Migration of di(2-ethylhexyl) phthalate, diisononylcyclohexane-1,2-dicarboxylate and di(2-ethylhexyl) terephthalate from transfusion medical devices in labile blood products: A comparative study.

BACKGROUND AND OBJECTIVES: Polyvinyl chloride (PVC) plasticized with di(2-ethylhexyl) phthalate (DEHP) is a widely used material for medical transfusion devices. Not covalently bound to PVC, DEHP can migrate into blood products during storage. Recognized as an endocrine disruptor and raising concerns about its potential carcinogenicity and reprotoxicity, DEHP is gradually being withdrawn from the medical device market. Therefore, the use of alternative plasticizers, such as diisononylcyclohexane-1,2-dicarboxylate (DINCH) and di(2-ethylhexyl) terephthalate (DEHT), as potential candidates for the replacement of DEHP in medical transfusion devices has been investigated. The purpose of this study was to evaluate the quantity of PVC-plasticizers in the blood components according to their preparation, storage conditions and in function of the plasticizer. MATERIALS AND METHODS: Whole blood was collected, and labile blood products (LBPs) were prepared by the buffy-coat method with a PVC blood bag plasticized either with DEHP, DINCH or DEHT. DINCH and DEHT equivalent concentrations were quantified in LBPs by liquid chromatography-tandem mass spectrometry or coupled with UV and compared to DEHP equivalent concentrations. RESULTS: The plasticizer equivalent concentration to which a patient is exposed during a transfusion depends on the preparation of LBPs as well as their storage conditions, that is, temperature and storage time. At day 1, for all LBPs, the migration of DEHP is 5.0 and 8.5 times greater than DINCH and DEHT, respectively. At the end of the 49 days storage period, the DEHP equivalent concentration in red blood cells concentrate is statistically higher when compared to DINCH and DEHT, with maximal values of 1.85, 1.13 and 0.86 µg/dm2 /mL, respectively. CONCLUSION: In addition to lower toxicity, transfused patients using PVC-DEHT or PVC-DINCH blood bags are less exposed to plasticizers than using PVC-DEHP bags with a ranging exposure reduction from 38.9% to 87.3%, due to lower leachability into blood components.

A simple and easy non-derivatization gas chromatography-mass spectrometry method for simultaneous quantification of valproic acid, gabapentin, pregabalin, and vigabatrin in human plasma.

Immunoassays are currently not available in commercial kits for the quantification of valproic acid, vigabatrin, pregabalin, and gabapentin, which also cannot suffer the limitations of interferences of substances with similar structures. Chromatography is a good alternative to immunoassay. In this study, a simple and robust non-derivatization gas chromatography-mass spectrometry method for simultaneous determination of the above four drugs in human plasma was developed and validated for therapeutic drug monitoring purposes. This method employed benzoic acid as the internal standard with hydrochloric acid for plasma acidification and ACN for precipitate protein. The supernatant was directly injected into gas chromatography-mass spectrometry for analysis. Good linearity was obtained with linear correlation coefficients of the four analytes of 0.9988-0.9996. Extraction recoveries of valproic acid, vigabatrin, pregabalin, and gabapentin were respectively in the ranges of 91.3%-94.5%, 90.0%-90.9%, 90.0%-92.1%, and 88.0%-92.2% with the relative standard deviation values less than 12.6%. Intra- and inter-batch precision and accuracy, and stability assays were all acceptable. Taken together, the novel method developed in this study provided easy plasma pretreatment, good extraction yield, and high chromatographic resolution, which has been successfully validated through the quantification of valproic acid in the plasma of 46 patients with epilepsy.

Derivatization of γ-Amino Butyric Acid Analogues for Their Determination in the Biological Samples and Pharmaceutical Preparations: A Comprehensive Review.

γ-Aminobutyric acid (GABA) plays an important role in regulating neuronal excitability. Four structurally related drugs to GABA including pregabalin (PGB), gabapentin (GBP), vigabatrin (VGB), and baclofen are used for the treatment of central nervous system disorders. These drugs are small aliphatic molecules having neither fluorescent nor strong absorbance in the ultraviolet/visible region; therefore, direct determination of these analytes by optical methods is difficult. Additionally, their high boiling point makes gas chromatography impossible. Accordingly, the amine or acid moiety in these drugs is derivatized in order to improve their selectivity and sensitivity during determination in the biological samples. This review focuses on derivatization based methods and their different reactions for determination of PGB, GBP, VGB, and baclofen in the biological samples and pharmaceutical preparations reported between 1980 and 2020. High-performance liquid chromatography methods coupled with different detectors are a commonly used methods for determination of GABA analogs after derivatization. These methods cover 38.89% of all developed methods for determination of GABA analogs.

Biotransformation of gabapentin in surface water matrices under different redox conditions and the occurrence of one major TP in the aquatic environment.

Laboratory-scale incubation experiments in water/sediment systems were conducted to test the transformation behavior of the anticonvulsant gabapentin (GBP) under different environmental conditions (aerobic, anaerobic, with abiotic controls). GBP was transformed by biological processes as it was eliminated quickly under aerobic conditions (dissipation time 50% of initial concentration (DT50): 2-7 days) whereas no decrease was observed under anaerobic conditions. Measurements via high resolution mass spectrometry (LC-Orbitrap-MS) revealed eight biological transformation products (TPs). Three of them were identified with reference standards (GBP-Lactam, TP186, TP213), while for the other five TPs tentative structures were proposed from information by MS2/MS3 experiments. Furthermore, the quantitatively most relevant TP GBP-Lactam was formed via intramolecular amidation (up to 18% of initial GBP concentration). Incubation experiments with GBP-Lactam revealed a higher stability against biotic degradation (DT50: 12 days) in contrast to GBP, while it was stable under anaerobic and abiotic conditions. Besides GBP, GBP-Lactam was detected in surface water in the µg L-1 range. Finally, GBP and GBP-Lactam were found in potable water with concentrations up to 0.64 and 0.07 µg L-1, respectively. According to the elevated environmental persistence of GBP-Lactam compared to GBP and its presumed enhanced toxicity, we recommend to involve GBP-Lactam into monitoring programs.

Exposure marker discovery of di(isononyl)cyclohexane-1,2-dicarboxylate using two mass spectrometry-based metabolite profiling data processing methods.

Di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH) is a plasticizer used in polyvinyl chloride (PVC) products, such as toys and food packaging. Because the use of DINCH is on the rise, the risk of human exposure to this chemical may likewise increase. Discovering markers for assessing human chemical exposure is difficult because the metabolism of chemicals within humans is complex. In this study, two mass spectrometry (MS)-based metabolite profiling data processing methods, the mass defect filter (MDF) method and the signal mining algorithm with isotope tracing (SMAIT) method, were used for DINCH metabolite discovery, and 110 and 18 potential DINCH metabolite signal candidates were discovered, respectively, from in vitro DINCH incubation samples. Of these, the 21 signals were validated as tentative exposure marker signals in a rat model. Interestingly, the two methods generated rather different sets of DINCH exposure markers. Five of the 21 tentative exposure marker signals were verified as the probable DINCH structure-related metabolite signals based on their MS/MS product ion profiles. These five signals were detected in at least one human urine sample. Of the five probable DINCH structure-related metabolite signals, two novel signals might be suitable exposure markers that should be further investigated for their application in human DINCH exposure assessments. These observations indicate that the MDF and SMAIT methods may be used to discover a relatively different set of potential DINCH exposure markers.

Exposure of hospitalised pregnant women to plasticizers contained in medical devices.

BACKGROUND: Medical devices (MDs) in polyvinyl chloride (PVC) are not a well-known source of exposure to plasticizers, in particular during pregnancy. Because of its toxicity, the di-(2-ethylhexyl) phthalate (DEHP) has been replaced by other plasticizers such as di (isononyl)-cyclohexane-1,2-dicarboxilic acid (DINCH), tri-octyltrimellitate (TOTM) and di-(isononyl) phthalate (DiNP). Our study aimed to quantify the plasticizers (DEHP and alternative plasticizers) contained in PVC medical devices used for hospitalised pregnant women and to describe which these MDs had been used (type, number, duration of exposure). METHODS: The plasticizers contained in the MDs used for daily care in the Obstetrics Department of a French University Hospital were extracted from PVC (after contact with a chloroform solution), identified and quantified by gas-chromatography-mass-spectrometry analysis. A total of 168 pregnant women hospitalised in the Obstetrics Department with at least one catheter were included in the observational study. The median number of MDs containing plasticizers used and the daily duration of exposure to the MDs were compared in three groups of pregnant women: "Pathology group" (women hospitalised for an obstetric disorder who did not give birth during this hospitalisation; n = 52), "Pathology and delivery group" (hospitalised for an obstetric disorder and who gave birth during this stay; n = 23) and "Delivery group" (admitted for planned or spontaneous delivery without obstetric disorder; n = 93). RESULTS: DiNP, TOTM and DINCH were the predominant plasticizers contained in the MDs at an amount of 29 to 36 g per 100 g of PVC. Women in the "Pathology group" (preterm labour or other pathology) were exposed to a median number of two MDs containing TOTM and one MD containing DiNP, fewer than those in the "Pathology and delivery group" (p < 0.05). Women in the "Pathology group" had a median exposure of 3.4 h/day to MDs containing DiNP and 8.2 h/day to MDs containing TOTM, longer than those in the "Delivery group" (p < 0.01). CONCLUSIONS: Our study shows that the medical management of pregnant women in a hospital setting entails exposure to MDs containing alternative plasticizers (DiNP, TOTM and DINCH).

Stacking-cyclodextrin-microchip electrokinetic chromatographic determination of gabapentinoid drugs in pharmaceutical and biological matrices.

A facile, rapid, and highly sensitive microchip-based electrokinetic chromatographic method was developed for the simultaneous analysis of two gabapentinoid drugs, gabapentin (GPN) and pregabalin (PGN). Both drugs were first reacted with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F) via nucleophilic substitution reactions to yield highly fluorescent products with λex/em 470/540nm. Analyses of both fluorescently labeled compounds were achieved within 200s in a poly(methyl methacrylate) (PMMA) microchip with a 30mm separation channel. Optimum separation was achieved using a borate buffer (pH 9.0) solution containing methylcellulose and ß-cyclodextrin (ß-CD) as buffer additives. Methylcellulose acted as a dynamic coating to prevent adsorption of the studied compounds on the inner surfaces of the microchannels, while ß-CD acted as a pseudo-stationary phase to improve the separation efficiency between the labeled drugs with high resolution (Rs>7). The fluorescence intensities of the labeled drugs were measured using a light emitting diode-induced fluorescence detector at 540nm after excitation at 470nm. The sensitivity of the method was enhanced 14- and 17-fold for PGN and GPN, respectively by field-amplified stacking relative to traditional pinched injection so that it could quantify 10ngmL-1 for both analytes, with a detection limit lower than 3ngmL-1. The developed method was efficiently applied to analyze PGN and GPN in their pharmaceutical dosage forms and in biological fluids. The extraction recoveries of the studied drugs from plasma and urine samples were more than 89% with%RSD values lower than 6.2.

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.

Sensory classification of table olives using an electronic tongue: Analysis of aqueous pastes and brines.

Table olives are highly appreciated and consumed worldwide. Different aspects are used for trade category classification being the sensory assessment of negative defects present in the olives and brines one of the most important. The trade category quality classification must follow the International Olive Council directives, requiring the organoleptic assessment of defects by a trained sensory panel. However, the training process is a hard, complex and sometimes subjective task, being the low number of samples that can be evaluated per day a major drawback considering the real needs of the olive industry. In this context, the development of electronic tongues as taste sensors for defects' sensory evaluation is of utmost relevance. So, an electronic tongue was used for table olives classification according to the presence and intensity of negative defects. Linear discrimination models were established based on sub-sets of sensor signals selected by a simulated annealing algorithm. The predictive potential of the novel approach was first demonstrated for standard solutions of chemical compounds that mimic butyric, putrid and zapateria defects (≥93% for cross-validation procedures). Then its applicability was verified; using reference table olives/brine solutions samples identified with a single intense negative attribute, namely butyric, musty, putrid, zapateria or winey-vinegary defects (≥93% cross-validation procedures). Finally, the E-tongue coupled with the same chemometric approach was applied to classify table olive samples according to the trade commercial categories (extra, 1st choice, 2nd choice and unsuitable for consumption) and an additional quality category (extra free of defects), established based on sensory analysis data. Despite the heterogeneity of the samples studied and number of different sensory defects perceived, the predictive linear discriminant model established showed sensitivities greater than 86%. So, the overall performance achieved showed that the electrochemical device could be used as a taste sensor for table olives organoleptic trade successful classification, allowing a preliminary quality assessment, which could facilitate, in the future, the complex task of sensory panelists.

Dried blood spot analysis of gabapentin as a valid alternative for serum: a bridging study.

We evaluated the applicability of a validated GC-MS method for the determination of gabapentin in dried blood spots (DBS). Important for the acceptance of DBS sampling as an alternative sampling strategy is the possibility to base solid conclusions on the quantification. Therefore, bridging studies -studies in which the correlation between both DBS and a reference matrix (e.g. serum) is evaluated statistically- need to be conducted. To this end, a comparative study was set up to quantify gabapentin in both blood (DBS) and serum samples. Statistically significant differences between DBS and serum concentrations were found (p<0.001). A mean blood-to-serum ratio of 0.85 was observed, which is in line with expectations. Calculated serum concentrations (obtained by dividing the DBS concentrations by 0.85) demonstrated a good correlation with measured serum concentrations, with 87% of samples fulfilling the criterion for incurred sample reanalysis. Furthermore, our data indicate a good correlation between capillary and venous concentrations. Conclusively, this study demonstrated that DBS are a valid alternative to serum for the determination of gabapentin.

Gabapentin, Pregabalin and Vigabatrin Quantification in Human Serum by GC-MS After Hexyl Chloroformate Derivatization.

A simple, sensitive and robust method for simultaneous determination of antiepileptic drugs (gabapentin, pregabalin and vigabatrin) in human serum using GC-MS was developed and validated for clinical toxicology purposes. This method employs an emerging class of derivatization agents - alkyl chloroformates allowing the efficient and rapid derivatization of both the amino and carboxylic groups of the tested antiepileptic drugs within seconds. The derivatization protocol was optimized using the Design of Experiment statistical methodology, and the entire sample preparation requires less than 5 min. Linear calibration curves were obtained in the concentration range from 0.5 to 50.0 mg/L, with adequate accuracy (97.9-109.3%) and precision (<12.1%). The method was successfully applied to quantification of selected γ-aminobutyric acid analogs in the serum of patients in both therapeutic and toxic concentration ranges.

Evaluation of exposure to phthalate esters and DINCH in urine and nails from a Norwegian study population.

Phthalate esters (PEs) and 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) used as additives in numerous consumer products are continuously released into the environment, leading to subsequent human exposure which might cause adverse health effects. The human biomonitoring approach allows the detection of PEs and DINCH in specific populations, by taking into account all possible routes of exposure (e.g. inhalation, transdermal and oral) and all relevant sources (e.g. air, dust, personal care products, diet). We have investigated the presence of nine PE and two DINCH metabolites and their exposure determinants in 61 adult residents of the Oslo area (Norway). Three urine spots and fingernails were collected from each participant according to established sampling protocols. Metabolite analysis was performed by LC-MS/MS. Metabolite levels in urine were used to back-calculate the total exposure to their corresponding parent compound. The primary monoesters, such as monomethyl phthalate (MMP, geometric mean 89.7ng/g), monoethyl phthalate (MEP, 104.8ng/g) and mono-n-butyl phthalate (MnBP, 89.3ng/g) were observed in higher levels in nails, whereas the secondary bis(2-ethylhexyl) phthalate (DEHP) and DINCH oxidative metabolites were more abundant in urine (detection frequency 84-100%). The estimated daily intakes of PEs and DINCH for this Norwegian population did not exceed the established tolerable daily intake and reference doses, and the cumulative risk assessment for combined exposure to plasticizers with similar toxic endpoints indicated no health concerns for the selected population. We found a moderate positive correlation between MEP levels in 3 urine spots and nails (range: 0.56-0.68). Higher frequency of personal care products use was associated with greater MEP concentrations in both urine and nail samples. Increased age, smoking, wearing plastic gloves during house cleaning, consuming food with plastic packaging and eating with hands were associated with higher levels in urine and nails for some of the metabolites. In contrast, frequent hair and hand washing was associated with lower urinary levels of monoisobutyl phthalate (MiBP) and mono(2-ethyl-5-hydroxyhexyl) phthalate (5-OH-MEHP), respectively.

A Validated Fluorometric Method for the Rapid Determination of Pregabalin in Human Plasma Applied to Patients With Pain.

BACKGROUND: Pregabalin has been used for the treatment of pain. A clinically accepted method applied to patients with pain has not been published for the determination of pregabalin in human plasma. This study developed a fluorometric ultrahigh-performance liquid chromatography (UHPLC) method to measure pregabalin concentration in patients with pain. METHODS: After plasma pretreatment involving protein precipitation, pregabalin and gabapentin as an internal standard were derivatized with 4-fluoro-7-nitrobenzofurazan (NBD-F) under the following reaction conditions: 1 minute, pH 10, and 60°C. The UHPLC separation was performed using a 2.3-µm particle size octadecylsilyl column. The fluorescence detector was set at excitation and emission wavelengths of 470 and 530 nm, respectively. The predose blood samples were collected from 40 patients with pain who have been treated with 75 mg of pregabalin twice daily. RESULTS: The chromatographic run time was 1.25 minutes. No interfering peaks were observed in the blank plasma at the retention times of NBD derivatives. The calibration curve of pregabalin was linear at a range of 0.05-10 mcg/mL (r > 0.999). The lower limit of quantification was 0.05 mcg/mL. The intra-assay accuracy and precision were 98.3%-99.8% and within 4.3%, respectively. The inter-assay accuracy and precision were 103.2%-107.1% and within 4.1%, respectively. The predose plasma concentration of pregabalin in patients with pain ranged from 0.14 to 8.5 mcg/mL. CONCLUSIONS: This study provides a validated fluorometric UHPLC method with fast analytical performance for the determination of pregabalin in human plasma. The present method could be applied to patients with pain and be used for the clinical research or therapeutic drug monitoring of pregabalin.

Gabapentin concentrations and postmortem distribution.

Gabapentin is a widely prescribed medication used primarily for the treatment of epilepsy and neuropathic pain. Gabapentin has a favorable adverse effect profile in therapeutic dosing with the most common reported effects being dizziness, fatigue, drowsiness, weight gain, and peripheral edema. Even with intentional self-poisonings, serious effects are generally rare. In this report, gabapentin analyses were performed on 30 postmortem cases that had peripheral blood, central blood and liver tissue. Overall the central to peripheral blood (C/P) ratio mean was 0.90±0.24 (mean±standard deviation), and a median of 0.97. The liver to peripheral blood (L/P) ratio mean was 0.68±0.26L/kg (mean±standard deviation), and a median of 0.65L/kg. An additional case, where both antemortem blood and postmortem peripheral blood specimens were available, revealed the same gabapentin concentration in both specimens. Taken together, the data presented suggests that gabapentin is unlikely to show postmortem redistribution.

Development and validation of a stability-indicating RP-HPL C-CAD method for gabapentin and its related impurities in presence of degradation products.

The objective of the current study was to develop and validate a sensitive and specific LC-MS compatible stability indicating reversed phase liquid chromatographic method for the quantitative determination of Gabapentin and its related substances using Corona charged aerosol detection (CAD). The chromatographic conditions were optimized using a Kinetix Biphenyl column with gradient elution using a mobile phase composed of pH 4.2 ammonium acetate, acetonitrile, and methanol. Forced degradation was observed in basic and peroxide conditions and the major degradants were identified by LC-MS/MS analysis. The developed RP-HPLC CAD method was validated according to ICH guidelines. The LOD and LOQ values for Gabapentin and all its related impurities ranged from 0.075µg/mL to 0.18µg/mL and 0.25µg/mL to 0.60µg/mL, respectively. The recovery for all impurities ranged from 91.0 to 105.6%w/w. Solutions were stable for 7days at room temperature. The validated method produced acceptable precision, linearity, accuracy, robustness and ruggedness.

Quantitative target and systematic non-target analysis of polar organic micro-pollutants along the river Rhine using high-resolution mass-spectrometry--Identification of unknown sources and compounds.

In this study, the contamination by polar organic pollutants was investigated along the Rhine River, an important source of drinking water for 22 million people in central Europe. Following the flow of the river, a traveling water mass was sampled using weekly flow-proportional composite samples at ten different downstream sites, including main tributaries. Using a broad analytical method based on solid phase extraction and high-resolution mass spectrometry, the water was analyzed for more than 300 target substances. While the water in Lake Constance contained only 83 substances in often low concentrations, the number of detects found in the water phase increased to 143 substances and a weekly load of more than 7 tons at the last sampling site, the Dutch-German border. Mostly present were chemicals originating from wastewater treatment plants, especially the artificial sweetener Acesulfam and two pharmaceuticals, Metformin and Gabapentin, which dominate the weekly load up to 58%. Although the sample campaign was performed in a dry period in early spring, a large variety of pesticides and biocides were detected. Several industrial point sources were identified along the waterway's 900 km journey, resulting in high concentrations in the tributaries and loads of up to 160 kg. Additionally, an unbiased non-target analysis was performed following two different strategies for the prioritization of hundreds of potentially relevant unknown masses. While for the first prioritization strategy, only chlorinated compounds were extracted from the mass spectrometer datasets, the second prioritization strategy was performed using a systematic reduction approach between the different sampling sites. Among others, two substances that never had been detected before in this river, namely, the muscle relaxant Tizanidine and the solvent 1,3-Dimethyl-2-imidazolidinone (DMI), were identified and confirmed, and their loads were roughly estimated along the river.

An acute gabapentin fatality: a case report with postmortem concentrations.

Gabapentin (GBP) (Neurontin®, Horizant®, Gralise®) is a widely prescribed medication used primarily for the treatment of epilepsy and neuropathic pain. GBP has a favorable adverse effect profile in therapeutic dosing with the most common reported effects being dizziness, fatigue, drowsiness, weight gain, and peripheral edema. Even with intentional GBP self-poisonings, serious effects are rare. A 47-year-old female was found dead at work with her daughter's bottle of GBP 600 mg. There were 26 tablets missing and the decedent's only known medication was hydrocodone/acetaminophen. Following initial detection by an alkaline drug screen (GC-MS), analysis utilizing specific liquid chromatography-mass spectrometry revealed an elevated postmortem GBP peripheral blood concentration of 37 mg/L, central blood 32 mg/L, liver 26 mg/kg, vitreous 32 mg/L, and gastric contents 6 mg. Screening for volatiles, drugs of abuse, alkaline compounds, and acid/neutral compounds was negative with the exception of ibuprofen (<2 mg/L) detected in peripheral blood. This report presents a fatality that appears to be associated with an isolated and acute GBP ingestion.

Migrability of PVC plasticizers from medical devices into a simulant of infused solutions.

Medical devices (MD) for infusion and artificial nutrition are essentially made of plasticized PVC. The plasticizers in the PVC matrix can leach out into the infused solutions and may enter into contact with the patients. In order to assess the risk of patient exposure to these plasticizers we evaluated the migration performance of DEHP, DEHT, DINCH, and TOTM using a model adapted to the clinical use of the MDs. Each PVC tubing sample was immersed in a simulant consisting of a mixture of ethanol/water (50/50v/v) at 40°C and migration tests were carried out after 24h, 72h, and 10 days.DEHP had the highest migration ability, which increased over time. The amount of TOTM released was more than 20 times less than that of DEHP, which makes it an interesting alternative. DEHT is also promising, with a migration level three times smaller than DEHP. However, the migration ability of DINCH was similar to DEHP, with the released amounts equaling 1/8th of the initial amount in the tubing after 24h of contact. Taking into account the available toxicological data, TOTM and DEHT appear to be of particular interest. However, these data should be supplemented and correlated with clinical and toxicological studies on plasticizers and their metabolites.

Determination of 2-, 3-, 4-methylpentanoic and cyclohexanecarboxylic acids in wine: development of a selective method based on solid phase extraction and gas chromatography-negative chemical ionization mass spectrometry and its application to different wines and alcoholic beverages.

A method to analyse 2-methylpentanoic, 3-methylpentanoic and 4-methylpentanoic acids as well as cyclohexanecarboxylic acid has been developed and applied to wine and other alcoholic beverages. Selective isolation with solid phase extraction, derivatization with 2,3,4,5,6-pentafluorobenzyl bromide at room temperature for 30 minutes, and further analysis by gas chromatography-mass spectrometry in negative chemical ionization mode provides detection limits between 0.4 and 2.4 ng/L. Good linearity up to 3.6 µg/L, satisfactory reproducibility (RSD<10%) and signal recovery of around 100% represent a robust method of analysis. Concentration data of these analytes in wine and other alcoholic beverages are reported for the first time. The levels found ranged from the method detection limits to 2630 ng/L, 2040 ng/L and 3810 ng/L for 2-, 3- and 4-methylpentanoic acids, respectively, and to 1780 ng/L for cyclohexanecarboxylic acid. There are significant differences depending on the type of wine or beverage. Distilled beverages, beer and aged wines have higher contents in methylpentanoic and cyclohexanecarboxylic acids.