Analytical approaches for the evaluation of data deficient simulated leachable compounds in ENDS products: a case study.

Leachable investigations are routinely undertaken across a range of sectors (e.g., pharmaceuticals, medical devices, etc.) to determine whether chemicals from a container closure system transfer into a product under normal conditions of use. For Electronic Nicotine Delivery Systems (ENDS) the container closure system includes all materials in contact with the e-liquid that is aerosolized and subsequently inhaled by the user. Currently, there is no guidance for conducting leachable studies for ENDS products, however, there are relevant guidance documents for orally inhaled drug products that can be applied to an ENDS container closure system. We present a case study of the analytical investigation of two leachable compounds identified in simulated leachable studies using aged JUULpods filled with unflavored e-liquid (PG/VG/nicotine/benzoic acid). Both compounds had limited toxicological information and were considered data deficient. A qualitative analysis of the aerosol collected from aged commercial JUULpods (Virginia Tobacco and Menthol), using a similar analytical method (LC-MS/MS) used in the simulated leachable studies, showed no trace or detectable levels of either leachable compound. Therefore, this qualitative analysis did not provide semi-quantitative values for the data-deficient leachable compounds necessary to support toxicological risk assessment. Further, no commercial authentic standards or reasonable synthetic route were available due to the molecular size and structural complexity of the compounds. Instead, method limits were established using an alternative approach to standard ICH guidelines. The experimentally determined method limit of quantitation, using spiked samples of simulated leachable e-liquid, provided conservative semi-quantitative values for each data deficient leachable compound in the aerosol that enabled a transfer efficiency from e-liquid to aerosol to be estimated. The transfer efficiency of each leachable compound was experimentally determined to be less than 2% based on the limit of quantitation, which then could be used to define a relevant exposure limit for the toxicological risk assessment. This work details a novel analytical approach for determining the transfer efficiency of data deficient leachable compounds from ENDS container closure systems into the ENDS aerosol to support toxicological health risk assessments.

Corrigendum: Analytical approaches for the evaluation of data deficient simulated leachable compounds in ENDS products: a case study.

[This corrects the article DOI: 10.3389/fchem.2023.1212744.].

Self-assembly of dendritic tris(crown ether) hexagons and their complexation with dibenzylammonium cations.

The construction of a new series of dendritic tris(crown ether) hexagons via coordination-driven self-assembly is described. Combining 120° crown ether-containing diplatinum(II) acceptors with 120° dendritic dipyridyl donors in a 1:1 ratio allows for the formation of a new family of dendritic triple crown ether derivatives with a hexagonal cavity in quantitative yields. The number and the position of these pendant groups can be precisely controlled on the hexagonal metallacycle. The structures of all dendritic multiple crown ether hexgaons are confirmed by multinuclear NMR ((1)H and (31)P), ESI-MS and ESI-TOF-MS, and elemental analysis. The complexation of these dendritic trivalent receptors with dibenzylammonium cations was investigated by (1)H NMR titration experiments. The thermodynamic binding constants between the receptors and guests were established by using the nonlinear least-squares fit method based on (1)H NMR titration experiments. It was found that the association constants of each assembly decrease correspondingly upon the increase of the generation of the dendrons from [G0] to [G3], which might be caused by the steric effect of the dendrons on host-guest complexation.

Dendritically encapsulated, water-soluble fe(4)s(4): synthesis and electrochemical properties.

Amphiphilic, Fe(4)S(4) cluster core dendrimers can be prepared via ligand exchange with dendrons containing carboxylic acid peripheral groups and a thiol focal group. These amphiphilic dendrons are more susceptible to oxidative disulfide formation than their non-amphiphilic analogues reported previously. Thus, an in situ deprotection of an aromatic thioacetate was necessary to prepare the dendrimers. These molecules showed the expected decrease in rate with increasing generation. A slower rate of heterogeneous electron transfer was found when these molecules were compared with non-amphiphilic analogues. This behavior correlated with their larger size and thus a larger effective distance of electron transfer. Voltammetry in DMSO with added water makes the dendrimers easier to reduce, but the change in redox potential is much smaller for all dendrimers when compared to a non-dendritic analogue. This behavior is consistent with the idea that the dendrimers encapsulate the cluster to some degree, creating a hydrophobic microenvironment around the cluster.

Synthesis of six-component metallodendrimers via [3 + 3] coordination-driven self-assembly.

A new class of 120 degrees dendritic di-Pt(II) acceptor subunits has been designed and synthesized, from which six-component hexagonal metallodendrimers were easily formed with 120 degrees dendritic dipyridine donors via [3 + 3] coordination-driven self-assembly. The structures of all metallodendrimers are confirmed by multinuclear NMR, ESI-TOF-MS/ESI-FTMS, and elemental analysis. MMFF force-field simulations indicates that all metallodendrimers have a hexagonal ring with an internal radius of approximately 1.4 nm.

Construction of coordination-driven self-assembled [5 + 5] pentagons using metal-carbonyl dipyridine ligands.

The coordination-driven self-assembly of two metal-carbonyl-cluster-coordinated dipyridyl donors, (4-C(5)H(4)N)(2)C[triple bond]CCo(2)(CO)(6) (1) and (4-C(5)H(4)N)(2)C[triple bond]CMo(2)Cp(2)(CO)(4) (2), with a linear diplatinum(II) acceptor ligand was investigated. The structures of the resulting self-assembled polygons were found to be controlled by the steric bulk of the metal-carbonyl cluster adduct. The use of a sterically less imposing ligand 1 resulted in a pentagon-hexagon mixture, which was characterized by electrospray ionization time-of-flight mass spectroscopy. The exclusive formation of a [5 + 5] pentagon was achieved by the self-assembly of the bulkier molybdenum donor ligand 2 with a linear organoplatinum(II) acceptor ligand. Molecular force field modeling was used to study the structural details of the pentagonal and hexagonal architectures. The first Fe(3)-Co(6)-Pt(6) trimetal [3 + 3] hexagon was also synthesized via the combination of 1 with a 120 degrees ferrocenyldiplatinum(II) acceptor.

Coordination-driven self-assembly of cavity-cored multiple crown ether derivatives and poly[2]pseudorotaxanes.

The synthesis of a new 120 degree diplatinum(II) acceptor unit and the self-assembly of a series of two-dimensional metallacyclic polypseudorotaxanes that utilize both metal-ligand and crown ether-dialkylammonium noncovalent interactions are described. Judiciously combining complementary diplatinum(II) acceptors with bispyridyl donor building blocks, with an acceptor and/or donor possessing a pendant dibenzo[24]crown-8 (DB24C8) moiety, allows for the formation of three new rhomboidal bis-DB24C8, one new hexagonal tris-DB24C8, and four new hexakis-DB24C8 metallacyclic polygons in quantitative yields. The size and shape of each assembly, as well as the location and stoichiometry of the DB24C8 macrocycle, can be precisely controlled. Each polygon is able to complex two, three, or six dibenzylammonium ions without disrupting the underlying metallacyclic polygons, thus producing eight different poly[2]pseudorotaxanes and demonstrating the utility and scope of this orthogonal self-assembly technique. The assemblies are characterized with one-dimensional multinuclear ((1)H and (31)P) and two-dimensional ((1)H-(1)H COSY and NOESY) NMR spectroscopy as well as mass spectrometry (ESI-MS). Further analysis of the size and shape of each assembly is obtained through molecular force-field simulations. (1)H NMR titration experiments are used to establish thermodynamic binding constants and poly[2]pseudorotaxane/dibenzylammonium stoichiometries. Factors influencing the efficiency of poly[2]pseudorotaxane formation are discussed.

A new family of multiferrocene complexes with enhanced control of structure and stoichiometry via coordination-driven self-assembly and their electrochemistry.

The design and synthesis of a new family of multiferrocene complexes with enhanced control of structure and stoichimetry via coordination-driven self-assembly is described. Insight into the structure and electronic properties of all supramolecules was obtained by electrochemical studies. The collective results provide an enhanced understanding of the influence of structural factors on the electrochemistry of multifunctional electroactive supramolecular architectures.

Mass measurement accuracy comparisons between a double-focusing magnetic sector and a time-of-flight mass analyzer.

We report a direct comparison of the mass measurement accuracies (MMAs) obtained on different mass spectrometry instrument types; a magnetic sector as the 'gold standard' and an electrospray ionization time-of-flight (ESI-TOF) instrument. Sixty samples, obtained from the Department of Chemistry at North Carolina State University, were analyzed on each instrument. Data are presented and compared between the different instruments. The average absolute MMAs achieved for the magnetic sector and Agilent ESI-TOF mass spectrometers were 3.0 and 1.1 ppm, respectively.