Document y7ZE0Q3oBKODkwknnQ3DVO1n

Environmental risk evaluation report: 3,3,4,4,5,5,6,6,6-Nonafluorohexene (CAS no. 19430-93-4) (Perfluorobutylethylene; PFBE) Chief Scientist's Group report July 2022 Version: XXXXXX/R (project code number / if required) Commented [MCC1]: To be added. Page numbers to be updated after final review. We are the Environment Agency. We protect and improve the environment. We help people and wildlife adapt to climate change and reduce its impacts, including flooding, drought, sea level rise and coastal erosion. We improve the quality of our water, land and air by tackling pollution. We work with businesses to help them comply with environmental regulations. A healthy and diverse environment enhances people's lives and contributes to economic growth. We can't do this alone. We work as part of the Defra group (Department for Environment, Food & Rural Affairs), with the rest of government, local councils, businesses, civil society groups and local communities to create a better place for people and wildlife. Published by: Environment Agency Horizon House, Deanery Road, Bristol BS1 5AH www.gov.uk/environment-agency Environment Agency 2022 All rights reserved. This document may be reproduced with prior permission of the Environment Agency. Further copies of this report are available from our publications catalogue: www.gov.uk/government/publications or our National Customer Contact Centre: 03708 506 506 Email: research@environmentagency.gov.uk Author(s): Chemicals Assessment Unit Keywords: Polyfluorinated alkyl substances; PFAS; Perfluorobutylethylene; PFBE Environment Agency's Project Manager: Simon Hoy Citation: Environment Agency (2022) Environmental risk evaluation report: 3,3,4,4,5,5,6,6,6Nonafluorohexene (CAS no. 19430-93-4). Environment Agency, Bristol. 2 of 115 Contents Research at the Environment Agency .................................................................................6 Acknowledgements .............................................................................................................. 7 Executive summary .............................................................................................................8 Introduction ........................................................................................................................10 1 Substance identity .......................................................................................................12 1.1 Name and other identifiers.....................................................................................12 1.2 Structurally related substances ..............................................................................13 1.3 Transformation products ........................................................................................14 2 Analytical chemistry.....................................................................................................16 2.1 Regulatory and academic methods........................................................................16 3 Import, manufacture and uses.....................................................................................17 4 Summary of relevant regulatory activities....................................................................19 4.1 Europe ...................................................................................................................19 4.2 Regulatory activity outside Europe.........................................................................20 4.3 Other international agreements .............................................................................21 5 Physicochemical properties.........................................................................................22 5.1 Vapour pressure ....................................................................................................23 5.2 Surface tension ......................................................................................................25 5.3 Water solubility.......................................................................................................26 5.4 Partition co-efficient (n-octanol/water; log KOW) .....................................................29 5.5 n-Octanol/air partition coefficient (log KOA).............................................................31 5.6 Dissociation constant .............................................................................................33 6 Environmental fate properties .....................................................................................34 6.1 Degradation ...........................................................................................................34 6.2 Environmental distribution......................................................................................37 3 of 115 6.3 Bioaccumulation.....................................................................................................41 7 Ecotoxicology ..............................................................................................................44 7.1 Aquatic compartment .............................................................................................44 7.2 Terrestrial compartment.........................................................................................49 7.3 Microbiological activity in sewage treatment systems ............................................49 7.4 Atmospheric effects ...............................................................................................49 8 Mammalian toxicology.................................................................................................50 8.1 Toxicokinetics ........................................................................................................50 8.2 Acute Toxicity .......................................................... 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Bookmark not defined. 8.3 Repeated dose toxicity...........................................................................................50 8.4 Mutagenicity...........................................................................................................52 8.5 Carcinogenicity ......................................................................................................54 8.6 Toxicity to reproduction (effects on fertility and developmental toxicity).................55 8.7 Summary of mammalian toxicology .......................................................................56 9 Environmental hazard assessment .............................................................................57 9.1 Classification and labelling.....................................................................................57 9.2 Assessment of endocrine disrupting (ED) properties .............................................58 9.3 PBT and vPvB assessment ...................................................................................58 9.4 Groundwater hazard ..............................................................................................58 9.5 Greenhouse gas hazard ........................................................................................59 9.6 Limit values ............................................................................................................60 10 Exposure assessment..............................................................................................62 10.1 Environment........................................................................................................62 11 Risk characterisation................................................................................................65 12 Conclusions and recommendations .........................................................................66 12.1 Conclusion ..........................................................................................................66 4 of 115 12.2 Recommendations ..............................................................................................66 13 References...............................................................................................................68 14 List of abbreviations .................................................................................................83 Appendix A: Literature search............................................................................................88 15 Appendix B: Structural analogues............................................................................89 Appendix B: QSAR models..............................................................................................112 Would you like to find out more about us or your environment? ......................................115 5 of 115 Research at the Environment Agency Scientific research and analysis underpins everything the Environment Agency does. It helps us to understand and manage the environment effectively. Our own experts work with leading scientific organisations, universities and other parts of the Defra group to bring the best knowledge to bear on the environmental problems that we face now and in the future. Our scientific work is published as summaries and reports, freely available to all. This report is the result of research commissioned by the Environment Agency's Chief Scientist's Group. You can find out more about our current science programmes at https://www.gov.uk/bovernment/orbanisations/environment-abency/about/research If you have any comments or questions about this report or the Environment Agency's other scientific work, please contact (@,environment-aciency.gov.uk. Professor Doug Wilson Chief Scientist 6 of 115 Acknowledgements The co-operation and additional information provided by the sole UK importer, AGC Chemicals Europe Ltd, is acknowledged. 7 of 115 Executive summary There is growing regulatory concern at international level about the emissions of per- and polyfluoroalkyl substances (PFAS) to the environment. This is due to their extreme persistence, which leads to long-term exposure of both people and wildlife. High levels of exposure to certain PFAS has also been shown to cause harmful effects in humans and some have been declared to be `Persistent Organic Pollutants' (POPs) under the United Nations Environment Programme (UNEP) Stockholm Convention. The UK Government is developing an action plan to address the concerns arising from PFAS. As a contribution to this work, the Environment Agency is reviewing PFAS that are known to be used at two UK production facilities. The substance reviewed in this evaluation report is 3,3,4,4,5,5,6,6,6-nonafluorohexene, also known as perfluorobutylethylene or PFBE (CAS number 19430-93-4). PFBE is a PFAS that belongs to the group of hydrofluorocarbons. The Environment Agency has identified publicly available information on the regulatory status, uses, physico-chemical properties, environmental fate and (eco)toxicity of PFBE and has reviewed this information for reliability. Further information has also been sought from the UK importer. The data were then used to conduct an environmental hazard and risk assessment. Human health hazards have only been reviewed in so far as they are relevant for the environmental assessment. Potential risks to people following environmental exposure have not been addressed. PFBE is not readily biodegradable, does not hydrolyse and is not expected to undergo photolysis in air. In addition, there is no information on degradation rates or half-lives available from simulation studies. PFBE is therefore considered to be potentially persistent or very persistent (P/vP). Based on screening data, PFBE is not considered to be bioaccumulative (B) in aquatic organisms. Bioaccumulation in air-breathing organisms is unlikely to be high, but there is some uncertainty in this conclusion. PFBE does not meet the criteria to be considered toxic (T). PFBE is therefore not considered to be PBT or vPvB. Draft criteria have been proposed to identify chemicals that are persistent, mobile and toxic (PMT) or very persistent and very mobile (vPvM). PFBE does not meet the draft PMT criteria, but does screen as vPvM. On the basis of low releases and lack of significant adverse effects according to the information currently available, the Environment Agency considers that the direct risk to the environment from PFBE is likely to be low. However, PFBE is expected to have a long atmospheric half-life and it could make a contribution to global warming based on analogy with other hydrofluorocarbons. A number of recommendations are made to the UK importer of PFBE to improve the data package to allow a more robust assessment of the environmental hazards and risks posed by PFBE. This report, along with others in this series, will be used by the Environment 8 of 115 Commented [MS2]: See comment on p59. GWP = 0.16 and ODP = 0.000. Agency to inform the UK Government action plan on PFAS and the PFAS Regulatory Management Options Analysis (RMOA) being conducted under the UK REACH Regulation. 9 of 115 Introduction There is growing international concern about the emissions of per- and polyfluoroalkyl substances (PFAS) to the environment. This is principally due to their extreme persistence, which could lead to long-term irreversible exposure of both people and wildlife. High levels of exposure to certain PFAS has also been shown to cause harmful effects in humans and some have been declared to be `Persistent Organic Pollutants' (POPs) under the United Nations Environment Programme (UNEP) Stockholm Convention. The UK Government is developing an action plan to address the concerns arising from PFAS. As a contribution to this work, the Environment Agency is reviewing substances that are being used at two known production facilities in the UK, namely AGC Chemicals Europe, Ltd of Thornton Cleveleys, Lancashire and F2 Chemicals Ltd of Preston, Lancashire. Based on information provided by these companies, a provisional list of PFAS for further consideration was drawn up. This was narrowed down to the following twelve substances which were, at the time, registered at more than 1 tonne per annum under the EU REACH Regulation (European Commission, 2020). Additionally a potential unregistered substitute for perfluoroctanesulfonic acid (PFOS, which is a known POP) was included that had been identified from UK surface water monitoring. All of the substances chosen for further evaluation are listed below, initially using their EU-registered name: Ammonium difluoro[1,1,2,2-tetrafluoro-2-(pentafluoroethoxy)ethoxy]acetate - also known as perfluoro(2-ethoxy-2-fluoroethoxy)acetic acid ammonium salt or EEA-NH4 (CAS no. 908020-52-0) Trideca-1,1,1,2,2,3,3,4,4,5,5,6,6-fluorohexane - also known as 1H-Perfluorohexane or 1H-PFHx (CAS no. 355-37-3) 3,3,4,4,5,5,6,6,6-Nonafluorohexene - also known as perfluorobutylethylene or PFBE (CAS no. 19430-93-4) 1,1,1,2,2,3,3-Heptafluoro-3-[(trifluorovinyl)oxy]propane - also known as perfluoro(propyl vinyl ether) or PPVE (CAS no. 1623-05-8) (E)-1,1,1,2,3,4,5,5,5-nonafluoro-4-(trifluoromethyl)pent-2-ene - also known as perfluoro(4-methyl-2-pentene) or PFMP (CAS no. 3709-71-5) 1,1,1,2,2,3,3,4,5,5,5-Undecafluoro-4-(trifluoromethyl)pentane - also known as perfluoroisohexane or PFiHx (CAS no. 355-04-4) 1,1,2,2,3,3,4,5,5,6-Decafluoro-4,6-bis(trifluoromethyl)cyclohexane - also known as perfluoro-1,3-dimethylcyclohexane or PFDMC (CAS no. 335-27-3) Perfluorooctane or PFO (CAS no. 307-34-6) Perflunafene - also known as perfluorodecalin or PFD (CAS no. 306-94-5) Perfluoroperhydrophenanthrene - also known as perfluorophenanthrene or PFPh (CAS no. 306-91-2) 10 of 115 Commented [DS3]: This intro needs to be updated to reflect the fact that we are producing a smaller number of reports (so needs to be consistent with Simon's updated section).  Hexafluoropropene or HFP (CAS no. 116-15-4) Octafluoropropane - also known as perfluoropropane or PFP (CAS no. 76-19-7) The additional unregistered substance also being considered is: 6:2 Chlorinated polyfluorinated ether sulfonate - also known as `F-53B' (CAS no. 73606- 19-6) This report summarises the evaluation of the substance highlighted above in bold (i.e. PFBE), to address the following questions: 1. What data are currently available, and are they sufficiently reliable to assess its environmental hazards and risks? 2. Can we establish numerical exposure limits for assessing environmental impacts (e.g. for use under permitting regimes)? 3. Is it potentially able to reach remote environments and what is its groundwater contamination potential? 4. Is it a potential candidate for future risk management? 5. What information gaps remain, and what is the most appropriate way of obtaining this information? Information on the substance's properties and uses is provided on the European Chemicals Agency (ECHA) public dissemination website. Unless stated otherwise, the website and data provided by the Registrant are the source of the information for this report. This report describes the substance and its structural analogues, its analytical chemistry, manufacture and use, regulatory status and then various environmentally relevant properties. This is followed by an environmental hazard assessment in Section 9, and an exposure and risk assessment in Sections 10 and 11. The final section (Section 12) summarises our findings. Although the focus of this evaluation is on environmental hazards and risks, there is a summary of mammalian toxicology information, where available and relevant. However, this report is not intended to provide a full consideration of hazards, exposure and risks to human health. This is not a formal UK REACH Evaluation. 11 of 115 1 Substance identity 1.1 Name and other identifiers Table 1.1 Substance identifiers Public name IUPAC name CAS name EC number CAS number Index number in Annex VI of the CLP Regulation Molecular formula Molecular weight SMILES code Synonyms Type of substance 3,3,4,4,5,5,6,6,6-nonafluorohexene 3,3,4,4,5,5,6,6,6-nonafluorohex-1-ene Perfluorobutyl(ethylene) 243-053-7 19430-9-34 Not applicable C6H3F9 246.07 g/mol C=CC(C(C(C(F)(F)F)(F)F)(F)F)(F)F (Perfluorobutyl)ethylene ; 3,3,4,4,5,5,6,6,6Nonafluoro-1-hexene ; Perfluorobutylethylene ; 1H,1H,2H-Perfluoro-1-hexene ; 3,3,4,4,5,5,6,6,6-nonafluorohex-1-ene ; 1h,1h,2h-perfluorohexene ; (Perfluorobutyl)ethene ; 1-Hexene, 3,3,4,4,5,5,6,6,6-nonafluoro- ; 3,3,4,4,5,5,6,6,6Nonafluorohexene ; (Perfluoro-n-butyl)ethylene ; perfluorobutyl ethylene ; 1h,1h,2hperfluorohex-1-ene ; Nonafluorobutylethene ; 1h,1h,2h-nonafluorohex-1-ene ; Zonyl(R) PFBE fluorotelomer intermediate ; 3,3,4,4,5,5,6,6,6Nonafluoro-1-hexene ; 3,3,4,4,5,5,6,6,6nonakis(fluoranyl)hex-1-ene ; MP7360000 ; PFBE mono-constituent 12 of 115 Figure 1.1 Structural formula of PFBE representing the atoms and how they are bonded to each other The substance is called PFBE throughout this report. 1.2 Structurally related substances PFBE has a perfluorinated chain of 4 carbon atoms with a non-fluorinated ethene group at one end of the chain. It is an example of a hydrofluorocarbon (HFC). Structurally related substances to PFBE were identified through the US Environmental Protection Agency (US EPA) CompTox Dashboard (US EPA, 2022a) and the PubChem Dashboard (NCBI, 2022). The dashboards identify related substances in their records using connectivity (first layer `InChI'), mixture components and isotopic isomers, and the Tanamito coefficient (>0.8). InChI is the IUPAC international identifier, and uses a software model to assign an identifier to a molecule which describes structure. The dashboards suggested 99 structural analogues, tabulated in Appendix C. Only 3 of the 99 substances have been subject to registration under EU REACH. The Environment Agency therefore selected these as suitable structural analogues for PFBE, based on chemical similarity (Tanamito coefficient >0.8) and the availability of relevant data. They are listed in Table 1.2. These analogues have slightly shorter or longer carbon chains with similar structural features to PFBE, and so provide additional context to support conclusions about the behaviour of this type of substance. 13 of 115 Table 1.2 Name Substance identifiers for selected analogues of PFBE Tridecafluorooctene 1,6-Divinylperfluorohexane 3,3,4,4,4Pentafluorobut-1-ene CAS number 25291-17-2 1800-91-5 374-27-6 EC number 246-791-8 217-288-0 206-775-3 Structural formula Molecular formula C8H3F13 C10H6F12 C4H3F5 Molecular weight 346.09 g/mol 354.14 g/mol 146.06 g/mol SMILES code FC(F)(F)C(F)(F)C(F)(F)C( F)(F)C(F)(F)C(F)(F)C=C FC(F)(C=C)C(F)(F)C(F) (F)C(F)(F)C(F)(F)C(F)( F)C=C FC(F)(F)C(F)(F)C=C Synonyms 3,3,4,4,5,5,6,67,7,8,8,8Tridecafluorooct-1-ene 3,3,4,4,5,5,6,6,7,7,8,8- Dodecafluorodeca-1,9diene Comment Differs from PFBE only in the length of the fluorinated carbon chain, with 2 additional fluorinated carbon atoms. Differs from PFBE in having 2 terminal ethene groups and 2 additional fluorinated carbon atoms. Differs from PFBE only in the length of the fluorinated carbon chain, with 2 fewer fluorinated carbon atoms. Reference ECHA, 2022d US EPA, 2022c ECHA, 2022c US EPA, 2022n ECHA, 2022e US EPA, 2022ck 1.3 Transformation products There is no information relating to identified or predicted transformation products of PFBE in the REACH registration. Although the carbon-fluorine bond is very strong, a slow reaction occurred in the ready biodegradation test (Section 6). The transformation 14 of 115 products were not identified but could be shorter perfluorinated chains following removal of the ethene group, either perfluoropentanoic acid or perfluorobutanoic acid. These would be expected to be highly resistant to further transformation. 15 of 115 2 Analytical chemistry 2.1 Regulatory and academic methods According to Corrigendum 1 of REACH (EC, 2007) and Article 119 (Electronic Public Access) the Registrant has to be able to provide "analytical methods if requested in accordance with Annexes IX or X which make it possible to detect a dangerous substance when discharged into the environment as well as to determine the direct exposure of humans". PFBE is not classified as hazardous, and the EU Registrant has not provided such analytical details in their registration dossier (ECHA, 2022a). The Environment Agency searched the academic literature for analytical methods for the detection of PFBE in environmental matrices (water, fresh and marine; soil, sediment, sludge and air). Thousands of hits for methods relating to short chain perfluorocarbons (PFCs) were obtained, although no specific methods for PFBE were identified. Analytical monitoring of PFBE in environmental matrices is not documented as part of national or international monitoring programmes. It is, however, present in databases operated by the Swedish Chemicals Agency, OECD Global Database, EPA ToxCast/Tox21 and several others. No validated associated analytical methods were presented alongside. The US EPA states that methods for measurement of volatile PFAS in air are under development and undergoing validation (US EPA, 2022da). The website of the contract laboratory Eurofins Test America (www.EurofinsUS.com/PFAS) indicates they have a validated method for the quantification of volatile perfluoroalkyl carboxylic acids in air. This method may be adaptable to allow measurement of PFBE. The Environment Agency considers that a robust analytical method will include the following details: Instruments and consumables including chromatographic column, temperature, mobile phase composition, flow rates, gradient or isocratic separation and the detector optimisation and configuration. Certified reference standards, calibration range and sensitivity, limit of detection, limit of quantification, column recoveries, stability and reproducibility. Sample preparation including clean-up consumables, concentration techniques and use of internal standards (plus justification for choice) for validation and recoveries, etc. Identification and discussion of technical limitations. 16 of 115 3 Import, manufacture and uses Although the UK left the European Union (EU) at the end of January 2020, European legislation in place by December 2020 has been retained in UK law, and ECHA is still the most relevant source of information about chemicals on the UK market at the time of writing. PFBE is registered under the EU REACH Regulation at a supply level of 100 to 1 000 tonnes/year. There are two EU REACH Registrants, AGC Chemicals Europe Ltd (www.agcce.com) and Chemours Netherlands B.V. (both located in the Netherlands). There is a single grandfathered registration under UK REACH at a supply level of 100 to 1000 tonnes/year. The substance is imported into the UK for use at AGC Chemicals Europe, Ltd's manufacturing site at Thornton Cleveleys near Blackpool, Lancashire. AGC Chemicals Europe, Ltd has an environmental permit (ref: EPR/BU5453IY) under the Environmental Permitting (England and Wales) Regulations 2016. It produces two main product streams: polytetrafluoroethylene (PTFE) with a capacity up to 4 000 tonnes/year ethylene-tetrafluoroethylene (ETFE) with a capacity up to 2 000 tonnes/year PFBE is used as a co-monomer to manufacture PTFE and ETFE. AGC Chemicals Europe, Ltd has informed the Environment Agency that their polymer products are used in many applications including for wire coatings, cables and tubing in the semi-conductor industry and cable insulation in the automotive and aerospace industry. An overview of uses provided in the EU REACH registration information on the ECHA website is presented in Table 3.1. Table 3.1 Overview of uses Life cycle stage Use(s) ERC6a: Use of intermediate ERC 6c: Use as a monomer in polymerisation process Uses at industrial sites PROC 1: Chemical production or refinery in closed process without likelihood of exposure or processes with equivalent containment conditions PROC 2: Chemical production or refinery in closed continuous process with occasional controlled exposure or processes with equivalent containment conditions PROC 3: Manufacture or formulation in the chemical industry in closed batch processes with occasional controlled exposure or processes with equivalent containment conditions 17 of 115 Life cycle stage Use(s) PROC 8b: Transfer of substance or mixture (charging and discharging) at dedicated facilities PROC 15: Use as laboratory reagent Uses by professional workers None identified in registration dossier Consumer Uses None identified in registration dossier Article service life None identified in registration dossier Note: PROC codes are Process Codes, which describe process types. 18 of 115 4 Summary of relevant regulatory activities 4.1 Europe 4.1.1 European Chemicals Agency (ECHA) The Public Activities Co-ordination Tool (PACT) (https://echa.europa.eu/pact accessed March 2022) provides an overview of the substance-specific activities that EU regulatory authorities are working on under the EU REACH and CLP Regulations. To date the only substance-specific activities identified for PFBE are dossier evaluation and a testing proposal for a sub-chronic toxicity study (90 days) (inhalation) according to OECD Test Guideline (TG) 413 in the rat (OECD, 2018b), which was concluded on 11 January 2016. Between May and July 2020, the national authorities of Germany, the Netherlands, Norway, Sweden and Denmark invited interested parties to send in evidence and information on the use of PFAS in preparation for a joint EU REACH restriction proposal. The current scope of the work is wide and includes all substances that contain at least one aliphatic -CF2- or -CF3 element (ECHA, 2022b). PFBE is therefore within scope of this initiative. 4.1.2 European Food Safety Agency (EFSA) EFSA provides scientific advice on safety of food additives, enzymes, flavourings, processing aids and other substances intentionally added to food; safety of food packing and other food contact materials. A search of the EFSA website (http://www.efsa.europa.eu/) identified PFBE as noted under three published scientific opinions. These were: Scientific opinion on the safety evaluation of the substance, (perfluorobutyl)ethylene, CAS No. 19430-93-4, for use in food contact materials (February 2011) 62nd plenary meeting of the European Food Safety Authority (EFSA) panel on food contact materials, enzymes, flavourings and processing aids (CEF), request for the re-evaluation of PFBE (June 2016) 5th plenary meeting of the EFSA panel on food contact materials, enzymes and processing aids (CEP) panel, request for the re-evaluation of PFBE (February 2019) 19 of 115 4.1.3 Oslo and Paris Convention for the Protection of the Marine Environment of the North-East Atlantic (OSPAR) The Oslo and Paris Convention for the Protection of the Marine Environment of the NorthEast Atlantic (OSPAR) is a mechanism by which 15 national governments and the EU cooperate to protect marine resources. Much of OSPAR's work on chemicals is now being addressed by REACH activities. PFBE is not on the OSPAR List of Substances of Possible Concern (www.ospar.org/workareas/hasec/chemicals/possible-concern/list, accessed March 2022). PFBE is also not on the list of Chemicals for Priority Action adopted in 2002 (www.ospar.org/workareas/hasec/chemicals/priority-action, accessed March 2022). 4.2 Regulatory activity outside Europe 4.2.1 United States PFBE is listed as one of the substances undergoing risk evaluation as part of US EPA's existing chemical initiative under the Toxic Substances Control Act (TSCA) to determine whether they present an unreasonable risk to public health or the environment under the conditions of use (US EPA, 2022). 4.2.2 Canada A search did not identify PFBE as being under assessment under the Prohibition of Certain Toxic Substances Regulations, 2012 (https://www.canada.ca/en/environmentclimate-change/services/canadian-environmental-protection-act-registry/substanceslist/toxic.html, accessed March 2022). 4.2.3 Australia A search did not identify PFBE as being under assessment under the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) (https://www.nicnas.gov.au/chemical-information/imap-assessments/imap-assessments, accessed March 2022), or on the list of chemicals with high hazard (https://www.industrialchemicals.gov.au/help-and-guides/list-chemicals-high-hazardscategorisation) accessed March 2022). 4.2.4 New Zealand A search did not identify PFBE as being under assessment under the Hazardous Substances and New Organisms Act 1996 (https://www.epa.govt.nz/industryareas/hazardous-substances/, accessed March 2022; https://www.epa.govt.nz/industryareas/hazardous-substances/chemical-reassessment-programme/screened-chemicalslist/, accessed March 2022). 20 of 115 4.2.5 Japan Industrial chemicals are managed under the Chemical Substances Control Law (CSCL), most recently amended in 2009 (https://www.nite.go.jp/chem/jcheck/list3.action?category=141&request_locale=en, accessed March 2022). Under the Act there are 3 lists: Class I Specified Chemicals - 34 substances (persistent, bioaccumulative, toxic) Class II Specified Chemicals - 23 substances (toxic and high risk) Priority Assessment Chemical Substance (PACS), currently 227 substances PFBE is not on any of the above lists. 4.3 Other international agreements 4.3.1 United Nations Stockholm Convention on Persistent Organic Pollutants (POPs) PFBE is not identified as a POP, and is not currently under evaluation (http://chm.pops.int/TheConvention/ThePOPs/AllPOPs/tabid/2509/Default.aspx, accessed March 2022). 4.3.2 Greenhouse gases Although not a gas, PFBE is a volatile liquid and environmental exposure is therefore likely to result in atmospheric exposure. Fluorinated gases (`F-gases') may contribute to climate change due to their global warming potential and they are often used as substitutes for ozone-depleting substances, because they do not damage the atmospheric ozone layer (EC, n.d.). F-gases are regulated under the Ozone-Depleting Substances and Fluorinated Greenhouse Gases (Amendment etc.) (EU Exit) Regulations (2019) which aims to reduce the emission of these gases into the environment. Annex I and II list the F-gases subject to the Regulation and PFBE is not included. 21 of 115 5 Physicochemical properties This evaluation focusses on vapour pressure, water solubility and n-octanol/water partition coefficient, as they are the key physicochemical end points for the environmental assessment of most organic chemicals. Surface tension and dissociation constant are also considered. The available information is discussed in this section, and a conclusion drawn about which value the Environment Agency considers most suitable for the further evaluation of this substance. The source of this information is the publicly available EU REACH registration database (ECHA, 2022a; accessed March 2022) unless otherwise indicated. The reliability scores provided in the full registration for individual studies are cited. These scores have presumably been generated in accordance with the ECHA R.4. Guidance Document (ECHA, 2011). The Environment Agency has not evaluated original study reports. Where an independent evaluation has not been possible for a study, or the EU REACH registration dossiers lack sufficient supporting information, this is noted in the text (except in the case of data presented in academic journals or obtained using quantitative structure-activity relationship (QSAR) models). Where an endpoint value is missing from the EU REACH registration dossier, or an initial review raised questions around the validity of an experimentally derived value, the assessment has been supplemented with information from analogues (see Section 1) and openly available in silico QSAR models. REACH registration data for the analogues are taken at face value, although preference is given to regulatory reviews (if available). QSAR models are generally considered to be a screening-level tool and measured values are preferable provided that they are sufficiently reliable. Further information is provided in Appendix B. An overview of physicochemical data provided by the Registrant or generated by the Environment Agency is presented in Table 5.1. 22 of 115 Table 5.1 Property Summary of physicochemical properties for PFBE Value(s) Reliability Physical state at 20 C and 101.3 kPa Clear colourless liquid with an ether like odour Registrant: 2 (key study) Melting / freezing point <-20C at 101.3kPa (GLP, EU Method A.1) Registrant: 1 (key study) Boiling point 58C at 101.3kPa (ACGIH handbook) Registrant: 2 (key study) Relative density 1 400 g/L (1.4 g/cm3 at 20 C (ACGIH handbook) Registrant: 2 (key study) Vapour pressure 22 kPa at 20 C (167 mmHg) (Du Pont study) Registrant: 2 (key study) Surface tension Data waiver n/a Water solubility n-Octanol/water partition coefficient (log KOW) n-Octanol/air partition coefficient (log KOA) Dissociation constant 15.6 mg/L at 20 C and pH 7 (GLP, OECD TG 105) 4.13 at 25 C and pH 7.4 (GLP, OECD TG 117) Registrant: 1 (key study) Registrant: 1 (key study) 0.47 (KOAWIN v1.10 estimate, EPIsuiteTM, Log Kow used 4.99) Not applicable Environment Agency: n/a - Source EU REACH Registration dossier EU REACH Registration dossier EU REACH Registration dossier EU REACH Registration dossier EU REACH Registration dossier EU REACH Registration dossier EU REACH Registration dossier EU REACH Registration dossier Environment Agency - 5.1 Vapour pressure 5.1.1 Measured data The reported vapour pressure of PFBE in the EU REACH registration dossier was 22 kPa at 20 C (ECHA, 2022a). This key experimental study was not performed according to an accepted test guideline. No further details on the method were provided, although the Registrants rate it reliable with restrictions (Klimisch 2). The Environment Agency has been unable to review the full study report and therefore cannot comment on its reliability. An additional experimentally derived vapour pressure of 31.7 kPa at 20 C is available on the PubChem database (NCBI, 2022), acquired from NIOSH 2008. The reliability of this result is unknown. 5.1.2 Predicted data No in silico predictive data were presented by the Registrant for this endpoint as there is an experimental result. For comparative purposes, the Environment Agency has considered readily available QSARs to test how they perform for this type of substance. The ChemSpider database 23 of 115 and the US EPA CompTox dashboard contain predicted vapour pressures for PFBE generated from EPISuiteTM v4.0 (T.E.S.T.), ACD/Labs and OPERA software (RSC, 2022; US EPA, 2022a). Median predicted values are presented in Table 5.2. The Environment Agency converted the values from mmHg to kPa. Table 5.2 Source Predicted vapour pressures for PFBE Prediction method ACD/Labs (US EPA 2022a) ACD/Labs (RSC 2022) Not available Not available EPISuiteTM Estimation programme MPBPWIN v 1.42 (RSC 2022) T.E.S.T. (EPISuiteTM v 4.00) (US EPA 2022a) OPERA (US EPA 2022a) Mean of Antoine and Grain methods BP = 7.79 C MP = -105.83 C Not available Not available Predicted vapour pressure (kPa/mmHg) at 25 C 44.26 kPa 332 mmHg 44.32 kPa 332.4 mmHg 183.98 kPa 1 380 mmHg 55.86 kPa 419 mmHg 285.31 kPa 2.14 103 mmHg In silico predicted values should always be treated with caution where substances in the training set and external test set are not visible. For the ACD/Labs and MPBPWIN models this information was not available. Therefore, no assessment of applicability could be performed. The good agreement between predicted and measured value using the ACD/Labs model may be coincidental. Structural analogues of PFBE were included in both the training set and external test sets for the T.E.S.T. and OPERA models. Predicted vapour pressure values could therefore be within the applicability domain of both models, although this was not clear. Despite this, there is a large difference between the predicted and experimental values, illustrating the difficulty in prediction of properties of PFAS and that the OPERA model in particular is not reliable in this case. 5.1.3 Data from structural analogues Experimentally derived vapour pressures were presented for two of the selected structural analogues of PFBE, namely: 3,3,4,4,5,5,6,6,7,7,8,8-dodecafluorodeca-1,9-diene: 1 200 Pa (1.2 kPa) at 20 C and 1 900 Pa (1.9 kPa) at 25 C (ECHA, 2022c; US EPA, 2022n) 3,3,4,4,4-pentafluorobut-1-ene: 1.9 to 2.1 105 Pa (190 to 210 kPa) at 25 C (ECHA, 2022e; US EPA, 2022ck) 24 of 115 5.1.4 Additional sources Due to the availability of experimentally derived values for vapour pressure for PFBE as well as two of its structural analogues no additional sources were consulted. 5.1.5 Recommended value An experimental vapour pressure value of 22 kPa at 20 C was reported for PFBE by the Registrant (ECHA, 2022a). Furthermore, a similar experimentally derived vapour pressure (31.7 kPa at 20 C) has been reported separately (NCBI, 2022). Neither of these values were accompanied by adequate supporting information to allow an assessment of reliability. In silico predicted values range from 44.26 kPa to 285.31 kPa (both at 25 C; US EPA, 2022a and NCBI, 2022). There is large variation between predicted and measured values even with temperature taken into account, and the Environment Agency does not consider any of these predicted values to be reliable. Vapour pressures for two of the selected structural analogues were available. These were 1.2 kPa at 20 C for 3,3,4,4,5,5,6,6,7,7,8,8-dodecafluorodeca-1,9-diene, and between 19 and 21 kPa at 25 C for 3,3,4,4,4-pentafluorobut-1-ene. The vapour pressure for PFBE would be expected to lie between these two values, because it is intermediate in terms of molecular size. Assuming that the analogue data are reliable (which has not been checked), this could suggest that the measured vapour pressures for PFBE are overestimated. The Environment Agency assumes that the vapour pressure of PFBE is likely to be around 22 kPa at 20 C, and this value is taken forward for this evaluation because it is reasonably consistent with an apparently independent measurement available on the PubChem database. It may however be an over-estimation. 5.2 Surface tension 5.2.1 Measured data The EU REACH registration dossier waives this endpoint based on the structure of PFBE. No data for the surface tension of PFBE could be found in the literature. 5.2.2 Predicted data No predicted data for surface tension were provided by the Registrant. The US EPA CompTox dashboard presents predicted surface tension endpoint values for PFBE generated from T.E.S.T. and ACD/Labs software (US EPA, 2022a). These were 11 mN/m and 12.9 mN/m, respectively. Commented [MS4]: What is the basis for this speculative assumption? The value reported is that from the SDS and studies. 25 of 115 The ChemSpider database also contains a predicted surface tension of 12.93 dyne/cm [mN/m] performed using ACD/Labs software (RSC, 2022). In silico predicted values should always be treated with caution where substances in the training set and external test set are not visible. For the T.E.S.T. model structural analogues of PFBE were included in the training set and external test sets (US EPA, 2022a). This information was not available for the ACD/Labs models. 5.2.3 Data from structural analogues No data on surface tension were presented for any of the three structural analogues of PFBE. 5.2.4 Recommended value No experimental data for the surface tension of PFBE was in the registration dossier, nor were any to be found in the literature. The Environment Agency considers that in silico predicted values of surface tension for PFCs relate to the neat substance rather than that of an aqueous solution and so are not relevant for this evaluation. Surface tension in water is important because it affects the measurement and interpretation of other physico-chemical properties such as water solubility and partition coefficients. The Environment Agency notes that PFBE does not have any hydrophilic structural groups that can form hydrogen or Van der Waals bonds in water. This suggests that it is unlikely to be significantly surface active in aqueous solutions. 5.3 Water solubility 5.3.1 Measured data The EU REACH registration dossier summarises a water solubility value of 15.6 mg/L at 20 C and pH 7, measured using a shake flask method in accordance with OECD TG 105 (OECD, 1995a; ECHA, 2022a). The reference, deemed GLP compliant, is dated 2001 but is not named. Water solubility was assessed across 4 flasks with measurements taken at day 4, 6, 8 and 12, ranging from 11.50 mg/L to 249.56 mg/L. All of the high values originated from one vessel and these data were excluded as outliers. The Registrants consider the data reliable without restrictions (Klimisch score 1). The Environment Agency notes that there were variations in the measured concentrations. From the Registrants' summary it is unclear whether any amendment to the study design was made to take into account the volatility of PFBE, which could have contributed to the observed variations. Other types of PFAS have the potential to form micelles in water, and it is not known whether this is the case for PFBE. 26 of 115 5.3.2 Predicted data No in silico predictive data were presented by the EU REACH Registrant for this endpoint as there is an experimental result. For comparative purposes, the Environment Agency has considered readily available QSAR software to test how they perform for this type of substance. The ChemSpider database and US EPA CompTox dashboard contained predicted water solubility endpoint values generated from EPISuiteTM, in addition, the CompTox database also included data from T.E.S.T. and OPERA software (RSC, 2022; US EPA, 2022a). These values are presented in Table 5.3. Values were converted by the Environment Agency from mol/L to mg/L using a molecular weight of 246.07 g/mol. Table 5.3 Predicted water solubility values for PFBE Model EPISuiteTM water solubility estimate from log KOW (WSKOW v1.41) EPISuiteTM water solubility estimate from fragments (WATERNT v1.01 est.) T.E.S.T. (EPISuiteTM v 4.00) OPERA Details - Water solubility 1.36 mg/L at 25 C - 0.15 mg/L Predicted value: 7.23 10-6 mol/L Reasonable confidence, low mean absolute error Predicted value: 3.04 10-5 mol/L Global applicability domain: outside Local Applicability domain index: 0.491 Confidence Interval 0.572 27.31 mg/L 22.40 mg/L In silico predicted values should always be treated with caution where substances in the training set and external test set are not visible. Guidance provided with the WSKOWWIN model indicates that the relationship between the experimental and predicted values for a training set of 1 450 compounds was good, with a correlation coefficient (R2) of 0.97, standard deviation of 0.409 and an average deviation of 0.313. The validation set contained several PFCs (see Appendix B) and it is likely that the predicted value for PFBE falls within the applicability domain of the model. Guidance provided with the WATERNT model indicates that the relationship between the experimental and predicted values for a training set of 4 636 compounds was good, with an R2 of 0.85, standard deviation of 1.045 and an average deviation of 0.796. The validation set contained several PFCs (see Appendix B) and it is likely that the predicted value for PFBE falls within the applicability domain of the model. 27 of 115  Data generated by T.E.S.T model for PFBE were assessed as having reasonable confidence with low mean absolute error. Two analogues with reasonable tanamito similarity (>0.80) are included in the training set. These data should still be considered with caution. Structural analogues of PFBE were not included in the training set for the OPERA model. A low global applicability domain score is also given, so the prediction should therefore not be considered reliable. The in silico predictions therefore suggest that the water solubility of PFBE may lie in the range 0.15 to 27.3 mg/L. The model which predicts the closest value to the measured water solubility was T.E.S.T., which may just be coincidence. 5.3.3 Data from structural analogues Experimentally derived water solubility were presented for two of the selected structural analogues of PFBE, namely: 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooct-1-ene: 1.21 mg/L at 25 C and pH 6 (ECHA, 2022d; US EPA, 2022c). 3,3,4,4,5,5,6,6,7,7,8,8-dodecafluorodeca-1,9-diene: 1.61 mg/L at 20 C and at pH 5.5 (ECHA, 2022c; US EPA, 2022n). These data have not been evaluated by the Environment Agency, so it is not known if steps were taken to address volatility. 5.3.4 Recommended value A water solubility of 15.6 mg/L at 20 C is reported for PFBE from a modern experimental study, which the EU REACH Registrant considers to be fully reliable. Variations in concentrations were noted between vessels in the study, which were excluded from the results. The influence of micelle formation and volatility is unclear, so the Environment Agency suggests that the study may be reliable with restrictions (Klimisch 2), subject to receipt of a full study report. Predicted values of water solubility ranged from 0.15 to 27.3 mg/L. Water solubility measurements for two of the selected structural analogues were 1.21 mg/L at 25 C for 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooct-1-ene, and 1.61 mg/L at 20 C for 3,3,4,4,5,5,6,6,7,7,8,8-dodecafluorodeca-1,9-diene. The solubility of PFBE would be expected to be somewhat higher than these two values, because it has a smaller molecular size, so the reported value is consistent. The Environment considers that the water solubility of 15.6 mg/L at 20 C is a suitable estimate for the purposes of this evaluation. Commented [MS5]: Why is this opinion included? Formatted: Strikethrough 28 of 115 5.4 Partition co-efficient (n-octanol/water; log KOW) 5.4.1 Measured data The key experimental study for n-octanol/water dissociation constant in the EU REACH registration dossier was carried out according to OECD TG 117 (OECD, 2004) (high performance liquid chromatography (HPLC) method) and was GLP compliant (ECHA, 2022a). A log KOW value of 4.13 at 25 C and pH 7.4 was measured. The test material was Zonyl PFBE provided at 96% purity and the reference substances were formamide, naphthalene, phenanthrene, fluoranthene, perylene, dibenz(ah)anthracene and benzo(ghi)perylene. Three repeats and the mean of the three were presented for each chemical. Experimental retention times from triplicate measurements were consistent. OECD TG 117 states that the method is suitable for chemicals with a log KOW in the range 0 to 6 and that retention times should be measured in duplicate. The Registrants met these requirements. Little further information was given relating to the specific HPLC methodology. The EU REACH Registrants consider the data to be reliable without restrictions (Klimisch 1), and the Environment Agency agrees that the study appears to have been well performed. The Chemspider database (RSC, 2022) contains an experimental log Kow for PFBE of 4.5 but provides no further details about the method used. Therefore the reliability of this value is unknown (Klimisch 4). As noted in Section 5.3.4, PFAS may form colloids in water. It is possible that the same may occur in organic liquids like n-octanol. The reliability of a measured KOW is therefore uncertain. 5.4.2 Predicted data No predicted data for log KOW were presented by the Registrants. For comparative purposes, the Environment Agency has considered readily available QSAR software to test how they perform for this type of substance. The US EPA CompTox dashboard and ChemSpider database contained estimated log KOW values for PFBE from ACD/Labs, ACD/Labs consensus, EPISuiteTM and OPERA (RSC, 2022; US EPA, 2022a) (Table 5.4). Table 5.4 Model Predicted log KOW values for PFBE Details ACD/Labs ACD/LogP Chemspider ACD/LogD (pH 5.5) ACD/LogD (pH 7.4) log KOW 4.15 3.71 3.71 29 of 115 Model EPISuiteTM Chemspider & CompTox ACD/Labs CompTox ACD/Labs Consensus CompTox OPERA Details KOWWIN v 1.67 estimate - - Global applicability domain: Inside Local Applicability domain index: 0.472 Confidence Interval 0.482 log KOW 4.99 4.15 3.71 3.00 In silico predicted values should always be treated with caution where substances in the training set and external test set are not visible. This information was not available for the ACD/labs model, so no assessment of the applicability can be performed. Guidance provided with the KOWWIN model indicates that the relationship between the experimental and predicted values for a validation set of 10 331 compounds was good, with an R2 of 0.94 and standard deviation of 0.47. The training set contained several PFCs (see Appendix B) and it is likely that the predicted value for PFBE falls within the applicability domain of the model. For the OPERA model, PFBE is considered inside the global applicability domain and has a local applicability domain index of 0.472. The predicted value therefore has moderate confidence. The in silico predictions therefore suggest that the log KOW of PFBE may lie in the range 3.0 to 4.99. The model which predicts the closest value to the measured log KOW is ACD/Labs, but the reliability of this model for this type of substance is unknown and so it may just be coincidence. 5.4.3 Data from structural analogues Log KOW values of 5.2 and 4.9 have been determined for 3,3,4,4,5,5,6,67,7,8,8dodecafluorodeca-1,9-diene and 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooct-1-ene, respectively (US EPA, 2022c; US EPA, 2022n; ECHA, 2022c; ECHA, 2022d). The Environment Agency has not evaluated the reliability of these values, but it suggests that this type of substance may have a high affinity for organic phases such as lipids. 30 of 115 5.4.4 Recommended value The key log KOW value for PFBE provided by the Registrants was 4.13 (ECHA, 2022a). This value was measured in a study performed according to OECD TG 117 and was GLP compliant. The Registrants assigned a reliability score of Klimisch 1 (reliable without restriction). An apparently independent measured log KOW value of 4.5 is also available on the ChemSpider database, without supporting data or information (RSC, 2022). Several predicted log KOW values for PFBE were acquired from Chemspider (RSC, 2022) and US EPA Comptox (US EPA, 2022a), ranging ranged from 3.00-4.99. The methods appear to be reasonably reliable for this type of compound. Measured log KOW values of 5.2 and 4.9 have been determined for 3,3,4,4,5,5,6,67,7,8,8dodecafluorodeca-1,9-diene and 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooct-1-ene, respectively. These substances have a higher molecular weight than PFBE, so solubility in water and n-octanol may differ. Nevertheless, these values suggest that this type of substance may have a high affinity for organic phases such as lipids. The Environment Agency considers that the log KOW 4.13 (at 25 C) presented by the Registrants should be taken forward for this evaluation. 5.5 n-Octanol/air partition coefficient (log KOA) The octanol-air partition coefficient is non-standard endpoint for hazard assessment under REACH. It is used to predict the partitioning behaviour of organic compounds between air and environmental matrices such as soil, vegetation, and aerosol particles (Meylan and Howard, 2005). Methods for measurement and calculation of the value are discussed in Environment Agency (2009). 5.5.1 Measured Data No experimental log KOA values were presented for PFBE by the EU REACH Registrant (ECHA, 2022a). 5.5.2 Predicted data There are no predicted data for log KOA in the EU REACH registration dossier. The Environment Agency has estimated a KOA value using the dimensionless Henry's Law constant (log KAW) of 2.17 (see Section 6.2.4) and the recommended log KOW value of 4.13 (Section 5.4) (KOA = KOW/KAW). The resulting log KOA is 1.96. As there is uncertainty in the KAW, the reliability of the derived KOA value is unknown The US EPA CompTox dashboard and ChemSpider database contained predicted KOA values for PFBE generated from KOAWIN v1.10 and OPERA software (RSC, 2022, US EPA, 2022a). These values are presented in Table 5.5. 31 of 115 Table 5.5 Source Predicted log KOA for PFBE Details EPISuiteTM Estimation programme KOAWIN v1.1 Log KOA (log KOW used: 4.13 and log KAW used: 3.657 estimated) Log KOA OPERA CompTox Calculation Global applicability domain: Inside Local Applicability domain index: 0.973 Confidence Interval: 0.781 Calculated from log KAW of 2.17 and a log KOW value of 4.13 (KOA = KOW/KAW) log KOA 0.47 (Environment Agency) 1.33 (ChemSpider; RSC, 2022) 1.60 1.96 In silico predicted values should always be treated with caution where substances in the training set and external test set are not visible. For the KOAWIN model, the values for log KOW presented by the Registrants were used with the predicted log KAW value (EPIsuite v4.11). The training sets for KOWWIN and HENRYWIN contain several PFCs (see Appendix B) and it is likely the predicted value for PFBE falls within the applicability domains of the two models. Therefore, the predicted KOA for PFBE can be considered to be predicted with reasonable confidence. PFBE is considered inside the global applicability domain of the OPERA model and has a high local applicability domain index (> 0.6; 0.973), so the prediction has high confidence. 5.5.3 Data from structural analogues A calculated log KOA of 2.15 was presented in the EU REACH registration of 3,3,4,4,5,5,6,6,7,7,8,8-dodecafluorodeca-1,9-diene (ECHA 2022c). However, the Environment Agency considers that the Henry's Law constant used to calculate the value may be incorrect, so it is not considered further. 5.5.4 Recommended value In silico predictions for the log KOA of PFBE are between 0.47 and 1.60, depending on the input parameters and models used. The Environment Agency has estimated a log KOA is 1.96 from the dimensionless Henry's Law constant and recommended log KOW value, although there may be some uncertainty in this value. 32 of 115 The Environment Agency considers that the log KOA likely falls in the range of 0.47 to 1.96, although there are uncertainties. A value of 1.0 is therefore suggested for the purposes of this evaluation. 5.6 Dissociation constant No experimental dissociation constants were presented for PFBE by the Registrants (ECHA, 2022a). The Environment Agency notes that a dissociation constant is irrelevant for PFBE as it has no ionisable functional groups. 33 of 115 6 Environmental fate properties The same comments about sources of data, reliability scoring and use of supplemental information apply as for Section 5. 6.1 Degradation 6.1.1 Abiotic degradation 6.1.1.1 Hydrolysis The EU REACH registration dossier contains a data waiver for hydrolysis. The justification given is that PFBE is a highly volatile liquid of low water solubility (15.6 mg/L). Volatilisation from the aquatic environment is expected to be rapid, based on the estimated Henry's Law constant (3 - 100 atm.m3/mol) and a high vapour pressure (22 kPa at 20 C). Consequently, detectable concentrations will be hard to achieve in the aquatic environment. The Environment Agency considers that the substance does not contain readily hydrolysable functional groups, so agrees hydrolysis is unlikely to be a major degradation pathway. 6.1.1.2 Phototransformation in air No relevant information is available in the EU REACH registration dossier. A statement in the PBT assessment section of the dossier indicates that PFBE is expected to have a short atmospheric lifetime of 6.4 hours, although no supporting information is provided (ECHA, 2022a). Direct photolysis of a carbon-fluorine chain is expected to be very slow, with stability expected to be sustained for more than 1,000 years (Environment Canada, 2012). Slow indirect photodegradation in air has been suggested for perfluorooctanoic acid (PFOA) by analogy with shorter chain perfluorinated acids, with an atmospheric lifetime of 130 days. The Environment Agency considers that PFBE, like highly fluorinated chemicals, is likely to have a long atmospheric half-life, although the double bond at the end of the alkyl chain may be susceptible to hydroxyl radical attack. AOP v1.91 (EPISuite v4.11) indicates an atmospheric half life of 6.421 hours based on indirect photolysis of the double bond. Gomis et al. (2015) note that the predictive power of AOPWIN for PFAS is limited despite the inclusion of some fluorinated substances in the training set, and that based on comparisons of predicted and measured photodegradation rates for 7 fluorinated substances they expect that AOPWIN may underestimate the true half-life in air. 6.1.1.3 Phototransformation in water 34 of 115 No studies are available from the EU REACH registration dossier or from published data sources. 6.1.1.4 Phototransformation in soil No studies on are available from the EU REACH registration dossier or from published data sources. 6.1.2 Biodegradation in water 6.1.2.1 Measured data Table 6.1 Summary of screening biodegradation studies Method OECD TG 301 D (Ready Biodegradability: Closed Bottle Test) GLP Results Not readily biodegradable 15.9% degradation after 28 days (DOC removal) Reliability Registrant: 1 (key study) Reference Unnamed study report (2001), cited in ECHA, 2022a The EU REACH registration dossier summarises a biodegradation screening study (OECD, 1992; OECD TG 301 D; Ready Biodegradability: Closed Bottle Test) carried out according to GLP to determine the biodegradability of PFBE in water (Unnamed Study report, 2001; ECHA 2022a). PFBE was solubilised in 1,4-dioxane, and biodegradation investigated over a 28-day period in closed bottles using microorganisms from a sewage treatment plant mainly fed with municipal wastewater. PFBE was biodegraded by 15.9 % over 28 days. The substance is volatile but use of closed bottles should have minimised the likelihood of significant losses through evaporation. PFBE is therefore not readily biodegradable. No toxic effects on the microorganisms were observed and the reference substance (sodium benzoate) was degraded by 78.4 % during the same timeframe. The Environment Agency notes that 1,4-dioxane is not a standard solvent for ready biodegradability testing. The result appears to be acceptable although there is insufficient detail in the summary to confirm that the validity criteria were met. 6.1.2.2 Predicted data The Environment Agency consulted the US EPA CompTox (US EPA, 2022a) database as well as EPIsuite v4.11 for estimated water biodegradation. The predicted biodegradation half-life from CompTox is 4.46 days. The QSAR Model Reporting Format (QMRF) states that the endpoint units are log days. The 35 of 115 antilog (assuming base e) equals 86.5 days. However, PFBE falls outside the applicability domain of the model, so this prediction is considered unreliable. Predicted half-life in water based on BIOWIN is 4 320 hours (EPIsuite v4.11), The validation set contained several PFCs (see Appendix B) and it is likely that the predicted value for PFBE falls within the applicability domain of the model. Neverless, Gomis et al. (2015) note that the predictive power of BIOWIN3 for PFAS is limited. This prediction should therefore be treated with caution 6.1.2.3 Data from structural analogues Not considered. 6.1.2.4 Discussion The only experimental study available indicates that PFBE is not readily biodegradable. Although some details are missing from the robust study summary, the Environment Agency does not consider that further information is required. The reported degree of mineralisation (up to 15.9 % over 28 days) is unexpected for such a highly fluorinated substance. The transformation products were not identified but could be shorter perfluorinated chains following removal of the ethene group, either perfluoropentanoic acid or perfluorobutanoic acid. These would be expected to be highly resistant to further transformation. 6.1.3 Biodegradation in sediment This is a standard information requirement for the level of EU supply, but a data waiver is presented by the Registrants, stating that neither direct nor indirect aquatic nor sediment exposure is likely due to high volatility. No further information is available from published data sources. 6.1.4 Biodegradation in soil A data waiver is presented by the Registrants for this endpoint, stating that neither direct nor indirect soil exposure is likely due to high volatility. No further information is available from published data sources. 6.1.5 Summary and discussion on degradation The Registrants provide waivers for hydrolysis and simulation degradation studies. The justification for these waivers state that PFBE is too volatile and/or of too low water solubility. 36 of 115 The Environment Agency considers that hydrolysis is unlikely to be a significant degradation mechanism due to the chemical structure. Slow phototransformation in air is a possibility. The substance is not readily biodegradable, though may be a source of perfluoropentanoic acid or perfluorobutanoic acid in the environment. There are no environmental simulation data so a half-life in relevant media is not available. 6.2 Environmental distribution 6.2.1 Adsorption/desorption 6.2.1.1 Measured data The EU REACH registration includes an organic carbon-water partition coefficient (KOC) study performed according to OECD TG 121 (HPLC method) (OECD, 2001) in accordance with GLP (Unnamed study report, 2001). The Registrants assigned a Klimisch score of 1 (reliable without restriction). Eight reference substances were used (formamide, acetanilide, atrazine, monuron, tiapenthenol, linurone, fenthione, and trigluraline, with calculated log KOC values ranging from 1.61 to 3.94). The log KOC of PFBE was 2.96, based on a retention time of 8.08 minutes which was within the range covered by the reference substances. The calculated log KOC of PFBE is moderately high and suggests that despite high volatility this substance may adsorb to soils or sediments (contrary to the claims made by the Registrants that direct or indirect exposure of these compartments is unlikely). The Environment Agency notes that the HPLC method may overcome the handling issues associated with volatile substances that would occur if an alternative study design were used to determine this endpoint (i.e. the OECD TG 106 batch equilibrium method (OECD, 2000)). However, OECD TG 121 is an indirect method which uses the stationary phase of the column as a surrogate for organic matter in the environment. It provides an estimate of KOC only. 6.2.1.2 Predicted data For comparative purposes, the Environment Agency has considered readily available QSAR software to test how they perform for this type of substance. The US EPA CompTox dashboard contains a predicted KOC of 452 L/kg (log KOC of 2.67) (US EPA, 2022a). The Environment Agency used KOCWIN v2 model prediction within EPISuiteTM v4.11 to estimate a log KOC of 3.9. The validation set contained several PFCs (see Appendix B) and it is likely that the predicted value for PFBE falls within the applicability domain of the model. 37 of 115 6.2.1.3 Data from structural analogues Experimentally derived log KOC values were available for two of the three selected structural analogues of PFBE: 3,3,4,4,5,5,6,6,7,7,8,8-dodecafluorodeca-1,9-diene: log KOC 4.3 (ECHA, 2022c; HPLC estimation method OECD TG 121) 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooct-1-ene: log KOC 2.65 (ECHA, 2022d; HPLC estimation method OECD TG 121) Since the first substance has two non-fluorinated double bonds, it is likely to be more adsorptive than PFBE so is probably less relevant. 6.2.1.4 Recommended value An indirectly measured log KOC of 2.96 is considered reliable without restriction by the Registrants. This is broadly consistent with predicted values (2.67 and 3.9), and similar to the log KOC 2.65 of the larger analogue 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooct-1-ene. The Environment Agency considers that the available data indicates a log KOC around 3, and therefore the value presented by the Registrants of 2.96 is appropriate for further evaluation. 6.2.2 Volatilisation 6.2.2.1 Measured data No measured data were available in the literature. 6.2.2.2 Calculated data The EU REACH registration dossier includes a Henry's Law constant (HLC) calculation using the following equation: HLC = 1 standard atmospheric pressure (Pascals) molecular weight water solubility (mg/L) This is 101 300 Pa (246/15.6 mg/L (Section 5.3.1)) = 1 597 423 Pa m3/mol or 15.77 atm m3/mol. The Environment Agency notes that this result is wrong, as it ignores the vapour pressure of PFBE (Section 5.1.1) and litres must be converted to m3. The Environment Agency recalculated the HLC using the equation from the ECHA R7.a guidance text (ECHA, 2017) using the following variables. The water solubility of 15.6 mg/L converts to 6.34 10-5 mol/L and 6.34 10-2 mol/m3, using the molar weight of PFBE as 246 g. The vapour pressure is 22 kPa or 0.2171 atm at 20 C (Section 5.1.1). Ideally, the Environment Agency would adjust the vapour pressure to 25 C using the Clausius-Clayperon equation. This is not possible as the enthalpy of vaporisation of PFBE is unknown. Commented [MS6]: Noted, at the next update, the robust Summary in IUCLID dossier to be revised. 38 of 115 HLC = vapour pressure (Pa) / water solubility (mol/m3) = 347 000 Pa.m3/mol or 3.42 atm.m3/mol There is some uncertainty in the input parameters, which affects the reliability of this estimate. 6.2.2.3 Predicted data The US EPA CompTox dashboard contained a predicted HLC value for PFBE (US EPA, 2022a). For comparative purposes, the Environment Agency generated a HLC constant through EPIsuite v4.11. These values are presented in Table 6.2. The Environment Agency has converted the values from atm.m/mol to Pa.m/mol. Table 6.2 Source EPISuiteTM Estimation programme Predicted Henry's Law constant for PFBE HLC 1.125 x 107 Pa.m/mol or 111 atm.m3/mol (Environment Agency) 440.763 Pa.m/mol or 0.00435 atm.m3/mol (CompTox) HENRYWIN v3.1 CompTox US EPA, 2022a (OPERA) 440.763 Pa.m/mol or 0.00435 atm.m3/mol In silico predicted values should always be treated with caution where substances in the training set and external test set are not visible. The training and validation sets for the HENRYWIN model contained several PFCs (see Appendix B) and it is likely that the predicted value for PFBE falls within the applicability domain of the model. However, the prediction relies on predicted values for vapour pressure and water solubility, so the output should be treated with additional caution. The CompTox prediction falls outside the applicability domain of the OPERA model and is therefore unreliable. 6.2.2.4 Data from structural analogues A Henry's Law constant was only available for one of the structural analogues of PFBE: 263 952 Pa.m3/mol for 3,3,4,4,5,5,6,6,7,7,8,8-dodecafluorodeca-1,9-diene calculated by the Registrants; HLC=(VPxMOLW)/WS) (ECHA, 2022c). 6.2.2.5 Recommended value The relatively high vapour pressure and moderate water solubility implies that PFBE will tend to partition to air from water under environmentally relevant conditions. There is uncertainty in the input parameters and QSARs, but in the absence of further information the Environment Agency recommends the calculated Henry's Law constant of 347 000 Pa.m3/mol (3.42 atm.m3/mol) for modelling purposes (as it is derived using measured water solubility and vapour pressure values). Commented [MS7]: 1/3rd lower than current adopted value 39 of 115 6.2.3 Distribution modelling To estimate the distribution of PFBE in the environment, the Environment Agency has run the EQC v3.0 Mackay Level III fugacity model using the input parameters indicated in Table 6.3. Table 6.3 Estimated distribution of PFBE Input Parameter Value Molecular mass 246.07 g/mol Melting point <-20 C Water solubility 15.6 mg/L Vapour pressure 22 000 Pa Henry's Law constant 347 000 Pa m3/mol Log KOW 4.13 Half-life in air (hours)a 2.1 x 1041 Half-life in water (hours)a 2.1 x 1041 Half-life in soil (hours)a 2.1 x 1041 Half-life in sediment (hours)a 2.1 x 1041 Model output Scenario 1 - all emissions to water Scenario 2 - all emissions to air Air % 20.0 100.0 Water % 79.9 0.0 Soil % 0.2 0.0 Sediment % 0.0 0.0 Note: a - The upper bound value for biodegradation of a non-readily biodegradable substance in EUSES is 1 x 1040 days to represent infinity (equivalent to 2.1 x 1041 hours). Based on these input parameters and the assumption that PFBE does not degrade significantly in the environment, the model predicts that nearly all the substance would remain in the water compartment if released to water. If released to air, all the substance would remain in the air compartment. The reliability of this modelling is uncertain because of the assumptions around half-life in different compartments. PFBE degraded by 15 % over 28 days in a ready biodegradation study (see Section 6.1.2), so the assumption of an infinite half-life may be misleading. 6.2.4 Long-range transport potential The OECD has produced a decision support tool for estimating the long-range transport potential (LRTP) of organic chemicals at a screening level (Wegmann et al., 2009). It is a 40 of 115 Commented [MS8]: Half-lives are excessively high persistent is not the same as permanent. From p 34: AOP v1.91 (EPISuite v4.11) indicates an atmospheric half life of 6.421 hours based on indirect photolysis of the double bond. Gomis et al. (2015) Commented [MS9]: Comment for water, soil and sediment: Half-lives are excessively high - persistent is not the same as permanent. steady state non-equilibrium model in a standardised evaluative environment, predicting three characteristics that can be used to indicate the LRTP of a substance: Characteristic Travel Distance (CTD), Transfer Efficiency (TE) and overall persistence (POV). To estimate the LRTP of PFBE, the Environment Agency has performed calculations using the input parameters indicated in Table 6.4. Table 6.4 Estimated long range transport potential of PFBE Input Parameter Value Molecular mass (g/mol) 246.07 Log KAW a 2.17 Log KOW 4.13 Half-life in air (hours)b 2.1 x 1041 Half-life in water (hours)b 2.1 x 1041 Half-life in soil (hours)b 2.1 x 1041 LRTP output parameter Characteristic Travel Distance (km) 1 350 000 Transfer Efficiency (%) 1 055 POV (days) 1.26 x 1040 Note: a - This is the log of the dimensionless HLC calculated using Equation R.16-5 of ECHA (2016). b - The upper bound value for biodegradation of a non-readily biodegradable substance in EUSES is 1 x 1040 days to represent infinity (equivalent to 2.1 x 1041 hours). The OECD LRTP screening tool allows comparisons of the CTD and TE characteristics for a range of substances, some of which are POPs, provided in Figure 6.1. Figure 6.1 Long range transport potential of PFBE for predictive modelling Commented [MS10]: See Table 6.3 re half-lives Based on this screening tool and the assumption that PFBE does not degrade in the environment, it appears that PFBE may be capable of long-range transport as it falls into the top right quadrant of Figure 6.1. The reliability of this modelling is uncertain because of the assumptions around half-life in different compartments. PFBE degraded by 15 % over 41 of 115 28 days in a ready biodegradation study (see Section 6.1.2), so the assumption of an infinite half-life may be misleading. Evidence of occurrence (or not) of PFBE in the Arctic and other remote regions also needs to be taken into account (noting the proximity of industrial activity and population centres). This is beyond the scope of this evaluation. 6.3 Bioaccumulation 6.3.1 Bioaccumulation in aquatic organisms 6.3.1.1 Measured data A data waiver is presented by the Registrants for this endpoint, on the basis that neither direct nor indirect aquatic or sediment exposure is likely due to high volatility. No further information is available from published data sources. 6.3.1.2 Predicted data A fish bioconcentration factor (BCF) can be calculated based on log KOW and the QSAR equation in ECHA (2017c). The Environment Agency has used the experimental log KOW of 4.13 to calculate a BCF of 646. The reliability of this QSAR for this type of substance is unknown. The Environment Agency also used EPISuiteTM v4.11 software to predict the BCF of PFBE using the values in Section 5 of this report. A predicted BCF of 247 L/kg wet weight (ww) was generated using BCFBAF v3.01. The validation set contained several PFCs (see Appendix B) and it is likely that the predicted value for PFBE falls within the applicability domain of the model. The Henry's Law Constant (HLC) cannot be overridden in EPISuiteTM. The BCF prediction therefore relies on the predicted HLC of the model which differs from the calculated HLC. The prediction should therefore be treated with caution. The US EPA CompTox dashboard contains predicted fish BCF values for PFBE generated from both the OPERA and T.E.S.T. software (US EPA, 2022a). The OPERA model predicts a BCF of 92, but notes that PFBE is outside of the applicability domain, so the prediction is not valid. The T.E.S.T. model predicts a BCF of 234, and structural analogues of PFBE are included in the training set so this value might be more reliable. The PubChem database (NCBI, 2022) contains a predicted BCF of 370 for PFBE, and the RSC ChemSpider portal includes two BCF values: 1 393 generated from the BCFWIN v2.17 software and 387 from ACD/Labs (RSC, 2022). None of these sources provide further information. 6.3.1.3 Data from structural analogues One experimental study is available for 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooct-1-ene (ECHA, 2022d). The study was performed over 60 days according to OECD TG 305 42 of 115 Commented [MS11]: The point made with regard the values used in tables 6.3 and 6.4. Commented [MS12]: Which prediction? BCF or HLC? (1996) and GLP with Common Carp Cyprinus carpio via the aqueous phase at a nominal test concentration of 0.1 and 1.0 g/L. Due to the substance's volatility, the study used special test vessels and a flow-through test design with a high daily renewal rate, which resulted in measured concentrations close to nominal. The steady-state BCF was 380 (1 g/L) or 300 (0.1 g/L) based on whole body wet weight. 6.3.1.4 Recommended value There are no measured data for the substance itself. Predicted BCF values of variable reliability range from 234 to 646 (with 1 393 as an outlier, the reliability of which cannot be evaluated). These compare well with a measured BCF of 300 to 380 for a higher molecular weight analogue. In the absence of experimental data for the substance itself, the Environment Agency recommends a predicted BCF of 646 as a reasonable worst case for the purposes of this evaluation. 6.3.2 Terrestrial bioaccumulation The EU REACH Registrants do not assess the potential for terrestrial bioaccumulation. No information on bioaccumulation is available from the available mammalian toxicity studies. Evidence from other highly fluorinated substances suggests that terrestrial bioaccumulation (or bioaccumulation in air-breathing organisms) may be more relevant for some PFAS than aquatic bioaccumulation, although this is mainly related to the ability of perfluorocarboxylic acids to bind to proteins. In terms of bioaccumulation in air-breathing organisms, the screening criteria are log KOW > 2 and log KOA > 5 (ECHA, 2017c). Although the log KOW 4.13 exceeds the first threshold the log KOA of 1 (Section 5.5.4) does not, so this criterion is not met. 6.3.3 Summary and discussion of bioaccumulation The log KOW of 4.13 suggests that PFBE has potential for bioaccumulation by partitioning to lipids. However, it appears unlikely to bioaccumulate significantly in aquatic gillbreathing organisms, based on a predicted fish BCF of 646. The value is comparable to similar low BCFs seen for other PFAS. The bioaccumulation potential of PFBE in air-breathing organisms is uncertain but there are no indications of concern based on currently available data. Commented [DF13]: See later re classification. This is a calculated value and is unreasonable, in my view, given that there are other predicted values <400. 43 of 115 7 Ecotoxicology 7.1 Aquatic compartment The same comments about sources of data, reliability scoring and use of supplemental information apply as for Section 5. The Environment Agency notes that PFBE has a low solubility in water (Section 5.3) and high Henry's Law constant (Section 6.2.2) which indicates that the substance will tend to volatilise from water to air. Measurement of test concentrations is therefore important for aquatic toxicity studies, as consistent exposure concentrations may be difficult to maintain (especially in static test systems). 7.1.1 Fish 7.1.1.1 Short-term (acute) toxicity Table 7.1 Method Summary of acute toxicity to fish Species Analytical method Results Reliability Reference Ecotoxicological testing of petroleum products (CONCAWE 1992) and aquatic toxicity testing of lubricants by ASTM (standard protocol 0608197) Zebra fish Confidential (Danio rerio) 96-h LC50 >1.86 mg/L based on the arithmetic mean initial measured concentration Registrant: 1 (key study) Similar or equivalent to OECD TG 203 (semi-static) GLP Unnamed (2001) cited in ECHA, (2022a) One acute fish toxicity study was presented in the EU REACH registration dossier as the key study (Unnamed, 2001, cited in ECHA, 2022a). The CONCAWE and ASTM methods were reported to be similar to OECD TG 203 (OECD, 2019), and the study was carried out in accordance with GLP. The test was conducted using PFBE with an analytical purity of 96%. Semi-static conditions were used with a 24-hour renewal period, and volatile loss of 44 of 115 PFBE from the test system was minimised through the use of closed test vessels. The test temperature was maintained at 221 C. Test solutions were prepared as WAFs, with initial nominal loading rates of 0 (control), 100, and 1 000 mg/L. Details about how the WAF was prepared are provided on the ECHA website. The first portion of the WAF was used to rinse the test vessels to saturate the surfaces. After filling, the test vessels were sealed immediately and only opened again to introduce the test organisms and "again at the end of the test" (sic - presumably between renewals too). Care was taken to ensure that any undissolved material was not transferred to the test vessels. The WAFs were not stored for more than 1 to 2 hours prior to testing. The concentration of PFBE in the WAFs was measured in vessels without fish at 0 h, 24 h (end of initial exposure), 24 h (fresh solutions), 48 h (fresh solutions), 72 h (fresh solutions), and 96 h (end of exposure). Prior to chemical analysis, 100 mL aliquots of test media were filtered to remove particulate matter. The sieve was pre-rinsed with the corresponding WAF prior to filtration. Concentrations of PFBE ranged from 0.11 to 0.75 mg/L (mean 0.34 0.29 mg/L) and 1.56 to 2.57 mg/L (mean 1.86 0.35 mg/L) for loading rates of 100 and 1 000 mg/L, respectively. During the initial exposure period of 24 h the concentration of PFBE decreased 19 to 27 % and 34 to 44 % for the loading rates of 100 and 1 000 mg/L, respectively. All measurements indicated that PFBE was below the water solubility of 15.6 mg/L (see Section 6.3.4). The measured concentrations were used by the Registrants to generate the concentration-effect relationship. The pH ranged from 7.48 to 8.23 and mean dissolved oxygen was greater than 79% saturation for all vessels. No significant mortality was observed in either treatment or control groups (10% in mid and high group, but within tolerable limits of study). The validity criteria of < 10% mortality in control groups and > 60% dissolved oxygen (DO) saturation were met. Most other test parameters were closely related to the standards recommended in OECD TG 203 (OECD, 2019). Information on the frequency of feeding before the test and the intervals for the measurement of pH and temperature were not available in the registration dossier. The results were reported as 96-h NOEC 1 000 mg/L and EC50 > 1 000 mg/L (nominal WAFs), corresponding to 96-h NOEC 1.86 mg/L and EC50 > 1.86 mg/L based on the measured concentrations. The Registrants consider the study to be reliable without restriction (Klimisch score 1). The Environment Agency notes that the measured concentrations were an order of magnitude lower than the measured water solubility (15.6 mg/L). It is not clear why this should be the case, because steps were taken to minimise evaporative losses during the test. In addition, WAFs are usually prepared for complex mixtures whose constituents have a variety of different solubilities (like petroleum products). PFBE is a monoconstituent substance of moderate water solubility, so it is possible that a different test solution preparation technique (or flow-through conditions) might have achieved greater dissolved concentrations. 45 of 115 7.1.1.2 Long-term (chronic toxicity) Long-term fish toxicity tests are not available, and the Registrants use a data waiver (no details of this waiver are provided on the ECHA website). 7.1.2 Aquatic invertebrates 7.1.2.1 Short-term (acute) toxicity Table 7.2 Method Summary of acute toxicity to aquatic invertebrates Species Analytical method Results Reliability Reference Ecotoxicological testing of petroleum products (CONCAWE 1992) and aquatic toxicity testing of lubricants by ASTM (standard protocol 0608197) Daphnia magna Confidential Acute immobilisation test 48-h EC50 >1 mg/L Similar or equivalent to OECD TG 202 (static) GLP Registrant: 1 (key study) Unnamed study report (2001) cited in ECHA (2022a) One acute aquatic invertebrate toxicity study is included in the EU REACH registration dossier as the key study (Unnamed 2001, cited in ECHA 2022a). This study was reported to be similar or equivalent to an OECD TG 202 (OECD, 2004) study and carried out to GLP using Daphnia magna. Substance purity and test solution preparation was identical to the acute fish test, with WAF loading rates of 0, 100 and 1 000 mg/L. Static exposure conditions were used. The validity criteria for <10% immobility in the controls and 3 mg/L DO were met. The pH ranged from 8.64 to 8.99 and the test temperature was maintained at 201 C. Measured concentrations were 0, 0.27, and 1.0 mg/L, respectively, on day 0; and 0, 0.19, and 0.80 mg/L, respectively, on day 2. Losses were reportedly due to high volatility. 46 of 115 No significant increase in immobility was seen for any of the treatment groups compared to controls. The 48-h NOEC was reported as 1 mg/L, with a 48-h EC50 1mg/L. The Registrants consider the study to be reliable without restriction (Klimisch score 1). The Environment Agency notes that the measured concentrations were around 1 to 2 orders of magnitude lower than the measured water solubility (15.6 mg/L). Losses of around 20 to 30 % were observed between day 1 and day 2, which the Registrants attribute to evaporation even though steps were taken to minimise this. WAFs are usually prepared for complex mixtures whose constituents have a variety of different solubilities (like petroleum products). PFBE is a mono-constituent substance of moderate water solubility, so it is possible that a different test solution preparation technique might have achieved greater dissolved concentrations. As a minor point, the Environment Agency considers that the result should be reported as a 48-h EC50 0.8 mg/L, as this was the highest concentration measured in the test. 7.1.2.2 Long-term (chronic) toxicity Long-term invertebrate toxicity tests are not available, and the Registrants use a data waiver (no details of this waiver are provided on the ECHA website). 7.1.3 Algae and aquatic plants Table 7.3 Method Summary of toxicity to algae Species Analytical method Results Reliability Reference Ecotoxicological testing of petroleum products (CONCAWE 1992) and aquatic toxicity testing of lubricants by ASTM (standard protocol 06081-97) Similar or equivalent to OECD TG 201 (static) GLP Pseudokirchneriella subscapita Confidential Algal growth rate 72-h ErC50 >1.5 mg/L 72-h NOErC 1.5 mg/L Registrant: 1 (key study) Unnamed study report (2001), ECHA (2022a). The algal growth inhibition study presented in the EU REACH registration dossier as the key study (Unnamed study report, 2001, cited in ECHA 2022a). The methods were reported to be similar or equivalent to OECD TG 201 (OECD, 2011) and the study was 47 of 115 carried out in accordance with GLP using the green alga Pseudokirchneriella subscapita. Substance purity and test solution preparation was identical to the acute fish test, with WAF loading rates of 0, 100 and 1 000 mg/L. Static exposure conditions were used. The starting cell concentration was 1 000 cells/mL and the test vessels were completely full and sealed. The purpose of the decreased cell number (10 times lower than recommended in the guideline) was to prevent the development of a large biomass by the end of the study. This was considered necessary because of the risk of depleting the carbonate concentration which could have made the solutions alkaline and artificially limited the growth rate. The cell concentrations were determined at the start of the test and after 24, 48 and 72 h. The volume of test solution removed for evaluation and that displaced by the stopper were replaced using spare WAF which had been stored in a sealed vessel. A separate spare vessel was prepared for each replacement interval (1 vessel per test concentration). The reason was to prevent re-equilibration of the volatile test substance from the WAF to the head-space above the WAF. The culture vessels were incubated at 22 1 C. Measured concentrations were <0.05, 0.92, and 1.52 mg/L for the 3 loading rates, respectively, at the start of the test. The concentration of PFBE was below the detection limit of 0.05 mg/L in all vessels but one at the end of the test (the single positive detection was a concentration of 0.11 mg/L in one of the 5 vessels used at the 1 000 mg/L loading rate). Test vessels had to be opened daily for sampling, so the Registrants attribute the decline of PFBE concentration to evaporation during the sampling procedure. No significant inhibitory effect on growth rate was observed compared to the controls (an increase in biomass (36.5% compared to control) was observed at the highest loading rate by the end of the test). The 72-h NOErC was reported as 1.5 mg/L with the 72-h ErC50 >1.5 mg/L. The Registrants consider the study to be reliable without restriction (Klimisch score 1). The Environment Agency notes that the initial measured concentrations were an order of magnitude lower than the measured water solubility (15.6 mg/L). Almost a complete loss of test substance had occurred by 72 h, which is presumably due to evaporation, but may possibly also be due to adsorption to the algal cells. WAFs are usually prepared for complex mixtures whose constituents have a variety of different solubilities (like petroleum products). PFBE is a mono-constituent substance of moderate water solubility, so it is possible that a different test solution preparation technique might have achieved greater dissolved concentrations. Given the observed drop in concentration, it is unclear how long the cells were exposed to significant amounts of PFBE, and so it may be more precautionary to report the results as a 72-h ErC50 >0.05 mg/L, and a 72-h NOErC 0.05 mg/L. 7.1.4 Sediment organisms No relevant information is available in the EU REACH registration dossier. The Registrants include a data waiver, arguing that the substance has only moderate affinity to sediment 48 of 115 (log KOC 2.96), has high volatility from water, and direct and indirect exposure of sediment is unlikely (ECHA 2022a). 7.1.5 Other aquatic organisms No other relevant information is available. 7.2 Terrestrial compartment No relevant information is available in the EU REACH registration dossier. The Registrants include a data waiver, arguing that the substance has only moderate affinity to soil (log KOC 2.96), has high volatility, and direct and indirect exposure of soil is unlikely (ECHA 2022a). 7.3 Microbiological activity in sewage treatment systems A test to determine the toxicity of PFBE to sewage microorganisms is not available and the Registrants use a data waiver (no details of this waiver are provided on the ECHA website). The Environment Agency notes that no toxicity to the inoculum was observed in the ready biodegradation test (see Section 6.1.2). 7.4 Atmospheric effects The Henry's Law constant indicates that PFBE is likely to significantly partition to air (see Section 6.2.2). No data about biotic effects from aerial exposure are available in the EU REACH registration dossier (ECHA, 2022a), but this is not a standard information requirement. The available data in the EU REACH registration dossier suggest that PFBE is unreactive to ozone, and therefore is unlikely to be an ozone depleting substance. PFCs are known to be potent greenhouse gases, and this is considered further in Section 9.5. 49 of 115 8 Mammalian toxicology The following information is taken directly from the ECHA public dissemination website entry for PFBE (ECHA, 2022a). The focus is on those mammalian endpoints which are potentially relevant for determination of the substance as Toxic (`T') according to the REACH Annex 13 criteria (see Section 9.3) or for a wildlife secondary poisoning assessment (see Section 9.5). No acute data are included and no human health hazard assessment has been undertaken. The study details and their reliability (Klimisch) scores are as presented by the EU REACH Registrants and the Environment Agency has not evaluated this information. 8.1 Toxicokinetics No information on toxicokinetics have been presented by the Registrants. 8.2 Repeated dose toxicity Table 8.2 Method Summary of mammalian repeated dose toxicity endpoints Species Brief study Results details Reliability (Klimisch) score Reference Short-term repeated dose toxicity: inhalation Rat (Wistar) OECD TG 412 (Subacute inhalation toxicity: 28day study) GLP Nose only exposure, analytical verification of doses / concentrations using Flame ionisation detector (FID) 28-day exposure 6 hours per day 401, 2069, and 9879ppm doses N=5/sex/dose 10 000 ppm haematological effect in males Clinical biochemistry effects in males at 2 000 ppm and females at 10 000 ppm Histopathological effects seen - nonneoplastic NOAEC 2 000 ppm (2 069179 ppm measured), despite effects seen at 2 000 ppm Registrant: 1 (key study) Unnamed study report (2001) cited in ECHA (2022a) 50 of 115 Method Species Brief study Results details Reliability (Klimisch) score Subchronic toxicity: inhalation OECD TG 413: Subchronic inhalation toxicity: 90 Day study GLP Rat (Wistar) PFBE >99.9% purity Nose only exposure N=10 male and 10 female per group 0, 1 000, 3 000 and 10 000 ppm with analytical verification of dose In males decreased mean body weight gain at all exposure levels (0.9, 0.86, and 0.89 times control respectively) Haematological (immunological) effect at 3 000 and 10 000 ppm NOAEL 10 000 ppm (despite effects seen) Registrant: 1 (key study) 6 hours per day for 5 days per week for 90 days Reference Unnamed study report (2017) cited in ECHA (2022a) 51 of 115 Method Species Brief study Results details Reliability (Klimisch) score Short-term repeated dose toxicity: inhalation Similar to OECD TG 412: Subacute inhalation toxicity 28day study CD1 rats PFBE 99% purity Whole body inhalation study N=10 male and 10 female per dose (analytical confirmation of dose) Males: 0, 541, 4 750, and 46 300 ppm Females: 0, 473, 5 140 and 46 800 ppm 6 hours per day for 5 days per week for 28 days Haematological effects observed at 50 000 ppm in males and 5 000 and 50 000 ppm in females Increased liver and kidney weight relative to body weight in males at 50 000 ppm, increased kidney weight only in females at same dose. NOAEC for clinical chemistry 500 ppm NOAEC for histopathology 50 000 ppm Registrant: 1 (supporting study) Reference Unnamed study report (1981) cited in ECHA (2022a) 8.3 Mutagenicity Three in-vitro genetic toxicity studies are included in the EU REACH registration dossier. Table 8.3 Method Summary of mammalian mutagenicity endpoints Species Brief study details Results Reliability (Klimisch) score Reference In vitro gene mutation study in bacteria Bacterial Reverse Salmonella typhimurium and Escherichia coli strains PFBE 100% purity With and without metabolic activation Negative (no adverse effects reported at these concentrations) The test article is not mutagenic with or without Registrant: 1 (key study) Unnamed study report (2010) cited in ECHA (2022a) 52 of 115 Method Species Mutation Assay, OECD TG 471 GLP Brief study details Results (S9 rat liver metabolic activation homogenate) under the test conditions 0, 0.062, 0.158, 0.556, 1.667, and 5.0 L/plate Negative control slightly elevated revertants Reliability (Klimisch) score Reference In vitro cytogenicity/ chromosome aberration study in mammalian cells Chinese hamster Ovary (CHO) Mammalian Chromosome Aberration Test, OECD TG 473 GLP PFBE 100% purity With and without metabolic activation (S9 liver homogenate) Negative for genotoxicity Cytotoxicity observed at 1 250 and 2 460g/mL (in Executive summary the Registrants claim non-cytotoxic) Test 1: 0, 600, 1 230 and 2 460 g/mL Test 2: 0, 100, 1 250 and 2 460 g/mL Registrant: 1 (key study) Unnamed study report (2010) cited in ECHA (2022a) In vitro gene mutation study in mammalian cells Mammalian Cell Gene Mutation Test, OECD TG 476 GLP Mouse lymphoma L5178Y cells PFBE 100% purity. With and without metabolic activation (S9 liver homogenate with cofactors) Negative, not mutagenic/ genotoxic to TK locus of L5178Y mouse lymphoma cells Slight cytotoxicity noted in the presence of S9 Registrant: 1 (key study) Unnamed study report (2010) cited in ECHA (2022a)) 0, 1.2, 2.4, 4.9, 7.0, and 10 mmol/L doses 53 of 115 Method Species Brief study details Results Reliability (Klimisch) score Reference In vitro gene mutation study in bacteria Similar to guideline study Salmonella typhimurium PFBE 99% purity With and without metabolic activation (S9 rat liver homogenate) Negative (no adverse effects at these concentrations). No supporting information Registrant: 2 (supporting study) Unnamed study report (1980) cited in ECHA (2022a) 0, 100, 500, 1 000, 5 000 and 10 000 g/plate 8.4 Carcinogenicity No information is available in the EU REACH registration dossier. 54 of 115 8.5 Toxicity to reproduction (effects on fertility and developmental toxicity) Table 8.4 Method Summary of mammalian reproductive toxicity endpoints Species Brief study details Results Reliability (Klimisch) score Reference Developmental Toxicity test. Similar or equivalent to OECD TG 414 Prenatal developmental toxicity study. Rat: CD Inhalation (whole body) N=7 per exposure Analytical verification of doses 0, 994, and 70 700 ppm Mated females exposed daily for 6 hours from day 6-15 of gestation Decreased mean maternal body weight gain in high exposure group Decreased mean maternal body weight gain in high exposure group NOAEC >70 000 ppm for dams NOAEC >70 000 ppm for embryotoxicity NOAEC >70 000 ppm for teratogenicity Registrant: 2 (key study) Unnamed study report (1981) cited in ECHA (2022a) One reproductive toxicity study is included in the EU REACH registration dossier as the key study (Unnamed study report, 1981, cited in ECHA, 2022a). This study was conducted in 1981 and reported to be similar to OECD TG 414. The test substance was administered through inhalation to groups of rats (n=7, CD strain) at 0, 994, 70 700 ppm. Pregnant females received daily doses for 6 hours/day between day 6 and 15 of gestation. There were no treatment-related effects on male or female foetuses. Mean body weight gain was decreased in the highest exposure maternal group. 55 of 115 8.6 Summary of mammalian toxicology Based on the available mammalian toxicology data, the EU REACH Registrant concludes that no effects were demonstrated in studies conducted at maximally attainable vapour concentrations, limit doses, or other limits imposed by safety considerations. 56 of 115 9 Environmental hazard assessment 9.1 Classification and labelling 9.1.1 Harmonised classification PFBE does not have a harmonised classification under Classification, Labelling and Packaging (CLP) legislation. 9.1.2 Self-classification The EU REACH registration dossier proposes that the substance is Not Classified, and no environmental hazards are identified on ECHA's CLP inventory [accessed May 2022]. 9.1.3 Conclusions for classification and labelling PFBE is not readily biodegradable and there is no evidence that it degrades significantly via abiotic mechanisms in aquatic media (see Section 6.1). It is therefore considered to be "not rapidly degradable" for the purposes of hazard classification. No experimentally derived values for fish BCF are available. The log KOW exceeds 4 (4.13), so PFBE meets the bioaccumulation criterion for the purposes of hazard classification. Despite the limited reliability of predicted BCFs for this substance, the Environment Agency's preferred BCF of 646 also meets the bioaccumulation criterion (>500 L/kg). Acute ecotoxicity studies are available for fish, aquatic invertebrates and algae (see Section 7). None demonstrated any adverse effects up to the concentration limits achieved. However, the maximum concentrations achieved were at least an order of magnitude below the measured water solubility limit of 15.6 mg/L. In addition, test concentration maintenance was poor in the invertebrate and algal tests, with the latter experiencing almost complete loss of substance over a 72-h period, despite efforts to limit volatilisation. Nevertheless, based on the available evidence, Aquatic Acute classification is not required. This is consistent with the EU REACH Registrant's view. No adverse chronic effects were observed in the algal toxicity test, resulting in a 72-h NOEC of 1.5 mg/L based on TWA, although as noted above, there was a significant loss in test concentration during this study. In the absence of further long-term toxicity information for fish and aquatic invertebrates, classification as Aquatic Chronic 4 is warranted because the substance is poorly water soluble, not rapidly degradable and meets the bioaccumulation criterion. The Environment Agency recommends that the UK supplier updates their self-classification to reflect these findings. The human health hazard classification has not been considered. Commented [DF14]: As before Commented [MS15]: AGCCE's view is this is not warranted due to the volatility of PFBE. However, we will review this at the next dossier update. 57 of 115 9.2 Assessment of endocrine disrupting (ED) properties The ecotoxicity dataset does not include any studies that assess ED potential and no additional information was identified during the literature search (Appendix A). 9.3 PBT and vPvB assessment Persistence: No environmental half-life data are available for comparison with the definitive criteria in REACH Annex 13. PFBE is not readily biodegradable and there is no evidence that it degrades significantly via abiotic mechanisms in aquatic media (see Section 6.1). The EU REACH registration dossier includes a statement that any PFBE released to the environment will partition to atmosphere and that it would have a short atmospheric lifetime estimated as 6.4 hours, but no further details are provided. The EU REACH Registrant uses this information to conclude that the substance is neither persistent (P) nor very persistent (vP). However, the Environment Agency considers that PFBE meets the screening criterion for being P or vP. Bioaccumulation: PFBE has a reported log KOW of 4.13 (Section 5.4) which does not meet the screening criterion for bioaccumulation (B), as it is below 4.5. The predicted fish BCF of 646 similarly falls below the definitive B criterion in REACH Annex 13 (>2 000 L/kg). In terms of bioaccumulation in air-breathing organisms, the log KOW of 4.13 meets the screening criteria (>2), but the log KOA of 1 does not (as it is below 5). Toxicity: In terms of aquatic toxicity, a 72-h NOEC of 1.5 mg/L is available for algae, which does not meet the REACH Annex 13 criterion for toxicity (T) of <0.01 mg/L (see Section 7). There are no chronic aquatic toxicity data for fish or aquatic invertebrates, but no acute toxicity has been observed for these taxonomic groups. PFBE therefore does not meet the screening criterion for being potentially T based on toxicity to aquatic organisms. PFBE does not meet the T criterion based on mammalian toxicity as indicated by the industry self-classifications for human health hazards (see Section 9.1). No information is available on ED potential. Overall conclusion: PFBE screens as potentially P/vP, but does not screen as potentially B or T. It is therefore of low concern for PBT and vPvB hazards. 9.4 Groundwater hazard Draft persistence, mobility and toxicity (PMT) criteria have been developed by the German Federal Environment Agency as intrinsic hazard criteria to identify substances that are difficult to remove during normal wastewater treatment practices and may be a threat to remote aquatic environments and drinking water sources, including groundwater (Arp and Hale, 2019). The criteria for P and vP are consistent with those in REACH Annex 13, 58 of 115 whereas the mobile criterion is unique to PMT assessments. The T criteria include those in REACH Annex 13, in addition to considerations for carcinogenicity, effects via lactation, long-term toxicity to the general human population and ED potential. There is no legal basis for these criteria under the REACH Regulation, but for completeness, a brief evaluation is included here. Persistence: PFBE meets the screening criterion for being potentially P or vP (see Section 9.3). Mobility: The measured log KOC value of 2.96 (see Section 7.2.1) meets the criterion of being mobile (M) (log KOC 4) and vM (log KOC 3). Toxicity: PFBE does not meet the T criterion based on aquatic or mammalian toxicity (see Section 9.1). No information is available on ED potential. Overall conclusion: PFBE screens as potentially P/vP and M/vM, but not as T. It therefore meets the vPvM screening criteria. PFBE is a volatile liquid, and the influence of volatility is not considered under the criteria. In addition, PFBE has the potential to degrade to perfluoropentanoic acid and perfluorobutanoic acid. An assessment of their properties (and other contributing substances) is outside scope of this evaluation. However, they are both likely to be vPvM, and so PFBE would be relevant in terms of any risk management associated with these "arrowheads". 9.5 Greenhouse gas hazard PFBE is a volatile liquid, and a significant proportion of emissions are expected to end up in the atmosphere (see Section 6.2.3). Many fluorinated gases have very high global warming potentials (GWPs) relative to other greenhouse gases, so small atmospheric concentrations can have disproportionately large effects on global temperatures (US EPA, 2022cw). The GWP is defined by the Intergovernmental Panel on Climate Change (IPCC, 2014) as "an index measuring the radiative forcing following an emission of a unit mass of a given substance, accumulated over a chosen time horizon, relative to that of the reference substance, carbon dioxide (CO2). The GWP thus represents the combined effect of the differing times these substances remain in the atmosphere and their effectiveness in causing radiative forcing." In 2010, fluorinated gases covered under the Kyoto Protocol (F-gases) accounted for 2% of total anthropogenic greenhouse gas emissions (IPCC, 2014) and PFCs contribute to this. Greenhouse gas emissions for PFCs are quantified as CO2-equivalent emissions (in gigatonnes) (GtCO2-eq) using weightings based on the energy absorbed by a gas over 59 of 115 100 years (the 100-year GWP). PFBE is not listed in IPCC (2013) as it is not a gas. However, several other HFCs are listed. For example, 1,1,1,2,3,3,3-heptafluoropropane (also called HFC-227ea or HFC-227; CAS no. 431-89-0) has an atmospheric lifetime of 38.9 years and its GWP (100 years) is reported to be 3 350 GtCO2-eq (IPCC, 2013). The EU REACH registration dossier includes a statement in the PBT assessment section that PFBE is expected to have a short atmospheric lifetime of 6.4 hours, although no qualifying information was provided (ECHA 2022a). Further information is therefore needed to support this statement. In the absence of better evidence, PFBE might make a contribution to global warming based on analogy with saturated HFCs. 9.6 Limit values 9.6.1 Predicted No Effect Concentration (PNEC) derivation A PNEC is an indication of an acceptable environmental concentration based on evidence from toxicity studies. Available hazard data are discussed in Sections 7 and 8. No PNEC values were presented in the EU REACH registration dossier. PNECs have also been derived by the Environment Agency following REACH guidance (ECHA, 2008) and are shown in Table 9.1. Due to the lack of effects observed in the acute ecotoxicity studies, a reliable aquatic PNEC cannot be estimated. ECHA (2008) states that a long-term test (on invertebrates, preferably Daphnia) has to be carried out for substances showing no toxicity in short-term tests if the log KOW > 3 (or BCF > 100) and if the Predicted Environmental Concentration (PEC) local or regional is greater than 1/100th of the water solubility (>0.015 mg/L in this case). This is effectively a screening PNEC and so has been used here to give an indication of whether additional chronic ecotoxicity testing may be required. Due to the lack of a reliable aquatic PNEC, soil and sediment PNECs have not been calculated based on the Equilibrium Partitioning Method (EPM) at this time. Commented [MS16]: Name Capstone 42-U (= PFBE) CAS No. 19430-93-4 Chemical formula C6H3F9, CF3(CF2)3CH=CH2 Global warming potential (100 yr.) 0.16 From: Code of Federal Regulations (govinfo.gov) Note: This compound was added to Table A-1 in the final rule published on December 11, 2014, and effective on January 1, 2015. ODP reported as 00.00 (model-derived relative to R11). From: ARTI refrigerant database - Vol. 1: single-compound refrigerants (ahrinet.org), page 565. Note this report states an average atmospheric life time of 7.8 yr. Document is from 1999, is there a more recent update? Does AGC have any data? Commented [MS17]: So why use 'infinity' in Table 6.3 and 6.4? 60 of 115 Table 9.1 PNECs derived for PFBE by the Environment Agency Protection goal Most Assessment PNEC Justification/ remarks sensitive factor toxicity descriptor Fresh surface - - 0.015 A reliable PNEC cannot be water mg/L estimated based on the currently available ecotoxicity data set. A screening PNEC of 1/100th water solubility is used to indicate whether chronic ecotoxicity data is required. Freshwater Not calculated sediment Sewage No sludge respiration EC10 or treatment NOEC available. micro- organisms Marine surface Not calculated water Marine Not calculated sediment Soil Not calculated Secondary Not calculated poisoning 9.6.2 Qualitative/semi-quantitative descriptors for other critical hazards A safe threshold is assumed not to exist for PBT/vPvB substances for policy reasons. Since PFBE is not currently considered to be a PBT/vPvB substance, this is not relevant. However, the UK Government has not yet taken a position on how to control emissions of PMT/vPvM substances, and so this will need to be reconsidered once a policy position has been adopted. As noted in Section 9.5, PFBE may contribute to global warming, which could be considered a qualitative hazard. Commented [MS18]: See comment on p59. GWP = 0.16 and ODP = 0.000. 61 of 115 10 Exposure assessment 10.1 Environment 10.1.1 Environmental releases The information in this section is based on the Chemical Safety Report (CSR) submitted by the lead Registrant to ECHA when the UK was still a member of the EU, supplemented with other information from further dialogue with the company. Most of the available information is confidential, so only a summary is presented here. PFBE is used as a co-monomer in the production of both ETFE and a co-monomer, while also acting as a polymerisation inhibiter, in the production of and PTFE. Releases of PFBE occur to air and trace amounts to water during the manufacture of fluoropolymers. Both PTFE and ETFE have a wide variety of uses in industrial processes (e.g. in the semiconductor industry, in cable coating, in the automotive industry and architecture). PFBE is unlikely to be present as an impurity in the final consumer or industrial product of PTFE but could be present in trace amounts in ETFE. Environmental releases may therefore occur to wastewater and air during the processing and use of ETFE. 10.1.2 Exposure scenarios and measures for reducing emissions to the environment 10.1.2.1 Polymer manufacture PFBE is manufactured in Japan and imported to a single site in the UK (AGC Chemicals Europe Ltd, Fleetwood Road North, Thornton Cleveleys, Lancashire FY5 4QD). PFBE is used at this site as a co-monomer for the manufacture of ETFE and a polymerisation inhibitor and co-monomer in PTFE production. This involves two separate production plants. PFBE is received in sealed containers, pumped into storage tanks and then transferred as necessary to the reactors. Sampling for quality control is not undertaken on the site. In the ETFE process when the batch reaction in the reactor is complete, the ETFE slurry is dried and the water / solvent mix containing PFBE is driven off in a number of heating steps to recover and distil the solvent, which contains trace quantities of PFBE for reuse. The remaining water from this heating process is released as wastewater. In the PTFE process, most of the PFBE is used up in the reaction, but a very small quantity could be released to air at the end of each batch when the reactor vessel is purged although the majority of the purge gas is captured. The company has an environmental permit (ref: EPR/BU5453IY) under the Environmental Permitting (England and Wales) Regulations 2016. According to the permit, the fluoropolymer production capacity is 6 000 tonnes/year. The permit does not require any 62 of 115 Formatted: Strikethrough Formatted: Strikethrough, Not Highlight Commented [MS19]: It is a comonomer for PTFE as well. It is not as reactive as TFE hence it does reduce reaction rate but the use is not as a polymerisation inhibitor. Formatted: Strikethrough, Not Highlight Formatted: Strikethrough, Not Highlight Formatted: Strikethrough Commented [MS20]: Trace amounts, the PFBE is mostly (expectation is almost entirely) incorporated in to the polymer AGC does not have any data for residual dissolved PFBE in reactor water or to atmosphere. However, the polymerisation is carried out in a closed system so releases will be minimal. Formatted: Not Highlight Commented [MS21]: Correction, see comment above. Commented [MS22]: Reactor is purged to a sealed container (gas holder), not to air. Reactor is only open to air after the purge and the reactor is post-vacuumed (i.e. low pressure). monitoring for PFBE or require any specific control measures. The company undertook a mass balance calculation for each of the manufacturing lines and provided these for the evaluation. Routes of emission to surface water The wastewater from the recovery processes in the ETFE production line, along with wastewater from other processes on site, drains to the waste effluent pit prior to discharge to the River Wyre without further on-site treatment. AGC Chemicals Europe Ltd estimate an annual release of less than 1 kg/year PFBE, based on the mass balance. Given this small amount of release, and the dilution provided by the River Wyre, the Environment Agency has not performed any modelling to derive a predicted environmental concentration (PEC). Routes of emission to land There is no direct emission to land from the site, and since the wastewater is not treated in a municipal sewage treatment plant (STP), it is not present in sewage sludge that can be spread on agricultural land. Routes of emission to air There are 3 main release points is in the drying and recovery processes in the ETFE production plant. The first release point is in the reactor when the headspace is purged following each batch reaction. This gas is collected for high temperature incineration but as this part of the plant is not fully sealed some of the solvent/PFBE may be released to the atmosphere. The second one is storage of the water and solvent containing a trace amount of PFBE in a semi-open tank. This tank has a cover but is not sealed. The water enters the tank at approximately 90 C, and undissolved solvent and PFBE sinks to the bottom of this tank. Gaseous PFBE residing in the headspace of this tank is captured using carbon beds and recovered back to recycled solvent tanks as liquid. However, there are still atmospheric emissions from this tank. The third release point is the ETFE wastewater tank, which is not sealed. Gaseous PFBE from ETFE process is captured in solvent-laden-gas (SLG) recovery system by activated carbon bed and recovered back to the process as liquid. Releases to air occur from carbon adsorption unit which is a permitted emission point. AGC Chemicals Europe Ltd estimates a total annual PFBE release from all on-site release points of less than 900 kg/year, based on a mass balance undertaken each year. In the mass balance for PTFE, the company calculates that all the PFBE is consumed in the polymerisation process, but as a worst case have estimated a release to air of 0.5 kg/year (N.B. this is for all markets, not just the UK). Since distribution modelling suggests that any substance released to air will remain there (see Section 6.2.3), the Environment Agency has not performed any modelling to derive PECs for environmental media. Commented [MS23]: There is an effluent treatment plant but this is not designed for PFBE removal. 63 of 115 10.1.3 Polymer use The quantity of PFBE in the ETFE products supplied to customers is <0.5 kg/year (N.B. this is for all markets, not just the UK). This is based on the mass balance and an extrapolation from estimates of process solvent levels in the final polymer. PFBE is estimated to be present at approximately 0.5% in this solvent. This is fully described in the confidential annex. In their mass balance calculations for the PTFE process, the company estimates that all of the PFBE is used up in the reaction and that there would be no residual monomer in the final polymer product. 10.1.4 Monitoring data The company has not undertaken any monitoring for releases of PFBE to either wastewater or the atmosphere. 64 of 115 11 Risk characterisation Environmental releases from the UK manufacturing site are less than 900 kg/year to air and less than 1 kg/year to water. A reasonable worst-case estimate is that the residual PFBE content in polymers on the UK market (from all suppliers) will be lower than 0.5 kg/year. No significant adverse effects have been observed in the available aquatic ecotoxicity studies, although long-term data for fish and invertebrates are not available. Since the substance is not rapidly degradable, and has a log KOW above 4, it should be classified as Aquatic Chronic 4. Although aquatic PNECs have been derived, they are screening values based on the water solubility. The substance does not meet the PBT/vPvB or draft PMT criteria but does screen as potentially meeting the draft vPvM criteria and no information is available about endocrine disruption. On the basis of low releases and lack of significant adverse effects in the information currently available, the Environment Agency considers that the direct risk to the environment from PFBE is likely to be low. A conclusion cannot be drawn about risks arising from the vPvM properties of the substance until a UK Government policy position is available. However, aquatic emissions are very low. The influence of volatility is not considered under the criteria either. In the absence of better evidence, PFBE might contribute to global warming based on analogy with other HFCs. The Environment Agency recommends that this should be considered as part of any emission controls. Commented [MS24]: This data needs refining as the estimate from the mass balance feels too high given that the PFBE is consumed by polymerisation. Commented [MS25]: See comments on GWP and ODP. 65 of 115 12 Conclusions and recommendations 12.1 Conclusion PFBE is a PFAS that belongs to the HFC group. It is imported to the UK and used as a comonomer to manufacture fluorinated polymers at a single site. A low level of release occurs to air during the manufacture of fluoropolymers at this site, and there is also likely to be release of smaller quantities to the River Wyre. Very small releases may also occur at polymer processing sites. PFBE is volatile and is expected to partition significantly to the atmosphere. It may have a long atmospheric half-life and so has the potential to be transported to remote regions. Based on the available hazard data the following conclusions can be reached: PFBE meets the criteria to be classified as Aquatic Chronic 4 for aquatic environmental hazard under CLP legislation but does not meet the T criterion of REACH Annex 13. PFBE is not readily biodegradable and is not expected to degrade abiotically. PFBE therefore screens as potentially persistent or very persistent. The log KOW and log KOA indicate that the substance does not meet the Annex 13 bioaccumulation screening criteria. PFBE is unlikely to be PBT or vPvB, but does meet the draft vPvM criteria. A conclusion cannot be drawn about risks arising from the vPvM properties of the substance until a UK Government policy position is available. However, aquatic emissions are very low. The influence of volatility is not considered under the criteria either. On the basis of low releases and lack of significant adverse effects according to the information currently available, the Environment Agency considers that the direct risk to the environment from PFBE is likely to be low. PFBE might contribute to global warming based on analogy with other HFCs. PFBE is likely to be a source of perfluoropentanoic acid and perfluorobutanoic acid in the environment. An assessment of their properties (and other contributing substances) is outside scope of this evaluation. However, they are both likely to be vPvM, and so PFBE would be relevant in terms of any risk management associated with these "arrowheads". 12.2 Recommendations Although this evaluation is not a formal assessment under UK REACH, the Environment Agency proposes several recommendations to improve the data package to allow a more robust assessment of the hazards and risks posed by PFBE. The Environment Agency recommends that the REACH registration dossier is updated with: Commented [MS26]: Noted and agreed. Commented [MS27]: Not significant due to low GWP and ODP? 66 of 115  a self-classification of Aquatic Chronic 4 for aquatic environmental hazard under the CLP legislation, which in turn would trigger an exposure assessment; and justification for the atmospheric half-life of 6.4 hours stated in the PBT assessment of the EU REACH registration dossier, as well as information on likely transformation products. PFBE is expected to partition to the atmosphere and could contribute to global warming based on analogy with other HFCs. The UK importer is invited to provide further information on this issue, and consider the relevance of global warming as part of any emission controls. 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Product Properties Test Guidelines: OPPTS 830.7840 Water Solubility: Column Elution Method; Shake Flask Method [EPA 712-C-98-041], March 1998 (accessed March 2022). US EPA, 2022cz. U.S. Environmental Protection Agency. Product Properties Test Guidelines: OPPTS 830.7550 Partition Coefficient (n-Octanol/Water), Shake Flask Method [EPA 712-C-96-038], August 1996 (accessed March 2022). US EPA, 2022da. PFAS Analytical Methods Development and Sampling Research. https://www.epa.gov/water-research/pfas-analytical-methods-development-and-samplingresearch (Accessed March 2022) Wegmann, Cavin, MacLeod, Scheringer and Hungerbhler, 2009. The OECD software tool for screening chemicals for persistence and long-range transport potential. Environmental Modeling and Software, 24, 228-237 Williams, A.J., Grulke, C.M., Edwards, J. 2017. The CompTox Chemistry Dashboard: a community data resource for environmental chemistry. J Cheminform 9, 61. https://doi.org/10.1186/s13321-017-0247-6 (accessed July, 2020) 82 of 115 14 List of abbreviations % Percentage B Bioaccumulative BAF Bioaccumulation factor BCF Bioconcentration factor BMF Biomagnification factor CAS Chemical Abstracts Service CLP Classification, labelling and packaging (of substances and mixtures) cm Centimetre CoRAP Community Rolling Action Plan CSR Chemical Safety Report d Day DegT50 Degradation half-life or transformation half-life (days) DMEL Derived Minimal Effect Level DNEL Derived No Effect Level DSD Dangerous Substances Directive DT50 Dissipation half-life (days) dw Dry weight EC10 10% effect concentration EC50 50% effect concentration ELR50 50% effect loading rate ECETOC TRA European Centre for Ecotoxicology and Toxicology of Chemicals Targeted Risk Assessment ECHA European Chemicals Agency EPA Environmental Protection Agency EPM Equilibrium Partitioning Method 83 of 115 EQS ERC ES EU EUSES FSDT g GC GC/FID GC/MS GLP H HLC hPa HPLC HSE ISO IUCLID IUPAC kg kJ km KAW KOA KOC KOW Environmental Quality Standard Environmental release category Exposure Scenario European Union European Union System for the Evaluation of Substances Fish Sexual Development Test Gramme Gas chromatography Gas chromatography - Flame Ionisation Detection Gas chromatography - mass spectrometry Good laboratory practice Hours Henry's Law Constant Hectopascal High performance liquid chromatography Health and Safety Executive International Organisation for Standardisation International Uniform Chemical Information Database International Union of Pure and Applied Chemistry Kilogram Kilojoule Kilometre Air-water partition coefficient Octanol-air partition coefficient Organic carbon-water partition coefficient Octanol-water partition coefficient 84 of 115 kPa KSUSP-WATER kX L LC50 LEV LOD Log LOQ M m/z mg min mL mol MS nm NOAEL NOEC NOEL NONS OC OECD OSPAR NICNAS Kilopascal Suspended matter-water partitioning coefficient Rate constants (days-1) Litre 50% lethal effect concentration Local Exhaust Ventilation Limit of detection Logarithmic value Limit of quantitation Molar Mass to charge ratio Milligram Minute Millilitre Mole Mass spectrometry Nanometre No observed adverse effect level No-observed effect concentration No observed effect level Notification of New Substances Regulations 1993 Operational condition Organisation for Economic Co-operation and Development Oslo and Paris Convention for the Protection of the Marine Environment of the North-East Atlantic National Industrial Chemicals Notification and Assessment Scheme 85 of 115 p Pa PACT PBT PC PEC pg PFAS PFOS PFOA pKa PNEC POP ppb PPE ppm PROC QSAR OPERA r2 RCR REACH RMM RPE rpm SMILES Statistical probability Pascal Public Activities Co-ordination Tool Persistent, Bioaccumulative and Toxic Product category Predicted environmental concentration Picogramme Per- and polyfluorinated alkyl substances Perfluorooctanesulfonate Perfluorooctanoic acid Acid dissociation constant Predicted no effect concentration Persistent organic pollutant Parts per billion Personal Protective Equipment Parts per million Process Category Quantitative structure-activity relationship OPEn structure-activity/property Relationship App Correlation coefficient Risk characterisation ratio Registration, Evaluation, Authorisation and Restriction of Chemicals (EU Regulation No. 1907/2006) Risk Management Measures Respiratory protective equipment Revolutions per minute Simplified Molecular Input Line Entry System 86 of 115 SVHC t T.E.S.T TG TMF TSCA UNEP UK US EPA UV vB vP VP vPvB WAF WSF wt ww WWTP g Substance of Very High Concern Tonne Toxicity Estimation Software Tool Test Guideline Trophic Magnification Factor Toxic Substances Control Act United Nations Environment Programme United Kingdom United Stated Environmental Protection Agency Ultraviolet Very bioaccumulative Very persistent Vapour pressure Very persistent and very bioaccumulative Water Accommodated Fraction Water Soluble Fraction Weight Wet weight Wastewater Treatment Plant Microgram 87 of 115 Appendix A: Literature search A literature search was undertaken by the Environment Agency on the 8th April 2020 to identify published information relevant to the assessment of PFBE. The keywords listed in Table 10 were searched for in PubMed (https://pubmed.ncbi.nlm.nih.gov/) and Science Direct (https://www.sciencedirect.com/). In order to maximise the number of records identified keywords were based on the substance name only, and not on the endpoints of interest or year of publication. Table A. 1 Literature search terms and number of hits Search terms PubMed Science Direct 19430-93-4 5 8 3,3,4,4,5,5,6,6,6- 0 5 Nonafluorohexene 3,3,4,4,5,5,6,6,6- 0 2 nonafluorohex-1-ene Perfluorobutyl ethylene 1 28 PFBE AND fluoro 0 5 Total unique records 6 43 The identified records were screened manually for relevance to this assessment based on the title and abstract. Articles identified as of potential interest were obtained and reviewed for relevance. Those that were found to be relevant are discussed in the appropriate sections of this report. 88 of 115 15 Appendix B: Structural analogues The US EPA CompTox Chemicals database (US EPA, 2022a; accessed March 2022) was used to identify structures with Tanamito similarity coefficient >0.8. No experimental data were available for any of those included. Table C.1 Structural identifiers for analogues of PFBE IUPAC name CAS number EC number Structural formula Molecular formula Molecular weight (g/mol) SMILES code Source 3,3,4,4,5,5,6,6,7,7 ,7Undecafluorohept -1-ene 84100-13-0 282-095-0 C7H3F11 296.083 FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C( F)(F)C=C US EPA (2022b) 3,3,4,4,5,5,6,6,7,7,8 ,8,8Tridecafluorooct-1ene 25291-17-2 246-791-8 C8H3F13 346.091 FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C( F)(F)C(F)(F)C=C US EPA (2022c) 3,3,4,4,5,5,6,6,7,7,8 ,8,9,9,9Pentadecafluoronon -1-ene 25431-45-2 246-976-3 C9H3F15 396.099 FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C( F)(F)C(F)(F)C(F)(F)C=C US EPA (2022d) 3,3,4,4,5,5,6,6,7,7,8 ,8,9,9,10,10,10Heptadecafluorodec -1-ene 21652-58-4 244-503-5 3,3,4,4,5,5,6,6,7,7,8 ,8,9,9,10,10,11,11,1 1Nonadecafluoround ec-1-ene 57216-75-8 3,3,4,4,5,5,6,6,7,7,8 ,8,9,9,10,10,11,11,1 2,12,12Henicosafluorodode c-1-ene 30389-25-4 3,3,4,4,5,5,6,6,7,7,8 ,8,9,9,10,10,11,11,1 2,12,13,13,13Tricosafluorotridec1-ene 1270180-02-3 250-173-3 - C10H3F17 446.107 FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C( F)(F)C(F)(F)C(F)(F)C(F)(F)C=C US EPA (2022e) C11H3F19 496.115 FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C( F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F )C= US EPA (2022f) C12H3F21 546.122 FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C( F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F )C(F)(F)C=C US EPA (2022g) C13H3F23 596.13 FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C( F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F )C(F)(F)C(F)(F)C=C US EPA (2022h) 90 of 115 3,3,4,4,5,5,6,6,7,7,8 ,8,9,9,10,10,11,11,1 2,12,13,13,14,14,14 Pentacosafluorotetr adec-1-ene 67103-05-3 3,3,4,4,5,5,6,6,7,7,8 ,8,9,9,10,10,11,11,1 2,12,13,13,14,14,15 ,15,15Heptacosafluoropen tadec-1-ene 1270180-04-5 691-816-1 - 3,3,4,4,5,5,6,6,7,7,8 104564-28-5 - ,8,9,9,10,10,11,11,1 2,12,13,13,14,14,15 ,15,16,16,16- Nonacosafluorohex adec-1-ene 3,3,4,4,5,5,5Heptafluoropent-1ene 355-08-8 206-576-1 C14H3F25 646.138 FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C( F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F )C(F)(F)C(F)(F)C(F)(F)C=C US EPA (2022i) C15H3F27 696.146 FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C( F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F )C(F)(F)C(F)(F)C(F)(F)C(F)(F)C= C US EPA (2022j) C16H3F29 746.154 FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C( F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F )C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F )(F)C=C US EPA (2022k) C5H3F7 196.068 FC(F)(F)C(F)(F)C(F)(F)C=C US EPA (2022l) 91 of 115 3,3,4,4,5,5,6,6Octafluoroocta-1,7diene 678-65-9 3,3,4,4,5,5,6,6,7,7,8 ,8Dodecafluorodeca1,9-diene 1800-91-5 3,3,4,4,5,5,6,6,7,7,8 ,8,9,9,10,10Hexadecafluorodod eca-1,11- 35192-44-0 1,1,1,2,2,3,3Heptafluoronon-4ene 57325-40-3 (4E)-1,1,1,2,2,3,3Heptafluorodec-4ene 57325-42-5 (5E)1,1,1,2,2,3,3,4,4Nonafluorodec-5ene 131294-67-2 211-650-1 217-288-0 671-723-2 - C8H6F8 254.12 FC(F)(C=C)C(F)(F)C(F)(F)C(F)(F) US EPA C=C (2022m) C10H6F12 354.139 FC(F)(C=C)C(F)(F)C(F)(F)C(F)(F) US EPA C(F)(F)C(F)(F)C=C (2022n) C12H6F16 454.154 FC(F)(C=C)C(F)(F)C(F)(F)C(F)(F) US EPA C(F)(F)C(F)(F)C(F)(F)C(F)(F)C=C (2022o) C9H11F7 252.176 CCCCC=CC(F)(F)C(F)(F)C(F)(F) F US EPA (2022p) C10H13F7 266.203 CCCCC\C=C\C(F)(F)C(F)(F)C(F)( F)F US EPA (2022q) C10H11F9 302.184 CCCC\C=C\C(F)(F)C(F)(F)C(F)(F )C(F)(F)F US EPA (2022r) 92 of 115 1,1,1,4,4,5,5,6,6,7,7 887111-62-8 - ,7- Dodecafluorohept- 2-ene 1,1,1,2,2,3,3,4,4- 383145-46-8 - Nonafluoroundec-5- ene (5E)- 113999-54-5 - 1,1,1,2,2,3,3,4,4- Nonafluorododec-5- ene (5E)- 104504-30-5 - 1,1,1,2,2,3,3,4,4- Nonafluorotetradec- 5-ene (2E)- 80793-20-0 - 4,4,5,5,6,6,7,7,8,8,9 ,9,9- Tridecafluoronon-2- ene C7H2F12 314.074 FC(F)(F)C=CC(F)(F)C(F)(F)C(F)( F)C(F)(F)F US EPA (2022s) C11H13F9 316.211 CCCCCC=CC(F)(F)C(F)(F)C(F)(F US EPA )C(F)(F)F (2022t) C12H15F9 330.238 CCCCCC\C=C\C(F)(F)C(F)(F)C(F US EPA )(F)C(F)(F)F (2022u) C14H19F9 358.292 CCCCCCCC\C=C\C(F)(F)C(F)(F) C(F)(F)C(F)(F)F US EPA (2022v) C9H5F13 360.118 C\C=C\C(F)(F)C(F)(F)C(F)(F)C(F) US EPA (F)C(F)(F)C(F)(F)F (2022w) 93 of 115 4,4,5,5,6,6,7,7,8,8,9 63967-46-4 - ,9,9- Tridecafluoronon-2- ene 1,1,1,2,2,5,5,6,6,7,7 84808-65-1 - ,8,8,8- Tetradecafluorooct- 3-ene 1,1,1,4,4,5,5,6,6,7,7 935476-95-2 - ,8,8,8- Tetradecafluorooct- 2-ene 1,1,1,2,2,3,3,4,4- 131851-20-2 - Nonafluorohexadec- 5-ene C9H5F13 360.118 CC=CC(F)(F)C(F)(F)C(F)(F)C(F)( F)C(F)(F)C(F)(F)F US EPA (2022x) C8H2F14 364.082 FC(F)(F)C(F)(F)C=CC(F)(F)C(F)( F)C(F)(F)C(F)(F)F US EPA (2022y) C8H2F14 364.082 FC(F)(F)C=CC(F)(F)C(F)(F)C(F)( F)C(F)(F)C(F)(F)F US EPA (2022z) C16H23F9 386.346 CCCCCCCCCCC=CC(F)(F)C(F)( F)C(F)(F)C(F)(F)F US EPA (2022aa) 94 of 115 (2E)- 89889-22-5 - 4,4,5,5,6,6,7,7,8,8,9 ,9,10,10,10- Pentadecafluorodec -2-ene 1,1,1,2,2,5,5,6,6,7,7 935477-04-6 - ,8,8,9,9,9- Hexadecafluoronon- 3-ene 1,1,1,4,4,5,5,6,6,7,7 935477-01-3 - ,8,8,9,9,9- Hexadecafluoronon- 2-ene C10H5F15 410.126 C\C=C\C(F)(F)C(F)(F)C(F)(F)C(F) US EPA (F)C(F)(F)C(F)(F)C(F)(F)F (2022ab) C9H2F16 414.089 FC(F)(F)C(F)(F)C=CC(F)(F)C(F)( F)C(F)(F)C(F)(F)C(F)(F)F US EPA (2022ac) C9H2F16 414.089 FC(F)(F)C=CC(F)(F)C(F)(F)C(F)( F)C(F)(F)C(F)(F)C(F)(F)F US EPA (2022ad) 95 of 115 1,1,1,2,2,3,3,6,6,7,7 935477-07-9 - ,8,8,9,9,9- Hexadecafluoronon- 4-ene 1,1,1,2,2,3,3,4,4Nonafluorooctadec5-ene 160460-03-7 6E)8,8,9,9,10,10,11,11, 12,12,13,13,13Tridecafluorotridec6-ene 350608-60-5 1,1,1,2,2,3,3,4,4,5,5 ,6,6Tridecafluorotetrade c-7-ene 120464-26-8 1,1,1,2,2,3,3,4,4,5,5 ,6,6Tridecafluoropentad ec-7-ene 1980786-99-9 671-503-6 - C9H2F16 414.089 FC(F)(F)C(F)(F)C(F)(F)C=CC(F)( F)C(F)(F)C(F)(F)C(F)(F)F US EPA (2022ae) C18H27F9 414.4 CCCCCCCCCCCCC=CC(F)(F)C( F)(F)C(F)(F)C(F)(F)F US EPA (2022af) C13H13F13 416.226 CCCCC\C=C\C(F)(F)C(F)(F)C(F)( F)C(F)(F)C(F)(F)C(F)(F)F US EPA (2022ag) C14H15F13 430.253 CCCCCCC=CC(F)(F)C(F)(F)C(F) (F)C(F)(F)C(F)(F)C(F)(F)F US EPA (2022ah) C15H17F13 444.28 CCCCCCCC=CC(F)(F)C(F)(F)C( F)(F)C(F)(F)C(F)(F)C(F)(F)F US EPA (2022ai) 96 of 115 7,7,8,8,9,9,10,10,11 52717-05-2 - ,11,12,12,13,13,13- Pentadecafluorotrid ec-5-ene 1,1,1,2,2,3,3,4,4,5,5 120464-27-9 - ,6,6- Tridecafluorohexad ec-7-ene (7E)- 152128-75-1 - 1,1,1,2,2,3,3,4,4,5,5 ,6,6- Tridecafluorohexad ec-7-ene 4,4,5,5,6,6,7,7,8,8,9 67103-04-2 - ,9,10,10,11,11,11- Heptadecafluoround ec-2-ene C13H11F15 452.207 CCCCC=CC(F)(F)C(F)(F)C(F)(F) C(F)(F)C(F)(F)C(F)(F)C(F)(F)F US EPA (2022aj) C16H19F13 458.307 CCCCCCCCC=CC(F)(F)C(F)(F)C (F)(F)C(F)(F)C(F)(F)C(F)(F)F US EPA (2022ak) C16H19F13 458.307 CCCCCCCC\C=C\C(F)(F)C(F)(F) C(F)(F)C(F)(F)C(F)(F)C(F)(F)F US EPA (2022al) C11H5F17 460.134 CC=CC(F)(F)C(F)(F)C(F)(F)C(F)( F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F US EPA (2022am ) 97 of 115 1,1,1,2,2,3,3,6,6,7,7 935477-16-0 - ,8,8,9,9,10,10,10- Octadecafluorodec- 4-ene 1,1,1,2,2,5,5,6,6,7,7 86563-87-3 - ,8,8,9,9,10,10,10- Octadecafluorodec- 3-ene 1,1,1,2,2,3,3,4,4,7,7 84551-43-9 - ,8,8,9,9,10,10,10- Octadecafluorodec- 5-ene 8,8,9,9,10,10,11,11, 38787-60-9 - 12,12,13,13,14,14,1 4- Pentadecafluorotetr adec-6-ene C10H2F18 464.097 FC(F)(F)C(F)(F)C(F)(F)C=CC(F)( F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F US EPA (2022an) C10H2F18 464.097 FC(F)(F)C(F)(F)C=CC(F)(F)C(F)( F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F US EPA (2022ao) C10H2F18 464.097 FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C= CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F US EPA (2022ap) C14H13F15 466.234 CCCCCC=CC(F)(F)C(F)(F)C(F)(F US EPA )C(F)(F)C(F)(F)C(F)(F)C(F)(F)F (2022aq) 98 of 115 (7E)- 125081-49-4 - 1,1,1,2,2,3,3,4,4,5,5 ,6,6- Tridecafluorooctade c-7-ene 1,1,1,2,2,3,3,4,4,5,5 131851-05-3 - ,6,6- Tridecafluorooctade c-7-ene (5E)- 210491-04-6 - 7,7,8,8,9,9,10,10,11 ,11,12,12,13,13,14, 14,14- Heptadecafluorotetr adec-5-ene 1,1,1,2,2,3,3,4,4,5,5 52717-06-3 - ,6,6,7,7- Pentadecafluorohep tadec-8-ene C18H23F13 486.361 CCCCCCCCCC\C=C\C(F)(F)C(F) (F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F US EPA (2022ar) C18H23F13 486.361 CCCCCCCCCCC=CC(F)(F)C(F)( F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F US EPA (2022as) C14H11F17 502.215 CCCC\C=C\C(F)(F)C(F)(F)C(F)(F )C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F )(F)F US EPA (2022at) C17H19F15 508.315 CCCCCCCCC=CC(F)(F)C(F)(F)C (F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)( F)F US EPA (2022au) 99 of 115 1,1,1,2,2,3,3,6,6,7,7 100603-63-2 - ,8,8,9,9,10,10,11,11 ,11- Icosafluoroundec-4- ene 1,1,1,2,2,3,3,4,4,7,7 100508-28-9 - ,8,8,9,9,10,10,11,11 ,11- Icosafluoroundec-5- ene 1,1,1,2,2,3,3,4,4,5,5 160460-04-8 - ,6,6- Tridecafluoroicos-7- ene (6E)- 350608-65-0 - 8,8,9,9,10,10,11,11, 12,12,13,13,14,14,1 5,15,15- Heptadecafluoropen tadec-6-ene C11H2F20 514.105 FC(F)(F)C(F)(F)C(F)(F)C=CC(F)( F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C( F)(F)F US EPA (2022av) C11H2F20 514.105 FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C= CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C( F)(F)F US EPA (2022aw ) C20H27F13 514.415 CCCCCCCCCCCCC=CC(F)(F)C( F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F )F US EPA (2022ax) C15H13F17 516.242 CCCCC\C=C\C(F)(F)C(F)(F)C(F)( F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C( F)(F)F US EPA (2022ay) 100 of 115 (7E)- 84201-60-5 - 9,9,10,10,11,11,12, 12,13,13,14,14,15,1 5,16,16,16- 1,1,1,2,2,3,3,4,4,5,5 1244062-15-4 - ,6,6- Tridecafluorodocos- 7-ene (9E)- 113999-61-4 - 1,1,1,2,2,3,3,4,4,5,5 ,6,6,7,7,8,8- Heptadecafluorooct adec-9-ene (5E)- 51249-66-2 - 1,1,1,2,2,3,3,4,4,7,7 ,8,8,9,9,10,10,11,11 ,12,12,12- Docosafluorododec- 5-ene (9E)- 124921-25-1 - 1,1,1,2,2,3,3,4,4,5,5 ,6,6,7,7,8,8- Heptadecafluoroico s-9-ene C16H15F17 530.269 CCCCCC\C=C\C(F)(F)C(F)(F)C(F )(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F) C(F)(F)F US EPA (2022az) C22H31F13 542.469 CCCCCCCCCCCCCCC=CC(F)(F )C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F )(F)F US EPA (2022ba) C18H19F17 558.323 CCCCCCCC\C=C\C(F)(F)C(F)(F) C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F) (F)C(F)(F)F US EPA (2022bb) C12H2F22 564.113 FC(F)(F)C(F)(F)C(F)(F)C(F)(F)\C =C\C(F)(F)C(F)(F)C(F)(F)C(F)(F) C(F)(F)C(F)(F)F US EPA (2022bc) C20H23F17 586.377 CCCCCCCCCC\C=C\C(F)(F)C(F) (F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C (F)(F)C(F)(F)F US EPA (2022bd) 101 of 115 1,1,1,2,2,3,3,4,4,5,5 ,6,6,7,7,8,8Heptadecafluorodoc os-9-ene 118642-84-5 1,1,1,2,2,3,3,4,4,5,5 ,6,6,7,7,8,8Heptadecafluorotetr acos-9-ene 1244062-16-5 (7E)1,1,1,2,2,3,3,4,4,5,5 ,6,6,9,9,10,10,11,11 ,12,12,13,13,14,14, 14Hexacosafluorotetra dec-7-ene 51249-67-3 (5E)1,1,1,2,2,3,3,4,4,7,7 ,8,8,9,9,10,10,11,11 ,12,12,13,13,14,14, 14Hexacosafluorotetra dec-5-ene 51249-69-5 671-615-5 - C22H27F17 614.431 CCCCCCCCCCCCC=CC(F)(F)C( F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F )C(F)(F)C(F)(F)F US EPA (2022be) C24H31F17 642.485 CCCCCCCCCCCCCCC=CC(F)(F )C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F )(F)C(F)(F)C(F)(F)F US EPA (2022bf) C14H2F26 664.128 FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C( F)(F)C(F)(F)\C=C\C(F)(F)C(F)(F) C(F)(F)C(F)(F)C(F)(F)C(F)(F)F US EPA (2022bg) C14H2F26 664.128 FC(F)(F)C(F)(F)C(F)(F)C(F)(F)\C =C\C(F)(F)C(F)(F)C(F)(F)C(F)(F) C(F)(F)C(F)(F)C(F)(F)C(F)(F)F US EPA (2022bh) 102 of 115 1,1,1,2,2,3,3,4,4,5,5 56523-43-4 - ,6,6,9,9,10,10,11,11 ,12,12,13,13,14,14, 14- Hexacosafluorotetra dec-7-ene 1,1,1,2,2,3,3,4,4,5,5 907206-01-3 - ,6,6,7,7,8,8- Heptadecafluorohex acos-9-ene 1,1,1,2,2,3,3,4,4,5,5 1244062-18-7 - ,6,6,7,7,8,8,9,9,10,1 0- Henicosafluorohexa cos-11-ene (8E)- 35709-15-0 - 1,1,1,2,2,3,3,4,4,5,5 ,6,6,7,7,10,10,11,11 ,12,12,13,13,14,14, 15,15,16,16,16- Triacontafluorohexa dec-8-ene C14H2F26 664.128 FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C( F)(F)C(F)(F)C=CC(F)(F)C(F)(F)C( F)(F)C(F)(F)C(F)(F)C(F)(F)F US EPA (2022bi) C26H35F17 670.539 CCCCCCCCCCCCCCCCC=CC( F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F )C(F)(F)C(F)(F)C(F)(F)F US EPA (2022bj) C26H31F21 742.5 CCCCCCCCCCCCCCC=CC(F)(F )C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F )(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F) F US EPA (2022bk) C16H2F30 764.144 FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C( F)(F)C(F)(F)C(F)(F)\C=C\C(F)(F) C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F) (F)C(F)(F)F US EPA (2022bl) 103 of 115 (7E)- 51249-68-4 - 1,1,1,2,2,3,3,4,4,5,5 ,6,6,9,9,10,10,11,11 ,12,12,13,13,14,14, 15,15,16,16,16- Triacontafluorohexa dec-7-ene 1,1,1,2,2,3,3,4,4,5,5 1151525-71-1 - ,6,6,7,7,8,8,9,9,10,1 0,11,11,12,12- Pentacosafluorooct acos-13-ene (9E)- 51249-70-8 - 1,1,1,2,2,3,3,4,4,5,5 ,6,6,7,7,8,8,11,11,1 2,12,13,13,14,14,15 ,15,16,16,17,17,18, 18,18- Tetratriacontafluoro octadec-9-ene 4,4,5,5,6,6,6- 2317-84-2 - Heptafluorohex-1- ene C16H2F30 764.144 FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C( F)(F)C(F)(F)\C=C\C(F)(F)C(F)(F) C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F) (F)C(F)(F)F US EPA (2022bm ) C28H31F25 842.516 CCCCCCCCCCCCCCC=CC(F)(F )C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F )(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F) C(F)(F)C(F)(F)F US EPA (2022bn) C18H2F34 864.16 FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C( F)(F)C(F)(F)C(F)(F)C(F)(F)\C=C\ C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F) (F)C(F)(F)C(F)(F)C(F)(F)F US EPA (2022bo) C6H5F7 210.095 FC(F)(F)C(F)(F)C(F)(F)CC=C US EPA (2022bp) 104 of 115 4,4,5,5,6,6,7,7,7- 129846-67-9 - Nonafluorohept-1- ene 4,4,5,5,6,6,7,7,8,8,9 80793-18-6 - ,9,9- Tridecafluoronon-1- ene 4,4,5,5,6,6,7,7,8,8,9 61589-64-8 - ,9,10,10,11,11,11- Heptadecafluoround ec-1-ene 4,4,5,5,6,6,7,7,7- 132673-98-4 - Nonafluorohepta- 1,2-diene 3,3,4,4,5,6,6,6- 139060-76-7 - Octafluoro-5- (trifluoromethyl)hex- 1-ene C7H5F9 260.103 FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C C=C US EPA (2022bq) C9H5F13 360.118 FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C( F)(F)C(F)(F)CC=C US EPA (2022br) C11H5F17 460.134 FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C( F)(F)C(F)(F)C(F)(F)C(F)(F)CC=C US EPA (2022bs) C7H3F9 258.087 FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C= C=C US EPA (2022bt) C7H3F11 296.083 FC(F)(F)C(F)(C(F)(F)F)C(F)(F)C( F)(F)C=C US EPA (2022bu) 105 of 115 4,4,5,5,6,6,6- 355-95-3 - Heptafluorohex-2- ene (2E)-4,4,5,5,6,6,6- 1081782-31-1 - Heptafluorohex-2- ene 5,5,6,6,7,7,7- 355-98-6 - Heptafluorohept-3- ene 1,1,1,2,2,3,3- 2707-72-4 - Heptafluorooct-4- ene (2E)- 83227-62-7 - 1,1,1,4,4,5,5,6,6,6- Decafluorohex-2- ene C6H5F7 210.095 CC=CC(F)(F)C(F)(F)C(F)(F)F US EPA (2022bv) C6H5F7 210.095 C\C=C\C(F)(F)C(F)(F)C(F)(F)F US EPA (2022bw ) C7H7F7 224.122 CCC=CC(F)(F)C(F)(F)C(F)(F)F US EPA (2022bx) C8H9F7 238.149 CCCC=CC(F)(F)C(F)(F)C(F)(F)F US EPA (2022by) C6H2F10 264.066 FC(F)(F)\C=C\C(F)(F)C(F)(F)C(F) (F)F US EPA (2022bz) 106 of 115 1,1,1,2,2,5,5,6,6,7,7 887111-61-7 - ,7- Dodecafluorohept- 3-ene 1,1,1,2,2,3,3,6,6,7,7 3910-82-5 - ,8,8,8- Tetradecafluorooct- 4-ene (4E)- 35709-14-9 - 1,1,1,2,2,3,3,6,6,7,7 ,8,8,8- Tetradecafluorooct- 4-ene 1,1,1,2,2,5,5,6,6,9,9 35208-08-3 - ,10,10,10- Tetradecafluorodec- 3-ene C7H2F12 314.074 FC(F)(F)C(F)(F)C=CC(F)(F)C(F)( F)C(F)(F)F US EPA (2022ca) C8H2F14 364.082 FC(F)(F)C(F)(F)C(F)(F)C=CC(F)( F)C(F)(F)C(F)(F)F US EPA (2022cb) C8H2F14 364.082 FC(F)(F)C(F)(F)C(F)(F)\C=C\C(F) (F)C(F)(F)C(F)(F)F US EPA (2022cc) C10H6F14 392.136 FC(F)(F)C(F)(F)CCC(F)(F)C(F)(F )C=CC(F)(F)C(F)(F)F US EPA (2022cd) 107 of 115 (3E)5,5,6,6,7,7,8,8,9,9,1 0,10,10Tridecafluorodeca1,3-diene 148626-04-4 4,4,5,5,6,6,7,7,8,8,9 ,9,9-Tridecafluoro2-methylnon-2-ene 112343-55-2 3,3,4,4,5,5,6,6,7,7,8 ,8,8-Tridecafluoro1-iodooct-1-ene 150223-14-6 813-764-2 (1E)- 329698-26-2 - 3,3,4,4,5,5,6,6,7,7,8 ,8,8-Tridecafluoro- 1-iodooct-1-ene 3,3,4,4,4- 189154-79-8 - Pentafluoro-2- (trifluoromethyl)but- 1-ene C10H5F13 372.129 FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C( F)(F)C(F)(F)\C=C\C=C US EPA (2022ce) C10H7F13 374.145 CC(C)=CC(F)(F)C(F)(F)C(F)(F)C( F)(F)C(F)(F)C(F)(F)F US EPA (2022cf) C8H2F13I 471.988 FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C( F)(F)C(F)(F)C=CI US EPA (2022cg) C8H2F13I 471.988 FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C( F)(F)C(F)(F)\C=C\I US EPA (2022ch) C5H2F8 214.058 FC(F)(F)C(=C)C(F)(F)C(F)(F)F US EPA (2022ci) 108 of 115 4,4,5,5,5Pentafluoro-2(trifluoromethyl)pent -1-ene 90277-98-8 3,3,4,4,4Pentafluorobut-1ene 374-27-6 3,3,4,4Tetrafluorohexa1,5-diene 1763-21-9 4,4,5,5,5Pentafluoropent-1ene 135671-20-4 5,5,6,6,6Pentafluorohex-1ene 106128-16-9 4,4,5,5,6,6,7,7Octafluorodeca-1,9diene 170804-07-6 206-775-3 217-178-2 - C6H4F8 228.085 FC(F)(F)C(=C)CC(F)(F)C(F)(F)F US EPA (2022cj) C4H3F5 146.06 FC(F)(F)C(F)(F)C=C C6H6F4 154.108 FC(F)(C=C)C(F)(F)C=C C5H5F5 160.087 FC(F)(F)C(F)(F)CC=C C6H7F5 174.114 FC(F)(F)C(F)(F)CCC=C US EPA (2022ck) US EPA (2022cl) US EPA (2022cm ) US EPA (2022cn) C10H10F8 282.177 FC(F)(CC=C)C(F)(F)C(F)(F)C(F)( F)CC=C US EPA (2022co) 109 of 115 (1E)-3,3,4,4,5,5,5- 157430-71-2 - Heptafluoro-1- iodopent-1-ene 3,3,4,4,5,5,5Heptafluoro-1iodopent-1-ene 376-97-6 1,1,3,3,4,4,5,5,6,6,7 ,7,8,8,8Pentadecafluorooct1-enato 103712-63-6 4,4,5,5,6,6,7,7,8,8,9 ,9Dodecafluorododec a-1,11-diene 170804-09-8 3,3,4,4,5,5Hexafluorocyclopen t-1-ene 1005-73-8 3,3,4,4,5,5,6,6Octafluorocyclohex1-ene 775-40-6 688-377-3 - C5H2F7I 321.964 FC(F)(F)C(F)(F)C(F)(F)\C=C\I US EPA (2022cp) C5H2F7I 321.964 FC(F)(F)C(F)(F)C(F)(F)C=CI US EPA (2022cq) C8HF15 382.072 FC(F)=CC(F)(F)C(F)(F)C(F)(F)C( F)(F)C(F)(F)C(F)(F)F US EPA (2022cr) C12H10F12 382.193 FC(F)(CC=C)C(F)(F)C(F)(F)C(F)( F)C(F)(F)C(F)(F)CC=C US EPA (2022cs) C5H2F6 176.061 FC1(F)C=CC(F)(F)C1(F)F US EPA (2022ct) C6H2F8 226.069 FC1(F)C=CC(F)(F)C(F)(F)C1(F)F US EPA (2022cu) 110 of 115 2,3,3,4,4,5,5,6,6,7,7 -Undecafluorohept1-ene 94228-81-6 671-278-4 C7H3F11 296.083 FC(F)C(F)(F)C(F)(F)C(F)(F)C(F)( F)C(F)=C US EPA (2022cv) 111 of 115 Appendix B: QSAR models Two main databases were used to source in silico data for this evaluation when required. These were the United States Environmental Protection Agency (US EPA) CompTox Dashboard (US EPA, 2022a) and the Royal Society of Chemistry (RSC) ChemSpider portal (RSC, 2022). Both integrate diverse types of relevant domain data through a cheminformatics platform, and are built upon a database of curated substance properties linked to chemical structures (Williams et al., 2017). The QSAR models available from these two platforms are presented in Table B.1 (data from other open access models are available in the CompTox dashboard, but for the sake of brevity, these have not been used for the purposes of this evaluation). Table B.1 QSAR model outline Name Brief description ACD/Labs Predicts physicochemical properties via the Percepta Platform1. EPISuiteTM Estimation Programs Interface SuiteTM for Microsoft Windows A Windows-based suite of physical/chemical, environmental fate and ecotoxicity property estimation programs developed by the US EPA and Syracuse Research Corp. It uses a single input (typically a SMILES string) to run the following estimation programs: AOPWINTM, AEROWINTM, BCFBAFTM, BioHCwin, BIOWINTM, ECOSARTM, HENRYWINTM, HYDROWINTM, KOAWINTM, KOCWINTM, KOWWINTM, LEV3EPITM, MPBPWINTM, STPWINTM, WATERNTTM, WSKOWWINTM and WVOLWINTM. OPEn structure- activity/property Relationship App (OPERA) Open source suite of QSAR models providing predictions and additional information including applicability domain and accuracy assessment, as described in Williams et al. (2017). All models were built on curated data and standardized chemical structures as described in Williams et al. (2016). All OPERA properties are predicted under ambient conditions of 760 mmHg (103 kPa) at 25 C. T.E.S.T. Toxicity Estimation Software Tool US EPA software application for estimating the toxicity of chemicals using QSAR methods. EPISuiteTM is the model used to generate some physicochemical data, although T.E.S.T. does not report KOW values and uses a different database for surface tension. (US EPA, 2016). 1 http://www.acdlabs.com/products/percepta/ EPISuiteTM Table B.2 summarises the PFCs identified in the training/validation sets for EPISuiteTM. Applicability domain (US EPA, 2022cx). Table B.2 EPISuiteTM PFCs included in training and validation sets EPISuite model MPBPVP v 1.42 WSKOWWIN v 1.41 Water solubility estimate from fragments (WATERNT v 1.01 est) KOAWIN v 1.1 KOCWIN v 1.66 KOWWIN v 1.67 HENRYWIN v 3.1 Training set Validation set tetrafluoromethane hexafluoroethane tetrafluoroethylene octafluoropropane hexafluoropropene decafluorobutane not available perfluorocyclobutane perfluoro-n-hexane perfluorocyclohexane perfluoroheptane perfluoromethylcyclohexane none identified octafluoropropane octafluorocyclobutane tetrafluoromethane hexafluoroethane trifluoromethane octafluoropropane perfluorocyclobutane tetrafluoroethylene Uses KOWWIN and HENRYWIN databases none identified none identified tetrafluoromethane hexafluoroethane perfluorocyclohexane tetrafluoromethane hexafluoroethane tetrafluoroethene octafluoropropane perfluorocyclobutane Open Structure-activity/property Relationship App (OPERA) OPERA is a free and open-source/open-data suite of QSAR models providing predictions for physicochemical properties, environmental fate parameters, and toxicity endpoints. Applicability domain (AD) (Williams et al., 2017): If a chemical is considered outside the global AD and has a low local AD index (< 0.4), the prediction can be unreliable. If a chemical is considered outside the global AD but the local AD index is average (0.4-0.6), the query chemical is on the boundary of the training set but has quite similar neighbours (average reliability). If the local AD index is high (> 0.6), the prediction can be trusted. 113 of 115 Commented [MS28]: None of these are HFCs like PFBE.  If a chemical is considered inside the global AD but the local AD index is average (0.4- 0.6), the query chemical falls in a "gap" of the chemical space of the model but still falls within the boundaries of the training set and is surrounded with training chemicals. The prediction therefore should be considered with caution. If a chemical is considered inside the global AD and has a high local AD index (> 0.6), the prediction can be considered reliable. T.E.S.T. (Toxicity Estimation Software Tool) Data sets used in T.E.S.T. (US EPA, 2016) for parameters reported at 25 C: Surface tension: Dataset for 1 416 chemicals obtained from the data compilation of Jasper 1972; Water solubility: Dataset of 5 020 chemicals was compiled from the database in EPI SuiteTM. Chemicals with water solubilities exceeding 1,000,000 mg/L were omitted from the overall dataset; Vapour pressure: Dataset of 2 511 chemicals was compiled from the database in EPI SuiteTM. T.E.S.T. displays structures for substances from the test and training sets that are closest to the substance where a predicted value is required. A comparison between the experimental and predicted value for the substances in the test and training sets provides a similarity coefficient. If the predicted values match the experimental values for similar chemicals in the test and training set (and the similar chemicals were predicted well), there is greater confidence in the predicted value for the substance under evaluation 114 of 115 Would you like to find out more about us or your environment? Then call us on 03708 506 506 (Monday to Friday, 8am to 6pm) Email: @environment-adency.dov.uk Or visit our website www.dov.uk/environment-agency incident hotline 0800 807060 (24 hours) floodline 0345 988 1188 (24 hours) Find out about call charges (https://www.gov.uk/call-charges) Environment first Are you viewing this onscreen? Please consider the environment and only print if absolutely necessary. If you are reading a paper copy, please don't forget to reuse and recycle. 115 of 115