N,N-dibutylformamide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: Expert statement

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Expert statement, no study available

Data source

Reference

Reference Type:

other: Expert statement

Title:

Unnamed

Year:

2017

Report date:

2017

Materials and methods

Principles of method if other than guideline:

Expert statement

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

N,N-dibutylformamide

EC Number:

212-090-0

EC Name:

N,N-dibutylformamide

Cas Number:

761-65-9

Molecular formula:

C9H19NO

IUPAC Name:

N,N-dibutylformamide

Test material form:

liquid

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Absorption is a property of a substance to diffuse across biological membranes. Generally, oral absorption is favored for molecular weights below 500 g/mol and log Pow values between -1 and 4. In the GI tract absorption of small water-soluble molecules (molecular weight up to around 200 g/mol) occurs through aqueous pores or carriage of such molecules across membranes with the bulk passage of water. Therefore, it can be considered as likely that N,N-dibutylformamide becomes bioavailable following the oral route, as indicated by its physicochemical properties. This assumption is confirmed by the results of the acute oral and repeated-dose prenatal developmental oral toxicity studies where clinical signs up to mortality was observed indicating systemic bioavailability.
Absorption via the respiratory route also depends on physico-chemical properties like vapor pressure, log Pow and water solubility. In general, highly volatile substances are those with a vapor pressure greater than 25 kPa or boiling point below 50°C. Substances with log Pow values between -1 and 4 are favored for absorption directly across the respiratory tract epithelium by passive diffusion. Due to its low vapor pressure of 2 Pa (0.002 kPa) and boiling point of 244.5°C N,N-dibutylformamide is unlikely to be available as a vapor to a large extent.
This assumption was confirmed in an inhalation hazard test, were rats were exposed to vapors of the test item at a concentration of 0.2 mg/L for 7 hours. No clinical signs, mortality or gross pathological findings were detected. Therefore, exposure and uptake via inhalation is considered as negligible.
In general, dermal absorption is favored by small molecular weights and high water solubility of the substance. Log Pow values between 1 and 4 favor dermal absorption, particularly if water solubility is high. For N,N-dibutylformamide high dermal absorption is predicted because of its high water solubility and an estimated log Pow value of 2.01. This is confirmed by results of an acute dermal study where systemic toxicity was observed accompanied by local skin findings. In addition, the test item is corrosive to the skin and damage to the skin surface may enhance skin penetration.

Details on distribution in tissues:

In general, the smaller the molecule the broader is its distribution. Small water-soluble molecules will diffuse through aqueous channels and pores in the membranes. After being absorbed into the body, N,N-dibutylformamide is expected to distribute through-out the body water. Due to its low log Pow the test item is unlikely to bioaccumulate in tissue, and there are no other physicochemical properties indicating bio-accumulating properties. A passage over the placental barrier is not expected since in the prenatal developmental toxicity studies no teratogen or specific embryotoxic effects were reported.

Details on excretion:

In general, urinary excretion in favored by low molecular weight (below 300 g/mol in the rat) and good water solubility. Therefore, N,N-dibutylformamide and its breakdown products are expected to be excreted mostly via urine. In rats, biliary excretion for substances with molecular weight below 300 g/mol is unlikely, aw not more than 5-10% is expected in the bile for organic cations. Therefore, only a much lower excretion via the faeces may occur.

Metabolite characterisation studies

Details on metabolites:

In a study of Mraz et al it was reported that hepatic P450 2E1 is an important catalyst of the metabolism of low-molecular weight amides. Thus, it can be considered as likely that the substance will be sufficiently metabolized (Mráz et al., 1993, Investigation of the Mechanistic Basis of N´N-Dimethylformamide Toxicity. Metabolism of N´,N-Dimethylformamide and its Deuterated Isotopomers by Cytrochrome P450 2E1; Chem.Res.Toxicol. 1993, 6, 197-207).