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Administrative data

Endpoint:
epidemiological data
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
restrictions: low number of workers in cohort, only 21 workers in high exposure group; no exposure data of control group reported [minor restriction]

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Monitoring acrylic fiber workers for liver toxicity and exposure to dimethylacetamide 2. Serum clinical chemistry results of dimethylacetamide-exposed workers
Author:
Spies GJ, Rhyne RH, Evans RA, Emmonds Wetzel K, Ragland DT, Turney HG, Leet TL, Oglesby JL
Year:
1995
Bibliographic source:
J Occup Environ Med 37: 1102-1107
Reference Type:
study report
Title:
Unnamed
Year:
1995
Report Date:
1995

Materials and methods

Study type:
cohort study (prospective)
Endpoint addressed:
basic toxicokinetics
repeated dose toxicity: inhalation
repeated dose toxicity: dermal
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The study was conducted to investigate the relationship between occupational DMAC exposure and hepatotoxicity. As part of the study, a biological monitoring of urinary levels of DMAC, N-methylacetamide (NMAC), and acetamide in humans after occupational inhalation (and dermal) exposure was done.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Specific details on test material used for the study:
- Name of test material: dimethylacetamide (DMAC)
No details available.

Method

Type of population:
occupational
Ethical approval:
not specified
Details on study design:
Study subjects were male employees in an acrylic fiber manufacturing facility, who worked in two departments using DMAC: solution preparation and spinning; employees worked fixed 12-hour schedules (2 days on, 2 off, 3 on, 3 off, 2 on, 2 off, etc.) in 4 shifts (each shift employed 27 workers); during the 1-year study period, a total of 127 DMAC-exposed workers were participants of the study.
In-plant control consisted of 217 employees working in 6 departments of the plant during the study period with no current or previous contact with DMAC.
At least once during the 1-year study period, a blood sample for serum clinical chemistry assessment was obtained from all study participants; additional blood samples may have been drawn from certain participants. The serum biochemistry tests were not coordinated with exposure monitoring. Additional serum clinical chemistry testing was conducted if a worker's biomonitoring result exceeded one of the "trigger" values established for the study: 60 mg N-methylacetamide (NMAC)/g creatinine (Cr) or 136 mg DMAC equivalent (DMAC Eq)/g Cr. These blood samples for clinical chemistry determination were immediately requested of "confirmed exposure" employees and subsequent blood samples were obtained 1 week and 2 weeks after the first (to investigate the rise or fall of serum biochemistry results).

Clinical chemistry
Serum clinical chemistry tests were used to measure liver injury; blood samples were collected by standard phlebotomy and analyzed for total bilirubin (TBILI), AST, ALT, alkaline phosphatase (ALKPHOS), and y-glutamyltranspeptase (GGTP). 490 sets of serum clinical chemistry results were obtained from 127 workers in the 2 "DMAC departments" and from the 217 workers in the control group. Log-transformed serum clinical chemistry results were used in all subsequent analyses.
The null hypothesis that there is no correlation between the serum biochemistry and biomonitoring results in the high-exposure group was investigated by multiple regression, with a random selection of one of the three postbiomonitoring serum biochemistry results as the dependent variable and one of the postshift biomonitoring results, urinary NMAC or acetamide, or urinary DMAC Eq, and the confounding variables, alcohol consumption and age, as the independent variables.

Toxicokinetics
Personal air monitoring for DMAC und biological monitoring for levels of DMAC, NMAC, and acetamide in spot urine samples.
Exposure assessment:
measured
Details on exposure:
60 out of the 127 workers who worked in two departments using DMAC were monitored bimonthly (employees participated in air and biological monitoring). Air and biological monitoring was targeted toward those job classes for which previous air monitoring had suggested a higher potential for DMAC exposure; effort was made to sample the same person each month for job classes in which virtually everyone was monitored (potential exposure), such as dope prep, utility, and jet room (28 persons).
During the first 10 months, full-shift air and post-shift biological monitoring was conducted on the second consecutive workday after the 3-day break. During the last 2 months of the 1-year study period, air and biological monitoring was conducted both on the first and the second day.
DMAC in air was sampled with 3M passive dosimeters and analyzed by gas chromatography. Post-shift urine samples were collected for DMAC, MMAC, and acetamine (ACET) and analysed by gas chromatography.
Statistical methods:
Geometric Mean (GM), Geometric Standard Deviation (GSD), and t- Test
Scheffe's test
Level of significance: p<0.05.

Results and discussion

Results:
Biomonitoring results from 21 of 127 workers (in the 2 DMAC departments) participating in the air and biological monitoring study exceeded one of the biomonitoring trigger values (formed a high-exposure group), leaving 106 individuals in an unspecified-exposure group. All 217 controls formed a no-exposure group.
DMAC in air, and NMAC and DMAC Eq in urine results for each exposure group were compared (t-test) and for all exposure indexes, the mean result from the high-exposure group exceeded the mean from the unspecified group (see Table below).
Serum clinical chemistry data were available from 127 DMAC exposed workers plus the 217 controls (clinical chemistry results from 9 workers without data on alcohol consumption were excluded as well as the result of one control with diagnosed liver condition).
The exposure indexes tested - urinary ACET, urinary NMAC, and urinary DMACEq - were not correlated with the serum biochemistry results.
None (0 of 21) of the high exposure group individuals had an abnormal serum biochemistry result during the study period; in both replicates of the analysis, only one (1 of 106) of the unspecified exposure group and four (4 of 217) of the no-exposure group individuals had abnormal clinical chemistry values.

Toxicokinetics:
- Personal air monitoring for DMAC und biological monitoring for levels of DMAC, NMAC, and acetamide in spot urine samples.
- Biological monitoring of urinary levels of DMAC, N-methylacetamide (NMAC), and acetamide was conducted in humans after occupational inhalation (and dermal) exposure. 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.
Conclusion: 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.
- Details on Excretion: 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.
- Metabolites identified: NMAC and acetamide in urine
Confounding factors:
Sufficiently considered:
1) Age (capable of confounding serum clinical chemistry results)
2) Alcohol consumption (data from medical questionnaire; alcohol consumption categories 0-3)
3) Liver disease (data from plant physician)
Strengths and weaknesses:
Low number of exposed workers

Any other information on results incl. tables

Exposure indices in high and unspecified exposure groups

High exposure if one biomonitoring result exceeded one of the trigger values (see details of study design)

Geometric means ± geometric standard deviation (SD)

Exposure index

Exposure group

Number of samples

Mean ± SD

DMAC concentration in air, 12 h TWA
(ppm)

High

96

1.9 ± 2.6

Unspecified

294

1.3 ± 2.1

Urinary NMAC concentration (mg/g creatinine)

High

98

26.7 ± 2.7

Unspecified

295

13.5 ± 2.3

Urinary DMAC Eq

(mg/g creatinine)

High

98

81.2 ± 2.2

Unspecified

295

43 ± 1.8

TWA: time weighted average

Clinical chemistry results versus exposure group

Geometric means ± geometric standard deviation (SD); abbreviation see text

Clinical chemistry parameter

Non-exposure group

(n = 217)

Unspecified exposure group

(n = 106)

High-exposure group

(n = 21)

TBILI

0.52 ± 1.48

0.45 ± 1.58

0.37 ± 1.35*

AST

25.8 ± 1.37

24.7 ± 1.36

24.8 ± 1.25

ALT

27.0 ± 1.49

25.1 ± 1.48

25.5 ± 1.48

ALKPHOS

81.8 ± 1.30

76.6 ± 1.27

85.3 ± 1.31

GGTP

19.1 ± 1.64

16.8 ± 1.62

16.1 ± 1.55#

*: significantly different from non-exposure and unspecified exposure group
#: significantly different from non-exposure group

Applicant's summary and conclusion

Conclusions:
There was no liver injury in workers exposed to DMAC and excreting > 60 mg N-methylacetamide/g creatinine (trigger value) via the urine (2-fold BEI value).
Executive summary:

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. 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). 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.