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HEALTH SURVEILLANCE DATA


In a health record publication for hepatoxicity in workers related to DMAC exposure, 1045 workers exposed to DMAC from January 2001 to July 2004 in 2 Korean plants producing polyurethane elastic fibres and using DMAC as solvent are described. There were some indications for DMAC-induced hepatic injuries in 38 out of 1045 monitored workers but no sufficient quantitative data on exposure (Jung et al., 2007).


While NMAC in the end-of-shift urine samples remains a preferential biomarker of DMAC exposure during that shift, AMMA determined at the end of a work-week reflects cumulative exposure over the last few days (Princivalle et al., 2010).


Urinary DMAC and NMAC are suitable biomarkers in humans for monitoring occupational exposure via the dermal and inhalation route. The metabolite S-acetamidomethyl-mercapturic acidn (AMMA) was identified (Perbellini et al., 2003).


One ppm DMAC in air corresponds to approximately 10 ppm NMAC in urine (DuPont, 1987; Kennedy & Pruett, 1989).


Examination of 8 workers in the Netherlands showed no significant correlation between personal airborne DMAC (dimethylacetamide) exposure and the amount of NMAC (N-methylacetamide) in urine (Borm et al., 1987). Thus, dermal exposure may be contributing to the variability in NMAC concentrations noted in urine samples, demonstrating the need for biological monitoring.


EPIDEMIOLOGICAL DATA


The results of a retrospective cohort study with workers in European Man-Made fibres included industries do not support a relationship between DMAc exposure and elevation in liver enzymes or liver injuries even with DMAc exposures equal or above existing occupational exposure limits (Antoniou, 2021).


In a prospective cohort study with acrylic fiber plant-workers observed over a period of 1 year (12 h full-shift) to investigate the relationship between occupational DMAC exposure and hepatotoxicity, no DMAC exposure related trends in hepatic serum clinical chemistry results were detected. Besides, none (0 of 21) of the high exposure group had an abnormal serum biochemistry result during the study period (Spies et al., 1995).


The relationship between the incidence of hepatic injury among new employees in a cohort study of Korean elastane fibre workers and exposure to DMAC was studied which resulted into some indication for increased hepatic injury in workers but there was not sufficient evidence for the dose dependency of these effects (Lee at al., 2006).


No increase in chromosome aberrations in lymphocytes of workers exposed to 5-10 mg/m³ DMAC was observed by Katosova & Pavlenko, 1985.


There was no evidence for increased mortality from tumors in workers of an acrylic fibre factory exposed to acrylonitrile and DMAC (Mastrangelo et al., 1993).


 


DIRECT OBSERVATIONS


In human volunteers the dermal absorption was 40% of the total DMAC uptake (Nomiyama et al., 2000). The biological half-lives of NMAC in urine after DMAC exposure were 9.0 ± 1.4 h and 5.6 ± 1.3 h via skin and respiratory tract, respectively. No accumulation was observed at the OEL of 10 ppm.


The difference in the amount of NMAC excreted following dermal with or without inhalation exposure indicated that more DMAC was absorbed through the lungs (70 %) than the skin (30 %) (Maxfield et al., 1975).


In a repetitive human exposure study with 8 volunteers under controlled whole-body exposure conditions for 5 days, 6 h/d no toxic effects were reported after inhalation exposure to 10 ppm (36 mg/m³; DuPont, 1974).


There are two case reports of U.S. American woman who showed clinical signs of possible toxic hepatitis after repeated, unintentional occupational dermal exposure to DMAC during maintenance and cleaning at manufacturing plants for acrylic-fiber production sites (Baum et al., 1997).


An accidental inhalative and dermal case report of a male worker (32 year old) with exposition to a mixture of chemicals including DMAC as the main component is reported. The results give supporting evidence for hallucinogenic effects. Besides, symptoms of skin burns, cellulitis, conjunctivitis and chemical-induced hepatitis are discussed (Marino et al., 1994).


In clinical observations in cancer patients no antitumor effects were observed for DMAC but liver toxicity and CNS effects (abnormal mental status: depression, lethargy, disorientation, confusion, visual and auditory hallucinations) were described after i.v. application (Weiss et al., 1962).

Additional information

HEALTH SURVEILLANCE DATA


Jung et al. 2007 and Lee et al. 2006 (see epidemiological data) reported indication for increased hepatic injury in monitored Korean workers, but no sufficient quantitative and/or no sufficient evidence for dose dependency data on exposure were given:
In a study with 1045 workers exposed to DMAC from January 2001 to July 2004 in 2 Korean plants producing polyurethane elastic fibres, DMAC as solvent was used and is described. A pre-placement and post-placement health examinations every 10 days for the next three months, and semi-annual periodic health examinations thereafter were performed; pre-placement health examination included hepatic function tests, AST, ALT, and y-glutamyl transpeptidase (GGT) and tests for viral hepatitis; urine NMAC (N-methylacetamide, marker for DMAC exposure) were tested at the semi-annual periodic health examinations. Urine sampling was conducted only during the period 2003-2004. Correlation between DMAC exposure and hepatotoxic effects was not clear (exposure was related to the biological exposure index of 30 mg NMAC/g creatinine but urine sampling was conducted only during the second half of the monitoring period; there were no data about inhalation exposure concentration or dermal exposure; low number of urine samples). Data on biological exposure index are not suitable for quantitative estimation of DMAC exposure (samples related to the corresponding department of the plant but not to the DIHI cases; urine samples were only available during the second half of the monitoring period; no clear difference between control and DIHI values). There were some indications for DMAC-induced hepatic injuries in 38 out of 1045 monitored workers but no sufficient quantitative data on exposure (Jung et al., 2007).


Urine samples were collected from workers in an acrylic fibres factory at various time points of the working shifts (Princivalle et al., 2010). The approximate half-lives or NMAC and AMMA (means) in the exposed workers were about 9 and 29 h, respectively. Thus, while NMAC in the end-of-shift urine samples remains a preferential biomarker of DMAC exposure during that shift, AMMA determined at the end of a work-week reflects cumulative exposure over the last few days.


The concentrations of DMAC and its metabolite NMAC was studies in the urine of 223 workers, occupationally exposed to DMAC in a factory producing synthetic acrylic fibres (Perbellini et al., 2003). Even at low environmental DMAC concentrations, the absorption of DMAC may be considerable via the dermal route. Urinary DMAC and NMAC were considered to be useful biomarkers for occupational biomonitoring. Additionally, S-acetamidomethyl-mercapturic acid was identified as a new metabolite of DMAC, whereas NMAC is mainly derived from N-hydroxymethyl-N-methylacetamide.


After determination of 8-hr TWAs for DMAC using personal samples and end-of-shift urinary MMAC concentrations, it was concluded, that one ppm DMAC in air corresponds to approximately 10 ppm MMAC in urine (DuPont, 1987; Kennedy & Pruett 1989).


The urinary excretion of N-methylacetamide (NMAC) was measured in workers after occupational exposure to vapour of dimethylacetamide (DMAC) (Borm et al., 1987). 3 female and 5 male worker were occupationally exposed to DMAC in a production hall for 7 h per day for 5 days. Stationary monitoring in the production hall revealed a mean test substance concentration of 14.7 ppm (range: 11.8-17.2 ppm). Personal monitoring: individual test substance data ranged between 6.1 and 22.2 ppm. In exposed workers (n = 6) buildup in the NMAC excretion during the week was found, the steady state was reached after 2 -3 days (constant NMAC excretion rate: 0.56 ± 0.20 µmol/h x kg bw). No significant correlation between DMAC exposure and urinary NMAC excretion was detected. Half-live for NMAC excretion via urine was calculated: 16 ± 2 h (n = 6). Subjects 3 to 8 excreted 13.5 ± 3.3 % (n = 6) of the cumulative inhaled dose as NMAC in urine. In subjects 1 and 2 this value was ca. 32 %. Monday morning after the 5-day shift the NMAC concentration in urine had returned to control values (4 control subjects: 1.25 ± 0.39 mg/L). There was no significant correlation between test substance vapour concentration and the amount of NMAC in urine suggesting biological monitoring instead of airborne concentration monitoring for occupational exposure assessment. Dermal exposure may be contributing to the variability in NMAC concentrations noted in urine samples, and demonstrates the need for biological monitoring. There is no bioaccumulation potential based on study results.


EPIDEMIOLOGICAL DATA


In a more recent retrospective cohort study (Antoniou, 2021) the relationship between DMAC and induced hepatic injury among workers in European Man-Made Fibres (MMF) included industries was examined. Four companies provided their calculated 90th percentiles of DMAC 8h-TWA exposure measurement (in ppm) in the fibre production and other working areas. Observations of the liver enzyme values (ALT, AP, GGT, AST) for each year were provided where available and matched with years of exposure. Concentrating on ALT with a cut-off of 40 IU/L as the upper limit of normal (ULN), elevated ALT liver values and liver injuries as well as the change of ALT per unit of DMAc exposure on a continuous scale were calculated. Furthermore, logistic random effects regressions were performed to investigate the association between exposure and elevated liver values, while linear regressions were performed on the change of ALT values on a continuous scale. Very few observations indicative of liver injuries was observed in this study. Overall, the results of this study do not support a relationship between DMAc exposure and elevation in liver enzymes or liver injuries even with DMAc exposures equal or above existing occupational exposure limits. 


The relationship between the incidence of hepatic injury among new employees in a cohort of Korean elastane fibre workers and exposure to DMAC was studied (Lee et al., 2006). Elastane fibre workers exposed to DMAC were monitored for hepatic injury. Four hundred and forty (440) new workers employed from 1 January 2002 to 31 July 2004 were included as study subjects. DMAC exposure estimates were based on urinary N-methylacetamide (NMAC) concentrations (already discussed in the section ‘Basic toxicokinetics’). Each new worker completed a preplacement health examination (serum hepatic function tests such as alanine transaminase (ALT), aspartate transaminase (AST), and gamma glutamyl transpeptidase (GGT) levels, and serological tests for viral hepatitis B and C). No relevant effects were detected at this pre-placement examination. The new workers were monitored with follow up hepatic function tests every 10 days for 3 months, and all DMAC exposed workers had a periodic health examination every 6 months. Urinary NMAC measurement was added to the biannual regular health examination from 2003 (comment: no data from 2001). There were 28 cases of DMAC induced hepatic injury. Incidence rates were 7 (cut-off exposure classification >30 mg NMAC/g creatinine) or 10 times (cut-off exposure classification >20 mg NMAC/g creatinine) higher in high exposure groups than in low exposure groups. Fewer DMAC induced hepatic injuries occurred among workers employed for a longer period; workers whose exposure duration was more than 7 months showed no hepatic injury in either the high or low exposure groups. The results showed some indication for increased hepatic injury in workers employed with DMAC exposure but there was not sufficient evidence for the dose dependency of these effects.


Exposure of workers to N,N-dimethylacetamide (DMAC) in an acrylic fiber plant was measured over a 1-year study period, by full-shift (12 h) personal air monitoring of DMAC and biological monitoring for levels of DMAC, N-methylacetamide (NMAC) and acetamide in post-shift spot urine samples (Spies et al., 1995). Evidence of liver toxicity was assessed by serum clinical chemistry tests (total bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and y-glutamyl transpeptidase) at least once during the study period for all 127 male workers in the 2 study departments and for 217 male in-plant controls with no previous or current exposure to DMAC. Additional serum clinical chemistry tests were conducted at weekly intervals for 3 weeks in workers showing increased DMAC (>132 mg/g creatinine) or NMAC (>60 mg/g creatinine) levels in urine (trigger values). DMAC-exposed workers were classified as either high exposure (if one biomonitoring result exceeded one of the trigger values), or unspecified exposure (trigger value not reached). Control employees were classified as no-exposure. Mean DMAC levels in air differed for the high- and unspecified exposure group (mean DMAC in air levels of 1.9 and 1.3 ppm, 12-hour time-weighted average, respectively) as well as mean urinary NMAC values (26.7 vs 13.5 mg/g creatinine). This corresponds to 8-hour time-weighted average values of 3 ppm (10 mg/m³) and 2 ppm (7 mg/m³), respectively. No DMAC exposure related trends in hepatic serum clinical chemistry results were detected. None (0 of 21) of the high exposure group had an abnormal serum biochemistry result during the study period. A level of 35 mg NMAC/g creatinine in a postshift spot urine sample (12-h shift) was recommended as a biomonitoring index.


In a cytogenic analysis of lymphocytes in workers (20 exposed workers, 16 control volunteers) who were in contact with DMAC the chromosome aberration frequency was tested (Katosova & Pavlenko, 1985). The exposure concentration of DMAC was 5-10 mg/m³. The result was 4.9 ± 0.5 % chromosome aberrations versus 3.7 ± 0.36 % in controls (p > 0.05). Thus, there was no increase in chromosome aberrations in lymphocytes of workers exposed to 5-10 mg/m³ DMAC.


A retrospective cohort study revealed no evidence for increased mortality from tumors in workers (n = 671) of an acrylic fibre factory exposed to acrylonitrile and DMAC (Mastrangelo et al., 1993).


DIRECT OBSERVATIONS


Dermal versus inhalation absorption of DMAC vapour in 12 human volunteers, and half-lives of DMAC and N-methylacetamide (NMAC) in urine were determined by Nomiyama et al., 2000. In the dermal exposure group, the volunteers wore cotton pants, and 90% of their skin were naked; volunteers were exposed to DMAC vapour while inhaling fresh air via a respirator in a sitting position in an exposure chamber of 1.7 m³ (L x W x H: 1.2 x 0.8 x 1.8 m). In the inhalation exposure group, volunteers sat outside the chamber and inhaled the air in the chamber. The individual dermal absorption rates defined as dermal absorption over dermal plus respiratory absorption fluctuated widely between 12.9 and 73.3% (mean: 40%); this was possibly related to intra-individual differences in absorption dynamics, metabolism, accumulation, and excretion of DMAC. The mean urinary NMAC value after 4-h DMAC exposure at 6.1 ppm was 11.2 mg/g creatinine; extrapolation to 8 h exposure duration and exposure concentration of 10 ppm: 31.1 mg/g creatinine (no saturation of metabolism at <=30 ppm). Half-lives obtained in this study (see below) indicated little accumulation of NMAC over a span of workdays; the estimated NMAC value after 5 consecutive workdays (8 h per day) at concentrations of 10 ppm DMAC was 30.7 mg/g creatinine (16.5-65 .9 mg/g Cr). Thus, in human volunteers the dermal absorption was 40% of the total DMAC uptake; the biological half-lives of NMAC in urine after DMAC exposure were 9.0 ± 1.4 h and 5.6 ± 1.3 h via skin and respiratory tract, respectively. No accumulation was observed at the OEL of 10 ppm.


Two male volunteers were exposed to a vapour at a concentration of 10 ppm for 6 h and DMAC was absorbed a) via inhalation and dermal route in an exposure chamber (most part of the body naked) or b) only via the dermal route (breathing of normal air outside the chamber via mask). The highest urine concentration of N-methylacetamide (NMAC, 45-100 ppm) was found in a). In b) the values were in the range of 6 to 23 ppm. The difference in the amount of NMAC excreted following exposure with and without the mask in a) and b) indicated that more DMAC was absorbed through the lungs (70 %) than through the skin (30 %) during an exposure to the vapour. The results show that dermal absorption contributes significantly to the overall amount of systemically available DMAC following vapour exposure (Maxfield et al., 1975).


In a clinical study with 8 male volunteers no toxic effects were reported after repeated inhalation exposure to 10 ppm (36 mg/m³). The volunteers were exposed to 10 ppm at 6 h per day for 5 consecutive days. Behaviour was recorded during and after the exposure period. Blood samples were collected prior and after the exposure period for hematology and clinical chemistry assessment. Urine was collected during and after the exposure period for urinalysis and porphyrin excretion determination. No treatment related effects were detected (DuPont, 1974).


There are two reports on human hepatic injury due to inhalation and/or dermal exposure to DMAC. They are case reports of effects related to accidental overexposure with unclear exposure levels. Toxic hepatitis observed in two female (25 years and 39 years old) workers in western U.S. manufacturing plants at acrylic-fiber production sites after repeated and unintentional dermal contact to DMAC is discussed as the main exposure route occuring mainly during maintenance and cleaning at the site. Clinical signs in both woman were jaundice and icterus as well as dark urine. Besides, pruritus was reported by the 39 year old Caucasian woman. In clinical chemistry liver effects were revealed in both females with altered liver functions and severe effects observed in the older woman. The liver biopsy of this female revealed toxic hepatitis (Baum et al., 1997).


A case of a worker (32 year old) is presented by the authors who accidentally was exposed to a mixture of chemicals by inhalation and dermal routes. The worker was exposed for 90 minutes to a mixture of 0.5 % unreacted 1,2 -ethanediamine, 34.5 % polyurethane, and 65 % N,N-dimethylacetamide in a confined space after falling accidentally into a mixing vet. The effects observed were acute delirium/hallucinations, skin burns, cellulitis, conjunctivitis, chemical-induced hepatitis, secondary coagulopathy, esophagitis (grade 2 severity) and rhabdomyolysis. The patient was discharged from hospital after he fully recovered on the 13th hospital day. The report gives evidence for suspected signs of central nervous system reactions (seen as confusion, agitation, and delirium) and skin burns after the exposure to DMAC in humans (Marino et al., 1994; study limited by co-exposure).


In a clinical observation case study 17 patients with malignant tumors were treated adequately in a phase 1 study with DMAC to discover its potential antitumor activity. After repeated i.v. application of DMAC 15 patients survived long enough for effect evaluation and only 2 gave any evidence of objective remission of disease. DMAC was applied as a 10% solution at dose levels from 100-610 mg/kg bw/day up to 5 days. Within 24 h after application, severe vomiting occurred and seven patients experienced liver toxicity (measured as SGOT; old for aspartate transaminase [AST]). DMAC exposure resulted in influence to the CNS (≥400 mg/kg bw abnormal mental status: depression, lethargy, disorientation, confusion, visual and auditory hallucinations). The signs appeared with delay (indicating an effect of DMAC-metabolites), were accompanied by slowed EEG signals and were reversible at the end of the therapy. The study was too limited to eliminate DMAC as an effective chemotherapeutic agent for human malignancy. The authors discussed a potential in the field of neuropsychiatry for hallucinogenic effects of DMAC (Weiss et al., 1962).

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