Alternatives to DEHP as plasticizers in blood bags

For nearly 70 years, blood product collection and storage bags for whole blood and red blood cell (RBC) storage have been manufactured with di(2-ethylhexyl) phthalate (DEHP) to increase flexibility. Because of potential toxicity, alternative plasticizers are being implemented. The Biomedical Excellence for Safer Transfusion (BEST) Collaborative recently reviewed actions to this end and made recommendations for what premarket laboratory studies, premarket clinical data, and postmarket surveillance are needed prior to and after the implementation of DEHP-free products.¹

The European Union (EU) will ban DEHP in medical devices, including blood bags, beginning on July 1, 2030.² All stakeholders—including blood bag manufacturers, blood suppliers, regulators, and hospitals—must collaborate to comply with all required regulations.

The European Blood Alliance (EBA)^3,4 and the EU-funded Joint Action for facilitating the Authorisation of Preparation Process for blood and tissues and cells (GAPP Joint Action)⁵ have outlined recommendations for in vitro evaluation of blood components that are manufactured and stored in DEHP-free medical devices. However, neither the EU nor the FDA has defined the specific in vivo studies needed to license blood bags containing alternative plasticizers, although the FDA has historically required 24-hour recovery studies using radiolabeled autologous RBCs in healthy volunteers.

DEHP binds noncovalently to polyvinyl chloride (PVC) in blood bags and may leach into blood products.  Because of its lipophilic nature, DEHP integrates into RBC membranes. It stabilizes those membranes^6,7 as evidenced by decreased osmotic fragility and increased deformability. Initial in vitro testing with DEHP-free collection bags showed increased hemolysis compared to current collection kits, but second- and third-generation storage solutions such as AS-3 prevented this effect. Platelets and plasma have not been found to be affected by DEHP.^8-10 Platelets are currently collected in DEHP-free bags using alternative plasticizers.

The BEST Collaborative believes that if comprehensive in vitro assessments using EBA guidance characterize RBC structure and function for DEHP-free bags as noninferior to those for DEHP bags, 24-hour recovery studies may not be needed. If the switch to DEHP-free bags is accompanied by other significant changes—for example, a new plastic, an unlicensed additive solution, or shelf-life extension—recovery studies might be warranted. At this time no studies have been done to assess RBCs in DEHP-free bags following washing; however, irradiated units in DEHP-free bags are acceptable by in vitro criteria.

The Collaborative notes that small premarket studies are unlikely to detect infrequent adverse events, and the same could be said of other infrequent findings. Accordingly, once premarket studies demonstrate noninferiority of DEHP-free bags and a CE mark is granted, EU Medical Device Regulations require postmarket surveillance and postmarket clinical follow-up. It is recommended to collect data on how new bags affect both donors (bag integrity, user issues, donor adverse events, hemolysis) and recipients (transfusion reactions, transfusion intervals, product utilization, hemoglobin increment, and corrected count increment) as appropriate for the product type. This would be an enhancement of current hemovigilance, which focuses on adverse events. This type of surveillance should be started prior to the introduction of DEHP-free kits to provide data on historic controls. Collaboration across the blood industry would help cross-leverage data. This data should provide sufficient power to show noninferiority at scale and minimize unexpected results.

In summary, the Collaborative feels that premarket in vitro testing results adequately assess safety and efficacy of DEHP-free bags in the absence of major changes such as a new additive solution or anticoagulant, and pre- and postmarket hemovigilance should capture low-frequency adverse reactions and establish noninferiority at scale.

1. Brown B, Klei TRL, Kanias T, de Korte D, Cancelas JA, Cardigan R; Biomedical Excellence for Safer Transfusion (BEST) Collaborative. Clinical evaluation of novel blood collection and storage bags containing alternative plasticizers to DEHP: Recommendations from the BEST collaborative. Transfusion. 2025;65(12):2414-22. https://doi.org/10.1111/trf.18470
2. Document 02006R1907-20251023: Consolidated text: Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), establishing a European Chemicals Agency, amending Directive 1999/45/EC and repealing Council Regulation (EEC) No 793/93 and Commission Regulation (EC) No 1488/94 as well as Council Directive 76/769/EEC and Commission Directives 91/155/EEC, 93/67/EEC, 93/105/EC and 2000/21/EC (Text with EEA relevance) [Internet]. Luxembourg: Publications Office of the European Union; [cited 2026 Mar 8]. Available from: https://eur-lex.europa.eu/eli/reg/2006/1907/2025-10-23
3. Klei TRL, Begue S, Lotens A, Sigurj onsson ÓE, Wiltshire MD, George C, et al. Recommendations for in vitro evaluation of blood components collected, prepared and stored in non-DEHP medical devices. Vox Sang. 2023;118(2):165–77. https://doi.org/ 10.1111/vox.13384
4. de Korte D. Reclassification of DEHP: impact on BEs [Internet]. Strasbourg (FR): Council of Europe; [cited 2026 Mar 8]. Available from: https://www.edqm.eu/documents/52006/247256/reclassification-of-dehp-impact-on-bes-by-dirk-dekorte-phd.pdf/23e835c0-294b-3457-8742-8977b01d7664
5. GAPP Joint Action. Facilitating the authorisation of preparation process for blood, tissues, and cells (GAPP): good practice guideline to authorisation on preparation processes in blood, tissues and cell establishments [Internet]. [place unknown]: GAPP Joint Action, c2022 [cited 2026 Mar 8]. Available from: https://www.gapp-ja.eu/wp-content/uploads/2022/01/GAPP-volume-Guide-and-Technical-Annexes.pdf
6. Horowitz B, Stryker MH, Waldman AA, Woods KR, Gass JD, Drago J. Stabilization of red blood cells by the plasticizer, diethylhexylphthalate. Vox Sang. 1985;48(3):150–5. https://doi.org/10.1111/j.1423-0410.1985.tb00162.x
7. Rock G, Tocchi M, Ganz PR, Tackaberry ES. Incorporation of plasticizer into red cells during storage. Transfusion. 1984;24(6):493–8. https://doi.org/10.1046/j.1537-2995.1984.24685066808.x
8. Larsson L, Sandgren P, Ohlsson S, Derving J, Friis-Christensen T, Daggert F, et al. Non-phthalate plasticizer DEHT preserves adequate blood component quality during storage in PVC blood bags. Vox Sang. 2021;116(1):60–70. https://doi.org/10.1111/vox.12982
9. Lagerberg JW, Gouwerok E, Vlaar R, Go M, de Korte D. In vitro evaluation of the quality of blood products collected and stored in systems completely free of di(2-ethylhexyl)phthalateplasticized materials. Transfusion. 2015;55(3):522–31. https://doi.org/10.1111/trf.12870
10. 10. Valeri CR, Contreras TJ, Feingold H, Sheibley RH, Jaeger RJ. Accumulation of di-2-ethylhexyl phthalate (DEHP) in whole blood, platelet concentrates, and platelet-poor plasma. 1. Effect of DEHP on platelet survival and function. Environ Health Perspect. 1973;3:103–18. https://doi.org/10.1289/ehp.7303103