Document 3JQOGkeZJyRJ24yQ6dv9pm8D6

Organisation for Economic Co-operation and Development Unclassified ENVIRONMENT DIRECTORATE CHEMICALS AND BIOTECHNOLOGY COMMITTEE ENV/CBC/MONO(2021)25 English - Or. English 9 July 2021 Reconciling Terminology of the Universe of Per- and Polyfluoroalkyl Substances: Recommendations and Practical Guidance Series on Risk Management No.61 JT03479350 OFDE This document, as well as any data and map included herein, are without prejudice to the status of or sovereignty over any territory, to the delimitation of international frontiers and boundaries and to the name of any territory, city or area. 2 ENV/CBC/MONO(2021)25 Unclassified ENV/CBC/MONO(2021)25 3 OECD Environment, Health and Safety Publications Series on Risk Management No. 61 Reconciling Terminology of the Universe of Per- and Polyfluoroalkyl Substances: Recommendations and Practical Guidance Environment Directorate ORGANISATION FOR ECONOMIC COOPERATION AND DEVELOPMENT Paris 2021 Unclassified 4 ENV/CBC/MONO(2021)25 About the OECD The Organisation for Economic Co-operation and Development (OECD) is an intergovernmental organisation in which representatives of 38 industrialised countries in North and South America, Europe and the Asia and Pacific region, as well as the European Commission, meet to co-ordinate and harmonise policies, discuss issues of mutual concern, and work together to respond to international problems. Most of the OECD's work is carried out by more than 200 specialised committees and working groups composed of member country delegates. Observers from several countries with special status at the OECD, and from interested international organisations, attend many of the OECD's workshops and other meetings. Committees and working groups are served by the OECD Secretariat, located in Paris, France, which is organised into directorates and divisions. The Environment, Health and Safety Division publishes free-of-charge documents in eleven different series: Testing and Assessment; Good Laboratory Practice and Compliance Monitoring; Pesticides; Biocides; Risk Management; Harmonisation of Regulatory Oversight in Biotechnology; Safety of Novel Foods and Feeds; Chemical Accidents; Pollutant Release and Transfer Registers; Emission Scenario Documents; and Safety of Manufactured Nanomaterials. More information about the Environment, Health and Safety Programme and EHS publications is available on the OECD's World Wide Web site (www.oecd.org/chemicalsafety/). This publication was developed in the IOMC context. The contents do not necessarily reflect the views or stated policies of individual IOMC Participating Organizations. The Inter-Organisation Programme for the Sound Management of Chemicals (IOMC) was established in 1995 following recommendations made by the 1992 UN Conference on Environment and Development to strengthen co-operation and increase international coordination in the field of chemical safety. The Participating Organisations are FAO, ILO, UNDP, UNEP, UNIDO, UNITAR, WHO, World Bank and OECD. The purpose of the IOMC is to promote co-ordination of the policies and activities pursued by the Participating Organisations, jointly or separately, to achieve the sound management of chemicals in relation to human health and the environment. Unclassified ENV/CBC/MONO(2021)25 15 This publication is available electronically, at no charge. Also published in the Testing and Assessment link For this and many other Environment, Health and Safety publications, consult the OECD's World Wide Web site (www.oecd.orgichemicalsafety/) or contact: OECD Environment Directorate, Environment, Health and Safety Division 2 rue Andre-Pascal 75775 Paris Cedex 16 France Fax: (33-1) 44 30 61 80 E-mail: @oecd.org OECD 2021 Applications for permission to re roduce or translate all or part of this material should be made to: Head of Publications Service, @oecd.org, OECD, 2 rue Andre-Pascal, 75775 Paris Cedex 16, France OECD Environment, Health and Safety Publications Unclassified 6 ENV/CBC/MONO(2021)25 Acknowledgements: This report was prepared under the framework of the OECD/UNEP Global PFC Group and developed with financial support of Switzerland. In particular, the report was prepared by a writing group of the following members, led by Zhanyun Wang (ETH Zrich, Switzerland) and benefited from the review and input of other members of the group: Robert C. Buck (Chemours), Andreas Buser (Swiss Federal Office for the Environment), Ian T. Cousins (Stockholm University, Sweden), Silvia Demattio (European Chemicals Agency), Wiebke Drost (German Environment Agency), Audun Heggelund (Norwegian Environment Agency), Olof Johansson (Swedish Chemicals Agency), Eeva Leinala (OECD), Koichi Ohno (National Institute for Environmental Studies, Japan), Grace Patlewicz (US EPA), Ann Richard (US EPA), Simone Schalles (German Environment Agency), Glen Walker (Australian Department of Agriculture, Water and the Environment), Graham White (Health Canada), with earlier contributions by Urs Berger (UFZ, Germany), Stellan Fischer (Swedish Chemicals Agency) and Laurence Libelo (US EPA). The report is published under the responsibility of the OECD Chemicals and Biotechnology Committee. The OECD Per- and Polyfluoroalkyl Substances (PFAS) project has been produced with the financial assistance of the European Union. The views expressed herein can in no way be taken to reflect the official opinion of the European Union. Unclassified ENV/CBC/MONO(2021)25 7 Executive Summary This report summarizes recent efforts by the OECD/UNEP Global PFC Group between June 2018 and March 2021 in reviewing the universe and terminology of per- and polyfluoroalkyl substances (PFASs) to provide recommendations and practical guidance to all stakeholders with regard to the terminology of PFASs. In particular, this report highlights (1) a revised PFAS definition to comprehensively reflect the universe of PFASs and a comprehensive overview of the PFAS universe (Chapter 2), (2) practical guidance on how to use the PFAS terminology (Chapter 3), (3) a systematic approach to characterization of PFASs based on molecular structural traits to assist stakeholders, including non-experts, in making their own categorization based on their needs (Chapter 4), and (4) areas in relation to the PFAS terminology that warrant further development (Chapter 5). It should be noted that this report does not address the nomenclature and understanding of individual PFASs, including the sources of exposure and the actual composition of commercial products. PFASs comprise a class of synthetic compounds that have attracted much public attention since the late 1990s and early 2000s, when the hazards and ubiquitous occurrence of two PFASs, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS), started to be reported and recognized. Since then, research and risk management measures have expanded from these two PFASs to a wider range of PFASs. Early communications used many different terminologies (e.g. per- and polyfluorinated chemicals, perfluorinated organics, perfluorochemical surfactants, highly fluorinated compounds). In 2011, to unify and harmonize communication on PFASs, Buck et al. published a milestone paper, providing a first clear structural definition of PFASs and recommendations on names and acronyms for over 200 individual PFASs. Currently, there is a growing interest by regulators and scientists across the globe to assess legacy and novel PFASs. In 2018, the OECD/UNEP Global PFC Group prepared a new list of PFASs that may have been on the global market. In total, a set of substances with over 4730 CAS numbers have been identified, including substances that contain such fully fluorinated carbon moieties, but do not meet the PFAS definition in Buck et al. (2011) due to a lack of a -CF3 group in the molecular structures. In addition, recent advancement of non-target screening analytical techniques using high-resolution mass spectrometry has enabled identification of many unknown substances in different environmental and product samples. The identification of these substances motivates the present work to reconcile the terminology of the universe of PFASs, including a renewed look at the PFAS definition in Buck et al. (2011). It is key to have a coherent and consistent logic behind the PFAS definition to adequately reflect all compounds with the same structural traits, i.e. the PFAS universe. Building on the OECD 2018 PFAS List and recent non-target screening studies, Chapter 2 first identifies four major gaps in the previous PFAS definition by Buck et al. (2011) in representing the PFAS universe. Then, Chapter 2 recommends a revised PFAS definition, with detailed elaboration on individual changes provided: PFASs are defined as fluorinated substances that contain at least one fully fluorinated methyl or methylene carbon atom (without any H/Cl/Br/I atom attached to it), i.e. with a few noted exceptions, any chemical with at least a perfluorinated methyl group (-CF3) or a perfluorinated methylene group (-CF2-) is a PFAS. The rationale behind the revision is to have a general PFAS definition that is coherent and consistent Unclassified 8 ENV/CBC/MONO(2021)25 across compounds from the chemical structure point of view and is easily implementable for distinguishing between PFASs and non-PFASs, also by non-experts. The decision to broaden the definition compared to Buck et al. is not connected to decisions on how PFASs should be grouped in regulatory and voluntary actions. Based on the revised definition of PFASs, Chapter 2 further illustrates (1) how PFASs fit into organofluorine compounds, (2) a comprehensive overview of PFAS groups, their structural traits, examples and notes on whether common nomenclatures (including acronyms) exist for them, and (3) some common synthesis routes of different individual or groups of PFASs. As PFASs are a chemical class with diverse molecular structures and physical, chemical and biological properties, it is highly recommended that such diversity be properly recognized and communicated in a clear, specific and descriptive manner. The term "PFASs" is a broad, general, non-specific term, which does not inform whether a compound is harmful or not, but only communicates that the compounds under this term share the same trait for having a fully fluorinated methyl or methylene carbon moiety. In particular, Chapter 3 provides practical guidance to governments and other stakeholders on how to use the PFAS terminology, starting from the distinction between the general definition and user-specific working scopes of PFASs. In particular, the general definition of PFASs is based on molecular structure alone and serves as a starting and reference point to guide individual users to have a comprehensive understanding of the PFAS universe and to keep the big picture of the PFAS universe in mind. At the same time, individual users may define their own working scope of PFASs for specific activities according to their specific needs by combining the general definition of PFASs with additional considerations (e.g. specific properties, use areas). This report does not make any recommendation on how working scopes should be set up, in terms of which factors to be considered (which depends highly on specific local context), nor on PFAS grouping. However, when a working scope of PFASs is used, this report highly recommends that users clearly provide the context and rationale for selecting their PFAS working scope in order to provide transparency and avoid confusion by others. Further, the report recommends to use and build upon existing common terminologies such as in this report, in Buck et al. (2011) and common practices in organic chemistry as set by IUPAC and CAS, unless it is essential to deviate from existing naming conventions, in order to keep the consistence and coherence of the PFAS terminology. As users often define their own working scope of PFASs according to their specific needs, they need to characterize PFASs based on pre-defined traits and categorize them (e.g. whether a compound with certain traits falls or does not fall into their working scope). However, given the high complexity and diversity of PFASs, it can be a challenging task to characterize and categorize PFASs based on chemical structures in a coherent and consistent manner, particularly for non-experts. In addition, different users may have very different needs, and there is no single categorization/grouping system that can meet all needs. Therefore, Chapter 4 provides a standardized approach for systematic characterization of different PFASs based on molecular structural traits that will allow stakeholders to make their own categorization in a coherent and consistent manner. In addition to the manual application of the system to characterize and categorize PFASs, the elements presented here may also be used as inputs for developing cheminformatic tools that would allow automated characterization and categorization of PFASs. While this report makes advancement on several important points regarding PFAS terminology and practical guidance of how to use the PFAS terminology, Chapter 5 also recognizes four areas that warrant further work, in order to facilitate clear and unambiguous communication of PFASs and Unclassified ENV/CBC/MONO(2021)25 9 beyond: (1) a centralized PFAS nomenclature database/platform; (2) further development of cheminformatics-based tools for automated systematic characterizing and categorizing PFASs; (3) further work on the characterization and reporting of polymers; and (4) work on organofluorine compounds other than PFASs including many fluorinated aromatics. Unclassified 10 ENV/CBC/MONO(2021)25 List of Acronyms ADONA Br CAS CAS Nos. Cl CTFE ECHA ETFE EU FASAs FASEs FEP FPs FTABs FTEOs FTIs FT(MA)ACs FTOs FTOHs FTSAs HFCs HFEs HFOs HFP HFPO HFPO-DA H I ICCM InChI InChIKey ITRC IUPAC OBS OECD PACFs Ammonium 4,8-dioxa-3H-perfluorononanoate Bromine atom Chemical Abstracts Service Chemical Abstracts Service registry numbers Chlorine atom Chlorotrifluoroethylene European Chemicals Agency Ethylene-tetrafluoroethylene copolymer European Union Perfluoroalkane sulfonamides Perfluoroalkane sulfonamidoethanols Fluorinated ethylene propylene co-polymer Fluoropolymers Fluorotelomer sulfonamide alkylbetaines Fluorotelomer ethoxylates Fluorotelomer iodides Fluorotelomer (meth)acrylates Fluorotelomer olefins Fluorotelomer alcohols Fluorotelomer sulfonic acids Hydrofluorocarbons Hydrofluoroethers Hydrofluoroolefins Hexafluoropropylene Hexafluoropropylene oxide Hexafluoropropylene oxide dimer acid Hydrogen atom Iodine atom International Conference on Chemicals Management International chemical identifier A hashed version of the full InChI Interstate Technology & Regulatory Council in the United States International Union of Pure and Applied Chemistry Sodium p-perfluorous noenoxybenzenesulfonate Organisation for Economic Co-operation and Development Perfluoroalkanoyl fluorides Unclassified PASFs PCTFE PFA PFAAs PFAIs PFASs PFCAs PFdiCAs PFdiSAs PFECAs PFEI PFESAs PFHxS PFOA PFOS PFPAs PFPEs PFPIAs PFSAs PFSIAs PolyFCAs PolyECAs PolyESAs POPs POSF PPVE PTFE PVDF PVF REACH SaMPAPs SFAs SMILES TFE THV UNEP VDF ENV/CBC/MONO(2021)25 11 Perfluoroalkane sulfonyl fluorides Polychlorotrifluoroethylene Perfluoroalkoxyl polymer Perfluoroalkyl acids Perfluoroalkyl iodides Per- and polyfluoroalkyl substances Perfluoroalkyl carboxylic acids Perfluoroalkyl dicarboxylic acids Perfluoroalkane disulfonic acids Perfluoroalkylether carboxylic acids Perfluoroethyl iodide Perfluoroalkylether sulfonic acids Perfluorohexane sulfonic acid Perfluorooctanoic acid Perfluorooctane sulfonic acid Perfluoroalkyl phosphonic acids Perfluoropolyethers Perfluoroalkyl phosphinic acids Perfluoroalkane sulfonic acids Perfluoroalkane sulfinic acids Polyfluoroalkyl carboxylic acids Polyfluoroalkylether carboxylic acids Polyfluoroalkylether sulfonic acids Persistent Organic Pollutants Perfluoroctane sulfonyl fluoride Perfluoropropylvinyl ether Polytetrafluoroethylene Polyvinylidene fluoride Polyvinyl fluoride Registration, Evaluation, Authorisation and Restriction of Chemicals (EC 1907/2006) Perfluorooctane sulfonamidoethanol phosphate esters Semifluorinated alkanes Simplified molecular input line entry specification Tetrafluoroethylene Terpolymer of tetrafluoroethylene, hexafluoropropylene and vinylidene fluoride United Nations Environment Programme Vinylidene fluoride Unclassified 12 ENV/CBC/MONO(2021)25 Table of contents 1. Background, motivation and scope ......................................................................................13 2. Reconciling Terminology of the Universe of PFASs ...........................................................16 2.1. The previous PFAS definition in Buck et al. (2011) .........................................................16 2.2. Gaps in the previous PFAS definition by Buck et al. (2011) ............................................16 2.3. A revised PFAS definition ................................................................................................18 2.4. A comprehensive overview of the PFAS universe............................................................21 3. Practical Guidance on How to Use the PFAS Terminology...............................................25 3.1. Distinction between the General Definition and User-Specific Working Scopes of PFASs ....................................................................................................................................... 25 3.2. Practical guidance on how to identify and use suitable PFAS terms ................................26 4. Systematic characterization and categorization of PFASs.................................................29 5. Areas for Future Work..........................................................................................................33 References ................................................................................................................................... 34 FIGURES Figure 1. PFOA and examples of substances with similar molecular structures, but having functional groups (including single atoms such as hydrogen) on both ends of the perfluoroalkanediyl moiety. 16 Figure 2. PFOS, an example of a cyclic PFSA, and a shorter-chain homologue of the cyclic PFSA 17 Figure 3. 6:2 FTOH, and a 6:2 fluorotelomer iodide derivative with one aromatic ring in the functional group 17 Figure 4. 6:2 FTOH and two 6:2 fluorotelomer derivatives, and their corresponding fluorine contents 17 Figure 5. Examples of PFASs. The fully fluorinated methyl or methylene carbon atoms are highlighted in red. 19 Figure 6. Examples of compounds that are not PFASs due to a lack of fully fluorinated methyl or methylene carbon atoms. 20 Figure 7. An example of side-chain fluorinated aromatics. 21 Figure 8. An illustrative scheme of how PFASs fit into the universe of organofluorine compounds 22 Figure 9. A comprehensive overview of PFAS groups, their structural traits, examples and notes on whether corresponding common nomenclatures (including acronyms) exist. 23 Figure 10. An overview of some common synthesis routes of different individual or groups of PFASs based on publicly accessible source 24 Figure 11. A visual guide to identify the best terms to use for a specific statement with four examples (increasing level of specificity illustrated with same colour within examples). 27 TABLES Table 1. Examples of ambiguous statements and associated good practices of using more specific PFAS terminology to refine these statements 27 Table 2. Molecular structure-based elements of a characterization system for PFASs. 30 Table 3. Examples using the proposed characterization system. 32 Unclassified ENV/CBC/MONO(2021)25 13 1. Background, motivation and scope The OECD/UNEP Global PFC1 Group was established to respond to the Resolution II/5 adopted at the second session of the UN International Conference on Chemicals Management (ICCM 2) in 2009, which calls upon intergovernmental organizations, governments and other stakeholders to "consider the development, facilitation and promotion in an open, transparent and inclusive manner of national and international stewardship programmes and regulatory approaches to reduce emissions and the content of relevant perfluorinated chemicals of concern in products and to work toward global elimination, where appropriate and technically feasible". Further work on this resolution was reaffirmed in Resolution III/3 adopted at ICCM 3 in 2012 noting that a significant need remains for additional work to support implementation of Resolution II/5. This report is prepared within the framework of the Group. For more details on the Group and its work, see the OECD PFAS web portal (https://oe.cd/2M9). This report summarizes recent efforts by the OECD/UNEP Global PFC Group between June 2018 and March 2021 in reviewing the universe and terminology of per- and polyfluoroalkyl substances (PFASs2) to provide recommendations and practical guidance to all stakeholders (governments, industry, academia, civil society organizations, etc.) regarding the terminology of PFASs. In particular, this report highlights (1) a revised PFAS definition to comprehensively reflect the universe of PFASs and a comprehensive overview of the PFAS universe (Chapter 2), (2) a practical guidance on how to use the PFAS terminology, from a general PFAS definition to userspecific working scopes to naming conventions of individual PFASs (Chapter 3), (3) a systematic approach to characterization of PFASs based on molecular structural traits to assist stakeholders, including non-experts, in making their own categorization based on their needs (Chapter 4), and (4) areas in relation to the PFAS terminology that warrant future work (Chapter 5). It should be noted that this report does not address the nomenclature and understanding of individual PFASs, including the sources of exposure and the actual composition of commercial products. It also does not address organofluorine compounds other than PFASs. PFASs comprise a class of synthetic compounds that have attracted much public attention since the late 1990s and early 2000s, when the hazards and ubiquitous occurrence of two PFASs, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS), started to be reported and recognized. Since then, research and risk management measures have expanded from these two PFASs to a wider range of PFASs [e.g. 3M's voluntary global phase-out of C6-10 perfluoroalkane sulfonic acids (PFSAs), PFOA and related chemistries in 2000-2002]. It is noted that early communications 1 "PFCs" here refer to "per- and polyfluorinated chemicals", and not to "perfluorocarbons". As stated below, "per- and polyfluorinated chemicals" was a term commonly used before the term "per- and polyfluoroalkyl substances" was recommended by Buck et al.. As it is part of the Group official name, it remains unchanged. 2 This report uses the acronym "PFASs" for "per- and polyfluoroalkyl substances" as stated in Buck et al. (2011), and its corresponding singular form "PFAS" refers to either a perfluoroalkyl or polyfluoroalkyl substance. It is noted that there is a notion of using "PFAS" as the acronym for both the singular and plural forms. This report does not make any recommendation to address this notion, as it is a trivial point that is difficult for everyone to comprehend, particularly for non-PFAS experts and non-English native speakers. While recognizing that readers may make their own decision which acronym they would use, this report encourages readers to always use the acronym consistently in their documents (for more details on practice guidance on how to identify and use the PFAS terminology, see Section 3.2 below). Unclassified 14 ENV/CBC/MONO(2021)25 used many different terminologies (e.g. per- and polyfluorinated chemicals, perfluorinated organics, perfluorochemical surfactants, highly fluorinated compounds). In 2011, to unify and harmonize communication on PFASs, Buck et al. published a milestone paper on a first comprehensive overview of PFASs detected in the environment, wildlife, and humans. It provided a first clear structural definition of PFASs. A particular emphasis of Buck et al. (2011) was placed on long-chain perfluoroalkyl acids [PFAAs, i.e., perfluoroalkyl carboxylic acids (PFCAs) with seven or more perfluorinated carbons and PFSAs with six or more perfluorinated carbons]3, substances related to the long-chain PFAAs, and substances intended as alternatives to the long-chain PFAAs or their precursors4. In addition, Buck et al. (2011) provided a list of 42 families and subfamilies5 of PFASs and 268 selected individual compounds, including recommended names and acronyms, structural formulas, and Chemical Abstracts Service registry numbers (CAS Nos.). Today, several long-chain PFAAs have been recognized as global contaminants of high concern. For example, PFOS, its salts, and perfluorooctane sulfonyl fluoride (POSF6), as well as PFOA, its salts, and PFOA-related compounds have been listed under the Stockholm Convention on Persistent Organic Pollutants (POPs) for global actions. In addition, the POPs Review Committee to the Stockholm Convention decided in 2019 to recommend that the Conference of the Parties to the Stockholm Convention consider listing perfluorohexane sulfonic acid (PFHxS, C6 PFSA), its salts and PFHxS-related compounds at its tenth meeting. In response to these actions, an industrial transition has taken place to replace long-chain PFAAs and their precursors with alternative chemicals, many of which are still PFASs, including short-chain PFAAs and their precursors as well as perfluoroalkylether-based substances (for examples, see Buck et al., 2011, Wang et al., 2013, 2016 and references therein). It is noted that there is a growing interest by regulators7 and scientists across the globe to assess legacy and novel PFASs other than long-chain PFAAs and their well-known precursors. In particular, various efforts have been made to identify overlooked PFASs. In 2018, the OECD/UNEP Global PFC Group prepared a new list of PFASs8 that may have been 3 Note that the definition of "long-chain PFAAs" here is based on the OECD definition (https://www.oecd.org/chemicalsafety/portal-perfluorinated-chemicals/aboutpfass/), and the definitions of "long-chain PFAAs" may differ by jurisdiction. 4 PFAA precursors refer to chemicals that can transform and form PFAAs in the environment and biota. 5 Note that in the literature, some authors have used other taxonomy terminologies, e.g. "groups and subgroups" instead of "families and subfamilies". This report does not propose a new taxonomy terminology for PFASs, but makes some practical guidance on how to use taxonomy terminologies (see Chapter 3 below). 6 Note that the acronym "POSF" here is used in accordance with the recommendations by Buck et al. (2011), whereas under the Stockholm Convention, another acronym "PFOSF" is used. 7 For example, five European Union (EU) member states have agreed to prepare a joint REACH restriction proposal to limit the risks to the environment and human health from the manufacture and use of a wide range of PFASs, and thus launched a public call for evidence in May 2020 with regard to substances that contain at least one aliphatic -CF2- or -CF3 element. For more details, see https://echa.europa.eu/hottopics/perfluoroalkyl-chemicals-pfas. In addition, multiple PFASs other than long-chain PFAAs and their precursors are listed in ECHA's Public Activities Coordination Tool (PACT) to be assessed by ECHA or EU member states (https://echa.europa.eu/pact). 8 The Excel Spreadsheet version of the OECD 2018 PFAS list can be found at https://www.oecd.org/chemicalsafety/risk-management/global-database-of-per-and-polyfluoroalkylsubstances.xlsx. In addition, several other entities have curated the OECD 2018 PFAS list into their databases, with features such as an easier overview of chemical structures and links to other information, including the US EPA CompTox Chemicals Dashboard (https://comptox.epa.gov/dashboard/chemical_lists/PFASOECD), Unclassified ENV/CBC/MONO(2021)25 15 on the global market using a systematic search of substances that have a -CnF2n- (n 3) or -CnF2nOCmF2m- (n and m 1) moiety in different publicly accessible sources. In total, a set of substances with over 4730 CAS Nos. have been identified, including substances that contain fully fluorinated carbon moieties and are structurally similar to or related to commonly known PFASs [e.g. perfluoroalkyl dicarboxylic acids (PFdiCAs) to PFCAs], but do not meet the PFAS definition in Buck et al. (2011) due to a lack of a -CF3 group in the molecular structures (for more details, see Section 2.2). Meanwhile, recent advancement of non-target screening analytical techniques using high-resolution mass spectrometry has enabled identification of many unknown substances in different environmental and product samples [e.g. H-(CF2CH2)n- CF2COOH by Newton et al. (2017)]. The identification of overlooked PFASs motivates the present work to reconcile the terminology of the universe of PFASs, including a renewed look at the PFAS definition in Buck et al. (2011) (see Chapter 2). In light of these newly identified substances and building on existing common terminology provided in Buck et al. (2011), this report and others, this report also looks into practical guidance on how to use the PFAS terminology, including uses of user-specific working scopes (see Chapter 3). In addition, the OECD 2018 PFAS List and recent non-target screening studies show the complexity and diversity of the PFAS universe, resulting in challenges for non-experts in conducting their own categorization of PFASs based on molecular structures. Therefore, this report also looks into systematic approaches to characterization and categorization of PFASs to assist stakeholders in making their own categorization based on their needs (see Chapter 4). Further, this report highlights open questions in relation to PFAS terminology for future consideration (see Chapter 5). NORMAN Network (https://www.norman-network.com/?q=suspect-list-exchange) and PubChem (https://pubchem.ncbi.nlm.nih.gov/classification/#hid=101). In addition, the US EPA CompTox Chemicals Dashboard also provides a number of other PFAS lists intended to address different research and regulatory interests, including PFASSTRUCT that is compiled from all the records with a structure assigned in the Dashboard using a pre-defined set of substructural filters and contains over 8000 compounds, as of 23 November, 2020 (for more details including the list of substructural filters, see https://comptox.epa.gov/dashboard/chemical_lists/PFASSTRUCT). Note that these lists may also include substances that are not regarded as PFASs in accordance with the revised PFAS definition below. Unclassified 16 ENV/CBC/MONO(2021)25 2. Reconciling Terminology of the Universe of PFASs 2.1. The previous PFAS definition in Buck et al. (2011) In Buck et al. (2011), PFASs were defined as "the highly fluorinated aliphatic substances that contain 1 or more C atoms on which all the H substituents (present in the nonfluorinated analogues from which they are notionally derived) have been replaced by F atoms, in such a manner that they contain the perfluoroalkyl moiety CnF2n+1-" (i.e. must contain at least -CF3). The definition highlights the presence of at least one fully fluorinated saturated carbon atom in the PFAS molecules. 2.2. Gaps in the previous PFAS definition by Buck et al. (2011) It is key to have a coherent and consistent logic behind the PFAS definition to reflect all compounds with shared structural traits, i.e. the PFAS universe. Building on the OECD 2018 PFAS List and recent non-target screening studies, this section identifies gaps in the previous PFAS definition by Buck et al. (2011) in representing the PFAS universe. Note that the gaps identified in this report are not exhaustive and additional gaps in the PFAS definition may be identified in the future; therefore, an iterative approach is guaranteed to ensure the consistency between the PFAS universe and terminology when new knowledge of gaps in the PFAS definition is generated. Case 1: The fully fluorinated saturated carbon moiety9 is connected with functional groups on both ends, including having a single H/Br/Cl atom on one end. As such, it does not meet the structural requirement of "-CnF2n+1" in the previous definition. In the example of a1 in Figure 1, it is a PFdiCA with a similar structure to PFCAs (e.g. PFOA in the example of A in Figure 1), but having carboxylic groups on both ends of the perfluoroalkanediyl moiety. In addition, for the example of a2 in Figure 1, it would meet the previous definition if the H atom was moved to a secondary carbon atom (i.e. CF3CFHCF2CF2CF2CF2CF2COOH, a positional isomer). Figure 1. PFOA and examples of substances with similar molecular structures, but having functional groups (including single atoms such as hydrogen) on both ends of the perfluoroalkanediyl moiety. Furthermore, functionalized fluoropolymers and perfluoropolyethers10 (i.e. those that have functional groups on both ends of the polymer backbone, e.g. Fomblin HC/P2 100011) do not meet the structural requirement of "-CnF2n+1" in the previous definition, 9 Note that a "saturated carbon moiety" means no unsaturated bonds occurring in the moiety, including double bond (=), triple bond () or aromatic rings, and thus, a saturated carbon moiety is always considered aliphatic. 10 According to Buck et al., fluoropolymers are "carbon-only polymer backbone with F directly attached to backbone C atoms", whereas perfluoropolyethers are "ether polymer backbone with F atoms directly attached" (i.e. having -C-O-C- moieties on the polymer backbone). 11 (HO)2(O)PO-(CH2CH2O)n-CH2CF2-(OCF2)p-(OCF2CF2)q-OCF2CH2-(OCH2CH2)n-OP(O)(OH)2; Trier X, Granby K, Christensen JH. Polyfluorinated surfactants (PFS) in paper and board coatings for food packaging. Environ Sci Pollut Res Int. 2011;18(7):1108-1120. doi:10.1007/s11356-010-0439-3 Unclassified ENV/CBC/MONO(2021)25 17 whereas their closely related analogues with only fluorine atoms on each end of the polymer backbone would meet the previous definition. Case 2: The substance is a fully fluorinated aliphatic cyclic compound which may or may not have a fully fluorinated alkyl side chain. As such, it may not meet the structural requirement of "-CnF2n+1" in the previous definition. For example, b1 in Figure 2 meets the previous definition, whereas its shorterchain homologue, b2 in Figure 2, does not meet the previous definition. Figure 2. PFOS, an example of a cyclic PFSA, and a shorter-chain homologue of the cyclic PFSA Case 3: The functional group contains an aromatic ring. Thus, it may not meet the term "aliphatic substances" in the previous definition, although the example of c1 in Figure 3 is a derivative of 6:2 fluorotelomer iodide, i.e. a 6:2 fluorotelomer-based compound. F F FF F F F FF F OH F F OH F F F FF FF F C. 6:2 FTOH, CAS No. 647-42-7 F FF FF F c1. CAS No. 356055-76-0 Figure 3. 6:2 FTOH, and a 6:2 fluorotelomer iodide derivative with one aromatic ring in the functional group Case 4: The description "highly fluorinated" in the previous definition is an ambiguous, problematic term. It cannot and should not be literally translated to, e.g., the weight percentage of fluorine atoms in the molecules, using three 6:2 fluorotelomer-based compounds as an example (see Figure 4): C6F13C2H4OH (6:2 FTOH; CAS No. 647-42-7) has a fluorine content of 67.8 wt%, C6F13C2H4SO2NHC3H6N(O)(CH3)2 used in Forafac 1183 (CAS No. 80475-32-7) has a fluorine content of 46.7 wt%, and 6:2 fluorotelomer ethoxylates [C6F13-(CH2CH2O)n-H, n = 0-13] in a commercial product (Frmel and Knepper, 2010) would have even lower fluorine content when n>4. But they are all 6:2 fluorotelomer-based compounds and may act as precursors to perfluorohexanoic acid (PFHxA) in the environment and biota. Figure 4. 6:2 FTOH and two 6:2 fluorotelomer derivatives, and their corresponding fluorine contents Unclassified 18 ENV/CBC/MONO(2021)25 2.3. A revised PFAS definition Therefore, there is a need to revisit the previous definition in Buck et al. (2011) to address these gaps (i.e. the previous definition was not comprehensive enough and contained ambiguous descriptions). A clear distinction of the logical relationship needs to be made here: the intention of the revision of the PFAS definition is not to expand the PFAS universe, but to comprehensively reflect it. More concretely, the rationale behind the revision is to have a general PFAS definition that is coherent and consistent across compounds from the chemical structure point of view and is easily implementable for distinguishing between PFASs and non-PFASs, also by non-experts. This revised PFAS definition reads, PFASs are defined as fluorinated substances that contain at least one fully fluorinated methyl or methylene carbon atom (without any H/Cl/Br/I atom attached to it), i.e. with a few noted exceptions, any chemical with at least a perfluorinated methyl group (-CF3) or a perfluorinated methylene group (-CF2-) is a PFAS. Both a perfluorinated methyl group and a perfluorinated methylene group are saturated and aliphatic. Note that the carbon in a R-CF2-O- or R-CF2-Si- group (R H/Cl/Br/I) is a perfluorinated methylene carbon. A perfluorinated methylene group may also be represented as ">CF2", where ">" denotes two single bonds. A fully fluorinated carbon that is bound to the rest of the molecule by a double bond is a perfluorinated methylidene carbon atom (=CF2). This distinction is important. Further, a perfluorinated methine carbon moiety (>CF-) alone does not meet this revised PFAS definition. It should be noted that this general PFAS definition is based only on chemical structure, and the decision to broaden this definition compared to Buck et al. (2011) is not connected to decisions on how PFASs should be grouped and managed in regulatory and voluntary actions. For further practical guidance on how to use this general PFAS definition, see Section 3.1. Figure 5 illustrates substances that are PFASs, and Figure 6 shows those that are not PFASs. Note that tetrafluoroethylene (TFE, CAS No. 116-14-3, CF2=CF2) is not a PFAS as both fully fluorinated carbon atoms are unsaturated; its longer-chain homologue hexafluoropropylene (HFP, CAS No. 116-15-4, CF2=CF-CF3) is a PFAS due to the presence of a fully fluorinated methyl carbon atom (-CF3). Unclassified ENV/CBC/MONO(2021)25 19 Figure 5. Examples of PFASs. The fully fluorinated methyl or methylene carbon atoms are highlighted in red. Unclassified 20 ENV/CBC/MONO(2021)25 Figure 6. Examples of compounds that are not PFASs due to a lack of fully fluorinated methyl or methylene carbon atoms. The rationale for making such changes is detailed as follows. Change from "highly fluorinated aliphatic substances" to "fluorinated substances that contain at least one fully fluorinated methyl or methylene carbon atom (without any H/Cl/Br/I atom attached to it)": First, the qualifier "highly" is removed from the definition, as it is not meaningful when the fluorinated carbon chain can cleave from the substance to produce a new molecule that is more highly fluorinated [see Section II in FOEN (2017) and references therein]. Second, the term "aliphatic" is removed from the definition. As shown in Case 3 in Figure 3, aromatic ring(s) may be present as a part of the functional group connecting to a fully fluorinated methyl or methylene carbon moiety. Using the previous definition by Buck et al. (2011), such compounds would not be recognized as PFASs, whereas compounds with similar structures but without aromatic ring(s) are recognized as PFASs. This may easily create confusion as to when a substance is or is not a PFAS, particularly for non-experts. The change of wording here is also to make the definition more straightforward. At the same time, the new wording "substances that contain at least one fully fluorinated methyl or methylene carbon atom" means that this revised definition is still constrained to the key trait of having an aliphatic fully fluorinated saturated carbon moiety and excluding those fluorinated aromatics that only have fluorine directly attached to the aromatic rings. Overall, this revised definition includes side-chain fluorinated aromatics [i.e. aromatics that have one or more aliphatic fully fluorinated saturated carbon moiety on the side chain(s) attached to the aromatic ring(s), an analogy to "side-chain fluorinated polymers"12 as in Buck et al. 2011] as PFASs; for examples, see c1 in Figure 3 and Figure 7 below. 12 In Buck et al. (2011), side-chain fluorinated polymers are defined as "nonfluorinated polymer backbone with fluorinated side chains". Unclassified ENV/CBC/MONO(2021)25 21 Figure 7. An example of side-chain fluorinated aromatics. Change from "the perfluoroalkyl moiety CnF2n+1-" to "at least one fully fluorinated methyl or methylene carbon atom (without any H/Cl/Br/I atom attached to it)": This change is to accommodate those that have functional groups on both ends of the fully fluorinated saturated carbon moieties (Case 1) and those that have cyclic structure(s) at the end of the fully fluorinated saturated carbon moieties (Case 2). In addition, two more specific descriptions are made here to make the definition clearer. First, the term "methyl or methylene carbon atom" is added to describe the fully fluorinated saturated carbon moiety, which was not clear from the description "that contain only 1 or more C atoms on which all the H substituents ... have been replaced by F atoms", but only implicitly mentioned in the description "in such a manner that they contain the perfluoroalkyl moiety CnF2n+1-". Second, adding "without any H/Cl/Br/I atom attached to it" highlights that the carbon atom is considered non-fully fluorinated, when a H/Cl/Br/I atom is attached to it. 2.4. A comprehensive overview of the PFAS universe Based on this revised definition of PFASs, a first scheme can be drawn to illustrate how PFASs fit into organofluorine compounds (see Figure 8). It can be seen that besides PFASs, there are many other organofluorine compounds, including (1) fluorinated aliphatic substances that do not have a fully fluorinated methyl or methylene carbon atom [e.g. trifluoromethane (HFC-23) and difluoromethane (HFC-32)], (2) fluorinated aromatic substances with no side chain(s) (e.g. hexafluorobenzene, CAS No. 392-563), and (3) fluorinated aromatic substances with non-fluorinated side chain(s) (e.g. pentafluorobenzoic acid, CAS No. 602-94-8). These other organofluorine compounds are beyond the scope of this report, and future work on them is encouraged. Looking at the PFAS universe, it is a highly complex chemical class with compounds having diverse functional groups attached to the fully fluorinated saturated carbon moiety/-ies. Figure 9 provides a comprehensive overview of PFAS groups, their structural traits, examples and notes on whether common nomenclatures (including acronyms) exist for them, building on Buck et al. (2011) and the OECD 2018 List. Figure 10 illustrates some common synthesis routes of different individual or groups of PFASs based on publicly accessible sources. It should be noted that, while Figures 9 and 10 aim to be comprehensive, they are by no means exhaustive. For more information on individual PFAS groups (e.g. major compounds in the group, synthesis routes, major uses, regulatory status, environmental occurrence, etc.), readers may consult the PFAS Fact Cards published on the OECD PFAS Web portal: https://www.oecd.org/chemicalsafety/portal-perfluorinated-chemicals/. Unclassified 22 ENV/CBC/MONO(2021)25 other fluorinated ALIPHATIC subst ances t hat do not have a fully fluorinat ed met hyl or met hylene carbon at om F F HFC-32*, CASNo. 75-10-5 F F F HFC-23*, CASNo. 75-46-7 R-12*, CASNo. 75-71-8 organofluorine compounds fluorinated ALIPHATIC subst ances fluorinated ALIPHATICsubstancesthat have a fully fluorinated methyl or methylene carbon atom Per- and Polyfluoroalkyl Substances(PFASs) e.g. R- CnF2n+1or R- CnF2n- R', n 1 (for examples,see Figure 5 above) non-fluorinated AROMATICring(s) with fluorinated ALIPHATICside-chain(s) that have a fully fluorinated methyl or methylene carbon atom FF F F F F F CASNo. 378-98-3 fluorinated AROMATIC subst ances fluorinated AROMATICring(s) with fluorinated ALIPHATICside chain(s) that have a fully fluorinated methyl or methylene carbon atom (non-)fluorinated AROMATICring(s) with fluorinated ALIPHATICside chain(s) that do NOT have a fully fluorinat ed met hyl or met hylene carbon at om F F F F F F F F CASNo. 434-64-0 CASNo. 458-87-7 CASNo. 127399-61-5 fluorinated AROMATICring(s) with non-fluorinated ALIPHATICside chain(s) CASNo. 602-94-8 fluorinated AROMATICsubstances w it hout a side chain Substances that are not PFASs and are not addressed in this report CASNo. 392-56-3 * HFC-32, HFC-23 and R-12 are not PFASs, despite the presence of moieties such as - CF2- or - CF3,because not all H on the fluorinated carbon atom are replaced by F, i.e., they do not have a fully fluorinated carbon atom. Figure 8. An illustrative scheme of how PFASs fit into the universe of organofluorine compounds Unclassified ENV/CBC/MONO(2021)25 23 Figure 9. A comprehensive overview of PFAS groups, their structural traits, examples and notes on whether corresponding common nomenclatures (including acronyms) exist. Unclassified 24 ENV/CBC/MONO(2021)25 Figure 10. An overview of some common synthesis routes of different individual or groups of PFASs based on publicly accessible source Unclassified ENV/CBC/MONO(2021)25 25 3. Practical Guidance on How to Use the PFAS Terminology As shown above, PFASs are a chemical class with diverse molecular structures (e.g. neutral, anionic, cationic or zwitterionic; with or without aromatic rings; non-polymers or polymers; low molecular weight or high molecular weight) and thus diverse physical, chemical and biological properties (e.g. involatile or volatile; water soluble or water insoluble; reactive vs. inert; bioaccumulative or non-bioaccumulative). Therefore, it is highly recommended that such diversity be properly recognized and communicated in a clear, specific and descriptive manner. The following sections aim to provide practical guidance to governments and other stakeholders on how to use the PFAS terminology, starting from the distinction between the general definition described here and userspecific working scopes of PFASs. An overarching rationale behind the practical guidance is to use and build upon existing common terminologies such as in this report, in Buck et al. (2011) and common practices in organic chemistry as set by IUPAC and CAS, unless it is essential to deviate from existing naming conventions in order to keep the consistence and coherence of the PFAS terminology. 3.1. Distinction between the General Definition and User-Specific Working Scopes of PFASs It should be noted that the revised definition of PFASs in Section 2.3 refers to a general definition of PFASs that is coherent and consistent across compounds based on chemical structure and is easily implementable for distinguishing between PFASs and nonPFASs, also by non-experts. It does not include any minimal or maximal chain length requirements, or any other considerations beyond chemistry. It also does not conclude that all PFASs have the same properties, uses, exposure and risks. While this general definition of PFASs may be viewed as too broad, encompassing thousands or more compounds, for anyone to address all of them at once, it serves as a starting and reference point to guide individual users to have a comprehensive understanding of the PFAS universe and to keep the big picture of the PFAS universe in mind. At the same time, individual users may define their own PFAS working scope for a specific activity according to their specific needs by combining this general definition of PFASs with additional considerations (e.g. specific properties, use areas). For example, the US Interstate Technology & Regulatory Council (ITRC)13 used a working scope of "CnF2n+1" (n>2) in making its own PFAS fact sheets. Another example is the working scope used in compiling the OECD 2018 PFAS List, namely -CnF2n- (n 3) and -CnF2nOCmF2m- (n and m 1). Also, the addition of criteria such as bioavailability and persistence in Gore Fabrics' Goal and Roadmap14 for Eliminating PFCs of Environmental Concern may be regarded as a way of setting working scopes. This report does not make any recommendation on how a working scope should be set up regarding which factors to consider (which depend on specific local context)15, nor 13 The latest version of the fact sheet on naming conventions of PFASs is from April 2020: https://pfas1.itrcweb.org/fact_sheets_page/PFAS_Fact_Sheet_Naming_Conventions_April2020.pdf 14 Here it refers to the version published on January 31, 2017, which can be found at: https://drive.google.com/file/d/0BxvQ_I44P_9eeTlwYUJCekhLNlE/view 15 Future work compiling various existing practices of defining working scope under different context may be beneficial to provide further guidance to governments and other stakeholders on this matter. Unclassified 26 ENV/CBC/MONO(2021)25 on PFAS grouping16. However, when a working scope of PFASs is used, this report highly recommends that users clearly provide the context and rationale for selecting their PFAS working scope in order to provide transparency and avoid confusion by others. 3.2. Practical guidance on how to identify and use suitable PFAS terms The term "PFASs" does not inform whether a compound is harmful or not, but only communicates that the compounds under this term share the same trait for having a fully fluorinated methyl or methylene carbon moiety. In addition, particularly for PFASs without an assigned CAS No., a lot of parallel and often non-intuitive acronyms are employed, potentially prohibiting effective communication and creating barriers for synthesizing knowledge. This section aims to provide practical guidance on how to identify and use suitable terms to foster communication around PFASs with the aim of being accurate, precise, understandable by others, and consistent. First, it is strongly recommended that the PFAS terminology be used in a clear, specific and descriptive manner. It should be noted that "PFASs" is a broad, general, nonspecific term, which should only be used when talking about all the substances included in the PFAS definition described here (or the user should clearly define the scope of which substances are being referred to as PFASs in the documents they prepare). Otherwise, it would introduce ambiguity and even factual error in the statements (as occurred sometimes in past literature). For example, not all PFASs are surfactants, and thus, a statement "PFASs are surfactants" is factually inaccurate. Table 1 highlights examples of ambiguous statements, which when are overgeneralized may lead to ambiguity, and factual inaccuracies and miscommunication in some cases. Therefore, it is recommended that users always ask the following two questions when drafting a statement: (1) Am I referring to all PFASs or not? (2) If not, what term(s) would mostly clearly describe the substance(s) that my statement is referring to? There could be multiple ways by users to locate the right levels of terms that are clear, specific and descriptive for specific statements, by combining and ordering traits such as polymeric vs. non-polymeric, PFAAs vs. PFAA precursors, or side-chain fluorinated polymers vs. fluoropolymers vs. perfluoropolyethers. Figure 11 shows different levels of PFAS terms and their respective characteristics in terms of clarity and specificity, along with examples; one may either start from Level 1 (most general) and move downwards (with the question of whether it is specific enough), or Level 5 (most specific) and move upwards (with the question of whether it can be further generalized), to locate the right level of terms for a specific statement. Table 1 also includes examples of good practice to refine ambiguous statements using more suitable terms. Furthermore, individual PFASs need to be named in a clear, specific and descriptive manner. 16 In a recent scientific article, various grouping strategies for PFASs were reviewed and the motivations, advantages and disadvantages for each approach were discussed; for more details, see Cousins et al. 2020. Environmental Science: Processes & Impacts, 22, 1444-1460, https://doi.org/10.1039/D0EM00147C Unclassified ENV/CBC/MONO(2021)25 27 Table 1. Examples of ambiguous statements and associated good practices of using more specific PFAS terminology to refine these statements Examples of ambiguous statements (which may also result in factual inaccuracy in some cases) PFASs were investigated in human milk. PFASs are used to make protective coatings on common household products. PFASs are relatively ubiquitous in the environment at low concentrations. (factually inaccurate) PFASs are water repellent, oil, grease and dirt repellent surfactants. (factually inaccurate) Examples of good practices of using the PFAS terminology to avoid errors and reduce ambiguity (1) Using more specific PFAS terms C4-C14 PFCAs were investigated in human milk. (2) Adding qualifiers (less favorable than (1), as it remains quite ambiguous) 15 non-polymeric PFASs were investigated in human milk. Fluorotelomer-based side-chain fluorinated polymers are used to make protective coatings on common household products. A number of polymeric PFASs are used to make protective coatings on common household products. PFCAs are relatively ubiquitous in the environment at low concentrations. A number of PFASs are relatively ubiquitous in the environment at low concentrations. Many perfluorooctane sulfonyl fluoride-based derivatives are water-, as well as oil-, grease- and dirt-repellent surfactants. A number of PFASs are water-, as well as oil-, grease- and dirt-repellent surfactants. Most GENERAL Level 1 Explanations When describing all chemicals with at least a perfluorinated methyl (-CF3) or methylene group (-CF2-) Level 2 When describing groups of PFASs that are separated by simple traits (e.g. perfluoroalkyl vs. polyfluoroalkyl chain; fluoroalkyl vs. fluoroalkylether chain; fluoroalkyl(ether) chain and/or functional group being polymeric vs. non- polymeric specificity Level 3 When describing groups of PFASs that share the same or similar structural components (including deri vatives from the same parent compounds) Examples of best terms to be used - per- and polyfluoroalkyl substances (PFASs) A-2. perfluoroalkyl non-polymers B-2. perfluoroalkyl non-polymers C-2. polyfluoroalkyl substances (including both non-polymers and polymers) D-2. fluoropolymers (i.e. PFASs that have a polymeric fluoroalk yl chain as the backbone) A-3. perfluoroalkyl acids (PFAAs, e.g. CnF2n+1-acidic groups) B-3. perfluoroalkyl acids (PFAAs, e.g. CnF2n+1-acidic groups) C-3. n:2 fluorotelomer-based substances (CnF2n+1-C2H4-R, R = any groups), including side-c hain fluorinated polymers (R = polymeric) D-3. polytetrafluoroethylene [PTFE; [R-(CF2)n-R', R, R' = any groups] Level 4 When describing a group of PFASs that belong to the same homologue series with different perfluorinated carbon chain lengths A-4. perfluoroalkyl carboxylic acids (PFCAs, CnF2n+1-COOH) B-4. perfluoroalkane sulfonic acids (PFSAs, C nF2n+1-SO3H) C-4. n:2 fluorotelomer alcohols, (n:2 FTOHs, CnF2n+1-C2H4OH) D-4. non-functionalized PTFE [F3C-(CF2)n-CF3] Most SPECIFIC Level 5 When describing indi vidual substances (identifiers suc h as names, CAS numbers, molecular formula, InChI(Key), SMILES, etc.) A-5. perfluorooctanoic acid (PFO A, C7F15-COOH) B-5. perfluorooctane sulfonic acid (PFOS, C 8F17-SO3H) C-5. 8:2 fluorotelomer alcohol (8:2 FTOH, C6F13-C2H4OH) D-5. specific PTFE products [F3C-(CF2)n-CF3; X<n<Y; X,Y = integers] Figure 11. A visual guide to identify the best terms to use for a specific statement with four examples (increasing level of specificity illustrated with same colour within examples). Second, if users are not sure about how to name a specific compound, it is recommended to first check whether a common nomenclature (including a common acronym) already exists, e.g., in Buck et al. (2011), Barzen-Hanson et al. (2017)17, this report and other studies, before creating their own naming conventions. For example, for CAS No. 67839-7, a common name "8:2 fluorotelomer alcohol" and a common acronym "8:2 FTOH" already exist, and should be used instead of other synonyms. 17 In the Supporting Information, Barzen-Hanson et al. developed a simplified, manual IUPAC-based naming system for the PFASs that they identified in their non-target screening. For more details, see Barzen-Hanson et al. 2017. Environmental Science & Technology. 51(4), 2047-2057. https://doi.org/10.1021/acs.est.6b05843 Unclassified 28 ENV/CBC/MONO(2021)25 Third, acronyms are often necessary in communicating PFASs to avoid writing very long names all the time; however, the same acronym may refer to different full names or different forms of the same substance (e.g. the parent acid, the anion form, and various salt forms), depending on context and personal understanding. To avoid confusion, it is recommended that acronyms be spelled out when being mentioned for the first time in the text and used consistently throughout the text. Fourth, while chemical names and associated acronyms are the most common chemical identifiers being used, it is also recommended that other more specific identifiers such as CAS No., SMILES (simplified molecular input line entry specification), InChI (international chemical identifier), InChIkey (a hashed version of the full InChI) and/or structural formula18 are provided for possibilities of cross-checking. This may also be useful in reporting the chemical identities of PFASs that have been registered as substances of unknown or variable composition, complex reaction products, or biological materials (UVCBs, e.g., CAS No. 69991-67-9 = 1-propene, 1,1,2,3,3,3hexafluoro-oxidized, polymd.)8. 18 These identifiers may be found and verified using online databases, such as the CAS Common Chemistry (https://commonchemistry.cas.org), ChemSpider (http://www.chemspider.com), NORMAN Suspect List Exchange (https://www.norman-network.com/?q=suspect-list-exchange), OECD eChemPortal (https://www.echemportal.org/echemportal/), PubChem (https://pubchem.ncbi.nlm.nih.gov/classification/#hid=101), SciFinder (http://scifinder.cas.org) and US EPA CompTox Chemicals Dashboard (https://comptox.epa.gov/dashboard/chemical_lists/PFASOECD). Unclassified ENV/CBC/MONO(2021)25 29 4. Systematic characterization and categorization of PFASs As users often define their own working scope of PFASs according to their specific needs (see Section 3.1), they need to characterize PFASs based on molecular structures (and other considerations) and then categorize them by comparing characterization traits against specific needs (e.g. whether a compound falls or does not fall into their working scope). For example, the recent listing of PFOA and PFOA-related compounds under the Stockholm Convention requires regulators across the world to be able to identify PFOA-related compounds from a pool of PFASs. However, given the high complexity and diversity of PFASs, it can be a challenging task to characterize and categorize PFASs based on their chemical structures in a coherent and consistent manner, particularly for non-experts. Detailed challenges may include needs of specialized chemistry knowledge (e.g. on transformation), different interpretations of structural traits by users for different groups of PFASs, and potential for human errors including oversights and typing errors (Sha et al. 2019). In addition, different users may have very different needs, and there is no single categorization/grouping system that can meet all needs. Therefore, this section provides a standardized system for systematic characterization of different PFASs based on molecular structural traits that will allow stakeholders to make their own categorization in a coherent and consistent manner. Molecular structurebased elements of such a characterization system are provided in Table 2, with some examples of applications given in Table 3. For example, if someone would like to have the grouping of linear PFCAs, they would just need to search for molecules with the right characterization traits as defined in Table 3: under "fluorinated carbon chain (A)", having "alkyl", "perfluoro", "linear", "saturated", "non-polymeric"; under "functional group B", having "COOH" and "non-polymeric"; and under "stoichiometry between A and B", having "1:1". The system is flexible for future refinement including possible addition of new elements as needed and also applications to new groups of PFASs as identified. In addition to manual application of the system to characterize and categorize PFASs, the elements presented here may also be used as inputs for developing cheminformatic tools that would allow automatized characterization and categorization of PFASs, as demonstrated in Sha et al. (2019). In that study, an algorithm was developed to systematically parse a PFAS molecule into three fragments namely CnF2n+1-X-R, where CnF2n+1- refers to the fluorinated carbon moiety and -X-R refers to functional group moiety. X was used to identify whether a PFAS molecule falls into the target group of perfluoroalkane sulfonyl fluoridederivatives (where X = SO2), perfluoroalkanoyl fluoride derivatives (where X = CO), n:1 fluorotelomer-based compounds (where X = CH2 and R does not have a CH2 or CH moiety connecting with X), or n:2 fluorotelomer-based compounds (where X = CH2CH2). The algorithm was applied to a set of 770 PFASs from the OECD 2018 PFAS List and identified PFASs from the target four groups as intended. The algorithm was also able to identify PFASs that were mis-categorized in the OECD 2018 PFAS List, as the original categorization was done manually. The algorithm developed in Sha et al. (2019) serves as a proof-of-concept, and thus has its limitations in terms of its purpose (i.e. to identify whether a PFAS falls into one of the four target groups) and function (e.g. it cannot handle PFASs with more than one Unclassified 30 ENV/CBC/MONO(2021)25 functional group moieties). However, it shows the potential of such cheminformatics approaches, which can be expanded using the elements provided here for systematic characterization and categorization of PFASs in a coherent and consist manner, particularly for non-PFAS experts. It needs to be noted that tools proposed here that integrate the concept presented in Sha et al. (2019) and the proposed elements of a characterization system is one way of developing cheminformatics-based tools for systematic characterization and categorization of PFASs. Depending on the needs, there may also be other ways of doing so, including adding other elements into consideration (e.g. a ToxPrints approach that also considers structures related to adverse outcomes19) or implementing in other ways (e.g. using Markush structures to annotate existing lists20). An outlook of future developments is provided in the next section. Table 2. Molecular structure-based elements of a characterization system for PFASs. PFASs may be Molecular structure- Note parsed into the based elements to be following two considered structural parts Fluorinated carbon alkyl vs. alkylether chain (A) Whether the fluorinated carbon chain is carbon only or has oxygenlinkage(s) between fluorinated carbons e.g., -CnF2n- vs. -CnF2n-O-CmF2m- perfluoro vs. polyfluoro Whether all hydrogen on the fluorinated carbon chain are replaced by fluorine (i.e. perfluoro) or not (i.e. polyfluoro) e.g., H-C2F4-, Cl-C2F4-, CF3CF2-C2H4-C2F4-C2H4-, CF3CF2-CH2- CF2-CH2-CF2-, etc. = polyfluoro linear vs. branched vs. Whether the fluorinated carbon chain is linear, branched or cyclic cyclic e.g., -C6F13 vs. -C3F6CF(CF3)2 vs. -cyclo(C6F12) saturated vs. non-saturated Whether there is any unsaturated bond (a double or triple bond) in the fluorinated carbon chain e.g., -CF2CF2- vs. -CF=CF- 19 For an example, see https://figshare.com/articles/presentation/PFAS_Toxprints_A_Hierarchical_StructureBased_Categorization_Method_for_Characterization_of_Per-_and_Polyfluoroalkyl_Substances/12834329. Currently, the US EPA is preparing a manuscript on this approach, including means for applying it. 20 A Markush structure is a generic type of description of chemicals used to summarize a potentially very large set of closely related chemicals in a single condensed representation. It may consist of a "core" chemical structure and a list of possible substituents attached to it, with four substituent options: substituent variation (allowing different substituents at a position), position variation (allowing different attachment points for a substituent), frequency variation (allowing substituents to occur multiple times) and homology variation (using generic expressions covering many specific substituents like "alkyl"). For more details, see, e.g., Geyer P. 2013. World Patent Information, 35(3), 178-182, https://doi.org/10.1016/j.wpi.2013.05.022. The US EPA CompTox Chemicals Dashboard uses "Markush structures" to organize its PFAS list. In brief, the Dashboard has curated 112 PFAS Markush structures with unique DTXSIDs assigned (e.g. DTXSID80893896 HOOC-(CF2)n-COOH for perfluoroalkyl (linear) dicarboxylic acids, i.e. homology variation). Each PFAS Markush structure is considered a generalized substance or "parent ID" that can be associated with one or many "child IDs" within the Dashboard (e.g. DTXSID80893896 are linked to 12 linear perfluoroalkyl dicarboxylic acids with different fluorinated carbon chain lengths in the Dashboard). For more details, see https://comptox.epa.gov/dashboard/chemical_lists/EPAPFASCAT. Unclassified ENV/CBC/MONO(2021)25 31 polymeric vs. non- Whether the fluorinated carbon chain is polymeric or non-polymeric polymeric e.g. using the OECD definition (http://www.oecd.org/env/ehs/oecddefinitionofpolymer.htm) [Note: this may require additional consideration, e.g. whether a minimum perfluorocarbon moiety chain length of 20 would be required]21 chain length of the fluorinated carbon chain e.g., for perfluoroalkylether-based substances, the total length of perfluoroalkylether moieties including both carbon and oxygen atoms will be counted, and additional information on the number of oxygen atoms will be provided as supplementary information, similarly to what is in the OECD 2018 list. Functional group (B) types and structures functional groups of As there is no common classification system of functional groups, here a simplified scheme is proposed that is intended to distinguish those reactive and non-reactive (or those not so reactive) groups under natural conditions, which can be used to differentiate e.g. PFAAs and PFAA precursors. 1. Non-reactive groups (or those not so reactive) 1.1. H, Cl, Br 1.2. N, P 1.3. COOH 1.4. SO3H 1.5. PO3H2 2. Reactive groups 2.1. I 2.2. SO2H - sulfinic acids 2.3. PO2H 2.4. CH2-R - possibly n:1 fluorotelomers 2.5. CH2CH2-R - possibly n:2 fluorotelomers 2.6. CO-R (other than COOH) - alkanoyl fluoride-derivatives 2.7. SO2-R (other than SO2OH) - sulfonyl fluoride-derivatives 2.8. CmH2m+1, OCmH2m+1, CmH2m-1 3. Others (which may be refined in future work) polymeric vs. non- Whether the non-fluorinated functional group is polymeric or non- polymeric polymeric, e.g. using the OECD definition (http://www.oecd.org/env/ehs/oecddefinitionofpolymer.htm) [Note: this may require additional consideration of additional qualifier, e.g. whether a minimum chain length of 20 would be required] stoichiometry between A and B How are fluorinated carbon chain(s) connected with non-fluorinated carbon chain(s)/functional groups? 1:0 = no functional group 1:1/1:2/1:3 = one fluorinated carbon chain connected with 1/2/3 functional group(s) 2:1 = two fluorinated carbon chains connected with one functional group, e.g. PFPIAs 21 In many jurisdictions, a polymer is defined as a substance that has over 50 percent of the weight consisting of polymer molecules and the amount of polymer molecules presenting the same molecular weight must be less than 50 weight percent of the substance. A polymer molecule is defined as a molecule that contains a sequence of at least 3 monomer units, which are covalently bound to at least one other monomer unit or other reactant. Thus, a mixture of 8:2, 10:2 and 12:2 fluorotelomers (each 33%) can theoretically be regarded as a polymer. Unclassified 32 ENV/CBC/MONO(2021)25 Table 3. Examples using the proposed characterization system. Possible elements to be considered alkyl vs. alkylether Example 1: Linear PFCAs Alkyl Example 2: PFOA precursors Alkyl perfluoro vs. polyfluoro linear vs. branched vs. cyclic saturated vs. non- Fluorinated saturated carbon (A) chain polymeric vs. nonpolymeric chain length Nonfluorinated functional group (B) types and structures of functional groups polymeric vs. nonpolymeric Connection between A and B How are fluorinated carbon chain(s) connected with non- fluorinated carbon chain(s)? Perfluoro Linear Saturated Non-polymeric 1-20 1.3 COOH Non-polymeric 1:1 Perfluoro Linear + Branched Saturated Non-polymeric >=7 (in the case of when A and B connects via a carbon atom); >=8 (in the case of when A and B connects via other atoms other than a carbon atom) 2 Reactive groups Non-polymeric; polymeric 1:1 Example 3: ADONA Alkylether Polyfluoro Linear Saturated Non-polymeric 6 + 2O 1.3 COOH Non-polymeric 1:1 Example 4: 6:2 FT-acrylate polymer Alkyl Perfluoro Example 5: PTFE with - COOH on each end Alkyl Perfluoro Linear Linear Saturated Saturated Non-polymeric Polymeric 6 XX 2.5 CH2CH2-R - possibly n:2 fluorotelomers Polymeric n:1 1.3 COOH Non-polymeric 1:2 Unclassified 5. Areas for Future Work ENV/CBC/MONO(2021)25 33 While this report makes advancement on several important points regarding the PFAS terminology and practical guidance of how to use the PFAS terminology, it also recognizes that the following four areas warrant further work within the field of PFASs (i.e. areas one and two) and beyond (i.e. areas three and four), in order to facilitate clear and unambiguous communication of PFASs. First, a centralized PFAS nomenclature database/platform may be considered. With the further advancement and application of non-target screening methods, many more unknown PFASs are expected to be discovered in the future. Such a centralized nomenclature database/platform can help foster the use of harmonized names and acronyms for the same compounds. It can also help to link different common names and acronyms that have been used over time to specific substances. Second, further development of cheminformatics-based tools for automated systematic characterizing and categorizing PFASs would advance the field. A solely structure-based approach proposed in the report (i.e. Chapter 4) may serve as one starting point for possible joint development of an open source tool by experts from different online databases/platforms so that such a tool may be compatible for different online databases/platforms. In addition, as cheminformatics is a fast-developing field, future work may be conducted to monitor, assess and communicate which cheminformatics tools are developed for which purposes. Third, further work on the characterization and reporting of polymers should be considered, as well as assessment of their properties. The current definitions of polymers in many jurisdictions originate from the OECD definition of polymer that was developed in the early 1990s, and in some cases, substances containing a significant fraction of low-molecularweight molecules may be identified as polymers, as indicated in Footnote 21. This may impact how individual substances are registered (or not registered) and subsequent regulatory requirements of safety information. Thus, chemical compositions in substances that are identified as polymers may warrant a closer look, particularly in terms of their lowmolecular-weight content, based on lessons learned in the past three decades. In addition, the current reporting of many polymers are often rather ambiguous (e.g. a polymer may be named as a co-polymer of three monomers A, B and C without indicating how the monomers are connected and in which molecular ratios, reaction schemes and molecular weight range of individual compositions, which could have implications on assessing the fate, behavior and risks of specific polymer products). Thus, future international efforts are needed to look into ways to improve the understanding of polymer structures including access to necessary information, focusing on polymeric PFASs or on polymers in general. Fourth, as shown in Figure 8, there are many groups of organofluorine substances other than PFASs. Future work could also look into these compounds, including the terminology of many fluorinated aromatics. Unclassified 34 ENV/CBC/MONO(2021)25 References Barzen-Hanson KA, Roberts SC, Choyke S, Oetjen K, McAlees A, Riddell N, et al. 2017. Discovery of 40 classes of per- and polyfluoroalkyl substances in historical aqueous film-forming foams (AFFFs) and AFFF-impacted groundwater. Environ Sci Technol 51(4), 2047-2057. https://doi.org/10.1021/acs.est.6b05843 Buck RC, Franklin J, Berger U, Conder JM, Cousins IT, De Voogt P, et al. 2011. Perfluoroalkyl and polyfluoroalkyl substances in the environment: terminology, classification, and origins. Integrated Environmental Assessment and Management 7(4), 513-541, https://doi.org/10.1002/ieam.258 FOEN (Swiss Federal Office for the Environment). 2017. Additional information in relation to the risk management evaluation of PFOA, its salts, and related compounds. http://www.pops.int/TheConvention/POPsReviewCommittee/Meetings/POPRC12/POPRC12Followup/P FOAComments/tabid/5950/Default.aspx. (submitted on 31 May 2017). Newton S, McMahen R, Stoeckel JA, Chislock M, Lindstrom A, Strynar M. 2017. Novel polyfluorinated compounds identified using high resolution mass spectrometry downstream of manufacturing facilities near Decatur, Alabama. Environ Sci Technol 51(3), 1544-1552. https://doi.org/10.1021/acs.est.6b05330. Sha B, Schymanski EL, Ruttkies C, Cousins IT, Wang Z. 2019. Exploring open cheminformatics approaches for categorizing per- and polyfluoroalkyl substances (PFASs). Environmental Science: Processes & Impacts 21(11), 1835-1851. https://doi.org/10.1039/C9EM00321E. Wang Z, Cousins IT, Scheringer M, Hungerbuehler K. 2013. Fluorinated alternatives to long-chain perfluorocarboxylic acids (PFCAs), perfluorosulfonic acids (PFSAs) and their potential precursors. Environ Int, 60, 242. https://doi.org/10.1016/j.envint.2013.08.021. Wang Z, Cousins IT, Berger U, Hungerbhler K, Scheringer M. 2016. Comparative assessment of the environmental hazards of and exposure to perfluoroalkyl phosphonic and phosphinic acids (PFPAs and PFPiAs): Current knowledge, gaps, challenges and research needs. Environ Int, 89, 235. https://doi.org/10.1016/j.envint.2016.01.023. Unclassified