Document baXj6ER99mQ1kkBK2GRVn8X9D

HONEYWELL ADVANCED LIMITED RIVERVIEW HOUSE HARVEY'S QUAY APARTMENTS LIMERICK V94R3DE IRELAND 27June 2023 PFAS REACH Annex XV Restriction Report 1ST Public Consultation (22 March - 25 September 2023) Request for Exclusion or Derogation of pMDIs Propellants from PFAS REACH Restriction Proposal Executive summary Honeywell International Inc. (hereinafter - Honeywell)1 is a global manufacturer and importer of various fluorinated gases to the European Union (EU), including hydrofluorocarbons (HFC) and hydrofluoroolefins (HFO). In particular, Honeywell plans to supply EU pharmaceutical companies with the gas HFO-1234ze(E)2 for uses as an excipient in medicinal products, including among other the use as propellant agents in Pressurised Medical Dose Inhalers (pMDIs). On 13 January 2023, the competent authorities of five EU/EEA Members States (Dossier Submitters) submitted to the European Chemical Agency (ECHA) the PFAS REACH Annex XV Restriction Report (Proposal).3 Substance HFO-1234ze(E) falls within the definition of PFAS used in the Proposal. However, contrary to what the Dossier Submitters claim, there is a range of PFAS substances, including various fluorinated HFC/HFO gases that are low-hazard, have low-Global Warming Potential (GWP), not (v-)persistent (not P/vP) and do not degrade to vP substances in any meaningful amounts. For instance, the REACH registration dossier and Chemical Safety Report (CSR) for the fluorinated gas HFO-1234ze(E)4 contain conclusive scientific evidence demonstrating that it is not persistent and does not exhibit risks similar to PBT/vPvB substances under Article XIII REACH. According to the most recent scientific data, upon release HFO-1234ze(E) ultimately degrades in the atmosphere to carbon dioxide (CO2), Hydrogen fluoride (HF) and trifluoroacetic acid (TFA).5 The TFA is a PFAS arrowhead substance: this happens in approximately 19 days and leads to an insignificant/negligible amount of TFA. The respective TFA amounts results in de minimis increases in overall TFA environmental concentrations by comparison with pre-existing TFA levels. 6 7 In this respect, highly qualified independent assessments ongoing for several years already by UNEP panels repeatedly conclude that "The current low concentration of trifluoroacetic acid (TFA) produced by the degradation of several hydrofluorocarbons (HFCs) and hydrofluoroolefins (HFOs), is currently 1 See the list of acronyms and abbreviations (aligned with the Proposal) in Annex I below. 2 1-Propene, 1,3,3,3-tetrafluoro-, EC no: 471-480-0, CAS no.: 1645-83-6, Mol. formula: C3H2F4 3 On 22 March 2023, ECHA published the PFAS REACH Annex XV Restriction Report in the Registry of restriction intentions until outcome and started the 1st Annex XV report consultation with a final deadline for comments on 25 September 2023. 4 Harmonised CLP classification: Hazard category: Liquefied gas; Hazard statement: H280: Contains gas under pressure; may explode if heated. 5 See Fig. 12 at page 282 and sections SI 4.3.2 at page 317 of the of the Environmental Effects of Stratospheric Ozone Depletion, UV Radiation, and Interactions with Climate Change, EEAP 2022 Assessment Report. 6 According to the conclusions in Chapter 6, section 3.8 of the Environmental Effects of Stratospheric Ozone Depletion, UV Radiation, and Interactions with Climate Change, EEAP 2022 Assessment Report, respective "releases will add to the existing load of TFA in the environment but predicted amounts are well below the threshold for concern with respect to human and environmental health." 7 See also detailed EFCTC position paper on the topic Published evidence supports very low yield of TFA from most HFOs and HCFOs. 1 judged not to pose a risk to human health or to the environment." 8 and that "available evidence indicates that this breakdown product [TFA] is of minimal risk to human health".9 The most recent EEAP 2022 Assessment Report also concludes that "based on projected future use of these precursors of TFA [incl. HFC/HFO], no harm is anticipated" and that TFA "is unlikely to cause adverse effects out to 2100".10 Q&A 10 of Addendum to the EEAP Assessment Report states that "Now and in the distant future, predicted TFA concentrations in surface waters and terminal basins are thousands of times less than thresholds of concern for human or environmental health." 11 Detailed analysis on degradation of HFC/HFO and relevant hazard, exposure and risks assessments of TFA is provided in the Honeywell submission reference no: 76bb3d12-2101-4390-82cf-3498b47e8015. In addition, there is solid scientific experimental and modelling body evidence demonstrating that atmospheric decomposition of HFO-1234ze(E) does not result in formation high-GWP substances like HFC-23 (CF3H).12 Therefore, the Dossier Submitters erroneously consider (in section 1.1.6 of the Proposal) HFO1234ze(E) together with other PFAS (i.e., as a group) for the hazard, exposure and risks characterisation purposes. They also erred when concluding that HFO-1234ze(E) is among "non-threshold substances" with the overall concerns "very similar to those of the PBT/vPvB substances" and using its emissions "as a proxy for risk".13 Moreover, HFO-1234ze(E) as a propellant in pMDIs is subject to rigorous risk management measures (RMMs) and assessments under the current EU legislation on medicinal products and medical devices, including Medical Devices Regulation (MDR)14, rules and procedures of European Medicines Agency (EMA) as well as relevant provisions of the EU medicines and veterinary laws.15 Therefore, all respective risks are already adequately controlled and the proposed REACH restriction (i.e. ban) is disproportionate and would result in "double regulation". Hence, ECHA should consult, exchange information and coordinate with EMA respective activities to ensure coherence in scientific opinions/evaluations to avoid potential contradictions.16 The EMA has approved the running of larger-scale human, clinical trials with pMDIs using HFO-1234ze(E). At present both HFO-1234ze(E) and HFC-152a are at clinical trial stage, preparing for possible marketing authorisation with the EMA. 8 Page 9, Environmental effects of stratospheric ozone depletion, UV radiation, and interactions with climate change: UNEP Environmental Effects Assessment Panel, Update 2020 9 Pages 8-9, Summary Update 2021 for Policymakers, UNEP Environmental Effects Assessment Panel 10 See pages 25 and 259 of the EEAP 2022 Assessment Report. 11 Q&A 10, Questions and Answers about the Effects of Ozone Depletion, UV Radiation, and Climate on Humans and the Environment, EEAP 2022 Assessment Report. 12 See a summary A new study demonstrates that HFC-23 (CF3H) is not formed during the decomposition of HFOs and HCFOs in the troposphere, 04 February 2022; and Refrigerant Degradation: Is HFC-23 (CF3H) formed due to the decomposition of HFOs and HCFOs in the troposphere?, 03 June 2021; also Tropospheric photolysis of CF3CHO, M ads Peter Sulbaek Andersen, Ole John Nielsen, March 2022. 13 See analysis and conclusions of section 1.1.6 (Risk characterisation) of the Proposal. 14 Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC. (Medical Devices Regulation or MDR) 15 According to Article1.9 of the Medical Devices Regulation (MDR), IMD propellants form a "single integral product" with the administered medicinal product and thus are also governed by the relevant provisions of the EU legislation on regulation of medicinal products for human or veterinary use (i.e., Regulation (EC) No 726/2004, Directive 2001/83/EC, Directive 2001/82/EC), including EMA or national marketing authorization requirements/procedures. 16 See sections 1-4 of the Memorandum of Understanding on Working Arrangements Between the European Medicines Agency (EMA) and the European Chemicals Agency (ECHA), 14 May 2014. 2 The fluorinated gas HFC-152a17 is suggested in the Proposal as the only available non-PFAS alternative in pMDIs. HFC-152a is classified as an extremely flammable gas (Cat. 1A)18 resulting in significant safety issues from both a manufacturing perspective and patient use.19 Moreover, HFC-152a has 1.6 years of atmospheric lifetime as well as GWP of 164 (i.e., much higher than 1.37 of HFO-1234ze(E) 20. Generally, according to the Montreal Protocol, Kigali Amendment and EU F-Gas Regulation. Its use should be phased down from 2024 via progressively decreasing volumes of permitted quotas in the ongoing revision of the F-gases Regulations.21 Therefore, the widespread use/emissions of this gas, including in pMDIs, is contrary to wider-EU decarbonization and climate change policies. This alternative propellant is a "regrettable substitute" in pMDIs applications, while HFO-1234ze(E) is not a regrettable substitute, but rather a "safe substitute", as demonstrated in the table below.22 In these circumstances, the introduction of the proposed REACH restriction (i.e., total ban in 1.5 years after the entry into force of the future restriction) for HFO-1234ze(E) uses in pMDIs applications: is not justified under REACH Regulation, is clearly disproportionate (see section 4 below) with any alleged risk from persistency of TFA will result in very high costs to society, including shortages and safety of vital medicines23. 17 1,1-difluoroethane, EC no: 200-866-1, CAS no: 75-37-6, Molecular formula: C2H4F2 18 Harmonised CLP classification - Hazard category: Flam. Gas 1A, Hazard statement: H220: Extremely flammable gas. 19 EMA - Questions and answers on data requirements when replacing hydrofluorocarbons as propellants in oral pressurised metered dose inhalers - Scientific guideline 20 See Table 7.SM.6 at pages 17-18 of The Earth's Energy Budget, Climate Feedbacks and Climate Sensitivity Supplementary Material, IPCC AR6 Report, 2021. 21 See Annex I of the Regulation (EU) No 517/2014 of the European Parliament and of the Council of 16 April 2014 on fluorinated greenhouse gases and repealing Regulation (EC) No 842/2006. 22 See in detail The Climate is Changing for Metered-Dose Inhalers and Action is Needed, John N Pritchard, 2020, should also carry appropriate "Flammability warning", section 3.6., Questions and answers on data requirements when 5 replacing hydrofluorocarbons as propellants in oral 6 pressurised metered dose inhalers, EMA, 30 March 2023, EMA/CHMP/83033/2023. 23 Reconfirmed by leading health experts in New England Journal of Medicine article on Hydrofluorocarbons, Climate, and Health -- Moving the Montreal Protocol beyond Ozone-Layer Recovery - https://www.nejm.org/doi/full/10.1056/NEJMp2302197 3 Honeywell requests that fluorinated gas HFO-1234ze(E) must be excluded from the scope of the Proposal. Alternatively, its uses in pMDIs applications should be subject to time-unlimited derogations, in line with the unlimited derogations already included into the Proposal and previous RAC/SEAC practices in similar circumstances.24 1. Introduction Asthma and chronic obstructive pulmonary disease (COPD) are serious, potentially life-threatening illnesses. Inhaled therapies, including pMDIs, Dry Powder Inhalers (DPIs) and Soft Mist Inhalers (SMIs), are the standard of care to treat asthma and COPD disease that impact millions of patients in the EU and worldwide. An pMDI is the most common type of inhaler. It uses a press and breathe method which delivers a specific dose of medication in aerosol form. It is indispensable for certain types of patients allowing young/elderly patients and patients with limited mobility/coordination, breathing problems, etc. access to automatic dosing. pMDIs are also both safe and cost-effective, while DPI and SMI have serious limitations (manual dexterity, dependence on external power supply, etc.). pMDIs remain an essential treatment for an important subset of asthma and COPD patients. There are comprehensive safety, health and environmental requirements for pMDIs propellants - "An inhalation propellant must be safe for human use and meet several other criteria relating to safety and efficacy. Traditionally the list would include: (i) liquefied gas, (ii) low toxicity, (iii) non-flammable, (iv) chemically inactive and stable, (v) acceptable to patients (in terms of taste and smell), (vi) appropriate solvency characteristics, and (vii) appropriate density."25 Currently the most used MDI propellants are fluorinated gases HFC-134a and some HFC-227ea. These have been in use for two decades, both are PFAS as defined in the Proposal having high-GWP characteristics (1430 and 3220, respectively) and should be phased down under the soon to be revised EU F-Gas Regulation. The following lower-GWP propellants for pMDIs HFO-1234ze(E) and HFC-152a are have been developed and currently are candidate substance in trial ahead of undergoing approvals and marketing authorisations by various competent medicinal authorities worldwide, including EMA.26 Upon release to the atmosphere HFO-1234ze(E), as well as certain other HFC/HFO, finally degrades to carbon dioxide (CO2), Hydrogen fluoride (HF) and, app. in 19 days, to insignificant amounts (est. 2%) of the only PFAS arrowhead substance - trifluoroacetic acid (TFA).27 However, the respective TFA amounts results in de minimis increases in overall TFA concentrations by comparison with pre-existing TFA levels.28 These HFC/HFO "releases will add to the existing load of TFA in the environment but 24 See e.g., Entries 28, 29 and 30 of Annex XVII REACH providing for time-unlimited derogations for use of certain carcinogenic, mutagenic or toxic substances in "(a) medicinal or veterinary products as defined by Directive 2001/82/EC and Directive 2001/83/EC; (b) cosmetic products as defined by Directive 76/768/EEC..."; Entry 51, Annex XVII REACH, restricting Phthalates such as DEHP, DBP, BBP, DIBP and providing time-unlimited derogation for "(i) the immediate packaging of medicinal products within the scope of Regulation (EC) No 726/2004, Directive 2001/82/EC or Directive 2001/83/EC, ... (g) medical devices within the scope of Directives 90/385/EEC, 93/42/EEC or 98/79/EC, or parts thereof, .... (f) materials and articles intended to come into contact with food within the scope of Regulation (EC) No 1935/2004 or Commission Regulation (EU) No 10/20111", and other. 25 Medical and Chemical Technical Options Committee 2018 Assessment Report. 26 Please see for further information EFCTC Meter Dose Inhalers portal. 27 See Fig. 12 at page 282 and sections SI 4.3.2 at page 317 of the of the Environmental Effects of Stratospheric Ozone Depletion, UV Radiation, and Interactions with Climate Change, EEAP 2022 Assessment Report. 28 See also detailed EFCTC position paper on the topic Published evidence supports very low yield of TFA from most HFOs and HCFOs. 4 predicted amounts are well below the threshold for concern with respect to human and environmental health." 29 There is solid scientific experimental and modelling body demonstrating that atmospheric decomposition of HFO-1234ze(E) does not result in formation high-GWP substances like HFC-23 (CF3H).30 In the meantime, the Proposal concludes in Table 8 (pages 100-101) that alternatives/substitutes are already readily available for pMDIs, and thus PFAS substances, including HFO-1234ze(E), could be substituted in 1.5 years upon the entry into force of the PFAS restriction with "likely very small costs" by substitution with no expected "additional administrative costs for industry or authorities". These conclusions are unjustified under Articles 68 and 69 of the REACH Regulation. They are incorrect because the Dossier Submitters failed to assess "carefully and impartially" all submitted information31 on safety, health and environmental properties of alternatives as well as existing regulations (RMMs) of pMDIs and costs on the society in case of substitutions. The immediate resulting substantive consequences of the proposed REACH restriction (almost immediate full ban) on PFAS propellants uses in pMDIs are difficult to underestimate as inter alia demonstrated below. 2. Hazard, exposure and risk assessments of HFO-1234ze(E) In section 1.1.6 of the Proposal the Dossier Submitters concluded that "all PFAS" (i.e., as a group) should "be treated as non-threshold substances for the purposes of risk assessment in a similar manner to PBT/vPVB substances" and that any of their releases "can be used as a proxy for risk". This conclusion is manifestly incorrect as far as HFO-1234ze(E) and its atmospheric degradation product trifluoroacetic acid (TFA) are concerned. 2.1. Objective assessments of HFO-1234ze(E) and its degradation products - Unjustified grouping of "all PFAS" Grouping of HFO-1234ze(E) with "all other PFAS" is not scientifically and legally justified. In this regard, the 2021 OECD's PFAS definition used in the Proposal is not conceived for regulatory purposes, which is also acknowledged by the Dossier Submitters. Moreover, according to the respective OECD report, it does not inform on hazards of substances, even regarding their very persistent (vP) properties, or uses, exposure and risks.32 In other words, the OECD itself is clear that its definition of PFAS was not intended to be used for regulatory action because it is too broad to enable an effective, science-based risk assessment, which would result in regulation of these (over 10,000) chemical compounds as an entire 29 See in Chapter 6, section 3.8 of the Environmental Effects of Stratospheric Ozone Depletion, UV Radiation, and Interactions with Climate Change, EEAP 2022 Assessment Report. 30 See a summary A new study demonstrates that HFC-23 (CF3H) is not formed during the decomposition of HFOs and HCFOs in the troposphere, 04 February 2022; and Refrigerant Degradation: Is HFC-23 (CF3H) formed due to the decomposition of HFOs and HCFOs in the troposphere?, 03 June 2021; also Tropospheric photolysis of CF3CHO, Mads Peter Sulbaek Andersen, Ole John Nielsen, March 2022. 31 I.e., under the EU general principle of good administration, Jean-Louis Burban v European Parliament, case C-255/90 P; Detlef Nolle v. Council of the European Union, case T-167/94; Przedsibiorstwo Energetyki Cieplnej sp. z o.o. v ECHA, case T625/16, para. 89; BASF and REACH & colours v ECHA, case T-806/17, para. 75; Technische Universitt Mnchen v Hauptzollamt Mnchen-Mitte, case C-269/90, para. 14. 32 See pages 8 and 25, Reconciling Terminology of the Universe of Per- and Polyfluoroalkyl Substances: Recommendations and Practical Guidance, ENV/CBC/MONO(2021)25, OECD, 9 July 2021 (available here): "The term "PFASs" is a broad, general, non-specific term, which does not inform whether a compound is harmful or not, but only communicates that the compounds under this term share the same trait for having a fully fluorinated methyl or methylene carbon moiety." 5 group. The UK Health and Safety Executive (HSE) 33 service and US Environmental Protection Agency (EPA) 34 share the same opinion. The most recent EEAP 2022 Assessment Report35, unequivocally cited a common agreement among the majority of experts that "all PFAS should not be grouped together, persistence alone is not sufficient for grouping PFAS for the purposes of assessing human health risk, and that the definition of appropriate subgroups can only be defined on a case-by-case manner" and that "it is inappropriate to assume equal toxicity/potency across the diverse class of PFAS".36 The Report further concludes that "Trifluoroacetic acid has biological properties that differ significantly from the longer chain polyfluoroalkyl substances (PFAS) and inclusion of TFA in this larger group of chemicals for regulation would be inconsistent with the risk assessment of TFA" 37 Please refer on the inconsistency of grouping methodologies in the Proposal to relevant sections of Honeywell submission reference no: bb6e00b6-571b-467a-ae79-7b046c6c9ab4. - Hazard and risk assessments of HFO-1234ez(E) and TFA Contrary to what the Dossier Submitters claim, there is a range of PFAS substances, including HFO1234ze(E) and certain other fluorinated HFC/HFO gases that are low-hazard, have low-Global Warming Potential (GWP), not (v-)persistent (not P/vP) and do not degrade to vP substances in meaningful amounts. For instance, the REACH registration dossier and Chemical Safety Report (CSR) for the fluorinated gas HFO-1234ze(E)38 contains conclusive scientific evidence demonstrating that this substance is not persistent and does not exhibit risks similar to PBT/vPvB substances under Article XIII REACH. Its REACH registration dossier also does not demonstrate an existence of any "supporting concerns" or hazards assessed in section 1.1.4. of the Proposal, including bioaccumulation, mobility, long range transport potential (LRTP), accumulation in plants, global warming potential (GWP), endocrine or (eco)toxicological effects, etc. Therefore, conclusions of the Dossier Submitters in section 1.1.6 of the Proposal, that HFO-1234ze(E) must be treated as a "non-threshold substances" with the overall concern "very similar to those of the PBT/vPvB substances" are not substantiated in the Proposal. 39 In the meantime, according to the trifluoroacetic acid (TFA)40 REACH registration dossier and CSR, this substance also does not fulfil the criteria for a PBT or vPvB substance under Annex XIII REACH. Neither 33 See also in section 1.3 of the Analysis of the most appropriate regulatory management options (RMOA), The UK HSE, April 2023, "A generic PFAS definition may not be particularly useful from a regulatory perspective, and it may be more appropriate to consider regulatory approaches on the basis of particular PFAS groups and/or uses." 34 The US EPA also uses a narrower working definition of PFAS as "Chemicals with at least two adjacent carbon atoms, where one carbon is fully fluorinated and the other is at least partially fluorinated" in their National PFAS testing strategy (see in section 3) as well as their PFAS strategic roadmap. EPA's use of this working definition provides focus on PFAS of concern based on their persistence and potential for presence in the environment and for human exposure. Regarding degradation products, the EPA Office of Chemical Safety and Pollution Prevention have opined that "trifluoracetic acid is a well-studied non-PFAS." 35 Environmental Effects of Stratospheric Ozone Depletion, UV Radiation, and Interactions with Climate Change, 2022 Assessment Report, Environmental Effects Assessment Panel (EEAP), available at - http://ozone.unep.org/science/eeap 36 Grouping of PFAS for human health risk assessment: Findings from an independent panel of experts, J.K. Anderson, et al., 2022 37 See pages 278 and 279 of the 2022 Assessment Report. 38 CLP classification: Hazard category: Liquefied gas; Hazard statement: H280: Contains gas under pressure; may explode if heated. 39 See analysis and conclusions of section 1.1.6 (Risk characterisation) of the Proposal. 40 Trifluoroacetic acid, EC no: 200-929-3, CAS no: 76-05-1, Molecular formula: C2HF3O2 6 does it raise equivalent levels of concern under Article 57(f) REACH.41 In this respect, ECHA already reviewed/evaluated the TFA dossier without concluding that further regulatory actions were needed.42 For detailed information and objective assessments of TFA, please refer to the previous Honeywell submission no: 76bb3d12-2101-4390-82cf-3498b47e8015. Regarding, exposure to HFO-1234ze(E) and TFA, even if one would assume that TFA formation yield for HFO-1234ze(E) can reach over 2% as suggested at page 50, Annex B of the Proposal, its contribution to overall tonnages/emissions43 and concentrations of TFA would remain genuinely negligible.44 In this respect, Q&A 10 of Addendum to the EEAP 2022 Assessment Report confirms that "However, for lakes and oceans, the effects of increased concentrations of naturally occurring mineral salts, such as sodium chloride, and other water-soluble minerals are greater and more biologically significant than those caused by TFA salts. Salts of TFA in soil are taken up by plant roots and concentrate in the leaves, where they appear to have no effects. If animals eat the leaves, TFA is rapidly excreted and does not accumulate in their bodies or in the food chain." 45 And further the EEAP concluded that "Based on current knowledge, [HFC/HFO] breakdown products do not pose environmental concerns. Based on estimates of current and future use of HFCs and other replacements for CFCs, additional inputs of TFA to the ocean will only slightly (less than 0.5% per year) increase the amounts that have been present historically. Now and in the distant future, predicted TFA concentrations in surface waters and terminal basins are thousands of times less than thresholds of concern for human or environmental health." 46 Therefore, HFO-1234ze(E) and TFA should not be treated as "none-threshold substances" and "any of their emissions" should not be used "as a proxy for risk" that is to say for exposure and risk characterisation purposes of REACH restrictions. The corresponding health and environmental risks from HFO-1234ze(E) in pMDIs applications could not be legitimately considered as unacceptable within the meaning of Article 68 REACH or to any extent proportional to the ban on this essential medical use envisaged in the Proposal. 2.2. Existing effective RMMs HFO-1234ze(E) does not exhibit and is not classified for any environmental hazard. Furthermore, human exposure of all substances in pMDIs, including propellants, is comprehensively tested and approved in accordance with pharmaceutical regulations. In this respect, HFO-1234ze(E) as a propellant in pMDIs is subject to rigorous risk management measures (RMMs) and assessments under the current EU legislation on medicinal products and medical devices, including Medical Devices Regulation (MDR)47, rules and procedures of European Medicines Agency (EMA) as well as relevant provisions of other EU medicines and veterinary laws.48 41 See e.g., Mammalian toxicity of trifluoroacetate and assessment of human health risks due to environmental exposure, Dekant et al, 17 February 2023. 42 E.g., in 2017-2021, ECHA concluded comprehensive dossier evaluation of Trifluoroacetic acid, without indications of the need for further actions. 43 See Fig. 12 at page 282 (Estimated Global Emissions) in the Environmental Effects of Stratospheric Ozone Depletion, UV Radiation, and Interactions with Climate Change, EEAP 2022 Assessment Report. 44 Please see the Honeywell submission reference no 76bb3d12-2101-4390-82cf-3498b47e8015. 45 Please also see, Q&A 10, Questions and Answers about the Effects of Ozone Depletion, UV Radiation, and Climate on Humans and the Environment, EEAP 2022 Assessment Report. 46 Ibid. 47 Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC. (Medical Devices Regulation or MDR) 48 According to Article1.9 of the Medical Devices Regulation (MDR), IMD propellants form a "single integral product" with the administered medicinal product and thus are also governed by the relevant provisions of the EU 7 In this respect, according to the most recent UNEP Medical and Chemical Technical Options Committee (MCTOC) Quadrennial Assessment Report 2022 "each new pMDI underwent extensive regulatory assessment of safety, efficacy, and quality, much the same as for the development of any new drug product."49 Therefore, all risks relevant for the placing on the market of propellant agents in pMDIs are already adequately controlled and the proposed REACH restriction (i.e., complete ban in 1.5 years) is disproportionate and excessive. In these circumstances, according to the Memorandum of Understanding on Working Arrangements Between the European Medicines Agency (EMA) and the European Chemicals Agency (ECHA) of 14 May 2014, in order to ensure coherence in scientific opinions/evaluations as well as to avoid potential contradictions and "double regulation", RAC/SEAC must consult, exchange information and coordinate with EMA assessments of HFO-1234ze(E) and other relevant PFAS within the REACH restriction process in question.50 Furthermore, in previous REACH restrictions, RAC/SEAC and the European Commission repeatedly provided time-unlimited derogations for substances that are already regulated under the respective medicines, veterinary, cosmetic and/or food contact (FCM) laws based on similar considerations as discussed above. For example, the Entry 51, Annex XVII REACH, restricts Phthalates such as DEHP, DBP, BBP, DIBP and provides a time-unlimited derogation for "(i) the immediate packaging of medicinal products within the scope of Regulation (EC) No 726/2004, Directive 2001/82/EC or Directive 2001/83/EC, ... (g) medical devices within the scope of Directives 90/385/EEC, 93/42/EEC or 98/79/EC, or parts thereof, .... (f) materials and articles intended to come into contact with food within the scope of Regulation (EC) No 1935/2004 or Commission Regulation (EU) No 10/20111". Also Entries 28, 29 and 30 of Annex XVII REACH provide for time-unlimited derogations for use of certain carcinogenic, mutagenic or toxic substances in "(a) medicinal or veterinary products as defined by Directive 2001/82/EC and Directive 2001/83/EC; (b) cosmetic products as defined by Directive 76/768/EEC...". In the current Proposal, the Dossier Submitters also applied the same approach to the regulation of PFAS as active substances in biocidal, plant protection and pharmaceutical products. In Honeywell's view, the use of HFO-1234ze(E) as a propellant in pMDIs applications should be either completely excluded or made subject to a time-unlimited derogation from the PFAS restriction in question. 3. Assessments of alternatives According to Table 8 at page 100 of the Proposal, pages 321-322 and section E.2.9.4.10 of Annex E thereof, the Dossier Submitters concluded that alternatives/substitutes are already readily available for MDIs. Thus, PFAS substances, including HFO-1234ze(E), could be substituted in 1.5 years upon the entry into force of the PFAS restriction with "likely to be very small costs" and with no expected "additional administrative costs for industry or authorities". These conclusions are manifestly erroneous. Fluorinated gas HFC-152a51 suggested in the Proposal as the only potentially available non-PFAS alternative for HFO-1234ze(E) in pMDIs, is an extremely flammable gas (Cat. 1A)52 with a lower legislation on regulation of medicinal products for human or veterinary use (i.e., Regulation (EC) No 726/2004, Directive 2001/83/EC, Regulation (EU) 2019/6), including EMA or national marketing authorization requirements/procedures. 49 See at page 242, Montreal Protocol on Substances that Deplete the Ozone Layer United Nations Environment Programme (UNEP) Report of the Medical and Chemical Technical Options Committee 2022 Assessment Report, December 2022. 50 Sections 1-4 of the Memorandum of Understanding on Working Arrangements Between the European Medicines Agency (EMA) and the European Chemicals Agency (ECHA), 14 May 2014. 51 1,1-difluoroethane, EC no: 200-866-1, CAS no: 75-37-6, Molecular formula: C2H4F2 52 CLP classification - Hazard category: Flam. Gas 1A, Hazard statement: H220: Extremely flammable gas. 8 explosive limit (LEL) of 3.9% by volume in air at room temperature. Its uses by consumers as pMDIs propellants agents implies considerable safety risks and are challenging.53 Moreover, HFC-152a has 1.6 years of atmospheric lifetime as well as GWP of 164 (much higher than 1.37 of HFO-1234ze(E)). Generally, according to the Montreal Protocol, Kigali Amendment and EU FGas Regulation, its uses should be phased down by 2030 via progressively decreasing volume quotas.54 Therefore, stimulation of widespread increase of use/emissions of this gas, including via pMDIs, is contrary to the wider-EU decarbonization and climate change policies. This alternative propellant should be considered as a "regrettable substitution" for HFO-1234ze(E) in pMDIs applications from safety and climate change points of view. Other non-fluorinated hydrocarbon propellant gases are also not suitable alternatives for pMDIs because they are very flammable and thus pose an inherent safety risk, and they still require clinical studies establishing human safety. All pMDIs propellants are required to be toxicologically safe, minimally flammable, and chemically inert with appropriate boiling points and densities. Hydrocarbon propellants (i.e., propane, n-butane, isobutane, n-pentane, isopentane, neopentane, and dimethylether) have been already explored by the industry and rejected on this basis. All propellants for medical uses must be non-toxic and must have specific physico-chemical characteristics to enable appropriate performance, meeting high standards of safety and efficacy; they cannot be replaced easily. According to the EMA, "[P]ropellant replacement constitutes a major change to the finished product formulation with potential impact also on the construction of the inhaler; therefore, data confirming maintenance of adequate finished product performance need to be provided for each modified product. In addition, data addressing possible toxicity and local tolerance of novel propellants need to be provided."55 The change in propellants also impacts many elements of the supply chain, including elastomers, valves, and any other device components in the drug delivery pathway. Many of these must be tested and/or redesigned with the new propellant for compatibility and final product tested for leachables. New manufacturing equipment must be developed and built to adapt to the characteristics of any new medical propellants (e.g., flammability). It is also important to understand that these changes involve regulatory assessment, and depend on regulatory approval, by the EMA and national regulatory authorities. Therefore, assessments and conclusions that feasible non-PFAS propellants alternatives are generally (and readily) available for pMDIs applications are erroneous and unjustified under Articles 68 and 69 of the REACH Regulation. This is because the Dossier Submitters failed to assess "carefully and impartially" all available information56 on the safety, health and environmental properties as well as applicable legal and regulatory requirements on alternatives. 4. Consequences of the proposed REACH restriction According to the Intergovernmental Panel on Climate Change (IPCC) and Technology and Economic Assessment Panel (TEAP), "An inhalation propellant must be safe for human use and meet several additional strict criteria relating to safety and efficacy: (i) liquified gas, (ii) low toxicity, (iii) non-flammable, 53 See in detail The Climate is Changing for Metered-Dose Inhalers and Action is Needed, John N Pritchard, 2020 54 See Annex I of the Regulation (EU) No 517/2014 of the European Parliament and of the Council of 16 April 2014 on fluorinated greenhouse gases and repealing Regulation (EC) No 842/2006. 55 Questions and answers on data requirements when replacing hydrofluorocarbons as propellants in oral pressurised metered dose inhalers - Scientific guideline. 56 I.e., under the EU general principle of good administration, Jean-Louis Burban v European Parliament, case C-255/90 P; Detlef Nolle v. Council of the European Union, case T-167/94; Przedsibiorstwo Energetyki Cieplnej sp. z o.o. v ECHA, case T625/16, para. 89; BASF and REACH & colours v ECHA, case T-806/17, para. 75; Technische Universitt Mnchen v Hauptzollamt Mnchen-Mitte, case C-269/90, para. 14. 9 (iv) chemically stable, (v) acceptable to patients, (vi) appropriate solvency characteristics, and (vii) appropriate density" and that "It was extremely difficult to identify compounds fulfilling all of these criteria." The IPCC/TEAP also concluded that with a hypothetical switch for one of the widely used medicines (salbutamol) from HFC pMDIs to DPI, the "projected recurring annual costs would be on the order of US$ 1.7 billion with an effective mitigation cost of between 150-300 US$ tCO2-equivalent."57 However, to assess risks and socio-economic impact of the proposed REACH restriction on pMDIs propellants, the burden and impacts of respiratory illnesses should be considered. Asthma is a lifethreatening condition affecting patients of all ages, from the very young to the very old.58 Similarly, COPD was responsible for 3.3 million deaths in 2019.59 In this respect, the pMDIs remain the product of choice for managing those conditions.60 In addition, a significant majority of the pMDIs manufactured in EU are exported all around the world. 61 Several pMDIs are included on the WHO's Essential Medicine list. Hence, potential consequences of the ban on HFO-1234ze(E) use in pMDIs will be overwhelmingly disproportionate with any alleged risks due to persistency of its atmospheric degradation product TFA. 5. Conclusions Any proposals to ban critical medications must take a patient-centric approach and Honeywell urges ECHA to proactively consult closely with patients, clinicians, and relevant government authorities (including EMA) before introducing "double regulations" and/or bans on HFO-1234ze(E) use in MDIs. In this regard, the Proposal failed to assess "carefully and impartially" all available information on safety, health and environmental properties of HFO-1234ze(E), TFA and potential alternatives as well as applicable legal and regulatory requirements on pMDIs propellants. These shortcomings resulted in scientifically and legally unjustified conclusions potentially leading to very high costs on the society and directly affecting lives of most vulnerable population which depends on these specific medicines. Considering the above, Honeywell submits that fluorinated gas HFO-1234ze(E) must be excluded from the scope of the Proposal. Alternatively, its uses as propellants in pMDIs applications should be subject to time-unlimited derogations. As reconfirmed by leading health experts "A global inhaler transition will probably take at least another decade and could lead to significantly increased cost to the 650 million patients with asthma or COPD"62. ________ Annex I - List of acronyms and abbreviations 57 See pages 355-357 of the Special Report on Safeguarding the Ozone Layer and the Global Climate System (2005). 58 See e.g., The Global Asthma Report 2022/ 59 See in Burden of chronic obstructive pulmonary disease and its attributable risk factors in 204 countries and territories, 1990-2019: results from the Global Burden of Disease Study 2019 | The BMJ). 60 See e.g., 2022 GINA Main Report - Global Initiative for Asthma - GINA (ginasthma.org) and 2023 GOLD Report - Global Initiative for Chronic Obstructive Lung Disease - GOLD (goldcopd.org) 61 See the International Pharmaceutical Aerosol Consortium (IPAC) survey of 2021. 62 New England Journal of Medicine article on Hydrofluorocarbons, Climate, and Health -- Moving the Montreal Protocol beyond Ozone-Layer Recovery - https://www.nejm.org/doi/full/10.1056/NEJMp2302197 10