Data on ADME parameters of bisphenol A and its metabolites for use in physiologically based pharmacokinetic modelling.

The paper presents the collection of physicochemical parameters of bisphenol A (BPA) and its sulfate (BPAS) and glucuronide (BPAG) conjugates, accompanied by data characterizing their absorption, distribution, metabolism and excretion (ADME) behavior following oral administration of BPA. The data were collected from open literature sources and publicly available databases. Additionally, data calculated by using the MarvinSketch 18.30.0 software or predicted by relevant QSAR models built in Simcyp® Simulator were also used. All data were analysed and are fit for purpose if necessary to ensure a reliable prediction of pharmacokinetics of BPA and its conjugates. The data selection process and reasoning for fitting is provided to allow critical assessment and to ensure data transparency. Finally, the sensitivity analysis was performed to assess the influence of the selected parameters on the PBPK model predictions.

Physiologically based modelling of dermal absorption and kinetics of consumer-relevant chemicals: A case study with exposure to bisphenol A from thermal paper.

Bisphenol A (BPA) is one of the best studied industrial chemicals in terms of exposure, toxicity, and toxicokinetics. This renders it an ideal candidate to exploit the recent advancements in physiologically based pharmacokinetic (PBPK) modelling to support risk assessment of BPA specifically, and of other consumer-relevant hazardous chemicals in general. Using the exposure from thermal paper as a case scenario, this study employed the multi-phase multi-layer mechanistic dermal absorption (MPML MechDermA) model available in the Simcyp® Simulator to simulate the dermal toxicokinetics of BPA at local and systemic levels. Sensitivity analysis helped to identify physicochemical and physiological factors influencing the systemic exposure to BPA. The iterative modelling process was as follows: (i) development of compound files for BPA and its conjugates, (ii) setting-up of a PBPK model for intravenous administration, (iii) extension for oral administration, and (iv) extension for exposure via skin (i.e., hand) contact. A toxicokinetic study involving hand contact to BPA-containing paper was used for model refinement. Cumulative urinary excretion of total BPA had to be employed for dose reconstruction. PBPK model performance was verified using the observed serum BPA concentrations. The predicted distribution across the skin compartments revealed a depot of BPA in the stratum corneum (SC). These findings shed light on the role of the SC to act as temporary reservoir for lipophilic chemicals prior to systemic absorption, which inter alia is relevant for the interpretation of human biomonitoring data and for establishing the relationship between external and internal measures of exposure.

Linear and cyclic oligomers in PET, glycol-modified PET and Tritan™ used for food contact materials.

Polyesters are commonly used as food contact materials. During manufacture of polyesters different low molecular mass oligomers (<1000 Da) are formed in the polymer melt. These so-called non-intentionally added substances (NIAS) are potential migrants into foods. In this work, different polyester samples made of polyethylene terephthalate (PET), glycol-modified PET (PETG) and Tritan™ were investigated on their qualitative and quantitative oligomer composition. The analysis of acetonitrile extracts by HPLC-DAD/ESI-MS revealed the presence of about 100 linear (different combinations of hydroxyl-, carboxyl-, methyl ester end groups) and cyclic oligomers depending on the main and co-monomers. The identified oligomers were quantified in different extracts and after reprecipitation by HPLC-DAD using bis-hydroxyethylene terephthalate (BHET) as external standard. The amount of oligomers isolated by reprecipitation ranged between 0.80 and 3.4% in the respective polyester. Cyclic oligomers generally made up 90% or more of the isolated oligomers. Compared to the exhaustive extracts the leaching of oligomers into 20% ethanol (1 h, 60 °C) resulted in a considerable change of the oligomer distribution with a predominant detection of linear oligomers. This suggests linear oligomers to be relevant for migration into aqueous foods despite the dominant amount of extractable cyclic oligomers in polyesters. Analysis of the extractable oligomers of a PET preform and a PETG container and their corresponding raw material pellets revealed that the injection moulding process did not significantly change the amount of cyclic oligomers but did increase the amount of low molecular mass linear oligomers about twofold.

Pharmacokinetics of bisphenol A in humans following dermal administration.

BACKGROUND: Human exposures to bisphenol A (BPA) are widespread. The current study addresses uncertainties regarding human pharmacokinetics of BPA following dermal exposure. OBJECTIVE: To examine the absorption, distribution, metabolism and excretion of BPA in humans following dermal administration. METHODS: We dermally administered deuterated BPA (d6-BPA) to 10 subjects (6 men and 4 women) at a dose of 100 µg/kg over a 12-hour period and conducted blood and urine analysis from the beginning of dosing through a three- or six-day period. We present time-course serum and urine concentrations of total and unconjugated ("free") d6-BPA and used this information to calculate terminal half-life and area under the curve. RESULTS AND CONCLUSIONS: Detectable serum levels of total d6-BPA were observed at 1.4 h after the start of dosing, and a maximum serum concentration (Cmax) of 3.26 nM was observed. Free d6-BPA was detectable in serum 2.8 h after start of dermal administration, with Cmax of 0.272 nM. Beginning at approximately seven hours and continuing to 12 h (which corresponds to cessation of exposure), the concentration of free and total serum d6-BPA plateaued. The terminal half-lives of total d6-BPA and free d6-BPA in the body were 21.4 ± 9.81 h and 17.6 ± 7.69 h, respectively. Elimination from the body was rate-limited by kinetics in the dermal compartment. Free d6-BPA was a greater percentage of the area under the curve of total serum BPA (8.81%) compared to the 0.56% observed in our previously published oral study. Recovery of total d6-BPA in urine was <2% of the applied dose after six days. Analysis of the area under the curve for dermal and oral administration revealed that 2.2% of the dermal dose became systemically available. These data are in line with prior studies indicating how pharmacokinetics of BPA differ following oral and dermal exposures. Dermal exposure resulted in a longer apparent half-life and higher free:total d6-BPA ratio compared to oral.

Linear and cyclic oligomers in polybutylene terephthalate for food contact materials.

Polybutylene terephthalate (PBT) is a polyester (PES) gaining more importance on the food contact material (FCM) market. However, little is known about the potential migration of PBT oligomers which are formed during polymer production. In this work, PBT pellets and a slotted spoon manufactured from this material by injection moulding were analysed on extractable oligomers and their migration potential into hydrophilic foods. Overall 27 oligomers (cycles and linears) could be identified in different extracts by HPLC-DAD/ESI-MS data, but without confirmation by reference substances. The oligomers were quantified by HPLC-DAD using bis(2-hydroxyethyl) terephthalate (BHET) as external standard and the total amount of oligomers isolated by reprecipitation from the pellets and the spoon were 0.69 and 0.71%, respectively. While cyclic oligomers made up for approximately 90% of the extractable oligomers, linear oligomers proved to be more relevant for migration into aqueous foodstuffs. Furthermore, it was shown that hydrolysis of oligomers can take place in water at elevated temperatures. Consequently, the qualitative and quantitative composition of PBT oligomers in aqueous foods from FCMs does not only depend on migration but also on hydrolysis. Migration testing of the PBT spoon under repeat use conditions with water at 100°C for 2 h resulted in 0.29 mg item-1 of linear oligomers and 0.05 mg item-1 of the cyclic PBT dimer in the third migrate.

Qualitative and quantitative analysis of monomers in polyesters for food contact materials.

Polyesters (PESs) are gaining more importance on the food contact material (FCM) market and the variety of properties and applications is expected to be wide. In order to acquire the desired properties manufacturers can combine several FCM-approved polyvalent carboxylic acids (PCAs) and polyols as monomers. However, information about the qualitative and quantitative composition of FCM articles is often limited. The method presented here describes the analysis of PESs with the identification and quantification of 25 PES monomers (10 PCA, 15 polyols) by HPLC with diode array detection (HPLC-DAD) and GC-MS after alkaline hydrolysis. Accurate identification and quantification were demonstrated by the analysis of seven different FCM articles made of PESs. The results explained between 97.2% and 103.4% w/w of the polymer composition whilst showing equal molar amounts of PCA and polyols. Quantification proved to be precise and sensitive with coefficients of variation (CVs) below 6.0% for PES samples with monomer concentrations typically ranging from 0.02% to 75% w/w. The analysis of 15 PES samples for the FCM market revealed the presence of five different PCAs and 11 different polyols (main monomers, co-monomers, non-intentionally added substances (NIAS)) showing the wide variety of monomers in modern PESs. The presented method provides a useful tool for commercial, state and research laboratories as well as for producers and distributors facing the task of FCM risk assessment. It can be applied for the identification and quantification of migrating monomers and the prediction of oligomer compositions from the identified monomers, respectively.