9-Decenamide, N,N-dimethyl-

Endpoint summary

Additional information

There were no studies available in which the toxicokinetic properties (distribution, metabolism, elimination) of the N, N-dimethyl 9-decenamide were investigated.

Information about the dermal absorption behaviour is reported in literature (W.J. Irwin, F.D. Sanderson and A. Li Wan Po 1990).  

The expected toxicokinetic behaviour is derived from the physicochemical properties, the results from the available toxicological studies and the available literature following the information given in guidance document 7c:  

N, N-dimethyl 9-decenamide having a molecular weight of ~197 g/mol is a liquid with a water solubility of 1.2g/L (20°C). It has a low volatility of 0.24 Pa (25°C) and has a lipophilic character (log Pow = 3.17). The structure shows no hydrolysable groups or ionic elements and it is surface active.

Oral and GI absorption: Based on the structure and solubility, it can be expected that substance is not hydrolysed in GI but soluble in GI fluid. Further it can be expected that the substance can be easily absorbed, but only parent compound or parent compound metabolites. An acute toxicity study (Kukulinski, 2014) shows a toxic effect (death) at ≥550 mg/kg and the oral bioavailability of the test material is indicated. This is supported by the observation of clinical signs in mice treated with 3 daily doses of the substance at up to 300 mg/kg in a micronucleus study (Weinberg 2014).

Inhalation absorption: It can be assumed that the substance will be effectively removed in the upper respiratory tract due to its solubility and limited vapour pressure. Nevertheless absorption is still possible via upper mucosa but is likely limited by the low vapour pressure.

Dermal absorption:Due to the physicochemical properties of the substance a good absorption via skin can be assumed.

Distribution:The physicochemical information points to a wide distribution of the substance. However, the results on an in vivo study in mice, which had received 3 daily dose of the substance, at up to 300 mg/kg, showed no cytotoxic effects on the bone marrow cells even though clinical signs were evident.

Accumulative potential:Due to the water solubility and distribution significant accumulation is not expected.

Metabolism:No detailed information can be concluded concerning the metabolism. Nevertheless due to the fact that normally substances with low molecular weight are not excreted via bile, enterohepatic recirculation could be excluded.

Reactivity:Available studies on genotoxicity were negative (Wells, 2014; Weinberg, 2014), i. e. there is no indication of a reactivity of the substance or its metabolites under the test conditions in a bacterial mutation test or an in vivo micronucleus test in the mouse. Furthermore, the substance was shown not to be a skin sensitiser in a mouse lymph node assay (Huygevoort, 2014), which suggests that it has no potential to react with macromolecules such as proteins.

Excretion: After degradation in the liver, Phase II metabolism, as well as direct elimination is possible, there no suggestion that a particular path is preferred. Based on the molecular weight and water solubility it can be assumed that the substance is mainly excreted via urine. If dermal application appears also a portion of the substance could be eliminated via exfoliation.  

In summary:The bioavailability of the substance can be confirmed through different routes. Possible uptake routes are dermal, oral and inhalation. It can be assumed that the substance is widely distributed, but unlikely to accumulate. It can also be assumed that metabolism (in liver, via N-demethylase or/and P450) is the primary route to degrade the substance. Afterward Phase II conjugation and also direct elimination is possible. The main route of excretion is expected to be via kidney.

Discussion on bioaccumulation potential result:

No valid studies are available investigating the basic toxicokinetics. Nevertheless investigations were published observing the route dependent toxicity of Hallcomids. The following information is given in the literature (Abstract (citation)):

"The toxicity of a homologous series of twelve N-dimethylamides (Hallcomids) was assessed by the intravenous, intraperitoneal, intragastric, and percutaneous routes in mice and rabbits. The ability of this unique and versatile class of dimethylamides to enhance skin penetration was studied by mixing the compounds with an organophosphorus compound (VX). The toxicity of the Hallcomids was compared with, the toxicity of other common dimethyl compounds (diracthylsulfolane, dimethylacetamide, dimethylformamide, dimethylsulfoxide). It was concluded that the Hallcomids are slightly to moderately toxic, and precautions to prevent skin contact should be taken for safe use and handling." Wiles, Joseph S.; Narcisse, John K., Jr.Acute toxicity of dimethylamides in several animal species American Industrial Hygiene Association Journal (1958-1999) (1971), 32(8),539-45

Discussion on absorption rate:

No valid studies are available investigating the dermal absorption.

Nevertheless in published literature Irwin, W. J., Sanderson, F. D. and, A. Li Wan, 1990 investigated the percutaneous absorption of ibuprofen and naproxen in the presence of  an amide transport enhancer through rat skin. In result n-Alkanoic N,N-dimethylamides were found to act as penetration enhancers for the transport of ibuprofen and naproxen from suspensions in 50% aqueous propylene glycol vehicles across rat skin. Greatest enhancement was observed with naproxen but both drugs demonstrated a bell-shaped dependence on the alkyl chain length of the enhancer. Maximum effect was observed with N,N-dimethyloctanamide and N,N-dimethyldecanamide. Measurement of the skin-vehicle partition coefficients indicated that the partition of the drug into the skin was also maximal when these enhancers were incorporated into the vehicle. Permeation studies monitoring the flux of enhancer indicated that these compounds also penetrated the skin most effectively.