Evaluation and optimization of a HS-SPME-assisted GC-MS/MS method for monitoring nitrosamine impurities in diverse pharmaceuticals.

The probable carcinogenic nitrosamine impurities, such as N-nitrosodiethylamine (NDEA) and N-nitrosodimethylamine (NDMA), have been detected from various pharmaceuticals in recent years. The sensitive chromatographic methods, including liquid chromatography (LC) and gas chromatography (GC), have been applied for analyzing nitrosamines in the pharmaceutical substrates, such as sartans, ranitidine and metformin. In comparison of LC, the efficacy of GC for analyzing multiple nitrosamines in diverse pharmaceuticals will be limited or attenuated owing to the chemical properties of target analytes or matrix hinderance of pharmaceutical substrates. To extend the applicability of GC analysis for multiple nitrosamines in pharmaceuticals, this study presented a gas chromatograph tandem mass (GC-MS/MS) method for monitoring 14 nitrosamines within 44 pharmaceuticals, whereas the headspace-solid phase microextraction (HS-SPME) sampling mode was introduced. Chromatographic separation was achieved on a DB-heavyWax column (30 m × 0.25 mm; i.d., 0.25 µm), whereas the HS-SPME sampling mode with a 50/30 µm DVB/CAR/PDMS extracting fiber was applied for comparison of the direct injection mode. Meanwhile, the HS-SPME conditions were optimized to evaluate the effects of the parameters on analyzing total nitrosamines in pharmaceuticals by GC-MS/MS. The optimal conditions of HS-SPME were as follows: extracting solution of 90% NaCl, HS incubation time 1 min, SPME adsorbing at 80 â„ƒ for 30 min, and desorbing at 250 â„ƒ for 5 min. The limit of quantification (LOQ) for 14 nitrosamines in pharmaceutical matrices under the optimal conditions was 0.05 µg/g for the optimal HS-SPME, whereas the value was 0.05-0.25 µg/g for direct injection.

Development of a new methodology for the determination of N-nitrosamines impurities in ranitidine pharmaceuticals using microextraction and gas chromatography-mass spectrometry.

Ranitidine drug products were recently recalled because they contained carcinogenic nitrosamines (NAs), such as N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA). This episode emphasises the importance of developing analytical methods to determine NAs in this type of product. This study describes the development and validation of an analytical method for the determination of nine NAs (NDMA, N-nitrosomethylethylamine (NEMA), NDEA, N-nitrosopyrrolidine (NPYR), N-nitrosomorpholine (NMOR) N-nitrosodi-n-propylamine (NDPA) N-nitrosopiperidine (NPIP), N-nitrosodi-n-butylamine (NDBA) and N-nitrosodiphenylamine (NDPhA)) in ranitidine drug samples using a combination of microextraction and gas chromatography-mass spectrometry. The procedure involved the dissolution of 1 g of sample in 10 mL of water. For the dispersive liquid-liquid microextraction, 0.5 g of NaCl was added to this aqueous solution, followed by a mixture containing 0.5 mL methanol as dispersant and 150 µL chloroform as extractant solvent. The recovered organic phase was injected into the GC-MS system and a 20 min oven programme was applied. Quantification limits were in the 0.21-21 ng g-1 range, corresponding the lower limit to NDPhA and the higher to NDMA. Relative standard deviations lower than 12% were achieved in all cases, which indicates the adequate precision of the method. Seven pharmaceutical products containing two different amounts of ranitidine (150 and 300 mg) were analysed. None of the samples contained NEMA, NDEA, NPYR, NMOR, NDPA or NPIP, while NDMA, NDBA and NDPhA were found in three products.

Primary evaluation of nine volatile N-nitrosamines in raw red meat from Tianjin, China, by HS-SPME-GC-MS.

Monitoring of N-nitrosamines in red meats is vital for food safety. The aim of this paper is to describe the effect of tissue selection, species and seasonal variation on the contents of nine N-nitrosamines in raw red meats obtained from Tianjin, China. Headspace solid-phase microextraction along with gas chromatography-mass spectrometry was used for the determination of nine N-nitrosamines in the collected samples. Radar chart visualization is applied to describe the data. The results show HS-SPME-GC-MS is a simple, sensitive, precise and accurate method. The concentrations of N-nitrosodipropylamine, N-nitrosodiethylamine and N-nitrosomethylethylamine were high in almost all investigated samples and the levels of N-nitrosodimethylamine in all samples were less than 3.00 µg/kg. The risk assessment for N-nitrosodimethylamine indicates that the potential risks posed by N-nitrosodimethylamine in raw red meats ingested by people in Tianjin, China are negligible.

Simultaneous detection of nitrosamines and other sartan-related impurities in active pharmaceutical ingredients by supercritical fluid chromatography.

Since July 2018, the pharmacological class of "sartans" has been the subject of considerable media and analytical interest, as it became known that they are contaminated with nitrosamines such as N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA) and N-nitrosodiisopropylamine (NDiPA). Previous compendial methods are not able to detect these new contaminants. Using the latest and innovative Quality-by-Design (QbD) approach, it has now been possible to develop an analytical method that enables to investigate sartans, such as valsartan and losartan. Also a large class of different nitrosamines in the ppb range and sartan-related impurities can thus be determined simultaneously in a single analysis using supercritical fluid chromatography (SFC). By using SFC, a broad spectrum of nonpolar and very polar impurities can be separated and analyzed in under 20 min. The analytical method developed is validated for limit testing according to ICH Q2(R1) and fulfills default thresholds of EMA and FDA for testing of drug substances and genotoxic impurities. Additionally, it can also be adapted to other pharmaceuticals that may be contaminated with nitrosamines, since tetrazole synthesis as the underlying cause of nitrosamine contamination is important for a set of other non-sartan drug substances.

Lesson Learnt from Recall of Valsartan and Other Angiotensin II Receptor Blocker Drugs Containing NDMA and NDEA Impurities.

The presence of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) impurities in angiotensin II receptor blocker (ARB) drugs containing tetrazole ring has triggered worldwide product recalls. The purpose of this article is to identify the potential gap area in current pharmaceutical industry practice that might have led to the NMDA and NDEA impurities escaping the drug manufacturer's and FDA's attention. The impact of process change was not adequately assessed by the manufacturer of contaminated APIs (active pharmaceutical ingredients), and potential for generation of mutagenic or other toxic impurities was not considered. The safety and risk associated with a chemical synthetic process was also not evaluated. This is primarily due to current industry practice which focuses on controlling the impurities above reporting threshold. ICH Q3A and FDA guidance on genotoxic and carcinogenic impurities in drug substances and products need to be integrated so that the ICH Q3A decision tree (attachment 3) begins by checking whether the synthetic process has been evaluated for the potential to generate toxic impurities. The compliance with ICH Q3A limits should be carried out only after the process has been determined to be safe without the risk of generating mutagenic and carcinogenic impurities.

Toxicokinetics and Biliary Excretion of N-Nitrosodiethylamine in Rat Supplemented with Low and High Dietary Proteins.

Although biliary excretion is one of the biological elimination processes for foreign compounds, intake of high-protein diets was hypothesized to enhance their detoxification rates. Hence, this study investigates the effect of differential dietary protein intake on toxicokinetics and biliary excretion in rats following exposure to N-nitrosodiethylamine (NDEA) and aflatoxin B1 (AFB1). The animals were divided into five groups. Groups I and II were exposed to low and high dietary proteins following a single intraperitoneal dose of 43 µg NDEA/kg body weight, respectively. Groups III and IV were equally treated after a combined single intraperitoneal dose of 43 µg NDEA plus 0.022µg AFBI/kg body weight, respectively. Group V was fed with low-protein diets following a single intraperitoneal dose of 0.022µg AFB1/kg body weight. The experiment lasted 35 days. The bile excreted higher amounts of unchanged NDEA than nitrite. The groups placed on high-protein diets (HPD = 64%) eliminated higher amounts of the unchanged NDEA and nitrite than the lower-protein diet (LPD = 8%) groups. Furthermore, the animals fed with high dietary protein (HPD = 64%) depicted short half-life with corresponding increase in elimination rate constant. The presence of AFB1 heightened the excretion of bound NDEA with AFB1 than NDEA only. Generally, this study advocates that N-nitrosodiethylamine and the corresponding metabolites follow hepatobiliary system potentiated by high intake of dietary proteins.

Risk assessment of N-nitrosodiethylamine (NDEA) and N-nitrosodiethanolamine (NDELA) in cosmetics.

N-nitrosamines and their precursors found in cosmetics may be carcinogenic in humans. Thus the aim of this study was to carry out risk assessment for N-nitrosamines (N-nitrosodiethanolamine [NDELA], N-nitrosodiethylamine [NDEA]) and amines (triethanolamine [TEA], diethanolamine [DEA]) levels in cosmetics determined using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) procedures. NDELA and NDEA concentrations were present at levels of "not detected" (N.D.) to 596.5 µg/kg and N.D. to 40.9 µg/kg, respectively. TEA and DEA concentrations ranged from N.D. to 860 µg/kg and N.D. to 26.22 µg/kg, respectively. The nitrite concentration (3-2250 mg/l), number of nitrosating agents to a maximum 5, and pH (3.93-10.09) were also assessed. The impact of N-nitrosamine formation on the levels of TEA, DEA, nitrite, and other nitrosating agents was also examined. N-nitrosamine concentrations correlated with the number of nitrosating agents and nitrite concentrations. Data demonstrated that higher nitrite concentrations and a greater number of nitrosating agents increased NDELA and NDEA yields. Further, the presence of TEA and DEA exerted a significant influence on N-nitrosamine formation. Risk assessments, including the margin of exposure (MOE) and lifetime cancer risk (LCR) for N-nitrosamines and margin of safety (MOS) for amines, were calculated using product type, use pattern, and concentrations. Exposure to maximum amounts of NDELA and NDEA resulted in MOE > 10,000 (based upon the benchmark dose lower confidence limit 10%) and LCR <1 × 10-5, respectively. In addition, TEA and DEA concentrations in cosmetic samples resulted in MOS values >100. Therefore, no apparent safety concerns were associated with cosmetic products containing NDELA, NDEA, TEA, and DEA in this study. However, since amines and nitrosating agents produce carcinogenic nitrosamines, their use in cosmetics needs to be minimized to levels as low as technically feasible.

Determination of N-nitrosodiethanolamine in cosmetic products by reversed-phase dispersive liquid-liquid microextraction followed by liquid chromatography.

A new analytical method for the determination of N-nitrosodiethanolamine (NDELA), a very harmful compound not allowed in cosmetic products, is presented. The method is based on a new approach of dispersive liquid-liquid microextraction (DLLME) useful for extraction of highly polar compounds, called reversed-phase DLLME (RP-DLLME), followed by liquid chromatography-ultraviolet/visible (LC-UV/Vis) determination. The variables involved in the RP-DLLME process were studied to provide the best enrichment factors. Under the optimized conditions, a mixture of 750µL of acetone (disperser solvent) and 125µL of water (extraction solvent) was rapidly injected into 5mL of toluene sample solution. The extracts were injected into the LC-UV/Vis system using ammonium acetate 0.02M as mobile phase. After chromatographic separation, the eluate passed throughout a photolysis unit in order to convert NDELA to nitrite, and then it was merged with a flow stream of Griess Reagent and passed throughout a post-column reactor at 50°C to derivatize nitrite into an azo-dye, which was finally measured spectrophotometrically at 540nm. The method was successfully validated showing good linearity, an enrichment factor of 31.5±0.9, limits of detection and quantification of 1.1 and 3.6ngmL-1, respectively, and a good repeatability (RSD <8%). Finally, the proposed analytical method was applied to the determination of NDELA in commercial cosmetic samples of different nature, specifically three lipophilic creams and a hydrophilic shower gel, with good relative recovery values (87 - 117%) thus showing that matrix effects are negligible. These results were compared with those obtained by applying the ISO 10130 official method, which uses the same detection approach. It was concluded that a great improvement in the sensitivity was achieved, whereas the use of organochlorine solvents is avoided and therefore it can be considered as a greener approach.

Hepatic preneoplasia induction in male Wistar rats: histological studies up to five months post treatment

Background: Liver preneoplasia development in rats can be mimicked by an initiation-promotion model that induces the ppearance of altered hepatocyte foci (FAH). Aims: We compare two initiation-promotion models to evaluate the presence of FAH or additional hepatic pathologies in which other organs were affected up to five month post treatment. Material and methods: FAH were induced in male adult Wistar rats with two doses of dietylnitrosamine (DEN, 150 mg/kg bw) followed by 4 doses per week (3 weeks) of 2-acetylaminofluorene (2-AAF, 20 mg/kg bw) or with one dose of DEN (200 mg/kg bw) followed by 2 doses per week (3 weeks) of 2-AAF. DEN 150, DEN 200 and control rats (received the vehicle of the drugs) groups were compared. Rats were euthanized immediately after the last dose of 2-AAF, at 3, 4 and 5 months (n = 3 for euthanasia times per group). Samples of livers, lungs, idneys, pancreatic tissue and small bowel were processed for histological and immunohistochemical analysis. Results: FAH persisted for 5 months in all livers of the DEN groups. Three months after withdrawal of 2-AAF, one rat from DEN 150 group developed fibrosis and 5 months after 2-AAF removal another rat from the same group presented a microscopic hyperplastic nodule. Only the lungs had damages compatible with lesions induced by gavage-related reflux in DEN groups. Conclusion: We concluded that up to five month post treatments, FAH persisted in all the livers from DEN groups; livers from DEN 200 group showed no other hepatic lesions besides FAH, and only the lungs suffered pathological alterations in both treated groups (AU)

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Identification and quantification of seven volatile n-nitrosamines in cosmetics using gas chromatography/chemical ionization-mass spectrometry coupled with head space-solid phase microextraction.

An analytical method was developed for the identification and quantification of seven volatile n-nitrosamines (n-nitrosodimethylamine [NDMA], n-nitrosoethylmethylamine [NMEA], n-nitrosodiethylamine [NDEA], n-nitrosodipropylamine [NDPA], n-nitrosodibutylamine [NDBA], n-nitrosopiperidine [NPIP], and n-nitrosopyrrolidine [NPYR]) in water insoluble cream type cosmetics. It was found that the head space-solid phase microextraction (HS-SPME) was suitable for extraction, clean up, and pre-concentration of n-nitrosamines in the cream type samples so its optimal conditions were investigated. Identification and quantification of n-nitrosamines using single quadrupole gas chromatography/mass spectrometry (GC/MS) in chemical ionization (CI) mode were carried out with accurate mass measurements. Their accurate masses of protonated molecular ions were obtained within 10 mDa of the theoretical masses when sufficiently high signal was acquired from the unique calibration method using mass and isotope accuracy. For the method validation of quantification, spiking experiments were carried out to determine the linearity, recovery, and method detection limit (MDL) using three deuterated internal standards. The average recovery was 79% within 20% relative standard deviation (RSD) at the concentration of 50 ng/g. MDLs ranged from 0.46 ng/g to 36.54 ng/g, which was satisfactory for the directive limit of 50 ng/g proposed by the European Commission (EC). As a result, it was concluded that the method could be provided for the accurate mass screening, confirmation, and quantification of n-nitrosamines when applied to cosmetic inspection.

Analysis of N-nitrosodiethylamine by ion chromatography coupled with UV photolysis pretreatment.

Nitrosamines such as N-nitrosodiethylamine (NDEA) are commonly detected by spectrophotometry after photolysis and Griess reaction (PG) in food industries for lower cost. Results of this research indicate that NDEA decays rapidly under UV irradiation, and concentrations of the generated NO2- and NO3- ions vary with photolysis conditions. Thus, the measurement of the PG method may be inconsistent because it is based on the amount of photoproduced NO2-. In addition, more errors may be present in the PG method since NO3- cannot be measured colorimetrically using Griess reagent. In this work, the sum of the concentrations of photoproduced NO2- and NO3- was found to be equivalent to the initial NDEA before photolysis, and a photolysis-ion chromatography method was validated, which may serve as a feasible and accurate method to determine nitrosamines.

Determination of N-nitrosodiethanolamine, NDELA in cosmetic ingredients and products by mixed mode solid phase extraction and UPLC-tandem mass spectrometry with porous graphitic carbon column through systemic sample pre-cleanup procedure.

A rapid, sensitive, accurate and specific ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) method for the detection of N-nitrosodiethanolamine (NDELA), a highly toxic contaminant in cosmetic raw materials and products was developed and validated. Systematized sample preparation steps were developed according to product types. Various SPE cartridges and columns were examined to establish the condition of SPE and chromatographic separation for NDELA. Sample cleanup steps consisting of solvent and liquid-liquid extraction tailored to the various sample matrix types were established prior to mixed mode SPE (Bond Elut AccuCAT). Chromatographic separation was achieved within 7 min on a porous graphitic carbon (PGC) column using a gradient elution with the mobile phase of 1mM ammonium acetate containing 0.1% acetic acid and methanol. NDELA was monitored using an electrospray positive ionization mass spectrometry in the multiple reaction monitoring (MRM) mode (m/z 134.9>103.7(quantifier) and 73.7(qualifier ion)) with d8-NDELA (m/z 143.1>111.0) as internal standard. The standard curves were linear over the concentration range of 1-100 ng/mL with a correlation coefficient higher than 0.99. The limit of detection (LOD) and the limit of quantification (LOQ) was 10 and 20 µg/kg, respectively (0.5 and 1 ng/mL in standard solution). The intra- and inter-day precisions were estimated to be below 11.1% and accuracies were within the range of 90.8-115.8%. The validated method was successfully applied to the analysis of real samples including raw materials, skin care, make-up, shampoos and hair products.

Association of mustard oil as cooking media with carcinoma of the gallbladder.

PURPOSE: Carcinoma of the gallbladder (CaGB) is a common health problem in Northern India. Exact causative factors are still obscure. Dietary habits are also known to be a major factor in the gallbladder carcinogenesis. Mustard oil is mostly used as cooking media, which is adulterated by sanguinarine, diethylnitrosamine and repeated frying. We tried to find out the association of mustard oil as cooking media with CaGB. METHODS: Twenty patients each of CaGB (group I) and cholelithiasis (group II) were included in the study. Sanguinarine and diethylnitrosamine (DEN) were extracted from the tissue and blood samples from both groups. Mean and standard error of mean of the concentration of the sanguinarine and DEN were calculated. Mann-Whitney U test was applied to test the level of significance between the two groups. RESULTS: The mean concentration of tissue sanguinarine in both groups (I and II) was 195.18 ng/mg and 24.05 ng/mg, respectively, and the difference was statistically highly significant (p < 0.001). The estimated concentration of blood sanguinarine was 230.96 ng/mL and 14.0 ng/mL in group I and II, respectively, and the difference was statistically highly significant (p < 0.001). The concentration of DEN in the tissue sample was 38.08 ng/mg in CaGB and 2.51 ng/mg in cholelithiasis patient, and these values were statistically highly significant (p < 0.001). Similarly, blood DEN concentration was 119.05 ng/mL and 4.22 ng/mL in group I and II, respectively, and the difference was statistically highly significant (p < 0.001). CONCLUSION: There is an increase in concentration of sanguinarine and diethylnitrosamine in CaGB blood and tissue in comparison to the cholelithiasis group suggesting an association with carcinoma of the gallbladder.

Influence of various cooking methods on the concentrations of volatile N-nitrosamines and biogenic amines in dry-cured sausages.

N-nitrosamines, biogenic amines, and residual nitrites are harmful substances and are often present in cured meats. The effects of different cooking methods (boiling, pan-frying, deep-frying, and microwave) were investigated on their contents in dry-cured sausage. The various N-nitrosamines were isolated by a steam distillation method and analyzed by gas chromatography mass spectrometry (GC-MS). The biogenic amines were determined after extraction with perchloric acid as dansyl derivatives by high-performance liquid chromatography (HPLC) method. The results showed that initial dry-cured raw sausage contained 5.31 µg/kg of total N-nitrosamines. Cooking by deep-frying or pan-frying resulted in products having the highest (P < 0.05) contents, compared with boiling or microwave treatments, which were not different from the raw. Although frying increased the content of N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), and N-nitrosopyrrolidine (NPYR), it decreased the contents of histamine and cadaverine. Boiling and microwave treatments decreased the total biogenic amines significantly (P < 0.05). Residual nitrite was significantly reduced by cooking treatments. The results suggest that boiling and microwave treatments were more suitable methods for cured meat.

Determination of eight nitrosamines in water at the ng L(-1) levels by liquid chromatography coupled to atmospheric pressure chemical ionization tandem mass spectrometry.

In this work, we have developed a sensitive method for detection and quantification of eight N-nitrosamines, N-nitrosodimethylamine (NDMA), N-nitrosomorpholine (NMor), N-nitrosomethylethylamine (NMEA), N-nitrosopirrolidine (NPyr), N-nitrosodiethylamine (NDEA), N-nitrosopiperidine (NPip), N-nitroso-n-dipropylamine (NDPA) and N-nitrosodi-n-butylamine (NDBA) in drinking water. The method is based on liquid chromatography coupled to tandem mass spectrometry, using atmospheric pressure chemical ionization (APCI) in positive mode with a triple quadrupole analyzer (QqQ). The simultaneous acquisition of two MS/MS transitions in selected reaction monitoring mode (SRM) for each compound, together with the evaluation of their relative intensity, allowed the simultaneous quantification and reliable identification in water at ppt levels. Empirical formula of the product ions selected was confirmed by UHPLC-(Q)TOF MS accurate mass measurements from reference standards. Prior to LC-MS/MS QqQ analysis, a preconcentration step by off-line SPE using coconut charcoal EPA 521 cartridges (by passing 500 mL of water sample) was necessary to improve the sensitivity and to meet regulation requirements. For accurate quantification, two isotope labelled nitrosamines (NDMA-d(6) and NDPA-d(14)) were added as surrogate internal standards to the samples. The optimized method was validated at two concentration levels (10 and 100 ng L(-1)) in drinking water samples, obtaining satisfactory recoveries (between 90 and 120%) and precision (RSD<20%). Limits of detection were found to be in the range of 1-8 ng L(-1). The described methodology has been applied to different types of water samples: chlorinated from drinking water and wastewater treatment plants (DWTP and WWTP, respectively), wastewaters subjected to ozonation and tap waters.

Assessing granular media filtration for the removal of chemical contaminants from wastewater.

Granular media filtration was evaluated for the removal of a suite of chemical contaminants that can be found in wastewater. Laboratory- and pilot-scale sand and granular activated carbon (GAC) filters were trialled for their ability to remove atrazine, estrone (E1), 17α-ethynylestradiol (EE2), N-nitrosodimethylamine (NDMA), N-nitrosomorpholine (NMOR) and N-nitrosodiethylamine (NDEA). In general, sand filtration was ineffective in removing the contaminants from a tertiary treated wastewater, with the exception of E1 and EE2, where efficient removals were observed after approximately 150 d. Batch degradation experiments confirmed that the removal of E1 was through biological activity, with a pseudo-first-order degradation rate constant of 7.4 × 10(-3) h(-1). GAC filtration was initially able to effectively remove all contaminants; although removals decreased over time due to competition with other organics present in the water. The only exception was atrazine where removal remained consistently high throughout the experiment. Previously unreported differences were observed in the adsorption of the three nitrosamines, with the ease of removal following the trend, NDEA > NMOR > NDMA, consistent with their hydrophobic character. In most instances the removals from the pilot-scale filters were generally in agreement with the laboratory-scale filter, suggesting that there is potential in using laboratory-scale filters as monitoring tools to evaluate the performance of pilot- and possibly full-scale sand and GAC filters at wastewater treatment plants.

Analysis of nitrosamines in water by automated SPE and isotope dilution GC/HRMS Occurrence in the different steps of a drinking water treatment plant, and in chlorinated samples from a reservoir and a sewage treatment plant effluent.

A method based on automated solid-phase extraction (SPE) and isotope dilution gas chromatography/high resolution mass spectrometry (GC/HRMS) has been developed for the analysis of nine nitrosamines in water samples. The combination of automated SPE and GC/HRMS for the analysis of nitrosamines has not been reported previously. The method shows as advantages the selectivity and sensitivity of GC/HRMS analysis and the high efficiency of automated SPE with coconut charcoal EPA 521 cartridges. Low method detection limits (MDLs) were achieved, along with a greater facility of the procedure and less dependence on the operator with regard to the methods based on manual SPE. Quality requirements for isotope dilution-based methods were accomplished for most analysed nitrosamines, regarding to trueness (80-120%), method precision (<15%) and MDLs (0.08-1.7 ng/L). Nineteen water samples (16 samples from a drinking water treatment plant {DWTP}, 2 chlorinated samples from a sewage treatment plant {STP} effluent, and 1 chlorinated sample from a reservoir) were analysed. Concentrations of nitrosamines in the STP effluent were 309.4 and 730.2 ng/L, being higher when higher doses of chlorine were applied. N-Nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) were the main compounds identified in the STP effluent, and NDEA was detected above 200 ng/L, regulatory level for NDMA in effluents stated in Ontario (Canada). Lower concentrations of nitrosamines were found in the reservoir (20.3 ng/L) and in the DWTP samples (n.d. -28.6 ng/L). NDMA and NDEA were respectively found in the reservoir and in treated and highly chlorinated DWTP samples at concentrations above 10 ng/L (guide value established in different countries). The highest concentrations of nitrosamines were found after chlorination and ozonation processes (ozonated, treated and highly chlorinated water) in DWTP samples.

Monitoring of N-nitrosodiethanolamine in cosmetic products by ion-pair complex liquid chromatography and identification with negative ion electrospray ionization mass spectrometry.

A high-performance liquid chromatographic (HPLC) method was developed for the determination of N-nitrosodiethanolamine (NDELA), which is a non-volatile N-nitrosoamine. In this method, sodium 1-octanesulfonate has been used as an ion complexation agent for NDELA. The resulting complex was analyzed by reversed-phase high-performance liquid chromatography (RP-HPLC) using a Eurospher-100 C18 column (250 x 4.6 mm, 5 microm), water/acetonitrile (95/5, v/v) and UV detection at 234 nm. The detector response was linear in the range 0.03-10.00 microg mL(-1) and the limit of detection was 0.01 microg mL(-1). The complexation of the NDELA and sodium 1-octanesulfonate was confirmed by negative ion electrospray ionization mass spectrometry at m/z 327 [M-Na](-) and also MS/MS measurements of the resulting fragments. For real sample analyses, NDELA was measured in cosmetic products after clean up by solid-phase extraction (SPE) with C(18) cartridge for water-soluble samples and liquid-liquid extraction (LLE) by methylene chloride for less water-soluble samples. The average values for NDELA recovery by SPE and LLE were 86.9 and 51.8% and relative standard deviations (RSDs%) were 0.9 and 5.6%, respectively. The presented method is easy to use, robust and can be implemented on any reversed-phase HPLC system with UV detection.

Research needs in drinking water: a basis in regulations in the United States.

Regulations are one of the primary drivers for research on contaminants in drinking water in the United States. Since the original Safe Drinking Water Act (SDWA), enacted in 1974, the United States Environmental Protection Agency (USEPA) has developed a series of drinking water regulations. These regulations are focused on protecting public health. When evaluating available information on whether or not to regulate a constituent in drinking water, USEPA considers available information on health effects and occurrence of the constituent. The authors provide their view of the research needed for these contaminants. For inorganics, more data are needed on perchlorate. For organics, greater treatment and health effects information is warranted for N-nitrosodimethylamine (NDMA), methyl tertiary butyl ether (MTBE) and pharmaceuticals and personal care products. Finally, more research is needed on analytical methods for noroviruses and other emerging pathogens.

Investigation of the formation of N-nitrosodiethanolamine in B6C3F1 mice following topical administration of triethanolamine.

To determine potential nitrosation of triethanolamine (TEA) to N-nitrosodiethanolamine (NDELA) at different physiological conditions of the GI tract, in vitro NDELA formation was examined in aqueous reaction mixtures at several pHs (2-10) adjusted with acetic, sulphuric or hydrochloric acids or in cultures of mouse cecal microflora incubated. In vivo NDELA formation was also determined in blood, ingesta, and urine of female B6C3F1 mice after repeated dermal, most relevant human route, or single oral exposure to 1000 mg/kg TEA in the presence of high oral dosages of NaNO(2). Appropriate diethanolamine (DEA) controls were included to account for this impurity in the TEA used. Samples were analyzed for NDELA using GC/MS. The highest degree of nitrosation of TEA to NDELA ( approximately 3%) was observed in the in vitro cultures at pH 4 and acetic acid with lower amounts obtained using sulphuric acid ( approximately 1.3%) and hydrochloric acid ( approximately 1.2%). At pH 7, <1% of the TEA was nitrosated to NDELA and at pH 2 (HCl) or pH 10 (NaOH) no NDELA was found above the limit of detection. In incubated cultures containing cecal microflora and nutrient broth, only 0.68% of TEA was nitrosated to NDELA. No NDELA was formed in rats repeatedly dermally dosed with TEA at the limits of detection in blood (0.001 microg/ml, ppm), ingesta (0.006 microg/ml, ppm), and urine (0.47 microg/ml, ppm). Levels of NDELA measured in blood and ingesta after a single oral dose of TEA and NaNO(2) were less than those in DEA controls. These findings in toto confirm the lack of any significant formation of NDELA from TEA in vivo.