Document aJjkZ4oV32ooDnrJakQXjb9we

The Essentiality of PFAS for Rigid Gas Permeable Contact Lenses Dr Mark D Eddleston Summary The safety and effectiveness of rigid gas permeable (RGP) contact lenses is reliant on the use of PFAS. Without PFAS, RGP lenses will lose performance in several key areas, notably oxygen permeability, deposit resistance and wettability. As a result, the 3.24 million RGP lens wearing patients in the EU would be at greater risk of contracting sight threatening microbial keratitis infections or of having to discontinue RGP lens wear due to intolerance resulting from discomfort or compromised eye health. For most RGP contact lens patients, changing to a different form of vision correction, such as soft contact lenses or spectacles, would result in a drop in visual acuity since many are fitted to those with irregular corneas and higher prescriptions. In the most extreme cases, estimated to be several thousand patients, the outcome of no longer being able to wear RGP lenses would be clinical blindness. There are currently no non-PFAS substances that can be used to replicate the high level of RGP lens performance achieved with PFAS, or even to generate RGP lens materials that would be viable for a majority of patients. It is anticipated that many potential alternatives to PFAS will be identified over the coming years for use in various industries. RGP contact lenses, however, present a unique challenge as a material must be identified that replicates not only the inertness and deposit resistance of PFAS, but also the oxygen permeability and hardness, and there is no guarantee of success. As so many of the beneficial properties of PFAS are critical to the performance of RGP contact lenses, and as from a chemical perspective it is impossible to replicate the properties of fluorine and the carbon-fluorine bond which make PFAS unique, it is almost certain that without PFAS there will be a significant and permanent decrease in the efficacy of RGP contact lenses. This will be to the detriment of patients, many of whom have complex prescriptions and vision correction needs, forevermore. 1 Contents Summary 1 1. Introduction 2 2. The essentiality of PFAS for RGP contact lenses 3 2.1 Potential complications of wearing contact lenses 3 2.2 Essential performance characteristics that PFAS bring to RGP lenses 6 2.3 Performance reduction on removing PFAS from RGP lens materials 9 2.4 The consequences of RGP contact lenses without PFAS for patients 12 2.5 Wider impacts of a PFAS restriction on the RGP contact lens sector 12 2.6 Silicones are environmentally persistent too 13 3. Lack of non-PFAS alternatives 14 3.1 No viable non-PFAS alternatives from the contact lens sector 14 3.2 No viable non-PFAS alternatives from other industries 15 3.2.1 Oxygen permeability from chemical constituents 15 3.2.2 Oxygen permeability from inefficient packing of polymer chains 18 3.2.3 Oxygen permeability from molecular porosity 20 3.3 Independently suggested non-PFAS alternatives are unsuitable 20 4. The irreplaceability of fluorine 22 5. Conclusions and outlook 24 References 25 Appendix A - Comments from world renowned optometrists on the consequences of removing PFAS from RGP lens materials 34 1. Introduction Despite the first contact lenses being made from rigid materials (PMMA and later RGP materials), the convenience and greater initial comfort of daily disposable and frequently replaced soft lenses has resulted in this modality coming to represent far more of the contact lens market. RGP contact lenses do, however, still have a critical role to play in correcting the vision of patients with the most challenging optical needs, as described in detail in Annex B of this submission.1 These lenses are either the only viable option, or provide the best visual outcomes, for patients who are highly short or long sighted, are highly astigmatic, have corneal injuries, have irregular corneal conditions such as keratoconus and keratoglobus or have had corneal grafts or refractive surgery.2 In addition, RGP lenses for orthokeratology are a vital tool in slowing the progression of childhood myopia,3-9 a sight defect which is now reaching epidemic proportions globally,5,10-11 and which brings a greatly increased risk of sight 2 threatening complications such as macular degeneration, cataracts, glaucoma, and myopic retinopathy in later life.12-15 Contemporary RGP contact lenses are manufactured from complex polymers which are typically composed of around ten different ingredients selected to impart beneficial properties to the finished lenses. Each of these polymers incorporates at least one of the fluorinated monomers hexafluoroisopropyl methacrylate (HFPM, CAS 3063-94-3), trifluoroethyl methacrylate (TFEM, CAS 352-87-4) or bis-hexafluoroisopropyl itaconate (BHI, CAS 98452-82-5). Using the OECD PFAS definition,16 all three of these monomers, as well as polymers incorporating them, are classified as being PFAS substances. This means that the restriction on PFAS recently proposed by 5 European countries will affect all RGP contact lenses. 2. The essentiality of PFAS for RGP contact lenses 2.1 Potential complications of wearing contact lenses In general, RGP contact lenses have an excellent safety record, but various types of adverse event do occasionally occur,17 the most serious of which is microbial keratitis, an infection of the cornea which can be bacterial, viral, protozoal or fungal in origin.18 Such infections are very rare, affecting around 1.2 in 10,000 wearers of RGP contact lenses,19 but even with rapid intervention can result in the formation of an ulcer, often causing irreversible damage to the structure of the cornea. Depending on the size and location of the ulcer this damage may result in partial sight loss or even blindness.20 A microbial keratitis infection costs on average an estimated 847 to treat,21 will at minimum require a temporary discontinuation of lens wear and will often lead to hospitalisation.22 Around 14% of cases result in sight loss.21 Since the early days of RGP contact lens wear, safety has improved significantly and incidences of microbial keratitis have dropped dramatically, largely driven by the introduction of PFAS containing materials and greater awareness of the dangers of non-compliance, for example non-prescribed overnight wear, poor hygiene and/or using tap water to clean lenses. Currently, an estimated 389 RGP lens wearers are affected by microbial keratitis each year within the EU (a figure calculated by applying the reported incidence of 1.2 per 10,000 wearers19 to the 3.24 million RGP wearers in the EU). Without PFAS, however, this number is expected to increase. Some wearers find it difficult to adapt to or tolerate the presence of an RGP contact lens and may need to stop or suspend wear, either fully or for a period each day, due to discomfort or in order to maintain eye health.17, 23 Factors contributing to intolerance to RGP lens wear include complications resulting from hypoxia induced by lens wear, corneal changes, lens deposits, lens awareness, visual aberrations such as glare and halos and dry eye symptoms, and all can be mitigated through the use of PFAS monomers.24-31 RGP lenses are typically employed for patients for whom other methods of vision correction (spectacles or soft contact lenses) do not give an 3 acceptable outcome. The consequences of a PFAS restriction, and the resulting increase in lens intolerance, for RGP lens wearers are, therefore, high as discontinuation of wear will result in a reduction in visual acuity.1 For many thousands of patients with the most severe sight deficiencies, no longer being able to wear RGP contact lenses would condemn them to clinical blindness. A summary of the various complications of contact lens wear which have been mitigated by the addition of PFAS monomers to RGP contact lens materials is given in Table 1. 4 Table 1. Complications associated with RGP contact lens wear which are mitigated through the use of PFAS monomers Category Complication Potential impact on patients Related material properties Safety Microbial keratitis Ulcer formation could permanently damage sight. Discontinuation of contact lens wear until resolved Oxygen permeability, deposit resistance Corneal neovascularisation Could temporarily affect sight. Discontinuation of contact lens wear until resolved Oxygen permeability Corneal infiltrates Discontinuation of contact lens wear until resolved Deposit resistance Endothelial changes Could ultimately affect the barrier properties of the endothelium Oxygen permeability Tolerability Inflammatory red eye Deposits on lenses Lens scratches Poor lubricity Lens flexure Lens distortion Intolerable discomfort, discontinuation of lens wear Oxygen permeability Reduction in visual clarity, discomfort, increased risk Deposit resistance of infection Reduction in visual clarity, increased risk of infection Hardness Discomfort Wettability Inconsistent visual quality, glare Flexural modulus (rigidity) Reduction in visual clarity, glare, discomfort Dimensional stability 5 2.2 Essential performance characteristics that PFAS bring to RGP lenses PFAS are utilised in many industries for their chemical inertness and ability to repel both oil and water. The three PFAS monomers which are incorporated into RGP contact lens polymers not only provide these advantages, but also make an essential contribution to oxygen permeability, deposit resistance, biocompatibility, comfort, wettability, rigidity, lathability, durability, scratch resistance and dimensional stability.24-31 The chemical structures of the three monomers are closely related (Figure 1) and a similarly high level of performance can be achieved with each. a b c Figure 1. The molecular structures of PFAS contact lens monomers (a) HFPM, (b) BHI and (c) TFEM. Chemical inertness Each pair of RGP contact lenses is typically worn for between 1 and 3 years and must remain chemically unchanged for this duration, withstanding tear fluids, UV from sunlight and atmospheric pollutants. Chemical inertness is therefore critical and is an important advantage of PFAS monomers. Oxygen permeability Many fluorine containing materials are highly permeable to oxygen, a characteristic which is necessary for all types of RGP lens to avoid hypoxic adverse events and both short- and long-term physiological changes, including endothelial blebs, edema, limbal 6 injection, myopic creep, epithelial microcysts, epithelial thinning, corneal vascularisation, polymegathism and pleomorphism.32-37 Highly permeable lenses also help to maintain the barrier function of the eye surface, making it less susceptible to bacterial binding and infection.38-39 While low oxygen permeability materials, such as poly(methyl methacrylate) (PMMA), can be tolerated by some patients for a period of time, the constant hypoxic challenge will be detrimental to eye health in the long term.40-45 The need for oxygen permeability is particularly great with both scleral lenses,46-47 which vault over the cornea and need to be thicker to avoid flexure, and with orthokeratology lenses, which are worn overnight to reshape the cornea,48-50 and is only met by highly performing materials. An oxygen permeability of 100 barrers or more is now the widely accepted level of performance required from an RGP contact lens material, and in many cases increasing the permeability further has been found to reduce complications (Figure 2) and increase comfort for wearers.51 Removing PFAS from RGP lens materials is expected to reduce oxygen permeability to around 30 barrers, a level which would significantly increase adverse events and make lens wear impossible for many thousands of patients due to intolerance. A B Figure 2. A patient's left eye (A) during extended wear with a 125 barrer material, showing corneal edema and endothelial bleb formation, and (B) after switching into a 180 barrer material, which resolved these issues (Images supplied by Michael Wyss of Eyeness AG, Switzerland). 7 Deposit resistance The uniquely low surface energy and hydrophobic+lipophobic nature of fluorinated materials makes them invaluable for use in an ocular environment where a contact lens is constantly exposed to chemical species with a wide range of polarities including hydrophilic proteins and hydrophobic lipids.52 Any build-up of deposits on RGP contact lenses has the potential to impair visual clarity,29 to cause abrasion to the eye surface, to increase risk of infection by providing sites where pathogens can adhere and to render lenses intolerably uncomfortable to wear.52 It has been demonstrated that even a small level of deposition, forming on contact lenses over a period of only six hours, is enough to more than triple the number of Pseudomonas aeruginosa bacteria adhering to lenses.53 Wettability Also critical to comfort is wettability, which promotes the formation and retention of a lubricious tear film on lenses, preventing irritation to the eyelids and ocular surface during blinking.54 While PFAS monomers are primarily added to an RGP lens material to confer oxygen permeability and deposit resistance, they are the only species that can do so without having a highly detrimental impact on wettability. Moreover, with PFAS containing wettable RGP lenses there is no tendency to dry the eye surface as may occur with soft lenses. Hardness, flexural strength and dimensional stability The manufacturing process for RGP contact lenses involves lathing a button of polymer into a bespoke shape tailored to a patient's eye. An RGP lens material must be sufficiently hard to facilitate this process and to provide enough durability for lenses to resist scratch formation over 1-3 years of use. Scratches tend to reduce the optical clarity of lenses and provide hard-to-clean sites which enable bacterial adhesion. Resistance to flexure and to deformation is also critical as otherwise optical clarity and comfort are impacted. PFAS monomers are unique in that they can be used to bring hardness, rigidity and dimensional stability to a material while maintaining a high level of oxygen permeability. Safety RGP lenses have been demonstrated to be a very safe contact lens modality during daily wear in terms of incidence of microbial keratitis.19,55 This level of safety performance is, however, reliant on patient compliance and, to a lesser degree, being able to maintain scratch free lens surfaces and to avoid deposit build up throughout the lifetime of the lenses, which will be unachievable without PFAS. 8 2.3 Performance reduction on removing PFAS from RGP lens materials In order to demonstrate the importance of PFAS for the performance of RGP lens materials analogues of three commercially available RGP lens materials (A, B and C) were prepared without a PFAS monomer. A first set of analogues was generated by replacing the fluorinated monomer by methyl methacrylate (MMA), an obvious choice both due to its widespread use in RGP contact lenses and due to having a closely related chemical structure without CF3 groups (Figure 3). a b Figure 3. The molecular structures of the contact lens monomers (a) MMA and (b) TRIS. The properties of the three MMA analogues were averaged and are compared with the averages for the three commercial fluorine containing materials in Table 2. The oxygen permeabilities of these analogues were too low to be viable for use in RGP contact lenses. A second set of analogues was prepared by replacing the fluorinated component of the three commercial RGP lens materials with 3-methacryloxypropyl tris(trimethylsiloxy)silane (TRIS), a silicone monomer which is the substance most widely utilised for increasing the oxygen permeability of RGP lens materials (Figure 3). The dimensional stability and hardness of these analogues was extremely poor (Table 2), making them completely unsuitable for use in RGP contact lenses. A third set of analogues was prepared by replacing the fluorinated component of the three commercial RGP lens materials with a 1:1 mixture of MMA and TRIS. These materials had sufficient hardness and dimensional stability, but were 47% less permeable to oxygen and also less wettable (Table 2). The images of lipid/dye deposition in Figures 4 and 5 show that all of the PFAS-free analogues are less resistant to lipid deposition than the commercial materials, increasingly so as the TRIS content (and oxygen permeability) is increased. The effect of removing PFAS on deposition is expected to be even greater with proteins.25,28 9 Table 2. Comparison of averaged properties of three commercial RGP contact lens materials with averaged properties of analogues prepared using MMA or TRIS or a 1:1 mixture of MMA and TRIS in place of the fluorinated component. Change in BCOR (back central optic radius) is a measure of dimensional stability. Contact angle is a measure of the wettability, and therefore comfort, of a material. Property Dk (barrers) Rest hardness (ShoreD) Flexural modulus (MPa) Change in BCOR (mm)* Contact angle dry ()* Contact angle soaked ()* Average for commercial lens materials 131.3 78.7 1307 0.054 101.6 81.5 Average for MMA analogues 17.5 82.4 1572 0.050 97.1 79.0 Average for TRIS analogues ** 69.7 ** 1.767 110.4 86.9 Average for MMA:TRIS analogues 69.3 77.5 1152 0.044 104.8 86.0 * Lower values indicate better performance, ** Insufficient dimensional stability A Control B HFPM MMA MMA:TRIS TRIS Control C HFPM MMA MMA:TRIS TRIS Control HFPM MMA MMA:TRIS TRIS Figure 4. Image of Sudan Black B stained lipid deposition on lenses of the commercially available RGP contact lens materials A, B and C (PFAS containing) and their fluorine free analogues. Lenses that are darker in appearance have a greater amount of surface lipid deposition. The control lenses were prepared from the commercially available materials, but were not subjected to the lipid/dye solution. 10 A B C A (MMA) B (MMA) C (MMA) Figure 5. Optical microscopy images of Sudan Black B stained lipid deposits on discs of the RGP lens materials A, B and C and the fluorine free analogues A (MMA), B (MMA) and C (MMA). Lipid deposits appear as darker regions on the micrographs. It would be possible to prepare further sets of analogues where the ratio of MMA to TRIS was varied. Increasing the MMA to TRIS ratio would increase deposit resistance, but decrease oxygen permeability and decreasing this ratio would have the opposite effect. Importantly, there is no ratio that would give an acceptable level of both deposit resistance and oxygen permeability. Historically, silicone containing RGP lens materials that were developed without the use of fluorinated monomers had oxygen permeabilities of between 10 and 30 barrers, presumably because increasing further would have been too detrimental to performance in other areas. This is consistent with the results presented above as the ratio of MMA to TRIS would have to be increased from 1:1 in order to reduce lens deposits to an acceptable level. It should be noted that for modern RGP lens materials an oxygen permeability of 100 barrers is considered to be the benchmark standard, and even higher permeabilities may be required for scleral and orthokeratology modalities,46,48,50 especially for patients who have compromised and irregular corneas. Further details and discussion of the work presented in the above table and figures are reported in a paper titled `The Consequences of Removing Fluorinated Compounds from RGP Contact Lenses'.56 11 2.4 The consequences of RGP contact lenses without PFAS for patients Leading eye care practitioners were asked to review the data presented in Table 2, Figure 4 and Figure 5 and comment on what such a decrease in performance resulting from removing PFAS from commercial materials would mean for patients. Selected excerpts are presented below: "these effects would make the lenses unsafe to wear due to the cornea being deprived of oxygen (taking us back to the sight affecting and serious eye health complications of the earliest contact lenses)" "Materials with high oxygen properties are fundamentally necessary in today's clinical practice, without which it would be impossible to wear RGP lenses in a safe and comfortable manner. If these very important material properties are reduced or eliminated, then a significant number of patients with very challenging eye conditions simply will not be able to function visually and leaving them without being able to maintain their work. It would reduce quality of life dramatically." "After years of research to optimize the characteristics of RGP materials, guaranteeing greater oxygenation of the cornea and reducing the interaction of materials with lipid and protein deposits, these indications from the EU take us back 50 years." "It is critical that GP materials have the highest Dk levels and surface wettability to achieve success and avoid complications. Any polymer substitutions that would negatively alter current GP material characteristics would be a devastating blow to my patients, as the complications from these changes could lead to failure with lens wear." The responses are given in full in Appendix A below. In general, the loss of performance on removing PFAS from RGP contact lenses would result in patients being more likely to suffer eye infections and being put at an increased risk of associated sight loss. In addition, many patients will no longer be able to tolerate the lenses that are essential for their vision. 2.5 Wider impacts of a PFAS restriction on the RGP contact lens sector Given the convenience of spectacles, daily disposable soft contact lenses, and frequently replaced soft contact lenses, the use of RGP contact lenses is now largely limited to the patients who have a medical need for them and have sufficient motivation to overcome the initial discomfort of wearing them. The percentage of contact lens wearers using RGP lenses has decreased over recent decades, and although this decline has stabilised recently, the continued viability of the RGP contact lens sector is by no means certain. A PFAS restriction, which would result in existing materials being replaced by vastly inferior ones, is an existential threat. 12 For eye care practitioners, fitting RGP lenses is a challenging skill to learn and establish, and a time-consuming activity to pursue with patients. If the safety and benefits of RGP lenses for wearers were to suddenly decrease, many practitioners would instead turn to soft contact lenses, despite the sub-optimal visual outcomes for many of these patients, leading to a further shrinkage of the RGP lens sector and further de-skilling in the industry. There will also be huge costs involved both for material manufacturers in developing new PFAS-free materials and for lens manufacturers in obtaining regulatory approvals for lenses made from the new materials. It is not clear that the RGP lens market would still be big enough to justify such expenditure and the sector could well undergo a collapse. Patients who are entirely reliant on RGP lenses for their vision may find they are no longer supported. 2.6 Silicones are environmentally persistent too All modern RGP contact lens polymers contain both fluorinated species (PFAS) and silicone species, which when combined together enhance oxygen permeability and confer a balance of beneficial properties. The PFAS Annex XV Restriction Report highlights silicone methacrylates/acrylates as an alternative to PFAS containing RGP contact lenses. Examples of silicone methacrylates include the three analogues presented in Section 2.3. As described above, these materials would not be suitable for maintaining the safety and eye health of potential wearers. There are also a few silicone methacrylates available on the market, but all were developed over 30 years ago and are now rarely used due to their low oxygen permeabilities (less than 30 barrers) and poor surface properties (low wettability and deposit resistance).25,28 Moreover, as part of the EU's chemical sustainability strategy, the use of all persistent chemicals will be restricted.57-58 The silicone 3-methacryloxypropyl tris(trimethylsiloxy)silane (TRIS), which is used in most RGP contact lenses, is potentially PBT.59 Silicone methacrylates do not, therefore, constitute a viable alternative to PFAS containing RGP contact lens materials. No significant environmental gain is anticipated from substituting RGP contact lens PFAS, which eventually convert to trifluoroacetic acid (relatively persistent, but non-toxic), with additional amounts of TRIS (potentially slightly less persistent, but more toxic). Neither is there a benefit to substituting silicones with additional amounts of PFAS. For wearers, RGP contact lens performance only becomes acceptable when PFAS and silicones are combined. Contact lens polymers without both PFAS and silicones are not sufficiently oxygen permeable. An example is PMMA, from which the first plastic contact lenses were manufactured. This material was associated with high levels of lens intolerance and hypoxia related ocular complications.40-44 Such low oxygen permeability in RGP contact lens materials would induce eye care practitioners to turn to soft lenses for safety reasons, despite worse visual outcomes, almost certainly triggering a collapse of the RGP lens sector. 13 3. Lack of non-PFAS alternatives 3.1 No viable non-PFAS alternatives from the contact lens sector The main non-PFAS contact lens monomers are listed in Table 3, where they have been grouped by type. Silicone containing species are typically used in an RGP lens material formulation to increase oxygen permeability, hydrophilic monomers are used to increase wettability and comfort, and alkyl monomers bring hardness and lathability. Whereas the PFAS monomers HFPM, TFEM and BHI bring good all-round performance to an RGP lens polymer, all potential alternatives are advantageous only for some material characteristics, and detrimental for others. When alternative monomers with different strengths and weaknesses are combined together within a polymer the material properties tend to be no better, and often worse, than would be expected based on the average performance of the monomers. There is currently no non-PFAS contact lens monomer, or combination of monomers, that comes close to replicating the level of performance which can be achieved using fluorinated species. Table 3. The performance characteristics of monomers used in RGP contact lens materials. Crosslinking agents are highlighted using a * symbol. Monomer type PFAS Examples HFPM TFEM BHI Properties Oxygen High permeability Deposit resistance High Chemical inertness Hardness Dimensional stability Wettability Other High Medium High Medium N/A Silicone containing species TRIS Styryl tris(timethyl siloxy) silane (CAS 18547-54-1) 3-Methacryloxy propyl bis(trimethyl siloxy)hydroxysilane (CAS 83692-44-8) Dimethacryloxybutyl PDMS macromer* (CAS 70877-62-2) TRIS dimer* (CAS 80722-63-0) High, but increased by presence of PFAS Low Less stable or PBT Low Low Hydrophilic monomers Methacrylic acid (CAS 79-41-4) 2-Hydroxyethyl methacrylate (CAS 868-77-9) N-Vinyl pyrrolidone (CAS 88-12-0) Low High for lipids, low for proteins Less stable High High Low Risk of dry eye complications High Risk of dry eye complications Alkyl monomers MMA Neopentyl methacrylate (CAS 2397-76-4) Ethylene glycol dimethacrylate* (CAS 97-90-5) Neopentyl glycol dimethacrylate* (CAS 1985-51-9) Vinyl benzyl methacrylate* (CAS 99413-45-3) Low High for lipids, low for proteins Less stable High High Medium Risk of dry eye complications 14 3.2 No viable non-PFAS alternatives from other industries A vast number of potential alternative materials are utilised in other industries, and it would be impractical to consider all, so focus is directed to the small number of substances which are permeable to oxygen, a property which will be critical in any PFAS replacement for RGP contact lenses. There are three main mechanisms of oxygen permeability in a material: the presence of certain chemical units, including fluorine groups and siloxane groups, which facilitate the passage of oxygen atoms; polymer chains that pack together inefficiently leaving channels of free space within a material; and the presence of chemical species comprised of atoms which arrange in such a way as to form intrinsic pores within a material. Any viable alternative will also have to be safe, non-toxic, deposit resistant, optically clear and compatible with other contact lens monomers. 3.2.1 Oxygen permeability from chemical constituents The oxygen permeability of RGP contact lens materials is derived from their chemical constituents. In silicone species it is the silicon-oxygen bonds which enable the passage of oxygen and in PFAS monomers it is the presence of fluorine atoms. As described above, the silicone species that are already in use in contact lenses cannot adequately replace PFAS monomers to provide a material with oxygen permeability as this would lead to too great a reduction in dimensional stability and hardness. There are, however, different silicone type molecules which are available and utilised in other sectors of industry. Silsesquioxanes Polymeric silsesquioxanes and polyhedral oligomeric silsesquioxanes (POSS) are examples of silicone species where instead of the silicon and oxygen atoms being arranged in simple chains with or without branching, as is the case with silicone contact lens monomers, the silicone groups are linked together to form ladder-like structures and cages.60 The potential advantage of such arrangements is greater rigidity, which could confer greater hardness to a material, possibly overcoming the limitations of conventional silicone contact lens monomers. In practice, while an increase in hardness is observed on replacing silicone contact lens monomers with silsequioxane species, there is also a corresponding reduction in oxygen permeability. This reduction in oxygen permeability is of greater magnitude than the increase in hardness. Table 4 shows experimental data for three formulations prepared using different ratios of a conventional silicone contact lens monomer and the cage type silsesquioxane isopropylmethacryl POSS (these formulations also contain a PFAS monomer). The formulation with the highest POSS concentration had a hardness 2.3 ShoreD units (2.9%) greater than that of the equivalent formulation without POSS, but the corresponding decrease in oxygen permeability was 82.6 15 barrers (52.5%). All materials had similar flexural moduli and adequate dimensional stability (change in BCOR < 0.600mm). Based on this evidence, silsesquioxanes do not confer a performance advantage over conventional silicone contact lens monomers as a replacement for PFAS. Table 4. Comparison of the properties of three experimental RGP contact lens materials prepared using different ratios of a silicone monomer and POSS monomer. Change in BCOR (back central optic radius) is a measure of dimensional stability. Formulation Property Dk (barrers) Rest hardness (ShoreD) Flexural modulus (MPa) Change in BCOR (mm)* 38.5% silicone 0% POSS 157.3 78.7 1317.6 0.047 * Lower values indicate better performance 33.5% silicone 5.0% POSS 123.2 79.3 1286.9 0.040 18.5% silicone 20.0% POSS 74.7 81.0 1301.1 0.020 Hybrid inorganic/organic glass Also known as ormosils or ceramers, hybrid inorganic/organic glasses are composed of silicate, or titanate, species bridged by organic linking groups.61 These materials are postulated to combine the best properties of the inorganic (strength) and organic (flexibility) components. The first attempts to generate contact lens materials using this chemistry were made nearly 40 years ago, and yielded wettable hybrid glasses which could be lathed into lens shapes.62 The oxygen permeabilities of these materials were, however, less than 15 barrers, which is very low by modern standards. Moreover, the ShoreD hardness was only 70, which is below that of marketed RGP lens materials. Increasing the oxygen permeability of these hybrid glasses would require the addition of another organic component such as a PDMS silicone species, but this type of change would further lower the hardness and potentially cause the material to become opaque.63 The properties of hybrid glasses make them less suitable for use in RGP contact lenses than conventional RGP lens polymers as evidenced by the absence of any commercial contact lens product based on this technology. Adamantyl methacrylate + PDMS macromer. Another possibility for increasing the performance of a PFAS-free RGP lens material could be to utilise a strengthening monomer in combination with an oxygen permeable silicone species to enable high permeability while maintaining enough hardness for the material to be lathable and scratch resistant etc. During an experimental investigation of this approach, polymers were prepared incorporating a highly permeable PDMS silicone macromer in addition to the strengthening monomer adamantyl methacrylate, with and without a crosslinking 16 agent. The oxygen permeabilities and hardnesses of these materials are shown in Table 5. The uncrosslinked polymer had a hardness lower than typical for an RGP contact material and also a relatively low oxygen permeability. The addition of crosslinker raised the hardness to a level typical for an RGP lens material, but caused a much greater reduction in oxygen permeability. Although the use of the strengthening agent adamantyl methacrylate does enable a relatively large percentage of PDMS silicone macromer to be incorporated into a formulation, while maintaining a hardness suitable for an RGP contact lens material, the oxygen permeabilities of such materials are surprisingly low, and do not represent a performance advantage over polymers prepared using conventional non-PFAS contact lens monomers (see Table 2). Table 5. Comparison of the properties of two experimental RGP contact lens materials prepared using adamantyl methacrylate and a PDMS silicone macromer. Change in BCOR (back central optic radius) is a measure of dimensional stability. Formulation Property Dk (barrers) Rest hardness (ShoreD) 40% Silicone macromer 60% Adamantyl methacrylate 45.3 75.0 40% Silicone macromer 54% Adamantyl methacrylate 6% Crosslinker 19.6 80.0 Fluorinated materials The fluorinated compound 4,5-difluoro-2,2-bis(trifluoromethyl)-1,3-dioxole (PDD, Figure 6), and related species, are routinely copolymerised with PTFE to generate polymers that are highly permeable to oxygen.64-66 The PTFE/PDD polymer Teflon AF 2400, for example, has a reported oxygen permeability of 990 barrers.64 PDD and related monomers, as well as the highly permeable fluorinated polymers incorporating them are, however, classified as PFAS under the OECD definition and so are not appropriate as alternatives. It is noted that PTFE, a polymer with a very high fluorine content, but comprised almost exclusively of -CF2- groups, has a low oxygen permeability of 4-10 barrers.67-68 This suggests that it is the presence of -CF3 groups in particular that is critical for conferring oxygen permeability to PDD and the contact lens monomers HFPM, BHI and TFEM. Figure 6. The molecular structure of PDD. 17 3.2.2 Oxygen permeability from inefficient packing of polymer chains Acetylenes Acetylenes have been explored as possible ingredients for contact lens materials for almost 40 years, but this research is yet to result in a commercial product. Poly(trimethylsilylpropyne) (PTMSP) is one of the earliest,69 and probably the best studied permeable acetylene polymer, with a reported oxygen permeability in excess of 10,000 barrers70 resulting from free space between the coil-like polymer chains. In pure form, however, it is too flexible and not wettable enough71 to be utilised as an RGP contact lens material. Moreover, it is not possible to polymerise trimethylsilylpropyne monomer within a normal contact lens formulation as a metal catalyst is required69,72 (and would remain in the final product leading to toxicity issues). Instead, research within the contact lens sector has focussed on combining the polymeric form, PTMSP, with contact lens monomers, but efforts have been hampered by its hydrophobicity. PTMSP is only sparingly soluble in even the most lipophilic contact lens monomers such as t-butyl styrene,73 and is not compatible with formulations containing hydrophilic monomers like methacrylic acid (which is added to all RGP lens materials to impart wettability). Another severe drawback with acetylenes is that they undergo ageing,74 a reduction in free space which decreases oxygen permeability.72 For example, it has been reported that the permeability of PTMSP decreases to 1% of its original value over time.75 Furthermore, all RGP contact lens polymers are cross-linked and it is known that cross-linking acetylene materials not only reduces the initial oxygen permeability, but also increases the rate and extent of ageing.74 Such changes in oxygen permeability over time would be unacceptable in a medical device such as a contact lens where oxygen permeability is critical to performance. Efforts have been made to prepare acetylene polymers with functionalisable side chains to enable polymerisable groups to be added and potentially the hydrophobicity to be reduced.76 That this approach has never yielded a commercial product is likely due to a combination of impractical complexity and expense of manufacture and the well documented problems with the ageing of acetylenes leading to reduction in oxygen permeability over time. It should be noted that the maximum reported oxygen permeability of any acetylenebased material proposed for use in contact lenses is 40 barrers, in a formulation with no wettable agent,73 meaning that the performance is well below the minimum requirements for a successful RGP lens material. Moreover, acetylenes such as PTMSP have been found to be chemically unstable under ambient conditions,72 making them unsuitable for use in a medical device such as a contact lens. 18 Norbornenes The polymerisation of norbornenes substituted with bulky -SiMe3 groups has been found to yield materials with oxygen permeabilities of over 2000 barrers.77 Such norbornenes are not commercially available and require the use of transition metal catalysts to induce polymerisation,77-78 which would be a toxicity concern for a contact lens material. Norbornenes are not compatible with other contact lens monomers as they do not undergo free radical polymerisation. Moreover, the oxygen permeabilities of polynorbornenes have been found to decrease over time.77 Polyimides An advantage of polyimides is their relatively high stiffness,79 which would be of use in an RGP contact lens. However, the oxygen permeability of the primary commercially available polyimide, Matrimid, is only 1.5 barrers.80 The additional of fluorinated groups to polyimides has led to oxygen permeabilities an order of magnitude higher,80-81 but such species would be subject to a PFAS restriction. Polymers of intrinsic microporosity The original polymer of intrinsic microporosity (PIM) was prepared by reacting 5,5,6,6tetrahydroxy-3,3,3,3-tetramethylspirobisindane with tetrafluoroterephthalonitrile.82 The resulting material, PIM-1, contained large amounts of free space and had an oxygen permeability of around 1500 barrers.83 Subsequently, modifications to the reacting species have yielded PIM materials with permeabilities of over 6000 barrers.84 Despite the impressive oxygen permeabilities, it is highly unlikely that PIMs will ever be utilisable within the contact lens sector. All reported PIMs have a vivid yellow colour, which would make a contact lens both impractical for the wearer and disconcerting to observers. Moreover, PIMs tend to be translucent rather than optically clear.85-86 The monomers used in the preparation of PIMs are not currently available in kilogram quantities and, costing over 150,000 per kg, are prohibitively expensive (for comparison TFEM is available for under 500 per kg). Furthermore, the oxygen permeabilities of PIMs have been found to decrease over time,87 though perhaps to a lesser extent than with acetylenes,84 and would also be reduced significantly in the aqueous environment of the eye due to water uptake into the free space within the material.85 The permeability also decreases several fold when PIMs are crosslinked,88 which would be necessary for use in a contact lens as they are otherwise highly flexible.89 In addition, PIMs are not compatible with other contact lens monomers. In general, materials which derive oxygen permeability from inefficient packing of polymer chains are highly unlikely to become commercially viable contact lens products because the loss of Dk over time is a ubiquitous problem. It is a regulatory requirement that the oxygen permeability of each batch of polymer used in contact lenses is within 20% of the reported value. If the permeability of the polymer decreases significantly over time it will be impossible to meet this requirement over the full lifetime of the lens. Furthermore, these materials typically require transition metal catalysts in their manufacture and there is no indication that they could match the deposit resistance and chemical inertness of fluorinated contact lens monomers. 19 3.2.3 Oxygen permeability from molecular porosity Cyclodextrins Cyclodextrins are large ring-shaped molecules with a central pore. Over time, they absorb large molecules within the pore, and the free space is lost.90 For this reason, if cyclodextrins are added to polymers it is not expected to result in any long-term increase in oxygen permeability. -cyclodextrin containing ethylene-vinyl alcohol copolymers were found to have negligible oxygen permeabilities, even at 30% loading, indicating that cyclodextrins are not inherently permeable to oxygen.91 Cucurbiturils Like cyclodextrins, cucurbiturils are large organic molecules that form a ring-like structure with free space in the middle. Their use as oxygen storage materials has been postulated,92 but over time, bound oxygen is replaced by larger molecules with a greater binding affinity. Again, this reduces the free space within the pores of the molecules, thereby removing any permeability to oxygen. 3.3 Independently suggested non-PFAS alternatives are unsuitable A large number of potential alternatives are included in Appendix E2 of the PFAS Restriction Dossier. The only class of compounds listed which provides oxygen permeability is silicones (based on the version of Appendix E2 available on 20 June 2023). As described above and elsewhere,56 while silicones can be employed to prepare materials with oxygen permeabilities suitable for use in RGP contact lenses, other properties of these materials such as deposit resistance, comfort, wettability, hardness and dimensional stability will be inadequate. Furthermore, the consultancy Fresh Perspectiv (London, UK) were independently tasked with identifying suitable PFAS-free materials or monomers for use in RGP contact lenses. Despite contacting over 25 chemical companies, industry experts and academic institutions worldwide, no promising solutions were identified. The full report from this study can be found as a confidential attachment to this consultation submission. Fresh Perspectiv encountered difficulties not only in finding viable technical solutions for replacing PFAS in RGP contact lenses, but also in finding potential partners to support in the development of alternatives for the sector. The larger chemical companies that were contacted either had no alternatives to offer or were not interested in contact lenses as an application (if they responded at all). This is understandable given that PFAS provide many critical benefits to RGP contact lenses, so their replacement represents a major challenge, whereas the amounts of PFAS used in the sector are relatively small, so the incentive for chemical companies to get involved is also small. Fresh Perspective were not presented with any alternatives that could immediately replace PFAS, nor with any research directions which are likely to 20 yield an alternative in the future. The potential alternatives postulated by Fresh Perspectiv are highly speculative and most are unsuitable for RGP contact lenses: Removal o Removal of PFAS not providing significant benefits in a particular application o Design of alternative approaches, products or devices to avoid use of PFAS Replacement o Drop-in solutions using a single replacement o Combination solutions utilising a combination of materials to achieve the desired properties o Artificial Intelligence o Historical materials Figure 7. Potential PFAS alternatives put forward by Fresh Perspectiv. For example, as described above PFAS cannot simply be removed from RGP contact lenses without impacting the safety and performance for wearers, nor can RGP contact lenses be substituted by spectacles or soft contact lenses for most wearers without a decrease in visual acuity.1-2,93 The proposed chemical replacements consist of: poly(2-ethylhexyl methacrylate) (PEHMA); fluoropolymers; and surface coatings. PEHMA is an alkyl methacrylate, a class of compounds which are not known to provide oxygen permeability. The similar alkyl methacrylate PMMA, which is over 20 times less expensive than PEHMA, was historically used in contact lenses but was superseded by fluorinated materials because of greater safety and improved eye health.40-45,56 Fluoropolymers were proposed to Fresh Perspectiv on the grounds that they are polymers of low concern, potentially being a lower toxicity risk than other PFAS due to chemical and biological inertness and therefore may be exempt from the EU PFAS restriction. In reality, it is clear that fluoropolymers are within the scope of the restriction and the Dossier Submitters have concerns over safety both due to the use of other PFAS in the manufacture of fluoropolymers and their possible eventual break-down into harmful small molecule PFAS at end of life. Moreover, fluoropolymers do not have the oxygen permeability,67-68 hardness, wettability and optical clarity to be suitable for use in RGP contact lenses. Coatings could be beneficial for imparting deposit resistance to a contact lens, but cannot increase hardness and will be detrimental to oxygen permeability. In addition, the many contact lens coatings developed to date have not been robust enough to withstand daily cleaning over 1-3 years as would be required for an RGP contact lens. Artificial intelligence has not been demonstrated to be applicable to research situations, such as this one, where there is no detailed catalogue of training data available. Historical materials used in RGP contact lenses, which include PMMA and silicone methacrylates/acrylates, are unsuitable for widespread use as described above and elsewhere.56 21 4. The irreplaceability of fluorine Fluorinated chemicals such as PFAS are unique and confer an extraordinary range of beneficial properties to materials including chemical inertness, thermal stability, resistance to acids and bases, immiscibility, repellence to both oil and water, biocompatibility, low toxicity (for many PFAS), optical clarity, durability, low friction, abrasion resistance, electrical resistance, dielectric properties and oxygen permeability. Alternative substances may have a good level of performance in one, or perhaps a few, of these areas but will not perform well in all. Moreover, for some properties, such as chemical inertness or the ability to repel other substances (including both those that are hydrophilic and hydrophobic), there are no other types of organic molecule that match up. The uniquely beneficial properties of PFAS result from the unique properties of the chemical element fluorine.97 Fluorine is the most electronegative element (Figure 8), and forms chemical bonds to carbon which are stronger (Table 6) and more polar than between carbon and any other element. Fluorine is the least polarizable element that can bond to carbon atoms (Figure 9), which confers the unique property of being both hydrophobic and hydrophilic. Fluorine also has the shortest Van der Waals radius of any atom that bonds to carbon apart from hydrogen, which results in minimal steric strain and confers temperature stability.97 Moreover, fluorine and carbon are light elements and so performance-to-weight ratio is high. There is no possibility to extend the toolkit of stable elements available to chemists. No amount of research will ever identify an element as electronegative as fluorine or one that is as non-polarizable. Nor will it ever identify organic chemical single bonds that are as strong, as stable or as polar as those between fluorine and carbon. PFAS are chemically irreplaceable. Figure 8. The electronegativity of the chemical elements 22 Table 6. Bond energies (strengths) of single bonds to carbon atoms (kJ/mol) Figure 9. The polarisibility of the chemical elements 23 This irreplaceability is reflected in the difficulties that have been encountered with finding alternatives for antifouling PFAS coatings on protective medical apparel.98 Finding alternatives for RGP contact lenses will be even more of a challenge as not only is antifouling still required, but also properties irrelevant to protective clothing are essential, such as hardness, optical clarity and oxygen permeability. For any application where performance is maximised by a particular property of PFAS, or where adequate performance is achieved through a combination of the beneficial properties of PFAS, it is highly likely that a PFAS ban will lead to a significant and permanent decrease in the effectiveness of that application. For medical devices, such as RGP contact lenses, such a permanent drop in effectiveness is unacceptable. 5. Conclusions and outlook Given that restricting PFAS use in RGP contact lenses will put the 3.24 million wearers at greater risk of sight threatening infections and condemn many thousands of patients to poor corrected vision/clinical blindness through RGP contact lens intolerance and inability to wear a suitable alternative vision correction method, this action is considered to be highly disproportionate, especially as the environmental gains are expected to be minimal. The break-down product which will ultimately be generated in the environment from RGP contact lens materials is trifluoroacetic acid,94 a substance which, though persistent, is unlikely to have ever caused anyone significant harm.95 Moreover, the reduction in trifluoroacetic acid generation resulting from a restriction on PFAS use in RGP lens materials is insignificant when compared either to total global emissions or to existing environmental levels.96 Fluorinated chemicals are completely unique and can be used to confer an extraordinary range of beneficial properties to materials. Within RGP contact lenses almost all of these beneficial properties are utilised to make lens wear a safe, healthy and comfortable experience for patients. There are no alternative chemicals, or combinations of chemicals, available in the contact lens industry or elsewhere, that can be employed to adequately match this level of performance. Silicone methacrylates, proposed by the Dossier Submitter as an alternative to PFAS containing RGP contact lens materials, are unsuitable due to poor performance. RGP contact lenses without both PFAS and silicones are unsafe due to their low oxygen permeability, and many patients would be faced with an unacceptable choice between poor eye health (if they continue to wear RGP contact lenses) or poor vision performance (if they change to spectacles or soft contact lenses). The number of scientists actively researching RGP lens materials is small, probably totalling less than 10 across the whole of Europe and the Americas. The sector would, therefore, be reliant on chemical innovations from other industries in order for a viable PFAS-free RGP contact lens material to become a reality. Such developments will be focussed on replicating the inertness and anti-fouling properties of PFAS, which are critical to most applications, and so may well prove to be unsuitable for adoption in the 24 RGP contact lens sector due to low oxygen permeability, low hardness and/or low optical clarity. Moreover, the unique chemical nature of fluorinated materials suggests that their performance will be impossible to replicate. As a result, when considering PFAS-free alternatives for RGP contact lenses it is far more appropriate to question if they will ever be identified, rather than when. References 1. See Annex B of this Comment Submission from EUROMCONTACT: Hepsen I. and Koppen C. 2022. The unique features and benefits of RGP contact lenses. Report prepared by the European Contact Lens Society of Ophthalmology (ECLSO) on behalf of EUROMCONTACT. 2. Mirsayafov D., Batres L. and Lovera M. 2021. Rigid gas permeable contact lenses and PFAS: clinical and technical considerations. EUROMCONTACT Report. Submitted to the 2021 PFAS Evidence Consultation. Available on Request. 3. Bullimore M. A., Johnson L. A. Overnight orthokeratology. Contact Lens and Anterior Eye, 2020, 43(4). 322-332. 4. Vincent S. J., Cho P., Chan K. Y., Fadel D., Ghorbani-Mojarrad N., GonzlezMijome J. M., Johnson L., Kang P., Michaud L., Simard P., Jones L. BCLA CLEAR - Orthokeratology. Contact Lens and Anterior Eye, 2021, 44(2). 240269. 5. Wolffsohn J. S., Calossi A., Cho P., Gifford K., Jones L., Li M., Lipener C., Logan N. S., Malet F., Matos S., Gonzlez-Mijome J. M., Nichols J. J., Orr J. B., Santodomingo-Rubido J., Schaefer T., Thite N., van der Worp E., Zvirgzdina M. Global trends in myopia management attitudes and strategies in clinical practice. Contact Lens and Anterior Eye, 2016, 39(2). 106-116. 6. Walline J. J., Jones L. A., Sinnott L. T. Corneal reshaping and myopia progression. British Journal of Ophthalmology, 2009, 93(9). 1181-1185. 7. Chen C., Cheung S. W., Cho P. Myopia Control Using Toric Orthokeratology (TO-SEE Study). Investigative Opthalmology & Visual Science, 2013, 54(10). 6510-6517. 8. Cho P., Cheung S. W. Retardation of Myopia in Orthokeratology (ROMIO) Study: A 2-Year Randomized Clinical Trial. Investigative Opthalmology & Visual Science, 2012, 53(11). 7077-7085. 9. Santodomingo-Rubido J., Villa-Collar C., Gilmartin B., Gutirrez-Ortega R., Sugimoto K. Long-term Efficacy of Orthokeratology Contact Lens Wear in Controlling the Progression of Childhood Myopia. Current Eye Research, 2016, 42(5). 713-720. 25 10. Holden B. A., Fricke T. R., Wilson D. A., Jong M., Naidoo K. S., Sankaridurg P., Wong T. Y., Naduvilath T. J., Resnikoff S. Global Prevalence of Myopia and High Myopia and Temporal Trends from 2000 through 2050. Ophthalmology, 2016, 123(5). 1036-1042. 11. World Health Organisation. The impact of myopia and high myopia; 2015. ISBN 978-92-4-151119-3. https://myopiainstitute.org/wpcontent/uploads/2020/10/Myopia_report_020517.pdf. (Accessed July 2022). 12. Modjtahedi B. S., Ferris F. L., Hunter D. G., Fong D. S. Public Health Burden and Potential Interventions for Myopia. Ophthalmology, 2018, 125(5). 628-630. 13. Flitcroft D. I. The complex interactions of retinal, optical and environmental factors in myopia aetiology. Progress in Retinal and Eye Research, 2012, 31(6). 622-660. 14. Jensen H. Myopia in teenagers. Acta Ophthalmologica Scandinavica, 2009, 73(5). 389-393. 15. Saw S. M., Gazzard G., Shih-Yen E. C., Chua W. H. Myopia and associated pathological complications. Ophthalmic and Physiological Optics, 2005, 25(5). 381-391. 16. Organisation for Economic Co-operation and Development (OECD). 2021. Reconciling Terminology of the Universe of Per- and Polyfluoroalkyl Substances: Recommendations and Practical Guidance, OECD Series on Risk Management, No. 61, OECD Publishing, Paris. 17. Alipour F., Khaheshi S., Soleimanzadeh M., Heidarzadeh S., Heydarzadeh S. Contact Lens-related Complications: A Review. Journal of Ophthalmic Vision Research, 2017, 12(2). 193-204. 18. Bartimote C., Foster J., Watson S. The Spectrum of Microbial Keratitis: An Updated Review. The Open Ophthalmology Journal, 2019, 13. 100-130. 19. Stapleton F., Keay L., Edwards K., Naduvilath T., Dart J. K. G., Brian G., Holden B. A. The Incidence of Contact Lens-Related Microbial Keratitis in Australia. Ophthalmology, 2008, 115(10). 1655-1662. 20. Zimmerman A. B., Nixon A. D., Rueff E. M. Contact lens associated microbial keratitis: practical considerations for the optometrist. Clinical Optometry, 2016, 8. 1-12. 21. Keay L., Edwards K., Naduvilath T., Forde K., Stapleton F. Factors Affecting the Morbidity of Contact Lens-Related Microbial Keratitis: A Population Study. Investigative Ophthalmology & Visual Science, 2006, 47. 4302-4308. 22. Morgan P. B., Efron N., Hill E. A., Raynor M. K., Whiting M. A., Tullo A. B. Incidence of keratitis of varying severity among contact lens wearers. British Journal of Ophthalmology, 2005, 89. 430-436. 26 23. Pucker A. D. Tichenor A. A. A Review of Contact Lens Dropout. Clinical Optometry, 2020, 12. 85-94. 24. Baker C. J., Watson A. E. Silicone acrylate vs. fluorosilicone acrylate: A study of base curve stability. Master's Thesis, Pacific University, College of Optometry, 1994. https://core.ac.uk/download/pdf/212800912.pdf. 25. Phillips A. J., Speedwell L. Eds. Contact Lenses, 4th Ed.; ButterworthHeinemann: Oxford, UK, 1997. pp323-327. ISBN 10: 0750618191. 26. Tomlinson A., Caroline P. J., Guillon J. P., Effect of Fluorine Content of RGP Contact Lens Polymers on Tear Film, Lens Wettability, and Deposit Resistance. International Contact Lens Clinic, 1991, 18(3-4). 53-58. 27. Bennett E.S. RGP Insights - Choose the Right RGP Lens Material for Your Patient. Contact Lens Spectrum, May 2001. https://www.clspectrum.com/issues/2001/may-2001/rgp-insights. 28. Giedd B. Understanding the nuances of contact lens materials - Learn just how important your choice of contact lens materials is to a successful fit. Contact Lens Spectrum, July 1999. https://www.clspectrum.com/issues/1999/july1999/understanding-the-nuances-of-contact-lens-material. 29. Novicky N. N. Fluorosulfone-silicone hydrogel, RGP contact lenses, optical medical devices and compositions thereof. From US Patent US7098282B2, 2006. 30. Hoepken J., Lohmann D., Domschke A. Polysiloxane-comprising perfluoroalkyl ether-based macromers for biomaterials, From PCT International Application, 1996, WO 9631791 A1 19961010. 31. Hughes T. C., Meijs G. F., Chaouk H., Steele J. G., Johnson G. Porous perfluoroalkyl acrylates: a potential ophthalmic biomaterial. From Polymer Preprints (American Chemical Society, Division of Polymer Chemistry), 2001, 42(2). 141-142. 32. Holden B. A., Williams L., Zantos S. G. The etiology of transient endothelial changes in the human cornea. Investigative Ophthalmology & Visual Science, 1985, 26. 1354-1359. 33. Papas E. B. The role of hypoxia in the limbal vascular response to soft contact lens wear. Eye & Contact Lens, 2003, 29, S72-74. 34. Dumbleton K. A. et al. Changes in myopic refractive error with nine months' extended wear of hydrogel lenses with high and low oxygen permeability. Optometry and Vision Science, 1999, 76. 845-849. 35. Keay L., et al. Microcysts: clinical significance and differential diagnosis. Optometry, 2001, 72. 452-460. 36. McNamara N. A., et al. Soft lens extended wear affects epithelial barrier function. Ophthalmology, 1998, 105, 2330-2335. 27 37. Holden B. A., et al. Effects of long-term extended contact lens wear on the human cornea. Investigative Ophthalmology & Visual Science, 1985, 26. 14891501. 38. Cavanagh H. D., Ladage P., Yamamoto K., Li S. L., Petroll W. M., Jester J. V. Effects of daily and overnight wear of hyper-oxygen transmissible rigid and silicone hydrogel lenses on bacterial binding to the corneal epithelium: 13-month clinical trials. Eye Contact Lens, 2003, 29(1 Suppl). S14-16. PMID: 12772723. 39. Ladage P. M., Yamamoto K., Ren D. H., Li L., Jester J. V., Petroll W. M., Cavanagh H. D. Effects of rigid and soft contact lens daily wear on corneal epithelium, tear lactate dehydrogenase, and bacterial binding to exfoliated epithelial cells. Ophthalmology, 2001, 108(7). 1279-88. 40. Bruce, A. S., Brennan, N. A., Lindsay R.G. Diagnosis and management of ocular changes during contact lens wear, Part II. Clinical Signs in Ophthalmology, 1995, 17. 2-11. 41. McMahon, T. T.; Zadnik, K. Twenty-five years of contact lenses: the impact on the cornea and ophthalmic practice. Cornea 2000, 19. 730-740. 42. Sweeney D. F. Corneal exhaustion syndrome with long-term wear of contact lenses. Optometry and Vision Science, 1992, 69(8). 601-608. 43. Zimmerman A. B. Contemporary CL Complications. Contact Lens Spectrum, December 2018. https://www.clspectrum.com/issues/2018/december2018/contemporary-cl-complications. 44. McMahon T. T., Polse K. A., McNamara N., Viana M. A. Recovery from induced corneal edema and endothelial morphology after long-term PMMA contact lens wear. Optometry and Vision Science, 1996, 73(3). 184-188. 45. Holden B., Stretton S., Lazon de la Jara P., Ehrmann K., LaHood D. The Future of Contact Lenses: Dk Really Matters. Contact Lens Spectrum, February 2006. https://www.clspectrum.com/supplements/2006/february-2006/protecting-yourpatient-s-eye-health/the-future-of-contact-lenses-dk-really-matters. 46. Michaud L., van der Worp E., Brazeau D., Warde R., Giasson C. J. Predicting estimates of oxygen transmissibility for scleral lenses. Contact Lens and Anterior Eye, 2012, 35(6). 266-271. 47. Compa V., Oliveira C., Aguilella-Arzo M., Moll S., Peixoto-de-Matos S. C., Gonzlez-Mijome J. M. Oxygen Diffusion and Edema with Modern Scleral Rigid Gas Permeable Contact Lenses. Investigative Ophthalmology & Visual Science, 2014, 55(10). 6421-6429. 48. Cheng H. C., Liang J. B., Lin W. P., Wu R. Effectiveness and safety of overnight orthokeratology with Boston XO2 high-permeability lens material: A 24 week follow-up study. Contact Lens & Anterior Eye, 2015, 39(1). 67-71. 49. Lum E., Swarbrick H. A. Lens Dk/t Influences the Clinical Response in Overnight Orthokeratology. Optometry and Vision Science, 2011, 88(4). 469-475. 28 50. Harvitt D. M., Bonanno J. A. Re-evaluation of the oxygen diffusion model for predicting minimum contact lens Dk/t values needed to avoid corneal anoxia. Optometry and Vision Science, 1999, 76(10). 712-719. 51. Dhallu S. K., Huarte S. T., Bilkhu P. S., Boychev N., Wolffsohn J. S. Effect of Scleral Lens Oxygen Permeability on Corneal Physiology. Optometry and Vision Science, 2020, 97(9). 669-675. 52. Wagner H. The How and Why of Contact Lens Deposits. Online Course from Review of Cornea and Contac Lenses. Published 15 May 2020. https://www.reviewofcontactlenses.com/article/the-how-and-why-of-contact-lensdeposits. 53. Sumide T., Suzuki C., Sasaki R., Imayasu M. Effects of artificial deposits on adhesiveness of Pseudomonas aeruginosa onto orthokeratology lens. Poster presented at the Global Speciality Lens Symposium, 2020. https://na-prodaventrifiles.s3.amazonaws.com/html_file_uploads/8ad0ce75c5f505b2b80cae176c6991 00_2020GSLSPosterTaizoSumide.pdf?response-contentdisposition=inline%3Bfilename%3D%222020GSLS%20Poster%20%28Taizo%2 0Sumide%29.pdf%22&response-contenttype=application%2Fpdf&AWSAccessKeyId=AKIA3OQUANZMGCIZWZ6F&Expi res=1661949096&Signature=MrcICKNYuBGJEfuzW2GRfsx%2Bjr0%3D. 54. Epstein A. Ensuring Wettability and Comfort. Contact Lens Spectrum, July 2009. https://www.clspectrum.com/supplements/2009/july-2009/new-perspectives-onpatient-satisfaction-the-scie/ensuring-wettability-andcomfort?oly_enc_id=1138A2701601G6U. 55. Dart J. K., Radford C. F., Minassian D., Verma S., Stapleton F. Risk factors for microbial keratitis with contemporary contact lenses: a case-control study. Ophthalmology, 2008, 115(10). 1647-54. 56. Eddleston M. D., Raduly L., Tapper T. T., Hughes R. J., Browne G. M., Conway M. J. The Consequences of Removing Fluorinated Compounds from Rigid Contact Lenses. Journal of Polymer Engineering, 2023. https://doi.org/10.1515/polyeng-2022-0189. 57. Ricardo. Economic Analysis of the Impacts of the Chemicals Strategy for Sustainability. Phase 1 Report for the European Chemicals Industry Council (Cefic), November 2021. https://cefic.org/app/uploads/2021/12/EconomicAnalysis-of-the-Impacts-of-the-Chemicals-Strategy-for-Sustainability-Phase1.pdf. 58. European Commission. Restrictions Roadmap under the Chemicals Strategy for Sustainability. Commission Staff Working Document SWD(2022) 128 final. 2022. file:///C:/Users/MarkE.DOMAIN/Downloads/SWD_2022_128_F1_STAFF_WORK ING_PAPER_EN_V3_P1_1918809.PDF. Accessed July 2023 29 59. ECHA. Registration Dossier for 3-[3,3,3-trimethyl-1,1bis[(trimethylsilyl)oxy]disiloxanyl]propyl methacrylate - PBT Assessment. ECHA website. 2023. https://echa.europa.eu/registration-dossier/-/registereddossier/23711/2/3. Accessed March 2023. 60. Kickelbick G. Silsesquioxanes. In: Scheschkewitz, D. (eds) Functional Molecular Silicon Compounds I. Structure and Bonding, 2013, vol 155. Springer, Cham. https://doi.org/10.1007/430_2013_108. 61. Mackenzie J. D., Bescher E. P. Structures, Properties and Potential Applications of Ormosils. Journal of Sol-Gel Science and Technology, 1998, 13. 371-377. 62. Philipp G., Schmidt H. New materials for contact lenses prepared from Si- and Ti-alkoxides by the sol-gel process. Journal of Non-Crystalline Solids, 1984, 63(1-2). 283-292. 63. Glaser R. H. Structure - Property Behaviour of Sol-Gel Derived Hybrid Materials. PhD Dissertation, Virginia Polytechnic Institute and State University, 1988. https://vtechworks.lib.vt.edu/bitstream/handle/10919/54327/LD5655.V856_1988. G585.pdf?sequence=1&isAllowed=y. 64. Pinnau I., Toy L. G. Gas and vapor transport properties of amorphous perfluorinated copolymer membranes based on 2,2-bistrifluoromethyl-4,5difluoro-1,3-dioxole/tetrafluoroethylene. Journal of Membrane Science, 1996, 109(1). 125-133. 65. Jinnouchi R., Kudo K., Kodama K., Kitano N., Suzuki T., Minami S., Shinozaki K., Hasegawa N., Shinohara A. The role of oxygen-permeable ionomer for polymer electrolyte fuel cells. Nature Communications, 2021, 12, 4956. 66. Teng H. Overview of the Development of the Fluoropolymer Industry. Applied Sciences, 2012, 2. 496-512. 67. Crowther O., Salomon M. Oxygen Selective Membranes for Li-Air (O2) Batteries. Membranes, 2012, 2(2). 216-227. 68. Aiba S., Ohashi M., Huang S-Y. Rapid Determination of Oxygen Permeability of Polymer Membranes. Industrial & Engineering Chemistry Fundamentals, 1968, 7(3). 497-502. 69. Masuda T., Isobe E., Higashimura T., Takada K. Poly[1-(trimethylsilyl)-1propyne]: a new high polymer synthesized with transition-metal catalysts and characterized by extremely high gas permeability. Journal of the American Chemical Society, 1983, 105(25). 7473-7474. 70. Fukui A., Hattori K., Hu Y., Shiotsuki S., Sanda F., Masuda T. Synthesis, characterization, and high gas permeability of poly(diarylacetylene)s having fluorenyl groups. Polymer, 2009, 50(17). 4159-4165. 71. Claes S., Vandezande P., Mullens S., Adriaensens P., Peeters R., Maurer F. H. J., Van Bael K. M. Crosslinked poly[1-(trimethylsilyl)-1-propyne] membranes: 30 Characterization and pervaporation of aqueous tetrahydrofuran mixtures. Journal of Membrane Science, 2012, 389. 459-469. 72. Starannikova L., Khodzhaeva V., Yampolskii Y. Mechanism of aging of poly[1(trimethylsilyl)-1-propyne] and its effect on gas permeability. Journal of Membrane Science, 2004, 244(1-2). 183-191. 73. Hoffman W. C. Highly Oxygen Permeable Rigid Contact Lenses from Polyacetylenes. United States Patent 8,153,726 (2012). 74. Sakaguchi T., Hu Y., Masuda T. Substituted Polyacetylenes. Chapter in: Yampolskii Y., Finkelshtein E. (Eds), Membrane Materials for Gas and Vapor Separation: Synthesis and Application of Silicon-Containing Polymers, 2017. John Wiley & Sons Ltd. ISBN: 9781119112716. 75. Toy L. G., Pinnau I. Natural Gas Treatment Process Using PTMSP Membrane. United States Patent Application US5501722A (1996). 76. Kunzler J. F., Percec V. Oxygen permeable polymeric materials. European Patent Application 88307433.8 (1988). 77. Gringolts M., Bermeshev M., Yampolskii Y., Starannikova L., Shantarovich V., Finkelshtein E. New High Permeable Addition Poly(tricyclononenes) with Si(CH3)3 Side Groups. Synthesis, Gas Permeation Parameters, and Free Volume. Macromolecules, 2010, 43. 7165-7172. 78. Janiak C., Lassahn P. G. The Vinyl Homopolymerization of Norbornene. Macromolecular Rapid Communications, 2001, 22(7). 479-492. 79. Hocker S., Hudson-Smith N., Schniepp H. C., Kranbuehl D. E. Enhancing polyimide's water barrier properties through addition of functionalized graphene oxide. Polymer, 2016, 93. 23-29. 80. Escorihuela S., Tena A., Shishatskiy S., Escolstico S., Brinkmann T., Serra J. M., Abetz V. Gas Separation Properties of Polyimide Thin Films on Ceramic Supports for High Temperature Applications. Membranes, 2018, 8(1). 16. 81. Park S-H., Kim K-J., So W-W., Moon S-J., Lee S-B. Gas separation properties of 6FDA-based polyimide membranes with a polar group. Macromolecular Research, 2003, 11(3). 157-162. 82. McKeown N. B. Polymers of Intrinsic Microporosity. International Scholarly Research Notices, 2012. 513986. 83. Guiver M. D., Yahia M., Dal-Cin M. M., Robertson G. P., Garakani S. S., Du N., Tavajohi N. Gas Transport in a Polymer of Intrinsic Microporosity (PIM-1) Substituted with Pseudo-Ionic Liquid Tetrazole-Type Structures. Macromolecules 2020, 53(20). 8951-8959. 84. Bezzu C. G., Fuoco A., Esposito E., Monteleone M., Longo M., Jansen J. C., Nichol G. S., McKeown N. B. Ultrapermeable Polymers of Intrinsic Microporosity 31 (PIMs) Containing Spirocyclic Units with Fused Triptycenes. Advanced Functional Materials, 2021, 2104474. 85. Lasseuguette E., Ferrari M-C., Brandani S. Humidity impact on the gas permeability of PIM-1 membrane for post-combustion application. Energy Procedia, 2014, 63. 194-201. 86. Wang Z. G., Liu X., Wang D., Jin J. Troger's base-based copolymers with intrinsic microporosity for CO2 separation and effect of Troger's base on separation performance. Polymer Chemistry, 2014, 5. 2793-2800. 87. Scholes C. A., Kanehashi S. Polymer of Intrinsic Microporosity (PIM-1) Membranes Treated with Supercritical CO2. Membranes, 2019, 9(3). 41. 88. Khan M. M., Bengtson G., Shishatskiy S., Gacal B. N., Rahman M. M., Neumann S., Filiz V., Abetz V. Cross-linking of Polymer of Intrinsic Microporosity (PIM-1) via nitrene reaction and its effect on gas transport property. European Polymer Journal, 2013, 49. 4157-4166. 89. Polak-Krana K., Dawson R., Holyfield L. T., Bowen C. R., Burrows A. D., Mays T. J. Mechanical characterisation of polymer of intrinsic microporosity PIM-1 for hydrogen storage applications. Journal of Materials Science, 2017, 52. 38623875. 90. Szente L., Fenyvesi E. Cyclodextrin-Enabled Polymer Composites for Packaging. Molecules, 2018, 23(7). 1556. 91. Lpez-de-Dicastillo C., Gallur M., Catal R., Gavara R., Hernandez-Muoz P. Immobilization of -cyclodextrin in ethylene-vinyl alcohol copolymer for active food packaging applications. Journal of Membrane Science, 2010, 353(1-2). 184-191. 92. Huber G., Berthault P., Nguyen A. L., Pruvost A., Barruet E., Rivollier J., Heck M-P., Prieur B. Cucurbit[5]uril derivatives as oxygen carriers. Supramolecular Chemistry, 2019, 31(10). 1-8. 93. See Annex F of this Comment Submission from EUROMCONTACT: Eddleston M. D. An analysis of risk and socioeconomic impact for PFAS in rigid contact lenses. 2023. EUROMCONTACT report. 94. See Annex D of this Comment Submission from EUROMCONTACT: Eddleston M. D. The Fate and Toxicity of Fluorinated Substances used in Contact Lenses. 2023. EUROMCONTACT Report. 95. UN Environment Report. Environmental Effects and Interactions of Stratospheric Ozone Depletion, UV Radiation, and Climate Change. 2018 Assessment Report. https://ozone.unep.org/sites/default/files/2019-04/EEAP_assessment-report2018%20%282%29.pdf. 96. Solomon K., Velders G., Wilson S., Madronich S., Longstreth J., Aucamp P., Bornman J. Sources, fates, toxicity, and risks of trifluoroacetic acid and its salts: 32 Relevance to substances regulated under the Montreal and Kyoto protocols. Journal of Toxicology and Environmental Health B, 2016, 19(7). 289-304. 97. Kirsch P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications. Wiley-VCH, 2013. ISBN 9783527331666. 98. Federal Institute for Occupational Safety and Health (BAuA), Bureau REACH, National Institute for Public Health and the Environment (RIVM), Swedish Chemicals Agency (KEMI), Norwegian Environment Agency, The Danish Environmental Protection Agency. ANNEX XV RESTRICTION REPORT - Per- and polyfluoroalkyl substances (PFASs). Annex E. 2023. https://echa.europa.eu/documents/10162/8bdc850c-ffd0-6f61-26f5ab9e4a0a34e3. Accessed March 2023. 33 Appendix A - Comments from world renowned optometrists on the consequences of removing PFAS from RGP lens materials Prof. James Wolffsohn (BSc(Hons), PgCertHE, PgDipAdvClinOptom, MBA, PhD, PFHEA, FRSB, FCOptom, FAAO, Diplomate-CCLRT, FIACLE, FBCLA) Thank you for alerting me to this proposal and your research on the impact this would have on oxygen permeability and deposition. As a clinician, researcher and educator in contact lenses, these effects would make the lenses unsafe to wear due to the cornea being deprived of oxygen (taking us back to the sight affecting and serious eye health complications of the earliest contact lenses) as well as the impact on vision. Please do pass on my comments to the necessary regulatory bodies Kind regards James James S. Wolffsohn BSc(Hons) PgCertHE PgDipAdvClinOptom MBA PhD PFHEA FRSB FCOptom FAAO Diplomate-CCLRT FIACLE FBCLA Professor of Optometry, Health and Life Sciences, Aston University Head of the School of Optometry; Subject lead: Audiology Adjunct Professor of Optometry, University of Houston Visiting Professor of West China Hospital, Sichuan University https://www2.aston.ac.uk/lhs/staff/az-index/wolffjsw Greg Denaeyer (OD, FAAO) Reading this report is worrisome. My statement: I have a large specialty contact lens practice that helps successfully manage patients with corneal irregularity and ocular surface disease. Almost all of these patients wear scleral lenses, which are critical for their rehabilitation and abiltiy to carry out activities of daily living. Without scleral lenses that are manufactured with current modern gas-permeable materials (GP), a majority of my patients would be disabled and visually non-functional. It is critical that GP materials have the highest Dk levels and surface wettability to achieve success and avoid complications. Any polymer substitutions that would negatively alter current GP material characteristics would be a devastating blow to my patients, as the complications from these changes could lead to failure with lens wear. Please let me know how else I can help you. Greg 34 Prof. Giancarlo Montani (D.Optom, FBCLA, FAAO) After years of research to optimize the characteristics of RGP materials, guaranteeing greater oxygenation of the cornea and reducing the interaction of materials with lipid and protein deposits, these indications from the EU take us back 50 years. It is important to remember that contact lenses made with RGP materials are mostly used for the management of irregular corneas, which can involves the use of scleral contact lenses, or for myopia control through orthokeratology, which involves the use of contact lenses with closed eyes. It easy to understand as these contact lenses must allow the the highest possible oxygen flow during wear. Materials with new compositions that significantly reduce this characteristic will not allow the use of contact lenses to many potential users with a significant impact on their quality of vision and consequently on their quality of life or in case of use of these new contact lens materials will increase the incidence of complications induced by contact lens wear. I hope that there will be a rethink from the legislator by still allowing the use of PFASs in the materials used for contact lens manufacture in order to guarantee contact lenses with characteristics necessary for their safe and comfortable use. Montani Giancarlo D.Optom FBCLA, FAAO CeRCA Lab (Center for research in advanced contact lenses) Department of Mathematics and Physics "Ennio De Giorgi" University of Salento Via per Arnesano 73100 Lecce (Italy) Martin Conway (FBDO, FIACLE, FBCLA) Contamac Ltd Patients with straightforward refractive errors have tended to migrate to soft contact lenses over the years as they offer easier adaptation, convenience and flexibility. Those patients that wear gas permeable lenses, therefore tend to do so out of need, as initial comfort is much reduced compared to that of soft and so it needs a degree of determination in order to fully adapt to wearing them. There are patients for whom no alternative is available, either spectacles or soft lenses, as their corneae are so distorted through keratoconus, or corneal graft, for example, that only a rigid lens can provide a standard of vision that will enable them to see sufficiently well to lead a normal existence. For those patients suffering from the effects of Stevens-Johnson, Sjgrens or other Ocular Surface Diseases, only a scleral gas permeable lens offers day-long relief from the debilitating pain than can be present with those conditions. Needless to say, these groups of patients need their lenses to be worn safely and in comfort for all of their waking hours. Reducing the deposit resistance and the permeability of these lenses will mean that their ocular health and well-being will be severely compromised and they will be left with no other suitable form of correction, leaving them significantly disabled as a result. 35 Dr Hans Bleshoy (PhD, MBCO, FAAO) stertorv 7D, 7800 Skive. www.visioncenter.dk Denmark, 31st May 2022 The role of PFAS in RGP lenses for patient visual management Oxygen permeability has been a central aspect in the development of new RGP materials over the last two decades. The positive impact on corneal, and thereby eye health, of the newer better materials has been tremendous. I have been in the RGP field for more than 35 years and I have experienced that many more patients may be fitted with RGP lenses to provide them with optimal visual function for many hours every day. I have experienced how patients have been able to increase their wearing time, been able to maintain stable vision and to reduce or even eliminate the adverse physiological impact that a foreign body like an RGP lens may have on the cornea / eye. Materials with high oxygen properties are fundamentally necessary in todays clinical practice, without which it would be impossible to wear RGP lenses in a safe and comfortable manner. If these very important material properties are reduced or eliminated, then a significant number of patients with very challenging eye conditions simply will not be able to function visually and leaving them without being able to maintain their work. It would reduce quality of life dramatically. Hans Bleshoy PhD, MBCO, FAAO Mark Darling (BSc, MBCO) Mark Darling Eyecare & Opticians I'm amazed to hear of this possible retrograde step in contact lens wear. I fit lenses to eyes already compromised from keratoconus, corneal grafts, and severe Dry Eye that need the best quality material in terms of oxygen permeability, and durability. Modern gas permeable lenses give life changing benefits to these patients. Going back to the `old' standards will condemn already visually impaired patients to a vastly reduced quality of life and to my mind is a form of discrimination. 36 Dr Eef van der Worp (PhD, FAAO, FIACLE, FBCLA, FSLS) To whom it may concern: "While I am by no means an expert in contact lens polymers or components of contact lens materials - I can testify as a practitioner, educator and researcher that specialty contact lenses such as corneal rigid lenses and scleral lenses can have a huge effect on patients quality of life, especially in the irregular cornea arena. In fact, many patients with a variety of corneal irregularities including (but certainly not limited too) keratoconus can be considered legally handicapped by many standards if they do not have access to these lenses. For the majority of patients described, rigid lenses will always provide superior vision compared to other lens modalities and compared to surgical options for their conditions. In orthokeratology, rigid lens materials are used within an array of therapy options to control or at least slow down the progression of myopia in children, which is becoming a world-wide epidemic. Optimal functioning rigid lens materials in terms of duration, transparancy and oxygen permeambility are crucial in all lens types (corneal rigid lenses, orthokeratology lenses and scleral lenses)." Dr Eef van der Worp Optometrist PhD FAAO FIACLE FBCLA FSLS Valeriusstraat 186-III 1075 GJ Amsterdam the Netherlands 37