CHAP TE R6RegulationandLegislationMaureenR.Gwinn1,BirgitSokull-Kluttgen21USEnvironmentalProtectionAgency,Washington,DC,USA2EuropeanCommission,JointResearchCentre,InstituteforHealthandConsumerProtection,UnitIO5Nanobiosciences,Ispra,ItalyOUTL I NEIssues with Current Studies for RiskAssessment of Nanomaterials 98Regulation Areas for Nanomaterials 100The USA 100Environmental/HumanHealth 103Toxic Substances Control Act (TSCA)103Federal Insecticide, Fungicide, andRodenticide Act (FIFRA) 103Other Regulations 104Nano-Scale Materials StewardshipProgram (NMSP) 104FoodSafety andMedicalApplications 104Consumer Products 104Occupational 105European Union 105Chemicals 106Industrial Chemicals 106Plant Protection Products andBiocidal Products 108Worker Protection 108Consumer Products 109Cosmetic Products Regulation 110FoodLegislation 110Medicinal Products andMedical Devices 112Environmental Protection 112Take-Home Messages 113Acknowledgments 113Disclaimer: The views expressed in this review are thoset of the authors and do not represent the views and/or policies of the US Environmental Protection Agency, the European Commission or a European Agency. Theauthors are not responsible for any use which might be made of this text.97AdverseEffectsofEngineeredNanomaterialsDOI:10.1016/B978-0-12-386940-1.00006-4 Copyright 2012ElsevierInc.Allrightsreserved.ISSUESWITHCURRENTSTUDIESFORRISKASSESSMENTOFNANOMATERIALSThe Organization for Economic Cooperation and Development (OECD) establisheda Working Party on Manufactured Nanomaterials (WPMN) [1] in 2006 in order to collaborateinternationally on the safety research of nanomaterials. This workgroup is a key example ofthe interdisciplinary nature of the work needed in nanomaterial research, including scientists(e.g. chemists, physicists, biologistsandtoxicologists)andregulatorsworkingonenviron-mentalhealthandsafety, exposure, andtestingofnanomaterials; inaddition, theWPMNcovers a vast geographical area that enables it to harvest many different approaches. Subcom-mittees (Steering Groups, SG) of the WPMN are looking at different issues such as databases;testguidelinesandriskassessment(Table6.1). ParticularlyimportantisSG3onTestingaRepresentativeSetofManufacturedNanomaterials,theso-calledsponsorshipprogram,organizedwithasponsorgroupforeachofthenanomaterialsunderstudy, withvariouscountriesincludingindustryservingassponsors(Table6.2). Theobjectiveof SG3istodevelopandtest arepresentativeset of manufacturednanomaterialsinaccordancewiththeGuidanceManualforsponsors[2].Theoutcomewillbeanunderstandingofthekindof information on intrinsic properties that may be relevant for hazard assessment of nanoma-terials, and practical experience and evidence on whether current OECD Test Guidelines andother methods are applicable. There is also an ongoing National Toxicology Program (NTP)bioassayonavarietyof nanomaterialsthat will informsomeof theissuesrelatedtotheeffects of nanomaterials [3]. Theseefforts will helptodesignstandardizedtests, whichrequirewell-controlledanddenedconditionsandtheavailabilityof well-characterizedmanufacturednanomaterialswill helptodesignstandardizedtests, whichrequirewell-controlledanddenedconditionsandtheavailabilityofwell-characterizedmanufacturednanomaterials.Variousattemptstoanalyzenanomaterialshavefocusedoncombiningtheriskassess-ment paradigmwithalife-cycleframework. Theuseof acomprehensiveenvironmentalassessment (CEA) entails all life-cycle stages in the context of hazard identicationandriskassessment. CEAinvolves bothqualitativeandquantitativeapproachestoriskcharacterizationofhumanorecological risk[4]. Recentcasestudiesandworkshopshaveaddressed the issues of nanomaterial risk assessment using this methodology[5,6].Risk assessment is generally performed based on the chemical composition of the materialinquestion.Inthecaseofnanomaterials,however,thismaynotbesufcientaschemicalsTABLE 6.1 OECD Working Party on Manufactured NanomaterialsSG 1/2 merged: OECD Database on Manufactured Nanomaterials to Inform and Analyse EHS Research ActivitiesSG 3: Safety Testing of a Representative Set of Manufactured NanomaterialsSG 4: Manufactured Nanomaterials and Test GuidelinesSG 5: Cooperation on Voluntary Schemes and Regulatory ProgrammesSG 6: Cooperation on Risk AssessmentSG 7: The Role of Alternative Methods in Nano ToxicologySG 8: Exposure Measurement and Exposure MitigationSG 9: Environmentally Sustainable Use of Manufactured NanomaterialsSG steering group6. NANOMATERIALREGULATION 98A.ENGINEEREDNANOMATERIALS:HAZARD,EXPOSUREANDSAFETY ASSESSMENTgenerallyconsiderednon-toxicinmacro-scalerangesmaybecometoxicinthenano-scalerange.Themoststudiedexampleistitaniumdioxidewhich, inthelargersizerange,doesnotappeartoexhibittoxicitytohumansortheenvironment.Exposurestonano-scaletita-niumdioxidehavebeenassociatedwithavarietyofpulmonaryeffectsinrats, includinginammation, pulmonary damage, brosis, and lung tumors [7,8]. Also, nano-scale titaniumdioxideparticlescanimpairmacrophagefunctionandincrease pulmonaryretention,enterthe epithelium faster and translocate to the subepithelium space more readily than ne parti-cles[9]. Thesehavealsobeenshowntoleadtomitoticdisturbances, DNAdamageandapoptosis.A key area of nanomaterial safety research is characterization of physicochemical proper-ties. While most researchers agree that characterization of nanomaterials is a necessary stepintoxicologicalanalysis,needsregardingthelevel,typeandtimingofcharacterizationarenot as clear. The increasingusage of nanomaterials takes advantage of the differencesbetween these materials and their larger scale counterparts. Research has focused on manyof these characteristics and their potential role in toxicity generally compared to their largerscale counterparts. Studies have examined the impact of their smaller size, increased surfaceareaandincreasedsurfacereactivity,andsomeexamplesinrelationtoenvironmentalandtoxicological behavior are given (see Chapters 1 and 2).TABLE 6.2 Nanomaterials Investigated in the Sponsorship Programme (SG 3) of the OECD Working Partyfor Manufactured NanomaterialsNanomaterial Lead Sponsors Co-Sponsors ContributorsFullerenes USA/Japan DK/China dSWCNT USA/Japan d CDN/FR/DE/EC/China/BIACMWCNT USA/Japan Korea/BIAC CDN/FR/DE/EC/China/ BIACSilver NP USA/Korea AUS/CDN/DE/Nordic FR/EC/ChinaIron NP BIAC/China d CDN/USA/EC/NordicTiO2FR/DE AT/CDN/ES/Korea/USA/ EC/BIACChina/DK/Japan/UKGold NP South Africa USA EC/NLAl2O3USA d dSiO2EC/FR BE/Korea/BIAC DK/JapanNanoclays USA/BIAC d ECDendrimers d ES/USA dCeO2USA/UK/BIAC AUS/NL/ES DK/DE/CH/EC/JapanZnO UK/BIAC AUS / ES / USA / BIAC CDN/DK / JapanSWCNT hsingle-walled carbon nanotubes; MWCNT h multi-walled carbon nanotubes; NP h nanoparticle; TiO2h titaniumdioxide; Al2O3h aluminium oxide; SiO2h silicon dioxide; CeO2h cerium dioxide; ZnO h zinc oxide; AT hAustria;AUS h Australia; BE h Belgium; BIAC h Business and Industry Advisory Committee; CH h Switzerland; CND h Canada;DE hGermany; DKhDenmark; EC hEuropean Commission; ES hSpain; FR hFrance; NL hThe Netherlands; Nordic hNordicCouncil of Ministers; UK h United Kingdom; USA h United States of America.ISSUESWITHCURRENTSTUDIESFORRISKASSESSMENTOFNANOMATERIALS 99A.ENGINEEREDNANOMATERIALS:HAZARD,EXPOSUREANDSAFETY ASSESSMENTREGULATIONAREASFORNANOMATERIALSAs nanomaterials are used in an increasing range of high-tech applications and consumerproducts there is growing concern about their safe use and possible impact on human healthand the environment. Current and future legislation will have to take this into account andaddress nanomaterials more specically. To date, there is no internationally accepted deni-tion for nanomaterials, and the questionremains whether or not a denition for regulatorypurposes is needed and useful [10].In the recent update of the US National Nanotechnology Initiative Environmental Healthand Safety Research Strategy [11], nanomaterials are dened to include more specically allmaterials designed to have at least one dimension less than 100 nm and exhibit unique qual-ities determined by this size. This denition may not apply to regulatory statutes or policiesrelevant to nanotechnology.IntheEuropeanUnion, theEuropeanParliament consideredit important toaddressnanomaterials explicitly within the scope of certain legislation and called for the introduc-tion of a comprehensive science-based denition of nanomaterials in community legislation[12].BasedonaReferenceReportonConsiderationsonaDenitionofNanomaterialforRegulatoryPurposes [13] of the EuropeanCommissions Joint ResearchCentre (JRC)and the opinion of the Scientic Committee on Emerging and Newly Identied Health Risks(SCENIHR)[14], entitledScienticBasisfortheDenitionof theTermNanomaterial[15], the European Commission published a recommendation on the denition of nanoma-terial [16]: Nanomaterial means a natural , incidental or manufactured material contain-ingparticles,inanunboundstateorasanaggregateorasanagglomerateandwhere,for50%ormoreoftheparticlesinthenumbersizedistribution,oneormoreexternaldimen-sions is in the size range 1 nme100 nm. In specic cases and where warranted by concernsfor the environment, health, safety or competitiveness the number size distributionthresholdof50%maybereplacedbyalowerthreshold. Fullerenes, grapheneakesandsinglewall carbonnanotubeswithoneormoreexternal dimensionsbelow1nmshouldalsobeconsideredasnanomaterials. Thetermsparticle, agglomerate andaggregateare dened. For a further discussion of the denition of nanomaterials, see Chapter 1.Some of the key questions surrounding the regulation of nanomaterials relate to whetheror not these should be considered a new material, or if they can be regulated based on theirmacroscale counterparts (if these exist). The following section will describe the current legis-lation that may play a role in the regulation of nanomaterials in the USA (Table 6.3) and theEuropean Union.THEUSANanotechnology policy in the USA is primarily coordinated through the National Scienceand Technology Council [17] through the Nano-scale Science, Engineering, and Technology(NSET) Subcommittee [18]. The NSET Subcommittee and its working groups, with supportfromtheNationalNanotechnologyCoordinationOfce(NNCO),preparethemultiagencyplanning, budget and assessment documents related to the National Nanotechnology Initia-tive(NNI). NNIisaUnitedStatesgovernment-wideefforttocoordinatefederally-funded6. NANOMATERIALREGULATION 100A.ENGINEEREDNANOMATERIALS:HAZARD,EXPOSUREANDSAFETY ASSESSMENTTABLE 6.3 Legislative Authorities that may Encompass Nanomaterial Usage in the USARegulation Description Potential Use Governing Body WebsiteToxic Substances ControlAct (TSCA)TSCA provides EPA with theauthority to require reporting,record-keeping and testingrequirements, and restrictionsrelating to chemical substancesand/or mixturesProposed case-by-case determinationof nanomaterials asnew materialsUnited StatesEnvironmental ProtectionAgency (US EPA)http://www.epa.gov/lawsregs/laws/tsca.htmlFederal Insecticide,Fungicide and RodenticideAct (FIFRA)FIFRA provides the basis forregulation, sale, distribution anduse of pesticides in the USADetermination ofunreasonableadverse humanhealth risks with theaddition ofnanomaterials toexisting pesticidesUnited StatesEnvironmental ProtectionAgency (US EPA)http://www.epa.gov/opp00001/regulating/laws.htmSafe Drinking Water Act(SDWA)The main federal law that ensuresthe quality of Americas drinkingwaterCurrently nomaximumcontaminant levelgoals set fornanoparticlesUnited StatesEnvironmental ProtectionAgency (US EPA)http://www.epa.gov/OGWDW/sdwa/ComprehensiveEnvironmental Response,Compensation, andLiability Act and ResourceConservation andRecovery Act (CERCLA/RCRA)Commonly known as Superfund,CERCLA was enacted in 1980 andcreated a tax on the chemical andpetroleum industries and provideda broad Federal Authority torespond directly to releases orthreatened releases of hazardoussubstances that may endangerpublic health or the environmentThis would coverthe evaluation andcontrol ofnanomaterials inwaste sitesUnited StatesEnvironmental ProtectionAgency (US EPA)http://www.epa.gov/superfund/policy/cercla.htmClean Air Act (CAA)/Clean Water Act (CWA)The Clean Air Act and Clean WaterAct both allow the EPA to set limitson certain air and water pollutantsin the USA. Under these Acts, theEPA also review and approvepermit applications for industriesor chemical processesRelease ofnanomaterials intothe air or waterwould fall underthese ActsUnited StatesEnvironmental ProtectionAgency (US EPA)http://www.epa.gov/air/caa/peg/understand.htmlhttp://www.epa.gov/oecaagct/lcwa.html(Continued)THEUSA101A.ENGINEEREDNANOMATERIALS:HAZARD,EXPOSUREANDSAFETYASSESSMENTTABLE 6.3 Legislative Authorities that may Encompass Nanomaterial Usage in the USAdcontdRegulation Description Potential Use Governing Body WebsiteFood, Drug and CosmeticAct (FDCA)The FDCA is a set of laws givingFDA the authority to oversee thesafety or food, drugs and cosmeticsin the USAAlready in use forpremarket testing offood additives, thismay coverregulation of the useof nanomaterials infood additives andcosmeticsUnited States Food andDrug Administration (USFDA)http://www.fda.gov/nanotechnology/regulation.htmlOccupational Safety andHealth Act of 1970 (29 US654)Section 5(a)(1) of the OSH Actrequires employers to furnish eachof his employees employment anda place of employment which arefree from recognized hazards thatare causing or likely to cause deathor serious physical harm to hisemployeesOSHA hasapproved plans for24 states to adoptfederal safetystandards forworkers exposed tonanomaterials inprivate industryUnited States OccupationalSafety and HealthAdministration (OSHA)http://www.osha.gov/dsg/nanotechnology/nanotech_standards.html6.NANOMATERIALREGULATION102A.ENGINEEREDNANOMATERIALS:HAZARD,EXPOSUREANDSAFETYASSESSMENTnanomaterial researchfocusingonmultiple topics, includingmetrology, environmentalhealthandsafetyandexposuretonanomaterials. Coordinationofeffortsisanimportantstep in making sure the most useful research is done in an efcient manner.The NNI releases an Environmental, Health and Safety Strategy document approximatelyevery2 years toprovide guidance tofederal agencies involvedinthe development of nanotech-nology. Written by members of the various federal agencies involved in NNI, these strategiesarebasedonthestateofthescience,ongoingresearchactivitiesandinputfromthepublicthrough workshops and public review [11]. The NNI is not a regulatory body; however, onegoal of the NNI is to give recommendations on the research needed for risk assessment andrisk management of nanomaterials to ensure responsible development of nanotechnology.Environmental/HumanHealthToxicSubstancesControlAct(TSCA)TheToxicSubstancesControl Act (TSCA) [19] isthemainlegislativeauthorityunderwhich the US EPA requires manufacturers of new chemicals to submit specic informationontheeffects ofthesematerials[20]. UnderTSCA, theUSEPAhastakenstepsto limittheexposuretonanomaterials,includingcarbonnanotubes(CNTs).TheEPAhasrequiredtheuseofpersonalprotectiveequipmentandlimitationsontheuseandenvironmentalexpo-suresof nanomaterials. TheUSEPAsOfceof PollutionPreventionandToxicsrecentlyreleased a factsheet describingthe plans to study nanomaterialson a case-by-case basis asnew chemicals, rather than existing chemicals.Under TSCA, the US EPA has reviewed new nano-scale chemical premanufacture noticesforcarbonnanotubes,nanosilverandothermaterialsrequiredpriortothemanufactureorintroductionofnewchemicals.ThisprocessallowsfortheUSEPAtocontroland/orlimitexposures to these chemicals through a variety of mechanisms (e.g. limiting use and releaseof materials, requiring use of personal protective equipment). The US EPA has permitted themanufactureofnewnano-scalechemicalmaterialsthroughtheuseoftheSignicantNewUse Rules (SNUR) under TSCA. Through this process, the US EPA is provided with a basicsetofinformationonnano-scalematerials,includingthechemicalproperties,toxicitydataandproductionvolume, whichwouldallowtheUSEPAtodetermineanunreasonablerisk of these new materials to human health or the environment.FederalInsecticide,Fungicide,andRodenticideAct(FIFRA)Nanomaterials added to pesticides would fall under the mandates of the Federal Insecti-cide,Fungicide, and RodenticideAct(FIFRA) todeterminewhethertheiradditionleadstoadversehealthrisks[21]. UnderFIFRA, theUSEPAhelditsrstScienceAdvisoryPanel(SAP) reviewof nanomaterialsinNovember2009, specicallyexaminingnanosilverandothernanometal pesticideproducts. Thepanel wasdesignedtoaddressissuesrelatedtowhether nanosilver andother nanometalsinthe1e100 nmhaveuniquebehavior underconditionsrelevanttohumanhealthandecological risk. TheSAPreviewfocusedmainlyonuseofnanosilverinpesticideproducts,withrecommendationsonhowtoconductriskassessmentsofpesticideproductscontainingnanosilver,particularlyrelatedtowhattypesof data would be needed to evaluate the risks. The panel determinations related to the roleTHEUSA 103A.ENGINEEREDNANOMATERIALS:HAZARD,EXPOSUREANDSAFETY ASSESSMENTof the silver ion release in the toxicity of silver (macro-scale and nano-scale), and the lack ofavailable data demonstrating any variability in the release of silver ions from nanomaterialsas opposed to macro-scale silver, and the specic biological impacts of particle size(both individual or agglomerated particles). In general, for risk assessment, the SAP reviewrecommended the need for a case-by-case evaluation of pesticide products containing nano-silver [22].OtherRegulationsThere are other environmental regulations that may play a key role in regulating the useanddisposal ofnanomaterials. TheComprehensiveEnvironmental Response, Compensa-tion, andLiabilityAct (CERCLA) andResourceConservationandRecoveryAct (RCRA)wouldbeusedtoevaluatetherisksofnanomaterialsatwastesites, althoughthishasnotyetbeenperformed[23].The1990CleanAirActAmendments(CAAA)[24]andthe1996Clean Water Act Amendments (CWAA) [25] would be used for regulation of nanomaterialsinambientairorambientwaterandwastewater. ForCAAA, thelevelstransportedinairwouldbe regulated basedon their danger to public health. TheCWAA wouldregulate theefuent limits of nanomaterials in the wastewater.Nano-ScaleMaterialsStewardshipProgram(NMSP)The Nano-scale Materials Stewardship Program (NMSP) [26] of the US EPAwas launchedin 2008 in order voluntarily to acquire information on the use and development of nanoma-terials. However, todate, limitedinformationhas beenacquiredthroughthis program.Following the rst year of the program, information on only approximately 100 nanomateri-als has been submitted, mostly from smaller companies with limited health and safety data.FoodSafetyandMedicalApplicationsTheFood, DrugandCosmeticAct (FDCA) hasbeenusedbytheFDAtoaddresstheimpact and use of nanomaterials in food, including additives and contaminants, medicinesandcosmetics[27]. TheFDCArequirespremarkettestingforfoodandcoloradditives, aswellasdrugs,butnotforcosmetics.TheFDAcanrequireinformationontheidentityandproperties of materials, regardless of the particle size of a material. The FDA also regulatescosmetics, including sunscreens, e.g. the use of nano-sized titanium dioxide and other nano-materials insunscreens. The FDAgenerallydoes not requirepremarket safetydataoncosmetics.There are currently no regulations specic for nanomaterials related to food or drug safety.Currently, all medical products that contain nanomaterials go through the traditional regu-latory process and include requirements for clinical, toxicological and other studies for deter-mining the safety and efcacy of these materials.ConsumerProductsThe use of nanomaterials in consumer products in the USA is under the oversight of theConsumer Product SafetyCommission(CPSC) [28]. TheCPSCmissionisprotectingthepublicfromunreasonablerisksof seriousinjuryordeathfromtheproductsundertheir6. NANOMATERIALREGULATION 104A.ENGINEEREDNANOMATERIALS:HAZARD,EXPOSUREANDSAFETY ASSESSMENTjurisdiction. Although there is no specic ruling for nanomaterials, if any of these productscontain nanomaterials, they would fall under the regulation of CPSC.OccupationalThe purpose of the Occupational Safety and Health Act of 1970 [29] is to assure safe andhealthyworkingconditionsinall occupational settings, generallybasedonrecommenda-tions from the National Institute for Occupational Safety and Health (NIOSH) and enforcedbytheOccupational SafetyandHealthAdministration(OSHA). Generally, occupationalexposure tonanomaterials falls under OSHAs General Industrystandards. OSHAhasapproved plans for 24 states to adopt federal safety standards for workers exposed to nano-materials in private industry [30].In 2011, NIOSH released a Current Intelligence Bulletin on the scientic hazards of occu-pational exposure to titanium dioxide (TiO2), including engineered nano-sized particles [31].This bulletin performed a risk assessment of the currently available scientic information onTiO2, including experimental animal toxicity and human health data, doseeresponse infor-mationandexposuremonitoringtechniquesandcontrol strategies. ThisNIOSHbulletinrecommendsexposurelimitsforbothneTiO2(2.4 mg/m3)andultraneTiO2(includingengineerednano-scaleTiO2; 0.3 mg/m3) astime-weightedaverage(TWA) concentrationsforupto10hoursperdayduringa40-hourworkweek. Further, NIOSHhascategorizedultraneTiO2as apotential occupational carcinogen, but therewas insufcient datatoconclude on carcinogenicity of ne TiO2.Recent examples of occupational exposures and human health effects reported in the liter-ature include two pulmonary disease occurrences in conjunction with exposure to nanoma-terials: workplaceexposurestomultiplechemicalswithlimitedventilationandpersonalprotectiveequipment[32]andexposuresofvolunteerstodustfollowingtheWorldTradeCenter collapse on September 11, 2001 [33]. Although limited, these are examples of potentialadverse human health effects following exposure to nanomaterials in the workplace.However, thesetwoexamplesdemonstratetheneedforclearinvestigationof thecausalfactors for theseevents whichcanprovideinsight intowhether productionanduseofnano-scale engineered materials are creating undue risk that needs to be controlled.EUROPEANUNIONThe main legal instrumentsin the European Union(EU) are Regulations andDirectives.AregulationisdirectlyapplicableinalltheMemberStates,whileaDirectiveisaddressedtotheMemberStatesandleavesthemthechoicehowtoadopttheCommunityobjectiveswithintheir national legal order. EUlegislationis accessible andsearchable on-line athttp://EUR-LEX.europa.eu/.With respect to regulatory aspects of nanomaterials within the EU, the Commission of theEuropeanCommunities(theEuropeanCommission) undertookin2008arst regulatoryreviewofEUlegislationinrelevantsectors.TheoutcomeisavailableinaCommunicationfrom2008 [34], which comes to the result that: Overall, it can be concluded that current legis-lation [in the EU] covers to a large extent risks in relation to nanomaterials and that risks canEUROPEANUNION 105A.ENGINEEREDNANOMATERIALS:HAZARD,EXPOSUREANDSAFETY ASSESSMENTbedealt withunderthecurrent legislativeframework. However, current legislationmayhavetobemodiedinthelight of newinformationbecomingavailable, forexampleasregards thresholds used in some legislation. It was recognized that knowledge on essentialquestions such as characterization of nanomaterials, their hazards, exposure, risk assessmentand risk management needs to be improved.Regulatory aspects of nanomaterials were also discussed in the European Parliament. Inits resolution of 2009 [12], the parliament considered it important to address nanomaterialsexplicitlywithinthescopeofcertainlegislationforareassuchaschemicals, biocidesandfood. BesidestheintroductionofadenitionofnanomaterialsinCommunitylegislation,the parliament called to compile an inventory of the different types and uses of nanomateri-als on the European market, and for better information to consumers on the use of nanoma-terials in consumer products: all ingredients present in the form of nanomaterials should beclearly indicated on the label of the product.The European Commission (July 2009) informed the Parliament that it intends to reviewrelevant legislation and instruments of implementation and will propose regulatory changeswhere necessary, agrees on the need to develop a denition, and intends to present informa-tion on types and uses of nanomaterials [35]. These reports are planned for the end of 2011.The following sectionsummarizes the main outcome of the above mentionedrstreview by the European Commission concerninglegislation relevant for health, safety andenvironment of nanomaterials [34], using also information from an accompanying Commis-sion staff working document [36], which provides additional details, and information fromother relevant documents, updated where necessary. Further reviews and other activities areexpected by 2011/2012, and thus the amount of information is increasing in a very dynamicway.ChemicalsIndustrialChemicalsThe REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals) Regu-lation[37]appliestochemicalsubstancesontheirown, inpreparationsorinarticles. Itisbased on the principle that manufacturers, importers and downstream users have to ensurethattheymanufacture, placeonthemarketorusesubstancesthatdonotadverselyaffecthuman health or the environment. Its provisions are underpinned by the precautionary prin-ciple. The European Chemicals Agency (ECHA) [38] based in Helsinki (Finland) is respon-sible for the implementation of REACH. Guidance documents [39] for industry andauthorities support the implementation.There are no provisions in REACH referring explicitly to nanomaterials. However, nano-materials are covered by the substance denition in REACH: Substance means a chem-ical element anditscompoundsinthenatural stateorobtainedbyanymanufacturingprocess, including any additive necessary to preserve its stability andany impurityderiving from the process used, but excluding any solvent which may be separated withoutaffecting the stability of the substance or changing its composition (Article 3 of the REACHRegulation). Thus, REACH addresses chemical substances, in whatever size, shape or phys-ical state [40]. Substances at the nano-scale are therefore covered by REACH and its provi-sions apply.6. NANOMATERIALREGULATION 106A.ENGINEEREDNANOMATERIALS:HAZARD,EXPOSUREANDSAFETY ASSESSMENTUnderREACH, manufacturersandimportershavetosubmit aregistrationdossiertoECHA for substances that they manufacture or import at or above 1 tonne per year. REACHhas staggered information requirements, increasing at the thresholds at or above 10, 100 and1000tonnes/year. At or above10tonnes/year, theregistrant is alsorequiredtosubmita chemical safety report.If a nanomaterial is considered to be a nanoform of a non-nano (bulk) substance, it can beregistered within the registration dossier of this substance; the dossier must then contain allrelevant information for all forms of the substance. The total volume (i.e. the sum of the nanoandthenon-nanovolume)determinestheneedandthetimingfortheregistrationandtheinformation requirements. The registration dossier has to include all relevant information onthe bulk and the nanomaterial covering the properties, uses, effects and exposure related infor-mation. REACH does currently not include specic information requirements for nanomateri-als; however, asthelistedinformationisstatedtobeminimuminformationrequirements(REACHArt. 12(1)) additional testingorinformationtodeterminethespecicpropertiesand hazards of the nanomaterial may therefore be required. Furthermore, standard test guide-lines may not be fully suitable for the testing of nanomaterials. The information on the nano-formneedsto be adequate for its Chemical Safety Assessment, if required (>10 tonnes/ga),as well as for the classication and labeling (according to CLP Regulation) [41]. Any differentclassicationandlabelingof thenanoformandadditional riskmanagement measures, ifneeded, have to be included in the registration dossier and have to be communicated to thesupply chain via the safety data sheet [42]. If a nanomaterial is considered to be a substanceon its own, a registration dossier addressing the nanomaterial needs to be submitted.While the content of the registrations dossier is the responsibility of the registrant(Industry), a minimum of 5% of the dossiers will be evaluated by ECHA to ensure compli-ancewithREACH(dossierevaluation). Furthermore, EUMemberStateAuthoritiesmayexamine any information on a substance (substance evaluation). If deemednecessary,ECHAcanrequireanyinformationonthesubstance, i.e. nanomaterial, inadditiontothestandardinformationrequirementsofREACH.AuthorizationsforsubstancesofveryhighconcernorrestrictionsforsubstanceswhichposeanunacceptableriskaretheregulatoryinstrumentsforriskmanagementunderREACH;theyareindependentfromtonnagetrig-gersorregistrationdutyandcouldthereforealsoapplytonanomaterialsoflowtonnagelevels as for any other substance.In conclusion, nanomaterials are substances and thus covered by the REACH Regulation,though there are no provisions in REACH referring explicitly to nanomaterials. Furthermore,there is currently no guidance for industry (or authorities) on how to implement REACH fornanomaterials. Therefore, the European Commission initiated REACHImplementationProjects for Nanomaterials (RIP-oNs) to provide scientic and technical advice on key aspectsoftheimplementationofREACHwithregardtonanomaterials,inparticularonsubstanceidentication, informationrequirements, andchemicalsafetyassessment. Thenalreportsof these projects canbe downloadedfromthe following website: http://ec.europa.eu/environment/chemicals/nanotech/index.htm#ripon. Theywillprovideadviceonhowthecurrent REACH guidance documents could be updated.As for all substances, REACHis fundamental to obtain information on properties,includinghazardousproperties, of nanomaterials, andtheCLPRegulationisessential totransfer this knowledgealongthesupplychain. TheresultinghazardidenticationhasEUROPEANUNION 107A.ENGINEEREDNANOMATERIALS:HAZARD,EXPOSUREANDSAFETY ASSESSMENTconsequencesformanyotherlegal instrumentssuchasoccupational andenvironmentallegislation.PlantProtectionProductsandBiocidalProductsThe placing on the EU market of Plant Protection Products (PPP) and Biocidal Products isregulated by the Plant Protection Product Regulation [43] and the Biocidal Products Directive[44]. ThePPPRegulationcoversclassicalpesticidessuchasinsecticidesandfungicidesused in agriculture by professional users. The Biocidal Products Directive covers 23 differentproducttypes, varyingfromdisinfectantstoantifoulingagentsandrodenticides, andthebiocidalproducts maybe usedby both professional users and by consumers. As PPPsandBiocidal Productscontainactivesubstances, whichduetotheirnaturehavethepotentialtobetoxicand/orecotoxic, theyareevaluatedandapprovedatEUlevel(i.e.inclusioninAnnexI). OnlyPPPsandBiocidal Productscontainingtheseapprovedactivesubstancescan be authorized.The Biocidal Products Directive uses the same and the PPP Regulation a similar substancedenition as REACH. Thus, both legal instruments address chemical substances, in whateversize, shape or physical state, and substances at the nano-scale are therefore covered.Nanomaterials could also be used as co-formulants in PPPs and Biocidal Products. Fullcompositionoftheproductsneedstobepresentedwhenapplyingforproductauthoriza-tion, andadditional data canbe requestedfor substances of concern, andcertainco-formulantscanbeprohibitedincaseofconcernforhumanandanimalhealthand/ortheenvironment.The implementation of the PPP Regulation on EU level is guided and monitored under theresponsibility of the European Food Safety Authority (EFSA) [45] located in Parma (Italy).ThescienticaspectsandtheevaluationoftheactivesubstancesfortheBiocidalProductsDirectiveiscurrentlymanagedbytheInstituteforHealthandConsumerProtectionoftheEuropeanCommissions Joint ResearchCentre(JRC-IHCP) [46], but will behandedover in the coming years to ECHA [38].In conclusion, nanomaterials are covered by the PPP Regulation and the Biocidal Prod-ucts Directive, although there are no provisions referring explicitly to nanomaterials. There-fore, current guidancedocuments (ondatarequirements, riskassessment anddecisionmaking) may need to be reviewedand amended where relevant in order to highlight thatthe legislative acts cover nanomaterials and to ensure that all aspects of risks of nanomate-rials are properly addressed. It should be mentioned that the Biocidal Products Directive iscurrently being reviewedandthe revisedversion is expectedspecically to addressnanomaterials.WorkerProtectionFramework Directive 89/391/EEC on the introduction of measures to encourage improve-ments in the safety and health of workers [47] places a number of obligations on employers totakemeasuresnecessaryforthesafetyandhealthprotectionof workers. It appliestoallsubstancesandworkactivitiesincludingmanufacturinganduseofchemicalsatalllevelsof the production process. Although this Directive does not specically address nanomateri-als, it fully applies to nanomaterials. Employers, therefore, must carry out a risk assessment6. NANOMATERIALREGULATION 108A.ENGINEEREDNANOMATERIALS:HAZARD,EXPOSUREANDSAFETY ASSESSMENTand, where a risk is identied, take measures to eliminate this risk. The Directive foresees thepossibility to adopt individual daughter Directives laying down more specic provisionswithrespect toparticularaspectsof safetyandhealth. Relevant directivesthusadoptedrelate, for example,to risks related tochemicalagentsatwork[48], theuseof workequip-ment by workers at work [49], and the use of personal protective equipment at the workplace[50]. Asthesedirectivesintroduceminimumrequirements, national authoritieshavethepossibility to introduce more stringent rules.Directive98/24/EContheprotectionofthehealthandsafetyofworkersfromtherisksrelatedtochemicalagents[48]isaimedatcontrollingandreducingoccupationalexposurerisks.Thisisachieved,amongothers, byestablishingindicativeandbindingoccupationalexposurelimit(OEL)values, aswellasbiologicallimitvaluesforspecicsubstances. Thetermoccupational exposurelimit valueisdenedintheDirective, article2(d), as.thelimitofthetime-weightedaverageoftheconcentrationofachemical agentintheairwithinthebreathingzoneofaworkerinrelationtoaspeciedreferenceperiod. Inthisdirectivethetermbiological limitvalueisdenedas. thelimitoftheconcentrationintheappropriatebiologicalmediumoftherelevantagent, itsmetabolite, oranindicatoreffect. WhileOELvaluesaddresstheconcentrationofthechemicalintheairinhaledbyworkers, thebiological limit isaninternal doseofachemical oritsmetaboliteforwhichtheroute ofentryisnotdened(soit maybeoral,dermaland/orinhalation).OELvaluesaregivenas8-hourstimeweightedaverageforairborneconcentrationsand/orasashort-termperiodof15minutes.Directive98/24/EChasbeenamendedseveraltimesincludinglistswithspecicsubstancesforwhichlimitvalueshavebeenagreed.SpecicOELvaluesfor nanoparticles do not yet exist. Currently, the limit values for amorphous silica(2e6 mg/m3)[51]andsilver[52]arealsoapplicabletotheirnanoforms,althoughitwouldberelevanttoconrmwhetherthesemass-basedOELsestablishedforbulksubstanceswould be appropriate for nanomaterials.The European Agency for Safety and Health at Work (EU-OSHA) [53] located in Bilbao inSpain, whichdealswithnanomaterialsandworkerprotectiononCommunitylevel, haspublishedaseries of expert forecasts onemergingrisks for theworkingenvironmentincludingareport onchemical risksrelatedtooccupational safetyandhealth[54]. Theexperts agreed that nanoparticles and ultrane particles pose the most signicant emergingrisk.Furthermore, EU-OSHAhas published a literature reviewon workplace exposure to nano-particles [55]. This report focuses on exposure measurements and assessments, health effectsof nanomaterials, and possible subsequent activities to manage the risk.ConsumerProductsProducts legislation lays down requirements regarding products, such as plant protectionproducts,biocidalproducts,cosmeticproductsandmedicalproducts.Consumerproductsnot coveredbyspecic regulations are coveredbythe Directive onGeneral SafetyofConsumerProducts[56]. Inmanycases, morethanonepieceoflegislationappliestothesame product. Where regulationcontains requirementsof a generalnature, theywill coveralsorisksrelatedtonanotechnology, eveniftheyhavebeenadoptedwithout specicallyintending to address risks associated with nanomaterials and nanotechnologies.EUROPEANUNION 109A.ENGINEEREDNANOMATERIALS:HAZARD,EXPOSUREANDSAFETY ASSESSMENTCosmeticProductsRegulationTheCosmeticProductsRegulationfromDecember2009istherst legal act intheEUwhichincludes specicprovisions for nanomaterials [57]. Most of theseprovisions willcome into force in 2013.Acosmeticproductmeansanysubstanceormixtureintendedtobeplacedincontactwiththeexternalpartsofthehumanbody(suchasskin,hair,nailsandlips)orwithintheoral cavitywithaviewtocleaning, perfuming, changingtheappearance, protectingorkeeping in good condition.The introduction of provisions specic to nanomaterials requires the adoption of a deni-tion. Thus, the new Cosmetic Products Regulation introduced the denition: nanomaterialmeansaninsolubleorbiopersistentandintentionallymanufacturedmaterial withoneormore external dimensions, or an internal structure, on the scale from 1 to 100 nm. This de-nitionmayberevisedinlinewiththeCommissionrecommendationonthedenitionofnanomaterial[16].Article16oftheRegulationconcernsnanomaterials.Cosmeticproductscontainingnanomaterialsshall benotied6monthspriortobeingplacedonthemarket.This notication shall contain additional information on the nanomaterial such as the spec-ication of the nanomaterial including size of particles; physical and chemical properties; anestimateofthequantityofnanomaterial containedincosmeticproducts; thetoxicologicalprole of the nanomaterial; safety data and the reasonably foreseeable exposure conditions.Furthermore, the Cosmetic Products Regulation includes a labeling obligation for ingredientspresent inthe formof nanomaterials, i.e. inthe list of ingredients the names of suchsubstances shall be followed by the word nano in brackets. This is not meant to be a hazardlabeling, but will allow consumers to make an informed choice.The Scientic Committee on Consumer Safety (SCCS) [58] provides guidance for the testingof cosmetic ingredients and their safety evaluation. The latest revision of its Notes of Guidance[59] addresses besides many other issues also basic requirements for nanomaterials.FoodLegislationRegulation178/2002laysdownthegeneral principlesandrequirements of foodlaw,establishes the European Food Safety Authority (EFSA) and applies horizontally to all foodsandfeed[60].Moreparticularlyrelevantinrelationtorisksassociatedwithnanomaterialsare the following Regulations and Directives: Novel Food Regulation No 258/97 concerning novel foods and novel food ingredients [61]NovelfoodisfoodnotconsumedtoanysignicantdegreeintheEUpriortoMay1997(whentherstNovelFoodslegislationenteredintoforce). Novelfoodcanbenewlydeveloped, innovativefood, foodproducedusingnewtechnologiesandproduction processes or food which has been traditionally consumed outside of the EU.A revision of the Novel Food Regulation from 1997, including specic requirements forfoodcontainingnanomaterials(suchasalabelingrequirement)wasdiscussed,buthasnotbeenendorsed. Food additivesDirective 89/107/EEC on food additives [62] covers substances added to food fora technological purpose inthe manufacture, processing, preparation, treatment, packaging,6. NANOMATERIALREGULATION 110A.ENGINEEREDNANOMATERIALS:HAZARD,EXPOSUREANDSAFETY ASSESSMENTtransport or storage of such food. Some of the currently used particulate food additives,such as anticaking powders (SiO2, CaCO3) may contain a fraction in the nano-size. Food supplementsFrameworkDirective2002/46/EC(anditsdaughterDirectives) onfoodsupplementsprovidesadenitionoffoodsupplements, specicrulesonlabeling, presentationandadvertisingof theseproductsandregulatestheircompositionsinvitaminsandminerals[63]. Positivelistsof vitaminsandmineralsandof theirsourcesthat canbeusedinfoodsupplementsaregivenintheAnnexesof theDirective. Priortotheauthorizationandinclusioninthepositivelists, everyvitaminandmineral and/oreverysourceneedstoundergoasafetyassessment carriedout byEFSA. It canbeenvisaged that substancesproducedin nanoformorpacked into nanoglobules (suchasvitamins) toimprovetheirsolubilityorbioavailabilitycouldbeusedasfoodsupplements. Food contact materialsRegulation (EC) 1935/2004 relates to materials and articles intended to come into contactwith food [64]. It covers also articles for contact with water intended for humanconsumption. Prior to authorization for their use in food contact materials substances needto undergo a safety assessment carried out by EFSA.Products deriving from nanotechnology seem to be promising for food contact materialssuch as materials with barriers or coatings against humidity, UV light or oxygen, orantibacterial materials. The new Regulation (EC) 10/2011 on plastic materials and articlesintended to come into contact with food [65] claries that authorizations which are basedon the risk assessment of the conventional particle size of a substance do not coverengineered nanoparticles. Nanoparticles risk should be assessed on a case-by-case basis.Nanoparticles are not covered by the functional barrier concept (i.e. the use of non-authorized substances behind a functional barrier, which separates the food from plasticby a multilayer material or article). An example for an authorized nanomaterial in a foodcontact material on the EU market is nano titanium nitrite for use in PET bottles up to20 ng/kg, with a dened primary particle size (20 nm).EFSA[45] haspublished a Guidanceon therisk assessmentof theapplication of nano-scienceandnanotechnologiesinthefoodandfeedchain[66]. Theguidancecoversriskassessmentsforfoodandfeedapplicationsincludingfoodadditives, enzymes, avorings,foodcontact materials, novel foods, feedadditives andpesticides. It concludes that theriskassessment paradigm(hazardidenticationandhazardcharacterizationfollowedbyexposureassessmentandriskcharacterization)isappropriatealsofornanomaterials. Thereport provides guidance on nano-specic considerations that need to be assessed in additionto conventional aspects. It stipulates the additional data needed for the physical and chemicalcharacterization of nanomaterials in comparison with conventional applications and outlinesdifferent toxicity testing approaches.Initsresolutionof6July2011, theEuropeanParliamentadoptednewrulestoprovidemore and better information to consumers so they can make informed choices when buyingfood[67]. Besidesinformationsuchasnutritionvalues, allergensorcountryoforigin, allingredientspresent intheformof engineerednanomaterialsshall beclearlyindicatedinthe list of ingredients. The names of suchingredients shall be followedby the wordEUROPEANUNION 111A.ENGINEEREDNANOMATERIALS:HAZARD,EXPOSUREANDSAFETY ASSESSMENTnano in brackets. Once the legislation is published in the EU Ofcial Journal, food compa-nies will have 3 years to adapt to most of the new rules.MedicinalProductsandMedicalDevicesNanotechnologyandnanomaterialsarepromisingfornewmedicinalproducts,medicaldevices,anddiagnosticagents.There are currently nospecicprovisionsfornano prod-uctsusedintheaboveareas. However, theusual comprehensivelegal frameappliesanddetailsarepublishedonthehomepageoftheEuropeanMedicinesAgency(EMA)[68]in London (UK). EMA has created an Innovation Task Force to ensure coordination of scien-tic and regulatory competence in the eld of emerging therapies and technologies,includingnanotechnologies, andtoprovideaforumforanearlydialoguewithapplicantson regulatory, scientic or other issues that may arise from the development. In the absenceof specic guidance, applicants are encouraged to contact the EMA from the early stages ofthe development of their products.EnvironmentalProtectionEnvironmental regulation relevant in this context relates in particular to integrated pollu-tion prevention andcontrol (IPPC), the control of major accident hazards involving dangeroussubstances (Seveso II), the water framework directive and a number of waste directives.The IPPC Directive [69] covers approximately 52 000 industrial installations across the EUandrequires installations fallingunder its scopetooperateinaccordancewithpermitsincluding emission limit values basedon the application of best available techniques(BAT). Inprinciple, theIPPCDirectivecouldbeusedtocontrolenvironmentalimpactsofnanomaterials.TheSevesoIIDirective[70]appliestocompanieswherenameddangeroussubstances(or substances falling within certain CLP classication categories) are present abovespecic quantities. It imposes a general obligationonoperators to take all measuresnecessarytoprevent major accidents andtolimit their consequences for humans andthe environment. If certainnanomaterials are foundto demonstrate a major accidenthazard, theymaybe categorized, together withappropriate thresholds, inthe contextoftheDirective.The Water Framework Directive 2000/60/EC [71] sets common principles and an overallframeworkforactiontoimprovetheaquaticenvironmentandprogressivelytoreducethepollutionfromprioritysubstances andphasingout emissions, discharges andlosses ofpriority hazardous substances to water. Nanomaterials could be included among the prioritysubstances depending on their hazardous properties. Environment Quality Standards wouldin these cases be proposed by the Commission.Directive 2006/12/EC on waste [72] sets the general framework and imposes an obligationon EU Member States to ensure that waste treatment does not adversely affect health and theenvironment. The Hazardous Waste Directive [73] denes which wastes are hazardous andlays down stricter provisions regarding such waste. Wastes containing nanomaterials couldbe classied as hazardous if the nanomaterial displays relevant properties which render thewaste hazardous.6. NANOMATERIALREGULATION 112A.ENGINEEREDNANOMATERIALS:HAZARD,EXPOSUREANDSAFETY ASSESSMENTTAKE-HOMEMESSAGESRisk assessment and regulation of nanomaterials would benet from continued efforts toaddress the many research needs remaining to inform the differential responses to nano-scalematerials in the environment. This includes comparative analysis of nanomaterials and theirmacroscalecounterpartsinbothstudiesforhumanhealthandtheenvironment. Furthercomparative analysis of various nanomaterials to each other may be necessary to understandwhich characteristics play a role in the toxic response to nanomaterials, and therefore shouldbe monitored in the production of new nanomaterials.As the use of nanomaterials increases rapidly, it is important that the ongoing researchis designed to address the risk assessment needs involving manufacture, use and disposalof nanomaterials. Riskassessment of nanomaterialsiscomplicatedbylimitedexposureandhazardinformation,noclear dosemetric andthelack ofcharacterizationof nanoma-terials in many early studies. There are clear data gaps in exposure assessment of nanoma-terials, particularly moving beyond occupational exposures [11]. Very limited informationis availableontheexposuretoconsumers throughtheuse, transport, anddisposal ofmultipleproducts.Thelackofadosemetricfortheanalysisoftoxiceffectsofnanomate-rialsisanotherlimitation. Onceariskassessment frameworkfornanomaterialscanbedesigned, it will bepossibletoconcludeontheadequacyof thelegislativeframeworkfornanomaterials.AcknowledgmentsThe authors wouldlike tothankBengt Fadeel, AntonioPietroiusti andAnnaShvedovafor the invitationtocontribute to this book. Furthermore, they are grateful to their colleagues in the USA and in Europe for their inputand useful suggestions, with special thanks to Kristen Rasmussen, Karin Aschberger, Hermann Stamm, BabasahebSonawane and Charles Ris.References[1] Organization for Economic Cooperation and Development (OECD) [homepage on the internet]. Paris: Safety ofManufactured Nanomaterials. Available at, http://www.oecd.org/about/0, 3347, en_2649_37015404_1_1_1_1_37465,00.html;[accessed27.07.11].[2] Organizationfor Economic CooperationandDevelopment (OECD) [publicationonthe Internet]. Paris:OECD2010. Guidance manual for the testing of manufactured nanomaterials: OECDs Sponsorshipprogramme; rst revision. ENV/JM/MONO(2009)20/REV. 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