Propanamide, 2-hydroxy-N,N-dimethyl-

Endpoint summary

Description of key information

An efficient absorption rate can be assumed after oral or dermal exposure. The absorption after inhalation is limited by the low vapour pressure and the solubility in mucus, which facilitates the removal from upper respiratory tracts. Once absorbed, the substance is expected to be effectively metabolized (liver as primary site of metabolism). As major metabolite, lactic acid is formed, which is further processed like dietary lactic acid. A second major metabolite is propanamide, 2-hydroxy-N-monomethyl, which is expected to be effectively excreted via the urine. This excretion pathway could also be undergone by the parental substance as such, due to high water solubility and small size. A bioaccumulation is considered unlikely.

Additional information

1.    Chemical and physico-chemical description

Generally, the substance propanamide, 2-hydroxy-N,N-dimethyl- (CAS 35123-06-9) belongs to the compound class of N,N-dimethylamides. It contains furthermore a lactic acid side chain with a free hydroxy group.

No experimental data on absorption, metabolism and distribution are available for the substance as such. In literature, the toxicokinetic behavior of a variety of N,N-dimethylamides is described (Wiles & Narcisse, 1971; Irwin et al., 1990). Further implications for the toxicokinetic assessment can be derived from the physic-chemical properties of propanamide, 2-hydroxy-N,N-dimethyl-.Description of the physico-chemical properties:

- physical state: liquid

- vapour pressure:1.2*10-4 atm ( <= 12 Pa;<=0,12 mbar) at 20 °C 

- molecular weight: appr. 116 Da 

- logPow: -0.94

- water solubility: >5000 g/L

- Boiling point: 224 °C (at 1031 mbar)

 

2.     Toxicokinetic assessment

 

2.1 Absorption:

In the gastro-intestinal tract, passive diffusion of propanamide, 2-hydroxy-N,N-dimethyl- is likely because of the low molecular weight (appr. 116 Da), the moderate log Pow (-0.94) and the high water solubility. An uptake via aqueous pores or through the epithelial barrier by the bulk passage of water is possible.

In spite of the relatively small molecular size, the substance to be registered has a low vapour pressure of 1.2*10-4 atm ( <= 12 Pa;<=0,12 mbar; at 20 °C) and a relatively high boiling point (224 °C at 1031 mbar), indicating that inhalation as a vapour will be limited. Because of the high water solubility, the substance is likely to dissolve in the mucus of the upper respiratory tract, and is thus expected to be removed effectively. If the substance reaches the respiratory tract, passive diffusion across the respiratory tract epithelium is favorable because of the low molecular weight (appr. 116 Da), the moderate log Pow (-0.94) and the high water solubility.

In the publication of Irwin et al., several N,N-dimethylamides were investigated for their potential to enhance the percutaneous absorption of ibuprofen and naproxen through rat skin. Among the tested N,N-dimethylamides themselves, those with a C10 alkyl chain penetrated most effectively (Kp = 9.26 – 10.05 x 10³cm h^-1). Smaller molecules had a lower penetration rate (e.g. N,N-dimethylhexanamide: Kp = 1.63 x 10³cm h^-1). As modeled with DERMWIN (v.1.43), a Kp of 3 x 10³cm h^-1can be assumed for propanamide, 2-hydroxy-N,N-dimethyl-, which points to a good dermal uptake. The results of Irwin et al. furthermore showed that the dermal barrier was not destroyed due to the application of N,N-dimethylamides.

In the study of Wiles and Narcisse, the acute toxicity after intragastric, percutaneous, intravenous or intraperitoneal aministration was evaluated with a variety of 12 N,N-dimethylamides. The authors observed that deaths occurred later after dermal exposure (15-20 hours after application) compared to parenteral administration (2-6 hours). The results confirm that N,N-dimethylamides are well absorbed by the skin, though not as effective as via the oral route.

2.2 Metabolism:

Once absorbed, a rapid distribution and metabolization of propanamide, 2-hydroxy-N,N-dimethyl- is expected, which takes primarily place in the liver. A stepwise demethylation is considered to be the major pathway. The product of the first demethylation step is propanamide, 2-hydroxy-N-monomethyl. This molecule can be further metabolized to lactic acid (2-hydroxypropanoic acid) via a second demethylation step. Lactic acid is also a dietary ingredient and/or formed during physiological processes; therefore efficient metabolic mechanisms are in place. Just like dietary lactic acid, the lactic acid formed in the degradation of of propanamide, 2-hydroxy-N,N-dimethyl- is reduced to lactate by the enzyme lactate dehydrogenase. The lactate is then either oxidized to pyruvate, which enters the Krebs cycle, or is converted to glucose via the gluconeogenesis process.

2.3 Excretion

The metabolite propanamide, 2-hydroxy-N monomethyl is expected to be excreted via urine. Because of the small size of the molecule and the high water solubility, the parent compound propanamide, 2-hydroxy-N,N-dimethyl- could leave the body unchanged by biliary excretion as well. Because of the high water solubility and the expected efficient metabolism and excretion, an accumulation of propanamide, 2-hydroxy-N,N-dimethyl- is unlikely.