on the traditional relationship Ngāi Tahu 6.29.

have with their taonga species. The settlement recognised that Ngāi Tahu and the government have

similar objectives in environmental and conservation management – that being to protect and enhance

what is special about New Zealand for future generations.

Taonga species, under the Ngāi Tahu Claims Settlement Act 1998 (“NTCS Act”) include native birds, 6.30.

plants and animals. The area of cultural significance and importance to Ngāi Tahu is defined by the Te

Rūnanga o Ngāi Tahu Act 1996 as being most of the South Island (excluding a northern segment) and

the islands to the south including Stewart Island (Rakiura) and others.

21


February 2015

Ngā Kaihautū and the submitters also touched on the absence of data from the Mainman application 6.31.

and commented that the data that was made available was extremely limited, lacking reference to any

relevant research. Ngāi Tahu continually comment on the lack of data made available within the

submission period, noting that due to this very fact it was impossible to evaluate the potential for risk.

The approval of an application for a hazardous substance, where significant uncertainty exists regarding 6.32.

the potential for adverse effects on taonga species and traditional Māori values and practices, may be

viewed as being inconsistent with the principle of active protection.

Whilst these frustrations are acknowledged, the staff note that given the risk assessment provided in 6.33.

this report, the level of uncertainty relating to the potential for impact to taonga species, Māori values

and practices is unlikely to be significant.

The staff have also considered that with proposed controls and measures in place, no significant risks 6.34.

are posed. With this in mind, the staff consider that the application is unlikely to be inconsistent with the

principles of the Treaty of Waitangi.

New Zealand’s international obligations

The staff have not identified any international obligations that might be affected by the use of Mainman. 6.35.

Assessment of benefits

The active ingredient of Mainman, flonicamid, has a different mode of action to currently available 6.36.

products. This is important for managing pesticide resistance, because it disrupts the natural

development of resistance to any particular class of active ingredient. The staff agree that the

availability of alternative chemistries is beneficial for growers.

The applicant also notes that Mainman has less hazards and lower hazard classifications than other 6.37.

insecticides used for the same purpose, and can therefore be considered a safer alternative to those

products. The low toxicity of Mainman means that it poses less risk to users than alternative products.

The staff consider that less hazardous products are beneficial to users both from a human health and

ease of use perspective.

The staff consider that Mainman will provide a benefit to growers and regional economic benefits to 6.38.

small organisations. Therefore the staff consider that there will be significant non-negligible benefits

associated with the approval of Mainman.

22


February 2015

The effects of the substance being unavailable

The effects of the substance being unavailable relate to fewer tools for disease management and 6.39.

pesticide resistance management. This could result in an adverse impact on crop quality and flow-on

economic impacts for individual growers.

7. Controls

A set of default controls are specified by regulations under the Act, based on the hazard classification 7.1.

determined for Mainman and form the basis of the controls set out in Appendix H. Based on the risk

assessment, the following additions, variations and deletions are considered applicable to Mainman.

Setting exposure limits

Tolerable Exposure Limits (TELs) and Acceptable Daily Exposure (ADE), Potential Daily Exposure 7.2.

(PDE) values can be set to control hazardous substances entering the environment in quantities

sufficient to present a risk to people. No TELs have been set for any component of Mainman. ADE and

PDE values have been set for flonicamid and the staff consider that these values are applicable to

Mainman; therefore the following PDE values have been applied:

ADE = 0.073 mg/kg bw/day8

PDEfood = 0.0511 mg/kg bw/day

PDEdrinking water = 0.0146 mg/kg bw/day

PDE other = 0.0073 mg/kg bw/day

The EPA typically adopts Workplace Exposure Standard (WES) values listed in WorkSafe New Zealand 7.3.

WES document9 to control exposure in places of work. WES values exist for component G but the staff

recommend that these should not apply to Mainman due to the low concentration of this component in

the substance.

Environmental Exposure Limits (EELs) can be set to limit hazardous substances from entering the 7.4.

environment in quantities sufficient to present a risk to it. The quantitative ecotoxicological risk

assessment (Appendix G) indicated that the risk posed to the soil environment was negligible and the

8 Units are mg of active ingredicent per kilogram bodyweitht per day

9 http://www.business.govt.nz/healthandsafetygroup/information-guidance/all-guidance-items/workplace-exposure-standards-

and-biological-exposure-indices/workplace-exposure-standards-and-biological-indices-2013.pdf

http://www.business.govt.nz/healthandsafetygroup/information-guidance/all-guidance-items/workplace-exposure-standards-and-biological-exposure-indices/workplace-exposure-standards-and-biological-indices-2013.pdf

http://www.business.govt.nz/healthandsafetygroup/information-guidance/all-guidance-items/workplace-exposure-standards-and-biological-exposure-indices/workplace-exposure-standards-and-biological-indices-2013.pdf

23


February 2015

risks to the aquatic environment were non-negligible. The staff consider that preventing exposure of the

aquatic environment to Mainman is the most effective way to manage the risks to the aquatic

environment. Consequently the proposed controls, set out in Appendix H, restricting the substance

from being applied to water, are recommended. No EELs have been proposed for any component of

Mainman at this time because the risk of adverse effects to the environment has been qualitatively

assessed as negligible provided that users comply with the controls as set out in Appendix H. The

default EEL values have been deleted.

Variation and deletion of controls

No controls have been varied or deleted. 7.5.

Additional controls

As no EEL has been proposed for Mainman, a maximum application rate is not required to be set under 7.6.

regulation 48 of the Hazardous Substances (Classes 6, 8, and 9 Controls) Regulations 2001. However,

the assessment of risk only takes into account the use patterns proposed by the applicant. The risk of

using higher application rates or different use patterns is unknown. Therefore it is considered

appropriate to take a precautionary approach and apply controls to limit the application of Mainman to

the established use-pattern parameters. Consequently a maximum application rate has been set under

section 77A of the Act. The following additional control is applied to Mainman to restrict the level of risk

to the environment:

The maximum application rate of this substance is 80 g of flonicamid/ ha.

The staff note that the active ingredient in Mainman, flonicamid, is associated with the toxicologically 7.7.

significant impurity toluene. When present in high enough concentrations such impurities may cause

adverse effects to people and/or the environment. Imposing a restriction on the maximum amount of

toluene that can be present in the active ingredient used to manufacture Mainman will prevent the

impurity from occurring in concentrations sufficient to cause adverse effects to people or the

environment. Consequently, the following additional control is applied to Mainman:

The flonicamid component of this substance must not contain more than 3 g/kg of toluene.

Due to the proposed use pattern as an insecticide for commercial horticultural crops, Mainman is 7.8.

expected to be applied in a wide dispersive manner, and significant environmental exposure could

occur. Staff note that it is not unusual for horticultural fields to be boarded by ditches, water-races, or

streams which may be inhabited by local and introduced aquatic species, or be used for drinking, stock

or irrigation water. Therefore people or the environment could be affected if Mainman was applied

24


February 2015

directly to water. Staff also note that this substance is not intended to be applied directly onto water

and has therefore not been assessed for such uses in this application. Staff propose applying the

precautionary approach (section 7 of the Act) and limiting the use to this substance to terrestrial

applications. Consequently, the following additional control is applied to Mainman to restrict the level of

risk to the environment:

This substance must not be applied onto, into or over surface water10

The staff note that although Mainman does not trigger a 9.4 (invertebrate ecotoxicity) classification, the 7.9.

ecological risk assessment identified risks to bees. Specifically, several tunnel and field studies

reported bee mortalities and sub-lethal effects on the day of treatment when bees are directly exposed

to the spray of Mainman. Therefore it is considered appropriate to apply controls to limit the application

of Mainman to crops or areas that are not attractive to bees; this includes non-flowering crops if

flowering weeds are present in the crop or field margins.

Control E3 (Section 49 of the Hazardous Substances (Classes 6, 8 and 9) Amendment Regulations 7.10.

2004) includes requirements for the protection of terrestrial invertebrates (including bees) where a

substance is sprayed into the environment. As Mainman is not classified as a 9.4 substance, this

control does not form part of the default controls and therefore the staff recommend applying the control

under section 77(3)(a) of the Act.

The proposed additional controls set certain requirements or restrictions on the users of the substance, 7.11.

such as a maximum application rate. The staff consider that the most effective way to communicate

these requirements to the user is through the substance label. Other communication mechanisms (e.g.

safety data sheets) can be used to convey this type of information, but label statements are more likely

to be read every time a substance is used, so are considered the most effective way of communicating

key requirements for a particular substance. Therefore, the staff recommend that the following

statements, or words to this effect, are provided on the label for Mainman.

“Do not apply this product to any plant likely to be visited by bees at the time of application;

or immediately after application until spray has dried; or in areas where bees are foraging"

The maximum application rate of this substance is 80 g of flonicamid/ ha

10 where ‘water‘ means water in all its physical forms, whether flowing or not, but does not include water in any form while in a pipe,

tank or cistern or water used in the dilution of the substance prior to application or water used to rinse the container after use

25


February 2015

The staff note that the exposure assessment for operators and re-entry workers showed that the risks of 7.12.

the proposed uses was acceptable even without PPE and the default controls requiring PPE were not

triggered. However it is considered good practice to wear PPE when handling agrichemicals and this

should be communicated to users. Therefore the staff recommend adding the following statement, or

words to this effect, on the substance label:

Do not allow entry into treated areas until the spray has dried, unless wearing cotton overalls

buttoned to the neck and wrist (or equivalent clothing) and chemical resistant gloves.

Clothing must be laundered after each day’s use

The staff note that the application of the proposed additional controls will be more effective than the 7.13.

specified (default) controls in terms of its effect on the management, use and risks of Mainman.

Environmental user charges

The staff consider that applying controls to Mainman is an effective means of managing risks associated 7.14.

with this substance. Therefore, it is not considered necessary to apply environmental user charges to

this substance as an alternative or additional means of achieving effective risk management.

Accordingly, no report has been made to the Minister for the Environment.

Review of controls for cost-effectiveness

The staff consider that the proposed controls are the most cost-effective means of managing the 7.15.

identified potential risks and costs associated with this substance.

8. Overall evaluation and recommendation

The benefits assessment indicated that there were non-negligible benefits of Mainman to human health, 8.1.

the environment and the local economy.

The risk assessment indicates that there is a negligible level of risk to society, community and the local 8.2.

economy when using Mainman with the proposed controls in place.

The cultural risk assessment indicated that there were potential impacts on kaitiakitanga, but that the 8.3.

default and additional controls could appropriately manage the cultural impacts of this substance, and

that approval of this application is unlikely to be inconsistent with the principles of the Treaty of

Waitangi.

26


February 2015

With the proposed controls in place, the overall level of benefit provided by the availability of Mainman 8.4.

will outweigh the overall risk. Therefore, it is recommended that the application be approved with the

controls documented in Appendix H, in accordance with clause 26 of the Methodology.

27


February 2015

Appendix A: Submissions received

The submissions received for Mainman are available on the EPA website at http://www.epa.govt.nz/search-

databases/Pages/applications-details.aspx?appID=APP202145#

(Click on the tag “Documents” of the webpage)

For future reference, the ‘keyword’ reference number for this application is APP202145.

http://www.epa.govt.nz/search-databases/Pages/applications-details.aspx?appID=APP202145

http://www.epa.govt.nz/search-databases/Pages/applications-details.aspx?appID=APP202145

28


February 2015

Appendix B: EPA standard risk descriptors

Table 2 shows the risk descriptors used by the staff. Risk descriptors are determined by a combination of

the magnitude of risk and the likelihood of it occurring. Table 3 shows the likelihood descriptors used, and

Tables 4 and 5 the magnitude descriptors used to assess risks and benefits respectively.

These tables are taken from Decision Making. A Technical Guide to Identifying, Assessing and

Evaluating Risks, Costs and Benefits (March 2009), ER-TG-05-02 03/09, further information about these

risk descriptors can be found in this document.

Table 2 Risk descriptors

Likelihood

Magnitude

Minimal Minor Moderate Major Massive

Highly improbable Negligible Negligible Negligible Low Low

Very unlikely Negligible Negligible Low Low Medium

Unlikely Negligible Low Low Medium Medium

Likely Low Low Medium Medium High

Highly likely Low Medium Medium High High

Table 3 Likelihood Descriptors

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 (occasional) Could occur, but is not expected to occur under normal operating conditions

Likely A good chance that it may occur under normal operating conditions.

Highly likely Almost certain, or expected to occur if all conditions met

29


February 2015

Table 4 Magnitude of adverse effect

Descriptor Examples of descriptions

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

30


February 2015

Table 5 Magnitude of beneficial effect

Descriptor Examples of descriptions

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)

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

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 the 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

31


February 2015

Appendix C: Classification of Mainman

Unless otherwise noted, all studies were conducted according to Good Laboratory Practice (GLP) and were

fully compliant with all requirements of the standard international test methods used. The classifications for

Mainman are shown in Table 6.

Data quality – overall evaluation

It is acknowledged 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 Programme11

, REACH12,

and European Regulation 1107/2009/EC13

are progressively working

towards filling these data gaps. As new information becomes available the staff will update the Hazardous

Substances and New Organisms (HSNO) classifications for those substances.

Table 6 Applicant and staff classifications of the mixture

Hazard Class/Subclass

Mixture classification Method of

classification

Remarks Applicant’s

classification

Staff’s

classification

Mix

ture

data

Read

acro

ss

Mix

ture

rule

s14

Class 1 Explosiveness No No Expert statement

instead of test

Class 2, 3 & 4 Flammability No No

Class 5 Oxidisers/Organic

Peroxides No No

Expert statement

instead of test

Subclass 8.1 Metallic

corrosiveness No ND

Subclass 6.1 Acute toxicity (oral) 6.1E No

The applicant based

this on the data for

the active not for

Mainman

Subclass 6.1Acute toxicity No No

11 OECD (1990) Manual for Investigation of HPV Chemicals. Retrieved on 23 January 2008 at http://www.icca-chem.org/Home/ICCA-

initiatives/High-production-volume-chemicals-initiative-HPV/

12 http://ec.europa.eu/environment/chemicals/reach/reach_intro.htm

13 http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2009:309:0001:0050:EN:PDF

14 Use of mixture rules may not adequately take into account interactions between different components in some circumstances and

must be considered of lower reliability than substance (formulation) data.

http://www.icca-chem.org/Home/ICCA-initiatives/High-production-volume-chemicals-initiative-HPV/

http://www.icca-chem.org/Home/ICCA-initiatives/High-production-volume-chemicals-initiative-HPV/

http://ec.europa.eu/environment/chemicals/reach/reach_intro.htm

http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2009:309:0001:0050:EN:PDF

32


February 2015

(dermal)

Subclass 6.1 Acute toxicity

(inhalation) No No

Subclass 6.1 Aspiration hazard No

Subclass 6.3/8.2 Skin

irritancy/corrosion No No

Subclass 6.4/8.3 Eye

irritancy/corrosion No 6.4A

The applicant and the

study author did not

consider that the

formulation should be

classified as an eye

irritant, based on

European Union

classification criteria.

However the HSNO

criteria for 6.4A

classification are met

(mean Draize score

≥1, but <3, for corneal

opacity.)

Subclass 6.5A Respiratory

sensitisation No ND

Subclass 6.5B Contact

sensitisation No No

Subclass 6.6 Mutagenicity No ND

Subclass 6.7 Carcinogenicity No ND

Subclass 6.8 Reproductive/

developmental toxicity No ND

Subclass 6.8 Reproductive/

developmental toxicity (via

lactation)

No ND

Subclass 6.9 Target organ

systemic toxicity15

6.9B ND

The applicant

anticipated that

flonicamid would be

classified 6.9B but

staff have not applied

this classification to

flonicamid.

Subclass 9.1 Aquatic ecotoxicity 9.1D based on

biocidal action No

Given the 9.3C

classification there is

15 When appropriate include separate rows to address single as well as repeat dose target organ toxicity, and any of the relevant routes

oral, dermal or inhalation.

33


February 2015

no need for 9.1D

biocidal classification

Subclass 9.2 Soil ecotoxicity No No

Subclass 9.3 Terrestrial

vertebrate ecotoxicity No 9.3C

Flonicamid and

component E

Subclass 9.4 Terrestrial

invertebrate ecotoxicity No No

ND: No Data or poor quality data (according to Klimisch criteria16

) --> There is lack of data. No: Not Classified based on actual relevant data available for the substance --> The data are conclusive and indicate the threshold for classification is not triggered

Physico-chemical properties of the mixture Table 7 Physical and chemical properties of the mixture

Property Results Test method Klimisch Score

(1-4) Reference

Colour brown Visual

observation 1

B. de Ryckel (2005) Shelf-

life stability of IKI-220

50%WG. Walloon

Agricultural Research centre

(CRA-W) Pesticides

Research Department B-

5030 Gembloux- Belgium.

Report number: ISK/FO

20353/Ch.2531/2001/207

Physical state

Free flowing

cylindrical

granules

Visual

observation 1

Odour Slight odour of

ammonia - 1

Oxidizing properties

Does not

contain

oxidizing

components

Expert

Statement 1

U Schmiedel (2001) Expert

statement on the oxidizing

properties of IKI-220 50%

WG. RCC Ltd,

Environmental Chemistry &

Pharmanalytics Division.

CH-4452 Itingen Switzerland

Report no 834107

pH 8.3 (1% in

distilled water) CIPAC MT 75.2 1



50%WG. Walloon


(CRA-W) Pesticides




20353/Ch.2531/2001/207

16 Klimisch,, H-J., Andrear, M., & U. Tillmann, 1997. A systematic approach for evaluating the quality of experimental toxicological and

ecotoxicological data. Reg. Toxicol. Pharmacol. 25, 1–5 (1997)

34


February 2015

Explosive properties

Does not

contain

explosive

components

Expert

Statement 1


statement on the explosive

properties of IKI-220 50%

WG. RCC Ltd,


Pharmanalytics Division.

CH-4452 Itingen Switzerland

Report no 834096

Tap Density

0.543 g/mL

before

compaction,

0.582 g/mL

after

compaction

CIPAC MT 169 1



50%WG. Walloon


(CRA-W) Pesticides




20353/Ch.2531/2001/207

Particle size distribution

90% particles >

250 µm

10% particles <

850 µm

CIPAC MT 170 1

Dustiness

Collected dust

9.2 mg: nearly

dust free

CIPAC MT 171 1

Attrition resistance and

friability of granules 97.1% CIPAC MT 178 1

Flammability

Does not

contain

flammable

components

Evaluation of the

classification of the

components

Mammalian toxicology - Robust study summaries for the mixture

Acute toxicity [6.1]

Acute Oral Toxicity [6.1 (oral)]

In the following study summaries Mainman is referred to as IKI-220 50%WG.

Acute toxicity



Type of study Acute oral limit toxicity test in rats

Flag Key study

Test Substance IKI-220 50%WG, Batch No. N88-0012-1

Endpoint LD50

35


February 2015

Value >2000 mg/kg bw (limit dose)

Reference Damme, B., IKI-220 50%WG, Acute oral toxicity study in rats, RCC Ltd,

Toxicology Division, Switzerland, 2001. ISK Document No.2606-822633

Klimisch Score 1

Amendments/Deviations None

GLP Y

Test Guideline/s OECD 423, 96/54/EEC, US EPA OPPTS 798.1175

Species Rat

Strain Han Brl: WIST

No/Sex/Group 3M and 3F

Dose Level 2000 mg/kg bw

Exposure Type Oral gavage

Study Summary There were no deaths, no adverse signs of reaction to treatment or any

macroscopic changes evident at necropsy.

Additional Comments No additional comments

Conclusion

IKI-220 50%WG should not be classified for 6.1 (oral), based on the lack of

adverse effects at the limit dose used in this study (Section 10.2; User Guide for

Thresholds and Classifications; EPA0109, 2012).

Acute Dermal Toxicity [6.1 (dermal)]

Type of study Acute dermal limit toxicity test in rats

Flag Key study


Endpoint LD50


Reference Damme, B., IKI-220 50%WG, Acute dermal toxicity study in rats, RCC Ltd,


Klimisch Score 1


GLP Y


Species Rat

36


February 2015

Strain HanBrl: WIST



Exposure Type Dermal to clipped skin (≥ 10% body surface area) with semi-occlusive dressing for

24 hours

Study Summary

There were no deaths. Slight spots of erythema were noted in 2 females on Days

2 and 3 and a single male on Day 2. There were no other clinical findings or any

macroscopic changes at necropsy


Conclusion

IKI-220 50%WG should not be classified for 6.1 (dermal), based on the lack of

adverse effects at the limit dose used in this study (Section 10.2; User Guide for


Acute Inhalation Toxicity [6.1 (inhalation)]

Type of study Acute inhalation limit toxicity test in rats (4-hour, nose only)

Flag Key study


Endpoint LC50

Value >5.360 mg/l (chemically determined mean concentration of formulated test item in

the test atmosphere)

Reference Decker, U., IKI-220 50%WG, 4-hour acute inhalation toxicity study in rats, RCC

Ltd, Toxicology Division, Switzerland, 2002. ISK Document No.2619-822666

Klimisch Score 1

Amendments/Deviations None of any significance

GLP Y


Species Rat

Strain HanBrl: WIST


Dose Level

5.360 mg/l

mass median aerodynamic diameters and (geometric standard deviations) were

3.09 µm (3.29) and 3.07 µm (3.18) respectively (measured on two occasions)

Exposure Type 4h nose only – dust aerosol

Study summary There were no deaths. Clinical signs consisted of bradypnea, rales (noisy

37


February 2015

breathing), red secretion from the nose, decreased activity, ruffled fur and

hunched posture observed from 1 hour after the end of treatment through to Day1

post exposure. Salivation was noted during the exposure period only. Bradypnea

and particularly rales persisted in both sexes for up to 9 days after exposure

before resolving. Marked transient weight loss was evident in all males and 4

females, the remaining female showing moderate weight loss during the first 3

days after exposure; however, recovery was evident by Day 8. There were no



Conclusion

IKI-220 50%WG should not be classified for 6.1 (inhalation), based on the lack of

adverse effects at the limit concentration used in this study (Section 10.2; User

Guide for Thresholds and Classifications, EPA 0109, 2012).

Skin Irritation [6.3/8.2]

Type of study Dermal irritation/corrosion study in rabbits

Flag Key study


Endpoint Skin irritation (mean of Draize scores at 24, 48 and 72 hours)

Value Non-irritant: 0.0 for erythema and oedema

Reference Arcelin, G., IKI-220 50%WG, Primary skin irritation study in rabbits, RCC Ltd,


Klimisch Score 1


GLP Y

Test Guideline/s OECD 404, EEC B.4, US EPA OPPTS 870.2500

Species Rabbit

Strain New Zealand White


Dose Level 0.5 g (moistened with distilled water)

Exposure Type 4h dermal, semi occlusive then rinsed

Study Summary There were no skin reactions in any animal. Scores for erythema/eschar and

oedema were 0 for all observations


Conclusion IKI-220 50%WG should not be classified for 6.3 (skin irritation) based on the

38


February 2015

results from this study (Section 11.2; User Guide for Thresholds and

Classifications; EPA0109, 2012).

Eye Irritation [6.4/8.3]

Type of study Eye irritation/corrosion study in rabbits

Flag Key study


Endpoint Eye irritancy (mean of Draize scores at 24, 48 and 72 hours)

Value Irritant: 1.78 conjunctival redness, 1.22 corneal opacity, 1 chemosis, 0 iritis

Reference Arcelin, G., IKI-220 50%WG, Primary eye irritation study in rabbits, RCC Ltd,


Klimisch Score 1


GLP Y

Test Guideline/s OECD 405, EEC B.5, US EPA OPPTS 870.2400

Species Rabbit



Dose Level 0.1 g undiluted

Exposure Type Ocular

Study Summary

Corneal opacities were seen in all animals from 24 hours after exposure persisting

to Day 10 post exposure in the male, Day 14 in one female and Day 2 in the

remaining female. There was no iritis. Slight to moderate reddening of the

conjunctivae was seen in the male from 1 hour to Day10 after treatment and from

1 hour to Day 7 or Day14 in the two females. Swelling of the conjunctivae (with

partial eversion of the lids or lids half closed) was evident in all animals 1 hour

after treatment. Swelling persisted in 2 animals for up to 72 hours and 24 hours in

the remaining animal. The mean scores were: corneal opacity 1.22, iritis 0,

conjunctivae redness 1.78 and chemosis 1


Conclusion

IKI-220 50%WG should be classified for 6.4 (eye irritation) based on the results

from this study (mean scores for corneal opacity above the threshold for

classification) (Section 12.2; User Guide for Thresholds and Classifications;

EPA0109, 2012).

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February 2015

Contact Sensitisation [6.5]

Type of study Sensitisation – modified Buehler test in guinea pigs

Flag Key study


Endpoint Contact sensitisation on challenge

Value Non sensitiser: <thresholds (negative)

Reference

Arcelin, G., IKI-220 50%WG, Contact hypersensitivity in albino guinea pigs, Buhler

test, RCC Ltd, Toxicology Division, Switzerland, 2002. ISK Document No. 2611-

823882

Klimisch Score 1


GLP Y

Test Guideline/s OECD 406, EEC B.5, US EPA 870.2600

Species Guinea pig

Strain Ibm: GOHI (Himalayan spotted)

No/Sex/Group 10F control group, 20F treated group

Dose Levels 15% in distilled water, once per week for 3 weeks induction phase. 15% in distilled

water for challenge (maximum non-irritating concentration)

Exposure Type Dermal – 6 hours

Study Summary

No skin reactions were evident after the challenge dose. Comparison was against

concurrent laboratory background data using the positive control 2-

mercaptobenzothiazole


Conclusion

IKI-220 50%WG should not be classified for 6.5B (contact sensitisation) based on

the results from this study (Section 13.2; User Guide for Thresholds and


General conclusion about acute toxicity classification:

IKI-220 50%WG was shown to have low acute toxicity to rats by the oral, dermal and inhalation routes, and

should be not classified: 6.1 (oral), 6.1 (dermal) or 6.1 (inhalation) (Table 10.1; User Guide for Thresholds

and Classifications; EPA0109, 2012).

IKI-220 50%WG was shown not to induce skin irritation of sufficient severity to require classification for 6.3,

however the scores for eye irritation are slightly over the threshold for classification and therefore IKI-220

40


February 2015

50%WG should be classified 6.4 (Sections 11.2 and 12.2; User Guide for Thresholds and Classifications;

EPA0109, 2012).

IKI-220 50%WG was shown not to have contact sensitisation potential, and should not be classified for 6.5B

(contact sensitisation) (Section 13.2; User Guide for Thresholds and Classifications; EPA0109, 2012).

Dermal absorption

The applicant submitted two dermal absorption studies with IKI-220 50%WG. The first was conducted at a

concentration similar to the lowest field use dilution (0.4 g flonicamid/L), while the second was conducted at

the highest field use dilution (0.07 g flonicamid/L).

Type of study Percutaneous penetration study with human skin in vitro

Flag Key study

Test Substance Field use dilution of [14

C]-IKI-220 50% WG, Lot No. CP-2173

Reference

Roper, C. S., The in vitro percutaneous absorption of radiolabelled

insecticide [14

C]-IKI-220 50% WG at one concentration (worst case

concentration field dilution) of a test preparation through human skin,

Inveresk Research, Scotland, 2005. ISK Document No. 2629

Klimisch Score 1


GLP Y

Test Guideline/s OECD 428, EEC Sanco/222/rev.6 2004

Test system/Dose levels

[14

C]-IKI-220 was applied in a single preparation (in-use spray dilution, ca

0.4g IKI-220.L-1

) to split-thickness skin membranes mounted in flow

through diffusion cells in-vitro. The dose was 10 µL.cm2 to give a target

application rate of IKI-220 of 0.4 µg.cm2 for 6 hours. Absorption was

assessed over 0 – 48 hours

Study Summary

[14

C]-IKI-220 was applied topically to human skin in vitro at a single

concentration (in-use spray dilution, ca 0.4g IKI-220/L). Most of the applied

dose was washed off the skin at 6 hours post dose with 92.52% of the

dose recovered in the 6h mean skin wash and tissue swab combined. At

6h post dose, the mean absorbed dose was 4.22% (0.18 µg equiv.cm2). At

48 hours post dose the mean absorbed dose and dermal delivery were

7.31% (0.31 µg equiv.cm2) and 7.46% (0.31 µg equiv.cm

2) respectively.

Additional Comments

Reviewers comment: the study report claims that the dilution tested was

the worst case field use dilution. However, a higher dilution is now

proposed for use of IKI-220 50% WG.

Conclusion Penetration of IKI-220 50%WG through human skin membranes was at a

41


February 2015

negligibly low rate and extent at the ‘worst case scenario in use spray

dilution’.

Type of study Percutaneous penetration study with human skin in vitro

Flag Key study

Test Substance Field use dilution of IKI-220 50% WG containing 3H-IKI-220

Reference

Gelis, C., In vitro percutaneous absorption of IKI-220. ADME

BIOANALYSES 75, chemin de Sommières, 30310 VERGEZE, France,

2005. ISK Document No. UL-2632.

Klimisch Score

Amendments/Deviations None considered to impact the integrity of the study

GLP Y

Test Guideline/s OECD 428

Test system/Dose levels

Rat and human split-thickness skin membranes

Highest in use dilution (0.07 g IKI-220/L)

10 mg/cm2 of formulation applied for 6 hours

Four static cells per species with continuous stirring

Study Summary

The diluted formulation was applied to the surface of dermatomed rat and

human skin mounted in static cells. Six hours after application the

formulation remaining on the skin surface was removed. Receptor fluid

was collected 1, 2, 4, 7, 8 and 24 hours after application.

Mean recoveries were 95.68% and 95.43% in humans and rats,

respectively.

The dermal penetration of IKI-220 was calculated based on the sum of

radioactivity measured in the stratum corneum, epidermis, dermis and

receptor fluid. Dermal penetration was 47.34% in rat skin and 12.83% in

human skin.

Additional Comments None

Conclusion Dermal penetration of IKI-220 is 12.83% and 47.34% in human and rat

skin, respectively.

Conclusion on dermal absorption

The dermal penetration of IKI-220 formulated as IKI-220 50% WG in human skin was 7% at the lowest field

use dilution of 0.4 g IKI-220/L. At the highest field use dilution of 0.07 g IKI-220/L, the dermal absorption in

human skin was 13%.

42


February 2015

Ecotoxicity - Robust study summaries for the mixture

In the following summaries Mainman is called IKI-220 50% WG.

Aquatic toxicity

Fish Acute Toxicity (Freshwater Species)

Type of study Full test

Flag Key study

Test Substance Formulation: IKI-220 50% WG

Species Oncorhynchus mykiss (Rainbow trout)

Type of exposure Semi-static for 96 hours. Renewal after 48 hours

Endpoint LC50

Value > 100 mg/L

Reference

A. Peither (2002) Acute toxicity of IKI-220 50% WG to Rainbow trout

(Oncorhynchus mykiss) in a 96-hour semi-static test. RCC Ltd, Environmental

Chemistry & Pharmanalytics Division. CH-4452 Itingen Switzerland. Report no

823307.

Klimisch Score 1


GLP Yes

Test Guideline/s OECD 203 (1992)

No/Group 7

Dose Levels 6.3, 12.5, 25, 50 and 100 mg/L

Analytical measurements

Yes from fresh medium on day 0 and at 48 h and from the old medium at 48 and

96 hours, by HPLC. All concentrations were analysed except 6.3 and 12.5 mg/L

because they were below the NOEC.

Study Summary

The acute toxicity of the test substance to rainbow trout was determined in a 96-hr

semi-static test. The test concentrations were 6.3, 12.5, 25, 50 and 100 mg/L.

The measured concentrations in the test medium were 94-101% of the nominal at

the start and at the end of the test substance so the results are expressed as

nominal concentrations.

The pH values in the test medium and in the control ranged from 7.8 to 8.0, the

oxygen concentration was always higher than 60% oxygen saturation (it was 7.3

mg/L or above) and the temperature was in the range of 13-15oC.

No mortalities were observed in any group.

43


February 2015

In the control and in the test concentrations up to 25 mg/L, no visible

abnormalities were observed, at 50 mg/L 1 fish was apathetic and at 100 mg/L, all

test fish showed symptoms of toxicity (apathy, tumbling during swimming, fish at

the bottom of the aquarium).

The LC50 is higher than 100 mg/L corresponding to > 51 mg a.i./L.

Conclusion The LC50 is higher than 100 mg/L (corresponding to > 51 mg a.i./L). No

mortality observed at 100 mg/L

Invertebrates Acute Toxicity (Freshwater Species)

Type of study Limit test

Flag Key study

Test Substance Formulation: IKI-220 50% WG

Species Daphnia magna

Type of exposure Static for 48 hours.

Endpoint EC50

Value > 100 mg/L

Reference

A. Peither (2002) Acute toxicity of IKI-220 50% WG to Daphnia magna in a 48-

immobilisation test. RCC Ltd, Environmental Chemistry & Pharmanalytics

Division. CH-4452 Itingen Switzerland. Report no 823320.

Klimisch Score 1


GLP Yes


No/Group 2 replicates of 10

Dose Levels 100 mg/L

Analytical measurements Yes from fresh medium on day 0 and at 48 h, by HPLC.

Study Summary

The acute toxicity of the test substance to Daphnia magna was determined in a

48-hr static test. A limit test was performed at 100 mg/L. The measured

concentrations in the test medium were 99-102% of the nominal at the start and at

the end of the test substance so the results are expressed as nominal

concentrations.




No immobilised or dead animals were observed in any group.

The EC50 is higher than 100 mg/L corresponding to > 51 mg a.i./L.

44


February 2015

Conclusion The EC50 is higher than 100 mg/L (corresponding to > 51 mg a.i./L). No

immobilisation observed at 100 mg/L

Algae Acute Toxicity (Freshwater Species)


Flag Key study

Test Substance IKI-220 50% WG

Species Pseudokirchneriella subcapitata

Type of exposure Static, 72 hours

Endpoint ErC50 and EbC50

Value > 100 mg/L (ErC50)

Reference

A. Peither (2002) Acute toxicity of IKI-220 50% WG to Pseudokirchneriella

subcapitata (formerly Selenastrum capricornutum) in a 72-hour algal growth

inhibition test. RCC Ltd, Environmental Chemistry & Pharmanalytics Division. CH-

4452 Itingen Switzerland. Report no 823342.

Klimisch Score 1


GLP Yes


No/Group 3 replicates for test concentrations and 6 for the control of 104 cells/mL

Dose Levels 4.6, 10, 22, 46 and 100 mg/L

Analytical measurements Yes, from fresh medium on day 0 and at 72 h, by HPLC. The concentrations

below 22 mg/L were not analysed because they are below the NOEC.

Study Summary

The influence of the test substance on the growth of the green algal species

Pseudokirchneriella subcapitata was determined in a 72-hr static test. The

nominal concentrations were 4.6, 10, 22, 46 and 100 mg/L. The measured

concentrations in the test medium were 103-108% of the nominal at the start and

at the end of the test substance so the results are expressed as nominal

concentrations.

The pH values in the test medium and in the control ranged from 7.9 to 8.0 at the

start of the study and from 8.1 to 9.3 at the end, and the temperature was 23oC.

The growth rate in the control was valid according to the guideline (at least a

factor of 16).

The test substance had a statistically significant inhibitory effect on the growth

(biomass and growth rate) at the concentration of 46 mg/L and above. The NOEC

was 22 mg/L (corresponding to 11 mg ai/L) and ErC50 is > 100 mg/L

45


February 2015

(corresponding to > 51 mg ai/L), EbC50 = 85 mg/L (corresponding to 43 mg ai/L).

Conclusion ErC50 is > 100 mg/L (corresponding to > 51 mg ai/L), EbC50 = 85 mg/L

(corresponding to 43 mg ai/L).

Other study

Type of study Activated sludge respiration inhibition

Flag Key study

Test Substance IKI-220 50WG

Species Activated sludge of a wastewater treatment plant treating predominantly domestic

wastewater

Type of exposure 3 hours

Endpoint EC50

Value > 1000 mg/L

Reference

I Gruetzner (2002) Toxicity of IKI-220 50% WG to activated sludge in a respiration

inhibition test. RCC Ltd Environmental Chemistry & Pharmanalytics division CH-

4452 Itingen Switzerland. Report number 834118

Klimisch Score 1


GLP Yes


No/Group 1 replicates for test concentration and 2 for the control

Dose Levels 12, 32, 100, 320 and 1000 mg/L

Analytical measurements Not required

Study Summary

The inhibitory effect of the test item IKI-220 50% WG on the respiration rate of

aerobic wastewater microorganisms of activated sludge was investigated in a 3-

hour respiration inhibition test

The following nominal concentrations were tested: 12, 32, 100, 320 and 1000

mg/L.

In addition, two controls and three different concentrations of the reference item

3,5-dichlorophenol (5, 16 and 50 mg/L) were tested in parallel. The results of

these treatments confirmed the suitability of the activated sludge and the method

used.

Up to and including the highest concentration of 1000 mg/L, the test substance

had no significant inhibitory effect ( <15%) on the respiration rate of activated

sludge after the incubation period of three hours. Thus, the 3-hour NOEC is 1000

mg/L. EC50 is higher than 1000 mg/L.

46


February 2015

Conclusion EC50 is higher than 1000 mg/L.

General conclusion about aquatic toxicity classification:

Mainman exhibits a very low aquatic toxicity. No classification is triggered except a 9.1D for biocidal activity

which doesn’t apply because Mainman is also classified as 9.3C.

Soil toxicity

Non-Target Plant Toxicity

Study type Seedling emergence

Flag Key study


Species

Cucumber (Cucumis sativus), corn (Zea mays), soybean (Glycine max), oats

(Avena sativa), tomato (Lycopersicon esculentum), radish (Raphanus sativus),

cabbage (Brassica oleracea), perennial ryegrass (Lolium perenne), carrot

(Daucus carotta), lettuce (Lactuca sativa), onion (Alium cepa)

Type of exposure Application to the soil surface

Endpoint Effects on emergence, heights and dry weight of seedling

Value No effects at 150 g ai/ha

Reference

E.R. Stewart (2002) Tier 1 seedling emergence study assessing IKI-220 50% WG

formulation. Stewart Agricultural Research Services Inc. 1893 Highway K

Clarence, Missouri 63437. Study number IB-2002-MG-003-00-00

Klimisch Score 1

Amendments/Deviations None that impacted the test results

GLP Yes

Test Guideline/s OPPTS 850.4000 and OPPTS 850.4100 (drafts, 1996)

No/Group 5 replicates of 10 seeds

Dose Levels 150 g ai/ha


Study Summary

Replicates of 10 seeds of 7 dicotyledons species and 4 monocotyledons species

were planted in a sandy loam. Then the test substance was applied on soil

surface at a dose corresponding to 150 g ai/ha. The pots were incubated in

greenhouse conditions. Seedling emergence was assessed at 10, 14 and 21

days after planting and application. Seedlings were also examined for phytotoxic

effects or abnormalities at the same intervals. At the end of the test (21 days),

plant height was measured and dry weight was determined.

No phytotoxic symptoms or abnormalities were detected among treated plots or

47


February 2015

non-treated control. No significant differences were observed on average height

or on average dry weight of any species included in the test.

Conclusion No effects at 150 g ai/ha

Study type Vegetative vigour

Flag Key study


Species

Cucumber (Cucumis sativus), corn (Zea mays), soybean (Glycine max), oats

(Avena sativa), tomato (Lycopersicon esculentum), radish (Raphanus sativus),

cabbage (Brassica oleracea), perennial ryegrass (Lolium perenne), carrot

(Daucus carotta), lettuce (Lactuca sativa), onion (Alium cepa)

Type of exposure Application on seedlings

Endpoint Effects on heights and dry weight of seedling, + phytotoxicity effects

Value No detrimental effects at 150 g ai/ha

Reference

E.R. Stewart (2003) Tier 1 vegetative vigour study assessing IKI-220 50% WG

formulation. Stewart Agricultural Research Services Inc. 1893 Highway K

Clarence, Missouri 63437. Study number IB-2002-MG-004-00-00

Klimisch Score 2: no information on the number of plants per replicates

Amendments/Deviations

The minimum number of plant per replicates (5 for dicots and 10 for monocots)

was not reached for some species and some replicates. No information in the

report about the actual number.

GLP Yes

Test Guideline/s OPPTS 850.4000 and OPPTS 850.4150 (drafts, 1996)

No/Group 5 replicates of an unknown number of plants

Dose Levels 150 g ai/ha


Study Summary

7 dicotyledons species and 4 monocotyledons species were planted in a sandy

loam. Then the test substance was applied on seedlings (growth stage tillering for

oat and ryegrass, and 2 to 5-6 leaves for the other species) at a dose

corresponding to 150 g ai/ha. The pots were incubated in greenhouse conditions.

Plant heights were recorded just before application and at 15 days after

application. Plants were also examined for phytotoxic effects or abnormalities at

the 7 and 15 days. At the end of the test (16 days), dry weight was determined.

No phytotoxic symptoms or abnormalities were detected among treated plots or

non-treated control. No significant differences were observed on average height

48


February 2015

of any species included in the test.

Analysis of dry weights indicated a slight increase in ryegrass treated by the test

substance (0.425 g and 0.351 g for treated and controls plants, respectively).

There was no other effect on dry weight on any of the other species.

Conclusion No detrimental effects at 150 g ai/ha

Study type Effects on adjacent crops and succeeding crops

Flag Disregarded study

Test Substance IKI-220 50 WG

Species

Effects on adjacent plants: beet, lettuce, maize, melon, oat, oil seed rape, pea,

soybean, wheat, pepper, eggplant

Succeeding crops: beet, cucumber, eggplant, lettuce, maize, melon, oat, oil seed

rape, pea, pepper, soybean, wheat, turnip, kidney bean, flax, onion, barley

Type of exposure Effects on adjacent plants: foliar spray

Succeeding crops: soil treatment prior sowing

Endpoint Phytotoxicity

Value None observed

Reference

M Morita & M Iwasa (2002) Impact of IKI-220 50 WG (IBE-3894) on adjacent

crops and succeeding crops. Ishihara Sangyo Kaisha Ltd. Central Research

Institute. Agrochemical Research Laboratory, Biology Group.3-1, 2-Chome, Nishi-

shibukawa; Kusatsu-shi, Shiga-ken, 525-0025 Japan. Report no AL-0201-I-08

Klimisch Score

3 not GLP, no guideline followed, visual assessment of phytotoxicity only, no

biomass endpoint. Monocotylodons are under-represented. Very few details in

the report


GLP No

Test Guideline/s None followed

No/Group

Not clear from the report. 6 replicates are mentioned for adjacent crops but no

information about the number of plant per replicate.

Succeeding crops: 5 to 20 plants per pot, no mention about the number of pot per

group.

Dose Levels

Effects on adjacent plants: 100 or 200 g ai/ha with volumes of 300, 500 and 1200

L/ha

Succeeding crops: 100 or 300 g ai/ha

Analytical measurements No

49


February 2015

Study Summary

Adjacent plants: plants grown in pots were treated with a spray solution of the

substance at 100 or 200 g ai/ha. All spray solutions were applied at volumes

rates of 300, 500 or 1200 L/ha using spray gun. After application the plants were

kept in a glasshouse. Phytotoxicity was visually assessed on days 7 and 14.

No phytotoxicity was observed in any conditions.

Succeeding crops: soil was treated with the spray solution of the substance at 100

or 300 g ai/ha using a flat spray tip. Seeds were sown in the treated soil; pots

were kept in a glasshouse. Phytotoxicity was visually assessed after 2, 3 and 4

weeks.

No phytotoxicity was observed in any conditions.

Conclusion No phytotoxicity observed after foliar application or soil treatment

Nitrogen Transformation Test

Study type Effects on nitrogen transformation

Flag Key study


Species Soil microflora

Type of exposure Static for 28 days

Endpoint Soil nitrogen content (nitrate, nitrite, ammonium, mineral nitrogen)

Value No significant long term effect

Reference

K-H Reis (2002) Effects of IKI-220 50% WG on the activity of the soil microflora in

the laboratory. IBACON GmbH Arheilger Weg 17 64380 Rossdorf Germany.

Report no 10722080

Klimisch Score 1

Amendments/Deviations None that impacted the results of the study

GLP Yes


No/Group 3 replicates

Dose Levels

0.104 mg/kg (corresponding to the worst case of 80 g ai)/ha for 1 application with

50 % foliage interception of IKI-220 50 % WG at 40 g ai)/ha) and 0.274 mg/kg soil

dry weight (corresponding to 3-times 70 g ai)/ha with 50 % foliage interception of

IKI-220 50 % WG at 105 g (ai)/ha).

Analytical measurements None required

Study Summary

The effects of the substance applied at 0.104 mg/kg and 0.274 mg/kg soil dry

weight on the soil nitrogen transformation of the soil micro-flora were tested in the

laboratory at 20 ± 2°C in the dark. At different sampling times (0, 7, 14 and 28

50


February 2015

days), the soil nitrogen content was determined.

The differences between the soil nitrogen content (nitrate-N) of the IKI-220 50%

WG treated soil and control was less than the trigger value of 25% according to

the OECD guideline 216 at days 0, 14 and 28.

At day 28 after application, the differences between the soil nitrate content of both

IKI-220 50% WG treated soils and control were 14.1% and 6.34% respectively.

The differences were statistically significant, but below the 25% threshold.

At day 28; the difference to control in mineral soil nitrogen content was clearly

below the trigger value of 25%.

The deviation of replicate control samples was below 15% at every sampling date

so the validity criteria were met.

Conclusion No long term influence on soil micro-flora when IKI-220 50% WG is applied

up to 0.274 mg/kg soil dry weight.

Carbon Transformation Test

Study type Effects on carbon transformation

Flag Key study


Species Soil microflora

Type of exposure Static for 28 days

Endpoint CO2 production

Value No significant long term effect

Reference

K-H Reis (2002) Effects of IKI-220 50% WG on the activity of the soil microflora in

the laboratory. IBACON GmbH Arheilger Weg 17 64380 Rossdorf Germany.

Report no 10722080

Klimisch Score 1


GLP Yes



Dose Levels

0.104 mg/kg (corresponding to 80 g ai)/ha for 1 application with 50 % foliage

interception of IKI-220 50 % WG at 40 g ai)/ha) and 0.274 mg/kg soil dry weight

(corresponding to 3-times 70 g ai)/ha with 50 % foliage interception of IKI-220 50

% WG at 105 g ai)/ha ).

Analytical measurements None required

Study Summary The effects of the substance applied at 0.104 mg/kg and 0.274 mg/kg soil dry

51


February 2015

weight on the carbon mineralisation of the soil micro-flora were tested in the

laboratory at 20 ± 2°C in the dark. At different sampling times (0, 7, 14 and 28

days), the soil respiration rate was determined.

The soil respiration rates of IKI-220 50% WG treated soils were clearly below the

OECD guideline 217 trigger value of 25 % at every sampling date.

At day 28 after application, the differences between the respiration rates of IKI-

220 50% WG treated soil and control was 0.88% and 7.90% respectively. The

difference to control of the 1st rate group was not statistically significant different,

whereas the difference of the 2nd rate group was.

With exception of day 14, the deviation of replicate control samples was below 15

%.

Conclusion No long term influence on soil micro-flora when IKI-220 50% WG is applied

up to 0.274 mg/kg soil dry weight.

General conclusion about soil toxicity classification:

No information is available on other organisms than plants so mixture rules will be used to classify Mainman.

Toxicity to terrestrial invertebrates

Bees - Laboratory Tests (acute oral and contact)

Study type Acute toxicity

Flag Supporting study


Species Apis mellifera

Type of exposure Oral or contact, for 48 or 96 hours (oral test)

Endpoint LD50

Value Contact: > 100 µg/bee

Oral: > 104.3 µg/bee

Reference

S Schmitzer (2002) Laboratory testing for toxicity (acute contact and oral) of IKI-

220 50% WG on honey bees (Apis mellifera L). IBACON GmbH Arheilger Weg 17

64380 Rossdorf Germany. Report no 10721036

Klimisch Score

1 for the contact test

3 for the oral test: no dose response relationship is observed in the test,

consequently it is impossible to estimate a LD50. The value reported (> 104

µg/bee) is highly doubtful.


GLP Yes

Test Guideline/s EPPO 170 (1992)

52


February 2015

No/Group 3 replicates of 10 for the oral test

5 replicates of 10 for the contact test

Dose Levels Contact: 100 µg/bee

Oral: 6.8, 14.1, 28.0, 57.0, 104.3 µg/bee (actual intake)


Study Summary

The acute toxicity of the substance on honey bees was determined in a laboratory

test with oral and contact exposure.

In the contact test, 10% mortality was observed at 100 µg product/bee after 48

hours. Behavioural impairments like discoordinated movement and apathy was

observed during the whole experiment.

In the oral test, the observation period was extended for 48 hours up to 96 hours

because of delayed mortality in all dose groups.

Oral doses of 104.3, 57.0, 28.0, 14.1 and 6.8 µg/bee led to 53.3%, 30.0%, 26.7,

53.3 and 23.3%, respectively. Behavioural abnormalities attributed to the

substance were discoordinated movement and apathy observed during the whole

experiment. The control mortality was 3.3%.

Control mortality was below the validity criteria of the guideline.

Conclusion

LD50 Contact: > 100 µg/bee (corresponding to 51.1 µg ai/bee)

LD50 Oral: > 104.3 µg/bee (corresponding to 53.3 µg ai/bee) – Unreliable

results

Bees - Tunnel Tests

Study type Tunnel test

Flag Weight of evidence



Type of exposure Direct spray + exposure to residues on sprayed flowers

Endpoint Behaviour, mortality, development of colonies

Value Immediate repellent effect and slight increase of mortality the day of treatment.

High mortality due to direct spray

Reference

G Maurin (2000) Tunnel trail assessment of the product IBE 3894 – short-term

toxicity on honey bees. ACTA 149 rue de Bercy Paris, France. Study number

LYT0001

Klimisch Score 2, not GLP no statistical analysis, uneven behaviour of the bees between tunnels


GLP No

53


February 2015

Test Guideline/s CEB no 129 (1996)

No/Group 1 tunnel per group divided in 4 plots: 2 treated and 2 untreated used as refuge

Dose Levels 140 g IKI 220 50 WG/ha, “soft” reference: phosalone at 600 g ai/ha


Study Summary

A tunnel test was conducted with the test substance to evaluate the effects of a

spray at 140 g/ha on foraging activity, bee behaviour, mortality and development

of colony.

3 tunnels were used over an oil seed rape crop in flower. Each tunnel was divided

in 4 plots: 2 were treated and 2 were left untreated as refuge for foraging bees.

Phosalone at 600 g ai/ha was used as soft reference. Control tunnel was sprayed

with water.

Hives were placed in the tunnel 4 days prior treatment. Foraging activity and

behaviour were observed once to 5 times per day, mortality was assessed once a

day and the colony status was determined before treatment and at the end of the

test (6 days after application).

An immediate (at 1 hour after treatment) repellent effect was observed in the

tunnel treated by the test substance. There was a slight increase in mortality due

to the test substance which was much lower than the direct effect of the spray.

Ratio of mortality before and after treatment is 3.27 for the test substance and

1.26 and 2.18 for the control and the reference, respectively.

There was no noticeable effect on colony development due to the test substance.

Comment

Foraging activity was not similar between tunnels (high activity in control tunnel,

very low in reference tunnel), consequently the mortality which is usually related to

the foraging activity was much higher in the control tunnel. However, there is a

clear pattern in the tunnel treated with the test substance with an increase of

mortality due to the direct spray.

Conclusion Immediate repellent effect and slight increase of mortality the day of

treatment. High mortality due to direct spray





Type of exposure Direct exposure to spray, or exposure to residues on flowers

Endpoint Effects on foraging activity, behaviour, mortality colony development.

Value Direct spray of the substance on bees has an effect on mortality and behaviour on

54


February 2015

the first day. No effects when the substance was sprayed when bees were not

foraging.

Dubious effects on colonies exposed to the substance, recovery within 6 weeks

Reference

M. Barnavon (2003) Tunnel test – acute and short-term effects of IBE 3894 (IKI-

220 50%WG), applied on oil seed rape, on honey bees (Apis mellifera). SOLEVI

SARL 12 rue Felix Perrier 26400 Crest France. Study report: S03ISB.F01VO33

Klimisch Score 1

Amendments/Deviations Pollen collect was impossible due to the small size of the pollen balls

GLP Yes

Test Guideline/s CEB no 129 (2003), EPPO 170 (1992)

No/Group 1 tunnel per group divided in 4 plots: 2 treated and 2 untreated used as refuge

Dose Levels 150 g IKI 220 50 WG/ha, toxic reference: dimethoate at 365 g ai/ha


Study Summary


spray at 150 g product/ha on foraging activity, bee behaviour, mortality and

development of colony.

4 tunnels were used over an oil seed rape crop in flower. Each tunnel was divided

in 4 plots of 16 m2: 2 were treated and 2 were left untreated as refuge for foraging

bees.

Dimethoate at 365 g ai/ha was used as toxic reference. Control tunnel was

sprayed with water. The test substance was either applied in the morning when

bees were foraging, either in the late evening when no bees were foraging.


behaviour were observed once a day except on the treatment day (15 min before

and after treatment and 60 min after treatment), mortality was assessed once a

day and the colony status was determined before treatment and at the end of the

test (7 days after application).

In this study, during the adaptation phase bee mortality was medium. The day

before treatment, mortality was slightly higher in tunnel n°2 (treatment with the test

substance during foraging activity). In the water (control) tunnel, mortality was

stable after treatment except on day 6 after treatment where a peak was noticed

for all the tunnels. This peak was not treatment related but, most probably, due to

the high temperatures (up to 37° in the tunnels) these days. In the dimethoate

tunnel, mortality was very high after treatment and stayed still at a quite high level

in the following days.

In this context, for the test substance, a slight effect was only seen the day after

application when applied during foraging activity. When the substance was

55


February 2015

applied the same day but in the evening, when there was no more foraging

activity, there was no product effect. Differences in the tox index values of test

substance applied in the morning, in the evening and water were mainly due to

differences between colonies in the different tunnels except for the morning

application, 24 hours after application.

Tox Index = (Mt x Ta)/(Ma x Tt) where Mt and Ma are daily mortality in the treated

tunnel after and before treatment respectively and Tt and Ta are daily mortality in

the control tunnel after and before treatment respectively.

Tox index

Treatment 24 h 48 h 72 h 96 h 120 h

Dimethoate 41.7 23.4 18.3 10.8 8.9

Control 1.0 1.0 1.0 1.0 1.0

Morning

application

5.8 1.3 0.9 0.9 1.0

Evening

application

2.4 3.5 2.5 2.1 2.7

Thus, it is considered that the test substance has a weak effect on bee mortality

the day of application when the product is applied during foraging activity and then

this effect disappeared immediately. When it was applied out of foraging activity

period no effect was not seen.

Dimethoate had a strong and long impact on the foraging activity. The substance

had some impact on foraging activity in the hour following the application and then

this effect disappeared 4 hours after application and the following days when

applied during foraging activity. During this transient period, the observations

have shown that bees were presenting symptoms of loss of their equilibrium when

they tried to forage the flowers. This was not observed when the substance was

applied in the evening without foraging activity.

At the end of the exposure period, colonies belonging to the tunnels treated with

the test substance were slightly weakened compared to the colony belonging to

the water tunnel but stiII much lesser than the colony belonging to the dimethoate

tunnel. The queen activity was not disturbed. After return to the apiary, for the

last assessment, 6 weeks after treatment, colonies were recovering and at that

time only the colony having received the dimethoate treatment appeared as weak.

It was difficult to conclude that the effects seen in the substance tunnels were

product related.

Reserves and brood were reduced during the study in the four tunnels, which was

normal for beehives staying within a tunnel. This reduction was however higher in

the dimethoate tunnel. After return to the apiary, for the last assessment, 6 weeks

56


February 2015

after treatment, reserves were much higher in all the tunnels, much probably due

to the excellent weather conditions of the summer. The dimethoate colony was

still weaker than the others. There was no difference anymore between the three

other tunnels even if the colony belonging to the substance treatment out of

foraging activity period had a slight heterogeneous brood.

Conclusion

Direct spray of the substance on bees has an effect on mortality and

behaviour on the first day. No effects when the substance was sprayed

when bees were not foraging.

Dubious effects on colonies exposed to the substance, recovery within 6

weeks





Type of exposure Direct exposure to spray, and exposure to residues on flowers


Value Weak effect on mortality and on bee behaviour and foraging activity the day of

treatment

Reference


220 50%WG), applied on white mustard, on honey bees (Apis mellifera). SOLEVI


Klimisch Score 1

Amendments/Deviations Assessment of beehive after return to apiary not done due to bad weather

conditions

GLP Yes


No/Group 2 tunnels for the treated group, 1 tunnel for water control divided in 4 plots: 2

treated and 2 untreated used as refuge

Dose Levels 160 g IKI 220 50 WG/ha


Study Summary


spray at 160 g product /ha on foraging activity, bee behaviour, mortality and


3 tunnels were used over a white mustard crop in flower. Each tunnel was divided

57


February 2015

in 4 plots of 16 m2: 2 were treated and 2 were left untreated as refuge for foraging

bees.

Control tunnel was sprayed with water. The test substance was applied early in

the afternoon when bees were foraging.



treatment and 15 min after treatment), mortality was assessed once a day and the

colony status was determined before treatment and at the end of the test (11 days

after application).

In this study, during the adaptation phase bee mortality was quite low. The

adaptation period was long due to the limited evolution of the crop stage (fresh

weather conditions).

The product effect was only seen immediately after application. The natural

mortality was the same for the three tunnels, respectively 41, 46 and 64 bees, at

the time of application and the number of bees foraging at the time of application

was between 191 and 270 bees for 85 m2. 46 and 12 bees died due test

substance in tunnel 2 and in tunnel 3 representing respectively less than 17 and

6.3% of the bees present at the treatment time.

The following days bee mortality was similar for the three tunnels. Thus, it is

considered that the substance has a weak effect on bee mortality the day of

application and then this effect disappeared quickly.

The substance had a very limited and transient impact on foraging activity

immediately after application in tunnel 3 and then this effect disappeared the

following days. This was not the case in tunnel 2.

Substance effects on bee behaviour were seen only the day of application and

nothing was observed later on.

After return to the apiary, no assessment was done due to the bad weather

conditions and the winter time.

Reserves and brood were reduced during the study in the three tunnels which was

normal for beehives staying five weeks within a tunnel. This reduction was similar

for the three tunnels.

Conclusion Weak effect on mortality and on bee behaviour and foraging activity the day

of treatment





58


February 2015



Value

Weak effect on mortality and on bee behaviour and foraging activity the day of

treatment.

Transient effect on bee colony

Reference


220 50%WG), applied on oil seed rape, on honey bees (Apis mellifera). SOLEVI


Klimisch Score 1

Amendments/Deviations Assessment of mortality was not done every day

GLP Yes


No/Group 2 tunnels for the treated group, 1 tunnel for water control divided in 4 plots: 2

treated and 2 untreated used as refuge



Study Summary




2 tunnels were used over oilseed rape crop in flower. Each tunnel was divided in

4 plots of 16 m2: 2 were treated and 2 were left untreated as refuge for foraging

bees.





treatment and 15 min after treatment), mortality was assessed once a day and the

colony status was determined before treatment and at the end of the test (23 days

after application).

In this study, during the adaptation phase bee mortality was quite low.

The product effect was only seen immediately after application. The natural

mortality was the same for the 2 tunnels, respectively 57 and 41 bees, at the time

of application and the number of bees foraging at the time of application was

between 549 and 604 bees for 85 m2. 120 bees died due test substance

representing respectively less than 20% of the bees present at the treatment time.

The following days bee mortality was similar for the three tunnels. Thus, it is

considered that the substance has a weak effect on bee mortality the day of

59


February 2015

application and then this effect disappeared quickly.


immediately after application and then this effect disappeared the following days.

Substance effects on bee behaviour were seen only the day of application and

nothing was observed later on. Nevertheless, queen activity seemed to be

perturbed (laying activity was lower and even stopped). However at the end of the

test, 23 days after application, no difference was observed between control and

treated colonies.

After return to the apiary, no assessment was done due to the bad weather

conditions and the winter time.

Reserves and brood were reduced during the study in the 2 tunnels which was

normal for beehives staying within a tunnel. This reduction was higher for the

treated colony during the study but was not observed at the end of the study.

Conclusion

Weak effect on mortality and on bee behaviour and foraging activity the day

of treatment.

Transient effect on bee colony






Endpoint Effects on foraging activity, behaviour, mortality, storage of food, area of frames

covered by brood or food.

Value Effects on foraging activity, bee behaviour and number of bees entering and

leaving the hives limited to the day of treatment. No other effects were observed.

Reference

M. Barnavon (2000) Tunnel test – acute and short-term effects of IBE 3894,

applied on white mustard, on honey bees (Apis mellifera). SOLEVI SARL 12 rue

Felix Perrier 26400 Crest France. Study report: S00ISB008IVO55

Klimisch Score 1


GLP Yes


No/Group

1 tunnel for the treated group, for water control and non-toxic reference phosalone

(Zolone Flo at 1.2 L/ha) divided in 4 plots: 2 treated and 2 untreated used as

refuge

60


February 2015



Study Summary




1 tunnel was used for each group over a white mustard crop in flower. Each

tunnel was divided in 4 plots of 16 m2: 2 were treated and 2 were left untreated as

refuge for foraging bees.




behaviour were observed twice a day except on the treatment day (15 min before

treatment and 15 min and 1 hour after treatment), mortality was assessed once a

day and the colony status was determined before treatment and 3 days after the

end of the 7-d exposure period.

There was no effect on bee mortality in all 3 tunnels, when pre-treatment and

post-treatment mortalities are compared.


immediately after application and then this effect disappeared the following days.

Substance effects on bee behaviour and number of bees entering and leaving the

hives were seen only the day of application and nothing was observed later on.

There was no effect on duration of flower visits.

There was no difference on the condition of the colony when compared with the

non-toxic reference.

Conclusion

Effects on foraging activity, bee behaviour and number of bees entering and

leaving the hives limited to the day of treatment. No other effects were

observed.

Bees - Field Tests

Study type Field test



Species Apis mellifera carnica

Type of exposure Exposure to dried residues on flower in field conditions

Endpoint Mortality, foraging activity (flight density), sublethal effects, colony assessment

(food stores, brood status, hive population), strength of colony

Value No effect

61


February 2015

Reference

S. Schmitzer (2008) Toxicity testing of Teppeki (IKI-220 50% WG) on Honey bees

(Apis mellifera L.) in the field. IBACON GmbH Arheilger Weg 17 64380 Rossdorf

Germany. Report no 36061040

Klimisch Score 1


GLP Yes


No/Group 1 treated plot + 1 untreated with 4 bee colonies

Dose Levels 80 g ai/ha (160 g formulation/ha in 400 L of water/ha)

Study Summary

The aim of the study was to determine the risk to honey bees after contact with

dried residues of the substance applied at 80 g ai/ha, under full field conditions.

Flowering crops (Phacelia tanacetifolia) were sprayed with the substance after

bee flight (evening application). The trial was carried out on 2 different plots of

about 2300 m2 and a distance of approximately 5 km. 4 bee colonies were set up

on each plot 4 days before application. The development of the colonies was

observed until test end on day 21 following application.

The mean number of dead bees per colony per day was 4.1 in the treated plot

after treatment and 24.3 before application. In control it was 13.4.

No statistical difference was observed in flight intensity: mean was 19.4

bees/m2/days on the treated plot and 16.3 in the control plot.

No poisoning symptom or marked reaction to exposure were noted at any time

until the end of the test.

No effects on brood were observed, each colony had a sufficient amount of all

brood stages without any indication of test item related effect.

No substance related influence on the overall strength of the colony were

observed, this was evaluated by counting the number of gaps occupied by bees.

In the treated colonies at days 14 and 21, the number was 93% of the initial value,

and 88 and 78% in the control plot.

Pollen was checked to confirm the exposure to the crop: 47-66% of the collected

pollen came from Phacelia.

Conclusion No effects at 80 g ai/ha in field conditions

Study type field test



Species Apis mellifera carnica

62


February 2015

Type of exposure Exposure to dried residues on flower in field conditions

Endpoint

Mortality, foraging activity (flight density), sublethal effects, colony assessment

(food stores, brood status, hive population), strength of colony, brood

development to adulthood

Value Reduction of development success of eggs from to 3 d-old. No other effects.

Reference

L. Jeker (2008) Teppeki (IKI-220 50% WG) A field study to evaluate side effects

on Honey bees (Apis mellifera L.) following the application on Phacelia

tanacetifolia after daily bee-flight in Germany. . RCC Ltd, Zelgliweg 1 CH-4452

Itingen Switzerland Report no B47520

Klimisch Score 2 due to bias on the assessment of foraging activity and mortality in field (see

comment below)

Amendments/Deviations None that had impacted the results of the study

GLP Yes


No/Group 1 treated plot + 1 untreated with 4 bee colonies

Dose Levels 80 g ai/ha (160 g formulation/ha in 300 L of water/ha)

Study Summary

The aim of the study was to determine the effects to honey bees after contact with

dried residues of the substance applied at 80 g ai/ha in 300 L water /ha, under full

field conditions. Flowering crops (Phacelia tanacetifolia) were sprayed with the

substance after bee flight (evening application). The trial was carried out on 2

different plots of about 2000 m2 and a distance of approximately 3 km. 4 bee

colonies were set up on each plot 13 days before application. The development

of the colonies was observed until test end on day 25 following application.

The study is considered as valid: less than 15% of mortality is observed in control

brood stages (observed mortality 7.4%).

A statistically significant reduction of development success of eggs of 1 to 3 days

was observed in the colonies of the treated plot (78.0% vs 89.5% in control). No

effects were observed on other brood stages.

There were no significant effects on mortality of pupae and adult worker bees

assessed in bee traps; and on condition of colonies (% of comb covered by stores

or by life stages or by vacant cells).

No significant effects were observed on foraging activity and mortality in field.

Comment

There were more colonies in the neighbourhood of the control plot than of the

treated plot so more bees were foraging in the control plot. Consequently the

foraging activity and mortality in field assessment are biased in this study.

The report concludes that the effects on eggs are not biologically significant

because there is no overall effect on brood.

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February 2015

Conclusion Reduction of development success of eggs from to 3 d-old. No other effects

Other non-target arthropods - Laboratory Tests

Study type Tests with glass plates

Flag Supportive study


Species Aphidius rhopalosiphi, T. pyri and C. septempunctata

Type of exposure Residues on glass plates, for 48 h for parasitic wasps, for 7 days for predatory

mites, till pupation for ladybirds

Endpoint Corrected mortality

Value

Aphidius rhopalosiphi: 22.2% at 80 g ai/ha, 55.5% at 210 g ai/ha

T. pyri: 100% at both application rates

C. septempunctata: 30% at both application rates

Reference

JP Jansen (2001) Screening test with IKI-220 50WG: side effects on Aphidius

rhopalosiphi, T. pyri and C. septempunctata on glass plates in the laboratory.

Agricultural Research Center - Department of Biological Control and Plant Genetic

Resources – Chemin de Liroux 2, B-5030 Gembloux Belgium. Report number

none

Klimisch Score 2 non GLP study but performed according to standard guidelines


GLP No

Test Guideline/s

A. rhopalosiphi: Mead-Briggs, 1992;

T. pyri: Overmeer, 1988;

C. septempunctata: Pinsdorf, 1988

No/Group

A. rhopalosiphi test: 3 replicates of 5 males and 5 females for control and treated

groups, 1 replicate for the toxic reference (deltamethrin at 1 g ai/ha).

T. pyri test: 3 replicates of 20 protonymphs for all groups

C. septempunctata test: 20 replicates of 1 larvae, 10 replicates for the toxic

reference

Dose Levels 80 g and 210 g a.i./ha in 200 L water/ha

Study Summary

In order to determine the initial toxicity of IKI-220 50WG to adult of the parasitoid

wasp Aphidius rhopalosiphi, protonymph of the predatory mite Typhlodromus pyri

and larvae of the ladybird Coccinella septempunctata, a screening test was

carried out in the laboratory. Test product was applied at rates of 80 g and 210 g

(ai)/ha on glass plates. Additional glass plates were treated with deltamethrin (1 g

(ai)/ha) as toxic standard.

64


February 2015

A. rhopalosiphi : At the end of exposure, corrected mortality with IKI-220 50WG at

80 g and 210 g (ai)/ha were, respectively, 22.5% and 55.5%. Mortality in units

treated with toxic standard reached 100.0%.

C. septempuncata : Young ladybirds larvae were exposed to test product applied

on glass plates till pupation occurred. Preimaginal corrected mortalities reached

30% for IKI-220 50WG at both application rate and 100.0% for toxic standard.

T. pyri: Mortality of protonymphs exposed to IKI-220 50WG at both doses and to

toxic standard reached 100.0%.

Conclusion

Aphidius rhopalosiphi: 22.2% at 80 g ai/ha, 55.5% at 210 g ai/ha

T. pyri: 100% at both application rates

C. septempunctata: 30% at both application rates

Study type Test with application on inert surface (sand) in laboratory

Flag Key study


Species Poecilus cupreus

Type of exposure 14 d- exposure to dried residues on sand

Endpoint Corrected mortality

Value 3.3%

Reference

JP Jansen (2002) Side effects of IKI-220 50WG on adults of the carabid beetle

Poecilus cupreus L. (Coleoptera, carabidae) in the laboratory. Agricultural

Research Center - Department of Biological Control and Plant Genetic Resources

– Chemin de Liroux 2, B-5030 Gembloux Belgium. Report number PC.01/2001

Klimisch Score 1

Amendments/Deviations None that had an impact on the results

GLP Yes

Test Guideline/s Heimbach, 1994

No/Group 5 units of 3 males and 3 females for control, treated groups, and for the reference

substance (dimethoate).

Dose Levels

45 g ai/ha in 400 L water /ha (the report mentions that this is equivalent to a worst

case PEC after two applications of 80 g ai)/ha at 21 days interval for a soil-

dwelling species, assuming 50% crop interception)

Study Summary

A laboratory study was carried out to determine the effects of the insecticide IKI-

220 50WG on adults of the carabid beetle Poecilus cupreus. The test product

was applied at a rate of 45 g ai/ha to 5 exposure unit made of plastic boxes filled

65


February 2015

with sand, each containing six beetles (3 males, 3 females). Additional groups of

5 exposure units were treated with water as control or dimethoate as toxic

standard. Beetles were fed with housefly pupae. Food consumption and

observation of the condition of the beetles were recorded throughout the 14 days

of the test.

After 14 days of exposure, no beetle was found dead in the units treated with

water and one with IKI-220 50WG. This corresponds to an observed and

corrected mortality of 3.3% for IKI-220 50WG. Three beetles were also found

affected in units treated with IKI-220 50WG between day 2 and day 4

assessments, but they recovered a normal behaviour at further assessment.

Mortality in the toxic standard reached 100.0%. No reduction of food consumption

was observed with IKl-220 50WG, compared with control.

These results showed that IKI-220 50WG is harmless (< 25% of effects) to adults

of the carabid beetle P. cupreus on inert surface in the laboratory.

Conclusion Corrected mortality: 3.3%

Other non-target arthropods - Extended Laboratory Tests

In the following studies, reduction of beneficial capacity (E) is calculated as follows:

E (%) = 100- {(100-M) x R}

with M = corrected mortality and R = reproductive ratio

Study type Test with bean leaves in laboratory

Flag Key study


Species Typhlodromus pyri

Type of exposure 7-d exposure to dried residues on bean leaves

Endpoint Mortality and fertility

Value No effect on fertility, 23.3% corrected mortality

Reference

JP Jansen (2002) Side effects of IKI-220 50WG on the predacious mite

Typhlodromus pyri Scheuten (Acari; Phytoseiidae) on detached bean leaves in the

laboratory. Agricultural Research Center - Department of Biological Control and

Plant Genetic Resources – Chemin de Liroux 2, B-5030 Gembloux Belgium.

Report number TE.01/2002

Klimisch Score 1


GLP Yes

Test Guideline/s IOBC/WPRS 1988, Hassan, 1994

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February 2015

No/Group 5 units of 20 protonymphs for control and treated groups, 2 for the reference

substance (lambda-cyhalothrin at 1 g ai/ha).

Dose Levels

85 g ai/ha in 200 L water /ha (the report mentions that this is equivalent to 2

applications of 80 g ai/ha at 21 days of interval considering the degradation rate of

the active)

Study Summary

A study was carried out to determine the effects of the insecticide IKI-220 50WG

on protonymphs of the predacious mite T. pyri (Acari; Phytoseiidae) under

extended laboratory test conditions.

Test product was applied at a dose of 85 g (ai)/ha on detached bean leaves.

Additional leaves were treated with water as control and with lambda-cyhalothrin

as toxic standard. Two set of leaves were treated at the same time. First set was

used for initial exposure, second set for assessment of fertility the second week of

experiments.

After treatment, leaves were carefully placed on wetted cotton pad and twenty 2-3

day old protonymphs of T. pyri were confined on each leaf. 5 exposure units were

assembled for control and test product and 2 for toxic standard. After 7 days,

surviving mites were harvested, sexed and transferred to second set of leaves for

fecundity assessment. Mean mortality in each group was corrected with the value

observed in the control. After 7 days, the number of protonymphs and eggs found

in each unit was counted and mean fertility performance calculated. Based on

mortality and reproductive performance, reduction of beneficial capacity was

calculated for each group and products were rated according the IOBC

classification for extended-laboratory test.

At day 7 of exposure, a mean mortality of 14.5%, 34.4% and 100.0% was

observed in control, IKI-220 50WG and toxic standard, respectively. Corrected

mortality for IKI-220 50WG was 23.3%.

Mean egg production was 2.71 eggs/female and 2.87 eggs/female for control and

IKI-220 50WG, respectively. As no females survived in toxic standard units,

fertility assessment was not realised with this product.

Reduction of beneficial capacity was equal to 18.8% compared to control for IKI-

220 50WG and 100.0% for toxic standard. Based on these results, IKI-220 50WG

is considered as harmless (less than 25% of effects) on natural substrate in the

laboratory.

Conclusion No effect on fertility. Corrected mortality: 23.3%

Study type Test with barley seedlings in laboratory

Flag Key study


67


February 2015

Species Aphidius rhopalosiphi

Type of exposure 48-h exposure to dried residues on barley seedlings



Reference

JP Jansen (2002) Side effects of IKI-220 50WG on adults of the parasitic wasp

Aphidius rhopalosiphi (Hym., Aphidiidae) on plants in the laboratory. Agricultural

Research Center - Department of Biological Control and Plant Genetic Resources

– Chemin de Liroux 2, B-5030 Gembloux Belgium. Report number AE.03/2001

Klimisch Score 1


GLP Yes

Test Guideline/s Mead-Briggs & Longley (1997), Hassan (1994)

No/Group 5 replicates of 5 wasps for control and treated groups, 2 for the reference

substance (dimethoate at 35 g ai/ha).

Dose Levels



the active)

Study Summary


on adults of the aphid parasitoid Aphidius rhopalosiphi (Hym; Aphidiidae) under

extended laboratory test conditions.

Test product was applied at a dose of 85 g ai/ha to barley seedlings. Additional

seedlings were treated with water as control and with dimethoate as toxic

standard. Five mated female wasps were confined on each seedling, using a

perspex cage, for a period of 48h. During exposure, wasps were observed 10

times and their position (treated or untreated surfaces) were noted to detect any

repellent effects. After 48 hours, surviving females were harvested, 14 were

selected randomly in each group - assuming that this number survive and were

assessed for reproductive performance. They were individually released for a

period of 24 hours onto barley seedlings infested with cereal aphids (Sitobion

avenae). 10 to 13 days later, number of parasitized aphids (mummies) was

counted in each seedling and mean mummy production calculated for each test

group. Based on mortality and reproductive performance, reduction of beneficial

capacity was calculated and products rated according to the IOBC classification

for extended-laboratory test.

After 48h of exposure to treated plants, 22/25 parasitoids were collected on plants

treated with IKI-220 50WG, 23/25 in the control and none in the toxic standard.

Corrected mortality for IKI-220 50WG was equal to 4.4 %. A mean production of

68


February 2015

8.14, and 7.36 mummies/female was obtained for control and IKI- 220 50WG. As

no females survived with toxic standard, no fertility assessment was realized with

this product.

Reduction in beneficial capacity with IKI-220 50WG was equal to 13.6%.

According to the IOBC rating, IKI-220 50WG can be considered as harmless (<

25% effects) to the parasitic wasp A. rhopalosiphi under extended laboratory test

conditions.



Flag Key study


Species Chrysoperla carnea

Type of exposure Exposure to dried residues on bean leaves, till pupation



Reference

JP Jansen (2002) Side effects of IKI-220 50WG on larvae of the green lacewing

Chrysoperla carnea (Neuroptera, Chrysopidae) on detached bean leaves treated

in the laboratory. Agricultural Research Center - Department of Biological Control

and Plant Genetic Resources – Chemin de Liroux 2, B-5030 Gembloux Belgium.

Report number CCE.02/2001

Klimisch Score 1


GLP Yes

Test Guideline/s Bigler 1988

No/Group 40 units of 1 larvae for control and treated groups, 20 for the reference substance

(lambda-cyhalothrin at 1 g ai/ha).

Dose Levels



the active)

Study Summary


on larvae of the green lacewing C. carnea (Neuroptera; Chrysopidae) under

extended-lab test conditions.

IKI-220 50WG was applied at a rate of 85 g ai/ha. Additional leaves were treated

with water as control and with lambda-cyhalothrin as toxic standard.

After treatment, one 2-3-day old larvae of C. carnea was released in each unit.

69


February 2015

Larvae were fed 5 times a week with Ephestia Kuhniella sterilised eggs, till

pupation.

Larval mortality was assessed daily. After pupation, pupae were carefully

transferred to plastic petri dishes for adult emergence. After emergence,

observed preimaginal mortalities were calculated and corrected with the value of

the corresponding control. When they emerged, adults were transferred in fertility

assessment units and egg production was followed during a 4-week period. Mean

number of viable eggs/female/day was used as a measure of reproductive

performance.

A preimaginal mortality of 20.0% was obtained for control. With IKI-220 50WG,

observed and corrected preimaginal mortality reached 35.0% and 18.8%

respectively. All larvae were killed by toxic standard. A mean production of 157.1

and 186.3 viable eggs/female was obtained in control and IKI-220 50WG units.

As no females survived, assessment of fertility with toxic standard was not

possible.

According to corrected mortalities and mean viable egg production, reduction of

beneficial capacity with IKI-220 50WG was equal to 3.65%. These results show

that IKI-220 50WG is harmless for larvae of C. carnea under extended laboratory

conditions.


Study type Test with broad bean leaves in laboratory

Flag Supportive study


Species Hoverfly Episyrphus balteatus

Type of exposure Exposure to dried residues on broad bean leaves, till pupation


Value No statistically significant effect on fertility, 2.6% corrected mortality

Reference

JP Jansen (2002) Side effects of IKI-220 50WG on larvae of the hoverfly

Episyrphus balteatus (DeGeer) (Diptera, Syrphidae) on plants in the laboratory.

Agricultural Research Center - Department of Biological Control and Plant Genetic

Resources – Chemin de Liroux 2, B-5030 Gembloux Belgium. Report number

EBE.01/2002

Klimisch Score 2: no existing guideline but the method similar to other non-target arthropods

method


70


February 2015

GLP Yes

Test Guideline/s None existing



Dose Levels



the active)

Study Summary


on larvae of hoverfly E. balteatus (Diptera; Syrphidae) under extended-lab test

conditions. As no standardised and validated methods exist, trials were

conducted according to an original method. Test products were applied till run-off

on broad bean seedlings. IKI-220 50WG was applied at a rate of 85 g (ai)/ha, and

additional seedlings were treated with water as control and with lambda-

cyhalothrin as toxic standard. 2 to 3 hours after treatments, E.balteatus larvae

were confined on treated seedling till pupation. After adult emergence, observed

preimaginal mortalities were calculated and corrected with the value of the

corresponding control. When they emerged, adults were transferred in fertility

assessment units and egg production was followed during five 2-day periods.

Mean number of viable eggs/female was used as a measure of reproductive

performance.

A preimaginal mortality of 22.0%, 24.0% and 100.0% was obtained for control, IKI-

220 50WG and toxic standard, respectively. Corrected preimaginal mortality

reached 2.6% for IKI-220 50WG. A mean production of 197.9 and 138.00 viable

eggs/female was obtained in control and IKI-220 50WG units. IKI-220 50WG

female fertility was not statistically different from control. As no females survived,

assessment of fertility with toxic standard was not possible.

According to corrected mortalities and mean viable eggs production, reduction of

beneficial capacity with IKI-220 50WG was equal to 32.1%. If reduction of

beneficial capacity was mostly the consequence of fertility test results, mean

viable egg production of IKI-220 50WG female was not statistically different from

control.

Conclusion No statistically significant effect on fertility, corrected mortality: 2.6%


Flag Key study


Species Coccinella septempunctata

71


February 2015

Type of exposure Exposure to dried residues on bean leaves, till pupation



Reference

JP Jansen (2002) Side effects of IKI-220 50WG on larvae of the ladybird

Coccinella septempunctata L. (Coleoptera, Coccinellidae) on detached bean

leaves in the laboratory. Agricultural Research Center - Department of Biological

Control and Plant Genetic Resources – Chemin de Liroux 2, B-5030 Gembloux

Belgium. Report number CSE.01/2002

Klimisch Score 1


GLP Yes

Test Guideline/s Bigler (1988)



Dose Levels



the active)

Study Summary


on larvae of the ladybird C. septempunctata (Coleoptera; coccinellidae) under

extended-lab test conditions. Trials were conducted with exposure units using

detached bean leaves treated in the laboratory instead of glass plates. IKI-220

50WG was applied at a rate of 85 g (ai)/ha. Additional leaves were treated with

water as control and with lambda-cyhalothrin as toxic standard.

After treatment, one 2-3-day old larvae of C. septempunctata was released in

each unit. 40 units were prepared for control and IKI-220 50WG and 20 for toxic

standard. Larvae were fed 5 times a week with aphids, till pupation. Larval

mortality was assessed daily and pupae were left to emerge. After emergence,

observed preimaginal mortalities were calculated and corrected with the value of

the corresponding control. When they emerged, adults were transferred in fertility

assessment units and egg production was followed during a 4-week period since

first eggs were found. Mean number of viable eggs/female was used as a

measure of reproductive performance.

A preimaginal mortality of 17.5%was obtained for control. With IKI-220 50WG,

observed and corrected preimaginal mortality reached 22.5% and 6.1%,

respectively. All larvae were killed by toxic standard. A mean production of 116.2

and 99.6 viable eggs/female was obtained in control and IKI-220 50WG units. As

no females survived, assessment of fertility with toxic standard was not possible.

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February 2015

According to corrected mortalities and mean viable eggs production, reduction of

beneficial capacity with IKI-220 50WG was equal to 19.50%.

Conclusion No effect on fertility, corrected mortality: 6.1%

General conclusion about toxicity to terrestrial invertebrates classification:

Tunnel tests and field studies on bees performed at rates of 70 to 80 g ai/ha show that whereas a direct

spray on bees would have a transient impact on mortality and foraging activity, applications when no bees

are foraging (in the evening) do not have any effect on bees.

Laboratory and extended laboratory tests performed with different types of non-target soil-dwelling or foliar

arthropods, show that no adverse effects are expected in the use conditions of Mainman.

73


February 2015

Appendix D: Active ingredient and metabolites

Identity

As this is the first full Part 5 application considered for this active ingredient, general data about flonicamid

are provided in the following tables.

Table 8 Identification of flonicamid

IUPAC name N-cyanomethyl-4-trifluoromethylnicotinamide

CAS name N-(cyanomethyl)-4-(trifluoromethyl)-3-pyridinecarboxamide

Common name Flonicamid, Code IKI-220

Molecular formula C9H6F3N3O

CAS Number 158062-67-0

Molecular weight 229.16 g/mole

Structural formula

Purity Minimum 97%

Other international classification &

labelling

Not classified in the EU yet but a classification acute cat4 H302 (Xn

R22) has been proposed.

Mode of action

Flonicamid is a selective homopteran feeding blocker in IRAC Group 9C, and is the only compound in this

chemical subgroup. Numerous assays on the mode of action of flonicamid have been performed. These

include: inhibition studies of acetylcholinesterase, nicotinic and muscarinic acetylcholine receptors,

respiration (including Complex I, II, III, and IV inhibitors, phosphorylation inhibitors, uncouplers of oxidative

phosphorylation), GABA-receptor (in vivo and in vitro), glutamate-receptor (agonist and antagonist),

octopamine receptor agonist, nitric oxide synthase, nitric oxide receptor agonist, Na-channel, L-type Ca-

channel, ryanodine Ca-channel, and calcium ATPase (body wall contraction assay). In all of the above

assays, flonicamid does not act on these targets as do commercial standards within that mode of action.

These assays cover most of the known insecticide modes of action.

The rapid onset of toxicity is inconsistent with chitin synthesis inhibition, juvenile hormone, and ecdysone

agonist activity, meaning it cannot be an insect growth regulator. Because flonicamid does not respond in

74


February 2015

these assays, it suggests a novel mode of action that is differentiated from other insecticides commonly

used. There is some evidence that flonicamid targets the insect potassium A-type channel.

Hazard classification

Table 9 Applicant and Staff classifications of the active ingredient

Hazard Class/Subclass

Active ingredient

classification

Method of

classification

Remarks

Ap

plican

t’s

cla

ssif

icati

on

Sta

ff’s

cla

ssif

icati

on

Test

resu

lts

Read

acro

ss

Class 1 Explosiveness No No Expert statement

instead of test

Class 2, 3 & 4 Flammability No No

Class 5 Oxidisers/Organic Peroxides No No Expert statement

instead of test

Subclass 8.1 Metallic corrosiveness No ND

Subclass 6.1 Acute toxicity (oral) 6.1E 6.1D

It is not clear why

the applicant

proposed 6.1E: the

LD50 is within the

range for 6.1DE

classification

Subclass 6.1Acute toxicity (dermal) No No

Subclass 6.1 Acute toxicity (inhalation) No No

Subclass 6.1 Aspiration hazard No ND

Subclass 6.3/8.2 Skin irritancy/corrosion No No

Subclass 6.4/8.3 Eye irritancy/corrosion No No

Subclass 6.5A Respiratory sensitisation No ND

Subclass 6.5B Contact sensitisation No No

Subclass 6.6 Mutagenicity No No

Subclass 6.7 Carcinogenicity No No

Subclass 6.8 Reproductive/ developmental

toxicity No No

Subclass 6.8 Reproductive/ developmental

toxicity (via lactation) No No

Subclass 6.9 Target organ systemic toxicity 6.9B No

No significant target

organ toxicity of

relevance for

human observed at

doses in the

guidance value

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February 2015

range for

classification

Subclass 9.1 Aquatic ecotoxicity No No

Subclass 9.2 Soil ecotoxicity No No

Subclass 9.3 Terrestrial vertebrate

ecotoxicity No 9.3C Based on bird data

Subclass 9.4 Terrestrial invertebrate

ecotoxicity No No

NA: Not Applicable --> For instance when testing is technically not possible: testing for a specific endpoint may be omitted, if it is

technically not possible to conduct the study as a consequence of the properties of the substance: e.g. very volatile, highly reactive or

unstable substances cannot be used, mixing of the substance with water may cause danger of fire or explosion or the radio-labelling of

the substance required in certain studies may not be possible.

ND: No Data or poor quality data (according to Klimisch criteria17

) --> There is lack of data.

No: Not Classified based on actual relevant data available for the substance --> The data are conclusive and indicate the threshold for

classification is not triggered.

Physico-chemical properties of the active ingredient

Table 10 Physico-chemical properties of flonicamid

Property Result Test

method

Klimisc

h Score

(1-4)

Reference

Colour

Light beige at 21.9°C (lot #9809)

(ref1)

Off-white at 25°C (lot #9803) (ref 2)

OPPTS

830.6302 1

1) JA Pelton (2000) IKI-220

TGAI – Appearance, pH, and

relative density. Ricerca Inc.

Analytical services 7528 Auburn

Road Painesville OH 44077-

1000. Report no 012575-1

2) GG Sweetapple (1999) IKI-

220 – Melting point, relative

density, physical state, colour

and door. Ricerca Inc. Analytical

services 7528 Auburn Road

Painesville OH 44077-1000.

Report no 010153-1

Physical state

Solid powder at 24.9°C (lot #9809)

(ref1)

Solid powder at 25°C (lot #9803) (ref

2)

OPPTS

830.6303 1

Odour Odourless at 24.9°C (lot #9809) (ref1)

Odourless at 25°C (lot #9803) (ref 2)

OPPTS

830.6304 1

Oxidizing

properties

The substance is not supposed to be

oxidizing as the oxygen and fluorine

in the molecule are bonded only to

UN

recommen

dations on

transport of

1


Statement on the oxidizing

properties of IKI-220 technical.

RCC Ltd , Environmental

17 Klimisch,, H-J., Andrear, M., & U. Tillmann, 1997. A systematic approach for evaluating the quality of experimental

toxicological and ecotoxicological data. Reg. Toxicol. Pharmacol. 25, 1–5 (1997)

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February 2015

carbon and hydrogen. Dangerous

Goods,

Annex 6 3rd

edition,

1999

Chemistry & Pharmanalytics

Division. CH-4452 Itingen

Switzerland. Report no 834030

pH 4.5 at 25 o

C (1% aqueous solution) OPPTS

830.7000 1

JA Pelton (2000) IKI-220 TGAI

– Appearance, pH, and relative

density. Ricerca Inc. Analytical



Report no 012575-1

Explosive

properties

Not explosive based on absence of

structural features and decomposition

energy (measured by differential

scanning calorimetry) which is below

the UN limit of concern of 500 J/g (it

was 374 J/g, the exothermic peak

was at 280oC.)

UN

recommen

dations on

transport of

Dangerous

Goods,

Annex 6 3rd

edition,

1999

1

U. Schmiedel (2001) Expert

statement on the explosive

properties of IKI-220 technical.

RCC Ltd , Environmental


Division. CH-4452 Itingen


Henry’s Law

constant 4.2 x 10

-8 Pa-m

3/mole at 20

oC

Estimation

based on

vapour

pressure

and water

solubility

1

JE Schetter (1999) IKI-220 –

Vapour pressure. Ricerca Inc.



1000. Report no 010341-1

Melting point 157.5 oC

OPPTS

830.7200 1

GG Sweetapple (1999) IKI-220

– Melting point, relative density,

physical state, colour and door.

Ricerca Inc. Analytical services

7528 Auburn Road Painesville

OH 44077-1000. Report no

010153-1

Boiling point Decomposition before boiling

OECD 103

(1995)

JMAFF 12

Nohsan

8147

1

A.Tognucci (2002)

Determination of the boiling

point / boiling range of IKI-220

PAI. RCC Ltd Environmental


Division CH-4452 Itingen

Switzerland. Study report

842001

Vapour pressure

(Pa)

At 20.0 oC: 9.43 x 10

-7

At 25.0 oC: 2.55 x 10

-6

OPPTS

830.7950

(gas

saturation

method)

1

JE Schetter (1999) IKI-220 –

Vapour pressure. Ricerca Inc.



1000. Report no 010341-1

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February 2015

Relative Density 1.531 (20

oC/20

oC) lot #9809

1.54 (20 o

C/20 o

C) lot #9803

OPPTS

830.7300 1

JA Pelton (2000) IKI-220 TGAI

– Appearance, pH, and relative

density. Ricerca Inc. Analytical



Report no 012575-1

GG Sweetapple (1999) IKI-220

– Melting point, relative density,

physical state, colour and door.




010153-1

Surface Tension

47.3 mN/m at 25 o

C±1

47.0 mN/m at 40 o

C±1

The substance is surface active

however the test was performed with

concentration > 1g/L (around 10 g/L)

Mettens

(equivalent

to EEC A5)

2

B de Ryckel (2002) Relative

self-ignition temperature,

flammability and surface tension

of IKI-220 TGAI. Centre de

recherches Agronomiques de

Gembloux. Departement de

Phytopharmacie 5030

Gembloux Belgique. Report no

20334.

Water Solubility 5.2 g/L at 20 o

C

OPPTS

830.7840

(shake

flask

method)

1

RT O’Donnell (1999) IKI-220,

PAI (Lot #9803) – Water

solubility. Ricerca Inc. Analytical



Report no 010251-1

Solvent

Solubility (20°C)

(g/100 mL

solvent)

Solvent Lot#9

809

lot

#980

3

Acetone 17.32 18.67

Ethylacetat

e

3.57 3.39

Methanol 9.76 11.06

Dichlorome

thane

0.40 0.45

Toluene 0.03 0.055

Hexane 0.000

03

0.000

02

n-octanol 0.26 0.30

Acetonitrile 12.04 14.61

Isopropyl

alcohol

1.46 1.87

OPPTS

830.7840 1

LP Dudones (1999) IKI-220, PAI

(lot #9809) – Organic solvent

solubility. Ricerca Inc. Analytical



Report no 011201-1

RT O’Donnell (1999) IKI-220,

PAI (lot #9803) – Organic

solvent solubility. Ricerca Inc.



1000. Report no 010250-1

78


February 2015

Log Kow Kow = 1.9

Log Kow = 0.3 at 29.8 o

C

OPPTS

830.7570

(HPLC)

1

LP Dudones (1999) IKI-220, PAI

(lot #9803) – Octanol/water

partition coefficient. Ricerca Inc.



1000. Report no 010252-1

Flammability

Not flammable. Substance melts on

contact with flame or become liquid

but it does not ignite.

EEC A10 B de Ryckel (2002) Relative

self-ignition temperature,

flammability and surface tension

of IKI-220 TGAI. Centre de

recherches Agronomiques de

Gembloux. Departement de

Phytopharmacie 5030

Gembloux Belgique. Report no

20334.

Auto

flammability

No relative self-ignition temperature

up to 400 o

C

- E

E

C

A

1

6

-

Dissociation

constant pKa = 11.60 ± 0.03 at 20 ± 1

oC

OPPTS

830.7370 1

RC Beckwith (1999) IKI-220 (lot

#9803) – dissociation constant.




010141-1

Thermal stability

in air

No relevant endothermic or

exothermic reaction up to 150 oC.

OECD 113

(by DSC) 1

A Tognucci (2002) Screening of

the thermal stability in air of IKI-

220 PAI. RCC Ltd ,


Pharmanalytics Division. CH-

4452 Itingen Switzerland.

Report no 842000

Particle size

distribution

% of

particles

Size of

particles

(mm)

10.34 > 1.190

35.13 1.190 –

0.500

47.21 0.500 -

0.250

6.44 0.250 -

0.106

0.76 < 0.106

OECD 110

(1981)

CIPACT

MT 59

1

L.F. Piasentini de Campos

(2002) Particle size distribution

of Flonicamid tecnico. Bioagri

Laboratorios Ltda Piracicaba

S.P. Brazil. Study number RF-

1213.018.080.02

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February 2015

Mammalian toxicology - Robust study summaries for the active ingredient and

metabolites

In the following study summaries the active ingredient flonicamid is referred to by the development code IKI-

220.



Type of study Acute oral toxicity test in rats

Flag Key study

Test Substance IKI-220 technical, Lot No.9809

Endpoint LD50

Value 884 mg/kg bw males, 1768 mg/kg bw females

Reference

Ridder, W. E., Yoshida, M., Watson, M., Acute oral toxicity study in rats

with IKI-220 technical, RCC Ltd, Toxicology and Metabolism, USA, 2001.

ISK Document No.2008 010276-1-1

Klimisch Score 1


GLP Y

Test Guideline/s OECD 401, US EPA OPPTS 870.1100

Species Rat

Strain Sprague Dawley Crl:CD®(SD)BR(IGS)

No/ Group 5M and 5F

Dose Levels 625, 1250, 2500, 5000 mg/kg bw


Study Summary

Treatment related deaths were 5/5 males and 5/5 females at 5000

mg/kg/bw, 5/5 males and 4/5 females at 2500 mg/kg bw and 5/5 males

and 1/5 females at 1250 mg/kg bw. There were no deaths at 625 mg/kg

bw. Deaths were generally within 4 hours of dosing but also occurred up to

48 hours post dosing. The principal clinical signs in decedents included

decreased activity, loss of mobility, laboured breathing, prostration,

convulsion, cold to touch and sensitive to noise. Ataxia was common

amongst females. Additional signs amongst surviving females were

laboured breathing, rales, prostration, cold to touch, tremors, anogenital

staining and few or no faeces. Initial weight loss was evident at all doses

with subsequent recovery in those animals that survived to Day 14.

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February 2015

Necropsy revealed dark red-black spots on the serosal surface of the

stomach in 1 male at 1250 mg/kg bw and 2 females each at 2500 and

5000 mg/kg bw. All were decedents within 48 hours of treatment


Conclusion

IKI-220 technical should be classified as 6.1D (oral), based on the male LD

50 value of 884 mg/kg bw in males and 1768 mg/kg bw in females (Section

10.2; User Guide for Thresholds and Classifications; EPA0109, 2012).

Acute Dermal Toxicity [6.1 (dermal)]

Type of study Acute dermal limit toxicity test in rats

Flag Key study

Test Substance IKI-220 technical, Lot No. 9809

Endpoint LD50


Reference

Ridder, W. E., Yoshida, M., Watson, M., Acute dermal toxicity (LD50) study

in rats with IKI-220 technical, RCC Ltd, Toxicology and Metabolism, USA,

2002. ISK Document No.2009 010278-1

Klimisch Score 1


GLP Y


Species Rat

Strain Sprague Dawley Crl:CD®(SD)BR(IGS)

No/ Group 5M and 5F

Dose Level 5000 mg/kg bw undiluted – moistened

Exposure Type Dermal, 24h occluded

Study Summary

There were no deaths. Principal clinical signs were coloured material

around the nose and eye(s) and anogenital staining observed in most

animals from 1 hour to 3 days post dosing but resolving by Day 4. There

were no treatment related effects on bodyweight gain or any macroscopic

changes evident at necropsy.


Conclusion IKI-220 technical should not be classified for 6.1 (dermal), based on the

lack of adverse effects at the limit dose used in this study (Section 10.2;

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February 2015

User Guide for Thresholds and Classifications; EPA0109, 2012).

Acute Inhalation Toxicity [6.1 (inhalation)]

Type of study Acute inhalation limit toxicity test in rats (4-hour, nose only)

Flag Key


Endpoint LC50

Value >4.90 mg/l

Reference

Paul, G. R., Bowden, A.M., Coombs, D.W., IKI-220 Technical Acute (four-

hour) inhalation in rats, Huntingdon Life Sciences Ltd, UK, 2000. ISK

Document No.2010-994326

Klimisch Score 1


GLP Y


Species Rat

Strain Sprague Dawley


Dose Levels

4.90 mg/l

mass median aerodynamic diameter and geometric standard deviation

were 4.8 µm and 2.37 respectively

Exposure Type 4h nose only – dust aerosol

Study summary

There were no deaths. Clinical signs were confined to exaggerated

breathing in some rats from 30 minutes of exposure and all rats from 3

hours into the exposure period, persisting up to Day 2 post dosing. Brown

staining around the snout and jaws was seen in all treated animals after

exposure, persisting up to Day 2 in females. All signs had resolved by Day

3 post dosing. There were no treatment related effects on bodyweight gain,

food or water intake, macroscopic pathology or organ weights.

Additional Comments

The mass median aerodynamic diameter of of the particulate atmosphere

was 4.8 µm and was marginally higher than the acceptable range (1 µm to

4 µm) for an acute inhalation study. This was reported to be attributable to

the nature of the test material. The authors note that approximately 66% of

the particulate were less than 7 µm in aerodynamic diameter and are

therefore considered of a respirable size.

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February 2015

Conclusion

IKI-220 technical should not be classified for 6.1 (inhalation), based on the

lack of adverse effects at the limit concentration used in this study (Section

10.2; User Guide for Thresholds and Classifications; EPA0109, 2012).

Skin Irritation [6.3/8.2]

Type of study Dermal irritation/corrosion study in rabbits

Flag Key study

Test Substance IKI-220 Technical, Lot No. 9809

Endpoint Dermal irritancy (mean of Draize scores at 24, 48 and 72 hours)

Value Non irritant: 0.0 for erythema and oedema

Reference

Ridder, W. E., Yoshida, M., Watson, M., Acute dermal study in albino

rabbits with IKI-220 technical, RCC Ltd, Toxicology and Metabolism, USA,

2000. ISK Document No.2011 010280

Klimisch Score 1


GLP Y


Species Rabbit


No/ Group 6M

Dose Levels 0.5g undiluted - moistened

Exposure Type 4h dermal, semi occlusive

Study Summary There were no skin reactions in any animal. Scores for erythema/eschar

and oedema were 0 for all observations


Conclusion

IKI-220 technical should not be classified for 6.3 (skin irritation) based on



Eye Irritation [6.4/8.3]

Type of study Eye irritation/corrosion study in rabbits

Flag Key


83


February 2015

Endpoint Eye irritancy (mean of Draize scores at 24, 48 and 72 hours)

Value Non irritant: 0.4 for conjunctival redness, 0.06 for chemosis, 0.0 for corneal

opacity and iritis

Reference

Ridder, W. E., Yoshida, M., Watson, M., Acute eye irritation study in albino

rabbits with IKI-220 technical, RCC Ltd, Toxicology and Metabolism, USA,

2000. ISK Document No.2012 010281-1

Klimisch Score 1


GLP Y


Species Rabbit


No/ Group 6M

Dose Levels 0.1 ml (approx.70 mg)

Exposure Type Ocular

Study Summary

There were no corneal or iridal effects. Conjunctival redness, chemosis

and discharge were seen in all animals 1 hour post application. Redness

became less severe by 24 hours and resolved by 72 hours. Chemosis

resolved in most animals by 24 hours and discharge in all animals resolved

by 24 hours. Draize scores were cornea 0, iris 0, conjunctival redness 0.4,

chemosis 0.06. There were no other treatment related effects.


Conclusion

IKI-220 technical should not be classified for 6.4 (eye irritation) based on



Contact Sensitisation [6.5]

Type of study Sensitisation study – Magnusson and Kligman Maximisation test in guinea

pigs

Flag Key

Test Substance IKI-220 Technical, Lot No. 9809

Endpoint Contact sensitisation on challenge

Value Non sensitiser: <thresholds (negative)

Reference Ridder, W. E., Watson, M., Dermal sensitisation study (maximisation

84


February 2015

design) in guinea pigs with IKI-technical, RCC Ltd, Toxicology and

Metabolism, USA, 2000. ISK Document No.2013 010282-1-2

Klimisch Score 1


GLP Y

Test Guideline/s OECD 406, US EPA 870.2600

Species Guinea pig

Strain Hartley albino

No/Sex/Group 10F control group, 20F treated group

Dose Levels

10% in mineral oil distilled water, once per week for 2 weeks induction

phase. 10% in mineral oil for challenge (maximum non irritating

concentration)

Positive control – dinitrochlorobenzene 0.8% in mineral oil

Exposure Type Dermal -24 hours occluded

Study Summary Only a slight response was seen on challenge equating to mild irritation

and thus assessed as negligible rather than sensitisation.


Conclusion

IKI-220 technical should not be classified for 6.5B (contact sensitisation)

based on the results from this study (Section 13.2; User Guide for


General conclusion about acute toxicity classification:

IKI-220 technical demonstrated acute oral toxicity albeit at a relatively low classification of 6.1D

(oral). No classifications are required for acute dermal or inhalation toxicity (6.1 dermal or

inhalation).

IKI-220 technical did not demonstrate skin or eye irritation and does not require classification for

6.3 and 6.4.

IKI-220 technical did not show contact sensitisation potential and should not be classified for

contact sensitisation (6.5B).

85


February 2015

Genotoxicity [6.6]

In Vitro Studies

Study type/Test Guideline Result Reference

Ames Reverse mutation test.

OECD 471, US EPA OPPTS

870.5100

Non mutagenic,

negative with or

without metabolic

activation

Matsumoto, K., IKI-220 technical: reverse

mutation test, Institute of Environmental

Toxicology, Japan, 2002. ISK Document No.

2018 IET 00-0147

In vitro cytogenetics test.

OECD 473, US EPA OPPTS 870.5375

Non clastogenic,

negative with or

without metabolic

activation

Matsumoto, K., IKI-220 technical: in vitro

cytogenetics test, Institute of Environmental

Toxicology, Japan, 2002. ISK No. 2018 IET 00-

0149

In vitro mouse lymphoma gene mutation test. OECD 476, US EPA OPPTS 870.5300

Non mutagenic,

negative with or

without metabolic

activation

Matsumoto, K., IKI-220 technical: in vitro

mouse lymphoma gene mutation test, Institute

of Environmental Toxicology, Japan, 2002. ISK

Document No. 2018 IET 00-0150

Comet assay in mouse colon, liver and lung. Tice et al., 2000 International Workshop on Genotoxicity Test Procedures, 1999

Non genotoxic in

tested tissues.

Sasaki, Y. F., A novel insecticide: the comet

assay with mouse colon, liver and lung.

Hachinohe National College of Technology,

Japan, 2002. ISK Document No.2412 AN-2106

Conclusion Results from the genotoxicity assays were

negative

In Vivo Studies

Type of study Mouse micronucleus test

Flag Key


Endpoint Clastogenicity

Value Non clastogenic

Reference Matsumoto, K., IKI-220 technical: micronucleus test in mice, Institute of

Environmental Toxicology, Japan, 2002. ISK Document No. 2018 IET 00-0148

Klimisch Score 1


GLP Y


86


February 2015

Species Mouse

Strain Crj:CD-1


Dose Levels

250, 500, 1000 mg/kg bw males; 125, 250, 500 mg/kg bw females - by oral

gavage

Positive control – mitomycin C

Study Summary

There were no deaths or clinical signs. There was no increase in the frequency of

micronucleated polychromatic erythrocytes or any decrease in the polychromatic

erythrocyte ratio. Treatment with IKI-220 technical did not induce micronuclei in

the bone marrow of mice.


Conclusion The test substance did not demonstrate any clastogenic activity

Type of study DNA repair test (Unscheduled DNA Synthesis) in rats

Flag Key


Endpoint DNA repair synthesis

Value Negative

Reference

Mehmood, Z., IKI-220 technical: In vivo DNA repair (UDS) test using rat

hepatocytes, Huntingdon Life Sciences Ltd., UK, 2003. ISK Document No. 269-

032007

Klimisch Score 1


GLP Y

Test Guideline/s OECD 486, 2000/32/EC Annex 4G-B.39, US EPA OPPTS 870.5550

Species Rat

Strain Sprague-Dawley

No/Sex/Group 5M

Dose Levels 600, 2000 mg/kg bw – oral gavage

Study Summary

There were no deaths. Clinical signs seen at both dosages were under activity,

flattened posture, abnormal gait, irregular respiration, reduced body tone and

reddened skin colour with the additional signs at 2000 mg/kg bw of prominent

eyes and partially closed eyelids. Treated animals did not show any increase in

the gross or net nuclear grain count compared with controls. Significant increases

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February 2015

were seen in the positive control groups treated with dimethylnitrosamine or 2-

acetylaminofluorene.


Conclusion IKI-220 technical was negative in the assay and did not cause any unscheduled

DNA synthesis

General conclusion about genotoxicity classification:

IKI-220 technical was not mutagenic or clastogenic. The combined in vitro and in vivo data indicate that no

classification for genotoxicity (6.6) is required.

Carcinogenicity [6.7]

Type of study Carcinogenicity/Toxicity in rats

Flag Key


Endpoints

Non-Neoplastic Effects

LOAEL: 1000 ppm (36.5 mg/kg bw/day) males, 5000

ppm (219 mg/kg bw/day)females – altered kidney

micropathology in males, liver and kidney in females,

decreased body weight and body weight gain

NOAEL: 200 (7.32 mg/kg bw/day) ppm males, 1000

ppm (44.1 mg/kg bw/day) females

Neoplastic Effects

LOAEL: N/A

NOAEL: 1000 ppm (36.5 mg/kg bw/day) males,

5000 ppm (219 mg/kg bw/day) females

Tumours N/A

Malignant/Benign N/A

Background Incidence N/A

Time of Onset N/A

Survival N/A

Reference

Kuwahara, M., IKI-220 technical: Combined chronic toxicity and carcinogenicity

study in rats, The Institute of Environmental Toxicology, Japan, 2002. ISK


Klimisch Score 1


GLP Y

Test Guideline/s 87/302/EEC 1987, US EPA OPPTS 870.4300

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February 2015

Species Rat

Strain Wistar Jcl:Wistar

No/Sex/Group 76M and 76F (14 and 10 per sex per group sacrificed after 26 and 52 weeks

respectively for toxicity assessments)

Dose Levels

0, 50 (males only), 100 (males only), 200, 1000, 2000 (females only) ppm –

equivalent to 0, 1.84, 3.68, 7.32, 36.5 mg/kg bw/day males and 0, 8.92, 44.1, 219

mg/kg bw/day females respectively

Exposure Type Admixture with the diet

Study Summary

There was no evidence of carcinogenic activity at any of the dosages investigated.

Females receiving 5000 ppm showed lower food intake and food efficiency with

concomitant lower weight gain during the first 52 weeks of treatment with

bodyweight at termination remaining lower than concurrent controls. Some

association with palatability cannot be discounted. There was a significant

decrease in rearing behaviour during weeks 5 to 12. Fluctuations in haematocrit,

haemoglobin concentration, erythrocyte count and/or mean corpuscular

haemoglobin concentration indicated mild anaemia, particularly in the later period

of treatment. Blood chemistry revealed increased ү-glutamyl transpeptidase and

cholesterol with decreased triglycerides. Significant increases in absolute and/or

relative liver (from Week 26) and kidney (from Week 52) weights were noted.

Necropsy revealed increased incidences of accentuated lobular pattern and dark

colour of the liver. Histopathology revealed hepatocellular hypertrophy of the liver

and cytoplasmic vacuolation of the proximal tubular cells of the kidney. Additional

histopathological findings noted in the later stages of treatment included increased

incidences of atrophy of striated muscle fibres (m.triceps surae – calf muscle),

cataract, retinal atrophy, hepatic foci of cellular alterations (eosinophilic cell foci),

chronic nephropathy and brown pigment deposition in renal proximal tubular cells.

At 1000 ppm a significant decrease in rearing behaviour was noted amongst

males during weeks 10 to 30, decreased body weight and body weight gain was

also observed although some association with palatability cannot be discounted.

Increased liver weight was evident from Week 26 and increased kidney weight

from Week 52. Histopathology in males revealed increased incidences of hyaline

droplet deposition and tubular basophilic changes and granular casts of the kidney

during the early phase of treatment. These changes during the later stages of

treatment occurred at an incidence comparable with controls whereas the

incidence of chronic nephropathy was significantly increased. There were no in life

or pathological changes seen in treated females

At 200 ppm although there was a significant increase in the incidence of hyaline

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February 2015

droplet deposition in kidney proximal tubular cells in males the finding was

considered not to be adverse as it was noted only at 26 weeks without any

increase in degenerative kidney lesions seen throughout the whole treatment

period. Liver weight was slightly increased from Week 26. There were no in life or

pathological changes seen in treated females.

At 100 and 500 ppm (males only) there were no treatment related changes.

Additional Comments

A short term GLP study1 revealed that IKI-technical had the potential of binding to

a male specific protein ‘α2µ-globulin’ (identified imunohistochemically in hyaline

droplets) and the protein-test substance complex deposited in the proximal tubules

caused degenerative changes in the kidney. In the present study similarly hyaline

droplets deposited in the proximal tubular cells were seen in males at 200 ppm or

higher in the early phases of treatment. Deposition of α2µ-globulin causes

degenerative changes consisting of tubular basophilic change and granular casts

in dilated tubules. Although seen early in the treatment period compared with

controls the incidences at termination were comparable, thus the absence of

degenerative renal lesions including tubular basophilic change and chronic

nephropathy in these males indicated the hyaline droplet deposition itself was

treatment related however it was not an adverse effect.

Conversely, the increased incidence of cytoplasmic vacuolation of proximal tubular

cells in the kidney of females at 5000 ppm at all examinations was considered to

be treatment related and adverse with a higher incidence of chronic nephropathy.

1 Kuwahara, M., IKI-220 technical: 28 day dose range finding study in rats, The

Institute of Environmental Toxicology, Japan, 2002. ISK Document No. 2025 IET

98-0140

Conclusion IKI-220 technical did not demonstrate any carcinogenic potential. Target organs

identified were the kidney and liver.

Type of study Carcinogenicity study in mice

Flag Supporting


Endpoints


LOAEL: 250 ppm – 29/38 mg/kg bw/day

males/females respectively – altered lung pathology

NOAEL: <250 ppm - 29/38 mg/kg bw/day

males/females respectively

Neoplastic Effects

LOAEL: 250 ppm - 29/38 mg/kg bw/day

males/females respectively – alveolar/bronchiolar

adenoma

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February 2015

NOAEL: <250 ppm - 29/38 mg/kg bw/day


Tumours Lung tumours – alveolar/bronchiolar

Malignant/Benign

Increased incidence of carcinoma in males at 750 ppm and 2250 ppm and

females at 2250 ppm. Increased incidences of adenoma in all dose groups of both

sexes. Combined incidences 45-60% males, 37-53% females, across all treated

groups

Background Incidence 17% males, 15% females

Time of Onset Terminal

Survival There was no adverse effect of treatment on mortality

Reference

Ridder, W. E., Watson, M., An oncogenicity study in mice with IKI-220 technical,

Ricerca Biosciences Ltd, Toxicology and Pharmacology, USA, 2003. ISK

Document No. 2002 011885-1

Klimisch Score 1


GLP Y


Species Mouse

Strain Crl:CD-1® (ICR) BR VAF/plus

No/Sex/Group 80M and 80 F (control and 2250 ppm groups – 10M and 10F sacrificed at 26 and

52 weeks for interim evaluations), 60M and 60F at 250 and 750 ppm

Dose Levels 0, 250, 750, 2250 ppm equivalent to 0, 29, 88, 261 mg/kg bw/day males and 0, 38,

112, 334 mg/kg bw/day females respectively


Study Summary

There were no treatment related effects on mortality, clinical signs, bodyweight

gain, food consumption or leucocyte differentials at any dose. Treatment related

increases in liver weight were evident in both sexes at all dosages at 26 and 52

weeks and termination. At termination necropsy revealed an increased number of

animals with lung masses or nodules in treated groups which correlated with an

increase in the incidence of primary lung tumours (alveolar/bronchiolar) in both

sexes at all doses. The incidence in males ranged from 45 – 60% and 37 – 53% in

females compared with 17% and 15% in male and female concurrent control

groups. Additional histopathological findings consisted of an increased incidence

of alveolar/bronchiolar hyperplasia in treated mice, an increased incidence of

hepatocellular hypertrophy in the liver of males at all dosages and females at 2250

ppm and an increased incidence of extramedullary haemopoiesis in the spleen of

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February 2015

males at all dosages. Decreased cellularity (hypocellularity) was noted in both

sexes at 2250 ppm. The incidence of this finding was increased in males at 750

and 2250 ppm and all treated groups of females.

Additional Comments No no effect level for tumour incidence or toxicity was established in this study

Conclusion

IKI-220 technical demonstrated carcinogenic potential in the lung manifest as

increased incidences principally of bronchiolar/alveolar epithelial adenoma. No

NOAEL was demonstrated in this study. The liver and kidney were identified as

target organs

Type of study Carcinogenicity study in mice

Flag Key


Endpoints


LOAEL: 250 ppm 30.3/36.3 mg/kg bw/day

males/females respectively – altered lung pathology

NOAEL: 80 ppm 10.0/11.8 mg/kg bw/day


Neoplastic Effects

LOAEL: 250 ppm males (30.3 mg/kg bw/day),

increased incidence of lung adenoma, >250 ppm

females (36.3 mg/kg bw/day)

NOAEL: 80 ppm males, 250 ppm females (10.0/36.3

mg/kg bw/day males/females)

Tumours Lung adenoma – alveolar/bronchiolar, males only 42%

Malignant/Benign Benign

Background Incidence Males 16%

Time of Onset Termination

Survival No treatment related effects

Reference

Nagaoka, T., Dietary carcinogenicity study of IKI-220 technical in mice, Shin

Nippon Biomedical Laboratories Ltd, Japan, 2004. ISK Document No. 2053 SBL

40-50

Klimisch Score 1


GLP Y


92


February 2015

Species Mouse

Strain Crj:CD-1 (ICR)


Dose Levels 0, 10, 25, 80 250 ppm equivalent to 0, 1.20, 3.14, 10.0, 30.3 and 0, 1.42, 3.67,

11.8, 36.3 mg/kg bw/day males/females respectively


Study Summary

There was no adverse treatment related effect on survival or any treatment related

effects on clinical signs, food consumption, bodyweight gain or organ weights at

any of the dosages investigated. Necropsy revealed in males only receiving 250

ppm to have an increased incidence of lung masses, histopathologically these

were identified as pulmonary alveolar/bronchiolar adenoma. In both sexes at 250

ppm there was an increase in the non neoplastic finding of

hyperplasia/hypertrophy of the epithelial lining of terminal bronchioles albeit slight

in all affected animals.


Conclusion

IKI-220 technical demonstrated carcinogenic potential in the lung manifest as

increased incidences principally of bronchiolar/alveolar epithelial adenoma in

males at the highest dose investigated. The lung was also identified as a target

organ.

Type of study Lung cell cycle analysis in the mouse


Test Substance IKI-220, Lot No. 9809

Reference

Nomura, M., IKI-220: Cell cycle analysis using BRDU in the mouse lung by

dietary admixture administration for three days, Safety Sciences Group,

Safety Science Research Laboratory, Ishihara Sangyo Kaisha, Japan,

2003. ISK Document No. 2047 AN-2110

Klimisch Score

2 – reliable with restrictions - on the basis that the study was conducted

‘in-house’ by the Applicant Ishihara Sangyo Kaisha. The Applicants’ own

Compliance Statement includes the comment ‘the study was not conducted

or reported in compliance with Good Laboratory Practice (GLP)

Regulations. However, we believe that the results of this study are

scientifically valid and would not have been different if the study had been

conducted under GLP regulations’


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February 2015

GLP Conducted in accordance with GLP principles

Test Guideline/s Not applicable

Species Mouse

Strain Crj: CD-1 (ICR)

No/Sex/Group 5M

Dose Levels

0, 80, 250, 750, 2250 ppm – equivalent to 0, 12.3, 40.9, 129.6, 339.3

mg/kg bw/day – admixture with the diet. Bromodeoxyuridine (Brdu – a cell

cycle marker) was injected 14 and 2 hours prior to sacrifice

Study Summary

There were no deaths or any adverse treatment related clinical signs.

There were no macropathological changes. Histopathological lung sections

were stained with anti-Brdu monoclonal antibody then examined

immunohistochemically. The terminal bronchiole was targeted for

assessment. The Brdu Index was higher at 250, 750 and 2250 ppm

compared with concurrent controls. At 80 ppm values were comparable

with the control indicating a threshold between 80 ppm and 250 ppm for

effects in the terminal bronchiolar epithelia of the lung – an increase in the

number of cells in the synthesis phase of the cell cycle. The results

correlate with the carcinogenicity study in which increased numbers of

bronchioloalveolar tumours were seen at 250 ppm or higher.


Conclusion IKI-220 demonstrated effects in the terminal bronchioles of the lung

causing increased numbers of cells in the synthesis phase.

Type of study Toxicity/reversibility study in the mouse



Reference

Nomura, M., IKI-220: Toxicological effect on the mouse lung and its

reversibility by dietary administration for 28 days followed by a 28-day

recovery period, Safety Sciences Group, Safety Science Research

Laboratory, Ishihara Sangyo Kaisha, Japan, 2003. ISK Document No. 2049

AN-2140

Klimisch Score





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February 2015







Species Mouse

Strain Crj:CD-1 (ICR)

No/Sex/Group

5F with 5 per group sacrificed at the end of 28 days of treatment then 5 per

group sacrificed after 7, 14 or 28 days recovery – admixture with the diet.

Bromodeoxyuridine (Brdu – a cell cycle marker) was injected 2 hours prior

to sacrifice.

Dose Levels 0, 2250 ppm equivalent to 0, 295 – 303 mg/kg bw/day

Study Summary

The reversibility of IKI-220 induced effects in the terminal bronchiolar

epithelial cells of mice was assessed by measuring the uptake of Brdu (a

measure of the number of cells in the synthesis (S) phase of the cell cycle.

The number indicates cells preparing to divide or have passed the

synthesis phase.

There were no deaths or any clinical signs considered attributable to

treatment. At necropsy slight enlargement of the liver noted at the end of

the treatment period however this was not evident in any of the recovery

groups.

The terminal bronchioles were examined for counting of Brdu positive cells.

Clara cells in the same tissues were also examined. The Brdu Index was

significantly increased in treated animals at the end of 28 days treatment

compared with concurrent controls, however, there was no difference

between the treated and control group after 7, 14 or 28 days of recovery.

There were no histopathological findings in any of the tissues. Anti-Clara

cell antibodies also increased in the terminal bronchioles at the end of the

treatment period. Morphologically altered Clara cells returned to normal

within 7 days of recovery. The altered morphology consisted of greater

length, elongation and protruded cytoplasm with enlarged and increased

numbers of secretory granules in the cytoplasm. These findings were

consistent with those seen with styrene toxicity with the difference that IKI-

220 was not cytotoxic to the terminal bronchioles and did not induce

necrosis. Whereas a metabolite of styrene has been shown to be the

cause of effects on Clara cells related metabolites of IKI-220 did not show

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February 2015

any cytotoxic or mitogenic activity on the target tissue. Thus, the effects of

IKI-220 on the terminal bronchioles of mouse lung were readily reversible

on withdrawal of exposure, returning to normal within 7 days and without

adverse findings in the lung.


Conclusion

IKI-220 demonstrated activity affecting the Clara cells in terminal

bronchioles, however, the effect was completely reversible with a few days

of withdrawal of exposure to the test substance.

Type of study Comparative study of cell cycle analysis between 3 strains of mice



Reference

Nomura, M., IKI-220: A comparative study among three mouse strains on

cell cycle analysis in the lung by dietary administration of IKI-220 or

Isoniazid for three days, Safety Sciences Group, Safety Science Research


AN-2200

Klimisch Score











Species Mouse

Strain Crj: CD-1 (ICR), Jcl: B6C3F1, Jcl: C57/6J

No/Sex/Group 5M

Dose Levels

0, 2250 ppm IKI-220 technical, 2250 ppm Isoniazid (positive control)

equivalent to:

IKI-220 mg/kg bw/day Isoniazid mg/kg bw/day

CD-1 299 298

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February 2015

B6C3F1 316 325

C57 306 290

Admixture with the diet

Study Summary


Macropathology did not reveal any treatment related changes. Histology

sections were then examined immunohistochemically after staining with

anti-Brdu monoclonal and anti-Clara cell antibody and CC-10 polyclonal

antibodies. The terminal bronchioles were then examined.

The Brdu index in the CD-1 strain was significantly increased compared

with the concurrent controls, however, the values for the B6C3F1 and C57

strains were comparable with the concurrent control group indicating an

overt difference between strains for IKI-220 induced mitogenic activity in

target cells of the lung terminal bronchioles. The CD-1 was the most

sensitive strain and was the strain used for the carcinogenicity

investigation. Isoniazid induced a more prominent effect than did IKI-220,

affecting all three strains, including the most resistant C57 strain. Isoniazid

increased cell turnover in the terminal bronchiolar cells of the lung of all

three strains whereas IKI-220 was only effective in the CD-1 strain.

CC-10 reaction percentages were similar in all three strains indicating

approximately 80% of the cells in the terminal bronchioles were Clara cells.

Although there were no quantitative differences between the cells

qualitative differences such as cell turnover labelled with Brdu did exist

between the strains. Thus, the Clara cells in the sensitive CD-1 strain

(higher background of spontaneous lung tumours) seemed to be

congenitally predisposed to divide more readily in response to mitogenic

stimuli. However, the Clara cells in the more resistant strains may not be

similarly predisposed. Consequently a unique adenoma related gene

named ‘pas: pulmonary adenoma susceptibility’ has been reported to

predispose some inbred mouse strains to the development of lung

tumours. Such a gene may in part be responsible for the effects caused by

administration on IKI-220 in mice.


Conclusion

IKI-220 demonstrated effects in the terminal bronchioles (Clara cells) in

CD-1 mice but was not clearly apparent in B6C3F1 and even less so in the

C57 strain, values being comparable with controls. Thus, there was a clear

differentiation in strain sensitivity of mice to IKI-220.

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February 2015

Type of study Comparative rat and mouse cell cycle analysis in the lung

Flag Supporting


Reference

Nomura, M., IKI-220: A comparative study between mice and rats on cell

cycle analysis in the lung by dietary admixture for three and seven days,

Safety Sciences Group, Safety Science Research Laboratory, Ishihara

Sangyo Kaisha, Japan, 2003. ISK Document No. 2048 AN-2130

Klimisch Score











Species Mouse. rat

Strain Crj: CD-1 (ICR) mouse, Jcl: Wistar rat

No/Sex/Group 5F

Dose Levels

0, 2250 ppm mice (equivalent to 374 – 286 mg/kg bw/day), 5000 ppm rats

(equivalent to 392 – 403 mg/kg bw/day). Admixture with the diet.

Bromodeoxyuridine (Brdu – a cell cycle marker) was administered 2 hours

prior to sacrifice.

Study Summary

There were no deaths or any adverse clinical signs of reaction. There were

no macropathological findings. Histopathological lung samples were

stained with Brdu monoclonal antibody then examined

immunohistochemically counting positive nuclei in terminal bronchioles.

The Brdu Index was significantly higher in the treated mice than concurrent

controls after 3 and 7 days indicating an increase in the number and

incidence of cells in the DNA synthesis (S) phase of cell cycle preparing for

cell division or past the S phase. Values for treated rat were comparable

with concurrent controls on both occasions indicating no such activity as

seen in the mouse. These results indicated IKI-220 had mitogenic activity

in the terminal bronchioles of the mouse but not the rat. The species

difference response was similar to that seen with styrene toxicity.

A much higher incidence of spontaneous bronchioloalveolar tumours in

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February 2015

aged mice than aged rats coupled with some toxic effect of IKI-220 that

stimulates cell turnover allowing expression of additional background

spontaneous tumours might be associated with this higher level of induced

increase of cell cycle marker of Brdu in terminal bronchioles. The results of

this study suggest the increased incidence of lung tumours in CD-1 mice

was due to an increased number of cells in the DNA synthesis phase of the

cell cycle. There was no similar response to IKI-220 in rats. Information in

the literature indicates that humans respond to similar chemicals (such as

Isoniazid) more like rats than mice and thus are unlikely to develop lung

tumours in response to exposure to IKI-220. Findings in the mouse are not

likely to translate to humans.


Conclusion IKI-220 demonstrated mitogenic effects in the terminal bronchioles of mice

but not rats indicating species specificity

Type of study Lung cell cycle analysis in the mouse


Test Substance IKI-220 Lot No. 9809 , TFNG Lot No. 0006, TFNA Lot No.0006, TFNA-AM

Lot No. 0006

Reference

Nomura, M., Cell cycle analysis using Brdu in the mouse lung following

short term dietary administration of IKI-220 and its metabolites: TFNG,

TFNA and TFNA-AM, Safety Sciences Group, Safety Science Research


AN-2163

Klimisch Score











Species Mouse

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February 2015

Strain Crj: CD-1 (ICR)

No/Sex/Group 5M

Dose Levels

0, 2250 ppm for 3 or 7 days equivalent to 389/330 (IKI-220), 402/318

(TFNG), 364/336 (TFNA), 385/332 (TFNA-AM) mg/kg bw/day for 3/7 days

respectively. – admixture with the diet. Bromodeoxyuridine (Brdu – a cell

cycle marker) was injected 3 hours prior to sacrifice

Study Summary


There were no macropathological changes. Histopathological lung samples

were treated with anti-Brdu monoclonal antibodies then examined

immunhistochemically.

The Brdu Index in the terminal bronchiole was significantly increased in the

groups treated with IKI-220, being higher after 3 days than 7 days. There

were no differences in the Brdu Index for groups receiving any of the

metabolites compared with concurrent controls. Thus, only IKI-220 induced

an increase of Brdu positive cells in the terminal bronchiolar epithelia of

mouse lung.


Conclusion Comparison of potential mitogenic activity of IKI-220 and its metabolites

showed only the parent material to have any effects.

Type of study Applicants review of lung findings in the mouse oncogenicity studies


Test Substance IKI-220 technical

Reference

Nomura, M., IKI-220: Discussion on lung finding observed in mouse

oncogenicity, Safety Sciences Group, Safety Science Research

Laboratory, Ishihara Sangyo Kaisha, Japan, 2003. ISK Document No.

2052A AN-2052

Study Summary

In summary:

Only the mouse showed significant increases in bronchioloalveolar

tumours in response to dietary administration of IKI-220 (Flonicamid)

technical. The tumours were not life threatening as nearly all were detected

at the terminal sacrifice.

There were no treatment related tumours seen in rats.

The increase in bronchioloalveolar tumours in mice was associated with an

increase in alveolar/bronchiolar hyperplasia/hypertrophy.

Short term investigations in mice with dietary administration of IKI-220

resulted in increased cell turnover of Clara cells of the terminal bronchioles

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February 2015

as measured by Brdu staining.

These short term studies did not result in any cytotoxic effects of IKI-220 in

the lung bronchioles, suggesting the effect of IKI-220 was a mitogenic

effect stimulating cell turnover.

IKI-220 is not mutagenic.

There is a threshold level for mitogenic activity between 80 and 250 ppm

administration.

There is a clear species difference between mice and rats as assessed by

lung tumour incidence and Brdu Index analysis.

IKI-220 induced a unique mitogenic activity in the terminal bronchiolar

epithelial cells (non-ciliated Clara cells) in mice but its three animal

metabolites had no similar effect.

The increased Brdu Index in Clara cells in mice and activated Clara cells in

target tissue were clearly reversible within a week of withdrawal from IKI-

220, with no damage to the lung.

The IKI-200 induced increase in the Brdu Index appears to be related to

the different sensitivity of strains of mice to development of spontaneous

tumours in the lungs as seen in CD-1 mice but not B6C3F1 (intermediate

sensitivity) and C57 (least sensitivity) mice.

Dietary administration of Isoniazid which is structurally similar to IKI-220

and which has also been shown to increase levels of spontaneous lung

tumours in mice but not in rats caused an increase in Brdu Index in all

three strains of mice. The effect of IKI-220 on the target cell of mice lungs

is clearly weaker than that of Isoniazid.

Thus, it was concluded that IKI-220 induction of increased

bronchioloalveolar tumours is unique to the mouse, especially to sensitive

strains such as the CD-1 strain which have incidences of spontaneous

tumours. A threshold between 80 and 250 ppm has been demonstrated for

the pre-neoplastic event in the CD-1 strain. This promoter effect is readily

reversible and lung tissue returns to normal within 1 week of cessation of

exposure to IKI-220. The absence of similar effects in the lung tissue of

rats suggest the effects seen in mice may not translate to other species

including humans.

Isoniazid, used to treat tuberculosis patients, has also been shown to

induce a high incidence of bronchioloalveolar tumours in mice but not in

rats. Comparison of IKI-220 and Isoniazid showed that Isoniazid was more

potent in causing cell turnover in mouse lungs than IKI-220. The IARC has

classified Isoniazid in Group 3 – cannot be classified as to its

carcinogenicity to humans. The overall conclusion is that a non-linear risk

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February 2015

assessment should be used to assess human risk for the effects observed

in mouse lungs treated with IKI-220 based on demonstration of a threshold

for effect, confirmation that IKI-220 is not mutagenic, there is rapid

reversibility without tissue damage and specificity of the effects to the CD-1

mouse strain with no effects in other mouse strains or the rat.


Conclusion

The mechanism of tumour induction is specific to the CD-1 mouse

exacerbated by its higher sensitivity due to the much higher numbers of the

target Clara cells in the bronchiolar/alveolar epithelium compared with

other mouse strains. No similar effect was demonstrated on other mouse

strains or in the rat. A threshold dose was demonstrated, there was no

dose relationship and the occurrence of tumours did not affect survival as

occurrence was observed at terminal sacrifice, primarily being benign

adenomas. Human lung has a much lower number of Clara cells in the

target tissue and thus classification (6.7) is considered not to be

appropriate.

General conclusion about carcinogenicity classification:

IKI-220 technical was not carcinogenic in the rat.

In the mouse exposure to IKI-220 technical resulted in increased incidences of primary lung tumours

(alveolar/bronchiolar adenomas and carcinomas) in both sexes. At dosages that did not induce tumours pre

neoplastic changes were noted in the lungs. Investigations to elucidate the aetiology of tumour formation in

the CD-1 strain demonstrated a dose related increase in cell proliferation in epithelial cells of the

alveolar/bronchiolar region. The induction of cell proliferation was shown to be readily and fully reversible

within 7 days of the withdrawal of treatment. The Clara cell was shown to be a specific target of IKI-220

undergoing reversible hypertrophy/hyperplasia and morphological elongation in response to the test

substance. Furthermore there was no evidence of secondary tissue responses in the areas surrounding the

activated Clara cells. Thus, the pattern of effects suggested a mitogenic rather than cytotoxic effect of IKI-

220 technical. These effects were seen only with the parent molecule, not with any of its metabolites.

Further investigation showed the effects to be species specific and strain sensitive. The proportion of Clara

cells in the lung of the mouse strains examined was approximately 80%, whereas in the rat this is only about

35%. The CD-1 mouse has the highest incidence of spontaneous bronchiola/alveolar tumours. This

combined with the proportion of immature Clara cells in the lung epithelium and higher sensitivity to

stimulated cell division would account for the high incidence of lung tumours seen.

Investigations demonstrated a threshold level for the mitogenic response, and IKI-220 technical did not

demonstrate any mutagenic or genotoxic effect at the DNA, gene and chromosome levels of organisation.

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February 2015

Thus, there is sound rationale to support the contention that IKI-220 induced bronchioalveolar tumours is

unique to the mouse and specifically to the CD-1 strain.

In the human lung the Clara cell complement is very low in respiratory and terminal bronchioles, 22% and

11% respectively. Epidemiological studies on Isoniazid, a structurally similar molecule, revealed no

relationship between its therapeutic use and the occurrence of human lung tumours. Thus, it is concluded

that a non-linear risk assessment is appropriate for IKI-220 technical based on the absence of genotoxicity,

the species specific nature of the lung effect, its ready reversibility without tissue damage and the

demonstration of consistent NOEL doses for both the mechanism and tumour formation. Consequently, it is

considered classification (6.7) is not required.

Reproductive/Developmental Toxicity [6.8]

Developmental Toxicity

Type of study Rat embryofoetal development study

Flag Key


Endpoints

Parental Toxicity

LOAEL: 500 mg/kg bw/day altered liver and kidney

micropathology

NOAEL: 100 mg/kg bw/day

Foetal Toxicity

LOAEL: 500 mg/kg bw/day – increased incidence of

skeletal anomalies


Reference Hojo, H., IKI-220 technical: A teratogenicity study in rats, The Institute of

Environmental Toxicology, Japan, 2002. ISK Document No. 2031 IET 00-0023

Klimisch Score 1


GLP Y


Species Rat

Strain Jcl:Wistar

No/ Group 24F

Dose Levels 0, 20, 100. 500 mg/kg bw/day

Exposure Type Oral gavage, Days 6 – 19 of gestation

Study Summary

The only treatment related findings amongst maternal rats were confined to 500

mg/kg bw/day. These consisted of slightly lower food intake during the dosing

period, a significant increase in liver weight, hypertrophy of centrilobular

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February 2015

hepatocytes in the liver (13/14) and vacuolation of proximal tubular cells in the

kidney (24/24). At necropsy there was an increase in placental weights whilst

examination of foetuses revealed an increase in skeletal anomalies (specifically

an increased incidence of cervical (extra) rib) considered to reflect maternal

toxicity.

There were no treatment related effects in maternal rats or foetuses at 20 or 100

mg/kg bw/day.


Conclusion

Maternal toxicity was confined to slightly lower food intake and changes to the

liver with a correlated finding of a slight increase in skeletal (extra rib) anomalies,

a foetal finding commonly considered an indicator of maternal toxicity.

Type of study Rabbit embryofoetal development study

Flag Key


Endpoints

Parental Toxicity LOAEL: 25 mg/kg bw/day – impaired weight gain

NOAEL: 7.5 mg/kg bw/day

Foetal Toxicity LOAEL: >25 mg/kg bw/day


Reference Takahashi. K., IKI-220 technical: Teratogenicity study in rabbits, The Institute of

Environmental Toxicology, Japan, 2002. ISK Document No. 2032A IET 00-0025

Klimisch Score 1


GLP Y


Species Rabbit

Strain Japanese white Kbl:JW

No/ Group 25F

Dose Levels 0, 2.5, 7.5, 25 mg/kg bw/day

Exposure Type Oral gavage, Days 6 to 27 of gestation

Study Summary

The only treatment related findings were significantly lower maternal bodyweight

gain and food intake during the dosing period seen at 25 mg/kg bw/day. There

were no adverse maternal findings at 2.5 or 7.5 mg/kg bw/day. There was no

adverse treatment related effects on embryofoetal development at any of the

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February 2015

dosages investigated.

External, visceral, and skeletal examinations of live fetuses revealed several types

of malformations and variations in all groups including the control. However, these

findings were not considered to be adverse for a number of reasons including that

many of the malformations were within the historical control range, and the

frequency of malformations did not significantly increase with dose.


Conclusion Maternal toxicity was limited to lower weight gain and food intake, however, there

were no adverse effects on embryofoetal development.

Reproductive toxicity

A preliminary study was performed but details are not reported here:

Takahashi, K., IKI-220 technical: Reproductive toxicity study in rats preliminary study, Institute of

Environmental Toxicology, Japan, 2002. ISK Docment No. 2046 IET 99-0084

Type of study Rat 2 generation reproduction study

Flag Key


Endpoints

Parental Toxicity –

F0 and F1 generation

LOAEL: 1800 ppm – 109.1/124.8 (F0),

163.8/176.8 (F1) males/females – altered kidney

pathology


males/females (The change in luteinizing hormone

seen in F1 females at 50 ppm was considered to

be a compensatory mechanism rather than a toxic

effect)

Reproductive Toxicity

LOAEL: Not identified


males/females F0 generation, 163.8/176.8 mg/kg

bw/day males/females F1 generation

Developmental

toxicity F1 and F2

offspring:

LOAEL: Not identified (males), 1800 ppm females

- 153.4 mg/kg bw/day – delayed vaginal opening in

F1 generation

NOAEL: 1800/300 ppm 163.8/30.5 mg/kg b/day

males/females F1 generation

NOAEL: 1800 ppm (females only F2 generation) –

176.8 mg/kg bw/day

105


February 2015

Reference

Takahashi, K., IKI-220 technical: reproductive toxicity study in rats, The

Institute of Environmental Toxicology, Japan, 2002. ISK Document 2037

No. IET 99-0085

Klimisch Score 1


GLP Y

Test Guideline/s US EPA OPPTS 870.3800, OECD 416

Species Rat

Strain Jcl:Wistar

No/Sex/Group 24 males and 24 females

Dose Levels

0, 50, 300, 1800 ppm equivalent to 0, 3.07, 18.3, 109.1 and 0, 3.39, 20.7,

124.8 mg/kg bw/day males/females F0 generation and 0, 4.67, 28.2, 163.8

and 0, 4.95, 30.5, 176.8 mg/kg bw/day males/females F1 generation

respectively respectively


Study Summary

There was no adverse effect of treatment on reproductive capacity at any

of the dosages investigated in either generation.

1800 ppm resulted in increased absolute and relative kidney weights in

adult males of both generations, often appearing pale at necropsy.

Micropathologically there were increased incidences of tubular basophilic

change and granular casts in dilated tubules in both generations.

Immunohistochemical examination of the hyaline droplets revealed the

presence of α2µ-globulin. Incidences of vacuolation of proximal tubular

cells in the kidney were increased in adult females of both generations.

Delayed vaginal opening was seen in F1 females at 1800 ppm (but not F2

generation females).

Findings at 300 ppm were confined to increased relative kidney weight in

F1 males with an increased incidence of hyaline droplet deposition in the

proximal tubule cells of males of both generations. Because of the absence

of any tubular basophilic changes or granular casts this change was

considered not to be adverse.

There were no treatment related findings at 50 ppm in either sex or

generation.


Conclusion Treatment with IKI-220 did not result in any in life signs of toxicity in either

generation. Reproductive capacity was unaffected in both generations.

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February 2015

Toxicity was confined to kidney changes consistent with findings in

subchronic and chronic toxicity studies. Developmental toxicity was

confined to F1 females at the highest dose where there was a delay in

sexual maturation manifest as delayed vaginal opening, however,

reproductive capacity was unaffected.

Type of study IKI-220 oestrogen receptor binding affinity study in rats



Endpoint Receptor binding affinity – very low binding affinity for both α- and β-

receptors

Reference

Takahasi, K., IKI-220 technical: reproductive toxicity study in rats additional

observations, The Institute of Environmental Toxicology, Japan, 2002. ISK


Klimisch Score 2 – reliable with restrictions


GLP Not specified


Species Rat

Strain Jcl:Wistar


Dose Levels 0, 50, 300, 1800 ppm equivalent to 0, 3.7, 22.3, 132.9 and 0, 4.4, 26.5,

153.4 mg/kg bw/day males/females respectively


Study Summary

The serum samples used for this investigation were those taken from F1

adults of the previously cited rat reproduction study.

Measurement of serum hormones revealed a significant increase in LH in

females at 300 ppm and a slight decrease in 17β- oestradiol in females at

1800 ppm. No changes were seen in the hormone levels of males.

Oestrogen receptor binding affinity was very low indicating this not to be

the mechanism for IKI-220 anti-oestrogen effects. IKI-220 may cause an

increase in gonadotrophin levels as a result of slight inhibition of 17β-

oestradiol production rather than an acceleration of gonadotrophin

production in females since no change were noted in treated males. Thus,

it was concluded that IKI-220 technical causes a decrease in blood 17β-

oestradiol levels of females at 1800 ppm resulting in decreases in ovary

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February 2015

and uterine weights and an increase in the day of age of vaginal opening.

Additional Comments

The study report does not contain an author signature page or any

reference to conduct in compliance with GLP principles, however, the data

are considered reliable.

Conclusion

The slightly later sexual maturation of F1 females at 1800 ppm in the

reproductive study was attributable to IKI-220 technical lowering 17β-

oestradiol blood levels.

General conclusion about reproductive/developmental toxicity classification:

IKI-220 technical did not adversely affect fertility or reproductive capacity. There were indications suggestive

of interference with sexual maturation of F1 offspring manifest principally as slightly delayed vaginal opening

in F1 offspring however this was not repeated for F2 offspring. Micropathological changes in the kidneys

were seen in adult males and females of the F0 and F1 generations, a finding consistent with the sub chronic

toxicity studies.

IKI-220 did not exert any adverse effect on embryofoetal development. Although an increased incidence of

extra (cervical) rib was noted in the rat at the highest dose investigated this is commonly associated with

maternal toxicity rather than a direct effect of treatment and thus is not relevant to human risk. (Preliminary

investigations in the rat up to 1000 mg/kg bw/day resulted in deaths and liver and kidney changes indicating

the highest dose in the main study (500 mg/kg bw/day) was on the margins of anticipated maternal toxicity).

Reviewers comment: It should be noted that the European Food Safety Authority (EFSA) and subsequent

European Chemical Agency (ECHA) reviews differed in their respective conclusions regarding embryofoetal

development. The EFSA concluded that there was evidence of adverse embryofoetal developmental effects

in the rat and the rabbit at (essentially) non-maternally toxic doses (500 and 7.5 mg/kg bw/day respectively)

consisting of an increased incidence of cervical ribs in rats and an increase in the incidence particularly of

visceral malformations in rabbits. In the rat study there was evidence of treatment related adverse maternal

effects at 500 mg/kg bw/day and thus a ‘disturbance’ in the number of foetuses with extra ribs (which was

within the historical background control range) is consistent with a ‘stress’ response rather than any direct

effect on development, if indeed it is an ‘effect’ at all. With regard to the rabbit the incidences of

malformations were in fact within the historical control range, were not consistent nor were they dose related.

Also, no increase in extra ribs was noted which, given the argument that this was an effect in the rat might

reasonably be expected to be seen in the rabbit if it were truly a treatment related direct effect on

embryofotal development. Thus, the Reviewer concurs with the conclusions of the ECHA that there is no

direct adverse effect of Flonicamid on embryofoetal development.

Given the marginal nature of the findings in the reproductive study, confined to delayed vaginal opening in

the high dose F1 females only but without any adverse effect on reproductive capacity no classification

(6.8B) is considered necessary. No classification for 6.8C is required.

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Target Organ Systemic Toxicity [6.9]

Preliminary dose range finding studies were conducted for the rat and the dog but the details are not presented:

Ridder., W.E., Yoshida, M., Watson, M., A 28-day oral toxicity study in dogs with IKI-220 technical, Ricerca LLC,

USA, 2001. Document No. 2014 010871-1

Kuwahara, M., IKI-220 technical: 28-day dose range finding study in rats, Institute of Environmental Toxicology,

Japan, 2002. ISK Document No. 2025 IET 98-0140

Type of study 28 day dermal toxicity study in rats

Flag Key


Endpoint

LOAEL: Not identified >1000 mg/kg bw/day


Reference

Ridder, W., A 28 day repeated dose dermal toxicity study in rats with IKI-220,

Toxicology and Pharmacology, Ricerca, LLC, USA, 2001. ISK Document No. 2017

012074-1

Klimisch Score 1


GLP Y


Species Rat

Strain Crl:CD® (SD) (IGS) BR


Dose Levels 0, 20, 150, 1000 mg/kg bw/day, 6h per day, occluded

Study Summary There were no treatment related effects on any of the parameters recorded at any

of the dosages investigated.


Conclusion No classification required

Type of study Mouse 90 day toxicity study

Flag Key


Endpoint LOAEL: 1000 ppm, equivalent to 153.9/191.5 mg/kg bw/day males/females

respectively – altered spleen micropathology in both sexes and liver in males

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February 2015

NOAEL: 100 ppm equivalent to 15.25/20.1 mg/kg bw/day males/females

respectively

Reference Ridder, W., A 13 week feeding study in mice with IKI-220, Toxicology and

Pharmacology, Ricerca, LLC, USA, 2001. ISK Document No. 2020 8090-1

Klimisch Score 1


GLP Y


Species Mouse

Strain Crl:CD-1® (ICR) BR


Dose Levels 0, 100, 1000, 7000 ppm equivalent to 0, 15.25, 153.9, 1069 and 0, 20.10, 191.5,

1248 mg/kg bw/day males/females respectively. By admixture with the diet

Study Summary

There were no deaths. There were no clear treatment related clinical signs seen at

any dosage. Lower weight gain in both sexes at 7000 ppm generally during the

first 5 weeks of treatment combined with lower food intake was considered to be

attributable to palatability rather than a toxic effect of treatment. Although

subsequent weight gain was evident comparability with controls was not regained

by termination. Haematological investigations revealed significantly lower numbers

of red blood cells, decreased haemoglobin, haematocrit, mean cell volume and

mean corpuscular haemoglobin in both sexes receiving 7000 ppm suggesting a

treatment related anaemia. There were no haematological changes at 100 or 1000

ppm. Blood chemistry revealed significantly increased creatinine, bilirubin, sodium

and chloride with decreased potassium in males at 7000 ppm whilst females at

this dose revealed increased blood glucose. The increased total bilirubin could be

due to the decreased red blood cell count reflecting a treatment related red blood

cell destruction whilst the increased blood sugar could reflect liver changes. At

necropsy absolute and relative liver and spleen weights were increased in both

sexes at 7000 ppm compared with controls, the spleen change possibly being

related to anaemia. Histopathological investigation revealed centrilobular

hepatocellular hypertrophy in the liver of both sexes at 7000 ppm and males at

1000 ppm, increased extramedullary haemopoiesis and pigment deposition in the

spleen of both sexes at 7000 ppm and 1000 ppm and increased pigment

deposition in the bone marrow in both sexes at 7000 ppm. The spleen and marrow

changes were considered to reflect the anaemia whilst the liver changes were

considered to reflect possible enzyme induction.


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February 2015

Conclusion The liver, spleen and bone marrow were identified as target organs.

Type of study Rat 90 day toxicity study

Flag Key


Endpoint

LOAEL: 1000/5000 ppm males/females equivalent to 60.0/340.1 mg/kg bw/day

males/females respectively – altered kidney micropathology both sexes, liver in

females

NOAEL: 200/1000 ppm males/females equivalent to 12.11/72.3 mg/kg bw/day


Reference

Kuwahara, M., IKI-220 technical: 90-day subchronic oral toxicity study in rats, The

Institute of Environmental Toxicology, Japan, 2002. ISK Document No. 2015 IET

98-0141

Klimisch Score 1


GLP Y


Species Rat

Strain Jcl:Wistar


Dose Levels

0, 50 (males), 200, 1000, 2000 (males), 5000 (females) ppm equivalent to 0,

3.079, 12.11, 60.0, 119.4 and 0, 14.52, 73.3, 340.1 mg/kg bw/day males/females

respectively. By admixture with the diet

Study Summary

Treatment at 5000 ppm, assessed in females only resulted in significantly lower

food intake compared with controls. Haematocrit was significantly decreased

whilst mean corpuscular haemoglobin concentration was increased. Triglyceride

was decreased. Absolute and relative liver and kidney weights were increased

with histopathology revealing increased incidences of centrilobular hypertrophy in

the liver and cytoplasmic vacuolation of proximal tubular cells in the kidney when

compared with concurrent controls

At 2000 ppm, assessed in males only, findings were confined to post sacrifice

investigations and consisted of increased absolute and relative kidney weight with

kidneys noted at necropsy to be pale. Histopathology revealed deposition of

hyaline droplets containing α2µ-globulin in proximal tubules of the kidney of all

animals. The incidences of granular casts in dilated tubules and basophilic change

of tubular cell, considered to be degenerative change due to α2µ-globulin

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February 2015

deposition were significantly increased. There was an increased incidence of

centrilobular hepatocellular hypertrophy in the liver.

At 1000 ppm findings were confined to males only and consisted of increased

absolute and relative kidney weight with hyaline droplet deposition in proximal

tubular cells, basophilic changes in tubular cells and granulated casts in dilated

tubules of the kidney. There were no treatment related effects in females.

At 200 ppm the only treatment related change in either sex was confined to 8/12

males showing hyaline droplet deposition in proximal tubular cells of the kidney,

however this was considered not to be an adverse effect.

There were no treatment related changes in any parameters at 50 ppm, assessed

in males only.

Additional Comments

Reviewers comment: the findings relating to alpha-2u-globulin-mediated

nephropathy are not considered relevant to humans. Therefore for human

health risk assessment purposes the LOAEL in males could be

considered to be 2000 ppm (equivalent to 119.4 mg/kg bw/day and the

NOAEL 1000 ppm (equivalent to 60 mg/kg bw/day).

Conclusion The liver and kidney were identified as target organs

Type of study Dog 90 day toxicity study

Flag Key


Endpoint

LOAEL: 20 mg/kg bw/day – acute vomiting episodes post dosing


Reference Ridder, W. E., A 90-day toxicity study in dogs with IKI-220 technical, Toxicology

and Pharmacology, Ricerca LLC, USA, 2001. ISK Document No. 2016 011509-1

Klimisch Score 1


GLP Y


Species Dog

Strain Beagle


Dose Levels 0, 3, 8, 20, 50 (females only) mg/kg bw/day. Oral capsule

Study Summary After the first dose, clinical signs of an acute response to the test substance –

vomiting, collapse, prostration, convulsions – were seen in 2 females receiving 50

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February 2015

mg/kg bw/day whilst vomiting was seen in 2 males receiving 20 mg/kg bw/day.

Clinical signs persisted amongst the females at 50 mg/kg bw/day with associated

decreased food intake, inappetance, anorexia and weight loss resulting in 1

female being sacrificed in Week 4 whilst another was removed from treatment in

Week 9 after which there was complete reversal of the acute signs. Vomiting post

dosing was a persistent sign amongst males at 20 mg/kg bw/day. Clinical

pathology revealed changes in red blood cell and reticulocyte counts in females at

50 mg/kg bw/day in Week 7 but which were not evident at termination. Increased

total protein in blood chemistry was evident in males at 20 mg/kg bw/day in Week

7 but was not evident at termination. No treatment related changes were evident

in urinalysis at any dosage. Histological examinations of tissues from the female

that was sacrificed at 50 mg/kg bw/day revealed mild oedema of the pancreas,

mild evolution of the thymus and vacuolation of the tubules in the inner cortex of

the kidney, the latter finding also seen in another female at this dose. A third

female at 50 mg/kg bw/day had mild haemorrhage at the ileo-colic junction. There

were no other treatment related changes in any animal at any dose.

Additional Comments

No additional comments.

Reviewer comment - The report author indicated a suggested treatment related

effect on thymus weight (decreased) in males at 20 mg/kg bw/day however did not

indicate this in the report summary. There were no histopathological changes

reported for the thymus.

Conclusion

Clinical signs were considered principally attributable to an immediate acute

response to the test substance rather than systemic. Systemic toxicity was evident

with decreased food intake and weight loss in females. No obvious target organs

were identified.

Reviewer comment – The changes in kidney micropathology seen in 2 females at

50 mg/kg bw/day are consistent with renal changes seen in female rats.

Type of study Dog 52 week toxicity

Flag Key


Endpoint

LOAEL: 20 mg/kg bw/day – acute vomiting episodes post dosing and

haematological changes in both sexes, lower weight gain in females


Reference

Ridder, W. E., Watson, M., A 52 week oral toxicity study in dogs with IKI-220

technical, Toxicology and Pharmacology, Ricerca, LLC, USA, 2002. ISK

Document No. 2044 012075-1-1

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February 2015

Klimisch Score 1


GLP Y


Species Dog

Strain Beagle


Dose Levels 0, 3, 8, 20 mg/kg bw/day. Oral capsule

Study Summary

There were no treatment related deaths at any dose. All males and 4/6 females at

20 mg/kg bw/day vomited after the first dose with one male and one female

showing decreased activity and ataxia. Incidences of vomiting continued post

dosing but eventually resolved as tolerance improved. These findings are an acute

response to the test substance rather than any systemic response. There were no

treatment related clinical signs at any other dosage. Lower bodyweight gain was

evident in females receiving 20 mg/kg bw/day. There were no treatment related

changes in clinical chemistry parameters at any dosage. The only notable

haematological change was a significantly increased reticulocyte count in both

sexes at 20 mg/kg bw/day at termination, a finding consistent with that seen in the

earlier 90 day study suggesting a pattern affecting red blood cells. There were no

treatment related macroscopic changes noted at necropsy or any

histopathological changes in any tissues at any dosage.


Conclusion

Initial clinical signs post dose were considered to be an acute response to the test

substance which were eventually tolerated. Indications of systemic toxicity were

confined to lower weight gain in females and haematological changes in both

sexes, however, no target organs were identified.

Type of study Acute neurotoxicity study in rats

Flag Key


Endpoint

LOAEL: Neurotoxicity: >600 (males), >1000 (females) mg/kg bw; systemic toxicity:

1000 mg/kg bw NB – neurotoxicity/pathology was evaluated only in males treated

at 600 mg/kg bw and females at 1000 mg/kg bw

NOAEL: Neurotoxicity: 600 (males), 1000 (females) mg/kg bw; systemic toxicity:

600 (males), 300 (females) mg/kg bw

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February 2015

Reference

Ridder, W. E., Watson, M., An acute neurotoxicity study in rats with IKI-220

technical, Toxicology and Pharmacology, Ricerca Biosciences LLC, USA, 2002.

ISK Document No. 2043 012076-1-2

Klimisch Score 1


GLP Y


Species Rat

Strain Sprague Dawley Crl:CD® (SD) IGS BR


Dose Levels 0, 100, 300, 600 (males only), 1000 (5M and 10F) mg/kg bw/day. Oral gavage

Study Summary

A single male at 1000 mg/kg bw exhibited impaired locomotion, decreased activity

and tremors at 30 and 60 minutes post dosing and was found dead the following

day. A single female at 1000 mg/kg bw exhibited slightly impaired mobility,

tremors and abnormal gait at 30 and 60 minutes post dosing but subsequently

recovered. These events, at a dosage higher than the LD50 value in males were

considered to be attributable to acute systemic toxicity rather than neurotoxicity.

There were no other clinical signs considered attributable to treatment at any

dosage. There were no treatment related neurotoxic or neuropathological effects

at the highest dosage investigated in each sex – 600 mg/kg bw in males and 1000

mg/kg bw in females, thus IKI-220 is not considered a neurotoxin.


Conclusion There was no evidence of neurotoxicity

Type of study 90 day repeat dose neurotoxicity study in rats

Flag Key


Endpoint

LOAEL: Neurotoxicity: >10000 ppm (625/722 mg/kg bw/day males/females).

Systemic toxicity: 10000 ppm (625/722 mg/kg bw/day males/females).

NOAEL: Neurotoxicity: 10000 ppm (625/722 mg/kg bw/day males/females).

Systemic toxicity: 1000 ppm (67/81 mg/kg bw/day males/females)

Reference

Schaefer, G. J., A dietary subchronic (90-day) neurotoxicity study on IKI-220

technical in rats, WIL Research Laboratories, USA, 2003. ISK Document No. 2039

449002

Klimisch Score 1

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February 2015


GLP Y


Species Rat

Strain Crl:CD® (SD) IGS BR


Dose Levels 0, 200, 1000, 10000 ppm equivalent to 0, 13, 67, 625 and 0, 16, 81, 772 mg/kg

bw/day males/females respectively – admixture with the diet

Study Summary

There were no deaths or any treatment related clinical signs at any dosage. Lower

weight gain was evident in both sexes at 10,000 ppm throughout the treatment

period, being 32% and 12% for males and females respectively compared with

concurrent controls by termination. Concomitant lower food intake was seen in

both sexes at 10,000 ppm. There were no signs indicative of neurotoxicity as

assessed by locomotor activity assessments at any dose nor were there any

treatment related macroscopic or neuromicropathological changes at any dose.


Conclusion There was no evidence of neurotoxicity

1. General conclusion about target organ systemic toxicity:

In the rat the liver and kidneys were identified as target organs in both sexes although there was a clear

difference between the sexes for morphological and sensitivity for renal changes. These can be separated

as a treatment related albeit not adverse effect in the kidney of males only resulting from hyaline deposition

resulting from IKI-220 binding to α2µ-globulin and a more chronic, degenerative renal change seen in both

sexes in the rat and to a lesser degree the dog. There was an indication of mild anaemia in the dog.

It should be noted that α2µ-microglobulin is a male rat specific protein and thus effects mediated by this

mechanism have no relevance to humans. The degerative renal changes in rats occurred with a LOAEL

greater than those within the guidance range values for classification.

In the mouse the principal target organs were the liver and haemopoietic system and lung. There was only

slight evidence of kidney dysfunction.

The liver changes seen in rats and mice were consistent irrespective of the duration of exposure, being

increased incidences of hepatocellular hypertrophy. There was no evidence of this change developing any

further and hepatocellular hypertrophy is consistent with a change associated with enzyme induction. Thus,

in the absence of any degenerative change this is considered not of any significant human relevance.

Dermal exposure is well tolerated.

IKI-220 technical does not induce any neurotoxic effects.

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February 2015

It is therefore concluded that no classification (6.9) is required.

2. Metabolites

Investigations were conducted on five metabolites, TFNA, TFNA-AM, TFNG, TFNG-AM and TFNA-OH

consisting of acute oral LD50 and bacterial reverse mutation assessments. 90 day toxicity studies were also

conducted with TFNA and TFNG.

Type of study Acute oral limit toxicity study in rats


Test Substance TFNA, Batch No. 0006

Endpoint LD50


Reference Damme, B., TFNA: Acute oral toxicity study in rats, RCC Ltd, Toxicology Division,

Switzerland, 2002. ISK Document No.2101 834142

Klimisch Score 1


GLP Y


Species Rat









Type of study 90 day toxicity study in rats


Test Substance TFNA, Lot No. 9709

Endpoint

LOAEL: >2000 ppm males (136 mg/kg bw/day), >5000 ppm females (409 mg/kg

bw/day)

NOAEL: 2000 ppm males (136 mg/kg bw/day), 5000 ppm females (409 mg/kg

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February 2015

bw/day)

Reference Nagaike, M., TFNA: 90-day subchronic oral toxicity study in rats, Ishihara Sangyo

Kaisha, Japan, 2003. ISK Document No. 2112 AN-1992



GLP N


Species Rat

Strain Jcl:Wistar


Dose Levels

0, 50 (males only), 200 (females only), 2000 (males only), 5000 (females only ppm

equivalent to 0, 3.42, 15.9, 136, 409 mg/kg bw/day respectively. Admixture with

the diet

Study Summary There were no treatment related changes in any of the parameters assessed at

any dosage.


Conclusion There was no evidence of toxicity

Type of study Acute oral limit toxicity in rats


Test Substance TFNA-AM. Batch No. 0006

Endpoint LD50


Reference Damme, B., TFNA-AM: Acute oral toxicity study in rats, RCC Ltd, Toxicology

Division, Switzerland, 2002. ISK Document No.2102 834750

Klimisch Score 1


GLP Y


Species Rat



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February 2015









Test Substance TFNG, Batch No. 0006

Endpoint LD50


Reference Damme, B., TFNG: Acute oral toxicity study in rats, RCC Ltd, Toxicology Division,

Switzerland, 2002. ISK Document No.2103 834761

Klimisch Score 1


GLP Y


Species Rat









Type of study 90 day toxicity study in rats


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February 2015

Test Substance TFNG, Lot No. 9709

Endpoint

LOAEL: >2000 ppm males (135 mg/kg bw/day), >5000 ppm females (411 mg/kg

bw/day)

NOAEL: 2000 ppm males (135 mg/kg bw/day), 5000 ppm females (411 mg/kg

bw/day)

Reference Nagaike, M., TFNG: 90-day subchronic oral toxicity study in rats, Ishihara Sangyo

Kaisha, Japan, 2003. ISK Document No. 2112 AN-1993



GLP No


Species Rat

Strain Jcl:Wistar


Dose Levels

0, 50 (males only), 200 (females only), 2000 (males only), 5000 (females only ppm

equivalent to 0, 3.56, 16.5, 135, 411 mg/kg bw/day respectively. Admixture with

the diet

Study Summary There were no treatment related changes in any of the parameters assessed at

any dosage.


Conclusion There was no evidence of toxicity



Test Substance TFNG-AM, Batch No. 0006

Endpoint LD50


Reference Damme, B., TFNG-AM: Acute oral toxicity study in rats, RCC Ltd, Toxicology


Klimisch Score 1


GLP Y

120


February 2015


Species Rat











Test Substance TFNA-OH, Batch No. 0010

Endpoint LD50


Reference Damme, B., TFNA-OH Acute oral toxicity study in rats, RCC Ltd, Toxicology


Klimisch Score 1


GLP Y


Species Rat









121


February 2015

Study type/Test Guideline Result Reference

Ames Reverse mutation test.

OECD 471, US EPA OPPTS 870.5100, Commission Directive 2000/32/EEC, L1362000, Annexe 4D

Non mutagenic,

negative with or

without metabolic

activation

Wollny, H-E., Salmonella typhimurium and

escherichia coli reverse mutation assay with

TFNA, RCC Cytotest Cell Research GmbH,

Germany, 2002. ISK Document No. 2106

716901

Ames Reverse mutation test. OECD 471, US EPA OPPTS 870.5100 Commission Directive 2000/32/EEC, L1362000, Annexe 4D

Non mutagenic,

negative with or

without metabolic

activation



TFNA-AM, RCC Cytotest Cell Research

GmbH, Germany, 2002. ISK Document No.

2106 716902

Ames Reverse mutation test. OECD 471, US EPA OPPTS 870.5100, Commission Directive 2000/32/EEC, L1362000, Annexe 4D

Non mutagenic,

negative with or

without metabolic

activation



TFNG-AM, RCC Cytotest Cell Research


2108 716904


Non mutagenic,

negative with or

without metabolic

activation

May, K., TFNG Bacterial reverse mutation test,

Huntingdon Life Sciences Ltd, UK, 2002. ISK

Document No. 2110 ISK 268-023923


Non mutagenic,

negative with or

without metabolic

activation



TFNA-OH, RCC Cytotest Cell Research


2109 716905

Conclusion None of the metabolites investigated

demonstrated mutagenic potential

General conclusion about mammalian toxicology of active ingredient and metabolites

In contrast to the parent material, IKI-220 technical, the metabolites TFNA and TFNG did not elicit adverse

effects in the liver or kidneys in 90-day studies in rats indicating them to be a lower order of toxicity. Similarly,

acute studies with the metabolites TFNA, TFNG, TFNA-AM, TFNG-AM and TFNA-OH indicated all to be a

lesser order of toxicity than the parent material IKI-220 technical.

The active ingredient IKI-220 should be classified 6.1D for acute oral classifitcation. No classification is

required for any of the metabolites to the extent to which they were investigated.

122


February 2015

Table 11 Summary of studies for the active ingredient with NOAEL and LOAEL values and key

effects.

Study type NOAEL LOAEL Key effect

Rat 28 day dermal toxicity 1000 mg/kg bw/day No effects No adverse findings

Mouse 90 day toxicity

100 ppm (15.25/20.1

mg/kg bw/day

males/females

respectively

1000 ppm (153.9/191.5

mg/kg bw/day

males/females

respectively)

Altered spleen

micropathology both

sexes and liver

micropathology in

males

Rat 90 day toxicity*

200/1000 ppm

males/females

(12.11/72.3 mg/kg

bw/day males/females

respectively)

1000/5000 ppm

males/females

(119.4/340 mg/kg


respectively)

Altered kidney

micropathology in

males, liver

micropathology in

females

Dog 90 day toxicity 8 mg/kg bw/day 20 mg/kg bw/day

Micropathological

changes in the kidney

in females

Dog 52 week toxicity 8 mg/kg bw/day 20 mg/kg bw/day Mild anaemia.

Rat toxicity/carcinogenicity

study

Non-neoplastic:

200/1000 ppm

males/females

(7.32/44.1 mg/kg


respectively)

Non-neoplastic:

1000/5000 ppm

males/females

(36.5/219 mg/kg bw/day

males/females

respectively)

Non-neoplastic: Altered

kidney micropathology

both sexes, liver in

females, reduced body

weight/body weight

gain

Neoplastic: 1000/5000

ppm males/females

(36.5/219 mg/kg bw/day

males/females

respectively)

Neoplastic:

No effects

Neoplastic: no

carcinogenic effects

Mouse carcinogenicity study

(2 studies assessed)

Non-neoplastic: 80 ppm

(10/11.8 mg/kg bw/day

males/females

respectively

Neoplastic: 80/250 ppm

males/females

(11.8/36.3 mg/kg


respectively)

Non-neoplastic: 250

ppm (30.3/36.3 mg/kg


respectively

Neoplastic: 250 ppm

males (30.3/38 mg/kg

bw/day).

Non-neoplastic: Altered

lung and liver pathology

Neoplastic: Increased

incidence

alveolar/bronchiolar

epithelial adenoma

Rat 2 generation study

Reproductive capacity:

1800 ppm, (109.1/163.9

mg/kg males/females

respectively)


No effects


No effects

123


February 2015

Parental toxicity:

300 ppm, (18.3/20.7

(F0), 28.2/30.5 (F1)

mg/kg bw/day

males/females

respectively)

Parental toxicity:

1800 ppm – 109.1/124.8

(F0), 163.8/176.8 (F1)

males/females

Parental toxicity:

Altered kidney

micropathology

Developmental toxicity:

1800/300 ppm

(163.8/30.5 mg/kg b/day

males/females F1

generation)


No effects (males), 1800

ppm (females) -153.4

mg/kg bw/day


Delayed vaginal

opening

Rat developmental

study

Maternal toxicity:

100 mg/kg bw/day

Maternal toxicity:

500 mg/kg bw/day

Maternal toxicity:

Altered liver and kidney

micropathology

Embryofoetal toxicity:

100 mg/kg bw/day


500 mg/kg/bw day


Increased incidence of

skeletal (extra rib)

anomalies

Rabbit developmental toxicity

Maternal toxicity: 7.5

mg/kg bw/day

Embryofoetal toxicity: 25

mg/kg bw/day

Maternal toxicity: 25

mg/kg bw/day


No effects

Maternal toxicity:

Impaired weight gain


No findings

* Note that for human health risk assessment purposes the LOAEL in males should be considered to be 2000 ppm

(equivalent to 119.4 mg/kg bw/day and the NOAEL 1000 ppm (equivalent to 60 mg/kg bw/day), based on the lack of

human relevance of the the findings relating to alpha-2u-globulin-mediated nephropathy

Toxicokinetics

Type of study Pharmacokinetics in rats – single dose

Flag Key

Test Substance [14

C]IKI-220, Lot No. CP-2173

Reference

Neal, T. R., Savides, M. C., Pharmacokinetics of an oral dose of [14

C]IKI-

220 in Sprague-Dawley rats, Ricerca, LLL, USA, 2001. ISK Document

No.2005 100002-1

Klimisch Score 1


GLP Y


Species Rat

124


February 2015

Strain Sprague-Dawley Crl:CD® (SD)IGS BR

No/Sex/Group 5M and 5F test groups, 1M and 1F control group

Dose Levels O, 2, 400 mg/kg bw. Oral gavage

Study Summary

Following administration the radiolabelled material was rapidly absorbed,

quickly achieved peak plasma radio-concentrations and was rapidly

eliminated at 2 mg/kg bw and in females at 400 mg/kg bw.. The

pharmacokinetic profile was similar between the sexes sat the low dose but

different at the high dose. In females at 400 mg/kg bw the half life was

about 6.8 hours. This was similar to the half life of about 4.5 hours at 2

mg/kg bw. The average half life for males at 2 mg/kg bw was similar to that

seen in females. At 400 mg/kg bw however the plasma concentrations of

the males reached a plateau that lasted for several hours and the average

half life increased to about 11.6 hours. This was significantly different from

the half life of females at 400 mg/kg bw and males at 2 mg/kg bw. The

AUC approximated being proportional to the dose level. The data

suggested that higher doses lead to greater bioavailability. There were no

significant differences in AUC between males and females at any given

dose level. The maximum plasma concentrations (Cmax) also approximated

being proportional to dose level.


Conclusion

Following a single dose the radiolabelled material was rapidly absorbed

and peak plasma concentrations rapidly achieved in both sexes at both

dosages.

Type of study Absorption, distribution, metabolism and excretion study in rats - single

dose

Flag Key study

Test Substance [14


Reference

Neal, T. R., Savides, M. C., Dow, P., Study of the elimination and

distribution of radiolabel following single oral administration of [14

C]IKI-220

to Sprague-Dawley rats, Ricerca, LLL, USA, 2002. ISK Document No.

2006 10005-1

Klimisch Score 1


GLP Y


125


February 2015

Species Rat


No/Sex/Group 14M and 14F test groups, 1M and 1F control group.

Dose Levels

0, 2, 400 mg/kg bw. Oral gavage

Both sexes at 2 mg/kg bw were sacrificed after 0.5, 6, 24 and 168 hours

post dosing.

Males at 400 mg/kg bw were sacrificed after 3, 14.5, 24 and 168 hours

post dosing

Females at 400 mg/kg bw were sacrificed after 1, 8, 24 and 168 hours after

dosing

Study Summary

Following oral administration radioactivity was readily absorbed and

excreted at both doses. Over 168 hours approximately 90% of

administered radioactivity was contained in urine, the majority occurring

within the first 24 hours. Faecal elimination accounted for only about 5% of

the administered dose.

Tissue levels of radioactivity rose rapidly with maximum concentrations

mirroring those of blood. Radioactivity was detected in all tissues for the

early time points although by 168 hours, where detectable, levels had

decreased generally by 50 to 100 fold. At 168 hours post dose less than

2% of the administered radioactivity was contained in the carcass. Tissues

contained negligible levels of radioactivity, the liver showing the highest

amount (<0.15%).

Increasing the dose level had little effect on the disposition of radioactivity

and there was no accumulation of radioactivity in tissues or the residual

carcass. No sex related differences were observed in any of the

parameters measured.


Conclusion

Following administration the radiolabelled dose was rapidly absorbed and

excreted in both sexes in the urine. Increasing the dose had little effect of

disposition of radioactivity and was without accumulation in tissues or

residual carcass nor were there any sex-related differences

Type of study Absorption, distribution, metabolism and excretion study in rats - multiple

dose

Flag Key study

Test Substance [14


126


February 2015

Reference

Neal, T. R., Savides, M. C., Dow, P., Study of the elimination and

distribution of radiolabel following multiple oral administrations of [14

C]IKI-

220 to Sprague-Dawley rats, Ricerca, LLL, USA, 2002. ISK Document No.

2006 10007-1

Klimisch Score 1


GLP Y


Species Rat


No/Sex/Group 14M and 14F test groups, 1M and 1F control

Dose Levels 2 mg/kg bw/day [

12C] for 14 days followed by a single dose of [

14C]

Animals were sacrificed 0.5, 6, 24 and 168 hours after the final dose.

Study Summary

Following oral administration radioactivity was readily absorbed and

excreted at both doses. Over 168 hours approximately 90% of

administered radioactivity was contained in urine, the majority occurring

within the first 24 hours. Faecal elimination accounted for only about 7% of

the administered dose.

Tissue levels of radioactivity rose rapidly with maximum concentrations

mirroring those of blood. Radioactivity was detected in all tissues for the

early time points although by 168 hours, where detectable, levels had

decreased generally by 50 to 100 fold. At 168 hours post dose less than

2% of the administered radioactivity was contained in the carcass. Tissues

contained negligible levels of radioactivity, the liver showing the highest

amount (<0.12%).

There was no accumulation of radioactivity in tissues or residual carcass.

No sex related differences were observed in any of the parameters

measured. Repeat dosing of IKI-220 to the rat had no effect on the

deposition of radioactivity compared with a single dose at the same dose

level.


Conclusion

Repeat administration of radiolabelled dose was rapidly absorbed and

excreted, predominantly in urine. There was no accumulation in tissues or

residual carcass nor were there any sex-related differences. Repeat dosing

had no effect on disposition of radioactivity compared with single dosing.

127


February 2015

Type of study Biliary excretion study in rats

Flag Key

Test Substance [14


Reference

Dow, P., Study of the biliary elimination of radiolabel following oral

administration of [14

C]IKI-220 to Sprague-Dawley rats, Ricerca LLC, USA,

2002. ISK Document No. 2034 13364-1

Klimisch Score 1


GLP Y


Species Rat

Strain Sprague-Dawley Crl:CD® (SD) IGS BR

No/Sex/Group 4m and 4 F. Control 1M and 1 F

Dose Levels 0, 2, 400 mg/kg bw. Single dose

Study Summary

Radioactivity was rapidly absorbed and excreted, predominantly in the

urine (80 – 85% of radioactivity at both doses). Biliary excretion was not a

principal route of elimination of radioactivity – accounting for only about 5%

of the administered doses. Increasing the dose had little effect on the

deposition of radioactivity and there was no accumulation of radioactivity in

the residual carcass. No sex related differences were observed in any of

the parameters measured.


Conclusion

Orally administered radiolabelled dose was rapidly absorbed and excreted,

predominantly in urine. Biliary excretion was not a significant route of

elimination of radioactivity. Increasing the dose had little effect on

radioactive disposition or accumulation in the residual carcass. There were

no sex-related differences in parameters assessed.

Type of study Metabolic pathway in rats

Flag Key study

Test Substance [14


Reference Gupta, K. S., Shah, J. F., McClanahan, R. H., Metabolism of [14

C]IKI-220 in

128


February 2015

rats, Ricerca, LLC, USA, 2002. ISK Document No. 2033 010052-1

Klimisch Score 1


GLP Y

Test Guideline/s US EPA 870.7485

Species Rat

Dose Levels

Analyses were conducted using biological samples obtained from earlier

cited studies assessing biliary excretion and absorption, metabolism

distribution and elimination of radiolabelled IKI-220 after single and multiple

administrations.

Study Summary

Excretion of IKI-220 and its metabolites occurred primarily in the urine and

to a much lesser extent the faeces. IKI-220 was metabolised by several

routes including nitrile hydrolysis, amide hydrolysis, N-oxidation and

hydroxylation of pyridine ring. Combinations of pathways occurred leading

to the formation of multiple metabolites.

The principal urinary metabolites were IKI-220 (unchanged) and TFNA-AM

with much lower detection of TFNA oxide, TFNG-AM, TFNA conjugate. A

range of other metabolites were detected at low levels

Biliary metabolites were confined to IKI-220 (unchanged) and TFNA-AM.

Faecal metabolites consisted of IKI-220 (unchanged), TFNA-AM, TFNA,

mix of TFNA-AM, N-oxide conjugate and TFNA conjugate.

The principal liver metabolites were IKI-220 (unchanged), TFNG, TFNG-

AM, and TFNA-AM.


Conclusion

Comparison of single and multiple doses studies revealed similar

metabolites observed in the urine indicating no induction of metabolism

had occurred. Distribution of residues was also similar between single and

multiple dose studies.

Summary of toxicokinetic studies

IKI-200 is rapidly absorbed following oral administration and is widely distributed. Excretion is primarily via

the urine, with a small proportion excreted via faeces and bile. Repeated dosing or increasing dose did not

influence the tissue distribution. There were no significant differences between sexes in the parameters

assessed. Metabolism is not extensive with the majority of IKI-220 being excreted via the urine, feces and

bile as the parent compound. A major urinary metabolite is TFNA-AM.

129


February 2015

Environmental fate - Robust study summaries for the active ingredient and

metabolites

List of metabolites mentioned in the following studies, their structure can be found in Figure 1, on page 134.

TFNG-AM: N-(4-trifluoromethylnicotinoyl)-glycinamide

TFNG: N-(4-trifluoromethyl-nicotinonyl)glycine

TFNA: 4- trifluoromethylnicotinic acid

TFNA-AM: 4-trifluoromethylnicotinamide

TFNA-OH: 6-hydroxy-4-trifluoromethylnicotinic acid

Water compartment

Ready Biodegradation

Type of study Ready biodegradation (respirometry)

Flag Supporting study as a higher tier study is available (water/sediment degradation

test)

Test Substance IKI-220

Species Domestic sewage

Endpoint Degradation rate measured by %CO2 evolved

Value 6.6% at 28 days

Reference

P. M. Bidinotto (2002) Immediate biodegradability of flonicamid tecnico, using the

open system. Bioagri Laboratorios Ltda Piracicaba/SP Brazil. Report no RF-

1213.211.039.02

Klimisch Score 1


GLP Yes

Test Guideline/s OECD 301B (1992)

Dose Levels 10 mg carbon/L

Analytical measurements CO2 evolved

Study Summary

The biodegradation of the test substance was studied with the respirometry

method over 28 days at 21 to 24oC.

The following conditions were included in the test (duplicates):

- Blank: mineral medium + inoculum - Reference substance: mineral medium + inoculum + sodium benzoate - Test substance: mineral medium + inoculum + IKI-220 - Inhibition control: mineral medium + inoculum + sodium benzoate + IKI-

220 - Abiotic control: IKI-220 + mercury chloride

More than 60% of degradation was reached in the reference substance after the

130


February 2015

10 day interval, and 72% at 28 days. More than 25% of degradation was observed

at 14 day in the inhibition treatment and 48.6% at 28 days.

No abiotic degradation was observed in the corresponding flasks.

The biodegradation of flonicamid was 6.6% at 28 days, so the substance is not

readily biodegradable.

Conclusion Not readily biodegradable

Hydrolysis

Study type Hydrolysis in function of pH and temperature

Flag Key study

Test Substance IKI-220 with 14

C labelling at the C-3 carbon in the pyridyl ring

Endpoint Hydrolysis rate at pH 5, 7 and 9 at 25 and 50oC

Value Stable at pH below 7 and 25 oC. At pH9 and 25

oC, Half-life = 204 d

Reference

KJ Walsh & MD Murray (2002) A hydrolysis study of 14

C-IKI-220 in water. Ricerca

LLC. Environmental and metabolic fate. 7528 Auburn Road Painesville Ohio,

44077-1000. Report no 008076-2

Klimisch Score 1

Amendments/Deviations None that impacted the results of the study.

GLP Yes


Dose Levels ca 1 µg/mL

Analytical measurements HPLC with radiochemical flow detection

Study Summary

The rate and route of hydrolysis of the substance labelled with 14

C at the C-3

carbon in the pyridyl ring, was determined in sterile buffer solutions as a function

of pH and temperature.

Buffer solutions prepared at pH 5, 7 and 9 were incubated for 30 days (120 days

for pH 9 samples) at 25 ± 1 o

C and for 120 days at 50 ± 1 o

C in darkness; treated

pH 4 buffer samples were also included in the experiment at 50 o

C.

No hydrolysis was observed below pH 7 and only at the elevated temperature at

this pH. The half-life was 578 days in these conditions.

The half-life at pH 9 and 25 oC was 204 days. The major hydrolytic product TFNG-

AM, rose to 30.5% by the last sampling point. A second product TFNG, was

initially observed at day 77 at 1.0%, increasing only to 2.0% by day 120.

IKI-220 is hydrolysed initially at the nitrile group to form the amide (TFNG-AM)

which can then be hydrolysed to the glycine (acid) derivative TFNG. The initial

step is observed under alkaline conditions.

131


February 2015

Conclusion Hydrolysis would not contribute significantly to the degradation of the

substance in use conditions.

Study type Hydrolysis in function of pH and temperature

Flag Key study

Test Substance Metabolite TFNA with 14


Endpoint Hydrolysis rate at pH 5, 7 and 9 at 25 and 50oC

Value Stable

Reference

MD Murray & KJ Walsh (2000) A hydrolysis study of 14

C-TFNA in water. Ricerca


44077-1000. Report no 008077-1

Klimisch Score 1


GLP Yes




Study Summary

The rate and route of hydrolysis of the substance labelled with 14

C at the C-3

carbon in the pyridyl ring, was determined in sterile buffer solutions as a function

of pH and temperature.

Buffer solutions prepared at pH 5, 7 and 9 were incubated for 30 days (120 days

for pH 9 samples) at 25 ± 1 o

C and for 120 days at 50 ± 1 o

C in darkness; treated

pH 4 buffer samples were also included in the experiment at 50 o

C.

No hydrolysis was observed in any samples at 25 o

C. Hydrolysis of TFNA

incubated at 50 o

C was minimal during the course of the study (120 days). The

radiopurity did not fall below 99% at the study termination.

Conclusion Hydrolysis would not contribute significantly to the degradation of the

substance in use conditions.

Aqueous Photolysis

Study type Aqueous photolysis

Flag Key study



Endpoint Photolysis half-life

132


February 2015

Value 267 days in continuous radiation.

Reference

KJ Walsh (2002) A photolysis study of [14

C]-IKI-220 in water. Ricerca LLC.

Environmental and metabolic fate. 7528 Auburn Road Painesville Ohio, 44077-

1000. Report no 011050-1

Klimisch Score 1


GLP Yes

Test Guideline/s OPPTS 835.2210



Study Summary

The substance at a concentration of ca. 1 µg/mL in pH 7.00 ± 0.05 phosphate

buffer was continuously exposed to simulated sunlight (xenon arc lamp with filters)

for 15 days at a temperature of 23 ± 2 oC. At days 0, 1, 3, 7, 10 and 15, light-

exposed and dark control samples were analysed directly by HPLC.

In the dark control samples, the substance did not degrade over the 15 days

period.

The substance degraded slightly after 15 days of continuous irradiation. None of

the degradates comprises more than 5% of the applied radioactivity. The major

degradate TFNA-AM was 2.4% at t0 and increased to 2.9% by day 15. The

calculated half-life was 267 days with continuous radiation. The quantum yield is

0.0319%.

Conclusion Photolysis is not a significant degradation pathway for the substance.

Water/sediment aerobic biodegradation

Study type Aerobic degradation in 2 water/sediment systems at 20oC, in the dark

Flag Key study



Endpoint Identification of metabolites and DT50

Value Whole system: 43.6 and 35.7 days

Reference

M. D. Murray & K J. Sandacz Herczog (2002) Aerobic Aquatic Sediment

Metabolism of [14

C]IKI-220. Environmental and metabolic fate. 7528 Auburn Road

Painesville Ohio, 44077-1000. Report no 011052-1

Klimisch Score 1

Amendments/Deviations None that had an effect on the study results.

GLP Yes

133


February 2015

Test Guideline/s SETAC-Europe (March 1995), U.S. EPA Pesticide Assessment Guidelines

Subdivision N Chemistry: Environmental Fate, Series 162-4.

Dose Levels 0.03 mg/L

Study Summary

The fate of [14

C]IKI-220, [pyridyl-14

C]-N-cyanomethyl-4-

trifluoromethylnicotinamide, in aerobic water/sediment systems was studied in

order to determine the rate of degradation of the test compound as well as the

pattern of metabolite formation.

IKI-220, labelled in the 3 position of the pyridyl ring, was applied to individual

samples from each of two different sediment/water test systems at an application

rate of 0.03 ppm, based on the total volume of water.

A system from river Rhine (called EFS 163) and another one from a pond from

Switzerland (EFS 164) were used in this study. They have the following

characteristics: silty clay loam with pH 7.11, 10.23% of organic carbon (EFS 164)

and sandy loam with pH 8.10 and 0.74% of organic carbon.

The test systems were sampled at intervals over a 145-day (EFS-163) and 136-

day (EFS-164) period under aerobic conditions. At each sampling interval the

water and sediment phases of the sample were separated and analysed for IKI-

220 and degradates. In addition, the release of radioactivity as 14

CO2 and

radiolabeled volatiles was monitored for the duration of the study. The mass

balance of the applied radioactivity (i.e., based on the sum of the water phase,

sediment extracts, volatile and bound radioactivity) was greater than 90% in both

water/sediment systems at all sampling points, averaging 99.1% in the EFS-163

system samples and 103.1% in the EFS-164 system samples.

Under aerobic aquatic conditions IKI-220 was extensively degraded over the

duration of the study. The DT50 and DT90 values for the EFS-163 sediment/water

system were 37.3 and 123.8 days, respectively, in the water phase and 43.6 and

144.8 days, respectively, in the entire system. In the EFS- 164 system, the DT50

and DT90 values were 30.3 and 100.5 days, respectively, in the water phase and

35.7 and 118.7 days, respectively, in the entire system.

In each test system, 14

C levels in the water phase and IKI-220 levels in the entire

system declined steadily over the sampling period, while radiolabel in bound

residues and the release of 14

CO2, increased over time. By Day 145 of the EFS-

163 test system, the bound residues exceeded 38% of the applied dose; while in

the EFS-164 test system, the bound residues increased to greater than 75% of

the applied dose by Day 136. The accumulated radioactivity in the NaOH traps

increased throughout the study to 59.1% (Day 145, EFS-163) and 15.6% (Day

136, EFS-164). The majority of the radioactivity trapped in the NaOH was

attributed to 14

CO2. Release of radiolabeled organic volatiles was minimal

throughout the study in both systems.

134


February 2015

The metabolic pathway for IKI-220 under aerobic aquatic conditions involved

hydrolysis of the cyano and amide bonds in the side chain to produce TFNG,

TFNA-AM and TFNA. Further hydroxylation of the 4- trifluoromethylnicotinic acid

(TFNA) produced TFNA-OH. TFNA-AM and TFNG were generated as degradate

intermediates in both soil sets. Further degradation of the radioactive residues

resulted in incorporation into the soil organic matter and mineralization to 14

CO2.

TFNA-OH and TFNA were the major degradation products in the EFS-164

sediment/water systems exceeding 10% of the applied dose, with levels rising

steadily over the first 6 weeks of the sampling period before declining TFNA-OH

and TFNA were present in the EFS-163 test system at levels not exceeding 2% of

the applied dose. TFNG and TFNA-AM were minor degradates in both test

systems (see Figure 1).

Comment

The European Food and Safety Authority Draft Assessment Report on Flonicamid

(Volume 3, Annex B, B8, July 2005) mentions DT50 for the 2 major metabolites: 60

days in water and 59 days in sediment for TFNA, and 49 days in water for TFNA-

OH, calculated from this study.

Conclusion DT50 whole system are 43.6 and 35.7 days, major metabolites are TFNA-OH

and TFNA.

Figure 1: Proposed metabolic pathway of IKI-220 in aerobic water/sediment systems

135


February 2015

Water/sediment anaerobic biodegradation

No data available.

Bioaccumulation potential

The log Kow is 0.3, indicating a low potential of bioaccumulation. However, the substance displays active

surface properties consequently the log Kow is not a proper indicator of the bioaccumulation potential. A

bioaccumulation study should have been conducted.

Soil compartment

Aerobic Degradation in Soil (routes and rates) – Laboratory studies

Study type Aerobic degradation on soil

Flag Key study



Endpoint Rate (DT50) and route of degradation

Value DT50 = 1.0 day

Reference

C. J. Hatzenbeler & K. J. S. Herczog (2002) An Aerobic Soil Metabolism Study with

[14

C]IKI-220. Ricerca LLC 7528 Auburn Road Painesville OH 44077-1000 USA.

Study number 6933-96-0186-EF-001-001.

Klimisch Score 2 study is valid but only one soil is tested


GLP Yes

Test Guideline/s SETAC 1995

Dose Levels 0.1 ppm corresponding to 100 g ai/ha

Analytical measurements Duplicate samples were analysed at 0, 0.5, 1, 2, 3, 7, 14 and 30 days after

treatment

Study Summary

A typical U.S. loamy sand agricultural soil was used for this study. The test soil was

treated with [14

C]IKI-220 at a rate of approximately 0.1 ppm. This concentration is

equivalent to the use rate of the compound (100 g a.i./ha) incorporated to a depth of

7 cm. The soil had an organic carbon content of 0.6% and pH of 7.2.

The test soil was acclimated for 43 days, at 20 ± 1 °C, in darkness, at 45% of its

maximum water holding capacity, prior to treatment with an aqueous solution of

[14

C]IKI-220. Duplicate samples were analysed at 0, 0.5, 1, 2, 3, 7, 14 and 30 days

after treatment. The average recovery of applied radioactivity over the 30-day

course of the study was 86.3%. The recovery of radiocarbon was low in the

definitive experiment for sampling times days 3, 7, 14 and 30 days due to very rapid

extensive metabolism and mineralisation which formed 14

CO2. A second set of soil

samples (mass balance experiment) was dosed and sampled at days 3, 7, 14 and

136


February 2015

30 to correct for mass balance and volatiles. The average recovery of applied

radioactivity for the mass balance experiment was 93.3% which is within the

acceptable limits of 90 to 110%.

Extractable radiolabel decreased from 101.4% on Day 0 to 13.7% after 30 days

incubation. Unextractable soil residues increased steadily from 0.7% on Day 0 to

35.2% on Day 30. Evolution of 14

CO2 increased throughout the study, reaching a

maximum of 47.0% of the applied radioactivity after thirty days in this experiment.

TFNA was the major degradate in the soil over the course of the study. TFNA

formed rapidly reaching a peak of 36.4% of the applied radioactivity 3 days after

treatment. Further metabolism of TFNA occurred readily, leading to residue levels of

less than 2% of the applied radioactivity after 14 days. Hydroxylation of TFNA led to

formation of TFNA-OH. This hydroxylated TFNA formed rapidly over a one-week

period, reaching 20.2% of the applied radioactivity then declined to 0.5% after thirty

days.

IKI-220 degraded easily in the loamy sand soil, principally via hydrolysis of the

cyano and amide functionalities on the aliphatic side chain of the molecule. These

reactions led to the formation of TFNA. TFNA was further metabolized to form a

hydroxy analog, TFNA-OH. The DT50 and DT90 values for IKI-220 in this loamy sand

soil, based on a first-order exponential decay, were 1.0 and 3.4 days respectively.

TFNG, TFNG-AM and TFNA-AM were formed as degradate intermediates.

Comment

R software has been used to recalculate the DT50 and DT90 according to the best fit:

best fit is 1st order with a DT50 of 1.04 and a DT90 of 2.04 days

The difference is not significant so the DT50 of the report is used.

Conclusion

DT50 = 1.0 day at 20oC, the proposed pathway is shown in

Figure 2.

Study type Aerobic degradation on soil

Flag Key study




Value DT50 from 0.7 to 1.8 days at 20oC

Reference N.R. Lentz (2002) Rate of degradation of [

14C]IKI-220 in soil. Ricerca LLC 7528

Auburn Road Painesville OH 44077-1000 USA. Study number 013066-1.

Klimisch Score 1


137


February 2015

GLP Yes


Dose Levels 0.1 ppm

Analytical measurements 0, 0.33, 0.67, 1, 2, 3, 7, 14 and 30 days after treatment

Study Summary

The degradation rate of IKI-220 under aerobic soil conditions was studied in three

European soils. 2 soils were obtained from the United Kingdom, a third standard soil

(2.1) was obtained from Germany.

Samples of each treated soil type were incubated at 50% maximum water-holding

capacity at 20oC in darkness. An additional soil set (U.K.#21) was also treated as

above but incubated at 10°C. The soils were extracted and analyzed by HPLC at

days 0, 0.33, 0.67, 1, 2, 3, 7, 14 and 30.

Recovery of applied radioactivity over the course of the study for the four sets

ranged from an average of 89.4 to 102.8%. Extractable radiolabel decreased to less

than 8.7% of the applied dose in all soils by the end of the sampling period.

Unextractable residues in all soils ranged from 29.6 to 43.3% by the end of

sampling. Evolution of 14

CO2 ranged from 49.3 to 56.6% of the radiolabel in all soil

sets by the end of the respective sampling periods.

IKI-220 degraded rapidly in all soils, principally via hydrolysis of the amide and

cyano functionalities on the aliphatic side chain to form TFNA and TFNG-AM,

respectively. Subsequent hydroxylation of the aromatic ring led to the formation of

TFNA-OH. Minor intermediates TFNG and TFNA-AM were also detected in all of

the soils. TFNA and TFNA-OH were major degradates detected in all of the soils

ranging from 12.2 to 30.6% and 12.1 to 32.7% at concentration maxima for all of the

soils, respectively. Degradate TFNG-AM ranged from 7.8 to 10.2% of applied dose.

Minor degradates TFNG and TFNA-AM were detected at less than 7. 7% of the

applied dose at all sampling points over the course of the study. All of the

degradates were metabolised and mineralised to carbon dioxide and immobilised as

soil-bound residue.

The DT50 and DT90 values ranged from 0.7 to 1.8 days and 2.3 to 6.0 days for the

soils incubated at 20 °C, respectively. The DT50 value was 2.4 days and the DT90

value was 7.9 days for the soil incubated at 10°C. A first-order kinetics model was

used to approximate parent IKI-220 degradation processes in all of the soil sets.

Bedfordshire

soil (UK21)

Birmingham

soil (UK39)

German soil

2.1

Type Loamy sand Loamy sand Sand

pH 6.9 7.0 6.2

% organic matter 2.4 4.6 0.9

Cation exchange capacity 8.5 16.9 3.3

138


February 2015

(meq/100g)

Max water holding capacity

(%)

41.0 64.8 29.5

1st order DT50 (days) 2.4 at 10

oC

(r2=0.9721)

0.7 at 20oC

(r2=0.9898)

0.7

(r2=0.989)

1.8

(r2= 0.9989)


oC

2.3 at 20oC

2.4 6.0

Comment

R software has been used to recalculate the DT50 and DT90 at 20oC according to the

best fit:

UK21 soil: best fit is 1st order with a DT50 of 0.635 and a DT90 of 2.11 days

UK39 soil: best fit is indeterminate order rate with a DT50 of 0.703 (= DT90/3

according to NAFTA guidelines) and a DT90 of 2.34 days.

German soil: best fit is indeterminate order rate with a DT50 of 1.84 (= DT90/3


These values are very similar to the initial ones so the initial ones of the report will

be used.

Conclusion DT50 from 0.7 to 1.8 days at 20oC.

139


February 2015

Figure 2: Degradation pathway of flonicamid in soils

Study type Aerobic degradation on soil study with metabolites

Flag Key study

Test Substance TFNA metabolite with 14


Endpoint DT50


Reference

C.J. Hatzenbeler & N.R. Lentz (2002) Rate of degradation of [14

C]TFNA in soil.

Ricerca LLC 7528 Auburn Road Painesville OH 44077-1000 USA. Study number

012064-1

Klimisch Score 1


GLP Yes


Dose Levels 0.1 ppm

Analytical measurements At 0, 0.5, 1, 2, 3, 7, 14 and 30 days after treatment

Study Summary

The degradation rate of TFNA under aerobic soil conditions was studied in three

European soils. 2 soils were obtained from the United Kingdom, a third standard

soil (2.1) was obtained from Germany.

140


February 2015




days 0, 0.5, 1, 2, 3, 7, 14 and 30.


ranged from 91.0 to 100.1%. Extractable radiolabel decreased to less than 16.2%

of the applied dose in all soils by the end of the sampling period.





TFNA degraded rapidly in all soils, principally via hydroxylation of the aromatic

ring to 6-hydroxy-4-trifluoromethylnicotinic acid (TFNA-OH). TFNA-OH was the

major degradate in all soils over the course of the study, ranging from 41.6 to

54.9% of the applied dose. TFNA-OH was metabolized and mineralized to carbon

dioxide and immobilized as soil-bound residue.




used to approximate parent TFNA degradation processes in all of the soil sets.

Bedfordshire

soil (UK21)

Birmingham

soil (UK39)

German soil

2.1


pH 6.8 6.4 5.7


Cation exchange capacity

(meq/100g)

4.97 13.01 2.02


(%)

21.23 39.88 18.41


oC

(r2=0.9864)

0.5 at 20oC

(r2=0.9687)

0.3

(r2=0.9899)

0.5

(r2= 0.9912)


oC

1.5 at 20oC

1.0 1.5

Comment

R software has been used to recalculate the DT50 and DT90 at 20oC according to

the best fit:


according to NAFTA guidelines) and a DT90 of 1.79 days

UK39 soil: best is 1st order with DT50 of 0.297 and a DT90 of 0.987 days.

141


February 2015




be used.



Flag Key study

Test Substance TFNA-AM metabolite with 14


Endpoint DT50



14C]TFNA-AM in soil. Ricerca LLC 7528

Auburn Road Painesville OH 44077-1000 USA. Study number 012696-1

Klimisch Score 1


GLP Yes


Dose Levels 0.01 ppm

Analytical measurements At 0, 0.04, 0.125, 0.25, 0.5, 1, 2, 3, 7, 14 and 30 days after treatment

Study Summary

The degradation rate of TFNA-AM under aerobic soil conditions was studied in

three European soils. 2 soils were obtained from the United Kingdom, a third

standard soil (2.1) was obtained from Germany.




days 0, 0.04, 0.125, 0.25, 0.5, 1, 2, 3, 7, 14 and 30.


ranged from 90.0 to 105%. Extractable radiolabel decreased to less than 13.3% of

the applied dose in all soils by the end of the sampling period.





TFNA-AM was metabolized and mineralized to carbon dioxide and immobilized as

soil-bound residue. 14

CO2 was the major metabolite in all soils over the course of

the study.

TFNA-AM degraded rapidly in all soils. The DT50 and DT90 values ranged from 1.0

142


February 2015

to 2.6 days and 3.4 to 8.5 days for the soils incubated at 20 °C, respectively. The

DT50 value was 4.5 days and the DT90 value was 14.8 days for the soil incubated

at 10°C. A first-order kinetics model was used to approximate parent TFNA-AM

degradation processes in all of the soil sets.

Bedfordshire

soil (UK21)

Birmingham

soil (UK39)

German soil

2.1


pH 6.9 7.0 6.2



(meq/100g)

8.5 16.9 3.3


(%)

41.0 64.8 29.5


oC

(r2=0.9944)

1.2 at 20oC

(r2=0.993)

1.0

(r2=0.9892)

2.6

(r2= 0.9571)


oC

3.8 at 20oC

3.4 8.5

Comment


the best fit:





German soil: best fit is 1st order with a DT50 of 3.82 and a DT90 of 12.7 days.


be used except for the German soil were the r2 is low.



Flag Key study

Test Substance TFNA-OH metabolite with 14


Endpoint DT50


Reference D.C. Findak & N.R. Lentz (2002) Rate of degradation of [

14C]TFNA-OH in soil.

Ricerca LLC 7528 Auburn Road Painesville OH 44077-1000 USA. Study number

143


February 2015

012066-1

Klimisch Score 1


GLP Yes


Dose Levels 0.1 ppm

Analytical measurements At 0, 0.5, 1, 2, 3, 7, 14 and 30 days after treatment

Study Summary

The degradation rate of TFNA-OH under aerobic soil conditions was studied in

three European soils. 2 soils were obtained from the United Kingdom, a third

standard soil (2.1) was obtained from Germany.




days 0, 0.5, 1, 2, 3, 7, 14 and 30.


ranged from 91.0 to 104.9%. Extractable radiolabel decreased to less than 13% of

the applied dose in all soils by the end of the sampling period.





TFNA-OH was metabolized and mineralized to carbon dioxide and immobilized as

soil-bound residue. 14

CO2 was the major metabolite in all soils over the course of

the study.

TFNA-OH degraded rapidly in all soils. The DT50 and DT90 values ranged from 1.0

to 2.6 days and 3.4 to 8.7 days for the soils incubated at 20 °C, respectively. The

DT50 value was 4.5 days and the DT90 value was 15 days for the soil incubated at

10°C. A first-order kinetics model was used to approximate parent TFNA-OH

degradation processes in all of the soil sets.

Bedfordshire

soil (UK21)

Birmingham

soil (UK39)

German soil

2.1


pH 6.8 6.4 5.7



(meq/100g)

4.97 13.01 2.02


(%)

21.23 39.88 18.41

144


February 2015


oC

(r2=0.9915)

1.0 at 20oC

(r2=0.9529)

1.3

(r2=0.9559)

2.6

(r2= 0.9521)


oC

3.4 at 20oC

4.2 8.7

Comment


the best fit:



UK39 soil: best fit is 1st order with a DT50 of 1.51 and a DT90 of 5.03 days.




be used except for the German soil where the r2 is low.



Flag Key study

Test Substance TFNG metabolite with 14


Endpoint DT50



14C]TFNG in soil. Ricerca LLC 7528


Klimisch Score 1


GLP Yes


Dose Levels 0.1 ppm


Study Summary

The degradation rate of TFNG under aerobic soil conditions was studied in three

European soils. 2 soils were obtained from the United Kingdom, a third standard

soil (2.1) was obtained from Germany.




145


February 2015

days 0, 0.04, 0.125, 0.25, 0.5, 1, 2, 3, 7, 14 and 30.


ranged from 89.5 to 108.8%. Extractable radiolabel decreased to less than 14.7%

of the applied dose in all soils by the end of the sampling period.





TFNG degraded rapidly in all soils via hydrolysis of the amide functionality on the

aliphatic side chain to form 4-trifluoromethylnicotinic acid (TFNA) and subsequent

hydroxylation of the aromatic ring to form 6-hydroxy-4- trifluoromethyl-nicotinic

acid (TFNA-OH). 4-trifluoromethylnicotinamide (TFNA-AM) was generated as a

minor degradative intermediate and was detected at a maximum of 8.3% of the

applied radioactivity. TFNA and TFNA-OH were the major degradates in all soils

over the course of the study. TFNA ranged from 24.5 to 56.7% of the applied dose

and TFNA-OH ranged from 31.5 to 53.5% of the applied dose at concentration

maxima. Both degradates were metabolized and mineralized to carbon dioxide

and immobilized as soil-bound residue.




used to approximate parent TFNG degradation processes in all of the soil sets.

Bedfordshire

soil (UK21)

Birmingham

soil (UK39)

German soil

2.1


pH 6.8 6.4 5.7



(meq/100g)

4.97 13.01 2.02


(%)

21.23 39.88 18.41


oC

(r2=0.9794)

0.1 at 20oC

(r2=0.9477)

0.2

(r2=0.9577)

1.1

(r2= 0.9739)


oC

0.4 at 20oC

0.7 3.5

Comment


the best fit:


146


February 2015







be used.



Flag Key study

Test Substance TFNG-AM metabolite with 14


Endpoint DT50



14C]TFNG-AM in soil. Ricerca LLC 7528


Klimisch Score 1


GLP Yes


Dose Levels 0.02 ppm


Study Summary

The degradation rate of TFNG-AM under aerobic soil conditions was studied in three

European soils. 2 soils were obtained from the United Kingdom, a third standard soil

(2.1) was obtained from Germany.




days 0, 0.04, 0.125, 0.25, 0.5, 1, 2, 3, 7, 14 and 30.

Recovery of applied radioactivity over the course of the study for the four sets ranged

from 90.4 to 104.2%. Extractable radiolabel decreased to less than 4.2% of the

applied dose in all soils by the end of the sampling period.

Unextractable residues in all soils ranged from 31.0 to 41.1% by the end of sampling.

Evolution of 14

CO2 ranged from 47.4 to 71.2% of the radiolabel in all soil sets by the

end of the respective sampling periods.

TFNG-AM degraded rapidly in all soils to form TFNG (N-( 4-

147


February 2015

trifluoromethylnicotinoyl)glycine). TFNG degraded rapidly via hydrolysis of the amide

functionality on the aliphatic side chain to form 4-trifluoromethylnicotinic acid (TFNA)

and subsequent hydroxylation of the aromatic ring to form 6- hydroxy-4-

trifluoromethyl-nicotinic acid (TFNA-OH). TFNG, TFNA and TFNA-OH were the major

degradates in all soils over the course of the study. TFNG ranged from 6.2 to 30.1%

of the applied dose. TFNA ranged from 29.4 to 63.8% of the applied dose and TFNA-

OH ranged from 12.4 to 25.3% of the applied dose. All of the degradates were

metabolized and mineralized to carbon dioxide and immobilized as soil-bound

residue.




used to approximate parent TFNG-AM degradation processes in all of the soil sets.

Bedfordshire

soil (UK21)

Birmingham

soil (UK39)

German soil

2.1


pH 6.9 7.0 6.2



(meq/100g)

8.5 16.9 3.3


(%)

41.0 64.8 29.5


oC

(r2=0.9933)

0.2 at 20oC

(r2=0.9933)

0.3

(r2=0.9669)

1.0

(r2= 0.9959)


oC

0.6 at 20oC

1.0 3.3

Comment

R software has been used to recalculate the DT50 and DT90 at 20oC according to the

best fit:

UK21 soil: best fit is indeterminate order rate with a DT50 of 0.159 (= DT90/3 according

to NAFTA guidelines) and a DT90 of 0.527 days

UK39 soil: best fit is simple 1st order with a DT50 of 0.3 and a DT90 of 0.998 days.

German soil: best fit is simple 1st order with a DT50 of 1.02 and a DT90 of 3.39 days.

These values are very similar to the initial ones so the initial ones of the report will be

used.


148


February 2015

Anaerobic Degradation in Soil (routes and rates) – Laboratory studies

Study type Anaerobic degradation on soil

Flag Key study




Value DT50 120 and 188 days in the whole system at 20oC


14C]IKI-220 in soil. Ricerca LLC 7528

Auburn Road Painesville OH 44077-1000 USA. Study number 013066-1.

Klimisch Score 1


GLP Yes

Test Guideline/s US EPA Assessment guidelines, subdivision N Chemistry: environment fate

section 162-3.

Dose Levels 0.05 ppm applied into the aqueous layer, corresponding to 0.1 ppm in soil

Analytical measurements 0, 1,3, 7, 14, 30, 45, 60, 91, 120, 179, 270 and 365 days after treatment

Study Summary

The degradation rate of IKI-220 in flooded soil under anaerobic soil conditions was

studied in one American soil, incubated at 20oC in dark. Soil properties

were:sandy loam with a pH of 5.4, cation exchange capacity 8.11 meq/100g,

3.85% of organic matter, 37.69% of maximum water holding capacity.

The test systems were sampled at intervals over a 365-day period under

anaerobic conditions. At each sampling interval the water and soil phases of the

sample were separated and analyzed for [14

C]IKI-220 and degradates. In addition,

the release of radioactivity as 14

CO2 and radiolabeled volatiles was monitored for

the duration of the study. The mass balance of the applied radioactivity (i.e.,

based on the sum of the water phase, soil extracts, volatile and bound

radioactivity) remained between 90% and 110% at all sampling points.

Under anaerobic aquatic conditions, the rate of degradation of [14

C]IKI-220 was

moderately rapid. Throughout the study the amount of radioactivity in the soil and

water phases of the system remained steady. The degradation of IKI-220 to TFNA

was prevalent in the system and TFNA increased steadily throughout the study. A

maximum mean TFNA level of 75.7 % of the applied radioactivity was obtained at

365 days. There was no other significant degradation product in the system. The

levels of TFNG, TFNG-AM, TFNA-AM and TFNA-OH did not reach significant

levels and all were <0.5% of the applied radioactivity at any given time in the total

system. Only small amounts of 14

CO2 were produced and reached 0.2% of the

applied radioactivity by 365 days. The amount of bound nonextractable

149


February 2015

radioactivity (PES) slowly increased during the study and reached a mean level of

3.6% of the applied radioactivity by 270 days. There were no volatile organic

compounds evolved in the flooded soil system.

The DT50 and DT90 values of IKI-220 in flooded anaerobic soil were 88 days and

490 days, respectively, in the water phase and 121 days and 555 days,

respectively, in the entire system.

Under anaerobic aquatic conditions, IKI-220 was metabolized at a moderately

rapid rate. The main metabolism process involved the formation of TFNA, most

likely, through the hydrolytic cleavage of the amide bonds in the side chain.

Water phase Total system

1st order DT50 (days) 88 (r

2=0.9847) 121 (r

2=0.9955)

1st order DT90 (days) 490 555

Comment

R software has been used to recalculate the DT50 and DT90 according to the best

fit:

Water phase: best fit is double 1st order with a DT50 of 98.1 days and a DT50 for

the slow phase of 174 days and a DT90 of 501 days.

Whole system: best fit double 1st order with a DT50 of 120 days and a DT50 for the

slow phase of 188 days and a DT90 of 1030 days.

These values are very different to the initial ones so these re-calculated values will

be used.

Conclusion DT50 120 and 188 days in the whole system at 20oC.

Soil photolysis

Study type Soil photolysis

Flag Key study



Endpoint Photolysis half-life

Value 22 days in continuous illumination, 53 days in dark.

Reference

KJ Walsh (2002) A photochemical degradation of [14

C]-IKI-220 in soil. Ricerca


44077-1000. Report no 011298-1

Klimisch Score 1


GLP Yes

Test Guideline/s OPPTS 835.2410

150


February 2015

Dose Levels ca 0.1 ppm dry soil


Study Summary

The photolysis of the substance was studied at a concentration of ca 0.1 ppm on

dried soil which was continuously exposed to simulated sunlight (xenon arc lamp

with filters) for 15 days at a temperature of 20 o

C ± 1. At days 0, 1, 3, 7, 9, 11 and

15, sample extracts were analysed by HPLC.

A typical US loamy sand agricultural soil was used for the study and was dried to

minimize the effects of microbial degradation.

The substance degraded slowly in both dark and light exposed samples. TFNG-

AM was the major metabolite in both dark and light-exposed samples at 13.8%

and 29.5%, respectively. TFNA-AM and TFNG were detected as minor

metabolites (2-5 %). The half-life in dark conditions is 53 days and is 22 days in

continuous illumination.

Conclusion Photolysis is not a significant pathway for the degradation of the substance

in use conditions.

Adsorption/ desorption on soil particles

Study type Batch equilibrium test

Flag Key study



Endpoint Koc

Value 8 to 42

Reference

KJ Sandacz (2000) Adsorption and desorption of [14

C]-IKI-220 in soils. Ricerca

Inc. Environmental and metabolic fate. 7528 Auburn Road Painesville Ohio,

44077-1000. Report no 6934-96-0185-EF-001

Klimisch Score 1


GLP Yes

Test Guideline/s OECD 106 (version not stated)

Dose Levels ca 1 and 5 µg/mL in 0.01 M calcium chloride solution

Analytical measurements HPLC

Study Summary

Screening test:

The adsorptive properties of the test substance were studied in 4 soils (3

European and 1 American soil): 2 loamy sands and 2 sandy loams with organic

matter content from 0.7 to 3.0% and pH from 6.5 to 7.6.

The percent of the test substance adsorbed to the soil using a 1:5 soil:test

151


February 2015

substance solution (ca 1 µg/mL ) ratio ranged from 2.8 to 8.3%.

In the run with 1:2 soil:test substance solution (ca 5 µg/mL), the percent of

adsorption remain below 15%.

The concentration of the test substance in the aqueous phase after adsorption

was used to estimate the adsorption coefficients.

EFS-097 EFS-099 EFS-101 EFS-072

Soil type Loamy sand Sandy loam Sandy loam Loamy sand

Origin UK UK Germany Ohio, USA

% organic

carbon 1.2 3.0 1.3 0.7

pH 7.6 6.9 6.8 6.5

% moisture 6.29 16.39 8.58 8.50

Koc for 1:5

ratio and no

HgCl2

12.1 15.1 22.7 34.9

Koc for 1:5

ratio and

0.01% HgCl2

16.2 13.3 18.8 42.1

Koc for 1:2

ratio and

0.01% HgCl2

7.9 11.2 13.4 20.7

The substance is highly mobile to mobile in soils according to the FAO

classification.

Conclusion Koc from 8 to 42. The substance is highly mobile to mobile in soils


Flag Key study

Test Substance Metabolite TFNA with 14


Endpoint Koc

Value 0.00 to 3.05

Reference

GJ Misich & KJ Sandacz Herczog (2002) Adsorption and desorption of [14

C]-TFNA

in soil. Ricerca LLC. Environmental and metabolic fate. 7528 Auburn Road


Klimisch Score 1


GLP Yes

152


February 2015


Dose Levels ca 5 µg/mL in 0.01 M calcium chloride solution


Study Summary

Screening test:


European and 1 American soil): 2 loamy sands and 1 sandy loam and 1 sand with

organic matter content from 0.93 to 5.49% and pH from 5.7 to 7.2.





EFS-165 EFS-166 EFS-167 EFS-072



% organic

carbon 0.727 3.19 0.599 0.541

pH 6.8 6.4 5.7 7.2

Koc 0.35 0.00 3.05 2.67

The substance is highly mobile in soils according to the FAO classification.

Conclusion Koc from 0.00 to 3.05. The substance is highly mobile in soils


Flag Key study

Test Substance Metabolite TFNA-AM with 14


Endpoint Koc

Value 4.53 to 12.11

Reference

KJ Sandacz Herczog et al (2002) Adsorption and desorption of [14

C]-TFNA-AM in

soils. Ricerca LLC. Environmental and metabolic fate. 7528 Auburn Road


Klimisch Score 1


GLP Yes



153


February 2015


Study Summary

Screening test:








EFS-165 EFS-166 EFS-167 EFS-072



% organic

carbon 0.727 3.19 0.599 0.570

pH 6.8 6.4 5.7 7.2

Koc 5.52 2.76 5.16 4.80

Adsorption equilibrium test

The adsorption equilibrium time was also investigated in four US soils and one

German soil.

EFS-116 EFS-150 EFS-167 EFS-170 EFS-200

Soil type Sandy

loam

Silt loam Sand Clay loam Clay loam

Origin Ohio, USA Oregon,

USA

Germany Ohio, USA Montana,

USA

% organic

carbon 3.081 1.948 0.599

4.302 0.872

pH 5.6 6.2 5.7 7.9 8.1

Koc 5.53 10.11 5.04 4.53 12.11

The adsorption equilibrium was approximately 24-hour for all soils tested.

The percent of the test substance adsorbed to the soil ranged from 2.92 to

16.16%. The Koc ranged from 4.53 to 12.11.


classification.

Conclusion Koc from 4.53 to 12.11. The substance is highly mobile to mobile in soils


Flag Key study

154


February 2015

Test Substance Metabolite TFNA-OH with 14


Endpoint Koc

Value 1.60 to 4.39

Reference

GJ Misich (2002) Adsorption and desorption of [14

C]-TFNA-OH in soil. Ricerca


44077-1000. Report no 012063-1

Klimisch Score 1


GLP Yes




Study Summary

Screening test:








EFS-165 EFS-166 EFS-167 EFS-072



% organic

carbon 0.727 3.19 0.599 0.541

pH 6.8 6.4 5.7 7.2

Koc 1.60 1.92 4.19 4.39




Flag Key study

Test Substance Metabolite TFNG with 14


Endpoint Koc

155


February 2015

Value 0.20 to 4.05

Reference

KJ Sandacz Herczog & GJ Misich (2002) Adsorption and desorption of [14

C]-

TFNG in soil. Ricerca LLC. Environmental and metabolic fate. 7528 Auburn Road


Klimisch Score 1


GLP Yes




Study Summary

Screening test:








EFS-165 EFS-166 EFS-167 EFS-072



% organic

carbon 0.727 3.19 0.599 0.541

pH 6.8 6.4 5.7 7.2

Koc 0.20 1.05 1.29 4.05




Flag Key study

Test Substance Metabolite TFNG-AM with 14


Endpoint Koc

Value 4.24 to 15.84

Reference W Song (2002) Adsorption and desorption of [14

C]-TFNG-AM in soil. Ricerca LLC.

156


February 2015

Environmental and metabolic fate. 7528 Auburn Road Painesville Ohio, 44077-

1000. Report no 012695-1

Klimisch Score 1


GLP Yes




Study Summary

Screening test:








EFS-165 EFS-166 EFS-167 EFS-072



% organic

carbon 0.727 3.192 0.599 0.570

pH 6.8 6.4 5.7 7.2

Koc 5.50 2.51 0.00 13.16

Adsorption equilibrium test

The adsorption equilibrium time was also investigated in four US soils and one

German soil.

EFS-116 EFS-150 EFS-167 EFS-170 EFS-200

Soil type Sandy

loam

Silt loam Sand Clay loam Clay loam

Origin Ohio, USA Oregon,

USA

Germany Ohio, USA Montana,

USA

% organic

carbon 3.081 1.948 0.599

4.302 0.872

pH 5.6 6.2 5.7 7.9 8.1

Koc 10.51 9.25 7.56 4.24 15.84

The adsorption equilibrium was approximately 24-hour for all soils tested.

The percent of the test substance adsorbed to the soil ranged from 4.54 to

157


February 2015

27.24%. The Koc ranged from 4.24 to 15.84.


classification.

Conclusion Koc from 4.24 to 15.84. The substance is highly mobile to mobile in soils

Photodegradation in air

Study type Photodegradation in air (estimation)

Flag Key study

Test Substance IKI-220

Endpoint Half-life

Value 13.737 days (12-hour day)

Reference

A van der Gaauw (2001) Estimation of the degradation of IKI-220 by photo-

oxidation in air. Model calculation according to Atkinson. RCC Ltd Environmental


835176

Klimisch Score 1


GLP yes

Test Guideline/s Calculation according to Atkinson method

Dose Levels Not relevant: calculation

Analytical measurements Not relevant: calculation

Study Summary

The rate constant for the atmospheric reaction between photochemically produced

hydroxyls radicals and the substance was estimated by AOPWIN.

An OH-concentration of 1.5 x 106 /cm

3 is used as an average concentration during

daylight, for the reaction with ozone, a concentration of 7 x 1011

molecules /cm3 is

assumed which is a concentration of ozone in unpolluted air in the lower

troposphere.

The half-life of the substance is estimated to be 13.737 days when a 12-hour day

is considered and 6.868 days when a 24-hour day is considered.

Conclusion Half-life = 13.737 days

General conclusion about environmental fate:

Flonicamid is persistent in aquatic environment according to HSNO criteria (DT50 > 16 days and not readily

biodegradable). But is not persistent in soil (DT50 < 30 days). The metabolites are also quickly degraded in

soils.

158


February 2015

Flonicamid and its metabolites are all mobile to highly mobile in soil according to their adsorption/desorption

coefficients.

Flonicamid bioconcentration properties are not fully characterised as no bioconcentration study is available

and the n-octanol-water partition coefficient is not a good predictor for surface active substances.

Metabolites to be considered for the risk assessment:

Soil: TFNA, TFNA-OH, TFNG-AM, TFNG, TFNA-AM

Water: TFNA, TFNA-OH

Ecotoxicity - Robust study summaries for the active ingredient and

metabolite(s)

Aquatic toxicity

Fish acute toxicity (Freshwater species)


Flag Key study



Type of exposure Static for 96 hours

Endpoint LC50

Value > 100 mg/L

Reference

A. Peither (2001) Acute toxicity of IKI-220 technical to Rainbow trout (Oncorhynchus

mykiss) in a 96-hour static test. RCC Ltd, Environmental Chemistry & Pharmanalytics


Klimisch Score 1


GLP Yes


No/Group 10


Analytical measurements Yes from fresh medium and at 48 and 96 hours, by HPLC

Study Summary

The acute toxicity of the test substance to rainbow trout was determined in a 96-hr

static test. A limit test was performed at 100 mg/L. The measured concentration in the

test medium was 98% of the nominal at the start and at the end of the test substance

so the results are expressed as nominal concentrations.


159


February 2015

oxygen concentration was always higher than 60% oxygen saturation (it was 8.7 mg/L

or above) and the temperature was constantly 15oC.

In the control and in the test concentration, no mortality or other signs of intoxication

were determined during the test period.

The LC50 is higher than 100 mg/L.

Conclusion The LC50 is higher than 100 mg/L. No mortality observed at 100 mg/L.


Flag Key study


Species Lepomis macrochirus (Bluegill sunfish)

Type of exposure Static for 96 hours

Endpoint LC50

Value > 100 mg/L

Reference

A. Peither (2001) Acute toxicity of IKI-220 technical to bluegill sunfish (Lepomis

macrochirus) in a 96-hour static test. RCC Ltd, Environmental Chemistry &

Pharmanalytics Division. CH-4452 Itingen Switzerland. Report no 807276.

Klimisch Score 1


GLP Yes


No/Group 10


Analytical measurements Yes from fresh medium and at 48 and 96 hours, by HPLC

Study Summary

The acute toxicity of the test substance to bluegill sunfish was determined in a 96-hr

static test. A limit test was performed at 100 mg/L. The measured concentration in the

test medium was 99% of the nominal at the start and at the end of the test substance

so the results are expressed as nominal concentrations.


oxygen concentration was always higher than 60% oxygen saturation (it was 7.4 mg/L

or above) and the temperature was in the range of 22-23oC.

In the control and in the test concentration, no mortality or other signs of intoxication

were determined during the test period.



160


February 2015


Flag Key study

Test Substance Metabolite TFNA



Endpoint LC50

Value > 100 mg/L

Reference

A. Peither (2002) Acute toxicity of TFNA to Rainbow trout (Oncorhynchus mykiss)

in a 96-hour semi-static test. RCC Ltd, Environmental Chemistry &


Klimisch Score 1


GLP Yes


No/Group 10


Analytical measurements Yes from fresh medium on day 0 and at 48 h and from the old medium at 48 and

96 hours, by HPLC

Study Summary

The acute toxicity of the test substance to Rainbow trout was determined in a 96-

hr semi-static test. A limit test was performed at 100 mg/L. The measured

concentration in the test medium was 102-103% of the nominal at the start and at


concentrations.




In the control and in the test concentration, no mortality or other signs of

intoxication were determined during the test period.




Flag Key study

161


February 2015

Test Substance Metabolite TFNA-AM



Endpoint LC50

Value > 100 mg/L

Reference

A. Peither (2002) Acute toxicity of TFNA-AM to Rainbow trout (Oncorhynchus

mykiss) in a 96-hour semi-static test. RCC Ltd, Environmental Chemistry &


Klimisch Score 1


GLP Yes


No/Group 10



96 hours, by HPLC

Study Summary





concentrations.









Flag Key study

Test Substance Metabolite TFNA-OH



162


February 2015

Endpoint LC50

Value > 100 mg/L

Reference

A. Peither (2002) Acute toxicity of TFNA-OH to Rainbow trout (Oncorhynchus



Klimisch Score 1


GLP Yes


No/Group 10



96 hours, by HPLC

Study Summary





concentrations.









Flag Key study

Test Substance Metabolite TFNG-AM



Endpoint LC50

Value > 100 mg/L

Reference A. Peither (2002) Acute toxicity of TFNG-AM to Rainbow trout (Oncorhynchus


163


February 2015


Klimisch Score 1


GLP Yes


No/Group 10



96 hours, by HPLC

Study Summary





concentrations.








Fish acute toxicity (Marine species)

No study provided.

Invertebrates acute toxicity (Freshwater species)


Flag Key study




Endpoint EC50

Value > 100 mg/L

Reference

A. Peither (2001) Acute toxicity of IKI-220 technical to Daphnia magna in a 48-

hour immobilization test. RCC Ltd, Environmental Chemistry & Pharmanalytics


164


February 2015

Klimisch Score 1


GLP Yes




Analytical measurements Yes, from fresh medium on day 0 and at 48 h, by HPLC

Study Summary





concentrations.


oxygen concentration was always higher than 8.1 mg/L and the temperature was

in the range of 20-21oC.

In the control and in the test concentration, no immobilisation or other signs of


The EC50 is higher than 100 mg/L.

Conclusion The EC50 is higher than 100 mg/L. No immobilisation observed at 100 mg/L.




Species Chironomus riparius (first instar larvae)


Endpoint LC50

Value > 200 mg/L

Reference

U. Memmert (2002) Acute toxicity of IKI-220 technical to first instar larvae of

Chironomus riparius in a 48-hour immobilization test. RCC Ltd, Environmental


834074.

Klimisch Score 1


GLP Yes

165


February 2015

Test Guideline/s

No official test guideline available. The administration of the test item is based on

OECD 202 (1984) guideline about daphnia immobilisation test; the species and

age of organisms are based on the draft OECD 2019 (2001): “Sediment-water

chironomid toxicity test using spiked water”.

No/Group 4 replicates of 20 larvae

Dose Levels 2.0, 6.3, 20, 63 and 200 mg/L

Analytical measurements Yes, from fresh medium on day 0 and at 48 h, by HPLC. Only the samples of the

highest concentration were analysed as it is also the NOEC.

Study Summary

The acute toxicity of the test substance to first instar larvae of Chironomus riparius

was determined in a 48-hr static test. The test substance was dissolved in water

and the larvae were introduced into these test media. The survival rate of the

larvae and symptoms of intoxication were recorded. No sediment was added

since otherwise the small larvae, dwelt in sediment cannot be observed.

The nominal concentrations were 2.0, 6.3, 20, 63 and 200 mg/L. The measured



concentrations.



in the range of 22oC.

In the control and in the test concentrations, no mortality or other signs of





Flag Key study




Endpoint EC50

Value > 100 mg/L

Reference

A. Peither (2002) Acute toxicity of TFNA to Daphnia magna in a 48-hour

immobilization test. RCC Ltd, Environmental Chemistry & Pharmanalytics


Klimisch Score 1

166


February 2015


GLP Yes





Study Summary



concentration in the test medium was 99% of the nominal at the start and at the

end of the test substance so the results are expressed as nominal concentrations.









Flag Key study




Endpoint EC50

Value > 100 mg/L

Reference

A. Peither (2002) Acute toxicity of TFNA-AM to Daphnia magna in a 48-hour



Klimisch Score 1


GLP Yes




167


February 2015


Study Summary













Flag Key study




Endpoint EC50

Value > 100 mg/L

Reference

A. Peither (2002) Acute toxicity of TFNA-OH to Daphnia magna in a 48-hour



Klimisch Score 1


GLP Yes





Study Summary






168


February 2015








Flag Key study




Endpoint EC50

Value > 100 mg/L

Reference

A. Peither (2002) Acute toxicity of TFNG-AM to Daphnia magna in a 48-hour



Klimisch Score 1


GLP Yes





Study Summary





concentrations.

The pH values in the test medium and in the control ranged from 7.8, the oxygen

concentration was always higher than 8.1 mg/L and the temperature was 21oC.





169


February 2015

Invertebrates acute toxicity (Marine species)

No study provided.

Algae acute toxicity (Freshwater species)


Flag Key study





Value > 100 mg/L

Reference

A. Peither (2001) Acute toxicity of IKI-220 technical to Pseudokirchneriella

subcapitata (formerly Selenastrum capricornutum) in a 72-hour algal growth

inhibition test. RCC Ltd, Environmental Chemistry & Pharmanalytics Division. CH-

4452 Itingen Switzerland. Report no 807298.

Klimisch Score 1


GLP Yes




Analytical measurements Yes, from fresh medium on day 0 and at 72 h of the 2 highest concentrations, by

HPLC

Study Summary


Pseudokirchneriella subcapitata was determined in a 72-hr static test. The nominal

concentrations were 4.6, 10, 22, 46 and 100 mg/L. The measured concentration in

the test medium was 94-97% of the nominal at the start and at the end of the test

substance so the results are expressed as nominal concentrations.

The pH values in the test medium and in the control ranged from 7.9 at the start of

the study to 9.0 at the end, and the temperature was 22oC.

The growth rate in the control was valid according to the guideline (at least a factor

of 16).


(biomass and growth rate) at the concentration of 100 mg/L. The NOEC was 46

mg/L and both ErC50 and EbC50 are > 100 mg/L.

Conclusion The ErC50 and EbC50 are higher than 100 mg/L.

170


February 2015


Flag Key study





Value > 100 mg/L

Reference

A. Peither (2002) Acute toxicity of TFNA to Pseudokirchneriella subcapitata

(formerly Selenastrum capricornutum) in a 72-hour algal growth inhibition test.

RCC Ltd, Environmental Chemistry & Pharmanalytics Division. CH-4452 Itingen

Switzerland. Report no 834164.

Klimisch Score 1


GLP Yes



Dose Levels 1.0, 3.2, 10 and 100 mg/L


HPLC

Study Summary



nominal concentrations were 1.0, 3.2, 10 and 100 mg/L. The measured



concentrations.

The pH values in the test medium were adjusted with diluted sodium hydroxide

solution at the start of the test. They ranged from 7.8 to 8.0 (after adjustment) at

the start of the study and from 8.8 to 9.0 at the end, and the temperature was

23oC.


factor of 16).





171


February 2015


Flag Key study





Value > 100 mg/L

Reference

A. Peither (2002) Acute toxicity of TFNA-AM to Pseudokirchneriella subcapitata




Klimisch Score 1


GLP Yes





HPLC

Study Summary


Pseudokirchneriella subcapitata was determined in a 72-hr static test. A limit test

was performed at 100 mg/L. The measured concentration in the test medium was

96-98% of the nominal at the start and at the end of the test substance so the

results are expressed as nominal concentrations.

The pH values ranged from 8.1 at the start of the study to 9.4-9.5 at the end, and

the temperature was 23oC.


factor of 16).

The test substance had no statistically significant inhibitory effect on the growth




172


February 2015


Flag Key study





Value > 100 mg/L

Reference

A. Peither (2002) Acute toxicity of TFNA-OH to Pseudokirchneriella subcapitata

(formerly Selenastrum capricornutum) in a 72-hour algal growth inhibition test. RCC

Ltd, Environmental Chemistry & Pharmanalytics Division. CH-4452 Itingen


Klimisch Score 1


GLP Yes



Dose Levels 2.2, 4.6, 10, 22, 46 and 100 mg/L


HPLC

Study Summary


Pseudokirchneriella subcapitata was determined in a 72-hr static test. The nominal

concentrations were 2.2, 4.6, 10, 22, 46 and 100 mg/L. The measured

concentration in the test medium was 91-106% of the nominal at the start and at the


The pH values in the test medium were adjusted with diluted sodium hydroxide

solution at the start of the test. They ranged from 7.7 to 7.9 (after adjustment) at the

start of the study and from 8.6 to 9.1 at the end, except at 100 mg/L where it was

5.5, and the temperature was 23oC.

The growth rate in the control was valid according to the guideline (at least a factor

of 16).



was 4.6 mg/L, ErC50 is > 100 mg/L and EbC50 is 29 mg/L.

Conclusion ErC50 > 100 mg/L and EbC50 = 29 mg/L.

173


February 2015


Flag Key study





Value > 100 mg/L

Reference

A. Peither (2002) Acute toxicity of TFNG-AM to Pseudokirchneriella subcapitata




Klimisch Score 1


GLP Yes





Study Summary



nominal concentrations were 4.6, 10, 22, 46 and 100 mg/L. The measured



concentrations.

The pH values ranged from 7.9 to 8.0 at the start of the study and from 8.4 to 8.6

at the end, and the temperature was 22oC.


factor of 16).



was 10 mg/L, both ErC50 and EbC50 are > 100 mg/L.

Conclusion ErC50 and EbC50 > 100 mg/L.

174


February 2015

Algae acute toxicity (Marine species)

No study provided.

Aquatic plants acute toxicity (Freshwater species)


Flag Key study


Species Lemna gibba G3

Type of exposure Semi-static, 7 days, renewal on days 3 and 5

Endpoint EC50

Value > 119 mg/L

Reference

D Desjardins et al (2002) IKI-220 technical: a 7-day static-renewal toxicity test with

duckweed (Lemna gibba G3). Wildlife International Ltd, 8598 Commerce drive

Easton, Maryland 21601 USA. Report no 272A-108.

Klimisch Score 1


GLP Yes

Test Guideline/s OPPTS 850.4400 (draft) and OECD 221 (draft)

No/Group 3 replicates of 5 plants, totalling 15 fronds

Dose Levels 7.5, 15, 30, 60 and 120 mg/L (nominal)

7.3, 15, 30, 59 and 119 mg/L (mean measured)

Analytical measurements Yes, from fresh medium and old medium on day 0, 3 and 5 and at the end of the

test, by HPLC

Study Summary

The influence of the test substance on the growth of the duckweed Lemna gibba

was determined in a 7-day semi-static test. The nominal concentrations were 7.5,

15, 30, 60 and 120 mg/L. The mean measured concentrations in the test medium

were 7.3, 15, 30, 59 and 119 mg/L.

The pH values ranged from 8.0 to 8.2 at the start of the study and from 9.3 to 9.4

at the end, and the temperature was 25.1-26.1oC. The light intensity ranged from

4480 to 5340 lux.

The toxicity was determined by evaluating the production of plants and fronds and

their general health over 7 days.

Inhibitions of frond growth and percent of growth rates were not statistically

significantly different from the control.

The NOEC was 119 mg/L, EC50 is > 119 mg/L.

Conclusion EC50 > 119 mg/L.

175


February 2015

Fish chronic toxicity (Freshwater species)


Flag Key study


Species Pimephales promelas (fathead minnow)

Type of exposure Flow-through, 33 days (5 days pre-hatch and 28 days post-hatch)

Endpoint NOEC for time of hatch, hatching success, growth and survival

Value 10 mg/L (based on growth)

Reference

SJ Palmer et al (2002) IKI-220 technical: an early life stage toxicity test with the

fathead minnow (Pimephales promelas). Wildlife International Ltd, 8598

Commerce drive Easton, Maryland 21601 USA. Report no 272A-104.

Klimisch Score 1


GLP Yes

Test Guideline/s OPPTS 850.1400 (draft) and OECD 210 (1992)

No/Group 4 replicates of 20 embryos

Dose Levels 1.3, 2.5, 5.0, 10 and 20 mg/L (nominal)

1.2, 2.6, 4.9, 9.5 and 20 mg/L (mean measured)

Analytical measurements Yes, from samples collected at the beginning of the test, on day 5 and weekly

thereafter and at the study termination, by HPLC

Study Summary

The influence of the test substance on the growth of the fathead minnow early-life

stages was determined in a 33-day flow-through test. The nominal concentrations

were 1.3, 2.5, 5.0, 10 and 20 mg/L. The mean measured concentrations in the test

medium were 1.2, 2.6, 4.9, 9.5 and 20 mg/L.

The pH values ranged from 8.1 to 8.4, and the temperature was in the range 25 ±

1oC. Dissolved oxygen concentration remained > 7.5 mg/L (92% saturation).

All embryos hatched between days 4 and 5, there was no apparent difference

among the experimental groups.

Hatching success in the control was 99%, and varied from 95 to 100% in the test

substance groups. There was no statistically significant difference.

Larval survival in the control was 91% at the end of the test; and varied from 92 to

96% in the test substance groups. There was no statistically significant difference.

Biological observations of sublethal effects during the 28-day post-hatch period

were the presence of curved spine and organisms that appeared smaller or weak

in comparison to the other fish in the replicate. However, these observations were

infrequent and did not occur in a concentration related pattern. Consequently they

176


February 2015

were not considered to be treatment-related.

Growth was evaluated at the end of the test by measuring the total length, wet

weight and dry weight of each surviving fish. Fish in the 20 mg/L group exhibited a

slight yet statistically significant reduction in total length and dry weight

measurements in comparison to the control.

The NOEC was 10 mg/L based on growth

Conclusion NOEC = 10 mg/L based on growth.

Fish chronic toxicity (Marine species)

No study provided.

Invertebrates chronic toxicity (Freshwater species)


Flag Key study



Type of exposure Semi-static, 21 days. Renewal on days 2, 5, 7, 9, 12, 14, 16, 19.

Endpoint NOEC for survival rate, reproduction rate and body length of the adults

Value 3.1 mg/L based on reproduction rate

Reference

A Peither (2002) Influence of IKI-220 technical on survival and reproduction of

Daphnia magna in a semi-static test over three weeks. RCC Ltd, Environmental


834052

Klimisch Score 1


GLP Yes


No/Group 10

Dose Levels 3.1, 6.3, 12.5, 25, 50 and 100 mg/L


Yes, from samples collected at the beginning of the test, on day 12 and 16 of

fresh medium and on days 14 and 19 for old medium incubated in the same

conditions but without daphnia and food particles, by HPLC. Only the samples

from the 3.1 and 6.3 concentrations (NOEC and LOEC) were analysed.

Study Summary

The influence of the test substance on the reproduction and survival of Daphnia

magna was determined in a 21-day semi-static test. The nominal concentrations

were 3.1, 6.3, 12.5, 25, 50 and 100 mg/L. The measured concentrations in the test

177


February 2015

medium were in the range of 93 to 101% of the nominal, so the results are

expressed as nominal concentrations.

The pH values ranged from 7.6 to 8.2, and the temperature was in the range 20-

21oC. Dissolved oxygen concentrations remained > 8.0 mg/L.

The survival rate was above 90% in the control and in concentrations up to 25

mg/L. At 50 mg/L, 60% of mortality was observed and 100% in the 100 mg/L

concentration.

The first offspring was observed on day 9 in the control and in concentrations up

to 25 mg/L. In the 50 mg/L group the observation was delayed on day 12.

The mean reproduction rate of the control was 78.7 ± 9.7 alive offspring per adult.

No effect was observed at 3.1 mg/L but there was a statistically significant

difference at 6.3 mg/L and above.

The mean body length in the control was 4.0 ± 0.06 mm, no effect was observed

at 6.3 mg/L but there was a statistically significant difference at 12.5 mg/L and

above.

The NOEC was 3.1 mg/L based on reproduction rate.

Conclusion NOEC = 3.1 mg/L based on reproduction rate.

Invertebrates chronic toxicity (Marine species)

No study provided.

General conclusion about aquatic toxicity classification:

Flonicamid exhibits a very low level of acute and chronic toxicity on aquatic organisms. No classification is

triggered except a 9.1D for biocidal activity which doesn’t apply because flonicamid is also classified as

9.3C.

All relevant metabolites have also been tested on aquatic organisms. They show a very low toxicity as well.

Consequently no specific quantitative risk assessment will be performed for these metabolites.

Sediment toxicity (freshwater and/or marine)


Flag Key study


Species Chironomus riparius

Type of exposure Water-sediment (spiked water), 27 days, static.

Endpoint NOEC for development time/rate, emergence ratio and toxicity effects

Value 25 mg/L

Reference U Memmert (2002) Effects of IKI-220 technical on the development of sediment-

178


February 2015

dwelling larvae of Chironomus riparius in a water-sediment system. RCC Ltd,

Environmental Chemistry & Pharmanalytics Division. CH-4452 Itingen


Klimisch Score 1


GLP Yes

Test Guideline/s OECD 219 (draft, 2001)

No/Group 20 larvae/group

Dose Levels 6.3, 12.5, 25, 50 and 100 mg/L (results are expressed as nominal concentrations

in the water phase)


Yes. Water, pore water and sediment samples were taken on day 0 (1 hour after

substance application), on day 7 and at termination (day 27) from control, and 25

and 100 mg/L systems.

Study Summary

The influence of the test substance on the development of sediment-dwelling

larvae of the midge Chironomus riparius was determined in a 27-day water-

sediment test. The nominal concentrations were 3.1, 6.3, 12.5, 25, 50 and 100

mg/L.

The mean measured concentrations of the substance one hour after application

was 93% of the nominal concentration in both analysed test concentrations. The

concentrations decreased only slightly in the water of the water-sediment systems

during the test period. Seven days after application, the concentrations in the

water column were 86% of the nominal and at the study termination they

corresponded to 77-79%.

In the pore water and sediment, the concentration of the active substance

continuously increased during the study period. At 25 mg/L, the concentration in

pore water was in maximum 14.2 mg/L and 6.6 mg/kg in the sediment at study

termination. At 100 mg/L, a maximum of 57.5 mg/L were found in the pore water

and 26.2 mg/kg in the sediment (based on dry sediment).

A statistically significant effect on the mean emergence ratio was observed at 50

and 100 mg/L. The mean development rates of the female midges were

statistically significantly reduced at 50 mg/L and higher, the mean development

rates of the males first at 100 mg/L.

The NOEC is 25 mg/L based on the emergence ratios, development rates and

toxicity symptoms.

Conclusion The NOEC is 25 mg/L based on the emergence ratios, development rates

and toxicity symptoms.

179


February 2015

General conclusion about sediment toxicity:

Flonicamid show a rather low toxicity on the reproduction of sediment dwelling arthropods.

Soil toxicity

Soil macro-invertebrates acute toxicity


Flag Key study


Species Eisenia fetida

Type of exposure Static, for 14 days

Endpoint LC50

Value > 1000 mg/kg dry soil

Reference

R Baetscher (2001) Acute toxicity of IKI-220 technical to the earthworm Eisenia

fetida in a 14-day test. RCC Ltd, Environmental Chemistry & Pharmanalytics

Division. CH-4452 Itingen Switzerland. Report no 807333

Klimisch Score 1


GLP Yes



Dose Levels 56, 100, 178, 316, 562, 1000 mg/ kg dry soil


Study Summary

The acute toxicity of the substance to the earthworm Eisenia fetida was

determined in a 14-day test with artificial substrate containing 10% of peat.

After 7 and 14 days of exposure, no mortality was observed at any of the test

concentrations up to and including the highest test concentration of 1000 mg ai/kg

dry soil. Moreover, no abnormal behaviour or symptoms of toxicity were recorded.

The body weight was not affected up to the highest concentration.

Conclusion LC50> 1000 mg/kg dry soil


Flag Key study



180


February 2015


Endpoint LC50


Reference

R Baetscher (2002) Acute toxicity of TFNA to the earthworm Eisenia fetida in a

14-day test. RCC Ltd, Environmental Chemistry & Pharmanalytics Division. CH-

4452 Itingen Switzerland. Report no 834221

Klimisch Score 1


GLP Yes



Dose Levels 100 mg/ kg dry soil


Study Summary



After 7 and 14 days of exposure, no mortality was observed at the test

concentration of 100 mg ai/kg dry soil. Moreover, no abnormal behaviour or

symptoms of toxicity were recorded. The body weight was not affected.



Flag Key study




Endpoint LC50


Reference

R Baetscher (2002) Acute toxicity of TFNA-AM to the earthworm Eisenia fetida in

a 14-day test. RCC Ltd, Environmental Chemistry & Pharmanalytics Division. CH-


Klimisch Score 1


GLP Yes


181


February 2015




Study Summary








Flag Key study




Endpoint LC50


Reference

R Baetscher (2002) Acute toxicity of TFNA-OH to the earthworm Eisenia fetida in



Klimisch Score 1


GLP Yes





Study Summary







182


February 2015


Flag Key study




Endpoint LC50


Reference

R Baetscher (2002) Acute toxicity of TFNG-AM to the earthworm Eisenia fetida in



Klimisch Score 1


GLP Yes





Study Summary







Soil macro-invertebrates chronic toxicity

No study provided.

Since flonicamid is rapidly degraded in soil, continued exposure of earthworms to the active ingredient is not

likely to occur, even with 2 applications at 7-day interval. Moreover, the relevant metabolites have been

tested for acute toxicity and no effect was observed up to 100 mg/kg dry soil.

Non-target plants toxicity

No study provided with the active ingredient but tests were performed with Mainman.

183


February 2015

Nitrogen transformation test

Flag Supporting study (endpoint already covered by the formulation test which is of

better quality)

Test Substance Flonicamid technical

Species Soil micro-flora

Type of exposure Static, 28 days

Endpoint Nitrate content

Value No effect

Reference

M das Gracas S. Raposo (2003) Side effects of Flonicamid tecnico on soil

microorganisms: nitrogen transformation test. Bioagri Laboratorios Ltda

Piracicaba/SP Brazil. Report no RF-1213.218.027.02

Klimisch Score 2 report is not very detailed, results are poorly described


GLP yes



Dose Levels 0.21 and 1.03 µg/g soil corresponding to 100 and 500 g ai /ha


Study Summary

The objective of this study was to assess the effects of the substance on the

nitrogen transformation in soil, determined by the nitrate content. The substance

was applied on soils at concentrations of 0.21 and 1.03 µg/g soil corresponding to

100 and 500 g ai /ha. 2 different types of soil were used, they are classified as

Rhodic Hapludox and Typic Hapludox according to the USDA soil taxonomy

(1990). Samples were taken at 0, 7, 14 and 28 days to determine the nitrate

content.

There was no significant effect of the substance at any time, on any soil and at

any concentration.

Conclusion No effect on the N transformation in soil at concentrations up to 500 g ai/ha

Carbon transformation test

Flag Supporting study (endpoint already covered by the formulation test which is of

better quality)

Test Substance Flonicamid technical

Species Soil micro-flora

Type of exposure Static, 28 days

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Endpoint CO2 release

Value No effect

Reference

M das Gracas S. Raposo (2003) Side effects of Flonicamid tecnico on soil

microorganisms: carbon transformation test. Bioagri Laboratorios Ltda

Piracicaba/SP Brazil. Report no RF-1213.201.153.02

Klimisch Score 2 report is not very detailed, results are poorly described


GLP Yes


No/Group 2 soils

Dose Levels 0.21 and 1.03 µg/g soil corresponding to 100 and 500 g ai /ha


Study Summary

The objective of this study was to assess the effects of the substance on the

carbon transformation in soil, determined by the CO2 production rate by the

microbial respiration. The substance was applied on soils at concentrations of

0.21 and 1.03 µg/g soil corresponding to 100 and 500 g ai /ha. 2 different types of

soil were used, they are classified as Rhodic Hapludox and Typic Hapludox

according to the USDA soil taxonomy (1990). Samples were taken at 0, 7, 14 and

28 days to determine the 14

CO2 production after addition of 14

C-glucose.

There was no significant effect of the substance at any time, on any soil and at

any concentration.

Conclusion No effect on the C transformation in soil at concentrations up to 500 g ai/ha

General conclusion about soil toxicity classification:

Flonicamid does not trigger any 9.2 classification. The relevant metabolites have also been tested on

earthworms and do not show any toxicity.

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Terrestrial vertebrate toxicity

For effects on terrestrial vertebrates other than birds, refer to the mammalian toxicity section.

Oral acute toxicity

Type of study Limit test extended to a full test



Species Colinus virginianus (Bobwhite quail)

Type of exposure Single dose, observation period of 14 days

Endpoint LD50

Value > 2000 mg/kg bw

Reference

R Burri (2002) IKI-220 technical: Acute oral toxicity test in the bobwhite quail. RCC

Ltd, Environmental Chemistry & Pharmanalytics Division. CH-4452 Itingen


Klimisch Score 1


GLP Yes

Test Guideline/s OPPTS 850.2100 (1996)

No/sex/Group 5 males and females for 2000 mg/kg bw, only 5 females for the lower doses.

Dose Levels 260, 432, 720, 1200 and 2000 mg/kg bw


Study Summary

Initially, a limit test was performed with one dose group of 5 males and 5 females

treated with 2000 mg/kg bw. Because 40 % of mortality occurred in the females at

this concentration, additional groups of females were treated with 260, 432, 720 and

1200 mg/kg bw. No mortality was observed in these additional groups.

Clinical symptoms were exclusively observed in females exposed to 2000 mg/kg bw.

There was a significant influence of the treatment on the body weights of males and

females. It was caused by reduced food consumption. This effect was reversible for

the males and also for the females treated by doses up to 1200 mg/kg bw but the

body weight of the females treated with 2000 mg/kg bw was still reduced at the end of

the observation period (14 days).

A lower food consumption was observed during the first week after administration for

the animals treated by 2000 mg/kg bw, and during the first 3 days for the other doses.

Average food consumption was back to normal level during the 2nd

observation week.

Conclusion LD50 > 2000 mg/kg bw

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Type of study Limit test extended to a full test

Flag Key study


Species Mallard duck (Anas platyrhynchos)

Type of exposure Single dose, observation period of 14 days

Endpoint LD50

Value 2621 mg/kg bw (males) and 1591 mg/kg bw (females)

Reference

R. Burri (2002) IKI-220 technical: acute oral test in the Mallard duck. RCC Ltd

Environmental Chemistry & Pharmanalytics Division. CH-4452 Itingen


Klimisch Score 1


GLP yes

Test Guideline/s OPPTS 850.2100 (1996)

No/sex/Group 5

Dose Levels 260, 432, 720, 1200 and 2000 mg/kg bw


Study Summary

Initially, a limit test was performed with one dose group of 5 males treated with

2000 mg/kg bw. Because mortality occurred at this concentration, additional

groups of males and females were treated with 260, 432, 720 and 1200 mg/kg bw.

40 and 60 % of mortality were observed at 2000 mg/kg in males and females,

respectively; 0 % at 1200 mg/kg, 20 in males and females at 720, 20% in males at

432 and 20% in females at 260 mg/kg bw.

Clinical symptoms were exclusively ataxia, dyspnea and ventral recumbency.

Most of the animals that died developed symptoms rapidly and died within 1 to 3

hours after administration.

There was no influence of the treatment on the body weights of the surviving

males and females and no general test substance related effect on the food

consumption.

The NOED is 260 mg/kg bw (males) and 432 mg/kg bw (females)

Conclusion LD50 = 2621 mg/kg bw (males) and 1591 mg/kg bw (females)

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Dietary acute toxicity





Type of exposure 5 days in diet followed by 3 days of observation

Endpoint LC50

Value > 5000 mg/kg diet corresponding to > 411.1 mg/kg bw/day

Reference

R Burri (2001) IKI-220 technical: avian dietary toxicity test in the bobwhite quail.

RCC Ltd Environmental Chemistry & Pharmanalytics Division. CH-4452 Itingen


Klimisch Score 1


GLP Yes

Test Guideline/s OECD 205 (1984) and OPPTS 850.2200 (1996)

No/Group 10 animals of undetermined sex because of their size and age (14 days)

Dose Levels 5000 mg/kg diet

Analytical measurements Concentration of ai in diet was confirmed, stability and homogeneity were checked

Study Summary

A limit test was performed. IKI-220Technical was administered to one group of 10

Bobwhite quails by dietary ingestion at a nominal dose level of 5000 mg test

item/kg diet for 5 treatment days followed by 3 observation days where the

animals obtained regular diet.

No mortality was observed in the main study at a dose level of 5000 mg test

item/kg diet therefore the LC50 of IKI-220 Technical was > 5000 mg/kg diet.

No symptoms and no macroscopic findings were observed for the treated animals.

Therefore, the NOEC was > 5000 mg/kg diet.

During treatment, a significantly lower average body weight was observed for the

treated animals as compared to the control groups, reflecting a reduced food

consumption of the treated animals.

During treatment, individual and relative food consumption was lower for the

treated animals as compared to the control animals. This indicated a repellency

potential of the test item.

The LC50 based on test item intake was > 411.0 mg test item/kg body weight/day.

Conclusion LC50 > 5000 mg/kg diet corresponding to > 411.1 mg/kg bw/day

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Flag Key study



Type of exposure 5 days in diet followed by 3 days of observation

Endpoint LC50

Value > 5000 mg/kg diet corresponding to > 301.8 mg/kg bw/day

Reference

R Burri (2001) IKI-220 technical: Avian dietary toxicity test in the Mallard duck.

RCC Ltd Environmental Chemistry & Pharmanalytics Division. CH-4452 Itingen


Klimisch Score 1


GLP Yes

Test Guideline/s OECD 205 (1984) and OPPTS 850.2200 (1996)

No/Group 10 animals of undetermined sex because of their size and age (14 days)

Dose Levels 5000 mg/kg diet


Study Summary

A limit test was performed. IKI-220 Technical was administered to one group of 10

ducks by dietary ingestion at a nominal dose level of 5000 mg test item/kg diet for

5 treatment days followed by 3 observation days where the animals obtained

regular diet.

No mortality was observed in the main study at a dose level of 5000 mg test

item/kg diet therefore the LC50 of IKI-220 Technical was > 5000 mg/kg diet.

No symptoms and no macroscopic findings were observed for the treated animals.

Therefore, the NOEC was > 5000 mg/kg diet.

During treatment, a significantly lower average body weight was observed for the

treated animals as compared to the control groups, reflecting a reduced food

consumption of the treated animals.

During treatment, individual and relative food consumption was lower for the

treated animals as compared to the control animals. This indicated a repellency

potential of the test item.

The LC50 based on test item intake was > 301.8 mg test item/kg body weight/day.

Conclusion LC50 > 5000 mg/kg diet corresponding to > 301.8 mg/kg bw/day

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Chronic toxicity (reproduction)





Type of exposure Dietary exposure for 21 weeks

Endpoint NOEC for reproduction and toxicity on adults

Value 1000 mg/kg diet corresponding to 90 mg ai /kg bw /day

Reference

LR. Mitchell et al (2002) A reproduction study with the Northern bobwhite (Colinus

virginianus). Wildlife International, Ltd. 8598 Commerce Drive Easton, Maryland

21601 USA. Report no 272-125

Klimisch Score 1


GLP Yes


No/sex/Group 16

Dose Levels 0, 160, 400 and 1000 ppm a.i.


Study Summary

The objective of this study was to evaluate the effects upon the adult northern

bobwhite (Colinus virginianus) of dietary exposure to IKI-220 over a period of

approximately 21 weeks. Effects on adult health, body weight, and feed consumption

were evaluated. In addition, the effects of adult exposure to IKI-220 on the number of

eggs laid, fertility, embryo viability, hatchability, offspring survival, and egg shell

thickness were evaluated.

Each treatment and control group contained 16 pairs of birds with one male and one

female per pen. Three treatment groups were fed diets containing either 160, 400, or

1000 ppm a.i. of IKI-220 for approximately 21 weeks. The control group was fed diet

comparable to the treatment groups, but without the addition of the test substance. All

adult birds were observed daily throughout the test for signs of toxicity or abnormal

behaviour. Adult body weights were measured at test initiation, on Weeks 2, 4, 6, 8,

and at adult termination and feed consumption was measured weekly throughout the

test. At the beginning of Week 8, the photoperiod was increased to induce egg

production. Following the start of egg production, eggs were set weekly for

incubation. Weekly, eggs were selected by indiscriminate draw for egg shell thickness

measurement and all remaining eggs were candled prior to incubation to detect egg

shell cracks or abnormal eggs. Eggs were also candled twice during incubation to

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detect infertile eggs or embryo mortality. On Day 21 of incubation, the eggs were

placed in a hatcher and allowed to hatch. Once hatching was completed, hatchlings

were removed from the hatcher and the group body weight of the hatchlings by pen

was determined. At 14 days of age, the average body weight by parental pen of all

surviving offspring was determined.

The estimated test substance intakes for northern bobwhite during Weeks 1 through

21 of the test were 13, 33 and 90 mg IKI-220/kg body weight/day for the 160, 400 and

1000 ppm a.i. treatment groups, respectively. There were no treatment-related

mortalities, overt signs of toxicity or treatment-related effects upon adult body weight

or feed consumption at any of the concentrations tested. Additionally, there were no

treatment-related effects upon any of the reproductive parameters measured at the

160, 400 or 1000 ppm a.i. test concentrations. The no-observed-effect concentration

for northern bobwhite exposed to IKI-220 in the diet during the study was 1000 ppm

a.i. (90 mg a.i./kg body weight/day), the highest concentration tested.

Conclusion NOEC = 1000 mg/kg diet corresponding to 90 mg ai /kg bw/day


Flag Key study



Type of exposure Dietary exposure for 20 weeks

Endpoint NOEC for reproduction and toxicity on adults

Value 400 mg/kg diet corresponding to 59 mg/kg bw/ day

Reference LR. Mitchell et al (2002) A reproduction study with the Mallard. Wildlife International,

Ltd. 8598 Commerce Drive Easton, Maryland 21601 USA. Report no 272-126

Klimisch Score 1


GLP Yes


No/sex/Group 16

Dose Levels 0, 160, 400 and 1000 ppm a.i.


Study Summary

The objective of this study was to evaluate the effects upon the adult mallard (Anas

platyrhynchos) of dietary exposure to IKI-220 over a period of approximately 20

weeks. Effects on adult health, body weight, and feed consumption were evaluated.

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February 2015

In addition, the effects of adult exposure to IKI-220 on the number of eggs laid,

fertility, embryo viability, hatchability, offspring survival, and egg shell thickness were

evaluated.

Each treatment and control group contained 16 pairs of birds with one male and one

female per pen. Three treatment groups were fed diets containing either 160, 400, or

1000 ppm a.i. of IKI-220 for approximately 20 weeks. The control group was fed diet

comparable to the treatment groups, but without the addition of the test substance. All

adult birds were observed daily throughout the test for signs of toxicity or abnormal

behaviour. Adult body weights were measured at test initiation, on Weeks 2, 4, 6, 8,

and at adult termination and feed consumption was measured weekly throughout the

test. At the beginning of Week 9, the photoperiod was increased to induce egg

production. Following the start of egg production, eggs were set weekly for

incubation. Weekly, eggs were selected by indiscriminate draw for egg shell thickness

measurement and all remaining eggs were candled prior to incubation to detect egg

shell cracks or abnormal eggs. Eggs were also candled twice during incubation to

detect infertile eggs or embryo mortality. On Day 24 of incubation, the eggs were

placed in a hatcher and allowed to hatch. Once hatching was completed, hatchlings

were removed from the hatcher and the group body weight of the hatchlings by pen

was determined. At 14 days of age, the average body weight by parental pen of all

surviving offspring was determined.

The estimated test substance intakes for mallards during Weeks 1 through 20 of the

test were 25, 59 and 138 mg IKI-220/kg body weight/day for the 160, 400 and 1000

ppm a.i. treatment groups, respectively. There were no treatment-related mortalities,

overt signs of toxicity or treatment-related effects upon adult body weight or feed

consumption at any of the concentrations tested. Additionally, there were no

treatment-related effects upon any of the reproductive parameters measured at the

160 or 400 ppm a.i. test concentrations. However, there were treatment-related

effects upon both viability and hatchability at the 1000 ppm a.i. treatment group that

resulted in statistically significant (p < 0.05) reductions in hatchlings and 14-day old

survivors as percentages of the number of eggs set. Based on the effects noted in the

1000 ppm a.i. treatment group, the no-observed-effect concentration for mallards

exposed to IKI-220 in the diet during the study was 400 ppm a.i. (59 mg a.i./kg body

weight/day).

Conclusion NOEC = 400 mg/kg diet corresponding to 59 mg/kg bw/ day

General conclusion about terrestrial vertebrate classification:

Flonicamid is classified as 9.3C on the basis of its acute effects on birds.

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Ecotoxicity to terrestrial invertebrates

Bees - Laboratory tests (acute oral and contact)

Type of study Limit test (contact), full test (oral)

Flag Key study



Type of exposure 48 h (contact) and 96 h (oral)

Endpoint LD50

Value > 60.5 µg ai/bee (oral)

> 100 µg ai/bee (contact)

Reference

S Schmitzer (2001) Laboratory testing for toxicity (acute contact and oral) of IKI-

220 TGAI on Honey bees (Apis mellifera L.). IBACON GmbH Arheilger Weg 17

64380 Rossdorf Germany. Report no 10731036

Klimisch Score 1


GLP Yes


No/Group 3 replicates of 10 (oral) and 5 replicates of 10 (contact)

Dose Levels Contact test: 100 µg ai/bee

Oral: 6.4, 11.6, 22.2, 47.7, 60.5 µg ai/bee (actual intake)


Study Summary

In the contact toxicity test, 8.0% mortality was observed at 100 µg ai/bee after 48

hours. Behavioural impairments like nervousness (during the first 4 hours),

discoordinated movement and apathy were observed during the 48 hours of the

experiment.

In the oral test, honey instead of syrup was used as a carrier. Since pre-tests have

demonstrated that the substance had a strong repellent effect, honey was used

because it is more attractive to bees. The maximum nominal test level of 100 µg

ai/bee corresponded to an actual intake of 60.5 µg ai/bee. After a starving period

of 90 min, the desired nominal dosage could not be applied since honeybees

rejected to ingest the full volume of treated honey even when offered over 6

hours. The observation period was extended to 96 hours because delayed

mortality occurred in 3 or the 5 groups.

Oral dose of 60.5 µg ai /bee led to 36.7% mortality at test end; 20, 26.7, 26.7 and

6.7% of mortality were observed at 47.7, 22.2, 11.6 and 6.4 µg ai/bee,

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February 2015

respectively.

Behavioural impairments like nervousness, discoordinated movement and apathy

was observed during the first 48 hours of observation. No further behavioural

abnormality was observed during the 72 and 96 hours check.

Conclusion Oral LD50 (48 + 96h) > 60.5 µg ai/bee

Contact LD50 (48h) > 100 µg ai/bee

Other non-target arthropods

No studies performed with the active ingredient itself, but tests are available with Mainman.

General conclusion about toxicity to terrestrial invertebrates classification:

Flonicamid does not trigger any 9.4 classification.

Appendix E: Staff’s risk identification

To assess the risks posed by the substance throughout its lifecycle, the most common potential sources of

risk to the environment and human health and safety were identified (Table 12). These are shown in Tables

13 and 14 with an assessment of risk that assumes an absence of controls and/or regulations.

Table 12 Potential sources of risks associated with hazardous substances

Lifecycle Activity Associated Source of Risk

Manufacture / Import

An incident during the manufacture or importation of the substance resulting in

a spill and the subsequent exposure of people or the environment to the

substance

Packing An incident during the packing of the substance resulting in a spill and the

subsequent exposure of people or the environment to the substance

Transport or storage

An incident during the transport, storage or handling or the substance, resulting

in a spill and the subsequent exposure of people or the environment to the

substance. For example, inadequate storage and security on farms resulting in

access by unauthorised persons (including children)

Use Application of the substance resulting in exposure of users or bystanders or the

environment

Disposal

Inadequate, incorrect or unlawful disposal of substance, excess tank mix or

empty packaging resulting in exposure of people or the environment to the

substance

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Appendix F: Qualitative risk assessment

Staff also carried out a qualitative assessment to assess risks to human health and the environment from the lifecycle of Mainman. A summary of the

results of the qualitative assessment are shown in Section 6 of this report and are detailed below. The process by which the risk assessment of

substances is undertaken is specified in the on risk assessment is provided on the EPA website. Methodology Guidance

Table 13 Qualitative assessment of human health risks

Lifecycle Description Likelihood Magnitude Level of risk

(matrix)

Comment Level of

risk

(EPA)

Manufacture

and

packaging

Eye irritation Highly

improbable

Moderate Negligible Manufacturing and packaging facilities in New Zealand will be

required to meet the HSNO requirements for equipment, emergency

management and WorkSafe New Zealand’s health and safety

requirements.

Negligible

Importation,

transport,

storage

Eye Irritation Very Unlikely Minimal Negligible Workers and bystanders will only be exposed to the substance

during this part of the lifecycle in isolated incidents if a spill occurs,

therefore only risks from acute exposure are considered here.

Compliance with HSNO controls (e.g. labels, SDS) and adherence

to the Land Transport Rule 45001, Civil Aviation Act 1990 and

Maritime Transport Act 1994 (as applicable) will make the likelihood

of exposure very unlikely Any exposure is only expected to have a

localised, reversible effect and is therefore considered minimal.

Negligible

Disposal Use Eye irritation Unlikely Minimal Negligible Eye irritation could occur during mixing, loading or application of

Mainman, or handling it for disposal. However, assuming the HSNO

controls and good practice for handling agrichemicals is followed

(e.g. use of eye protection when mixing or using chemicals) then it is

unlikely that someone will be affected by the substance. Any effects

are expected to be reversible and impact individuals handling the

substance therefore the impact of the effect is considered minimal.

All cases of disposal are required to be in accordance with the

requirements of the Hazardous Substances (Disposal) Regulations

2001. Compliance with these regulations will both reduce the

likelihood of adverse events occurring.

Negligible

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Table 14 Qualitative assessment of risks to the environment

Lifecycle Description Likelihood Magnitude Level of risk

(matrix)

Comment Level of

risk

Manufacture,

importation,

transport

and storage

Death or

adverse

effects to

terrestrial

vertebrates

Highly

improbable

Minimal Negligible The terrestrial environment will only be exposed to Mainman

during this part of the lifecycle in isolated incidents if a spill occurs.

Given adherence to the Controls, the Land Transport Rule 45001,

Resource Management Act 1991, Civil Aviation Act 1990 and the

Maritime Transport Act 1994 (as applicable), the staff consider a

spill to be highly improbable, and a spill is only likely to lead to

localised effects.

Negligible

Use

(application)

Death or

adverse

effects to

terrestrial

vertebrates

Very Unlikely Minimal Negligible Terrestrial invertebrates, such as bees, may be affected by

Mainman if it is applied to plants where bees are foraging.

Prohibiting application of Mainman where bees are foraging, will

reduce the likelihood of Mainman adversely affecting beneficial

invertebrates.

Negligible

Disposal Death or

adverse

effects to

terrestrial

vertebrates

Highly

improbable

Minimal Negligible Users will in most cases use all of the substance through normal

use as an insecticide. All cases of disposal are required to be in

accordance with the requirements of the Hazardous Substances

(Disposal) Regulations 2001. Compliance with these regulations

will both reduce the likelihood of adverse events occurring, and

diminish the quantity of substance released to the environment in

such an event. Accordingly, the overall level of risk to aquatic

organisms and terrestrial invertebrates will be assessed as

negligible.

Negligible

196

Application for approval to import Mainman for release (APP202145))

Feburary 2015

Appendix G: Human health risk assessment

Quantitative worker (operator) risk assessment

Critical endpoint definition

The EFSA peer review previously established an AOEL for flonicamid of 0.025 mg/kg bw/day, based on what

were considered adverse effects (malformations) in the rabbit developmental toxicity study. However, as

noted above, these effects are not considered to be a direct adverse effect of flonicamid (the incidences of

malformations were within the historical control range, were not consistent nor were they dose related). This

conclusion is consistent with a recent review by the European Chemicals Agency’s Risk Assessment

Committee. Therefore the staff have derived a new AOEL for flonicamid.

Table 15: Deriving an AOEL for flonicamid

Key systemic

effect

NOAEL

mg/kg

bw/day

Uncertainty

factors

Absorption

factor18

AOEL

mg/kg

bw/day

Justification

Micropathological

changes in the

kidney (females):

90-day study in

dogs

Mild anemia: 52-

week study in

dogs

8 100 1 0.08

Lowest NOAEL from the sub-

chronic toxicity studies in mice,

rats and dogs; also consistent

with the NOAEL for maternal

toxicity in the rabbit

developmental toxicity study (7.5

mg/kg bw/day)

18

100

n% Absorptio

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Other inputs for human worker (operator) and re-entry exposure modelling19

Table 16 Derivation of dermal absorption value in humans

Active

ingredient

Physical

form

Concentration

of each active

(g/L or g/kg)

Maximum

application rate

(for each active, for

each method of

application)

g (ai)/ha

Dermal absorption (%)

AOEL

mg/kg

bw/day Concentrate Spray

Flonicamid

Water

dispersible

granule

500 g/kg

80 (boom)

70 (high volume

directed, aerial)

7 13 0.08

Comments on inputs for human worker (operator) exposure modelling input parameters:

The dermal penetration of IKI-220 formulated as IKI-220 50% WG in human skin was 7% at the lowest field

use dilution of 0.4 g IKI-220/L. At the highest field use dilution of 0.07 g IKI-220/L, the dermal absorption in

human skin was 13%. Therefore it is proposed to use 7% for the concentrate and 13% for the spray. This

was also the approach taken by EFSA.

19 The Staff has undertaken an assessment of risks to operator health using the United Kingdom Pesticide Safety Directorate’s

interpretation of the German BBA Model to estimate operator exposure. This model estimates the exposure of workers to a

pesticide during mixing, loading and during spray application, in mg/kg person/day (http://www.pesticides.gov.uk/index.htm).

The derived values consider both dermal and inhalation exposure routes. The Staff typically uses the geometric mean model.

The BBA model provides for a range of different spray applications (tractor-mounted/trailed sprayers and hand-held sprayers)

and formulation types (liquid, wettable powder and wettable granule). Additionally, the BBA model also allows flexibility to vary

protective clothing (hands, head and body).

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Output of human worker (operator) mixing, loading and application exposure modelling

Table 17 Risk Quotients for Mainman: Potato – 80 g ai/ha, 2 applications at 7 days, ground based

Exposure Scenario Estimated operator

exposure (mg/kg bw/day) Risk Quotient

Boom

No PPE20

during mixing, loading and application 0.0095 0.12

Gloves only during mixing and loading 0.0063 0.08

Gloves only during application 0.0083 0.10

Full PPE during mixing, loading and application (excluding

respirator)

0.0005 0.01

Full PPE during mixing, loading and application (including

respirator)

0.0003 0.004

Table 18 Risk Quotients for Mainman: Confidential use 1 – 70 g ai/ha, 2 applications at 14 days,

ground based



Boom

No PPE21





respirator)

0.0004 0.01


respirator)

0.0003 0.003

Confidential use 2 – 70 g ai/ha, 2 applications at 14 days, aerial

The EPA’s exposure model does not include an evaluation of operator exposure during aerial application.

However, it is anticipated that exposure during mixing and loading prior to aerial application will be similar to

20 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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Feburary 2015

that during mixing and loading before ground based application. Operator exposure during aerial application

is expected to be lower than that during ground based application. Therefore overall operator exposure for

confidential use 2 is expected to be lower than operator exposure for confidential use 1.

Table 19 Risk Quotients for Mainman: Confidential use 3– 70 g ai/ha, 2 applications at 7 days, ground

based



Boom

No PPE22





respirator)

0.0004 0.01


respirator)

0.0003 0.003

Confidential use 4 – 70 g ai/ha, 2 applications at 7 days, aerial

The EPA’s exposure model does not include an evaluation of operator exposure during aerial application.

However, it is anticipated that exposure during mixing and loading prior to aerial application will be similar to

that during mixing and loading before ground based application. Operator exposure during aerial application

is expected to be lower than that during ground based application. Therefore overall operator exposure for

confidential use 4 is expected to be lower than operator exposure for confidential use 3.

Table 20 Risk Quotients for Mainman: Confidential use 5 – 70 g ai/ha, 3 applications at 21 days



Airblast

No PPE during mixing, loading and application 0.0133 0.17




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Feburary 2015



respirator)

0.0008 0.01


respirator)

0.0006 0.01

Outcomes of the worker (operator) exposure assessment

The results of the quantitative risk assessment indicate that PPE is not required to protect against adverse

effects resulting from systemic exposure to the active ingredient23

Output of the re-entry exposure assessment:

Table 21 Risk Quotients for Mainman: Re-entry exposure modelling24

Re-entry Activity

Internal (absorbed) dose available for

systemic distribution

(mg/kg bw/8 hours)

AOEL

(mg/kg bw/day)

Risk Quotient at

24 hours without

gloves

Potatoes

Vegetables – reach/pick

0.013 0.08 0.17

Confidential use 1 0.004 0.08 0.05





23 The staff 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 Staff notes that the HSNO PPE

requirements are not prescriptive allowing users to select an appropriate level of PPE.

24 The staff assessed the re-entry worker exposures using the generic exposure model for “Maintenance and harvesting

activities: Dermal exposure” provided by the UK Health & Safety Executive chemical Regulation Directorate, on the following

web site:

http://www.pesticides.gov.uk/applicant_guide.asp?id=1246&link=%2Fuploadedfiles%2FWeb%5FAssets%2FPSD%2FRe%2Den

try%2520worker%2520guidance%5Ffinal%2520version%2Epdf.

http://www.pesticides.gov.uk/applicant_guide.asp?id=1246&link=%2Fuploadedfiles%2FWeb%5FAssets%2FPSD%2FRe%2Dentry%2520worker%2520guidance%5Ffinal%2520version%2Epdf

http://www.pesticides.gov.uk/applicant_guide.asp?id=1246&link=%2Fuploadedfiles%2FWeb%5FAssets%2FPSD%2FRe%2Dentry%2520worker%2520guidance%5Ffinal%2520version%2Epdf

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Outcomes of the re-entry exposure assessment

Estimated re-entry worker exposures 24 hours following application are below the AOEL, even without the

use of gloves. As the estimated exposures are very low it is anticipated that risks for re-entry workers will

also be low immediately following application. However, to promote good practice staff consider that a label

statement along the following lines should be considered:

‘Do not allow entry into treated areas until the spray has dried, unless wearing cotton overalls buttoned to

the neck and wrist (or equivalent clothing) and chemical resistant gloves. Clothing must be laundered

after each day’s use.’

Quantitative bystander risk assessment25

Critical endpoints definition

The AOEL derived for operator and re-entry worker assessment above is also used for the bystander

assessment calculations.

Output of human bystander mixing, loading and application exposure modelling26

Table 22 Risk Quotients for Mainman: Use on Potatoes

Exposure Scenario

Estimated exposure of 15 kg toddler exposed

through contact to surfaces 8 m from an

application area (µg/kg bw/day)

Risk Quotient

Boom

High boom, fine droplets 0.78 0.0097

25 The Staff 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. EPA has agreed that the AOEL used for operator and re-entry worker exposure assessment

should be used for the bystander assessment, as the use of an oral chronic reference dose (CRfD) is usually likely to be over

precautionary.

26 Exposure is estimated using the equations from the UK Health & 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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High boom, coarse droplets 0.12 0.0015

Low boom, fine droplets 0.26 0.0033

Low boom, coarse droplets 0.06 0.0008

Table 23 Risk Quotients for Mainman: Confidential uses 1 and 2 – 70 g ai/ha, 2 applications at 14

days, ground based and aerial

Exposure Scenario

Estimated exposure of 15 kg

toddler exposed through

contact to surfaces 8 m from

an application area

(µg/kg bw/day)

Risk Quotient

Confidential use 1 – Boom





Confidential use 2 – Aerial – agriculture

Swath width 20 m, Med-coarse droplet size 0.80 0.0100

Swath width 20 m, coarse- v. coarse droplets 0.59 0.0074

Swath width 20 m, extremely coarse droplets 0.40 0.0050

Swath width 24 m, v. fine-fine droplets 2.39 0.0299

Swath width 24 m, fine-med. droplets 1.19 0.0148

Swath width 24 m, med.-coarse droplets 0.80 0.0099

Table 24 Risk Quotients for Mainman: Confidential uses 3 and 4 – 70 g ai/ha, 2 applications at 7 days,

ground based and aerial

Exposure Scenario

Estimated exposure of 15 kg toddler

exposed through contact to surfaces 8 m

from an application area

(µg/kg bw/day)

Risk Quotient

Confidential use 3 – Boom



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Confidential use 4 – Aerial – agriculture

Swath width 20 m, Med-coarse droplet size 0.94 0.0117

Swath width 20 m, coarse- v. coarse droplets 0.69 0.0087

Swath width 20 m, extremely coarse droplets 0.47 0.0059

Swath width 24 m, v. fine-fine droplets 2.80 0.0350

Swath width 24 m, fine-med. droplets 1.39 0.0174

Swath width 24 m, med.-coarse droplets 0.93 0.0116

Table 25 Risk Quotients for Mainman: Confidential use 5 – 70 g ai/ha, 3 applications at 21 days

Exposure Scenario

Estimated exposure of 15 kg

toddler exposed through

contact to surfaces 8 m from

an application area

(µg/kg bw/day)

Risk Quotient

Airblast

Airblast sparse orchard 1.57 0.0196

Airblast dense orchard 0.52 0.0065

Outcomes of the bystander exposure assessment

The risks to bystanders are acceptable for the use scenarios evaluated.

Summary and conclusions of the human health risk assessment

Estimated exposures for operators, re-entry workers and bystanders are below the AOEL for all of the use

scenarios assessed. Operator exposures are below the AOEL even without the use of personal protective

equipment (PPE); however, staff consider that it is appropriate to retain requirements for PPE since the use

of PPE when handling agrichemicals is good practice. In addition, although the exposure assessment

indicates acceptable risks for re-entry workers even without the use of PPE, staff consider that it is

appropriate to include a label statement along the following lines:

‘Do not allow entry into treated areas until the spray has dried, unless wearing cotton overalls

buttoned to the neck and wrist (or equivalent clothing) and chemical resistant gloves. Clothing must

be laundered after each day’s use.’

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Appendix H: Environmental risk assessment

Summary of the data on the active ingredient and its metabolites

A summary of the environmental fate and ecotoxicological data is provided in the following tables

Table 26 Summary of environmental fate data on flonicamid and its metabolites – Values in bold are

used for the risk assessment.

Test Flonicamid TFNA TFNA-AM TFNA-OH TFNG-AM TFNG

Hydrolysis

DT50 = 204 d

at pH 9, stable

at pH 7 and

below

Stable - - - -

Aqueous photolysis DT50 = 267 d - - - - -

Aerobic degradation

(water/sediment)

DT50 =43.6

and 35.7 d

(whole system)

DT50 = 59 d

whole

system

- - - -

Bioaccumulation Log Kow = 0.3 - - - - -

Aerobic degradation in soil

(laboratory)

DT50 = 1.0, 0.7,

0.7, 1.8 days

DT50 = 0.5,

0.3, 0.5

days

DT50 = 1.2,

1.0, 3.82

days

DT50 = 1.0,

1.3, 3.4

days

DT50 = 1.0,

0.3, 0.2

days

-

Soil photolysis

DT50 = 22 days

in continuous

illumination

- - - - -

Adsorption/desorption

Koc = 7.9

(sand), 11.2,

13.4, 20.7

(sand)

Koc = 0.35

(sand),

0.00, 3.05,

2.67 (sand)

Koc = 5.53,

10.11, 5.04

(sand),

4.53, 12.11

Koc = 1.60

(sand),

1.92, 4.19,

4.39 (sand)

Koc =

10.51, 9.25,

7.56

(sand),

4.24, 15.84

Koc = 0.20

(sand),

1.05, 1.29,

4.05 (sand)

Photodegradation in air DT50 = 13.74 d - - - - -

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Table 27 Summary of ecotoxicological data on flonicamid and its metabolites – Values in bold are

used for the risk assessment.

Test Flonicamid Mainman TFNA TFNA-AM TFNA-OH TFNG-AM

Acute / fish

LC50 > 100

mg/L (trout and

bluegill sunfish)

LC50 > 100 mg/L

(trout)

LC50 > 100

mg/L (trout)

LC50 > 100

mg/L (trout)

LC50 > 100

mg/L (trout)

LC50 > 100

mg/L (trout)

Acute / aquatic

invertebrates

EC50 > 100

mg/L

(Daphnia)

EC50 > 200

mg/L

(Chironomus)

EC50 > 100 mg/L

(Daphnia)

EC50 > 100

mg/L

(Daphnia)

EC50 > 100

mg/L

(Daphnia)

EC50 > 100

mg/L

(Daphnia)

EC50 > 100

mg/L

(Daphnia)

Algae ErC50 > 100

mg/L ErC50 > 100 mg/L

ErC50 > 100

mg/L

ErC50 > 100

mg/L

ErC50 > 100

mg/L

ErC50 > 100

mg/L

Aquatic plant EC50 > 119

mg/L - - - - -

Chronic / fish

NOEC = 10

mg/L (fathead

minnow)

- - - - -

Reproduction

daphnia

NOEC = 3.1

mg/L - - - - -

Reproduction

Chironomus

NOEC = 25

mg/L

Acute / earthworm LC50 > 1000

mg/kg soil -

LC50 > 100

mg/kg soil

LC50 > 100

mg/kg soil

LC50 > 100

mg/kg soil

LC50 > 100

mg/kg soil

Terrestrial plants -

No effects at 150

g ai/ha (seedling

emergence and

vegetative

vigour)

- - - -

Soil micro-

organisms

No effects on C

and N

transformation

at 500 g ai/ha

< 25% effects on

C and N

transformation at

0.274 mg

- - - -

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(1.03 mg ai/kg

soil)

formulation /kg

soil

Acute / bird

LD50 = 1591

mg/kg bw

(duck, females)

LD50 > 2000

mg/kg bw

(quail)

- - - - -

Short-term / bird

LC50 > 5000

ppm (quail and

duck)

- - - - -

Reproduction bird

NOEC = 59

mg/kg bw/d

(1000 ppm)

(duck)

NOEC = 90

mg/kg bw/d

(1000 pm)

(quail)

- - - - -

Acute / bees

LD50 > 100

µg/bee

(contact)

LD50 > 60.5

µg/bee (oral)

LD50 > 100

µg/bee (contact) - - - -

Non target

arthropods

(laboratory)

-

A. rhopalosiphi:

55.5% mortality

at 210 g ai/ha

T. pyri: 100%

mortality at 80 g

ai/ha

C.

septempunctata:

30% mortality at

- - - -

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80 g ai/ha

P. cupreus: 3.3

mortality at 45 g

ai/ha

Non target

arthropods

(extended

laboratory)

-

A. rhopalosiphi:

4.4% mortality at

85 g ai/ha

T. pyri: 23.3%

mortality at 85 g

ai/ha

C.

septempunctata:

6.1% mortality at

85 g ai/ha

C carnea: 18.8

mortality at 85 g

ai/ha

E. balteatus:

2.6% mortality at

85 g ai/ha

- - - -

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Appendix I: Controls applying to Mainman

Notes: The controls for this substance apply for the indefinite duration of the approval of this

substance. Please refer to the Hazardous Substances Regulations and the modifications listed below

for the requirements of each control. The regulations can be found on the New Zealand Legislation

website http://www.legislation.co.nz.

Table 28: Controls for Mainman

Hazardous Substances (Classes 6, 8, and 9 Controls) Regulations 2001

Code Regulation Description Variation

T1 11 – 27

Limiting exposure to toxic

substances through the

setting of TELs

No TEL values are set for any component of the

substance at this time. The following ADE and

PDE values have been set for flonicamid

ADE = 0.073 mg/kg bw/day

PDEfood = 0.0511 mg/kg bw/day

PDEdrinking water = 0.0146 mg/kg bw/day

PDE other = 0.0073 mg/kg bw/day

T2 29 – 30

Controlling exposure in

places of work through the

setting of WESs

WorkSafe New Zealand WES values exist for

component G but these should not apply to

Mainman due to the low concentration of these

components and/or the form of the substance

T4 7

Requirements for

equipment used to handle

substances

T7 10

Restrictions on the

carriage of toxic or

corrosive substances on

passenger service vehicles

E1 32 – 45

Limiting exposure to

ecotoxic substances

through the setting of EELs

No EEL values are set for this substance at this

time and the default EELs are deleted

E2 46 – 48

Restrictions on use of

substances in application

areas

A Maximum application rate has been set under

section 77A for this substance

E3 49

Controls relating to

protection of terrestrial

invertebrates e.g.

beneficial insects

E6 7

Requirements for

equipment used to handle

substances

http://www.legislation.co.nz/

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Hazardous Substances (Identification) Regulations 2001


I1 6, 7, 32 – 35,

36(1) – (7)

Identification requirements,

duties of persons in charge,

accessibility,

comprehensibility, clarity and

durability

I9 18 Secondary identifiers for all

hazardous substances

I11 20 Secondary identifiers for

ecotoxic substances

I16 25 Secondary identifiers for

toxic substances

I19 29 – 31

Additional information

requirements, including

situations where substances

are in multiple packaging

I21 37 – 39,

47 – 50

General documentation

requirements

I28 46

Specific documentation

requirements for toxic

substances

I29 51 – 52 Signage requirements

Hazardous Substances (Packaging) Regulations 2001


P1 5 – 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

PS4 Schedule 4 Packaging requirements as specified

in Schedule 4

Hazardous Substances (Disposal) Regulations 2001


D4 8 Disposal requirements for toxic and

corrosive substances

D5 9 Disposal requirements for ecotoxic

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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


EM1 6, 7, 9 – 11 Level 1 information requirements for

suppliers and persons in charge

EM6 8(e) Information requirements for toxic

substances

EM7 8(f) Information requirements for ecotoxic

substances

EM8 12 – 16,

18 – 20

Level 2 information requirements for

suppliers and persons in charge

EM13 42 Level 3 emergency management

requirements: signage

Hazardous Substances (Tank Wagon and Transportable Containers) Regulations 2004

Code Regulation Description

Tank Wagon 4 to 43

as applicable Controls relating to tank wagons and transportable containers

Additional controls


Water Section 77A The substance must not be applied

into, onto or over water.

The substance must not be applied into

or onto water27

App Rate Section 77A A maximum application rate is set for

this substance.

The maximum application rate of this

substance is 80 g of flonicamid/ ha.

27 where ‘water‘ means water in all its physical forms, whether flowing or not, and whether over or under ground, but does not

include water in any form while in a pipe, tank or cistern or water used in the dilution of the substance prior to application or

water used to rinse the container after use

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Max

Impure

Section 77A May not contain greater than a set

amount of a toxicologically

significant impurity

The flonicamid component of this

substance must not contain more than

3 g/kg of toluene.

Label Section 77A Additional label information has been

specified.

The following statements, or words to

this effect must appear on the product

label and safety data sheet

“Do not allow entry into treated areas

until the spray has dried, unless wearing

cotton overalls buttoned to the neck and

wrist (or equivalent clothing) and

chemical resistant gloves. Clothing

must be laundered after each day’s

use.”

“Do not apply this product to any plant

likely to be visited by bees at the time of

application; or immediately after

application until spray has dried; or in

areas where bees are foraging"

“The maximum application rate of this

substance is 80 g of flonicamid/ ha”

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Appendix J: Confidential information

This appendix contains the confidential information provided by the applicant and is not publically

available.

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Appendix K: Standard terms and abbreviations

ai active ingredient

ALD50 approximate median lethal dose,

50%

AOEL acceptable operator exposure level

ARfD acute reference dose

as active substance

BCF bioconcentration factor

bfa body fluid assay

BOD biological oxygen demand

BSAF biota-sediment accumulation factor

bw body weight

c centi- (x10-2

)

CA controlled atmosphere

CI confidence interval

CL confidence limits

CNS central nervous system

COD chemical oxygen demand

DFR dislodgeable foliar residue

DO dissolved oxygen

DOC dissolved organic carbon

DT50 period required for 50 percent

dissipation (define method of

estimation)

DT90 period required for 90 percent

dissipation (define method of

estimation)

dw dry weight

ED50 median effective dose

ERC environmentally relevant

concentration

F Field

F0 parental generation

F1 filial generation, first

F2 filial generation, second

fp freezing point

G glasshouse

GAP good agricultural practice

GC gas chromatography

GC-EC gas chromatography with electron

capture detector

GC-FID gas chromatography with flame

ionization detector

GC-MS gas chromatography-mass

spectrometry

GC-MSD gas chromatography with mass-

selective detection

GLC gas liquid chromatography

GLP good laboratory practice

GM geometric mean

H Henry’s Law constant (calculated

as a unitless value) (see also K)

ha hectare

Hb haemoglobin

HCG human chorionic gonadotropin

Hct haematocrit

HPLC high pressure liquid

chromatography or high

performance liquid

chromatography

HPLC-MS high pressure liquid

chromatography - mass

spectrometry

I indoor

I50 inhibitory dose, 50%

IC50 median immobilization

concentration or median inhibitory

concentration 6

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ID ionization detector

Im Intramuscular

inh Inhalation

ip Intraperitoneal

IPM integrated pest management

iv Intravenous

IVF in vitro fertilization

K Kelvin or Henry’s Law constant (in

atmospheres per cubic meter per

mole) (see also H)

Kads adsorption constant

Kdes apparent desorption coefficient

Koc organic carbon adsorption

coefficient

Kom organic matter adsorption

coefficient

kg Kilogram

LC liquid chromatography

LC-MS liquid chromatography- mass

spectrometry

LC50 lethal concentration, median

LCA life cycle analysis

LC-MS-MS liquid chromatography with tandem

mass spectrometry

LD50 lethal dose, median; dosis letalis

media

LDH lactate dehydrogenase

LOAEC lowest observable adverse effect

concentration

LOAEL lowest observable adverse effect

level

LOD limit of detection

LOEC lowest observable effect

concentration

LOEL lowest observable effect level

LOQ limit of quantification

(determination)

LPLC low pressure liquid

chromatography

LSC liquid scintillation counting or

counter

LSS liquid scintillation spectrometry

LT lethal threshold

M molar

μm micrometer (micron)

MDL method detection limit

MFO mixed function oxidase

μg microgram

MLT median lethal time

MLD median lethal dose

mol Mole(s)

MOS margin of safety

mp melting point

MS mass spectrometry

MSDS material safety data sheet

NAEL no adverse effect level

nd not detected

NEL no effect level

ng nanogram

nm nanometer

NOAEC no observed adverse effect

concentration

NOAEL no observed adverse effect level

NOEC no observed effect concentration

NOEL no observed effect level

NR not reported

OC organic carbon content

ODP ozone-depleting potential

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OM organic matter content

Pa pascal

PEC predicted environmental

concentration

PECS predicted environmental

concentration in soil

PECSW predicted environmental

concentration in surface water

PECGW predicted environmental

concentration in ground water

PHI pre-harvest interval

pKa negative logarithm (to the base 10)

of the dissociation constant)

PNEC predicted no effect concentration

POW partition coefficient between n-

octanol and water

ppb parts per billion (10-9

)

PPE personal protective equipment

ppm parts per million (10-6

)

ppp plant protection product

ppq parts per quadrillion (10-24

)

ppt parts per trillion (10-12

)

PTDI provisional tolerable daily intake

r correlation coefficient

r2 coefficient of determination

REI restricted entry interval

Rf retardation factor

RfD reference dose

RL50 median residual lifetime

RP reversed phase

RRT relative retention time

RSD relative standard deviation

sc subcutaneous

SD standard deviation

se standard error

SF safety factor

SIMS secondary ion mass spectroscopy

SOP standard operating procedures

sp species (only after a generic name)

SPE solid phase extraction

spp subspecies

SSD sulphur specific detector

STEL short term exposure limit

t½ half-life (define method of

estimation)

TCLo toxic concentration, low

TER toxicity exposure ratio

TIFF tag image file format

TOC total organic carbon

TWA time weighted average

UF uncertainty factor (safety factor)

ULV ultra low volume

UV ultraviolet

v/v volume ratio (volume per volume)

w/v weight per volume

ww wet weight

w/w weight per weight