This chapter describes the development of the cyclohexanoate plasticizer Hexamoll® DINCH, a sustainable, second-generation general-purpose plasticizer developed as substitute for phthalates in all those applications where the use of phthalates has come under scrutiny. These applications are predominantly those where plasticised PVC is in close human contact summarized under the term “sensitive applications”. Specific applications need premarket regulatory approvals by the respective competent authorities. The chapter also elaborates on the production process starting from Raffinate II, a C4 fraction from the steam cracker, the dimerization of n -butenes and the subsequent hydroformylation to the resulting strictly C9 isomeric oxo-alcohol (isononyl alcohol). After esterification with isononyl alcohol and phthalic anhydride, the intermediate aromatic phthalate ester is transformed in a closed high pressure production process under strictly controlled and rigorously contained conditions to the final core hydrogenated cycloaliphatic Hexamoll® DINCH. This non-phthalate plasticizer is characterized by a fixed cis−/trans ratio of 90% cis and 10% trans isomer, which exists predominantly in the energetically most stable chair conformation. All applications including consumer goods, toys, food contact and medical devices will be covered. The chapter summarizes the database that is necessary to support the safe use determinations for consumer applications and the benefit–risk assessment mandatory for the medical device applications. In conjunction with academic and industrial partners, analytical methods for human biomonitoring (HBM) have been developed and validated. HBM is the gold standard used worldwide for reliable exposure monitoring of the general public, including sensitive subpopulations such as children. Customers profit from the fact that Hexamoll® DINCH fulfills all the requirements as outlined in the EU Green Deal and the EUs Chemicals Strategy for Sustainability (CSS). An outlook will be provided on current portfolio extensions including certified biomass balance (BMB) and chemcycling (Ccycled™) variants of Hexamoll® DINCH.

Traditionally, the Amphibian Metamorphosis Assay (AMA; OECD TG 231) is performed by exposing Xenopus laevis tadpoles to test substances dissolved in laboratory water. Recently, the use of dietary administration has been proposed to combat poorly soluble test substances in ecotoxicologically-based regulatory endocrine disruption (ED) studies, specifically the AMA warranting an investigation into the efficacy of dietary administration. An efficacy study comprised of two phases: 1) evaluation of the physical influence of the loading process via solvent and 10, 1, and 0.1 mg/l test substance or surrogate (sunflower oil, SFO) on the Sera® Micron Nature (SMN) diet, and 2) performance of a modified AMA in which Nieuwkoop and Faber (NF) stage 51 X. laevis larvae were exposed to dechlorinated tap water using one concentration of the SFO in the diet for 21 days, was performed. In phase 1, the addition of acetone or acetone with bis(2-propylheptyl) phthalate (DPHP) or SFO to SMN with subsequent solvent purge altered the diet reducing the density of the liquified diet and dietary pellet size following centrifugation indicative of alteration of the physical properties of the diet. Treatments used in the modified AMA were acetone alone and 0.1 mg/l SFO dissolved in acetone. These treatments were evaluated against an SMN benchmark using standard AMA endpoints. Both the acetone-treated SMN and 0.1 mg/l SFO-treated diets significantly reduced survival rates, 67 and 70% relative to the SMN benchmark (100%), decreased developmental stage distribution and snout-vent length-normalized hind limb length relative to the SMN benchmark, and slightly increased the prevalence and severity of thyroid follicular cell hypertrophy. Although the acetone-treated diets may have impacted the hypothalamo-pituitary-thyroid axis, clinical signs of gastrointestinal impaction and tail flexure were also observed in the acetone-treated diets, but not the SMN diet alone. Ultimately, test substance exposure via the diet in an AMA study can produce results that may confound data interpretation, which suggests that the traditional aqueous exposure route is generally more appropriate.

The Front Cover illustrates a concept to switch the raw material basis for plasticizer production from fossil to bio-based feedstocks. The bicyclic plasticizers, which were synthesized as target molecules, are accessible from bio-based 2-methylfuran, maleic anhydride and 2-ethylhexanol. Evaluating the performance of this new bio-based plasticizer generation revealed promising plasticizing properties. More information can be found in the Full Paper by R. Otter, A. Liese, H. Gröger et al.

The recent publication “Association between Urinary Metabolites and the Exposure of Intensive Care Newborns to Plasticizers of Medical Devices Used for Their Care Management” by L. Bernard et al. (2021) [...]

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.

As a very durable material, soft polyvinyl chloride (PVC) is used for many applications in the field of consumer products. To enable the desired properties, for example for medical devices, the addition of plasticizers is required. For this purpose, mostly dialkyl phthalates are used being produced on a multi-million tons scale annually. Since some of these are associated with human health effects, there is an increasing demand for the search of alternatives. Besides reduced toxicity while maintaining excellent performance features, an economic access as well as biorenewable starting materials are further criteria, which should be ideally fulfilled by such a new plasticizer generation. Targeting these demands and in contrast to most available substitutes being based on petrochemical feedstock, we developed a synthetic route starting from bio-renewable platform chemicals. In detail, a Diels-Alder reaction of 2-methylfuran and maleic anhydride and subsequent dehydration leads to three phthalate derivatives with different alcohol components bearing a methyl group at the aromatic ring. As a representative substance, di(2-ethylhexyl) 3-methylphthalate was chosen for performance tests, and this new bio-based alternative offers properties similar to known plasticizers in such initial studies.

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Hexamoll (R) DINCH is an important alternative to phthalate plasticizers. Although regulatory reviews have not identified any potential hazards even in sensitive populations, an in vitro study by Campioli et al. (2015) suggested Hexamoll (R) DINCH might alter fat storage in adipocytes resulting in obesity. To evaluate this hypothesis, data from studies with Hexamoll (R) DINCH were reviewed for evidence of deposition in fat, changes in body weight, or changes in serum chemistry reflecting altered metabolic status. Body weights of F1 and F2 pups in a two-generation study did not differ from controls even at 1000 mg Hexamoll (R) DINCH/kg body weight. Mean relative liver weights from the 1000 and 300 mg/kg bw groups were increased, but without histopathologic changes. Triglyceride and cholesterol levels in serum were not affected. In addition, subchronic and chronic studies in rats did not give evidence of an obesogenic effect. Radioactivity from 20 or 1000 mg/kg bw C-14-labelled Hexamoll (R) DINCH dosed orally remained 2-3 times longer in adipose tissue than in well-perfused tissues; however, levels were 20-500% below other tissues at 1 and 8 h post dosing. Radioactivity concentrations in organs and tissues excluding the GI tract declined rapidly and continuously, and decreased in parallel to the concentration in plasma during the following 20 h. Both, initial and terminal half-lives of radioactivity concentration do not indicate a potential for accumulation. Furthermore, a metabolomic comparison of Hexamoll (R) DINCH with DEHP and other phthalates shows complete separation of the metabolomic profile of these two chemical classes, meaning that their effects on the body and the body's reaction to the substance are different. Hence, comprehensive in vivo data do not show any evidence of Hexamoll (R) DINCH altering fat metabolism or having obesogenic properties.

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.

Hexamoll® DINCH® (diisononyl-cyclohexane-1,2-dicarboxylate) is a new high molecular weight plasticizer and a non-aromatic phthalate substitute. In this follow-up study, we further investigated the extensive oxidative metabolism of Hexamoll® DINCH® after oral dosage of 50 mg to three male volunteers (0.552–0.606 mg/kg body weight). Urine samples were consecutively collected over 48 h post-dose. Chemical analysis was carried out by HPLC–MS/MS with labeled internal standards. New metabolites were tentatively identified and quantified via fragmentation analogies and new standard substances. In addition to the five urinary DINCH metabolites previously reported by us, we identified two groups of extensively oxidized metabolites characterized (a) by multiple side chain oxidation and breakdown and (b) by hydroxylation at the cyclohexane ring. The five newly identified carboxylated breakdown metabolites represented in sum 5.12 ± 0.49 % of the applied dose. MCHxCH (cyclohexane-1,2-dicarboxylic acid mono carboxyhexyl ester) was identified as a major metabolite (2.71 ± 0.34 %) and thus represents the second most important specific metabolite of DINCH after OH-MINCH (10.7 ± 2.1 %). Less than 1 % was excreted as ring-hydroxylated metabolites (four metabolites identified). Based upon a new reference standard, we can also update oxo-MINCH to 2.6 % of the applied dose. This follow-up study increases the total amount of the recovered dose from 39.2 to 45.7 % and describes a new major metabolite (MCHxCH) of DINCH that can be used as an additional valuable and specific biomarker to assess DINCH® exposure in future human biomonitoring studies.

Di(2-ethylhexyl) terephthalate (DEHTP) is used as a substitute for di(2-ethylhexyl) phthalate (DEHP), an ortho-phthalate-based plasticizer that is classified and labeled due to its toxicity to reproduction. In this study the metabolism and urinary excretion kinetics of DEHTP were investigated by single oral dosage of 50 mg DEHTP to three male volunteers (resulting in individual dosages between 0.55 and 0.59 mg/kg body weight). Separate urine samples were consecutively collected for 48 h. In analogy to DEHP, we quantified specific side-chain-oxidized monoester metabolites of DEHTP (5OH-MEHTP, 5oxo-MEHTP, 5cx-MEPTP and 2cx-MMHTP) by HPLC–MS/MS with online sample clean-up and isotope dilution. All postulated metabolites were detectable in all samples after dosage. The predominant, specific urinary metabolite was 5cx-MEPTP representing about 13.0 % of the applied dose as mean of the three volunteers (range 7.0–20.4 %) in urine, followed by 5OH-MEHTP (mean: 1.8 %; range 1.3–2.4 %) and 5oxo MEHTP (mean: 1.0 %; range 0.6–1.6 %). 2cx-MMHTP was a minor metabolite representing only 0.3 % (range 0.2–0.4 %). In total, about 16.1 % of the dose was recovered in urine as the above investigated specific metabolites within 48 h with the major share (95 %) being excreted within the first 24 h. Investigation of the glucuronidation patterns revealed that the carboxy-metabolites are excreted almost completely in their free form (>90 %), whereas for 5OH-MEHTP and 5oxo-MEHTP, glucuronidation is preferred (>70 %). With this study we provide reliable urinary excretion factors to calculate DEHTP intakes based on metabolite concentrations in environmental and occupational studies.

The knowledge-based search engine Go3R, www.Go3R.org, has been developed to assist scientists from industry and regulatory authorities in collecting comprehensive toxicological information with a special focus on identifying available alternatives to animal testing. The semantic search paradigm of Go3R makes use of expert knowledge on 3Rs methods and regulatory toxicology, laid down in the ontology, a network of concepts, terms, and synonyms, to recognize the contents of documents. Search results are automatically sorted into a dynamic table of contents presented alongside the list of documents retrieved. This table of contents allows the user to quickly filter the set of documents by topics of interest. Documents containing hazard information are automatically assigned to a user interface following the endpoint-specific IUCLID5 categorization scheme required, e.g. for REACH registration dossiers. For this purpose, complex endpoint-specific search queries were compiled and integrated into the search engine (based upon a gold standard of 310 references that had been assigned manually to the different endpoint categories). Go3R sorts 87% of the references concordantly into the respective IUCLID5 categories. Currently, Go3R searches in the 22 million documents available in the PubMed and TOXNET databases. However, it can be customized to search in other databases including in-house databanks.

Di(2-propylheptyl) phthalate (DPHP), a high molecular weight phthalate, is primarily used as a plasticizer in polyvinyl chloride and vinyl chloride copolymers for technical applications, as a substitute for other phthalates currently being scrutinized because of endocrine disrupting effects. We determined urinary excretion fractions of three specific DPHP metabolites (mono-2-(propyl-6-hydroxy-heptyl)-phthalate (OH-MPHP), mono-2-(propyl-6-oxoheptyl)-phthalate (oxo-MPHP) and mono-2-(propyl-6-carboxy-hexyl)-phthalate (cx-MPHxP)) after oral dosing of five volunteers with 50mg labelled DPHP-d4 and subsequent urine sampling for 48 h. These excretion fractions are used to back calculate external intakes from metabolite measurements in spot urine analysis. Following enzymatic hydrolysis to cleave possible conjugates, we determined these urinary metabolites by HPLC-NESI-MS/MS with limits of quantification (LOQ) between 0.3 and 0.5 μg/l. Maximum urinary concentrations were reached within 3-4h post dose for all three metabolites; elimination half-lives were between 6 and 8h. We identified oxo-MPHP as the major oxidized metabolite in urine representing 13.5±4.0% of the DPHP dose as the mean of the five volunteers within 48 h post dose. 10.7±3.6% of the dose was excreted as OH-DPHP and only 0.48±0.13% as cx-MPHxP. Thus, within 48 h, 24.7±7.6% of the DPHP dose was excreted as these three specific oxidized DPHP metabolites, with the bulk excreted within 24h post dose (22.9±7.3%). These secondary, oxidized metabolites are suitable and specific biomarkers to determine DPHP exposure. In population studies, however, chromatographic separation of these metabolites from other isomeric di-isodecyl phthalate (DIDP) metabolites is warranted (preferably by GC-MS) in order to distinguish DPHP from general DIDP exposure. Palatinol(®), Hexamoll(®) and DINCH(®) are registered trademarks of BASF SE, Germany.

Extracts of St. John's Wort (Hypericum perforatum) are known to cause interactions with certain conventional drugs. Herein, we focus on two clinically relevant concepts. First, St. John's Wort has been used by people of all ages as an herbal treatment for depression without medical prescription. Second, diazepam- like substances called endogenous benzodiazepines are found in cases of acute liver failure without previous exposure to diazepam. Currently diazepam has over 500 brands name and well marketed throughout the world and became one most frequently prescribed medication in different form (oral, injectable, inhalation and rectal forms) for four decades. Based on this concept, we investigated diazepam biotransformation by incubation of a widely accepted in vitro organotypical culture model with Hypericum methanolic extract, powdered drug, infusion, oil, and with the pure Hypericum compounds hyperforin and hypericin. The amounts of the preparations and compounds were chosen according to the recommended daily medication doses. We measured the activities of ethoxyresorufin-O-deethylase (EROD), ethoxy coumarin O-deethylase (ECOD) and the potential induction of diazepam metabolites (desmethyldiazepam, temazepam and oxazepam) during biotransformation. None of the preparations or substances induced EROD or ECOD. However, different preparations did induce the formation of desmethyldiazepam and temazepam. The strongest activity was caused by the extract, followed by the powdered drug and hyperforin. All preparations and compounds increased the formation of the diazepam metabolite oxazepam, but only the extract, the drug powder and the pure compounds had marked effects. Therefore, we report here the potential interference of St. John's Wort with all three metabolites of diazepam in an organotypical sandwich model that can be utilized to study potential interaction of metabolites of many drugs with herbal ingredients in preclinical stage of drug discovery process.

Injection drug use has been identified as a key source of morbidity and mortality, primarily from overdose and the transmission of blood-borne diseases such as HIV. Experts have therefore called for the prioritization of resources toward the prevention of injection drug use. However, these strategies have not been systematically assessed.PRISMA guidelines were used to systematically review and extract findings from the peer-reviewed literature evaluating the effectiveness of interventions to prevent injecting initiation. We searched 10 English language electronic databases (PubMed, PsycINFO, EMBASE, Cochrane CENTRAL, CINAHL, Web of Science, TOXNET, AIDSLINE, AMED and ERIC), the Internet (Google, Google Scholar), and article reference lists, from database inception to June 1st, 2012.Overall, out of 384 studies identified in the initial search, eight met the inclusion criteria. Studies evaluated four different types of interventions: social marketing, peer-based behavior modification, treatment, and drug law enforcement. Four studies observed a significant effect of the intervention on reducing rates of injecting initiation. Peer-based behavior modification and addiction treatment interventions were found to be most effective. Two of three studies assessing the impact of drug law enforcement on patterns of injecting initiation found no impact on injecting initiation, while one study reported inconclusive results.There exists a limited scientific literature on strategies to prevent injecting initiation. Resources should be allocated toward increased research and development of effective interventions to prevent this phenomenon.

Interspecies difference is an important issue in toxicology research. We compared the potential in vitro metabolism of human, porcine and rat hepatocytes over 2 weeks in culture in an organotypical culture model which reflects the in vivo situation. All three species show similar LDH-rates. Albumin measurements showed that rat cells are about twice as active as human and porcine hepatocytes. The ethoxyresorufin-O-deethylase (EROD) activity of the rat hepatocytes is with about 14 microU/10(6)cells distinctly higher than those of porcine and human cells (1.8 and 0.5 microU/10(6)cells respectively), furthermore, the activity of the rat EROD increases slightly during the prolonged time in culture, whereas those of porcine and human enzymes slightly decrease. Concerning ethoxycoumarin-O-deethylase (ECOD), the enzyme activities are found to be in three different ranges where rat cells show the highest activity with 66 microU/10(6)cells, porcine hepatocytes exhibit an activity of about 23 microU/10(6)cells, and human activity is lowest with 0.7 microU/10(6)cells. All three species show a similar decreasing trend of ECOD during the period of study. Regarding the biotransformation of testosterone, human and porcine liver cells form three major metabolites whereas rat cells form a mixture of all measured metabolites. Hence, in vitro metabolism using porcine hepatocytes would be much more scientific sense than one using rat hepatocytes since the metabolic pathways are much closer to human metabolism.

The differentiated hepatocyte phenotype remains difficult to maintain in culture. The duration over which phenotypically stable hepatocytes can be cultured ranges from a couple of days to a few weeks. Shortcomings in medium formulation may be a factor in this lack of success. We have investigated effects of medium formulation on primary porcine and human hepatocyte cultures. We tested seven culture medium compositions (DMEM, ExCell 400, HepatoZYME-SFM, L-15 Leibovitz, SF-3, Waymouth, and Williams' E) and the effects of serum, fibronectin and biomatrix in a sandwich culture configuration. Albumin, urea, cholesterol, GOT, GPT, LDH and triglyceride concentrations were measured over 14 days. For both human and porcine cultures, the best results were obtained with SF-3 medium. Cells cultivated with Williams' E medium and FCS had good morphology and synthetic function during the first days of culture. However, continued addition of serum, was associated with a subsequent loss of differentiated phenotype. Addition of fibronectin was associated with improved function in cultures maintained in SF-3 medium whilst biomatrix had no effect. In contrast, addition of fibronectin did not influence cultures maintained in Williams' E medium, but cultures with biomatrix were associated with improved function at longer time points.