N,N-dimethylformamide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well-documented publication (review) which meets basic scientific principles

Data source

Reference

Reference Type:

publication

Title:

Occupational Toxicants

Author:

Greim, H.

Year:

1992

Bibliographic source:

Critical Data Evaluation for MAK Values and Classification of Carcinogens, Vol.8

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test: Comprehensive review of available results regarding ADME of the test substance DMF
- Short description of test conditions: Rats were administered DMF via oral, dermal and inhalation routes of exposure

GLP compliance:

not specified

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:

Name of test material: N,N-dimethylformamide

Radiolabelling:

not specified

Test animals

Species:

rat

Sex:

male/female

Details on test animals or test system and environmental conditions:

no details given

Administration / exposure

Route of administration:

other: oral, dermal, inhalation

Vehicle:

not specified

Details on exposure:

No information given

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

N,N-dimethylformamide is readily absorbed after oral intake, dermal exposure or inhalation.

Main ADME results 2

Type:

distribution

Results:

N,N-dimethylformamide is rapidly and uniformly distributed in the organism.

Main ADME results 3

Type:

metabolism

Results:

Metabolization takes place mainly in the liver by microsomal enzymes.

Toxicokinetic / pharmacokinetic studies

Details on excretion:

The cysteine adduct N-acetyl-S-(N-methylcarbamoyl)cysteine is also found in urine at levels of 1 % to 5 % of the dose in urine of laboratory animals (mice, rat, hamsters) treated parenterally and at 10 % to 23 % of the dose in persons who had inhaled the substance. Formation and excretion of the cysteine adduct (N-acetyl-S-(N-methylcarbamoyl)cysteine) in the urine of persons inhaling N,N-dimethylformamide takes place with a half-time of 23 hours.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

N-hydroxymethyl-N-methylformamide is the main metabolite of N,N-dimethylformamide in animals and human beings and it is excreted with the urine. Mono-N-methylformamide which was once considered to be the main metabolite of N,N-dimethylformamide is found only in low levels in the urine. It could be shown that mono-N-methylformamide was mainly an artefact formed on the gas chromatographic column.

Any other information on results incl. tables

Moreover it was shown, that intermediary metabolism produces to a lower extent via a second pathway glutathione adducts and its degradation products. As carbamoylating species, which reacts with glutathione methyl isocyanate was postulated but not proven. Moreover, investigations in animals had shown that at least after administration in single high doses, N,N-dimethylformamide can inhibit its own metabolism (saturated metabolism). Metabolic interaction occurs between N,N-dimethylformamide and ethanol. Ethanol and probably the ethanol metabolite, acetaldehyde inhibit the breakdown of N,N-dimethylformamide. Conversely, N,N-dimethylformamide inhibits the metabolism of ethanol and acetaldehyde. Thus, increased N,N-dimethylformamide levels in the blood were found after the administration of alcohol and increased alcohol or acetaldehyde levels for up to 24 hours were reported after exposure to N,N-dimethylformamide.

Applicant's summary and conclusion

Conclusions:

Interpretation of results: no bioaccumulation potential based on study results
N,N-dimethylformamide is readily absorbed after oral intake, dermal exposure or inhalation. N,N-dimethylformamide is rapidly and uniformly distributed in the organism. Metabolization takes place mainly in the liver by microsomal enzymes. N-hydroxymethyl-N-methylformamide is the main metabolite of N,N-dimethylformamide in animals and human beings and it is excreted with the urine. Mono-N-methylformamide which was once considered to be the main metabolite of N,N-dimethylformamide is found only in low levels in the urine. It could be shown that mono-N-methylformamide was mainly an artefact formed on the gas chromatographic column. Another metabolite cysteine adduct (N-acetyl-S-(N-methylcarbamoyl)cysteine) is measured in the urine of persons inhaling N,N-dimethylformamide.

Executive summary:

Study design

This publication (review) provides an acceptable well-documented in vivo study (not according to OECD Test guideline) which meets basic scientific principles.

In this metabolism study, rats were administered N,N-dimethylformamide (DMF) via oral, dermal and inhalation routes of exposure.

Results

Metabolization took place mainly in the liver by microsomal enzymes. N-hydroxymethyl-N-methylformamide (DMF-OH or HMMF) was the main metabolite of DMF in animals and human beings and it is excreted with the urine. Mono-N-methylformamide (MMF) which was once considered to be the main metabolite of DMF was found only in low levels in the urine. It could be shown that MMF was mainly an artefact formed on the gas chromatographic column. Moreover it was shown, that intermediary metabolism produces to a lower extent via a second pathway glutathione adducts and its degradation products. As carbamoylating species, which reacts with glutathione methyl isocyanate was postulated but not proven. Moreover, investigations in animals had shown that at least after administration in single high doses, DMF can inhibit its own metabolism (saturated metabolism). Metabolic interaction occurs between DMF and ethanol. Ethanol and probably the ethanol metabolite, acetaldehyde inhibit the breakdown of N,N-dimethylformamide. Conversely, N,N-dimethylformamide inhibits the metabolism of ethanol and acetaldehyde. Thus, increased DMF levels in the blood were found after the administration of alcohol and increased alcohol or acetaldehyde levels for up to 24 hours were reported after exposure to N,N-dimethylformamide.

Conclusion

DMF was readily absorbed via all exposure routes and uniformly distributed throughout the organism.