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Appendix 2 JAIMA 25 September 2023 Appendix 2 Uses and substitutions of PFAS for Flow Cytometry Analyzer(IVD) 1. Fluorescence flow cytometry (FFC) Fluorescence flow cytometry (FFC) is used to analyze physiological and chemical properties of cells. It provides: Information about cell size and structure Information about a cell's interior In flow cytometry, cells and particles are examined while they are flowing through a very narrow flow cell. First a sample is aspirated and proportioned, then diluted to a pre-set ratio and labelled with a proprietary fluorescence marker that binds specifically to nucleic acids. Next the sample is transported into the flow cell. The sample is illuminated by a semiconductor laser beam, and some different signals are detected. 1 / 8 Appendix 2 JAIMA 25 September 2023 Cells with similar physical and chemical properties form a cluster in a graph known as a scattergram. The principle of fluorescence flow cytometry is used in different analyzers for haematology and urinalysis. In urinalysis analyzers, fluorescence technology is also used for counting bacteria, red blood cells, white blood cells and other elements. Furthermore, when a fluorescence flow cytometry analyzer is used in a medical setting, it is certified as a diagnostic device and is treated as an in vitro diagnostic device (IVD). On the other hand, when used in a laboratory, it is treated as a RUO (Research Use Only) device. These devices are the same, and the only difference is whether or not they have been certified as diagnostic devices. Figure1. IVD device Figure2. RUO device 2 / 8 Appendix 2 JAIMA 25 September 2023 2. PFAS parts used in Fluorescence flow cytometry In the chemical flow of fluorescence flow cytometry, strongly alkaline hypochlorous acid and organic solvents such as methanol, ethanol, and ethylene glycol flow. In addition, various specimens flow. Therefore, the parts that come in contact with reagents and specimens are basically required to have high chemical resistance. For example, joint parts between parts, O-rings, etc. However, the most important parts are the parts that are essential for producing accurate measurement results, so we will focus on these important parts here. Usage number 1 PFAS parts Chemical tube (fluororesin) Parts overview Utilizing hardness, it is used for parts related to quantitativeness Comes into contact with various reagents (strongly alkaline hypochlorous acid, organic solvents such as methanol, ethanol, ethylene glycol, etc.) and specimens. 2 Double layer tube Utilizing flexibility, it is used where there is (Inner layer is fluororesin, bending or where long distances are outer layer is polyurethane) connected. Comes into contact with various reagents (strongly alkaline hypochlorous acid, organic solvents such as methanol, ethanol, ethylene glycol, etc.) and specimens. 3 Fluorine coated pipette Used for dispensing reagents and inhaling specimens. Relates to quantitative nature. Comes into contact with various reagents (strongly alkaline hypochlorous acid, organic solvents such as methanol, ethanol, ethylene glycol, etc.) and specimens. 4 Diaphragm valve for Valves to control the flow of chemical chemical liquid solutions. The rubber membrane that comes into contact with the liquid inside the tube is 3 / 8 Appendix 2 JAIMA 25 September 2023 PFAS. Comes into contact with various reagents (strongly alkaline hypochlorous acid, organic solvents such as methanol, ethanol, ethylene glycol, etc.) and specimens. Left image: Fully open Right figure: Fully closed 5 Sample presence sensor A sensor that detects whether the sample remains on the stirring rod. The material of the sensor body (blue part in the left diagram) is PFAS. Comes into contact with various reagents (strongly alkaline hypochlorous acid, organic solvents such as methanol, ethanol, ethylene glycol, etc.) and specimens. 3. Substitutability verification results for each part using PFAS No.1: Chemical tube (fluororesin) (1) Required chemical resistance, water repellency, quantitative properties (high PFAS hardness and little volume change), low reactivity to reagents properties (2) Specifications Chemical resistance to various reagents and samples (strongly required in alkaline hypochlorous acid, etc.) the final Ensuring quantification of specimens and reagents (suppression product of variation in quantitative values, suppression of liquid droplets generated at the ejection port) Suppression of sample carryover Suppression of reagent carryover Low reactivity to reagents (material with high purity, little elution, high non-stickiness and little adhesion of impurities) (3) Candidates Nothing for alternative materials that can meet the required 4 / 8 Appendix 2 JAIMA 25 September 2023 specifications (4) Impact on the Durability decreases, failures increase, and waste increases. product when The accuracy of measurement results decreases, and the quality there is no of diagnosis and R&D deteriorates accordingly. alternative material (5) Necessity of Exemptions under PFAS Restrictions Exemption for more than 20 years is necessary since there are no other materials that can achieve (1) and (2). No.2: Double layer tube (Inner layer is fluororesin, outer layer is polyurethane) (1) Required Chemical resistance, water repellency, low reactivity to reagents PFAS properties (2) Specifications Chemical resistance to various reagents and samples (strongly required in alkaline hypochlorous acid, etc.) the final Low reactivity to reagents (substance with high purity, little product elution, high non-stickiness and little adhesion of impurities) Flexibility to fit compactly into equipment (3) Candidates Nothing for alternative materials that can meet the required specification (4) Impact on the Durability decreases, failures increase, and waste increases. product when If flexibility decreases, equipment becomes larger, there is no transportation load increases, and installation locations are alternative limited. material (5) Necessity of Exemption for more than 20 years is necessary since there are no Exemptions other materials that can achieve (1) and (2). under PFAS Restrictions 5 / 8 Appendix 2 JAIMA 25 September 2023 No.3: Fluorine coated pipette (1) Required Chemical resistance, water repellency PFAS properties (2) Specifications Ensuring quantitative quality of specimens and reagents required in (suppressing variation in quantitative values) the final Suppression of carryover of liquid adhering to the pipette product surface (If the pipette is used for dispensing reagents, the washing liquid will be brought into the reagent container, diluting the reagent and impairing the stability of the reagent.) Suppression of carryover between samples (cross contamination) (3) Candidates Nothing for alternative materials that can meet the required specification (4) Impact on the The accuracy of measurement results decreases, and the quality product when of diagnosis and R&D deteriorates accordingly. there is no alternative material (5) Necessity of Exemption for more than 20 years is necessary since there are no Exemptions other materials that can achieve (1) and (2). under PFAS Restrictions No.4: Diaphragm valve for chemical liquid (1) Required Chemical resistance PFAS properties (2) Specifications Chemical resistance to various reagents (strong alkaline required in hypochlorous acid, organic solvents such as methanol, ethanol, the final ethylene glycol, etc.) 6 / 8 Appendix 2 JAIMA 25 September 2023 product Accurate control of chemical flow rate (3) Candidates for alternative materials that can meet the required specification (4) Impact on the product when there is no alternative material (5) Necessity of Exemptions under PFAS Restrictions Nothing Durability decreases, failures increase, and waste increases. The accuracy of measurement results decreases, and the quality of diagnosis and R&D deteriorates accordingly. Exemption for more than 20 years is necessary since there are no other materials that can achieve (1) and (2). No.5: Sample presence sensor (1) Required Non-conducting, chemical resistance, water repellency PFAS properties (2) Specifications Suppression of sample carryover required in Improved sensor detection accuracy by improving liquid drainage the final (water repellency) product (3) Candidates Nothing for alternative (Evaluated with PVC, but there were many false detections due to materials that liquid residue) can meet the required specification (4) Impact on the The accuracy of measurement results decreases, and the quality product when of diagnosis and R&D deteriorates accordingly. there is no In the case of materials with low water repellency, detection alternative accuracy decreases because liquid remains. 7 / 8 Appendix 2 JAIMA 25 September 2023 material (5) Necessity of Exemptions under PFAS Restrictions Exemption for more than 20 years is necessary since there are no other materials that can achieve (1) and (2). 8 / 8