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RESEARCH ARTICLE

A methodology on how tocreate a real-life relevant riskprofile for a given nanomateria

With large amounts of nanotoxicology studies delivering contradicting results and a complex, movingregulatory framework, potential risks surrounding nanotechnology appear complex and confusing. Manyresearchers and workers in different sectors are dealing with nanomaterials on a day-to-day basis, and have arequirement to define their assessment/management needs. This paper describes an industry-tailoredstrategy for risk assessment of nanomaterials and nano-enabled products, which builds on recent researchoutcomes. The approach focuses on the creation of a risk profile for a given nanomaterial (e.g., determinewhich materials and/or process operation pose greater risk, where these risks occur in the lifecycle, and theimpact of these risks on society), using state-of-the-art safety assessment approaches/tools (ECETOC TRA,Stoffenmanager Nano and ISO/TS 12901-2:2014). The developed nanosafety strategy takes into accountcross-sectoral industrial needs and includes (i) Information Gathering: Identification of nanomaterials andhazards by a demand-driven questionnaire and on-site company visits in the context of human andecosystem exposures, considering all companies/parties/downstream users involved along the value chain;(ii) Hazard Assessment: Collection of all relevant and available information on the intrinsic properties of thesubstance (e.g., peer reviewed (eco)toxicological data, material safety data sheets), as well as identification ofactual recommendations and benchmark limits for the different nano-objects in the scope of this projects;(iii) Exposure Assessment: Definition of industry-specific and application-specific exposure scenarios takinginto account operational conditions and risk management measures; (iv) Risk Characterisation: Classifica-tion of the risk potential by making use of exposure estimation models (i.e., comparing estimated exposurelevels with threshold levels); (v) Refined Risk Characterisation and Exposure Monitoring: Selection ofindividual exposure scenarios for exposure monitoring following the OECD Harmonized Tiered Approachto refine risk assessment; (vi) Risk Mitigation Strategies: Development of risk mitigation actions focusing onrisk prevention.

By Christa Schimpel,Susanne Resch,Guillaume Flament,David Carlander,Celina Vaquero,Izaskun Bustero,Andreas Falk

INTRODUCTION

In the last decade, nanotechnologyentered the policy arena as a technologythat is simultaneously threatening andpromising.1 The combination of size,structure and physical/chemical prop-erties of nanomaterials (NMs) offerremarkable technological advancesand innovations but may also entail

new risks for human health and

environment.2–4 Thus, an approprmanagement of nano-related risks hbeen identified by the EU Commissas a vital empowering issue for the scess of NMs and nanotechnologiOne bottleneck that hinders

safe and sustainable developmennano-innovations in various indussectors is that nano-specific legisla

Christa Schimpel is affiliated with the BioNanoNet Forschungsgesellschaft mbH, Graz, Austria(E-mail address: christa.schimpel@bionanonet.at).

Susanne Resch is affiliated with the BioNanoNet Forschungsgesellschaft mbH, Graz, Austria.

Guillaume Flament is affiliated with the Nanotechnology Industries Association, Brussels, Belgium.

David Carlander is affiliated with the Nanotechnology Industries Association, Brussels, Belgium.

Celina Vaquero is affiliated with the Tecnalia Research & Innovation, Minano, Spain.

Izaskun Bustero is affiliated with the Tecnalia Research & Innovation, Minano, Spain.

12 ã 2017 The Authors. Published by Elsevier Inc. on behalf of Division of Chemical Health and Safety of the

American Chemical Society. This is an open access article under the CC BY license (http://creativecommons.

org/licenses/by/4.0/).

1871-5532

http://dx.doi.org/10.1016/j.jchas.2017.06.002

measures at the EU level are currentlyvague; while a decade of research innanotoxicology has failed to identifyspecific modes of action for nanomater-ial toxicity,6 the regulatory frameworkhas been growing disorderly, creatingan uncertain environment forindustry.7,8

In the European Union, NMs areconsidered as a chemical substanceand therefore fall in the existing regu-latory framework of regulation 1907/20061 concerning the Registration,Evaluation, Authorisation and Restric-tion of Chemicals (REACH). SinceREACH does not explicitly integrateprovisions regarding NMs, they arebound to registration like other sub-stances. Since February 2012, regis-trants can voluntarily declare that theirsubstance is in “nanomaterial form”and with the Second RegulatoryReview on NMs produced by the Com-mission in the same year, the regulatorpromised improvements to the regis-tration of such substances underREACH, including potential amend-ments of the Regulation’s annexes.This process is currently under prog-ress, but will not be ready for the 2018registration deadline for substancesmanufactured or imported in amountsexceeding one ton a year as a two-yearstandstill period applies.In addition, several pieces of sectoral

European regulation directly targetNMs and nanotechnology (e.g., foodand novel foods, cosmetics, biocides,electronic waste, etc.). To support aharmonized understanding of what

1 EC, 2006. Regulation (EC) 1907/2006 of the European Parliamentand of the Council on the Registration,Evaluation, Authorisation and Restric-tion of Chemicals (REACH), establish-ing a European Chemicals Agency,amending Directive 1999/45/EC andrepealing Council Regulation (EEC)No 793/93 and Commission Regula-tion (EC) No 1488/94 as well as Coun-cil Directive 76/769/EEC and Com-mission Directives 91/155/EEC, 93/67/EEC, 93/105/EC and 2000/21/EC. OJ L; http://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:02006R1907-20140410&from=EN.

Journal of Chemical Health & Safety, Janua

constitutes a nanomaterial, the Euro-pean Commission has published a Rec-ommendation for a Definition of ananomaterial (696/2011)2 whichdefines a nanomaterial as follows:‘2. ‘Nanomaterial’ means a natural,

incidental or manufactured materialcontaining particles, in an unboundstate or as an aggregate or as anagglomerate and where, for 50% ormore of the particles in the numbersize distribution, one or more externaldimensions is in the size range 1 nm–100 nm. In specific cases and wherewarranted by concerns for the environ-ment, health, safety or competitivenessthe number size distribution thresholdof 50% may be replaced by a thresholdbetween 1 and 50%.’While this definition has been taken

up in most of the European andnational legislation tackling NMs,there remains a variety of definitions(e.g. NMs for food, etc.). A review ofthis definition is also currently at workby the European Commission. Regula-tory measures specific to NMs rangefrom labelling requirements to addi-tional testing and pre-marketauthorisation.On top of this EU Framework, some

EU Member States, including France,Belgium, Denmark and Sweden, havedeveloped nanomaterial registerswhich condition the manufacturing,importation and distribution of NMsto their prior registration in a nationaldatabase.As a consequence, researchers are

unsure how to work safely withNMs. Industry dealing with NMs hasto cope with an unstable and unreli-able framework to develop safe andlegally compliant products, and con-sumer and public confidence of emerg-ing nano-innovations may severely beaffected.9

Another problem is that reliable tox-icity information and data on the levelsof NMs that the worker, consumer andenvironment may become exposed toare either limited or non-existent.Without such data, it is difficult to

2 European Commission 2011 (2011/696/EU). Commission recommenda-tion on the definition of nanomaterial.OJ L 275/38, 18 October 2011.

ry/February 2018

quantify exposures and it becomeseven more difficult to effectivelyrespond to any potential nano-relatedrisks.10,11

Although relatively limited data areavailable, the fact remains that NMsand/or nano-enabled products maypose a risk depending on their poten-tial hazard and exposure properties.Nonetheless, it cannot be concludedthat nano-related risks are higher com-pared to conventional materials/bulkcounterparts. Still, a strategic frame-work that can properly define thenature of nano-related risks isneeded.12–14

According to legislation and the cur-rent knowledge, NMs have to be trea-ted the same way as chemical sub-stances, which means the standardinformation requirements and theChemical Safety Assessment (CSA)described in the Annexes VII–X ofthe REACH regulation shall beapplied. Quantitative risk estimationrepresents the most important featureof a CSA. Under REACH, risk estima-tion/characterisation is defined as thecomparison of exposure levels andhazard levels leading to the calculationof a Risk Characterization Ratio(RCR). However, in the case of NMsquantitative risk assessment is not fea-sible due to the fact that presentlyneither agreed standardised, validatedand specific methods for measuringpersonal exposure (i.e., breathing zonemeasurements) to engineered NMs areavailable nor are there validated mod-els providing quantitative estimates ofhuman (worker and consumer) orenvironmental exposure.15 The techni-cal limitations of currently availablesampling and analytical methods mayalso raise issues and might not proposesufficient sensitivity to properly assessvery low exposure levels.16 The bestavailable guidance for exposure mea-surement suggests that in addition toan appropriate characterisation of par-ticle size distribution, measurementsshould at least encompass an assess-ment of mass, but where possible alsoinclude number and/or surface areaconcentration.17,18

Confronted with these limitations, itwas decided that the most sensiblecourse of action is to focus on (i) qual-itative risk assessment covering all

13

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eur-lex.europa.eu/legal-content/en/ALL/?uri=CELEX:32012L0019.5Directive 2011/65/EU of the Euro-pean Parliament end of the Council onthe Restriction of the use of CertainHazardous Substances in Electricaland Electronic Equipment (RoHS2);http://eur-lex.europa.eu/legal-content/en/TXT/?uri=CELEX:32011L0065.

stages of the lifecycle, (ii) hazard/riskavoidance rather than address them asan exposure (exercising an appropriatelevel of precaution) and (iii) stronginvolvement of industry, risk managersand relevant stakeholders.In addition, input from (i) experts

in the NanoSafety Cluster (NSC)community, (ii) EU institutions (e.g.,ECHA), (iii) international organisa-tions (e.g., OECD27), (iv) industryinitiatives (e.g., ECETOC28,29), (v)European Center for Nanotoxicology(EURO-NanoTox),54 and (vi) peer-reviewed scientific literature, havebeen considered to ensure consistencyat EU level and alignment to the state-of-the-art.In this framework, hazard/exposure

potentials are measured on scalescalled “bands” using the controlbanding approaches StoffenmanagerNano19 and ISO/TS 12901-2:2014.20

Additionally, risk values were calcu-lated via computational risk screeningmodel ECETOC TRA.21

FRAMEWORK FOR DEVELOPING ARISK PROFILE

In brief, the proposed nanosafety con-cept was developed by linking thestrategies of hazard assessment, lifecycle assessment, and risk analysiswithin the same toolbox. First, allavailable information and data onphysicochemical properties, exposure,toxicokinetics, fate, and hazard ofgiven NMs is collected to build generalexposure scenarios (case studies)throughout the whole life cycle of theNMs. Next, initial exposure estimatesare obtained on a PROC (process cat-egory)-specific basis. For each PROC,exposure values are calculated accord-ing to the selected/assigned PROC-class as well as several parameters suchas the frequency and duration of expo-sure, the presence of a local exhaustventilation (LEV), etc. The final outputis a library of critical hotspots associ-ated with initial exposure estimates,which are universally applicable acrossdiverse industrial and consumersectors. This may help to develop miti-gation plans designed to manage,eliminate, or reduce risk to an accept-able level and thus lowering the

commercialisation barrier for innotive nanotechnology driven produ

The proposed concept is curreused for the safety assessment in

H2020 pilot line projects (INSPIRand Hi-Response) dealing with hthroughput synthesis and scale-upNMs for printed electronic appltions. The following section(“Information gathering” to “Refirisk characterisation and exposmonitoring”) describe in more dethe actions to be considered wensuring the responsible developmof NMs and nano-enabled produ(taking into account the whole invation life cycle; i.e.; cradle-to-granalysis) from an occupational

environmental safety and heperspective.

Applicable Regulatory Framework

In this context, the NMs used are sject to a series of European regulatiwhere their size may trigger additiorequirements. Because they are chical substances, NMs fall under genterm of “substance” in REACH andclassified according to Regulationclassification, labelling and packag(CLP).3 Discussions towards the mification of REACH annexes to induce the term “nanoform”,

requirements to provide informaton the size, shape and surface modcation of individual nanoforms,

ongoing and will eventually applyEuropean nanomaterial manuturers and importers.

Under REACH, the responsibfalls on the registrant to assess

hazards of the substance in the retration dossier. In other instances,

ulations give the role of substance euation to European authorities

make use of positive lists of authorisubstances (e.g. food, food conmaterials). When used in electronNMs also need to comply with

3 Regulation 1272/2008 of the Eupean Parliament and of the Couof 16 December 2008 on classificatlabelling and packaging of substanand mixtures, amending and repeaDirective 67/548/EEC and 1999/EC and amending Regulation (EC)1907/2006

14

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Waste Electrical and Electronic Eqment Directive (WEEE) – 2012/EU4 and the Directive on the Resttion of the use of Certain HazardSubstances in Electrical and Etronic Equipment (RoHS2) – 2065/EU.5 In the WEEE directive fr2012, the legislator referred to

2009 Opinion of the Scientific Cmittee on Emerging and Newly Idefied Health Risks (SCENIHR) on ‘Rassessment of Products

Nanotechnologies’22 which considthat ‘when nanomaterials are firembedded in large structures,

example in electronic circuits, tare less likely to escape this strucand no human or environmental exsure is likely to occur.’ Article 8(2the Directive nevertheless states:

Commission is invited to evaluwhether amendments to Annex

are necessary to address nanomatercontained in EEE.’ At the momentaction has been taken to amend AnVII — Selective treatment for materand components of waste electrand electronic equipment

nanomaterials.RoHS2 sets restrictions for the us

hazardous materials in electrical

electronic equipment. The direcsuggests that NMs should be conered when reviewing Annex II — LisRestricted Substances. In 2012–20the Environment Agency Aus(Umweltbundesamt) wrote the modology for the review of the LisRestricted Substances under RoHSThe methodology does not prioriNMs among other materials, but sgests caution in the assessment of ssubstances.

4Directive 2012/19/EU of the Eupean Parliament and of the Counc4 July 2012 on waste electrical and etronic equipment (WEEE); http

Journal of Chemical Health & Safety, January/February 2018

Information Gathering

Effective risk assessment and manage-ment both assume a high degree ofinformation disclosure. In order tofocus on the risk assessment, stake-holders, especially employees as wellas health and safety representatives inthe risk assessment are activelyinvolved. The employees have a goodunderstanding of their area of workand the risks involved, so they areentitled to an opinion on how safetysystems of work are designed, devel-oped, monitored and assessed.The information gathering process is

split up in two individual steps. Thestarting point is the collection of gen-eral information, which are importantwith regard to nanosafety via a ques-tionnaire survey (see Section“Questionnaire survey” and Supple-mentary information). In the secondstep, companies are visited to gaindeep and detailed insight into realworking conditions on-site (see Sec-tion “Company visits” and Supplemen-tary information).

Questionnaire survey

A detailed questionnaire (see Supple-mentary information) is shared withtechnical experts and/or safety repre-sentatives in order to identify all mate-rials, processes, products and applica-tions, which may be relevant in termsof nanosafety. More precisely, this ini-tial assessment involves identifying thepotential source(s) of manufacturedNMs emissions by reviewing the typeof process, process flow, materialinputs and discharges, and workpractices.The elaborated safety strategy is

based on these case-by-case surveys,addressing the specific requirementsof the involved parties (i.e., data onthe characteristics of the NMs, as wellas contextual information on the oper-ative conditions and risk controlsapplied). The filled-in questionnaireswill be evaluated and uncertaintiesare going to be clarified.

Company visits

Analysis of the filled-in survey is com-plemented by in-depth interviews atthe sites and/or face-to-face meetingswith industrial partners to get anextensive impression of the on-site

Journal of Chemical Health & Safety, Janua

working conditions. The visits alsoinclude a guided tour through the labfacilities, discussions with technicaldevelopers, production experts as wellas health and safety managers. It is avaluable way of involving the staff whodo the work. They know the risksinvolved and scope for potentially dan-gerous shortcuts and problems.Employees are more likely to under-stand why procedures are put in placeto control risks and follow them if theyhave beeninvolved indeveloping healthand safety practices in their workplace.As a next step, the companies are

asked to fill in a template to itemise theprocesses into every single process step(see Supplementary information).

Hazard Assessment

Hazard assessment encompasses thecollection of all relevant and availableinformation on the intrinsic propertiesof the substance that may support theidentification of hazardous propertiesand critical effects.24

Thus, the collection of hazard dataincludes information related to: (i)Physicochemical properties (e.g., phys-ical form, vapour pressure, dustiness,solubility, nanomaterial concentra-tion) provided by material safety datasheets (MSDS), registration dossiersfor REACH; (ii) (Eco)toxicologicaloutcomes (e.g., acute and chronic sys-temic effects, genotoxicity, irritation)provided by case studies and/or peerreviewed publications, internal reportsregarding health and safety of NMs;(iii) Occupational and environmentalbenchmark/threshold limits (i.e., Pre-dicted no effect concentration(PNEC): Concentration of the sub-stance below which adverse effects inthe environmental sphere of concernare not expected to occur; Derived No-Effect Level (DNEL): Level of expo-sure to a substance above whichhumans should not be exposed).Particularly, the above-mentioned

exposure limit values are crucial, asthey represent the reference valuesfor assessing whether risks are con-trolled. A risk score (i.e., risk charac-terisation ratio) is then calculated viacomparing measured or estimatedexposure levels and the PNECs forthe environment and DNELs forhuman health.25

ry/February 2018

Exposure Assessment

The objective of the exposure assess-ment phase is to identify exposure sce-narios along the NMs lifecycle. UnderREACH, exposure scenarios covermanufacturing, all identified uses of asubstance and all risks related to con-sumers, workers and the environmentarising from such uses, considering theuse of the substance on its own, inmixtures or in an articles as definedby the identified uses.26

In order to cover as much of thespectrum of likely releases as possible,usually more than one scenario need tobedevelopedand modelled— represent-ing e.g., low, mean (i.e., realistic), andhigh release factors. Taken together,these various scenarios can cover thenthe entire value chain spectrum of pos-sible releases (and environmental con-centrations) — and the related environ-mental impacts taken into accountoperational conditions and necessaryrisk management measures.The exposure scenario mapping

plays a fundamental role within thesafety assessment, since it constitutesthe basis for the exposure estimationand risk characterisation.26

Risk Characterisation

In order to prioritise previously identi-fied exposure scenarios, the first Tiertool ECETOC TRA (=Targeted RiskAssessment) is used. ECETOC TRAwas selected as a result of extensiveliterature research and discussionswith experts from NANoREG. Theintegrated tool enables an assessmentof both occupational and environmen-tal exposure scenarios. The model isbased on a relation between PROCs/ERCs (process categories/environ-mental release categories describedin the REACH guidance27) and basicexposure threshold values. In particu-lar, the software calculates whether thepotential for exposure in a specificscenario is high or low.21,28,29 How-ever, it has to be considered that withrespect to nanomaterial exposures,ECETOC TRA is able to give an indi-cation of exposure levels. Since ECE-TOC was not initially designed to spe-cifically assess nanomaterial exposuresituations, the risk estimates may beinaccurate due to the limitations ofthe model.30

15

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The tool requires the user to inputsome basic information on the sub-stance (molecular weight, vapour pres-sure, substance form). The user canthen select scenarios, as PROCs/ERCs,which pre-define the point of depar-ture exposure value. A range of expo-sure modifiers are applied to establishthe set of operational conditions andrisk management measures thatappear in the final scenario (see Sup-plementary information).The output of ECETOC TRA is a

simple description of type and basicconditions of use which can then betranslated into calculated risk valuesvia comparison of estimated data withindicative reference values (DNEL,OEL (occupational exposure limit), i.e., maximum admissible concentrationat workplace, PNEC).For each exposure scenario, the soft-

ware calculates different risk charac-terisation ratios (RCR) according toEq. (1). To assess worker’s exposure,short-term and long-term inhalative aswell as dermal RCRs are calculated. Inaddition, a RCR for long term totalexposure is generated.For environmental exposure assess-

ment, a separate RCR for each envi-ronmental compartment is generated,i.e., marine water, freshwater, soil andsediment.

RCR human occupationalð Þ health

¼ exposure

DNELRCR environment

¼ PEC

PNECð1Þ

A RCR value >1 indicates that thereis risk in place for human health or theenvironment, while a value <1 meansthat no risk is present under theselected conditions.Ideally, the exposure assessment

should be based on quantitative mea-surements of the levels of the exposure,however, in practice, the availability ofreliable exposure data is scarce andmostly limited to the workplace. Useof single tool estimates is unlikely to bepersuasive enough for appropriate riskassessment. Hence, it has been recom-mended to use different methodsfor different risk-based decision con-texts.30,31 Therefore, semi-quantitative

assessment via ECETOC TRA is sported by qualitative assessment uscontrol banding tools (i.e., Stoffennager Nano and ISO/TS 1292:2014) to evaluate, if risks are aquately controlled in each pre-defiexposure scenario.

Control banding tools representalternative approach for risk assment that can be used to identify

recommend exposure control msures to potentially hazardous sstances with unknown or limited tcological properties and for whthere is a lack of quantitative exposestimations. Control banding todefine hazard bands and exposbands and combine these in a tdimensional matrix, resulting inscore for risk control (proacapproach). Hazard banding consin assigning a hazard band to a sstance on the basis of a comprehenevaluation of all available data on

material (often from a Material SaData Sheet, MSDS), taking iaccount parameters such as toxicand factors influencing the abilityparticles to reach and/or deposit inrespiratory tract. (i.e., physical

chemical properties such as surfarea, surface chemistry, shape, partsize). Following the hazard bandprocess, the second step is intento determine an expected levelworkers exposure which is designaas an exposure band. Matching

hazard band and the exposure bthrough a control banding madetermines the appropriate levelcontrol i.e. the control band.

greater the potential for harm

exposure, the greater the steps neefor control.32,33

The ISO/TS 12901-134 conbanding approach allocates five bafor hazard, four bands for exposand five risk level control bands. Othe hazard and exposure band

determined, a control measure stratis suggested. This means that a sstance with greater health hazaand higher exposure potential

have more stringent controls thasubstance with low health hazards

Stoffenmanager Nano applies

hazard bands, four exposure ba(emission potential) and three conbands for risk. The control ba

16

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(levels) are derived by combinatiof the hazard and exposure banda two-dimensional decision maEach control band (risk level) is aciated with general recommendatifor risk management and action

should be taken

consideration.35,36

Refined Risk Characterisation andExposure Monitoring

When risk cannot reasonably

excluded via qualitative and sequantitative risk assessment, refirisk assessment becomes necessare., additional estimation based

higher tier estimation models, gention of measured exposure data).Field-based, real-time workp

release and exposure measuremewill be performed according to

OECD.37 The proposed approcan be split into three tiers: At Tia decision has to be made, whethenot a release of nanoscale aerofrom NMs into workplace air canreasonably excluded. If this is notcase, a basic exposure or release assment is conducted utilizing easyuse, portable equipment/handhdevices for direct reading measuments (on-line) in Tier 2. Total partconcentration (TPC) is measured ding the nano-related tasks and is cpared with background concentratif the comparison shows a significincrease in TPC, then a potenrelease of NMs due to the task mhappen and a Tier 3 is suggested. Tiis an expert assessment where theof advanced on-line devices and

collection of samples for off-line aysis are simultaneously combined.

Risk Management and Strategies foRisk Mitigation

The main objective of this step is csidering and incorporating safety msures of potential health (workers

envisaged users) and environmesafety concerns from the very bening/at earliest stage in the innovaprocess and where necessary adapthe process and/or product designas to create safer outcomes. Thus,

mitigation actions focus on hazarisk avoidance rather than addthem as an exposure (i.e., SafeDesign).

Journal of Chemical Health & Safety, January/February 2018

Figure 1. Linkage of NanoSafety Cluster, European Pilot Production Network (EPPN) and projects contributing to the i2L group.

6 http://www.nanosafetycluster.eu/working-groups/industrial-innovation-liaison-i2l-wg10.html.

RESULTS AND DISCUSSION

Recommendations of the Organisationfor Economic Co-operation andDevelopment (OECD) for a responsi-ble strategy that aims to enable the safedevelopment and use of NMs andnanotechnology include the proposalof integrating risk assessment of che-micals at all stages of the life cycle of ananotechnology-based product.38

Within the European Parliament andCouncil Regulation (EC) No 1907/2006 (REACH), risk assessment andrisk characterisation is conductedunder the overall framework of thechemical safety assessment (CSA) pro-cess39 which basically encompassesthree steps:

1. Hazard Assessment: The hazardassessment involves the analysis ofavailable data on (eco)toxicologicaleffects with respect to human healthand the environment;

2. Exposure Assessment: The expo-sure assessment formulates expo-sure scenarios describing howa chemical is used by workers orconsumers or how it is released intothe environment (bearing in mind

Journal of Chemical Health & Safety, Janua

operational conditions and neces-sary risk management measures);and,

3. Risk Characterisation: The risk char-acterisation combines hazard andexposure to estimate risk; risk levelsare defined via comparing of esti-mated exposure levels with thresh-old/benchmark exposure limits.

In order to create a holistic andcross-sectorial approach for thenano-related safety assessment, theconcept is basically grounded on theclassical framework40 but has beenmodified — now covering six steps:

1. Information Gathering;2. Hazard Assessment;3. Exposure Assessment;4. Risk Characterisation;5. Refined Risk Characterisation and

Exposure Monitoring and6. Risk Management and Strategies

for Risk Mitigation.

In addition, the development of theproposed safety framework also incor-porates partnership and coordinationbetween nanosafety experts, industriesand other stakeholder groups. One

ry/February 2018

crucial step forward to better linksafety work and industry in ongoingprojects was the establishment of theNanoSafety Cluster sub-group“industrial innovation liaison (i2L)”,6

founded in September 2016 in Paris. Inbrief, this group aims to maximise thesynergies between ongoing nanosafetyresearch and industry-oriented pro-jects to identify possible cross-oversafety strategies/guidelines valid fordifferent sectors/markets, and to share“case study” experiences, includingevaluation of which methodologies/guidelines are most useful and whichknowledge gaps/limitations exist.Additionally, this group will supporttechnical development in the Euro-pean Pilot Production Network(EPPN) (see Figure 1).There have been a number of com-

plementary approaches proposed toevaluate the potential risks and/orserve as decision support tools forNMs/nano-enabled products.41 Inorder to assess the advantages andlimitations of existing RA frameworks

17

alth theion,di-fetyCHcalsointentver,tivetheerlyail-hlyanders

tan-ted

and tools, as a first step we conductedan extensive literature survey to collectinformation from completed andongoing European research projectsor by other international organisationsand committees to ensure consistencyat EU level and alignment to the state-of-the-art.The most important sources of

knowledge from relevant research pro-jects (including the most recent andrelevant publications and nanoEHStools) are outlined in Table 1.As indicated in the table above, sev-

eral approaches exist for risk estima-tion; however, none of these conceptsrepresent a seamless strategy to effec-tively manage the multidisciplinarynature of nanotechnology and their

related risks. Carrying out risk assment is strongly depended on infortion and data availability (e.g., naspecific exposure data/limits).28 Ting into account that recently a wvariety of NMs (e.g., raw materintermediate components) and natechnology-enabled consumer pducts are in the pipeline, we do

have the luxury to investigate evaspect of nanomaterial toxicitNanotechnology is reality nResponding to this challenge,

decided to focus on immediate sameasures. Thus, the main goal of

safety concept is the development oinstant plan/safety strategy for indtry workers which are handling Nby a day-to-day basis. The prim

Figure 2. Overv

18

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ow.wefetyourf anus-Msary

objective is to protect human heas well as the environment even inabsence of complete informatwithout stifling innovation. As incated in Figure 2, the proposed saconcept follows the general REA(CSA) approach applied to chemibut is strongly moving towards a japplication of risk/safety assessmand life cycle assessment. Moreoa strong focus is placed on “objecresearch” which suggests that

nature of the risk can be propdefined by making best usage of avable data and involvement of higrenowned players in the research

industrial field and other stakehold(e.g., active bodies in regulation/sdardization). Combining collec

iew of the different phases of the suggested nanosafety concept.

Journal of Chemical Health & Safety, January/February 2018

Table 1. Selection of State-of-the-Art RA Frameworks and Tools (in AlphabeticalOrder).

Framework Reference

GuideNano http://www.guidenano.eu/ITSnano Stone et al.42

LICARA Som et al.43

MARINA Framework Bos et al.44; http://www.marina-fp7.eu/NANEX/MARINA Sikorova et al.45; http://www.nanex-project.eu/NanoValid http://www.nanovalid.eu/REACHnano http://www.lifereachnano.eu/RIP-oN 3 Report Aitken et al.17

Scaffold http://scaffold.eu-vri.eu/SUN Malsch et al.46; http://www.sun-fp7.eu/

Tools Reference

ANSES Tool Brouwer33

ConsExpo Bremmer et al.47

Control Banding Tool(ISO/TS 12901-2:2014)

ISO34

ECETOC TRA Tool ECETOC21

GuideNano Tool http://www.guidenano.eu/LICARA NanoScan Van Harmelen et al.48

NanoRiskCat Hansen et al.49

NanoSafer Jensen et al.50

REACHnano ToolKit REACHnano Consortium28

SimpleBox4Nano Meesters et al.51

Stoffenmanager Nano Van Duuren-Stuurman et al.19

Swiss Precautionary Matrix Hoeck et al.52

hazard data with identified exposurescenarios (i.e., exposure assessmentstep) the result obtained is a libraryof critical hotspots associated with ini-tial exposure estimates (i.e., risk char-acterisation/prioritisation stage).

Fi

Journal of Chemical Health & Safety, Janua

For the calculation of risk values anddefinition of the likelihood of release,three tools were selected for qualitativeand semi-quantitative risk assessmentrespectively. General descriptions/background information related to

gure 3. Current vs future safety concept.

ry/February 2018

the tools, the selection criteria andobtained results are outlined inTable 2.As long as data and exposure limits

for NMs are not available, quantitativerisk assessment is not feasible. Thus, asa starting point we established animmediate safety concept based onqualitative risk assessment via theISO/TS 12901-2:2014 Control Band-ing Tool and the Stoffenmanager NanoTool on the one hand, and semi-quan-titative risk assessment using ECTEOCTRA on the other. In the future, how-ever, the objective is shifting prioritiesover time from a safety strategy com-pliant with the current provisions ofREACH to an effective and sustainablesafety concept which allows nano-spe-cific quantitative exposure estimation(built on nano-specific exposure limitsand measurement principles) andwhich will adapt to the future evolu-tions of REACH annexes regardingNMs (see Figure 3).In summary, the proposed approach

is based on the current state of knowl-edge and is flexible enough to identifycritical hotspots along the innovationchain/life cycle associated with initialexposure estimates. However, furtherelaboration and refinement is cruciallyneeded. Furthermore, the approachcan also be used to identify those situa-tions/processes where the use of nano-specific read-across, grouping, and (Q)SAR is likely to become realistic in the

19

Table 2. Overview of Selected Risk Assessment Tools Included in the Nanosafety Concept.

Qualitative Risk Assessment Tools Semi-Quantitative RiskAssessment Tool

Name ISO/TS 12901-2:2014(Control Banding)34,54

Stoffenmanager Nano(Control Banding)19,35

ECETOC TRA (Targeted RiskAssessment) Tool55

Description - Approach addressing likelihood of release, based on limitedamount of information

- Approach for calculating riskvalues via comparison ofestimated data with indicativereference values, based onmandatory inputs related tophysicho-chemical properties,operational settings, RMM

- Hazard/exposure potentials are measured on scales called “bands”� Bands are typically plotted on a two-dimensional matrix, whichresults in establishing a control band (ISO) or a risk band(Stoffenmanager Nano)

� Risk control is achieved through recommendations ofappropriate risk management measures (RMM) (e.g.,engineering and administrative controls) as well as personalprotective equipment (PPE)

GeneralStructure

- Information gathering - Information gathering

- Assignment of nanomaterial to a Hazard Band ! hazard banding - Definition of exposure scenarios(taking into account operationalconditions, RMM)

- Description of potential exposure characteristics ! exposurebanding

- Assignment of scenarios to aPROCs/ERCs (processcategories/environmentalrelease categories described inthe REACH guidance)

- Definition of recommended work environments and handlingpractises ! control banding

- Final output is a library of criticalhotspots associated with initialexposure estimates

- Evaluation of the control strategy (action plan) based on thechosen scenario

Output - Hazard band (HB) - Hazard band (HB) - Risk characterisation ratio (RCR)- Exposure Band (EB) - Exposure Band (EB)- Control Band (CB) - Risk Band (RB)

SelectionCriterion

U Standardised ISO-guideline

U Real case study tested (e.g., EU-funded project SCAFFOLD)

U Real case study tested (e.g.,EU-funded projectNANoREG)56

U Usable in the absence ofexposure andbenchmark limits

U Nano-specifity U Compliant with REACHregulation (i.e., using the ECHAuse descriptor system)

U Applicable in the absence ofexposure and benchmark limits

U Considers occupational,environmental & consumerexposure

U Stoffenmanager1 is included inthe official REACH Guidance(R.14) document as arecommended tool. Meaningthe European Commissionofficially recognizesStoffenmanager as instrumentto comply with the REACHregulation

U Not only qualitative riskasessemnt, but also semi-quantitative risk profiling,isfeasible

20 Journal of Chemical Health & Safety, January/February 2018

future, since conducting risk assess-ment for each individual nanomaterialon a case-by-case basis would require alot of resources as well as time, effort,and money.

CONCLUSIONS

This outlined Methodology on How toCreate a Real-life relevant Risk Profilefor a Given Nanomaterial relates toexisting risk assessment practice underthe current regulatory framework forthe safe use of chemicals (i.e., REACH)and its future evolution towards aninclusion of provisions for nanoformsin ECHA guidance documents and arevision of REACH annexes to specifi-cally address NMs.The present paper gives guidance on

how to create a risk profile for a givennanomaterial (e.g., determine whichmaterials and/process operation posegreater risk, where these risks occur inthe lifecycle, and the impact of theserisks) using state-of-the-art safetyassessment approaches/tools (ECE-TOC TRA, Stoffenmanager Nano andISO/TS 12901-2:2014). It focuses ongiving concrete, practical guidance toindustry and regulatory authorities(such as European agencies, scientificcommittees, national competentauthorities) on how to deal with envi-ronmental health and safety aspects(EHS) when dealing with NMs andnano-enabled products.NMs manufacturers need to stay in

phase with the latest evolutions of thelegislative framework for NMs. Cur-rently, the overarching Europeanchemical regulation, REACH, isundergoing adaptation of its annexesto clarify nanomaterial requirements.At the same time we see EuropeanMember States continue setting upnational nanomaterial registers. In thiscontext, putting NMs in the Europeanmarket has become increasingly diffi-cult and costly, thus significantly ham-pering the innovation potential of theregion.Some of the nanosafety projects

(NANoREG, NanoReg2, ProSafe)financed by the European Unionintend to support regulation; these col-lect large quantities of comparable andconsolidated data on toxicological

Journal of Chemical Health & Safety, Janua

endpoints. This is a first step towardsa facilitated use of grouping and read-across for NMs, thus improving thequality of dossiers and reducing theircost. At international level the OECDis actively supporting grouping andread-across for NMs57 and undertakescontinued efforts to deliver a sustain-able policy framework that ensuressafe products and a positive environ-ment for innovation.The presented approach may be

valuable both for policy makers/regu-lators and as well as industry. Policymakers/regulators can predominantlybenefit from using the concept to prior-itise those NMs and/or applicationsthat need to be addressed mosturgently. Industry can use theapproach as a forward-looking strat-egy aiming at making safety assessmentpractical and economically efficient.However, it needs to be emphasised

that the field of nanomaterial riskassessment is evolving, and the meth-odology provided is based on the cur-rent available knowledge developed indiverse European research projectsand other international organisationsand committees. In the future, themethodology presented in this articlemay therefore be revised in the light ofnew scientific knowledge.

ACKNOWLEDGEMENTSThis work was supported by ongoingprojects that received fundingfrom the European Union’s Horizon2020 research and innovation pro-gramme under grant agreement no646155 (INSPIRED), grant agree-ment no 646296 (Hi-Response)and grant agreement no 691095(NANOGENTOOLS).

APPENDIX A. SUPPLEMENTARYDATA

Supplementary data associated withthis article can be found, in the onlineversion, at http://dx.doi.org/10.1016/j.jchas.2017.06.002.

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