N,N-dimethyloctanamide

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
The toxicity of hallcomids decreases with the route of application (from intravenous to dermal). The highest toxicity can be observed for the mid chain length (C6-12, with maximum at C8-10) Hallcomids (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).
Short description of key information on absorption rate: 
N,N-dimethylamides act a penetration enhancer (Irwin W. J., Sanderson, F. D. and Po, A. Li Wan, 1990)

Additional information

There were no studies available in which the toxicokinetic properties (distribution, metabolism, elimination) of the N,N-dimethyloctan-1-amide were investigated.

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

 

N,N-dimethyloctan-1-amide having a molecular weight of ~171 g/mol is a liquid with a water solubility of 4.3 g/L. It has a low volatility of < 2.9 Pa (20°C) and has a lipophilic character (log Pow = 2.59). The structure shows no hydrolysable groups or ionic elements. The surface tension is 30.4 mN/m.

 

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.

Please note that the real behaviour may be different but can only be determined with ADME studies, which are not justified based on the very low toxicity of the substance. Additionally a few information are derived from acute or repeated dose studies of a N,N-dimethyloctan-1-amide / N,N-dimethyldecan-1-amide – mixture.

 

Oral and GI absorption:

Based on the phys. Chem. data, 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 that the major fraction is parent compound or parent compound metabolites. As an acute toxicity study shows a slight toxic effect (one death) in the highest dose group (LD50 = 2000 mg/kg bw) the oral bioavailability of the test material is indicated. A 90 day feeding study (Bayer 1993) with rats indicate also the systemic availability of the substance.

 

Inhalative absorption:

Regarding phys. chem. information the substance is expected to 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 limited by the low vapour pressure. These result were underlined by an acute inhalation study with C8/C10 mixture (Bayer 1991, LC50= 3551 mg/m³) and an repeated dose sighting inhalation study where 111.2mg/m³C8/C10 aerosol were tolerated (Bayer 1992; 5x6h)

 

Dermal absorption:Due to the physicochemical information of the substance a good absorption via skin can be assumed. Literature underlines this result showing a penetration of 6.44 µmol/(cm²*24h) and increased flux ratio for e.g. ibuprofen (2.3 C8 FADMA) compared to the control (W.J. Irwin, F.D. Sanderson and A. Li Wan Po 1990).The second result shows that N,N-dimethyloctan-1-amide additionally may acts as penetration enhancer.

 

Distribution:The physicochemical information points to a wide distribution of the substance.Due to a leak of neurotoxic effects in repeated dose studies, distribution to CNS does not appear or substance is not toxic to CNS.

 

Accumulative potential:Due to the water solubility and distribution an accumulation in general is unlikely. Nevertheless if accumulation happens the main site of accumulation is assumed to be the adipose tissue as well as skin. No accumulation in bone or in lung is predicted.

 

Metabolism:

No detail information can be followed concerning the metabolism. Nevertheless due to the fact that normally substances with low molecular weight are not excreted via bile an enterohepatic recirculation could be excluded. A literature study investigating the intensity of toxic effects shows a route dependency (increase from dermal to intravenous) (Wiles, J.S. and Narcisse, J.K. jr, 1971). For equal toxicity a factor of 100 could be determined between the intravenous and the oral route.

 

Reactivity:

Available studies on genotoxicity were negative, i. e. there is no indication of a reactivity N,N-dimethyloctan-1-amide or its metabolites under the test conditions.

 

Excretion:

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 assume that the substance is wide distributed, but unlikely to accumulate. It can also be assumed that metabolisation (in liver, via N-demethylase or/and P450) appears, degrading the substance. Afterward Phase II conjugation and also direct elimination is possible. The main route of excretion will be via kidney.

The following information is given in the literature (Abstract (citation)):

" The toxicity of a homologous series o£ 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 enhancers 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.

Determination of the enhancer self thru the skin delivers the following result:

           C8 FADMA: 6.44 µmol/(cm²*24h)