N,N-dimethylformamide

Additional toxicological data

Administrative data

Endpoint:

additional toxicological information

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Data source

Reference

Reference Type:

publication

Title:

Potency of monomethyl-, dimethylformamide and some of their metabolites to induce abnormal development in a limb Bud organ culture

Author:

Klug, S. et al

Year:

1998

Bibliographic source:

Toxicol. in Vitro 12, 123-132, 1998

Materials and methods

Type of study / information:

Developmental toxicity in a limb bud organ culture

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Developmental toxicity in a limb bud organ culture

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

Results and discussion

Any other information on results incl. tables

Neither N,N-dimethylformamide nor the predominant urinary metabolite N-hydroxymethyl-N-methylformamide exhibited developmental activity in the present investigation, whereas the metabolites resulting from the glutathione binding pathway, i.e. S-(N-methylcarbamoyl)glutathione, S-(N-methylcarbamoyl)cysteine and N-acetyl-S-(N-methylcarbamoyl)cysteine showed potent developmental activity on growth (300 µg/ml) and development (100 µg/mL) of day 12 old mouse limb buds after 24 hours as well as 6 days in culture. The three compounds appear to be equipotent on a molar basis.  Limb bud defects were not observed in in vivo studies, where typical malforamtions were seen in the form of vertebral, rib and tail defects and hernia of brain and omphalos.

Applicant's summary and conclusion

Conclusions:

Neither DMF, NMF nor the predominant urinary metabolite HMFF exhibited developmental activity in this test system. In contrast, all metabolites resulting from the glutathione binding pathway, SMG, SMC and AMCC showed potent developmental activity. Under the chosen exposure conditions, the developmental toxicity of DMF in different species appears to be related to the magnitude of glutathione binding.

Executive summary:

DMF, NMF and their major metabolites were investigated for their developmental toxicity in the mouse limb bud assay. We found that neither DMF, NMF nor the predominant urinary metabolite HMFF exhibited developmental activity. In contrast, all metabolites resulting from the glutathione binding pathway, SMG, SMC and AMCC showed potent developmental activity. Under the chosen exposure conditions, the developmental toxicity of DMF in different species appears to be related to the magnitude of glutathione binding. The results further show the value of using an in vitro system which is incapable of metabolic transformation of exogenous compounds for the identification of ultimate teratogenic species.