Abstract  Organic solvents are still essential in many industrial applications. To improve safety and health in the working environment lower occupational thresholds limits have been established and less toxic substitutes were introduced. N-Methyl-2-pyrrolidone (NMP) is a versatile solvent that is used as a substitute for dichloromethane in paint strippers. Due to conflicting results, there is a debate whether NMP causes irritations of the upper airways/eyes or not. In a human experimental study we examined the chemosensory effects of NMP under controlled conditions. Fifteen healthy males were investigated in a cross-over study. NMP vapor concentrations were 10, 40 and 80 mg/m(3) for 2 x 4h with an exposure-free lunch break of 30 min. To maximize chemosensory effects a peak exposure scenario (25mg/m(3) baseline, 160 mg/m(3) peaks 4 x 15 min, time-weighted average: 72 mg/m(3)) was tested. The four different conditions were conducted with and without moderate physical workload. Chemosensory effects were measured physiologically by anterior rhinomanometry, eye blink rate and breathing frequency. Subjectively, ratings of acute health symptoms and intensity of olfactory and trigeminal sensations were collected repeatedly throughout the exposures. All physiological variables were unaffected by the different NMP concentrations and even the peak exposures were non-effective on these measures. Olfactory mediated health symptoms increased dose-dependently. For these symptoms a strong adaptation was observable, especially during the first 4h of the exposures. Other acute symptoms were not significantly affected. Comparable to the symptoms, only olfactory sensations increased dose-dependently. Trigeminal sensations (e.g. eye and nose irritations) were evaluated as being barely detectable during the different exposures, only during 160 mg/m(3) exposure peak weak and transient eye irritation were reported. The results clearly suggest that NMP concentrations of up to 160 mg/m(3) caused no adverse sensory irritation or undue annoyance.

Abstract  N-methyl-2-pyrrolidone is a solvent that is increasingly used in a variety of industries, including petroleum refining, microelectronics, pesticide formulation, and veterinary medicine. Animal studies have demonstrated fetotoxic effects after maternal exposure to doses that have minimal to no adverse effect on the mothers. The fetotoxicity comprises resorption, stillbirth, and low birthweight and delayed ossification in surviving young. We report a human case of intrauterine growth retardation followed by fetal demise at 31 weeks gestation. The mother was a laboratory worker with no other apparent risk factors, who sustained occupational exposure to N-methyl-2-pyrrolidone throughout the first trimester of pregnancy. Laboratory work and solvent exposure have both previously been associated with adverse reproductive outcomes. Laboratories and other industries that use suspected reproductive toxins should have reproductive health policies in place that allow for decision-making based on toxicologic review, exposure assessment, and medical evaluation. These policies should allow for voluntary removal of prospective parents until environmental assessment and controls are instituted.

Abstract  This study was aimed at clarifying the effect of exposure to N-methyl-2-pyrrolidone (NMP) on workers' health. Fifteen male NMP-exposed workers and 15 referent male workers were recruited for this study. Exposure concentrations were assessed by determining NMP in the breathing zones and urinary NMP. Clinical examinations, motor and sensory nerve conduction velocities in the dominant arm, and neurobehavioral tests were carried out. The subjects were asked to complete self-administered questionnaires for subjective symptoms and psychological assessment. The mean NMP exposure concentrations ranged from 0.14 to 0.26 ppm, and urinary NMP levels at the end of each workday ranged from 0.17 to 0.22 mg/l, throughout the work week. In terms of clinical data, motor and sensory nerve conduction velocities, neurobehavioral tests, and subjective symptom assessments, there were no differences and no dose-dependent changes in either the means or the prevalence of abnormal findings between NMP-exposed and referent workers.

Abstract  To examine the value of urinary 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP) and 2-hydroxy-N-methylsuccinimide (2-HMSI) in a population of workers exposed to N-methyl-2-pyrrolidone (NMP) and to look for health effects of exposure to this organic solvent.

Airborne NMP was determined according to the NIOSH method. Urinary 5-HNMP and 2-HMSI (after and before next shift) were determined by liquid chromatography with tandem mass spectrometry. Outcomes were effects on lung, kidney, skin and mucous membranes, nervous system, haematopoiesis and liver determined by clinical examination and laboratory measurements. Univariate statistical methods and multiple regressions were used to analyse results. Skin resorption, smoking and other potential confounders were taken into account.

Three hundred twenty-seven workers were eligible out of which 207 workers (63 %) participated. Ninety-one of these worked with NMP. Occupational exposure to NMP did often not occur daily and ranged from non-detectable to 25.8 mg/m(3) (median = 0.18). Urinary 2-HMSI (mg/l; before next shift) was the best biomarker of exposure to NMP, explaining about 70 % of the variance, but most likelihood ratios did not allow for ruling exposure in or out, at these low levels of exposure. Creatinine adjustment did not improve the results clearly. No clear and consistent health effects could be associated with NMP exposure. No indication for a bias due to non-participation was found.

Biological monitoring, primarily urinary 2-HMSI (mg/l; before next shift), is of value to estimate exposure to NMP even when exposure is irregular and low. Likelihood ratios of urinary 5-HMNP or 2-HMSI are, however, not quite satisfactory at these low levels. No irritant or other health effects were found.

Abstract  OBJECTIVES: To study the acute effects of exposure to the increasingly used solvent, N-methyl-2-pyrrolidone (NMP) in male volunteers. Further, to determine the NMP concentration in plasma and urine during and after the exposure.

METHODS: Six male volunteers were exposed for eight hours on four different days to 0, 10, 25, and 50 mg/m3 NMP. Plasma was collected and urine was sampled during and after the exposure. Changes in nasal volume were measured by acoustic rhinometry and in airway resistance by spirometry.

RESULTS: The eight-hour experimental exposure to 10, 25, and 50 mg/m3 did not induce discomfort to eyes or upper airways. Acute changes in nasal volume were not found, and no changes in the spirometric data could be registered. The elimination curves suggested a non-linear pattern and at the end of exposure showed mean (range) half lifes of NMP in plasma of about 4.0 (2.9-5.8) hours and in urine 4.5 (3.5-6.6) hours. The unmetabolised NMP found in urine samples collected during exposure and at the subsequent 44 hours corresponded to about 2% of the calculated absorbed dose. At the end of the exposure there was a close correlation between exposures and the plasma concentration and urinary excretion of NMP.

CONCLUSIONS: NMP was absorbed through the respiratory tract and readily eliminated from the body, mainly by biotransformation to other compounds. Exposure to 10, 25, or 50 mg/m3 NMP did not cause nose, eye, or airway irritation. Thus, NMP is a mild irritant.

Abstract  The developmental toxicity of the three main metabolites of N-methyl-2-pyrrolidone (NMP) was studied in Sprague-Dawley rats. Pregnant rats were given 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP; 0, 250, 500, 750 or 1000 mg kg(-1) day(-1)), N-methylsuccinimide (MSI; 0, 500, 750, 1000 or 1250 mg kg(-1) day(-1)), or 2-hydroxyN-methylsuccinimide (2-HMSI; 0, 250, 500, 1000 or 1500 mg kg(-1) day(-1)), by gavage, on gestational days (GD) 6-20. No evidence of maternal toxicity was observed in dams given 5-HNMP. Administration of 2-HMSI resulted in overt maternal toxicity at 500 mg kg(-1) day(-1) and higher doses, as indicated by a significant reduction in weight gain and food consumption at the beginning of treatment. There was no evidence of embryo/fetal toxicity in any of the groups treated with 5-HNMP or 2-HMSI. MSI produced marked developmental toxicity in the presence of maternal effects. Maternal body weight gain and food consumption were affected at 750 mg kg(-1) day(-1) MSI, and above. A significant increase in post-implantation loss occurred at 1250 mg kg(-1) day(-1) MSI, and the incidence of fetuses with external or with visceral malformations was significantly increased at 1000 and 1250 mg kg(-1) day(-1) MSI. Malformations mainly consisted of anasarca, cardiovascular defects and diaphragmatic hernia. Fetal weight was significantly reduced at 1000 and 1250 mg kg(-1) day(-1). The incidence of skeletal variations (predominantly cervical ribs, and delayed ossification of skull bones and sternebrae) was significantly elevated at 750 mg kg(-1) day(-1) and higher doses. However, MSI was much less potent than the parent compound. These results indicate that the embryotoxic and teratogenic effects of NMP are not attributable to these metabolites.

Abstract  Risk assessment of chemicals is essential for the estimation of chemical safety, and animal toxicity data are typically used in the evaluation process, which consists of hazard identification, dose-response assessment, exposure assessment, and risk characterization. Hazard identification entails the collection of all available toxicity data and assessment of toxicity endpoints based on findings for repeated dose toxicity, carcinogenicity or genotoxicity and species-specificity. Once a review is compiled, the allowable lifetime exposure level of a chemical is estimated from a dose-response assessment based on several measures. For non-carcinogens and non-genotoxic carcinogens, the no-observed-adverse-effect-level (NOAEL) is divided by uncertainty factors (e.g. with environmental pollutants) or safety factors (e.g. with food additives) to derive a tolerable daily intake (TDI) or acceptable daily intake (ADI), respectively. These factors include interspecies and individual differences, duration of exposure, quality of data, and nature of toxicity such as carcinogenicity or neurotoxicity. For genotoxic carcinogens, low dose extrapolation is accomplished with mathematical modeling (e.g. linearized multistage model) from the point of departure to obtain exposure levels that will be associated with an excess lifetime cancer risk of a certain level. Data for levels of chemicals in food, water and air, are routinely used for exposure assessment. Finally, risk characterization is performed to ensure that the established 'safe' level of exposure exceeds the estimated level of actual exposure. These principles have led to the evaluation of several existing chemicals. To establish a guideline for residual solvents in medicine, the permitted daily exposure (PDE), equivalent to TDI, of N,N-dimethylformamide was derived on the basis of developmental toxicity (malformation) and of N-methylpyrrolidone on the basis of the developmental neurotoxicity. A TDI for di(2-ethylhexyl)phthalate was derived from assessment of testicular toxicity.

Abstract  Several workers in a small electrotechnical company in Norway experienced irritant reactions of the skin after a few days of working with the solvent N-methyl-2-pyrrolidone (NMP). Due to concern about the health risk of commonly-used organic solvents, the company had chosen to use NMP when one of its products had to be treated with a solvent. After 2 days of work with NMP, 10 of the 12 involved workers displayed acute irritant contact dermatitis of the hands. According to published reports, NMP is not considered to be particularly irritant to the skin. The Safety Data Sheet of a Norwegian sales firm contained no information on cutaneous hazards, but the Safety Data Sheet of an American producer of NMP stated the risk of severe dermatitis upon prolonged contact. NMP seems to be more irritant to the human skin than reported thus far.