Alternative plasticizer, 4‐cyclohexene‐1,2‐dicarboxylic acid dinonyl ester, for blood containers with protective effects on red blood cells and improved cold resistance

Abstract

Di (2-ethylhexyl) phthalate (DEHP), a typical plasticizer used for polyvinyl chloride (PVC), is eluted from PVC-made blood containers and protects against red blood cell (RBC) hemolysis. However, concerns have arisen regarding the reproductive and developmental risks of DEHP in humans, and the use of alternative plasticizers for medical devices has been recommended worldwide. In this study, we propose that the use of a novel plasticizer, 4-cyclohexene-1,2-dicarboxylic acid dinonyl ester (DL9TH), could help produce more useful and safe blood containers. PVC sheet containing DL9TH and di (2-ethylhexyl) 4-cyclohexene-1,2-dicarboxylate (DOTH) provides comparable or superior protective effects to RBCs relative to PVC sheet containing DEHP or di-isononyl-cyclohexane-1,2-dicarboxylate (DINCH , an alternative plasticizer that has been used in PVC sheets for blood containers). The total amount of plasticizer eluted from DOTH/DL9TH-PVC sheets is nearly the same as that eluted from DEHP-PVC sheets. In addition, DOTH/DL9TH-PVC has better cold resistance than DEHP- and DINCH -PVC sheets. In vitro and in vivo tests for biological safety based on International Organization for Standardization guidelines (10993 series) suggest that the DOTH/DL9TH-PVC sheet can be used safely. Subchronic toxicity testing of DL9TH in male rats in accordance with the principles of Organisation for Economic Co-operation and Development Test Guideline 408 showed that DL9TH did not induce adverse effects up to the highest dose level tested (717 mg/kg body weight/day). There were no effects on testicular histopathology and sperm counts, and no indications of endocrine effects: testosterone, thyroid-stimulating hormone, follicle-stimulating hormone, and 17β-estradiol were unchanged by the treatment, compared with the control group. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1052-1063, 2018.

Pilot study on novel blood containers with alternative plasticizers for red cell concentrate storage

“…Considering the improved safety of DOTH and DINCH in comparison with that of DEHP, the observed 1.59-fold increase in plasticizer levels is believed to be sufficiently low to avoid adverse effects in patients. We previously determined that the NOAEL of DL9TH is 717 mg/kg body weight/day in male rats, in a 90-day oral repeat dose toxicity study [ 19 ]. Therefore, similar plasticizer exposure levels between DEHP and DOTH/DL9TH blood containers indicates that the DOTH/DL9TH blood containers are safer for use than the DEHP blood container.…”

“…In conclusion, the data presented here demonstrates that DOTH/DINCH and DOTH/DL9TH blood containers represent suitable candidates for the replacement of DEHP blood containers, since they show improved safety and similar quality and total plasticizer exposure, compared with the DEHP blood containers. Considering that DOTH/DL9TH-PVC shows greater flexibility at lower temperatures than DOTH/DINCH-PVC [ 19 ], the DOTH/DL9TH-blood container is more promising. Currently, our group is also evaluating the quality of RCC samples stored in SAGM solution, an additive used worldwide.…”

“…Plasticizer levels in MAP/RCC (after 0, 1, 2, 3, 4, 5, and 6 weeks of storage; n = 6) were determined using a previously described protocol, with some modifications [ 15 , 19 – 23 ]. Briefly, aliquot (50 μL) of MAP/RCC was collected into screw-capped glass tubes, and sodium chloride (1 mL, 1 w/v%), DEHP-d4 (0.5 μg), and hexane (1 mL) were added.…”

“…The hemolysis test was performed after 0, 1, 2, 3, 4, 5, and 6 weeks of storage (n = 6), as described previously [ 19 ]. Briefly, an aliquot (50 μL) of MAP/RCC was collected into Eppendorf tubes (Eppendorf, Tokyo, Japan).…”

“…We recently reported that the concurrent use of DOTH and DINCH enabled the production of a safe PVC sheet with protective effects on red blood cells, which was comparable to that of DEHP [ 18 ]. Additionally, using a novel plasticizer, 4-cyclohexene-1,2-dicarboxylic acid dinonyl ester (DL9TH), we developed a PVC sheet for blood containers with comparable protective effects on red blood cells and improved cold resistance, compared to the characteristics of DEHP-PVC sheet [ 19 ]. Here, we compared the potential for red blood cell preservation in the DOTH/DINCH- and DOTH/DL9TH-PVC blood containers, and that in the DEHP blood containers.…”