Ecological Risk Assessment of Nano-enabled Pesticides: A

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Perspective

Ecological risk assessment of nano-enabled pesticides: A perspective on problem formulation Glen W Walker, Rai S Kookana, Natalie E Smith, Melanie Kah, Casey Doolette, Philip Reeves, Wess Lovell, Darren J Anderson, Terence W Turney, and Divina A Navarro J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.7b02373 • Publication Date (Web): 16 Aug 2017 Downloaded from http://pubs.acs.org on August 16, 2017

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Journal of Agricultural and Food Chemistry

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Ecological risk assessment of nano-enabled pesticides:

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A perspective on problem formulation

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Glen W. Walker,a Rai S. Kookana,*b Natalie E. Smith,a Melanie Kah,c Casey L. Doolette,a

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Philip Reeves,d Wess Lovell,e Darren J. Anderson,e Terence W. Turneyf,g and Divina A.

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Navarrob

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a

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Canberra, ACT 2601, Australia

Australian Government Department of the Environment and Energy, GPO Box 787,

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b

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Osmond, SA 5064, Australia

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c

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Science Research Network, Althanstrasse 14, UZA2, 1090 Vienna, Austria

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d

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Australia

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e

Vive Crop Protection, 112 College St., Toronto, Ontario, Canada, M5G1L6

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f

Sonic Essentials Pty Ltd, P.O. Box 258, Mooroopna, Victoria 3629, Australia

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g

Department of Materials Science and Engineering, Monash University, Clayton 3800,

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Victoria, Australia

Commonwealth Scientific and Industrial Research Organisation (CSIRO), PMB 2, Glen

University of Vienna, Department of Environmental Geosciences and Environmental

Australian Pesticides and Veterinary Medicines Authority (APVMA), Canberra, ACT 2604,

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* Author to whom correspondence should be directed

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Rai Kookana

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CSIRO Land and Water

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Email: [email protected] 1

ACS Paragon Plus Environment


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ABSTRACT

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Plant protection products containing nanomaterials that alter the functionality or risk profile

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of active ingredients (nano-enabled pesticides) promise many benefits over conventional

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pesticide products. These benefits may include improved formulation characteristics, easier

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application, better targeting of pest species, increased efficacy, lower application rates, and

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enhanced environmental safety. After many years of research and development, nano-enabled

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pesticides are starting to make their way onto the market. The introduction of this technology

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raises a number of issues for regulators, including: how does the ecological risk assessment

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of nano-enabled pesticide products differ from that of conventional plant protection products?

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In this paper, a group drawn from regulatory agencies, academia, research and the

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agrochemicals industry offers a perspective on relevant considerations pertaining to the

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problem formulation phase of the ecological risk assessment of nano-enabled pesticides.

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Keywords: Nanopesticides; Agrochemicals; Nanotechnology; Problem Formulation; Risk

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Assessment

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INTRODUCTION

Nanotechnology is being harnessed to develop new pharmaceutical drugs

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(Nanomedicines)1 as well as agrochemical products (Nanofertilisers and Nanopesticides).2-5

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These new medicines and agrochemicals exploit the properties of materials with dimensions

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on the nanoscale (the size range of approximately 1 nm to 100 nm), which can display very

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different or additional physical, chemical and biological properties compared to the properties

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of the bulk materials. The application of nanotechnology in agriculture presents significant

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new opportunities for developing more effective fertilisers and pesticides that may also have

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reduced impacts on the environment.

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There are a variety of possible ways in which nanotechnology may be used to produce

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new pesticide products. There are inert ingredients used in conventional formulations of

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pesticides that exist in a nanoscale form, and these nanoscale inert ingredients have been

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incorporated into a range of crop protection products. Examples include nanoscale titania as a

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UV blocker and whitener; nanoscale silica or clays as a rheology modifier; and many

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nanoscale polymers are used as surfactants. There are also microemulsion-type solvent based

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pesticides on the market that may be considered nano-enabled as many contain oil droplets

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with significant populations < 100 nm. In most cases, these products have a long history of

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safe use.

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There is growing interest in more deliberate applications of nanotechnology in the

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development of new plant protection products.6 Dendrimer technology is being applied to a

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number of a.i.s to develop nano-enabled pesticides with enhanced efficacy and some products

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are in an advanced stage of development.7 Some products utilising nanopolymers as carriers

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for targeted delivery of pesticides and for application with fertilizers have already been

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registered for use. These include soil applied AZteroidTM fungicide (azoxystrobin), soil 3



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applied BifenderTM insecticide (bifenthrin) and plant applied FenstroTM insecticide

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(azoxystrobin + bifenthrin).8 It is expected that an increasing number of nano-enabled

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pesticide products will be submitted to regulatory agencies for registration over the next five

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years.

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For the purposes of this perspectives article, a nano-enabled pesticide means a product

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in which a nanomaterial has been used to enhance the functionality, utility and/or alter the

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risk profile of a conventional a.i.

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RISK ASSESSMENT FRAMEWORKS FOR NANO-ENABLED PESTICIDES

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Ecological risk assessment of pesticide a.i.s and formulated products is a highly

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developed process which forms an integral part of pesticide regulatory frameworks.8-10 The

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issues associated with assessing the ecological risks of nanomaterials within the conventional

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risk-assessment paradigm used for chemicals and chemical products have been explored by

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the OECD Working Party on Manufactured Nanomaterials.11, 12 This work concluded that the

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existing risk-assessment paradigm used for chemicals can be adapted to the risk assessment

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of nanomaterials.

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Problem formulation is a key initial phase in the ecological risk assessment of

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chemicals. This phase of assessment is intended to define the nature of the problem to be

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addressed by risk assessment and to develop a plan or strategy by which the risks can be

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subsequently characterised.13 The consistent and structured application of problem

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formulation principles to the risk assessment of nano-enabled pesticide products will be

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essential in formulating sound recommendations to risk managers and decision makers in

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regulatory agencies. It will also help identify the most relevant assessment information

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including hazard and exposure data, and available risk reduction measures at an early stage in

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the risk assessment process. These are acknowledged to be key factors influencing the 4


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conduct of effective risk assessments.14 In this perspectives article, we describe an approach to problem formulation using a case

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study involving a hypothetical nano-enabled pesticide product. The approach taken is

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intended to demonstrate how a practical assessment strategy would be developed using

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principles adapted from the ecological risk assessment of conventional pesticide products. As

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part of this strategy, an initial planning phase was conducted in which representatives from

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key stakeholders including regulators, research scientists, and agrochemical scientists

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collaborated to identify key issues that should be considered before the problem formulation

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phase began. The key elements of this stage in the process are presented in the form of the

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following questions:

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● What is the agronomic context for the use of the nano-enabled pesticide formulation?

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● What is the nature and purpose of the nanomaterial in the formulation?

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● What are the ecological protection priorities that need to be considered in the risk

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assessment of the nano-enabled pesticide formulation?

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Following the collection of relevant information from the stakeholder group, the problem

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formulation phase was undertaken focussing on another set of key questions:

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● How does the environmental behaviour of the nano-enabled pesticide differ from

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conventional formulations of the same active ingredient?

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● How does the nanomaterial release the active ingredient in the environment?

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● What information is necessary to characterise the novel properties of the nano-enabled

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pesticide formulation?

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● What risk reduction measures can be used to manage any environmental risks that are

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considered possible from the intended use of the nano-enabled pesticide product?

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PENDIMETHALIN IN NANO-SIZED HYDROGELS – A CASE STUDY

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Background information and agronomic context

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Pendimethalin (CAS RN: 40487-42-1; benzeneamine, N-(1-ethylpropyl)-3,4-

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dimethyl-2,6-dinitro-, or N-(1-ethylpropyl)-2,6-dinitro-3,4-xylidene) is a dinitroaniline

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herbicide that is absorbed through the roots and shoots. It is used to control annual grasses

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and broadleaf weeds and is applied as a pre- or post-emergence spray.15 Conventional

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formulations of pendimethalin include aqueous capsule suspensions, granules, emulsifiable

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concentrates, and liquid formulations, all of which will include surfactants and other

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ingredients necessary for proper function of the formulation. Dry (granular) formulations will

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also typically use an inorganic carrier that is impregnated with the a.i..

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Pendimethalin is a lipophilic neutral organic chemical (log KOW = 5.2) that is slightly

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soluble in water (0.33 mg/L at 20 °C) and slightly volatile (0.0013 Pa at 25 °C). The Henry's

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Law constant for the chemical (0.087 Pa-m3/mol) indicates that it is moderately volatile from

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water and moist soil. The chemical adsorbs strongly to soil (KOC = 6,500 to 43,863 L/kg) and

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pendimethalin is generally considered immobile in soil. Pendimethalin is slightly degradable

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in aerobic soil and the reported half-life is in the range of 3 to 4 months.15

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Pendimethalin has high acute toxicity to aquatic life including fish, invertebrates,

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algae, and aquatic plants. The chemical has moderate to high chronic toxicity to aquatic life

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and is a bioaccumulation hazard in aquatic organisms based on the measured

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bioconcentration factor in fish (BCF = 5100). The chemical has low to moderate toxicity to

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non-target terrestrial organisms.16

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Description of the nano-enabled pesticide formulation and intended use

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A realistic nano-enabled formulation was chosen to allow this “thought experiment” to describe the process of problem formulation. This formulation is a simplified version of 6


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the technology developed by Vive Crop Protection. The hypothetical pendimethalin herbicide

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product considered in this case study is a suspension concentrate (SC) formulation containing

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20% by weight of a.i. and 5% by weight of lightly crosslinked polyacrylate polymer particles

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which function as a nano-scale carrier for the a.i.. Polyacrylates are a broad class of

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polymers; for this thought experiment, polyacrylates that are water-dispersible hydrogels with

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both hydrophilic and hydrophobic monomers are considered. Formulations with 20% a.i. and

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5% by weight polymer particles has been described previously [US patent 8741808]. The

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specific chemistry of the hydrogel necessary to increase soil mobility does not significantly

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impact the problem formulation provided in a later section. Therefore, for simplicity in this

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thought experiment, as well as to protect confidential information of Vive Crop Protection, a

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generic polyacrylate hydrogel was chosen as a model. The average size of the polyacrylate

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nanocarriers is in the range of 5 to 20 nm.

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The polyacrylate nanocarriers are hydrogels which are a class of materials that have

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been investigated for delivery of many different poorly-soluble bioactive pharmaceuticals as

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well as agrochemical molecules.17-18 A hydrogel is able to absorb large amounts of water or

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other fluids17 and swell (as a result of crosslinks formed during synthesis), as opposed to

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dissolving in an aqueous environment. The purpose of the polyacrylate hydrogel in this SC

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formulation is to assist with dispersion of the a.i. in aqueous media (such as water in spray

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tanks) and with a.i. mobility in soil. 18

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Pendimethalin is loaded into the matrix of the hydrogel nanocarrier to form a

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composite structure (the complex). This complex is a labile structure and is able to release the

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a.i. in soil for uptake by plants. The overall properties of the complex are determined by the

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hydrogel composition, the method and degree of crosslinking, a.i. loading, and the nature of

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the environment in which the complex is deployed (dry, liquid, pH, etc.). 18-19 The formation 7



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of this complex has the net effect that the properties of the external portion of the nanocarrier

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dominate the interaction with the environment for as long as the a.i. remains within the

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matrix of the hydrogel particles. For the purposes of this article, we are considering a

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complex where the hydrogel assists the pendimethalin to penetrate into soil, thereby

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increasing the amount of a.i. that reaches sub-surface weeds.

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This product will be applied as a pre-emergence herbicide at a maximum application

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rate of 4 kg a.i./ha. The product is intended to penetrate through surface residue into the soil

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without manual incorporation. It requires moderate rainfall or irrigation to be active against

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target species. In moderate to heavy rains or irrigation, the applied a.i. is expected to

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penetrate between 2.5 and 10 cm below the soil surface, with < 1% of applied a.i. penetrating

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below 10 cm. This effect has been observed with a modified version of the polyacrylate

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hydrogels described in this paper (Vive Crop Protection, Canada, Personal Communication).

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Formulation benefits are similar to existing techniques for increasing soil penetration such as

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soil conditioners or penetration aid surfactants.

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For the purposes of this case study, it is assumed that the product will be applied by

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ground spraying under conditions and using technology which minimises off-site movement

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of the pesticide through spray drift.

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Ecological protection priorities

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The nano-enabled pendimethalin SC product considered here is intended to be applied

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to a wide variety of agricultural crops for the control of annual grasses and weeds by ground

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spray application at a rate of nearly 4 kilograms a.i. per hectare. Similar to conventional

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pendimethalin herbicide products there is a potential risk to aquatic environments from the

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off-site movement of the a.i. in the nano-enabled pesticide product because pendimethalin is

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highly toxic to aquatic life and bioconcentrates in fish. The ecological risk assessment of the 8


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nano-enabled product will, therefore, need to establish that the proposed use pattern and

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application rate will not result in levels of pendimethalin in aquatic ecosystems in excess of

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the locally applicable water quality guideline values for this a.i.

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PROBLEM FORMULATION

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Pendimethalin is highly toxic to aquatic organisms and is also a bioaccumulation

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hazard in aquatic ecosystems. The off-site movement of this active ingredient from its

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application as a pre-emergence herbicide, which results in contamination of aquatic

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ecosystems, may cause adverse effects on the natural environment. The ecological risk

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assessment of the intended uses of the nano-enabled pendimethalin SC product will,

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therefore, need to establish whether aquatic ecosystems will be adversely impacted by the a.i.

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or any of the excipients in the product, including the polyacrylate nanocarrier.

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Comparative evaluation of the nano-enabled pendimethalin formulation and

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conventional formulations

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One key difference between traditional surfactants (used in conventional

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formulations) and the use of nano-scale hydrogel carriers is the durability of the complex in

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diverse environments. Surfactant systems are sensitive to exposure conditions such as surface

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interactions, pH, and concentration which may mean that the a.i.-surfactant complex is only

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stable over a relatively narrow range of operating conditions. The inclusion of cross-links in a

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hydrogel enables the nanocarrier complex to maintain its tertiary structure and retain its

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integrity under a wider range of conditions.20

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Similar to previous studies,21 the nanocarrier complex envisioned here would

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facilitate the dispersion of this poorly water soluble herbicide in water without the use of

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organic solvents and would also reduce the volatilization of the a.i. after application. These

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two formulation characteristics have the potential to increase the amount of a.i. available for 9



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weed control and reduce the amount of a.i. lost off-site through atmospheric transport

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processes. The complex would also enable the a.i. to penetrate the subsoil surface without the

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need for physical incorporation such as tilling.

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The nanocarrier is designed to enhance the soil penetration of pendimethalin.

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Consequently, the potential key differences between this formulation and a conventional

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formulation may include: penetration of pendimethalin into the subsoil water column;

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reduced biological and chemical degradation of the a.i. leading to increased persistence; and a

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reduction in off-site migration of the a.i. through volatilisation and other processes, such as

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surface runoff.

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Fate of the nano-enabled pesticide formulation in soil

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The fate and behaviour of nano-enabled pesticides in the environment is likely to be

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dependent on the functional characteristics of the carrier and the durability of the a.i.–carrier

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complex. Both characteristics should be considered in problem formulation of nano-enabled

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pesticides as the spatial and temporal nature of exposure to non-target organisms could

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change significantly when compared to conventional pesticide formulations.

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Durability is a measure of how long a pesticide-nanocarrier complex maintains its

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integrity after application in the field.22 The durability of pesticide-nanocarrier complexes can

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be categorised into three broad classes as shown in Figure 1.

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Durability is likely to be dependent on the exposure conditions. For example, a nano-

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enabled pesticide may release the a.i. at different rates in soil depending on factors, such as

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soil moisture or soil pH. These will be important considerations for the risk assessment.

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A conceptual model that can help identify the altered scenario of pesticide fate (mobility and

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persistence) relative to the pure a.i., depending on the properties of the nano-carrier and 10


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pesticide a.i. in the new formulation, has been presented in Figure 2. The figure provides an

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overview of the different combinations of nano-carrier and a.i. properties that are most

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relevant for environmental exposure assessment of the a.i. (here it is assumed that the

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exhausted nanocarrier is of low hazard, an assumption that may need to be verified in some

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cases).

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The most sensitive fate descriptors are expected to be: (i) the mobility of the

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nanocarrier (Figure 2A, and 2B); (ii) the mobility and persistence of the a.i. (x-axis and z-axis

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in Figure 2); and (iii) the rate at which the a.i. is released from the nanocarrier (y-axis).4, 23

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Distinguishing different combinations of nanocarrier and a.i. properties allows situations to

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be identified where the impact on fate is likely to be minimal (flag “OK” in Figure 2), and

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where particular attention to changes in the mobility (“M” flag) and/or persistence (“P” flag)

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of the a.i. is required.

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In cases where the release rate of the a.i. from the carrier is very fast compared to the

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time scale of the environmental processes of interest (e.g. complete release occurs upon

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dilution in the mixing tank or upon application in the field), no changes in the behaviour of

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the nano-enabled a.i. formulation are to be expected compared to that of the pure a.i..

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Therefore, an exposure assessment solely based on data derived with the pure a.i. should be

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adequate (indicated with the “OK” flag in Figure 2).

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Conversely, when the nanocarriers and a.i. remain associated for a significant time,

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effects of the formulation on the fate of the a.i. are to be expected in almost all cases. For

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instance, for an a.i. that is not excessively persistent, association with a nanocarrier may

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increase the persistence of the a.i. (“P” flag on Figure 2) as the availability of the a.i. for

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degradation processes is likely to be reduced until it is released from the nanocarrier. The 11



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impact of the formulation on the transport of an a.i. in this case depends on the mobility of

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the nanocarriers relative to that of the a.i.. Mobile carriers are likely to increase the mobility

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of a relatively immobile a.i. (“+M” flag in Figure 2A), while relatively immobile nanocarriers

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will decrease the mobility of a relatively mobile a.i. (“-M” flag in Figure 2B), which could

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lead to greater exposure concentrations in the surface soil compartment for longer periods.

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In the case study being considered here, the hydrogel is a mobile nanocarrier (Vive Crop

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Protection; Personal communication). Therefore, Figure 2A will be the relevant scheme for

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this formulation. The formulation is designed such that the a.i. remains encapsulated in the

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mobile nanocarrier long enough to facilitate its entry into soil. The formulation is, therefore,

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considered to be at least moderately durable and the upper plane in Figure 2 is relevant.

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Pendimethalin is inherently a relatively immobile and moderately persistent herbicide, as

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discussed above. Hence, the ultimate locus for the product will be at the low mobility end of

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the x-axis and at the moderate persistence location on the z-axis, as shown in Figure 2A.

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Hence, according to this conceptual scheme, +M/P is the most relevant flag, suggesting

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possible increased mobility and persistence of the nano-enabled pendimethalin relative to the

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pure a.i..

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However, as stated above, pendimethalin has a half-life in aerobic soil in the range of

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3 to 4 months. The durability of the a.i.-nanocarrier complex is assumed to be on the time

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scale of days in this case and the apparent increase in persistence of pendimethalin is,

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therefore, not expected to be consequential. In other cases, where the durability of the a.i.-

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nanocarrier complex is comparable or greater than the persistence of the a.i., the overall

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persistence of an a.i. could be significantly enhanced because the nanocarrier facilitates

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penetration of the a.i. into the deeper subsoil, where lower microbial activity is expected.

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Key end points An extensive set of aquatic toxicity data is available for pendimethalin that could be

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used to characterise the ecological risks to aquatic ecosystems, where the magnitude and

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frequency of exposure to the a.i. can be quantified. Similarly, the environmental fate and

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behaviour of this a.i. in conventional herbicide products are well studied and the available

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data are sufficient to allow models for environmental exposure to be developed. However, the

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conceptual model for the nano-enabled formulation of pendimethalin has identified some

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potentially significant modifications in the fate and behaviour of the a.i.. The significance of

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these particular properties of the nano-enabled formulation will need to be considered during

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the risk analysis and risk characterisation stage of the assessment.

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The two most significant environmental fate characteristics identified for the nano-

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enabled formulation through the conceptual model are the depth of penetration of the a.i.-

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nanocarrier complex through the soil column, and the rate of release of the a.i. from the

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carrier. The depth of penetration is expected to be unique to this particular formulation, as it

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is a functional characteristic that has been engineered by selection of the particular

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polyacrylate nanoparticles used as a carrier. Since the behaviour of the a.i.-polyacrylate

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complex is dominated by the properties of the nanocarrier, it may be possible to use surrogate

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information on the general soil penetration behaviour of polyacrylate nanoparticles with

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similar size distributions, chemical structure, and surface characteristics. However, where no

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reference data are available, or where the properties of the complex differ substantially from

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the nanocarrier alone, a specific evaluation of the soil penetration depth for the complex may

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be required.

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The rate of release of the a.i. from the complex has also been identified as a key environmental fate characteristic of the formulation, and needs to be considered during the 13



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risk analysis phase. If the rate of release of the a.i. from the carrier is slow compared to major

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transport processes such as leaching or transport in surface water run-off, then the aquatic

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environment may be exposed to pendimethalin in ways that are not well represented by

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available ecotoxicity data. In an exposure scenario involving release of a mobile and

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moderately durable a.i.–carrier complex into aquatic ecosystems, aquatic life may be exposed

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to the a.i. for a longer period at lower concentrations, resulting from the slow release of the

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a.i. from the carrier. Conversely, if the rate of release of the a.i. from the complex is fast

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compared to these transport processes, the environmental fate and effects of the a.i. may be

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indistinguishable from conventional formulations. It is for this reason that an early and

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reliable measure of the durability of the nanocarrier complex under environmentally relevant

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conditions would be considered a priority.

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Risk reduction and risk management options

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The focus of the risk assessment can be shaped by considering the available risk

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reduction measures and their effectiveness in the problem formulation stage of the

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assessment.12 For the purposes of this assessment, it is assumed that good agricultural

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practices will limit off-site movement of the pesticide following application. In addition,

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since the nano-enabled product will only be applied by ground spraying using spray-drift

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reduction technology there is a reduced potential for direct exposure of the aquatic

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environment to the a.i.–nanocarrier complex. This reduces both the need to consider the risks

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posed to the aquatic environment through slow release of the a.i. from the nanocarrier over an

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extended timeframe and the likelihood that additional aquatic ecotoxicity data will be

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required to determine the specific toxicity of the a.i.-nanocarrier complex. Conversely, if the

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typical application pattern were to be broadened to include aerial application of the nano-

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enabled formulation then the scope of the assessment would need to include factors such as 14


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the spray drift distances of the nano-enabled formulation and the effectiveness of no-spray

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buffer zones to mitigate impacts on aquatic ecosystems.

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Analysis plan

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The hypothetical nano-enabled pendimethalin SC product considered in this case

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study does potentially pose risks to the aquatic environment where off-site movement of the

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a.i. and/or the a.i.-nanocarrier complex occurs. A conceptual model for the fate and behaviour

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of the a.i.-nanocarrier complex in soil has identified some potential for the a.i. to have

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increased persistence in soil relative to conventional formulations of pendimethalin. The

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model also shows a potential for increased depth of penetration of the a.i. through the soil

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horizon because of transport of the more mobile polyacrylate nanoparticle carriers. There is,

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therefore, an increased potential for pendimethalin to reach ground water compared to

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conventional formulations.

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A key priority for the risk analysis phase of the assessment is to establish the

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durability of the a.i.-nanocarrier complex in soil. An understanding of this characteristic will

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allow further decisions to be made regarding both exposure assessment and hazard

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evaluation. The initial analysis of the ecological risks of the product will, therefore, focus on

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evaluating any available data on the durability of the a.i.-nanocarrier complex in soil. Where

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such data are lacking and no useful reference data can be identified, it may be necessary to

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recommend targeted evaluation of the durability of the complex in soil. Once this key

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property has been evaluated the problem formulation may need to be revised. For example, if

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the complex is determined to be not durable on the timescale of applicable off-site transport

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processes, then the risk analysis may be abbreviated as the risks of the nano-enabled product

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would not be considered significantly different from conventional formulations of

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pendimethalin. Conversely, if this initial evaluation demonstrates that the a.i.-nanocarrier 15



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complex is moderately durable in soil and the complex is significantly mobile in soil and

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water then the risk analysis phase may need to consider the need for specific environmental

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fate and effects data on the nano-enabled formulation.

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PROBLEM FORMULATION IS AN ITERATIVE PROCESS

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Problem formulation provides an important opportunity to properly define the scope

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of a risk assessment and to integrate the needs of the risk managers and decision makers, who

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ultimately decide how and when chemicals or chemical products can be safely introduced to

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the marketplace. The approach outlined above is based around a series of general questions

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that guide the process. The crucial step is to determine what information is necessary to

359

characterise the novel properties of the nano-enabled pesticide formulation. The use of

360

nanomaterials in formulations (such as nanocarriers) can significantly alter the fate of the

361

active ingredient in soil, and we describe a simple framework to help risk assessors determine

362

how the formulation is likely to affect mobility and persistence of the a.i., based on the

363

known persistence and mobility of the a.i. and the durability of the nano-enabled pesticide.

364

The problem formulation is guided by the nature of the product being assessed and

365

associated application scenario. The problem formulation presented here for the nano-enabled

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pendimethalin SC herbicide product shows only the first iteration of the process. An

367

important feature of the problem formulation phase of risk assessment is iteration.13 For

368

conventional chemicals and chemical products, the iterative cycle may be abbreviated

369

because there is a wealth of relevant experience that can be used when formulating the initial

370

risk assessment hypothesis. The major factors influencing the environmental fate and effects

371

of most major classes of chemical are well understood and the most important factors

372

influencing ecological risks have been established over decades of practice. However, for

373

unconventional chemicals and/or novel exposure scenarios there is often a need to revise the 16


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374

initial risk assessment hypotheses developed during the problem formulation phase, and to

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revise the risk analysis plan accordingly. This iterative approach is also likely to be important

376

in regulatory assessment of nano-enabled pesticides as there are as yet few registered nano-

377

enabled agrochemical products.

378 379

AUSTRALIAN GOVERNMENT DISCLAIMER

380

The views and opinions expressed in this publication are those of the authors and do not

381

necessarily reflect those of the Australian Government or the Minister for the Environment.

382

While reasonable efforts have been made to ensure that the contents of this publication are

383

factually correct, the Commonwealth does not accept responsibility for the accuracy or

384

completeness of the contents, and shall not be liable for any loss or damage that may be

385

occasioned directly or indirectly through the use of, or reliance on, the contents of this

386

publication.

387 388

ACKNOWLEDGEMENTS

389

The study was partially supported by the Division of Chemistry and Environment of the

390

IUPAC through a project on Nano-enabled pesticides (# 2016-016-2-600) and the

391

contributions from the project team are gratefully acknowledged. Dr Melanie Kah was

392

supported by the Austrian Science Fund (FWFV408-N28). The authors acknowledge Dr

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David Brittain (Department of the Environment and Energy, Australia) for assistance with

394

modelling of various scenarios for release of pesticides from nanocarriers, and for a critical

395

review of the manuscript. We are also thankful to the three anonymous reviewers for their

396

constructive comments on the manuscript.

397 17



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REFERENCES

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1. McCarthy, C. A.; Ahern, R. J.; Dontireddy, R.; Ryan, K. B.; Crean, A. M., Mesoporous silica formulation strategies for drug dissolution enhancement: a review. Expert Opin Drug Del 2016, 13, 93-108.

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2. Liu, F.; Wen, L. X.; Li, Z. Z.; Yu, W.; Sun, H. Y.; Chen, J. F., Porous hollow silica nanoparticles as controlled delivery system for water-soluble pesticide. Mater Res Bull 2006, 41, 2268-2275.

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3. Gogos, A.; Knauer, K.; Bucheli, T. D., Nanomaterials in plant protection and fertilization: current state, foreseen applications, and research priorities. J Agric Food Chem 2012, 60, 9781-9792.

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4. Kah, M.; Hofmann, T., Nanopesticide research: current trends and future priorities. Environ Int 2014, 63, 224-235.

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5. Mitter, N.; Worrall, E. A.; Robinson, K. E.; Li, P.; Jain, R. G.; Taochy, C.; Fletcher, S. J.; Carroll, B. J.; Lu, G. Q.; Xu, Z. P., Clay nanosheets for topical delivery of RNAi for sustained protection against plant viruses. Nat Plants 2017, 3, 1-10 DOI: 10.1038/nplants.2016.207

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6. APVMA, Nanotechnologies for pesticides and veterinary medicines: regulatory considerations. A draft APVMA report; Australian Pesticides and Veterinary Medicines Authority: 2015. http://apvma.gov.au/sites/default/files/docs/report-draft-regulatoryconsiderations-nanopesticides-veterinary-nanomedicines.pdf (Last Accessed: March 29, 2017).

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7. STARPHARMA, Starpharma Holdings Limited. Corporate overview. Presentation by Dr Jackie Fairley (CEO); February 2014. http://www.asx.com.au/spotlight/newyork/2014/documents/presentations/140226___SPL_Co rp_Presentation_NYC_pg1-33.pdf (Last Accessed: April 20, 2017).

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8. Vive Crop Protection: Products. http://vivecrop.com/products/ (Last Accessed: May 12, 2017).

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9. USEPA, United States Environmental Protection Agency. Ecological risk assessment for pesticides: technical overview. https://www.epa.gov/pesticide-science-and-assessingpesticide-risks/ecological-risk-assessment-pesticides-technical (Last Accessed: May 8, 2017).

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10. EFSA, European Food Safety Authority: Pesticides. https://www.efsa.europa.eu/en/topics/topic/pesticides (Last Accessed: May 8, 2017).

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11. OECD, Series on the Safety of Manufactured Nanomaterials No 21 Report of the workshop on risk assessment of manufactured nanomaterials in a regulatory context; 2010. http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?doclanguage=en&cote=e nv/jm/mono(2010)10 (Last Accessed: April 18, 2017).

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12. OECD, Series on the Safety of Manufactured Nanomaterials No 33. Important issues on risk assessment of manufactured nanomaterials; 2012. http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?cote=env/jm/mono(2012 )8&doclanguage=en (Last Accessed: March 29, 2017).

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13. USEPA, United States Environmental Protection Agency. Guidelines for ecological risk assessment; EPA/630/R-95/002F https://www.epa.gov/sites/production/files/201411/documents/eco_risk_assessment1998.pdf (Last Accessed: April 18, 2017).

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14. NRC, National Research Council. Science and decisions: advancing risk assessment. National Academies Press: Washington, DC, 2009. https://doi.org/10.17226/12209.

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15. HSDB, Hazardous Substances Data Bank. Toxicology Data Network: Pendimethalin. https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+6721 (Last Accessed: May 8, 2017).

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16. PPDB, Pesticide Properties Database: Pendimethalin. Univ. Hertfordshire. http://sitem.herts.ac.uk/aeru/ppdb/en/Reports/511.htm (Last Accessed: March 13, 2017).

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17. Hamidi, M.; Azadi, A.; Rafiei, P., Hydrogel nanoparticles in drug delivery. Adv Drug Deliver Rev 2008, 60, 1638-1649.

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18. Guilherme, M.R., Aouada, F.A., Fajardo, A.R., Martins, A.F., Paulino, A.T., Davi, M.F.T., Rubira, A.F., Muniz, E.C. Suprasorbent hydrogels based on polysaccharides for application in agriculture as soil conditioner and nutrient carrier: A review. European Polymer J. 2015, 72, 365-385.

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19. Campos, E. V. R.; de Oliveira, J. L.; Fraceto, L. F.; Singh, B., Polysaccharides as safer release systems for agrochemicals. Agron Sustain Dev 2015, 35, 47-66. 19



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21. Yang, F. L.; Li, X. G.; Zhu, F.; Lei, C. L., Structural characterization of nanoparticles loaded with garlic essential oil and their insecticidal activity against Tribolium castaneum (Herbst) (Coleoptera: Tenebrionidae). J Agric Food Chem 2009, 57, 10156-10162.

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22. Kookana, R. S.; Boxall, A. B. A.; Reeves, P. T.; Ashauer, R.; Beulke, S.; Chaudhry, Q.; Cornelis, G.; Fernandes, T. F.; Gan, J.; Kah, M.; Lynch, I.; Ranville, J.; Sinclair, C.; Spurgeon, D.; Tiede, K.; Van den Brink, P. J., Nanopesticides: guiding principles for regulatory evaluation of environmental risks. J Agric Food Chem 2014, 62, 4227-4240.

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FIGURE CAPTIONS

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Figure 1. Durability of nano-enabled pesticide with a core-shell structure: When a nano-

495

enabled pesticide comprised of a carrier/encapsulation material (represented in green) and an

496

a.i. (represented in yellow) is applied in the field, environmental durability can vary widely.

497

This variation is depicted for rapid release, slow release, and no release of the a.i. from the

498

complex. A represents a scenario when the a.i. is released rapidly (e.g. within hours after

499

application); B represents a slower release (over several days) of a.i. and C, when a.i. is not

500

released (e.g. over several weeks) from the nanocarrier.

501

Figure 2. Possible association between nanocarriers (either mobile (A) or immobile (B) in

502

the environment) and pesticide a.i. (exhibiting various degrees of mobility and persistence in

503

the environment). The durability of the complex is key to determining the extent to which the

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exposure profile is modified.

505

21



506

FIGURES

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508 509

Fig. 1

510

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511 512

Fig. 2

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23



514

LIST OF ABBREVIATIONS

515

a.i.

Active ingredient in a pesticide product

516

BCF

Bioconcentration factor

517

IUPAC

International Union of Pure and Applied Chemistry

518

Koc

Soil organic carbon:water partitioning coefficient

519

Kow

Octanol:water partition coefficient

520

OECD

Organization for Economic Cooperation and Development

521

UV

Ultraviolet radiation

522

SC

Suspension concentrate

523 524

24


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ToC graphical abstract 254x190mm (96 x 96 DPI)


Ecological Risk Assessment of Nano-enabled Pesticides: A

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