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Toxicological information

Direct observations: clinical cases, poisoning incidents and other

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Administrative data

Endpoint:
direct observations: clinical cases, poisoning incidents and other
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented case report.

Data source

Reference
Reference Type:
publication
Title:
Prolonged spontaneous and alcohol-induced flushing due to the solvent dimethylformamide.
Author:
Cox N.H. and Nustchin C.P.
Year:
1991
Bibliographic source:
Contact dermatitis. 1991:24:69.

Materials and methods

Study type:
other: case report
Endpoint addressed:
not applicable
Test guideline
Qualifier:
no guideline required
GLP compliance:
no

Test material

Constituent 1
Chemical structure
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:
DMF at a factory manufactoring printed circuit boards.

Method

Subjects:
- Number of subjects exposed: 1
- Sex: man
- Age: 30
- Race: no data
- Demographic information: no data
- Known diseases: no diseases
- Other: no medications
Ethical approval:
not applicable
Route of exposure:
other: inhalation and dermal
Reason of exposure:
unintentional, occupational
Exposure assessment:
measured

Results and discussion

Clinical signs:
Symptoms:
6-year history of episodic flushing of the face, upper chest and upper arms (especially after alcohol ingestion, but also was triggered by stress or heat); Onset was within minutes and duration of each episode generally less than an hour. Flushing episodes were associated with periorbital swelling, wheezing dysgeusia; reduced exercise tolerance and pulmonary functions were abnormal. Symptoms persisted for many months.

Any other information on results incl. tables

A 30-year-old man had a 6-year history of episodic flushing of the face, upper chest and upper arms. This occurred especially after alcohol ingestion, but was also triggered by stress or heat; onset was within minutes and duration of each episode generally less than an hour. Until 18 months previously, he had been employed at a factory manufacturing printed circuit boards, where DMF was used as a solvent in the resin production area. The patient felt that this agent was the cause of his symptoms as he had been asymptomatic in the same occupation until DMF was introduced, about 10 % of his workmates were affected, workers at European branches of the same factory had apparently experienced similar symptoms, and the symptoms had gradually become less frequent and less severe since he changed his occupation. During the period when he was still exposed to DMF, flushing episodes had also been associated with periorbital swelling, wheezing and dysgeusia. He had reduced exercise tolerance at this time and pulmonary function tests were abnormal (all expressed as a % of predicted value: FEV, 74 %, FVC 85 %, PEF 58 %). He was not atopic and had not taken any medication known to cause flushing or bronchoconstriction; chest X-ray and total serum IgE values were normal.

Applicant's summary and conclusion

Conclusions:
DMF-mediated alcohol intolerance can occur after exposure to either ingested or inhaled DMF, and it is also absorbed through skin. Alcohol-induced flushing may therefore be the presenting symptom of industrial exposure to DMF in vapour or liquid form.
Executive summary:

A 30-year-old man had a 6-year history of episodic flushing of the face, upper chest and upper arms. This occurred especially after alcohol ingestion, but was also triggered by stress or heat; onset was within minutes and duration of each episode generally less than an hour. Until 18 months previously, he had been employed at a factory manufacturing printed circuit boards, where DMF was used as a solvent in the resin production area. The patient felt that this agent was the cause of his symptoms as he had been asymptomatic in the same occupation until DMF was introduced, about 10 % of his workmates were affected, workers at European branches of the same factory had apparently experienced similar symptoms, and the symptoms had gradually become less frequent and less severe since he changed his occupation. During the period when he was still exposed to DMF, flushing episodes had also been assoeiated with periorbital swelling, wheezing and dysgeusia. He had reduced exercise tolerance at this time and pulmonary function tests were abnormal (all expressed as a % of predicted value: FEV, 74 %, FVC 85 %, PEF 58 %). He was not atopic and had not taken any medication known to cause flushing or bronchoconstriction; chest X-ray and total serum IgE values were normal.

Discussion

Alcohol-induced flushing can be related to ethnic origin, individual metabolism, tumours, medications, or chemical exposure. The most important chemicals are the thiuram disulphides (Antabuse®) and solvents such as trichloroethylene, carbon disulphide, and formamides including DMF. The mechanism of DMF-induced alcohol intolerance is probably depression of cytosylic alcohol dehydrogenase, leading to increased acetaldehyde levels after ingestion of ethanol. DMF-mediated alcohol intolerance can occur after exposure to either ingested or inhaled DMF, and it is also absorbed through skin. Alcohol- induced flushing may therefore be the presenting symptom of industrial exposure to DMF in vapour or liquid form. This disorder is probably not rare, Lyle et al. 1979 (see IUC Section 7.10.5) reported alcohol-induced flushing in 19 of 102 workers using DMF as a solvent. Although most flushing occurred within 24 h of the last exposure, attacks occurred up to 4 days after exposure (this was the longest interval between shifts). Spontaneous flushing is not generally reported as a feature of DMF exposure, but has been described after chronic exposure to the solvent trichloroethylene, which causes similar flushing after ingestion of alcohol. This feature may be more frequent than the available literature would suggest, as most publication on DMF have been based on short-term studies. The persistence of symptoms for many months after exposure ended is the most important feature of our patient. Trace amounts of DMF metabolites were still detectable 30 h after inhalation of 53 ppm of DMF for 2 h in one study, and alcohol delays excretion of DMF, but neither of these studies explain the months of symptoms in this patient. Several short-term studies have failed to show evidence of accumulation of DMF or its metabolites after sequential daily exposures, and the reason for these persistent symptoms remains unclear. The patient was aware of 2 colleagues with persistent alcohol- induced flushing after cessation of exposure to DMF, and, although this is not recognised as a notable problem by the manufacturers (personal communication), the authors recommend a careful history of any temporal relationship between flushing and occupation in workers exposed to solvents.