N,N-dibutylformamide

Endpoint summary

Link to relevant study record(s)

Reference

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

Principles of method if other than guideline:

Expert statement

GLP compliance:

no

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.

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).

Description of key information

Based on physico-chemical properties, oral and dermal absorption and distribution through-out the body is expected. These assumptions are supported by the results of single and repeated-dose toxicity studies in vivo. Absorption via the inhalation route is, due to physico-chemical properties of the test item, not expected. Bioaccumulation of the substance is not expected after continuous exposure. The test substance and/or its metabolites are expected to be predominantly excreted via urine and to a lower extent via faeces.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

N,N-dibutylformamide is a liquid with a molecular weight of 157.25 g/mol. The test has a water solubility of 8 g/L at 20°C. The log Pow is estimated to be 2.01 and the vapour pressure is 2 Pa at 20°C. The boiling point was determined to be 244.5°C.

 

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 andlog 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.

Distribution

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.

Metabolism

In a study of Mraz et al [1] 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, 197-20.)

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-dibutylformamideand 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.