TECHNICAL REPORT ISO/TR 18637 First edition 2016-12-01 Nanotechnologies — Overview of available frameworks for the development of occupational exposure limits and bands for nanoobjects and their aggregates and agglomerates (NOAAs) Nanotechnologies — Vue d’ensemble des cadres disponibles pour la définition de limites et bandes d’exposition pro fessionnelle applicables aux nano-objets, leurs agrégats et agglomérats (NOAA) Reference number ISO/TR 18637:2016(E) I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n © ISO 2016 ISO/TR 18637:2016(E) COPYRIGHT PROTECTED DOCUMENT © ISO 2016, Published in Switzerland All rights reserved Unless otherwise specified, no part o f this publication may be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting on the internet or an intranet, without prior written permission Permission can be requested from either ISO at the address below or ISO’s member body in the country o f the requester ISO copyright o ffice Ch de Blandonnet • CP 401 CH-1214 Vernier, Geneva, Switzerland Tel +41 22 749 01 11 Fax +41 22 749 09 47 copyright@iso.org www.iso.org ii I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n ISO/TR 18637:2016(E) Contents Page Foreword iv Introduction v Scope Normative references Terms and definitions Symbols and abbreviated terms Description of available processes for setting OELs and OEBs 5.1 General considerations 5.2 Description of evidence-based process 5.3 Substance-specific OELs 5.4 Categorical OELs 5.5 Initial or default occupational exposure bands Substance-specific OELs for nanomaterials 10 6.1 General overview 10 6.2 Available substance-specific OELs 10 6.2.1 Carbon nanotubes 10 6.2.2 Nanoscale TiO 11 6.2.3 Fullerenes 12 6.3 Evaluation of OEL methods 12 6.3.1 Similarities and differences 12 6.3.2 Influence o f methods on derived OEL values for nanomaterials 13 6.3.3 State of the science in support of risk assessment methods for nanomaterials OELs 14 Categorical OELs for nanomaterials 15 7.1 Summary o f options proposed 15 7.2 7.1.1 United Kingdom 15 7.1.2 Germany 15 7.1.3 NIOSH 17 7.1.4 Japan’s (AIST’s) approaches 17 7.1.5 OECD 18 Evaluation of categorical OEL 19 7.2.1 Similarities and differences 19 7.2.2 State of the science supporting categorical OELs 20 OEBs and control banding for nanomaterials 21 Overview of current hazard and control banding schemes 21 8.1.1 Comparison of hazard bands and OEBs as applied to inhaled NOAAs 22 8.1.2 ISO hazard banding scheme for NOAAs 25 8.2 Case studies on banding NOAAs 26 8.3 Evaluation of the evidence for initial (default) OEBs for categories of NOAAs 28 8.3.1 Categorical analyses and read-across 28 8.3.2 Utility o f in vitro data in OEL/OEB development for NOAAs 29 8.3.3 Options for deriving an OEL or OEB for NOAAs 30 Feasibility considerations in the OEL and OEB setting process 30 Annex A (informative) Standard processes for OEL setting 32 Bibliography 62 8.1 © ISO 2016 – All rights reserved I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n iii ISO/TR 18637:2016(E) Foreword I SO (the I nternational O rganiz ation for Standardiz ation) is a worldwide federation of national s tandards bodies (ISO member bodies) The work o f preparing International Standards is normally carried out through ISO technical committees Each member body interested in a subject for which a technical committee has b een es tablished has the right to b e represented on that committee I nternational organi zation s , governmental and non- governmental, in liaison with I SO, al so take p ar t in the work ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters o f elec trotechnical s tandardi z ation T he procedures used to develop this cument and those intended for its fur ther maintenance are describ ed in the I S O/I EC D irec tives , Par t I n p ar ticular, the different approval criteria needed for the di fferent types o f ISO documents should be noted This document was dra fted in accordance with the editorial ru les of the I SO/I E C D irec tives , Par t (see www iso org/direc tives) Attention is drawn to the possibility that some o f the elements o f this document may be the subject o f patent rights ISO shall not be held responsible for identi fying any or all such patent rights Details o f any patent rights identified during the development o f the document will be in the Introduction and/or on the I SO l is t of p atent declarations received (see www iso org/p atents) Any trade name used in this document is in formation given for the convenience o f users and does not cons titute an endorsement For an explanation on the meaning o f ISO specific terms and expressions related to formity assessment, as well as information about I SO ’s adherence to the World Trade O rganization ( WTO) principles in the Technical B arriers to Trade (TB T ) see the following URL: www iso.org/iso/foreword html T he comm ittee res p ons ible for this cument is I S O/ TC 2 9, iv I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n Nanotechnologies ISO/TR 18637:2016(E) Introduction Nano-objects and their aggregates and agglomerates (NOAAs) represent a subset o f particulate materials that can be dispersed in the air and can represent health risks via inhalation exposures NOAAs include structures with one, two or three external dimensions in the nanoscale from approximately nm to 100 nm, which may be spheres, fibres, tubes and others as primary structures NOAAs can consist o f individual primary structures in the nanoscale and aggregated or agglomerated structures, including those with sizes larger than 100 nm An aggregate comprises strongly bonded or fused particles (structures) An agglomerate is a collection o f weakly bound particles (structures) [1][2][3][4] The purpose of this document is to describe a general framework for the development of occupational exposure limits (OELs) or occupational exposure bands (OEBs) for individual NOAAs or categories of NOAAs with different levels of available data OELs and OEBs are important tools in the prevention o f occupational illness OELs have a long history in industrial hygiene and are based on observations o f workers or studies o f laboratory animals OELs are established to minimize the likelihood o f adverse e ffects from exposure to potentially hazardous substances in the workplace[5][6] An OEL is generally substance-specific (although sometimes generically expressed, such as dust) Su fficient data to develop an OEL may not be available, especially for substances such as NOAAs used in emerging technologies To aid in hazard communication and exposure control decisions for substances without OELs, hazard banding has been used for many years[7][8][9] Substances are assigned to a hazard band based on limited toxicity data usually from animal studies Hazard banding schemes typically consist o f qualitative bands ranging from low to high severity o f e ffects Thus, a hazard band represents a range o f potential toxicities for a particular substance or category o f substances Some hazard banding schemes include associated OEBs[10] The term OEB is a general term for exposure concentration ranges used in some hazard banding schemes that are related to the ranges of hazard potentials In contrast to an OEB, an exposure band is a range o f potential concentrations o f a substance (or category o f substances) to which workers may be exposed in a defined occupational scenario and which is based on factors such as the amount of NOAA processed or used, the nature of the process, and the form of the NOAA including dustiness[3] In control banding, the hazard band and the exposure band are combined to determine the control band for any particular occupational scenario (e.g ISO/TS 12901-2) OELs and OEBs are part o f an overall occupational sa fety and health (OSH) program and are not intended to identi fy and address all sa fety and health risks associated with a specific process or task OELs and OEBs are intended to provide occupational sa fety and health pro fessionals with a health basis for assessing the effectiveness of exposure controls and other risk management practices The exposure assessment of nanomaterials including carbon nanomaterials [such as fullerene, graphene, single-walled carbon nanotube (SWCNTs) and multi-walled carbon nanotube (MWCNTs)], metal oxides (TiO2 , SiO2 , zinc oxide, iron oxide), and metals (silver and gold nanoparticles) remains a challenge in the field o f occupational hygiene, as there have been relatively few studies on the characterization o f workplace exposures to NOAA Sampling and analytical methods that have the capabilities to accurately measure nanomaterials are still under development Most sampling devices that measure airborne particle count concentrations, such as condensation particle counters and optical particle counters, cannot differentiate ambient exposures to background nanoparticles from NOAA in the workplace environment Airborne measurements o f carbon nanotubes (CNTs) and carbon nanofibres (CNFs) using mobility particle sizers also sometimes could present a unique challenge due to the arcing caused by the charged airborne CNT and CNF agglomerates in the di fferential mobility analyser[11] Although several groups have attempted to measure and count CNT structures using transmission electron microscopy or other microscopic methods[12][13] , there are still no standard methods for measuring and counting CNT structures In addition, determining the mass concentration of CNTs and CNFs based on measuring the elemental carbon (EC) remains a challenge due to other sources of elemental carbon in the workplace, such as organic composite materials and air and diesel pollution that could interfere in the determination of CNT and CNF exposures Scientific and technical methodologies used to set exposure limits may di ffer from one entity to another, which can lead to disparities in worker protection from country to country[14] Therefore, harmonizing the scientific methodologies used in developing OELs, including using the best available evidence for interspecies extrapolation and speci fying the type o f data and uncertainties involved in the OEL determination is necessary for a robust health and sa fety evaluation framework for NOAAs © ISO 2016 – All rights reserved I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n v ISO/TR 18637:2016(E) T his cument provides a col lab orative, science-b ased platform to describ e and evaluate the s tate- ofthe-ar t in s uch data and metho ds Current risk assessment methods are likely to apply to NOAAs , although the l imited health haz ard data for many NOAAs and the considerable variety in the types o f manu factured NOAAs present a challenge to the e fficient development o f OELs for individual NOAAs To date, few OELs and OEBs have been developed for specific NOAAs and none have been formally regulated by a government agency [1 ] Standard OE L and OE B methodologies for NOA As are needed to evaluate the evidence on the hazard p otential of NOA As in the workplace to provide a health b as is for risk management decis ions , including selection and evaluation o f engineering control options One o f the goals o f this document is to identi fy both the similarities and di fferences in the methods used to develop OELs This evaluation may lead to improvements in metho ds for setting exp os ure l im its or b ands T his cument pres ents an over view of the s tate- of-the-ar t in the development of OE Ls and OE B s for NOAAs Current approaches for assigning de fault hazard bands in the absence o f NOAA-specific toxicity data are describ ed T hes e appro aches bui ld on c urrent hazard and control b anding s trategies , s uch as those develop ed in I SO/ TS 01-2 T he current s tate of the metho ds and data to develop OE Ls and OE B s for NOA As is describ ed in this cument, along with an evaluation of those metho ds used in developing the current OE Ls for NOA As C ategorical appro aches to derive OE B s for NOA As with limited data are also discussed, such as those based on biological mode-o f-action (MOA) and physico-chemical (PC ) prop er ties T he b as is for the framework describ ed in this cument is the U S N IO SH Current I ntel ligence B u l letin Nanomaterials [16 ] Approaches to Developing Occupational Exposure Limits or Bands for Engineered T his cument al so takes into cons ideration other s tate- of-the- science rep or ts , including outputs of the workshop “Strategies for S etting O ccup ational E xp os ure Limits for E ngineered Nanomaterial s ,” which was held on S ep temb er 10 -11 , 01 in Washington, D C , US A[6 ] and the OE C D Working Party on Manu factured Nanomaterials Expert Meeting on Categorization o f Manu factured Nanomaterial s , S ep temb er 17-19, 014 [17 ] The primary target audience o f this document is occupational sa fety and health pro fessionals in government, industry, and academia, who have the expertise to develop OELs or OEBs based on the guidance in this document I n addition, the evidence -b ased approach describ ed in this cument may be use ful in the evaluation and/or verification o f current hazard and control banding schemes and for identi fying the key data gaps Control banding requires in formation on both the applicable hazard category and exposure category Appropriately verified control banding tools would be broadly us efu l, as thes e to ols require les s s p ecialized exp er tise and resources (than for a comprehens ive risk as ses s ment) and are acces s ible to a wider group of individual s and s mal l bus ines ses T herefore, this document can be considered complementary to ISO/TS 12901-2 on control banding for nanomaterials as it describ es the s tate- of-the-ar t in the pro ces s of as s igning nanomaterials to hazard b ands/OE B s when the scientific evidence is not su fficient to develop an individual OEL Some o f the cited methods lead to results that are not necessarily consistent and this may be due to method selection biases o f the authors In these cases, diverse results will also make it di fficult to use in formation to confidently establish exposure and band levels It is beyond the scope o f this document to attempt to identi fy the methods which lead to both correct and consistent results In the event that metho ds lead to divers e res ults , it is hop ed that this rep or t wi l l lead to additional methods development that wi l l lead to improvements and that these improvements can b e rel ied on for setting exp os ure and b anding level s The objectives o f this document include a) des cribing an evidence-b ased s tate- of-the-ar t framework to develop OE Ls or OE B s for manufac tured NOA As , and b) examining the currently available data and other approaches and methods used (e.g benchmark s ub s tances and b enchmark exp os ure level s) in the o ccup ational risk management decis ion-making for NOA As I t is anticip ated that this cument wi l l contribute to the development of s tandard hazard and risk assessment methods and facilitate the systematic evaluation o f the potential health risk o f occupational exp os ure to NOA As vi I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n TECHNICAL REPORT ISO/TR 18637:2016(E) Nanotechnologies — Overview of available frameworks for the development of occupational exposure limits and bands for nano-objects and their aggregates and agglomerates (NOAAs) Scope This document provides an overview of available methods and procedures for the development of occupational exposure limits (OELs) and occupational exposure bands (OEBs) for manufactured nanoobjects and their aggregates and agglomerates (NOAAs) for use in occupational health risk management decision-making Normative references There are no normative references in this document Terms and definitions For the purposes o f this document, the terms and definitions given in following apply ISO/TS 80004-2 and the ISO and IEC maintain terminological databases for use in standardization at the following addresses: — IEC Electropedia: available at http://www.electropedia.org/ — ISO Online browsing platform: available at http://www.iso.org/obp 3.1 agglomerate collection o f weakly or medium strongly bound particles where the resulting external sur face area is similar to the sum of the surface areas of the individual components Note to entry: The forces holding agglomerates together are weak forces, for example, van der Waals forces or simple physical entanglement Note to entry: Agglomerates are also termed secondary particles and the original source particles are termed primary particles [SOURCE: ISO 26824:2013, 1.2] 3.2 aggregate particle comprising strongly bonded or fused particles where the resulting external sur face area is significantly smaller than the sum o f sur face areas o f the individual components Note to entry: The forces holding an aggregate together are strong forces, for example, covalent or ionic bonds, or those resulting from sintering or complex physical entanglement, or otherwise combined former primary particles Note to entry: Aggregates are also termed secondary particles and the original source particles are termed primary particles [SOURCE: ISO/TS 80004-2:2015, 3.5] © ISO 2016 – All rights reserved I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n ISO/TR 18637:2016(E) 3.3 bulk material material of the s ame chemical comp os ition as the NOA A, at a scale greater than the nanoscale 3.4 exposure contact with a chemical, phys ical or biological agent by s wallowing, breathing, or touching the skin or eyes N o te to entr y: E xp o s u re c a n b e s ho r t-ter m (ac ute e xp o s u re) , o f i nterme d i ate du ration , o r lo ng- ter m (ch ro n ic) 3.5 health hazard p otential source of harm to health [SOURC E: I SO 10 93 -17: 02 , ] 3.6 health risk combi nation o f the l i kel i ho o d o f o cc u rrence o f rm to he a lth and the s everity o f that rm [SOURC E: I SO 10 93 -17: 02 , 8] 3.7 nanofibre na no - obj e c t with two e xterna l d i men s ion s i n the na no s c a le and the th i rd d i men s ion s ign i fic antly larger N o te to entr y: T he l a rge s t e x ter n a l d i men s io n i s no t ne ce s s a r i l y i n the n a no s c a le N o te to entr y: T he ter m s n a no fibr i l a nd n a no fi l a ment c a n a l s o b e u s e d N o te to entr y: S e e N o te to entr y [SOURC E: I SO/ TS 0 -2 : 01 , ] 3.8 nano-object discrete piece of material with one, two or three external dimens ions in the nanoscale No te to entr y: T he s e cond and th i rd ex tern al d i men s ion s are or tho gon a l to the fi rs t d i men s ion and to e ach o ther [SOURC E: I SO/ TS 0 -1 : 010 , ] 3.9 nanoparticle na no - obj e c t with a l l e xterna l d i men s ion s i n the nano s c a le where the leng th s o f the longe s t and the shor te s t a xe s o f the nano - obj e c t no t d i ffer s ign i fic antly N o te to entr y: I f the d i men s ion s d i ffer s ign i fic a ntl y (typ ic a l l y b y more th a n ti me s) , term s s uch a s n a no fib re or n a nop l ate m ay b e pre fer re d to the ter m n a nop a r ticle [SOURC E: I SO/ TS 0 -2 : 01 , 4.4] 3.10 nanoscale leng th range approxi mately from n m to 10 n m N o te to entr y: P ro p er tie s th at a re no t e x trap ol ation s leng th range [SOURC E: I SO/ TS 0 -1 : 010 , 1] I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n from a l a rger s i z e a re p re dom i n a ntl y e x h ibite d i n th i s ISO/TR 18637:2016(E) 3.11 particle minute piece o f matter with defined physical boundaries Note to entry: A physical boundary can also be described as an inter face Note to entry: A particle can move as a unit Note to entry: This general particle definition applies to nano-objects [SOURCE: ISO 26824:2013, 1.1] 3.12 solubility maximum mass of a nanomaterial that is soluble in a given volume of a particular solvent under specified conditions Note to entry: Solubility is expressed in grams per litre o f solvent [SOURCE: ISO/TR 13014:2012, 2.27] 3.13 occupational exposure limit maximum concentration o f airborne contaminants deemed to be acceptable, as defined by the authority having jurisdiction [SOURCE: ISO 16972:2010, 3.133] 3.14 occupational exposure band quantitative representation of hazard band which describes hazard potential of a particular material or class of materials in workplace air 3.15 breathing zone space around the face of a worker from where he or she takes his or her breath [SOURCE: ISO 24095:2009, 3.1.2.1] Symbols and abbreviated terms ACGIH AGS AGW AIST BALF BAuA BEI BEL BMD BMDL American Con ference o f Governmental Industrial Hygienists Ausschuss für Gefahrstoffe (German Committee on Hazardous Substances) Arbeitsplatzgrenzwert (occupational exposure limit) Japanese National Institute o f Advanced Industrial Science and Technology bronchoalveolar lavage fluid Bundesanstalt für Arbeitsschutz und Arbeitsmedizin (German Federal Institute for Occu- pational Sa fety and Health) biological exposure index benchmark exposure level benchmark dose benchmark dose estimate, 95 % lower confidence limit © ISO 2016 – All rights reserved I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n ISO/TR 18637:2016(E) B SI B ritish Standards I ns titution C M AR carcinogenic, mutagenic, as thmagenic, or reproduc tive toxicant CNF carbon nanofibre CNT carb on nanotub e DFG D eutsche Forschungsgemeinschaft (G erman Research Foundation) DM E L derived minimum exp os ure level DN E L derived no - effec t level E PA United States Environmental Protection Agency EU Europ ean Union E U- O SH A European Agency for Sa fety and Health at Work GBP granu lar biop ers is tent p ar ticle GH S Globally Harmonized System o f Classification and Labelling o f Chemicals I ARC International Agency for Research on Cancer I FA Institut für Arbeitsschutz (German Institute for Occupational Sa fety and Health) I LV indicative limit value JSOH Japan Society for Occupational Health LC5 concentration associated with 50 % lethality LOAE L lowes t ob ser ved adverse effec t level M AK M a ximale Arb eits platzkonzentration (ma ximum workplace concentration) MOA biological mo de of ac tion MOE L Korean Ministry o f Employment and Labour M SH A United States Mine Sa fety and Health Administration M WC N T multi-wal led carb on nanotub e N IO SH United States National Institute for Occupational Sa fety and Health NOA As nano-objects, and their aggregates and agglomerates including those larger than 100 nm NOAE L no ob ser ved adverse effec t level N RV nano -reference value OEC D O rgani zation for E conomic C oop eration and D evelopment OE B o ccup ational exp os ure b and OE L o ccup ational exp os ure l imit OE L (PL) p eriod-l imited occup ational exp os ure limit I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n ISO/TR 18637:2016(E) Bibliography 762 8: 07, Workplace atmospheres — Ultrafine, nanoparticle and nano-structured aerosols — Inhalation exposure characterization and assessment [1] I S O/ TR [2 ] I SO/ TS 0 -2 : 01 , [3 ] I S O/ TS 01-2 : 014, [4] E ggersdor Nanotechnologies — Occupational risk management applied to engineered nanomaterials — Part 2: Use o f the control banding approach f er the gas phase [5 ] Nanotechnologies — Vocabulary — Part 2: Nano-objects M L , & P ratsinis Adv Powder Technol S.E Agglomerates and aggregates of nanop ar ticles made in pp 71–9 S ch ulte P A , M urashov V , Z um walde R , Kuempel E D , G eraci C L O ccup ational exp os ure J Nanopart Res limits for nanomaterial s: s tate of the ar t [6] 25 (1) 014, G ordon S C , B utal a J H , C arter J M , E lder 010 , A , G ordon 12 pp 19 71–19 87 T , G ray G Workshop rep or t: 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