Alternative plasticizers to di(2-ethylhexyl) phthalate (DEHP) for blood bags have been sought for many years. Cyclohexane-1,2-dicarboxylic acid, diisononylester (Hexamoll(®) DINCH(®)) is an alternative that has been evaluated in preliminary studies for compatibility and efficacy to preserve whole blood. While Hexamoll(®) DINCH(®) has an extensive database for mammalian toxicity via oral administration, data were needed to evaluate toxicity from intravenous (IV) administration to support the use of the plasticizer Hexamoll(®) DINCH(®) in blood bags. A series of studies was performed by slow IV injection or IV infusion of Hexamoll(®) DINCH(®), a highly viscous, hydrophobic substance, suspended in Intralipid(®) 20% (20% intravenous fat emulsion). Rats were injected once, followed by 14 days of recovery; injected daily for 5 days followed by 5 days of recovery, or infused for 29 days (4h/day) followed by 14 days of recovery. Dose levels were 0, 62, 125, and 250-300mg/kg body weight/day. These dose levels represent the limits of suspension and far exceed any anticipated exposures from migration out of plasticized blood bags. Animals were observed for signs of toxicity; body weight and feed consumption were measured; blood collected for clinical chemistry and hematology; and tissues collected and processed for histopathology. Special emphasis was placed on evaluating endpoints and tissues that are commonly associated with plasticizer exposure in rodents. Urine was collected during the 4-week study to quantify urinary metabolites of Hexamoll(®) DINCH(®). The results of the studies indicate that no substance-related toxicity occurred: no effects on behavior, no effects on organ weight, no effect on serum chemistry including thyroid hormones; and no effect on major organs, especially no testicular toxicity and no indication for peroxisome proliferation in the liver. The only effects seen were petechia and granulomas related to dissipation of suspended Hexamoll(®) DINCH(®) in the aqueous environment of the blood. However, the results of metabolite analyses demonstrate that Hexamoll(®) DINCH(®) was bioavailable. Therefore, based on the lack of Hexamoll(®) DINCH(®)-related systemic toxicity with the exception of the physical limitations, the no-observed-adverse-effect level for parenterally administered Hexamoll(®) DINCH(®) is considered to be 300mg/kg bw/day.

Di-(2-propylheptyl) phthalate (DPHP) is used as a plasticizer for polyvinyl chloride products. A tolerable daily intake of DPHP of 0.2 mg/kg body weight has been derived from rat data. Because toxicokinetic data of DPHP in humans were not available, it was the aim of the present work to monitor DPHP and selected metabolites in blood and urine of 6 male volunteers over time following ingestion of a single DPHP dose (0.7 mg/kg body weight). Concentration-time courses in blood were obtained up to 24 h for DPHP, mono-(2-propylheptyl) phthalate (MPHP), mono-(2-propyl-6-hydroxyheptyl) phthalate (OH-MPHP), and mono-(2-propyl-6-oxoheptyl) phthalate (oxo-MPHP); amounts excreted in urine were determined up to 46 h for MPHP, OH-MPHP, oxo-MPHP, and mono-(2-propyl-6-carboxyhexyl) phthalate (cx-MPHP). All curves were characterized by an invasion and an elimination phase the kinetic parameters of which were determined together with the areas under the concentration-time curves in blood (AUCs). AUCs were: DPHP > MPHP > oxo-MPHP > OH-MPHP. The amounts excreted in urine were: oxo-MPHP > OH-MPHP> > cx-MPHP > MPHP. The AUCs of MPHP, oxo-MPHP, or OH-MPHP could be estimated well from the cumulative amounts of urinary OH-MPHP or oxo-MPHP excreted within 22 h after DPHP intake. Not considering possible differences in species-sensitivity towards unconjugated DPHP metabolites, it was concluded from a comparison of their AUCs in DPHP-exposed humans with corresponding earlier data in rats that there is no increased risk of adverse effects associated with the internal exposure of unconjugated DPHP metabolites in humans as compared to rats when receiving the same dose of DPHP per kg body weight.

The search for more sustainable solutions for plastics production, moving away from petrochemical feedstocks as today's major raw material basis, is a research area of increasing interest. This task goes far beyond the issue of designing greener polymers and their related monomers as tailor‐made plastics require, besides the polymer itself, further components. These additives also need to be switched from typically fossil‐based to bio‐renewable raw materials. One of such necessary components for many applications are plasticizers, and a major application of them is related to polyvinyl chloride (PVC) as one of the leading polymers with a wide range of applications. Typically today‘s plasticizers are based on fossil feedstocks, and some of them such as specific ortho‐phthalates as the most important product class of plasticizers are now subject to restrictions and authorization by the EU's REACH legislation due to their toxicological profile. In this contribution, we report the synthesis and technical evaluation of alternative, novel bicyclic plasticizer candidates, which are fully accessible from renewable feedstocks. In detail, these new plasticizer target molecules are based on the use of the furan‐derivative 2‐methylfuran, maleic anhydride and 2‐ethylhexanol as bio‐based starting materials. The synthetic concept consists of an initial Diels‐Alder reaction with 2‐methylfuran and a subsequent hydrogenation and optional esterification step. The applied reactions are well‐known as economic and sustainable technologies. Thus, not only the starting materials (being of bio‐based origin) but also the selected reaction technologies for the syntheses of the target molecules are sustainable. Furthermore, a range of performance tests enabled an insight into structure‐performance relationships and revealed promising plasticizing properties of this new bio‐based plasticizer generation with, e. g., an attractive solution temperature fulfilling the criterium for a “fast fuser” as well as good compatibility with PVC.

This study investigates possible effects of in utero exposure of rats to a low dose (125 mg/kg bw/day) and a high dose (750 mg/kg bw/day) of Diisononyl phthalate (DINP) during the masculinisation programming window (MPW) which is embryonic days 15.5-18.5 (e15.5 - e18.5). Dibutyl phthalate (DBP) was used at a high dose level (750 mg/kg bw/day) as an established positive control substance for anti-androgenic effects on the developing male reproductive tract. We focussed on the MPW and measured a multitude of biological endpoints at various life stages and applied state of the art histopathology staining techniques to refine the characterization of potential changes to the testis, beyond what is currently available with DINP. If DINP can mediate testicular dysgenesis (TDS) disorders, this exposure window would be sufficient to induce androgen impacts and alter male reproductive tract development as shown earlier in this validated experimental model with DBP. Overall, the results of this systematic comparison provide convincing evidence on the differences between the effects occurring with DBP and DINP. In contrast to what was seen with DBP, DINP did not cause cryptorchidism or hypospadias, had no effect on anogenital distance/anogenital index (AGD/AGi) and Leydig cell aggregates on e17.5 and e21.5 did not increase. With DINP no reduction of intratesticular testosterone, no effects on sperm motility and sperm count and no effect on adult testosterone or luteinizing hormone (LH) levels were seen. Our results demonstrate that DINP does not cause the adverse reproductive effects known to occur with DBP, a well-established endocrine disruptor.