Percutaneous absorption of N,N-dimethylformamide in humans

Summary Skin penetration fo N,N-dimethylformamide (DMF) liquid or vapour was studied in volunteers. Exposure to liquid DMF was performed in two ways: in a dipping experiment, one hand was dipped up to the wrist in DMF for 2–20 min, while in a patch experiment, 2 mmol DMF was applied to the skin and allowed to be absorbed completely. The period of exposure to DMF vapour (50 mg · m^–3) was 4 h. The DMF metabolites N-hydroxymethyl-N-methylformamide (MF), N-hydroxymethylformamide (F), and N-acetyl-S-(N-methylcarbamoyl)cysteine (AMCC) were monitored in the urine. Liquid DMF was absorbed through the skin at a rate of 9.4 mg · cm^–2 · h^–1. Percutaneous absorption of DMF vapour depended strongly on ambient temperature and humidity and accounted for 13%–36% of totally excreted MF. The results suggest that skin absorption of liquid DMF is likely to contribute to occupational exposure substantially more than penetration of DMF vapour. The yield of metabolites after transdermal DMF absorption was only half of that seen after pulmonary absorption. Elimination of MF and F but not that of AMCC was delayed, which supports the contention that AMCC should be used instead of MF as the most suitable biomarker of DMF in cases where percutaneous intake can occur.     

Biological monitoring of workers exposed toN,N-dimethylformamide by determination of the urinary metabolites,N-methylformamide andN-acetyl-S-(N-methylcarbamoyl) cysteine

Biological monitoring of workers exposed toN,N-dimethylformamide (DMF) was carried out by determination of the urinary metabolites,N-methylformamide (MF, mainly fromN-hydroxymethylformamide) andN-acetyl-S-(N-methylcarbamoyl)cysteine (AMCC), which were derived from two different routes of metabolism of the solvent. The urinary levels of MF increased rapidly at the start of the work shift, and decreased almost to zero within 24 h after the beginning of the last exposure. The highest level was found between the end of the afternoon shift and bedtime. AMCC levels remained constant over the consecutive work days and increased after the cessation of exposure, with the peak concentration being observed at 16–40 h after the cessation of exposure. AMCC levels at the beginning of the next morning shift were closely correlated with personal exposure levels of DMF in air, although the correlation of MF and DMF in air was highest in the urine at the end of the shift. Hence urinary AMCC represents an index of the average exposure during several preceding work days and may indicate the internal dose. By contrast, MF represents an index of daily exposure.     

Occupational Exposure to N,N-Dimethylformamide in the Summer and Winter

We evaluated total body burden of N,N-dimethylformamide (DMF) taken through the lung and skin by personal exposure of workers to DMF and urinalysis of N-methylformamide (NMF) and N-acetyl-S(N-methylcarbamoyl)-cysteine (AMCC). A total of 270 workers were engaged in four different jobs in a workplace distant from main production lines emanating high levels of DMF. They were not required to wear any personal protective equipment including respirators or gloves. We found that log-transformed urinary levels of NMF and AMCC increased with an increase in log-transformed concentrations of exposure to DMF. Urinary levels of NMF and AMCC were significantly higher in the summer than the winter, although there was no significant seasonal difference in the concentrations of exposure to DMF. Our findings suggested that the increased urinary levels of NMF and AMCC in the summer resulted in increased skin absorption of DMF due to an increased amount of DMF absorbed by the moisturized skin under humid and hot conditions. Seasonal changes in the relative internal exposure index confirmed the present finding of enhanced summertime skin absorption of DMF. AMCC is thought to be a useful biomarker for assessments of cumulative exposure to DMF over a workweek and for evaluations of workers’ health effects.     

Biological monitoring of workers exposed to<Emphasis Type="Italic"> N</Emphasis>,<Emphasis Type="Italic">N</Emphasis>-dimethylformamide in synthetic leather manufacturing factories in Korea

Objectives To investigate the relationship between N,N-dimethylformamide (DMF) exposure and excretion of urinary N-acetyl-S-(N-methylcarbamoyl)cysteine (AMCC) and N-methylformamide (NMF) in workers at synthetic leather manufacturing factories in Korea, for the first time.Methods One-hundred forty-four male workers at nine synthetic leather manufacturing factories were surveyed. Exposure to DMF was evaluated through breathing zone air sampling followed by analysis via a gas chromatograph equipped with a flame ionization detector (GC-FID). The levels of NMF and AMCC were determined by a GC with a flame thermionic detector (GC-FTD). Urine samples were collected at the end of the workshift.Results and Conclusions Geometric mean of workplace air DMF and urinary NMF was 8.8 ppm and 47.5 mg/l, respectively, and the level of DMF and NMF was significantly correlated. The biological exposure limit for NMF (15 mg/ml) was exceeded in 89.5% of urine samples, and 37.9% of air samples exceeded the environmental DMF exposure limit (10 ppm), indicating a serious health risk to the employees of the synthetic leather industry in Korea. Exposure to 10 ppm DMF in the workplace air corresponded to a urinary NMF concentration of 53.4 mg/l. Alcohol intake the day before urine was sampled influenced NMF excretion into urine (40.5 mg/l NMF for the no-alcohol group and 94.6 mg/l for the group consuming more than 63.0 g alcohol/day). We could not find a significant relationship between air DMF and urinary AMCC concentration. Exposure to 10 ppm DMF corresponded to an AMCC concentration of 8.0 mg/l in the urine samples collected on the same day as the air was sampled.     

Biological monitoring of workers exposed to N-N-dimethylformamide

Some methods for analysing N,N-dimethylformamide and its metabolites [hydroxymethyl-N-methylformamide, hydroxymethylformamide and N-acetyl-S-(N-methylcarbamoyl)cysteine] in the urine of exposed workers are described. Unchanged dimethylformamide was measured after pretreatment of urine (2 ml) with silica gel cartridges and elution with methanol. The gas chromatographic analysis using a nitrogen phosphor detector made it possible to detect N,N-dimethylformamide in urine even when workers were exposed to low concentrations of the solvent (about 1 mg/m³). N-Hydroxymethyl-N-methylformamide and N-hydroxymethylformamide were analysed as N-methylformamide and formamide respectively after direct injection of urine into the gas chromatograph. The injection port temperature played an important role in the gas chromatographic determination of these products. Reliable results were obtained when direct or split injections were performed at 250°C. The splitless injection gave the same reliable results at 150°C. In urine samples from occupationally non-exposed persons, N-methylformamide could not be detected. In contrast, formamide (or its precursor, hydroxymethylformamide) was present in every urine sample. Our results in respect of 19 urine samples analysed with the injection port of the gas chromatograph at 250°C gave a mean of 8.6 mg/l of formamide. N-Acetyl-S-(N-methylcar-bamoyl)cysteine was determined using a modified method for analysing organic acid in urine samples. The metabolite was extracted with ethyl ether in an acid environment, treated with a silylating reagent and measured by gas chromatography/mass spectrometry.     

Metabolism studies of N,N-dimethylformamide

Summary In acute and subacute inhalation studies rats and dogs were exposed to N,N-dimethylformamide. In addition dogs were subjected to subchronic inhalation tests.The rats were subjected to N,N-dimethylformamide concentrations of 21, 146 or 2005 ppm during the 3-hr trial. During the 6-hr exposure they were subjected to 29 or 170 ppm.In the case of repeated exposures on rats the average concentration was 350 ppm.In the 6-hr test dogs were exposed to 20, 32, 143 or 172 ppm. In the 5-day test (6 hrs/day) they were exposed to 23 or 59 ppm, and in the 4-week test (6 hrs/day) the concentration was 20 ppm (MAC).The metabolisation of N,N-dimethylformamide was studied in rats and dogs. Methods for the analytical determination of the unchanged active substance and its metabolites (N-methylformamide and formamide) in blood and urine were developed.In addition to the already known metabolite N-methylformamide, a further metabolite, formamide, was found in the urine of rats and dogs. The elimination rate of N-methylformamide and formamide differed in dogs and rats. The elimination rate in dogs was much slower. In the group of dogs subjected to repeated inhalation of 59 ppm an accumulation of N-methylformamide was determined in the blood and urine. In the case of rats exposed to substantially higher subacute N,N-dimethylformamide concentration (350 ppm) this phenomenon was not observed.In the MAC-range (20 ppm) the dogs of the subacute and subchronic group showed no signs of accumulation.The results of the liver and kidney function studies in dogs exposed to 20 ppm N,N-dimethylformamide for 4 weeks were normal.     

N,N-dimethylbenzylamine: occupationa exposure,analysis and biological monitoring

Dimethylbenzylamine (DMBA) is used in the production of epoxy resins. The aims of this study were to assess occupational exposure to DMBA and evaluate the usefulness of monitoring the urinary excretion of DMBA and DMBA metabolites as indicators of exposure to DMBA. A sensitive gas chromatographic method for analysis of DMBA in air and in urine has been developed. The detection limit for DMBA in air for a 60-l air sample collected in 10 ml absorption solution was 2 g/m³ and in charcoal tubes, 0.3 g/m³. The detection limit for DMBA in urine was 0.02 mg/l. Ten male workers manufacturing epoxy resin were monitored during a full shift in the working environment and urine samples were collected at the end of exposure. The mean exposure and the highest DMBA concentration observed in air were 18 g/m³ (time-weighted average; range 3–48 g/m³) and 91 g/m³, respectively. The DMBA concentrations in the urine samples were below the detection limit. After reduction of the urine samples the DMBA concentrations in the urine samples were below the detection limit. After reduction of the urine samples the DMBA concentrations (U-SumDMBA) ranged from 0.02 to 0.22 mg/l. There was significant correlation between the exposure to DMBA and the U-SumDMBA. This observation suggests that the U-SumDMBA in urine samples collected at the end of a shift is a useful indicators of occupational exposure to DMBA.     

Uptake,metabolism and elimination of cyclohexanone in humans

The metabolism and toxicokinetics of cyclohexanone (CH-one), an important solvent and chemical intermediate, have been studied in volunteers during and after 8-h exposures to CH-one vapour at a concentration of 101, 207 and 406 mg · m^–3. The pulmonary ventilation in these experiments was typically 11 1 · min^–1 and retention in the respiratory tract was 58%. After exposure to CH-one, 207 mg · m^–3, the metabolic yields of cyclohexanol (CH-ol), 1,2- and 1,4-cyclohexanediol (CH-diol) as determined in urine by a gas chromatographic method involving hydrolysis of glucuronide conjugate were 1.0% ±0.3%, 39% ± 5% and 18% ± 2% (n = 8), respectively. Peak excretion of CH-ol was achieved at the end of the exposure period, after which it decayed rapidly. Elimination of 1,2- and 1,4-CH-diol reached maximum values a few hours following exposure, with subsequent elimination half-times of 16 ± 2 and 18 ± 4 h, respectively. Repeated exposure to CH-one vapour (around 200 mg · m^–3) for five consecutive days (8 h/day) resulted in cumulative excretion of CH-diols. The permeation rate of CH-one liquid through the skin was 0.037–0.069 mg · cm^–2 · h^–1 (n = 3), indicating that the contribution of percutaneous absorption to total CH-one occupational intake is of minor importance. CH-diols are recommended as biomarkers of exposure to CH-one.     

Difference in uptake,elimination, and metabolism in exposure to trichloroethylene, 1,1,1-trichloroethane and tetrachloroethylene

Summary The relatively high and almost constant absorption/min of trichloroethylene (TRI) is explained by the relatively high partition coefficient between blood and air (b/g = 15) combined with the rapid metabolism (75 %). Tetrachloroethylene (PERC) has about the same b/g as TRI, but the metabolism is insignificant (2 %); therefore, the amount taken up/min decreases in the course of exposure. The b/g (5) for 1,1,1-trichloroethane (MC) is smaller, the metabolism is insignificant (3.5 %), therefore the capacity of the body to absorb MC is relatively small and in consequence the uptake/min decreases fast in the course of exposure. Due to the lower b/g the excretion of MC after exposure is much faster than of PERC. As a result of the metabolism of TRI only a relatively small amount of TRI absorbed is excreted by the lungs after exposure.     

Experimental study on the metabolism of dimethylethylamine in man

Summary Dimethylethylamine (DMEA) is an aliphatic tertiary amine, which is used is a catalyst in the mould core manufacturing. During 8 h, four healthy volunteers were exposed to four different DMEA air concentrations (10, 20, 40 and 50 mg/m³; 20 mg/m³, two subjects only). DMEA was biotransformed into dimethylethyl-amine N-oxide (DMEAO). On average, DMEAO, accounted for 90% of the combined amount of DMEA and DMEAO excreted into the urine. The half-lives of DMEA and DMEAO in plasma were 1.3 and 3.0h, respectively. The urinary excretion of DMEA and DMEAO followed a two-phase pattern. The half-lives in the first phase were 1.5 h for DMEA and 2.5 h for DMEAO. In the second phase, which started about 9 h after the end of exposure, half-lives of 7 h for DMEA and 8 h for DMEAO were recorded. The combined concentration of DMEA and DMEAO, in both plasma and urine, showed an excellent correlation with the air concentration of DMEA. Thus, both urinary excretion and plasma concentration can be used for biological monitoring of exposure to DMEA. An 8-h exposure to 10 mg DMEA/m³ corresponds to a postexposure plasma concentration and 2-h postexposure urinary excretion of 4.9 mol/1 and 75 mmol/mol creatinine, respectively.     

Absorption, metabolism, degradation and urinary excretion of rosmarinic acid after intake of Perilla frutescens extract in humans

Summary Background Rosmarinic acid (RA) is a natural polyphenolic substance contained in many Lamiaceae herbs such as Perilla frutescens. Previous studies have shown RA has antioxidative and anti-inflammatory activity. However, little is known on the absorption, metabolism, degradation and excretion of RA. Aim of the study The aim of this study in healthy humans was to determine the absorption, metabolism, and urinary excretion of RA after a single intake of perilla extract (PE). Method Six healthy men (mean age 37.2 ± 6.2 y and mean body mass index 22.0 ± 1.9 kg/m²) were enrolled in the study that was a crossover design involving single intakes of PE containing 200 mg RA and placebo with a 10 day interval between treatments. Blood samples were collected before intake and at designated time intervals, while urine samples were collected over the periods 0-6 h, 6-24 h and 24-48 h after intake. RA and its related metabolites in plasma and urine were measured by LC-MS. Results RA, methylated RA (methyl-RA), caffeic acid (CAA), ferulic acid (FA) and a trace of m-coumaric acid (COA) were detected in the urine after intake of PE. In plasma, RA, methyl-RA and FA were detected, with maximum levels obtained 0.5, 2 and 0.5 h after intake of PE, respectively. The majority of these components in both plasma and urine were present as conjugated forms (glucuronide and/or sulfated). The proportion of RA and its related metabolites excreted in the urine was 6.3 ± 2.2% of the total dose,with approximately 75% of these components being excreted within 6h after intake of PE. Conclusions RA contained in PE was absorbed, conjugated and methylated following intake,with a small proportion of RA being degraded into various components, such as conjugated forms of CAA, FA and COA. These metabolites were then rapidly excreted in the urine.An erratum to this article can be found at     

毛细管气相色谱法测定工作场所空气中二甲基甲酰胺

目的:建立毛细管气相色谱法测定工作场所空气中二甲基甲酰胺的方法。方法:用HP-INNOWax毛细管柱(30 m×0.25 mm×0.25μm)分离检测。结果:该法分离效果好,检出限为0.5μg/ml,相关系数为0.9998,RSD<5%。结论:方法灵敏、准确。     

Biological monitoring of workers exposed to N,N-dimethylformamide in the synthetic fibre industry

Objectives: Monitoring of workplace air and biological monitoring of 23 workers exposed to N,N-dimethylformamide (DMF) in the polyacrylic fibre industry was carried out on 4 consecutive days. The main focus of the investigation was to study the relationship between external and internal exposure, the suitability of the metabolites of DMF for biological monitoring and their toxicokinetic behaviour in humans.Methods: Air samples were collected using personal air samplers. The limit of detection (LOD) for DMF using an analytical method recommended by the Deutsche Forschungsgemeinschaft (DFG) was 0.1 ppm. The urinary metabolites, N-hydroxymethyl-N-methylformamide (HMMF), N-methylformamide (NMF), and N-acetyl-S-(N-methylcarbamoyl)-cysteine (AMCC), were determined in one analytical run by gas chromatography with thermionic sensitive detection (GC/TSD). The total sum of HMMF and NMF was determined in the form of NMF. The LOD was 1.0 mg/l for NMF and 0.5 mg/l for AMCC. Results and conclusions: The external exposure to DMF vapour varied greatly depending on the workplace (median 1.74 ppm, range <0.1–159.77 ppm). Urinary NMF concentrations were highest in post-shift samples. They also covered a wide range (<1.0–108.7 mg/l). This variation was probably the result of different concentrations of DMF in the air at different workplaces, dermal absorption and differences in the protective measures implemented by each individual (gloves, gas masks etc.). The urinary NMF concentrations had decreased almost to zero by the beginning of the next shift. The median half-time for NMF was determined to be 5.1 h. The concentrations of AMCC in urine were determined to be in the range from <0.5 to 204.9 mg/l. Unlike the concentrations of NMF, the AMCC concentrations did not decrease during the intervals between the shifts. For the exposure situation investigated in our study, a steady state was found between the external exposure to DMF and the levels of AMCC excreted in urine about 2  days after the beginning of exposure. AMCC is therefore excreted more slowly than NMF. The half-time for AMCC is more than 16 h. Linear regression analysis for external exposure and urinary excretion of metabolites was carried out for a sub-group of 12 workers. External exposure to 10 ppm DMF in air (the current German MAK value) corresponds to an average NMF concentration of about 27.9 mg/l in post-shift urine from the same day and an average AMCC concentration of 69.2 mg/l in pre-shift urine from the following day. NMF in urine samples therefore represents an index of daily exposure to DMF, while AMCC represents an index of the average exposure over the preceding working days. AMCC is considered to be better suited for biomonitoring purposes because (1) it has a longer half-time than NMF and (2) its formation in humans is more closely related to DMF toxicity. Received: 25 June 1999 / Accepted: 2 October 1999     

Dermal absorption and urinary elimination of N-methyl-2-pyrrolidone

Objectives: The dermal absorption of the solvent N-methyl-2-pyrrolidone (NMP) and its elimination in urine was investigated in an experimental study. Methods: Seven volunteers were exposed to 1045 mg of liquid NMP under occlusive conditions for 2 h. Urine was collected before, during and up to 72 h after the exposure and analysed for NMP by GC/MS after liquid–liquid extraction. Additionally, the remaining NMP in the pads was determined to estimate the total dermal uptake. Results: The concentration of NMP in urine increased rapidly after beginning of the exposure up to 1 h after the exposure was completed. A peak concentration of 1,836±863 μg/l was observed, the half-life in urine was 3.2 h. About 0.5% of the absorbed dose was excreted metabolically unchanged. An average dermal absorption of 5.5 mg cm⁻² h⁻¹ was calculated. Conclusions: The results of this study show that the percutaneous absorption of NMP may contribute significantly to the overall uptake of the solvent, e.g. in the workplace. Therefore, a biological monitoring of NMP exposed workers is essential for occupational-medical surveillance.     

二甲基甲酰胺接触工人血清3项脂质过氧化指标的变化

目的探讨二甲基甲酰胺(DMF)作业工人血清丙二醛(MDA)水平、谷胱甘肽过氧化酶(GSH-Px)及超氧化物歧化酶(SOD)活力的变化。方法选取DMF作业工人105人作为接触组,健康献血员30名作为对照组。接触组按接触DMF空气浓度不同分为高浓度组和低浓度组;按接触DMF工作时间不同分为长工龄组和短工龄组。检测各组血清SOD、GSH-Px的活力和MDA水平。结果GSH-Px活力在低浓度组增高、显著高于高浓度组(P<0.05)。SOD活力、MDA水平随DMF浓度的上升呈上升趋势,SOD活力不同浓度组间差异均有显著性(P<0.05),MDA水平低浓度组与高浓度组比较差异有显著性(P<0.05),低浓度组与对照组比较差异无显著性。结论高浓度DMF接触对机体有致脂质过氧化作用,可引起血清GSH-Px的活力下降,MDA水平升高。     

Synthesis, antimicrobial activity and molecular modeling of cobalt and nickel complexes containing the bulky ligand: bis[N-(2,6-diisopropylphenyl)imino] acenaphthene

Two cobalt and two Nickel complexes of bis[N-(2,6-diisopropylphenyl)imino]acenaphthene (Pr-BIAN) ligand, have been synthesized. These complexes, namely [Co(Pr-BIAN)Cl2] 1, [Co(OAc)2 (Pr-BIAN)2](ClO4) 2, [Ni(Pr-BIAN)(NO3)2] 3 and [Ni(Pr-BIAN)2](ClO4)2 4, were characterized by elemental analyses, molar conductance, spectral (IR, UV-Visible and NMR) and magnetic moment measurements. In these complexes the geometries about the metal center are significantly different. While for complexes 2 and 3 an octahedral structure is proposed, in complex 4, square-planar coordination with an almost perfect planar arrangement of two Pr-BIAN ligands around the nickel center is suggested. In 1, two imine nitrogen atoms of Pr-BIAN and two chloride atoms are coordinating in a tetrahedral fashion around the cobalt center. Molecular mechanics (MM+) and semiempirical molecular orbital calculations have been performed for the most biologically active complex 1 and its free ligand Pr-BIAN and compared with inactive ligand bis[N-(p-tolylphenyl)imino]acenaphthene 6, to get insight into their molecular structures and to learn more about their stable molecular conformations.     

Drug-induced modifications of the immune response 8. N-(Substituted phenyl)-2,5-dihydro-2-oxo-4-[(substituted phenyl) amino]-3-furancarboxamide derivatives

The synthesis and anti-allergic activity of a series of novel N-(substituted phenyl)-2,5-dihydro-2-oxo-4-[(substituted phenyl)amino]-3-furancarboxamide derivatives (12) are described. The latter were obtained through a novel, and heretofore unknown rearrangement of 2-(N-phenylamino)-4,5-dihydro-4-oxo-3-furancarboxylic acids 8a to the 2(5H)-furanone amides 12.     

同时测定工作场所空气中二甲基甲酰胺和二甲基乙酰胺的气相色谱质谱联用测定法

目的建立工作场所空气中二甲基甲酰胺（DMF）和二甲基乙酰胺（DMA）的气相色谱质谱联用测定法。方法采用多孔玻板吸收管采集,经DB-5MS毛细管色谱柱分离后气相色谱质谱联用仪测定。结果该方法 DMF和DMA的分离效果好,检出限分别为1.2和1.1μg/ml;方法的重现性好,相对标准偏差分别为1.6%-3.1%和1.8%-3.5%;平均加标回收率分别为94.2%-102.5%和92.9%-104.4%。结论该方法精确、稳定、灵敏度高,适用于工作场所空气中DMF和DMA的同时测定。     

Solvatochromism, DNA binding, antitumor activity and molecular modeling study of mixed-ligand copper(II) complexes containing the bulky ligand: bis[N-(p-tolyl)imino]acenaphthene

Four mixed-ligand copper(II) complexes of the nitrogen ligand bis[N-(p-tolyl)imino]acenaphthene 1 (p-Tol-BIAN). These complexes, namely [Cu(p-Tol-BIAN)2](ClO4)2 2, [Cu(p-Tol-BIAN)(acac)](ClO4) 3, [Cu(p-Tol-BIAN)Cl2] 4 and [Cu(p-Tol-BIAN)(AcOH)(2)](ClO4)2 5, were prepared and characterized. Solvatochromism of the novel copper complexes in various solvents has been studied. Molecular mechanics (MM+) and molecular dynamic simulations have been performed to learn more about the solvatochromic behaviour and the DNA binding affinity of these complexes.     

Synthesis and aldose reductase inhibitory activity of N-(quinolinyl thiocarbonyl) glycine derivatives

The onset of diabetic complications may be prevented by the inhibition of aldose reductase. Derivatives of N-(quinolinyl thiocarbonyl) glycine were prepared and their in vitro and ex vivo aldose reductase inhibitory activities were tested on rat lens. The cincophen derivatives were the most potent in vitro with an enzyme inhibition value of 29% at 10⁻⁸ M and 91% at 10⁻⁷ M for the N-[(2-phenylquinolin-4-yl)thiocarbonyl]-N-methylglycine compound 10a. This activity was shown to be dependent on the nature of the substituents and seems to be optimal for the acids; esters were found to be inactive. No compound have shown ex vivo inhibitory activity. It is concluded that the lack of ex vivo activity is likely due to a poor bioavailability or a bad penetration of the compounds in target tissue (lens).