N,N-dimethylformamide

Exposure related observations in humans: other data

Administrative data

Endpoint:

exposure-related observations in humans: other data

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

published 1998

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: acceptable well-documented publication, which meets basic scientific principles

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Reference

Endpoint:

exposure-related observations in humans: other data

Type of information:

other: publication

Adequacy of study:

weight of evidence

Study period:

1998

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: not GLP study

Reason / purpose for cross-reference:

reference to other study

Type of study / information:

Examination of external and internal exposure to the DMF of 126 workers from a factory producing synthetic fibers.

Endpoint addressed:

basic toxicokinetics

Qualifier:

no guideline followed

Principles of method if other than guideline:

DMF air monitoring and biological monitoring of the DMF metabolite NMF in urine were carried out using instrumental analytical methods.

GLP compliance:

no

Ethical approval:

confirmed, but no further information available

Details on study design:

Diffusion tubes were used to collect personal air samples from workers exposed to DMF for 8 h. Before and after 8 h the concentration of metabolite NMF was determined for the internal exposure to DMF.

Exposure assessment:

measured

Details on exposure:

TYPE OF EXPOSURE MEASUREMENT: Area air sampling / Personal sampling / Biomonitoring (urine)


EXPOSURE LEVELS: DMF concentrations measured in the air ranged between <0.1 and 37.9 ppm (median 1.2 ppm). Concentrations of NMF varied from 0.05 to 22.0 mg/l (preshift values) and from 0.9 to 100.0 mg/l (postshift values).


EXPOSURE PERIOD: 8h


POSTEXPOSURE PERIOD: no


DESCRIPTION / DELINEATION OF EXPOSURE GROUPS / CATEGORIES: 126 workers

Results:

The range of DMF in air was 0.1 - 37.9 ppm. Before the working phase of 8 h the NMF in urine was found to be 0.05 - 22 mg/L. After the working day 0.86 - 100 mg/L NMF was detected in the urine. The creatinine related values: (0.02 - 44.6 mg/g preshift; 0.4 - 62.3 postshift). With usage of breathing masks NMF is found in urine with: 2.6 - 62.3 mg/L; without masks 0.4 - 42.7 mg/L. Usage of protective gloves result in 1.5 - 62.3 mg/L NMF in urine, whereas without gloves the range is 0.4 - 6.1 mg/L.
DMF did not accumulate in the organism.

117 pairs of values were available for determination of a correlation between external and internal exposure (DMF/NMF). The results are listed in Table 1. The level of exposure varied significant during different stages of production (see ranges of values in the table 1).

Table 1: External and internal exposure to DMF

	DMF air (ppm)	NMF urine (mg/L) preshift	NMF urine (mg/g creatinine) preshift	NMF urine (mg/L) postshift	NMF urine (mg/g creatinine) postshift
Range	<0.1 - 37.9	0.05 - 22.0	0.02 - 44.6	0.86 - 100.0	0.4 - 62.3

As shown in Table 2, it was found, as expected, that protective clothing worn as a result of the particular activities correlated significantly with higher DMF concentrations in the air. Despite the use of protective clothing, however higher levels of internal exposure were found, as expected, by consideration of the individual ambient air concentrations.

Table 2: External and internal exposure according to personal protective measures

	Breathing mask			Protective gloves
	Yes	No		Yes	No
DMF air (ppm)	0.1 - 37.9	<0.1 - 13.9	<0.001	<0.1 - 37.9	<0.1 - 16.4	< 0.001
NMF urine	2.6 - 62.3	0.4 - 42.7	<0.001	1.5 - 62.3	0.4 - 6.1	< 0.001

The results of our investigations also indicate, however, as stated in the available literature, that dermal absorption has a great influence on the level of internal exposure. Particularly in the 24 cases where the BAT value was exceeded without the MAK value being exceeded at the same time, increased dermal absorption must be regarded as the cause.

Due to DMF's good dermal absorption and its irritative effects on the skin and mucous membranes, a complete skin status was determined for all persons. Evaluation of the exposure conditions and internal exposure of the employees (n =27) who currently suffered from a skin disease showed that despite their average exposure to DMF, the median value of 16.1 mg NMF/g creatinine recorded for those with eczema (n=7) was higher than that noted for those with healthy skin (5.0 mg NMF/g creatinine). Considering the small number of cases, this can only be an indication that in persons with eczema the skin barrier against hazardous substances is impaired. As early as in subclinical stages the barrier function of the skin is impaired in person's with most kinds of dermatosis, as has been shown in studies on transepidermal water loss (Fartasch et al. 1992). The supposition that any pathological skin condition leads to increased penetration of hazardous substances (Grandjean 1990) was confirmed in a larger collective in the investigations of Drexler et al. (1995). Such an effect also seems probable for the easily absorbable DMF.

Conclusions:

From the point of view of the prevention of disease, biological monitoring is the best instrument for exposure assessment of workers exposed to DMF.

Executive summary:

Objective:

This study examined the external and internal exposure to the solvent N,N-dimethyl- formamide (DMF) of 126 workers from a factory pro- ducing synthetic fibers.

Methods:

Air measurements were carried out using personal air samplers with diffusion tubes (Dräder, ORSA 5). For the purpose of biological monitoring the levels of N-methylformamide (NMF) in urine were measured in preshift and postshift samples. Determinations were carried out using gas chromatography. Anamnestic data were collected with standardized questionnaires, including personal data, working history and current working conditions, and former and current illness with regard to the effects of DMF. Skin diseases were documented by a dermatologist.

Results: DMF concentrations measured in the air ranged between < 0.1 and 37.9 ppm (median 1.2 ppm). Concentrations of NMF varied from 0.05 to 22.0 mg/L (preshift values) and from 0.9 to 100.0 mg/L (postshift values). The creatinine-related values (0.02 - 44.6 mg/g preshift; 0.4 - 62.3 postshift) were subject to less variation and therefore represented the level of exposure better than the values related to volume. Additional investigation of a subcollective (n = 31) over a period of 4 days showed that NMF did not accumulate in the organism. The positive but relatively weak association observed between the DMF concentrations measured in the workplace air and the values recorded for internal exposure in this study can be explained by influencing factors such as dermal absorption or protective clothing. Interindividual differences in internal exposure were found for the specific work areas. The German BAT value (15 mg NMF/L urine) was exceeded in 36 persons (29 %) despite the use of breathing protection and protective gloves, without increased values being measured in the air. Increased absorption without higher-level exposure could particularly also be observed in employees with eczema.

Conclusions:

From the point of view of the prevention of disease, biological monitoring is the best instrument for exposure assessment of workers exposed to DMF.

Data source

Reference

Reference Type:

publication

Title:

Liver function in workers exposed N,N-dimethylformamide during the production of synthetic textiles

Author:

Wrbitzky, R.

Year:

1999

Bibliographic source:

Int Arch Occup Environ Health (1999) 72: 19-25

Materials and methods

Type of study / information:

In a factory producing synthetic fibers the hepatotoxic effects of the solvent N,N-dimethylformamide (DMF) were investigated in 126 male employees, especially with regard to the combination effects of DMF exposure and ethyl alcohol consumption.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

N,N-dimethylformamide

EC Number:

200-679-5

EC Name:

N,N-dimethylformamide

Cas Number:

68-12-2

Molecular formula:

C3H7NO

IUPAC Name:

N,N-dimethylformamide

Details on test material:

In a factory producing synthetic fibers using the solvent N,N-dimethylformamide (DMF), the DMF concentrations in the air ranged from <0.1 (detection limit) to 37.9 ppm (median 1.2 ppm). Reference is made to the results of air measurements and biological monitoring presented in a previous publication (Wrbitzky and Angerer, 1998).

Method

Ethical approval:

not specified

Details on study design:

In an extension of our previous publication on external and internal exposure to DMF, we now report on the parameters of effect, particularly for liver function, and on our attempt to differentiate between the effects of DMF and those of alcohol consumption.

Exposure assessment:

measured

Details on exposure:

The DMF concentrations in the air ranged from <0.1 (detection limit) to 37.9 ppm (median 1.2 ppm).
Concentrations of the DMF metabolite N-methylformamide (NMF) in urine were measured: 0.05 ± 22.0 mg/L (preshift) and 0.9 ± 100.0 mg/L (postshift), corresponding to 0.02 ± 44.6 mg/g creatinine (preshift) and 0.4 ± 62.3 mg/g creatinine (postshift).
Thus, the threshold values (MAK value ± Maximale Arbeitsplatz-Konzentration; BAT value ± Biologischer Arbeitsstoff-Toleranzwert) were exceeded both for external exposure (MAK value, 10 ppm DMF) and for internal exposure (BAT value, 15 mg NMF/L urine).

Results and discussion

Results:

In the DMF-exposed group, 22 (17.8 %) persons stated previous liver diseases, including in- creased liver function values, as opposed to only 7 (13.2 %) in the control group. Of these 22 DMF-exposed persons, 14 worked in areas of higher exposure and 7, in areas of lower exposure. Only one of them stated in the questionnaire that his pathological liver findings started when he began working at this plant. About 15 % of the exposed persons stated that they had drunk less alcohol since starting to work at the factory. Those not exposed did not change their alcohol consumption as a result of their work activity. These differences were found to be statistically significant. Complaints occurred after drinking of alcohol in 71.5 % of the exposed persons and 3.8 % of the control persons. Flush symptoms after alcohol consumption were mentioned by 86 (69.9 %) of the exposed workers and 2 (3.8 %) of the unexposed persons. These differences were statistically significant as well. Flush symptoms occurred in the group (n = 71) with higher levels of DMF exposure (n = 47; 66.2 %) as well as in the group (n = 55) with lower levels of exposure (n = 39; 70.9 %). No statistically significant difference between exposed and unexposed persons could be determined with regard to the complaints most frequently named at the workplace.

Any other information on results incl. tables

A comparison of the liver function values (c-GT, AST and ALT) found in exposed persons and in the control group yielded statistically significantly, higher values in the exposed groups for c-GT and AST (P < 0.05).

To test the dose-dependent effects of DMF on the liver we divided the total collective (n =180) into 3 subcollectives. Among the four work areas associated with different levels of exposure to DMF (see Wrbitzky and Angerer 1998), persons with higher levels of exposure from the areas of wet spinning and dry spinning and from the dyeing plant were combined and compared with persons with lower levels of exposure from the finishing department and with the control collective with no DMF exposure. The levels of the liver indices are represented in the box plots for these three subcollectives. It is shown that the low-exposure group is unexpectedly associated with a higher liver index as compared with the more highly DMF-exposed workers. A comparison of the amounts of alcohol drunk by these groups revealed that the persons with low levels of exposure consumed amounts of alcohol comparable with those consumed by the control collective, whereas for more highly exposed workers the amounts were markedly lower. This difference between the high- and low-exposure groups was statistically significant. In addition, these three groups with different levels of DMF exposure were divided according to the amount of alcohol drunk per day. The median of 50 g/day determined for all the test persons was used as the criterion for differentiation (persons who drank no alcohol, alcohol consumption of < 50 g/day, and consumption of > 50 g/day). Both the level of exposure to DMF and the amount of alcohol drunk were found to influence the liver index. Statistically significant differences were not found for the groups that drank no alcohol, irrespective of whether there was high-level, low-level, or no exposure to DMF. On the other hand, the differences found in the three subcollectives according to alcohol consumption were statistically significant. Two-factorial hierarchical variance analysis showed that the influence of alcohol (P < 0.001) on the level of the liver index was more pronounced than the influence of DMF (P = 0.043).

Applicant's summary and conclusion

Conclusions:

The findings in this study revealed no statistically significant difference for persons who had a known history of hepatitis or were found to have positive antibodies as compared with "healthy'' persons. Hepatitis does not primarily influence observed liver function disturbances in persons exposed to DMF.
It is suggested that under the given workplace conditions the hepatotoxic effects of alcohol are more pronounced than those of DMF.
Experience gained from former occupational health surveillance in DMF-exposed persons and the anamnestic data collected in this study show that there are individual differences in tolerance of the interactions between DMF and ethyl alcohol.

Executive summary:

As the investigation was carried out as a cross-sectional study (determination of the exposure and effect situation at a certain point in time), the interaction with the confounding factor alcohol can be analyzed only to a limited extent. The interpretation of the effects observed in this study must therefore mainly be carried out descriptively. In addition, employees who have stopped work for reasons of bad health are not included in cross-sectional studies. Thus, it must be assumed that alcohol intolerance and the results of occupational-medical health surveillance, mainly with regard to liver function disturbances, have resulted in selection in the sense of a ``healthy worker'' effect (Hernberg 1980).

With regard to the interaction of other influences on liver function, no consistent differences, e.g., regarding the intake of medicine, were found. However, with regard to liver diseases, 22 (17.8 %) persons in the DMF-exposed group stated previous liver diseases, including increased liver function values as opposed to only 7 (13.2 %) in the control group. Of these 22 DMF-exposed persons, 14 worked in areas of higher exposure and 7 worked in areas of lower exposure, but only 1 of them stated in the questionnaire that his pathological liver findings were detected after the beginning of his employment at this plant. On the other hand, hepatitis serology yielded positive findings only in some cases; in the exposed group, 9.5 % of the workers showed positive anti-HBc values and 0.8 % showed positive a-HCV values (control collective: 7.4 % and 1.9 %, respectively. The findings in this study revealed no statistically significant difference for persons who had a known history of hepatitis or were found to have positive antibodies as compared with ``healthy'' persons. Thus, the observation of Wang et al. (1991) that hepatitis does not primarily influence observed liver function disturbances in persons exposed to DMF can be confirmed. However, Wang et al. (1997) found a border- line statistical association between liver function disturbances and positive HBs-Ag carriers in their, assuming that after hepatitis there is increased sensitivity to DMF. The blood examination revealed on a group basis the normal values, although some individual cases were out of the normal range. Among the different laboratory tests used to determine liver function differences between exposed and unexposed persons, only c-GT and AST yielded statistically significantly higher values for the DMF-exposed group. Besides DMF, another reason for this effect may be the intake of alcohol, which for all persons averaged 50 g/ day. However, with regard to the amount of alcohol consumed, no statistically significant difference was found between the DMF-exposed group and the unexposed group. Taking into consideration a comparable average level of alcohol consumption, one could assume that the higher values recorded for c-GT and AST in the exposed group was an effect of DMF, especially as other con- founders could not be found. However, analysis of the subcollectives with regard to the level of exposure showed that in the group with the lowest level of exposure (finishing), both the daily amount of alcohol consumed and the c-GT values were significantly higher as compared with those with higher levels of exposure (wet spinning, dry spinning, dyeing). This may have been a result of the DMF-induced alcohol intolerance (ant- abuse effect) of the more highly exposed group. This suggests that under the given workplace conditions the hepatotoxic effects of alcohol are more pronounced than those of DMF. Nonetheless, intra- and interindividual deviations in the metabolic and excretion behavior of DMF may be relevant in view of the known interactions of DMF with alcohol metabolism. Such combination effects have also been described for other solvents, e.g., for the toxic effects of methylene chloride and methanol or of hydrogen tetrachloride and ethanol (Alessio et al. 1994; Marquard and Schäfer 1994). Experience gained from former occupational health surveillance in DMF-exposed persons and the anamnestic data collected in this study show that there are individual differences in tolerance of the interactions between DMF and ethyl alcohol. Even in the more highly exposed group, some workers mentioned no problem with the consumption of alcohol during exposure to DMF. Flush symptoms occurred in the group with higher levels of DMF exposure (66.2 %) as well as in the group with lower levels of exposure (70.9 %). Normally the flush symptoms occur within 24 h of exposure. Animal experiments have yielded evidence of differing susceptibility to the hepatotoxic effects of DMF in mice and rats; mice were found to have a higher capacity for the P-450 2E1- dependent oxidation that plays a role in DMF metabolism (Mraz et al. 1993; Chieli et al. 1995). These data point out that there seem to be individual degrees of susceptibility to DMF metabolism in humans as well.