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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).

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).

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 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).

The relationship between the incidence of hepatic injury among new employees in a cohort study of 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).

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 (Weiss et al., 1962) after i.v. application.

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).

Additional information

Exposure of workers to N,N-Dimethylacetamide 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 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). The mean DMAC in air levels (12-hour time-weighted average) were 1.9 ppm for a subgroup of 21 workers and 1.3 ppm for the remaining workers, corresponding 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. The authors concluded further, that short term exposure up to 6.7 ppm (24 mg/m³) does not cause liver toxicity.

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).

Jung and Lee reported indication for increased hepatic injury in monitored 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 plants producing polyurethane elastic fibres, DMAC as solvent was used and is described. A pre-placement health examination, 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).

The relationship between the incidence of hepatic injury among new employees in a cohort of elastane fibre workers and exposure to DMAC was studied. 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 (Lee et al., 2006).

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).

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 human

(Marino et al., 1994; study limited by co-exposure).

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; Maxfield et al., 1975). 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).  

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.

Biological monitoring of urinary levels of DMAC, N-methylacetamide (NMAC), and acetamide was conducted in humans after occupational inhalation (and dermal) exposure (Spiess et al., 1995). Male workers in two departments of an acrylic fiber manufacturing facility, where DMAC was used, were examined. Each shift employed 27 workers in seven job classes; Data on 97 workers were available for monitoring.

The workers were whole body exposed (via respiratory tract and skin) to the vapour. Employees worked fixed 12-hour schedules (2 days on, 2 days off, 3 days on, 3 days off, 2 days on, 2 days off, etc.) in four shifts (A, B, C, and D). Worker exposure to DMAC was measured over a 1-year study period. 93 workers of the plant were monitored on the second consecutive workday after at least 3 days off for the first 10 months of the study and on both the first and second days during the study's final 2 months. Personal air monitoring was performed for DMAC und biological monitoring for levels of DMAC, NMAC, and acetamide in spot urine samples. An air concentration of 6.7 ppm (12-hour time-weighted average (TWA)) corresponded to an urine NMAC level of 62 mg/g creatinine in a postshift spot urine sample obtained after the second consecutive workday. NMAC and acetamide were identified as metabolites in urine. A level of 35 mg NMAC/g creatinine in a postshift spot urine sample (12-h shift) was recommended as a biomonitoring index. DMAC demethylation metabolic mechanisms did not become saturated at the threshold limit value.