The oral bioavailability of di-2-ethylhexyl phthalate (DEHP), di-isononyl phthalate (DiNP) and di-(isononyl)-cyclohexane-1,2-dicarboxylate (DINCH®) in house dust.

Phthalates and other plasticizers are detected in high amounts in the indoor environment and therefore house dust can be an exposure source. Especially children have a relatively high unintended uptake of house dust, thus a higher exposure to plasticizers compared to adults may be possible. As accurate as possible exposure assessment data of the oral bioavailability of these compounds are necessary, however only one in vivo study with piglets is available so far. The aim of this study was to examine the oral bioavailability of phthalates and DINCH® in humans, which occur in typical house dust samples. We focused on the high molecular weight phthalates DEHP and DINP and their substitute DINCH®. Eleven volunteers ingested 6 g of house dust sieved to 2 mm. The urine was collected over a period of 36 h. The excreted plasticizers metabolites were quantified by an LC-MS/MS method. The mean recovery of urine metabolites was 51 % ± 20 % for DEHP, 26 % ± 13 % for DINP and 19 % ± 6% for DINCH® based on the parent compounds administered as dust samples. The metabolites of DEHP, DINP and DINCH® reached their maximum concentration after 2-19 hours post dose in urine. The bioavailability of DEHP was in agreement among the different dust samples. For DEHP, we were able to confirm previous findings from the oral bioavailability study with piglets and we could not observe a significant difference between the dust particle size (65 µm vs 2 mm) and the bioavailability. Considering the observed bioavailability, an estimated dust intake of 50 mg/d for toddlers can substantially contribute to the total plasticizer exposure.

Skin transferability of phthalic acid ester plasticizers and other plasticizers using model polyvinyl chloride sheets.

The transferability of phthalic acid esters (PAEs) and other plasticizers, from model polyvinyl chloride (PVC) sheets to the skin of 11 subjects was assessed by measuring the amount of substance transferred using PVC sheets containing PAEs and alternative plasticizers of different types and contents. For all subjects, the transferred amount, from sheets containing 28 wt% PAE or from mixed sheets containing 14 wt% each of di (2-ethylhexyl) phthalate (DEHP) and other PAE, was greater than that from sheets containing 15 wt% each of PAE or alternative plasticizer only. A comparison of the transferability of five types of PAE showed that transfer tended to occur more readily as the n-octanol-water partition coefficient increased, suggesting that PAE hydrophobicity affected its transferability. The transferability of the alternative plasticizers di(2-ethylhexyl) terephthalate and 1,2-cyclohexane dicarboxylic acid diisononyl ester showed a similar trend; however, the transferred amount tended to be higher from model PVC sheets containing 28 wt% PAE or mixed with DEHP. The transferability of PAEs and alternative plasticizers was higher for certain subjects, suggesting individual differences in the transferability of chemicals to the subject's skin surface and is the presence of a group of people comparatively more susceptible to such transfer.

Development of a physiologically based pharmacokinetic model of diisononyl phthalate (DiNP) in pregnant rat and human.

A physiologically based pharmacokinetic (PBPK) model for di-isononyl phthalate (DiNP) was developed by adapting the existing models for di(2-ethylhexyl) phthalate (DEHP) and di-butylphthalate (DBP). Both pregnant rat and human time-course plasma and urine data were used to address the hydrolysis of DiNP in intestinal tract, plasma, and liver as well as hepatic oxidative metabolism and conjugation of the monoester and primary oxidative metabolites. Data in both rats and humans were available to inform the uptake and disposition of mono-isononyl phthalate (MiNP) as well as the three primary oxidative metabolites including hydroxy (7-OH)-, oxo (7-OXO)-, and carboxy (7-COX)-monoisononyl phthalate in plasma and urine. The DiNP model was reliable over a wide range of exposure levels in the pregnant rat as well as the two low exposure levels in humans including capturing the nonlinear behavior in the pregnant rat after repeated 750 mg/kg/day dosing. The presented DiNP PBPK model in pregnant rat and human, based upon an extensive kinetic dataset in both species, may provide a basis for assessing human equivalent exposures based upon either rodent or in vitro points of departure.

Metabolism and urinary excretion kinetics of di(2-ethylhexyl) adipate (DEHA) in four human volunteers after a single oral dose.

Di(2-ethylhexyl) adipate (DEHA) is used as a substitute for the reprotoxic phthalate plasticizer di(2-ethylhexyl) phthalate (DEHP). This study reports the first quantitative data on human in vivo DEHA metabolism and urinary metabolite excretion with the aim of providing tools for DEHA exposure and risk assessments. After DEHA was administered to four healthy volunteers (107-164 µg/kg body weight (bw)), urine samples were continuously and completely collected for 48 h and analyzed for the specific oxidized monoester metabolites mono-2-ethyl-5-hydroxyhexyl adipate (5OH-MEHA), mono-2-ethyl-5-oxohexyl adipate (5oxo-MEHA), and mono-5-carboxy-2-ethylpentyl adipate (5cx-MEPA), as well as for the non-specific hydrolysis product adipic acid (AA) using stable isotope dilution analysis. AA was confirmed as a major (urinary excretion fraction (FUE): 10-40%), yet non-specific DEHA metabolite. 5cx-MEPA was the major specific DEHA metabolite with an FUE of 0.20% (range: 0.17-0.24%). FUEs for 5OH-MEHA and 5oxo-MEHA were 0.07% (0.03-0.10%) and 0.05% (0.01-0.06%), respectively. The three specific metabolites were excreted with two concentration maxima (tmax1 = 1.5-2.3 h, tmax2 = 3.8-6.4 h). Elimination half-lives (t1/2, calculated after the second tmax) for 5cx-MEPA were calculated between 2.1-3.8 h. The majority (98-100%) of metabolites was excreted within 24 h. The FUE of 5cx-MEPA was applied to demonstrate its applicability for calculating daily intakes based on urinary metabolite levels from three pilot populations. Daily intakes were generally far below the tolerable daily intake (TDI) for DEHA (300 µg/kg bw/day). The highest daily intake (114 µg/kg bw/day) was calculated in individuals after consuming food that had been wrapped in DEHA containing cling film.

Disposition and metabolism of N-butylbenzenesulfonamide in Sprague Dawley rats and B6C3F1/N mice and in vitro in hepatocytes from rats, mice, and humans.

N-Butylbenzenesulfonamide (NBBS) is a plasticizer detected in the environment suggesting potential human exposure. These studies investigated the in vitro hepatic clearance and disposition of [14C]NBBS in rodents following a single gavage (2, 20 or 200 mg/kg) or intravenous (IV) administration (20 mg/kg). NBBS was cleared slower in hepatocytes from humans compared to rodents. [14C]NBBS was well-absorbed in male rats following gavage administration and excreted extensively in urine (70-76 %) and feces (11-15 %) 72 h following administration. Following a 20 mg/kg gavage dose in male rats, 25 % of the dose was excreted in bile by 24 h suggesting that observed fecal excretion was due to biliary excretion. The radioactivity was distributed to tissues with 14 % and 8 % of the administered dose remaining in tissues at 24 and 72 h, respectively. There was no apparent dose-dependent effect in disposition in male rats. Disposition patterns were similar in female rats (urine, 83 %; feces, 14 %) and male (urine, 69 %; feces, 11 %) and female (urine, 72 %; feces, 9 %) mice following gavage administration of 20 mg/kg. The disposition following IV administration was similar to that of gavage. Urinary radiochemical profiles were similar between doses, routes, species, and sexes. Among numerous metabolites identified, oxidative metabolites of NBBS predominated.

Bioavailability of phthalate and DINCH® plasticizers, after oral administration of dust to piglets.

For decades, phthalates have been widely used as plasticizers in a large number of consumer products, leading to a complex exposure to humans via ingestion, inhalation or dermal uptake. Children may have a higher unintended dust intake per day compared to adults. Therefore, dust intake of children could pose a relevant exposure and subsequently a potential health risk. The aim of this study was to determine the relative bioavailability of certain phthalates, such as di(2-ethylhexyl) phthalate (DEHP), di-isononyl phthalate (DINP) and the non-phthalate plasticizer diisononyl 1,2-cyclohexanedicarboxylic acid (DINCH®, Hexamoll®), after ingestion of dust. Seven 5-week-old male piglets were fed five different dust samples collected from daycare centers. Overall, 0.43 g to 0.83 g of dust sieved to 63 µm were administered orally. The piglets' urine was collected over a period of 38 h. The excreted metabolites were quantified using an LC-MS/MS method. The mean uptake rates of the applied doses for DEHP, DINP, and DINCH® were 43% ± 11%, 47% ± 26%, and 9% ± 3.5%, respectively. The metabolites of DEHP and DINP showed maximum concentrations in urine after three to five hours, whereas the metabolites of DINCH®, reached maximum concentrations 24 h post-dose. The oral bioavailability of the investigated plasticizers was higher compared to the bioaccessibility reported from in vitro digestion tests. Furthermore, the bioavailability of DEHP did not vary substantially between the dust samples, whereas a dose-dependent saturation process for DINP was observed. In addition to other intake pathways, dust could be a source of plasticizers in children using the recent intake rates for dust ingestion.

A review of phthalate pharmacokinetics in human and rat: what factors drive phthalate distribution and partitioning?

Phthalates are a class of compounds that have been extensively used as plasticizers in different applications. Several phthalates have been recognized as substances of very high concern (SVHCs) in the EU, because of their toxicity for reproduction. However, high amounts of other phthalates are still produced and imported in the European Economic Area. In China and the US, recent studies show increasing concentrations of several phthalates in the air and in human urine, respectively. The understanding of phthalate absorption, distribution, metabolism, and elimination ('pharmacokinetics') in the organism is still limited. Specifically, phthalate partitioning among tissues is insufficiently understood. Here, we estimate partition coefficient (PC) values for different phthalates by using five algorithms and compare them to experimental (in-vivo and in-vitro) PC values. In addition, we review all pharmacokinetic steps for phthalates in human and rat, based on data from 133 peer-reviewed publications. We analyze the factors that determine phthalate partitioning and pharmacokinetics. Four processes are particularly relevant to phthalate distribution: protein binding, ionization, passive partitioning, and metabolism in different tissues. The interplay of these processes needs to be better represented in methods for determining the PC values of phthalates. The hydrophobicity of phthalates affects all pharmacokinetic steps. The exposure route has an influence on specific steps of phthalate pharmacokinetics but generally does not affect the pattern of metabolites in urine. The age of the organism has an influence on phthalate metabolism. More studies on the protein-bound fraction of phthalates in plasma and pharmacokinetic studies following inhalation and dermal exposure are desirable.

[Experimental Study on Migration Parameters of DEHP in PVC Infusion].

The work explored the DEHP migration parameters in PVC infusion in clinic,based on the previous research on the test model of DEHP migrated from PVC infusion,to assess the safety of PVC infusion.The leaching solution samples in different conditions were evaluated by analysis of the DEHP in leaching solution using GC-MS under simulated clinical transfusion way.The release behavior of DEHP was significantly affected by the storage time,storage temperature,surrounding temperature,dripping speed,sterilization process,volume of the leaching solution,and the property of the leaching solution.

Effect of plasticizers on manufacturing ritonavir/copovidone solid dispersions via hot-melt extrusion: Preformulation, physicochemical characterization, and pharmacokinetics in rats.

In this study, novel ritonavir solid dispersion (RTV SD) formulations were prepared with copovidone (PVPVA 64) and optimized plasticizers via hot-melt extrusion (HME) at different extrusion temperature to evaluate the effect of plasticizers on the process of HME. The optimized drug-loading content of RTV SD formulations was around 15% and RTV was converted to the amorphous state and integrated through physical interactions (possibly hydrogen bonding) with the polymeric carrier. Using Span 20 or HSPC as plasticizer, the HME extrusion temperature of RTV SD formulations suggested a decrease of 10 °C or 20 °C. Furthermore, the in vitro release and the in vivo pharmacokinetics analyses both showed that RTV SD formulations using Span 20 or HSPC as plasticizer possessed better release profiles and bioavailability over RTV bulk powder but showed equal physicochemical characteristics compared to RTV SD formulations without plasticizer. According to the increased drug solubility, enhanced dissolution profiles, superior bioavailability, but decreased extrusion temperature in HME process, the RTV SD formulation using HSPC as plasticizer could be potentially applied in the clinic as an efficient drug delivery system, and HSPC is recommended as an efficient plasticizer for manufacturing RTV SD formulations via HME.

Human metabolism and kinetics of tri-(2-ethylhexyl) trimellitate (TEHTM) after oral administration.

Tri-(2-ethylhexyl) trimellitate (TEHTM) is a plasticizer for PVC material and is used for medical devices as an alternative to di-(2-ethylhexyl) phthalate. As plasticizers are known to migrate easily into contact liquids, exposure of patients to TEHTM is highly probable. In the present study, human metabolism pathways of TEHTM and its elimination kinetics were investigated. For that purpose, four healthy volunteers were orally exposed to a single dose of TEHTM. TEHTM and its postulated primary metabolites were investigated in blood samples (up to 48 h after exposure), and in urine samples (collected until 72 h after exposure) using liquid chromatography tandem mass spectrometry (LC-MS/MS). TEHTM was found to be regioselectively hydrolyzed to its diesters di-2-(ethylhexyl) trimellitates (1,2-DEHTM, 2,4-DEHTM) with maximum blood concentrations at 3-h post-exposure, and to its monoester isomers mono-2-(ethylhexyl) trimellitates (1-MEHTM, 2-MEHTM) with peak blood concentrations 5-h post-exposure. For the elimination of investigated urinary metabolites, biphasic elimination kinetics was observed. The most dominant urinary biomarker was found to be 2-MEHTM (2-mono-(2-ethylhexyl) trimellitate), followed by several specific secondary metabolites. All in all, approximately 5.8% of the orally administered dose was recovered in urine over a period of 72 h, indicating a comparatively low resorption rate of TEHTM in humans in combination with an apparently rather slow metabolism and excretion rate. In fact, TEHTM and selected metabolites were still detectable in blood and urine 48-h and 72-h post-exposure, respectively. This study is the first to elucidate TEHTM metabolism pathways in humans and to identify metabolites of TEHTM in blood and urine by usage of especially designed human biomonitoring methods. Powerful tools for exposure monitoring and risk assessment of TEHTM are therewith available for future research.

Development of a human physiologically based pharmacokinetic (PBPK) model for phthalate (DEHP) and its metabolites: A bottom up modeling approach.

DEHP exposure to human comes from different sources such as food, diet, cosmetics, toys, medical products, and food wraps. Recently, DEHP was categorized as non-persistent endocrine disrupting compounds (EDCs) by the world health organization (WHO). Rat experimental studies showed that phthalate and its metabolite(s) can cause hepatic, developmental and reproductive toxicity. In human, DEHP rapidly metabolizes into a toxic metabolite MEHP. This MEHP further metabolizes into the different chemical forms of 5OH-MEHP, 5oxo-MEHP, 5cx-MEPP and phthalic acid. A simple DEHP pharmacokinetics model has been developed, but with a limited number of metabolites. A chemical like DEHP which extensively metabolised indicate the need of a detail metabolic kinetics study. A physiological based pharmacokinetics (PBPK) model of the DEHP considering all the major metabolites in human, has not been developed yet. The objective of this study is to develop a detailed human PBPK model for the DEHP and its major metabolites by using a bottom-up modelling approach with the integration of a in vitro metabolic data. This approach uses an in-vitro-in-vivo extrapolation (IVIVE) and a quantitative structure-activity relationship (QSAR) method for the parameterization of the model. Monte Carlo simulations were performed to estimate the impact of parametric uncertainty onto the model predictions. First, the model was calibrated using the control human kinetic study that represents the time course of DEHP metabolites concentration in both the blood and the urine. Then, the model was evaluated against the published independent data on different dosing scenarios. The results of model predictions for the DEHP metabolites in both the blood and the urine were well within the range of experimentally observed data. The model also captured the similar trend of time course profile to the observed data, shows model good predictability power. The current developed PBPK model can futher be used for the prediction of the time course of chemical concentrations for the different exposure scenarios not only in the blood and the urine but also in the other compartments. Moreover, this model can also be used to explore different biomonitoring studies for the human health risk assessment and might be useful for integrative toxicological study in improving exposure-target tissue dose-response relationship.

Fate of four phthalate plasticizers under various wastewater treatment processes.

The fate of four phthalate plasticizers during wastewater treatment processes at six different wastewater treatment plants (WWTPs) was investigated. Concentrations of benzyl butyl phthalate (BBP), di(2-ethylhexyl) phthalate (DEHP), diisononyl phthalate (DiNP), and diisodecyl phthalate (DiDP) were determined prior to either aerobic or anaerobic (conventional and advanced) treatment, after treatment, and in final, dewatered solids. Despite their elevated use worldwide, the fate of DiNP and DiDP during wastewater treatment have not been well characterized. DEHP was readily degraded during aerobic treatments while anaerobic digestion resulted in either no significant change in concentrations or an increase in concentration, in the case of more advanced anaerobic processes (thermal hydrolysis pretreatment and a two-phase acid/gas process). Impacts of the various treatment systems on DiNP, DiDP, and BBP concentrations were more varied - anaerobic digestion led to significant decreases, increases, or no significant change for these compounds, depending on the treatment facility, while aerobic treatment was generally effective at degrading the compounds. Additionally, thermal hydrolysis pretreatment of sludge prior to anaerobic digestion resulted in increases in DiNP, DiDP, and BBP concentrations. The predicted environmental concentrations for all four compounds in soils after a single biosolids application were calculated and the risk quotients for DEHP in soils were determined. The estimated toxicity risk for DEHP in soils treated with a single application of sludge from any of the six studied WWTPs is lower than the level of concern for acute and chronic risk, as defined by the US EPA.

Hexamoll® DINCH: Lack of in vivo evidence for obesogenic properties.

Hexamoll® 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® DINCH might alter fat storage in adipocytes resulting in obesity. To evaluate this hypothesis, data from studies with Hexamoll® 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® 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 14C-labelled Hexamoll® 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® 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® DINCH altering fat metabolism or having obesogenic properties.

Chemical stabilization of polymers: Implications for dermal exposure to additives.

Technical benefits of additives in polymers stand in marked contrast to their associated health risks. Here, a multi-analyte method based on gas chromatography coupled to tandem mass spectrometry (GC-MS/MS) was developed to quantify polymer additives in complex matrices such as low-density polyethylene (LDPE) and isolated human skin layers after dermal exposure ex vivo. That way both technical aspects and dermal exposure were investigated. The effects of polymer additivation on the material were studied using the example of LDPE. To this end, a tailor-made polymer was applied in aging studies that had been furnished with two different mixtures of phenol- and diarylamine-based antioxidants, plasticizers and processing aids. Upon accelerated thermo-oxidative aging of the material, the formation of LDPE degradation products was monitored with attenuated total reflectance-Fourier transformed infrared (ATR-FTIR) spectroscopy. Compared to pure LDPE, a protective effect of added antioxidants could be observed on the integrity of the polymer. Further, thermo-oxidative degradation of the additives and its kinetics were investigated using LDPE or squalane as matrix. The half-lives of additives in both matrices revealed significant differences between the tested additives as well as between LDPE and squalane. For instance, 2-tert-butyl-6-[(3-tert-butyl-2-hydroxy-5-methylphenyl)methyl]-4-methylphenol (Antioxidant 2246) showed a half-life 12 times lower when incorporated in LDPE as compared to squalane. As a model for dermal exposure of consumers, human skin was brought into contact with the tailor-made LDPE containing additives ex vivo in static Franz diffusion cells. The skin was then analyzed for additives and decomposition products. This study proved 10 polymer additives of diverse pysicochemical properties and functionalities to migrate out of the polymer and eventually overcome the intact human skin barrier during contact. Moreover, their individual distribution within distinct skin layers was demonstrated. This is exemplified by the penetration of the procarcinogenic antioxidant N-phenylnaphthalen-2-amine (Neozon D) into the viable epidermis and the permeation through the skin of the neurotoxic plasticizer N-butylbenzenesulfonamide (NBBS). In addition, the analyses of additive degradation products in the isolated skin layers revealed the presence of 2-tert-butyl-4-methylphenol in all layers after contact to a polymer with substances of origin like Antioxidant 2246. Thus, attention needs to be paid to absorption of polymer additives together with their degradation products when it comes to dermal exposure assessment.

Multi-pathway human exposure assessment of phthalate esters and DINCH.

Phthalate esters are substances mainly used as plasticizers in various applications. Some have been restricted and phased out due to their adverse health effects and ubiquitous presence, leading to the introduction of alternative plasticizers, such as DINCH. Using a comprehensive dataset from a Norwegian study population, human exposure to DMP, DEP, DnBP, DiBP, BBzP, DEHP, DINP, DIDP, DPHP and DINCH was assessed by measuring their presence in external exposure media, allowing an estimation of the total intake, as well as the relative importance of different uptake pathways. Intake via different uptake routes, in particular inhalation, dermal absorption, and oral uptake was estimated and total intake based on all uptake pathways was compared to the calculated intake from biomonitoring data. Hand wipe results were used to determine dermal uptake and compared to other exposure sources such as air, dust and personal care products. Results showed that the calculated total intakes were similar, but slightly higher than those based on biomonitoring methods by 1.1 to 3 times (median), indicating a good understanding of important uptake pathways. The relative importance of different uptake pathways was comparable to other studies, where inhalation was important for lower molecular weight phthalates, and negligible for the higher molecular weight phthalates and DINCH. Dietary intake was the predominant exposure route for all analyzed substances. Dermal uptake based on hand wipes was much lower (median up to 2000 times) than the total dermal uptake via air, dust and personal care products. Still, dermal uptake is not a well-studied exposure pathway and several research gaps (e.g. absorption fractions) remain. Based on calculated intakes, the exposure for the Norwegian participants to the phthalates and DINCH was lower than health based limit values. Nevertheless, exposure to alternative plasticizers, such as DPHP and DINCH, is expected to increase in the future and continuous monitoring is required.

De-novo identification of specific exposure biomarkers of the alternative plasticizer di(2-ethylhexyl) terephthalate (DEHTP) after low oral dosage to male volunteers by HPLC-Q-Orbitrap-MS.

CONTEXT: Human exposure biomonitoring relies on the availability of specific, sensitive biomarkers. For emerging chemicals, the identification (prediction, synthesis, verification) of such biomarkers is time and cost intensive. OBJECTIVE: This study aimed to further elucidate the urinary metabolic profile of the plasticizer di(2-ethylhexyl) terephthalate (DEHTP) in search of probably additional biomarkers of exposure. MATERIALS AND METHODS: Urine samples of an oral low-dose volunteer study were analysed by HPLC-Q-Orbitrap-MS combined with a commercial data mining software. Metabolite identification was based on isotopic pattern, accurate masses of product ions and excretion profiles. RESULTS: Nine phase I metabolites of DEHTP were tentatively identified by HPLC-Q-Orbitrap-MS. Four previously described, side chain oxidized monoester metabolites were confirmed in all samples. In addition, five previously unknown downstream metabolites were tentatively identified. DISCUSSION AND CONCLUSION: The excretion profiles obtained by HPLC-Q-Orbitrap-MS were in good agreement with quantitative HPLC-QqQ-MS data. For the newly discovered metabolites, plausible excretion profiles, similar to the ones of the known metabolites, were obtained. The presented approach proved to be successful for metabolite screening in urine samples after low-dose exposure and will be applied in future human metabolism studies for a fast, reliable and cost effective identification of specific biomarkers of exposure.

Safety evaluation of dermal exposure to phthalates: Metabolism-dependent percutaneous absorption.

Phthalates, known as reproductive toxicants and endocrine disruptors, are widely used as plasticizers in polyvinyl chloride products. The present study was conducted for risk identification of dermal exposure to phthalates. When dibutyl phthalate was applied to the skin of hairless rats and humans, only monobutyl phthalate appeared through the skin, and the permeability of the skin was higher than that after the application of the monoester directly. The inhibition of skin esterases made the skin impermeable to the metabolite following dermal exposure to dibutyl ester, whereas removal of the stratum corneum from the skin did not change the skin permeation behavior. Similar phenomena were observed for benzyl butyl phthalate. The skin permeability of monobenzyl phthalate was higher than that of monobutyl phthalate in humans, although the reverse was observed in rats. Species difference in skin permeation profile corresponded to the esterase activity of the skin homogenate. Di(2-ethylhexyl) phthalate, which was not metabolized by esterases in the skin, was not transported across the skin. These results suggest that highly lipophilic phthalates may be transported easily across the stratum corneum lipids. The water-rich viable layer may become permeable to these phthalates by their metabolism into monoesters, which are relatively hydrophilic. Skin metabolism is essential to the percutaneous absorption of phthalates. Because esterase activity has large inter-individual differences, further study will be needed for individual risk identification of dermal exposure to phthalates.

Exposure of Portuguese children to the novel non-phthalate plasticizer di-(iso-nonyl)-cyclohexane-1,2-dicarboxylate (DINCH).

Di-(iso-nonyl)-cyclohexane-1,2-dicarboxylate (DINCH) is used as substitute for high molecular weight phthalate plasticizers such as di-(2-ethylhexyl) phthalate (DEHP) and di-(iso-nonyl) phthalate (DINP). Due to a rapid substitution process we have to assume omnipresent and increasing DINCH exposures. The aim of this study was to evaluate DINCH exposure in 112 children (4-18years old) from Portugal, divided in two groups: 1) normal-/underweight following the usual diet; and 2) obese/overweight but under strict nutritional guidance. First morning urine samples were collected during the years 2014 and 2015. Oxidized DINCH metabolites (OH-MINCH, oxo-MINCH, cx-MINCH) were analyzed after enzymatic hydrolysis via on-line HPLC-MS/MS with isotope dilution quantification. We detected DINCH metabolites in all analyzed samples. Urinary median (95th percentile) concentrations were 2.14µg/L (15.91) for OH-MINCH, followed by 1.10µg/L (7.54) for oxo-MINCH and 1.08µg/L (7.33) for cx-MINCH. We observed no significant differences between the two child-groups; only after creatinine adjustment, we found higher metabolite concentrations in the younger compared to the older children. Median (95th percentile) daily DINCH intakes were in the range of 0.37 to 0.76 (2.52 to 5.61) µg/kg body weight/day depending on calculation model and subpopulation. Body weight related daily intakes were somewhat higher in Group 1 compared to Group 2, irrespective of the calculation model. However, in terms of absolute amounts (µg/day), DINCH intakes were higher in Group 2 compared to Group 1. In regard to age, we calculated higher intakes for the younger children compared to older children, but only with the creatinine-based model. This new data for southern European, Portuguese children adds information to the scarce knowledge on DINCH, confirming omnipresent exposure and suggesting higher exposures in children than adults. Significant sources and routes of exposure have yet to be unveiled. For now, all calculated daily intakes are far below established health benchmark levels (TDI, RfD). However, rapidly increasing exposures have to be expected over the next years.

Urinary concentrations of cyclohexane-1,2-dicarboxylic acid monohydroxy isononyl ester, a metabolite of the non-phthalate plasticizer di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH), and markers of ovarian response among women attending a fertility center.

Di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH), a non-phthalate plasticizer, was introduced commercially in 2002 as an alternative to ortho-phthalate esters because of its favorable toxicological profile. However, the potential health effects from DINCH exposure remain largely unknown. We explored the associations between urinary concentrations of metabolites of DINCH on markers of ovarian response among women undergoing in vitro fertilization (IVF) treatments. Between 2011 and 2015, 113 women enrolled a prospective cohort study at the Massachusetts General Hospital Fertility Center and provided up to two urine samples prior to oocyte retrieval. The urinary concentrations of two DINCH metabolites, cyclohexane-1,2-dicarboxylic acid monohydroxy isononyl ester (MHiNCH) and cyclohexane-1,2-dicarboxylic acid monocarboxyisooctyl ester (MCOCH), were quantified by isotope dilution tandem mass spectrometry. We used generalized linear mixed models to evaluate the association between urinary metabolite concentrations and markers of ovarian response, accounting for multiple IVF cycles per woman via random intercepts. On average, women with detectable urinary MHiNCH concentrations, as compared to those below LOD, had a lower estradiol levels (-325 pmol/l, p=0.09) and number of retrieved oocytes (-1.8, p=0.08), with a stronger association among older women. However, urinary MHiNCH concentrations were unrelated to mature oocyte yield and endometrial wall thickness. In conclusion, we found suggestive negative associations between urinary MHiNCH concentrations and peak estradiol levels and number of total oocyte yields. This is the first study evaluating the effect of DINCH exposure on human reproductive health and raises the need for further experimental and epidemiological studies to better understand the potential effects of this chemical on health.

Impact of the nature and concentration of plasticizers on the ability of PVC to sorb drug.

The sorption of a drug by an infusion set may dramatically reduce the drug delivery efficiency. In this paper, we investigated how the drug sorption, in static conditions, is affected by the plasticizer's nature and ratio in the case of plasticized PVC, one of the most common material for infusion set tubing. Within the study, the drug concentration in diazepam solutions was studied after contact with PVC films containing different amounts of DEHP, DEHT, TOTM and DINCH® plasticizers. Moreover the partition coefficients between material and water were calculated. The drug sorption levels were equivalent for the different plasticizers and there was a plasticizer ratio for which the drug uptake was enhanced. As a consequence, the amount of sorbed drug might not be only linked to the amount of plasticizer in the film and to the solubility of the drug in the plasticizer alone: it must probably depend on specific interactions between plasticizer and PVC.