N-[3-(dimethylamino)propyl]docosanamide

Endpoint summary

Description of key information

Experimental toxicokinetic studies are not available for DIMAPDO.
DIMAPDO has a molecular weight < 500 g/mol and a log Kow between -1 and 4 which is in general favourable for absorption from gastro-intestinal tract, by dermal route or from the lungs. The substance is protonated to a large extent (>99%) at pH<7. It is generally thought that ionised substances do not readily diffuse across biological membranes. DIMAPDO has a very low water solubility below 1 mg/L and forms micelles in aqueous solutions (CMC = 0.009 g/L) which will additionally limit the absorption rate.
Therefore an oral absorption rate of 50%, an worst case absorption rate of 100% via inhalation and a dermal absorption rate of 10% may be appropriate.
Based on physicochemical properties, no potential for bioaccumulation is to be expected.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

Data from in vitro or in vivo studies, which were designed to identify the toxicokinetic properties of DIMAPDO, are not available. But there are published toxicokinetic data of its most probable cleavage product behenic acid. Therefore for the assessment of the toxicokinetic behaviour of DIMAPDO all available relevant physical-chemical data of the substance itself and the published data of behenic acid were considered.

 

Table 1: Physical-chemical information that was considered for the toxicokinetic expert statement (cited from IUCLID5 data file, section 4):

Parameter	Value used for CSR
Molecular Weight	424.75 g/mol
Melting Point	79.4°C
Boiling Point	> 300°C
Density	0.947 g/cm^3
Vapour Pressure	7.1E-009 Pa
Partition coefficient n-octanol/water (log Kow)	2.85
Water solubility	< 0.1 mg/L
CMC	0.009 g/L (at 25°C)
pKa	9.2 (calculated)
Particle size	Flakes

 

Oral absorption

DIMAPDO has a molecular weight < 500 g/mol and a log Kowbetween-1 and 4which is in general favourable for absorption. The estimated pka(Base) of 9.2 ± 0.4 means that the substance will be present almost completely ionised in the stomach (pH 2) and below 10% unionised in the small intestine (pH 8) which is disadvantageous for the diffusion across the biological membranes in the gastro-intestinal tract. In general solids with a microscale particle diameter are too large to be directly taken up by pinocytosis and have to be dissolved before they can be absorbed. DIMAPDO has a very low water solubility below 0.1 mg/L and forms micelles in aqueous solutions (CMC = 0.009 g/L) which will additionally limit the absorption rate.

Based on its structure, DIMAPDO is likely to undergo hydrolysis by amidases. The hydrolysis of Behenic acid 3-(dimethylaminopropyl) amide would result in Behenic acid and 3-Aminopropyldimethylamine. Behenic acid has been reported to be poorly orally absorbed (3 -19% absorption) in animal studies using behenic-acid containing fats such' as superglycerinated hydrogenated rapeseed oil and caprenin due to its long carbon chain length (Carroll 1958, Nolen 1982, Webb & Saunders 1991, Webb et al. 1991 ) while absorptions from peanut oils is reported to be as high as 59% (Bezard & Sawadogo 1983, Tso et al. 1984). The results from another study of the appearance of behenic acid in lymph samples from rats suggest that only 11–24% of dietary behenic acid is absorbed (Mattson & Streck 1974). The results from a study of the fecal content of behenic acid in hamsters suggests that 19–29% of behenic acid is absorbed (Jandacek et al. 1993). In humans, who are known to have a greater capacity for absorbing stearic acid than do animals, fecal recovery of behenic acid suggests that the mean absorption of behenic acid is ≈30% (Peters et al. 1991).

Therefore an estimated absorption rate of 50 % both for animals and humans may be appropriate for DIMAPDO, until specific data will be available.

 

Respiratory absorption

DIMAPDO is solid at room temperature and has a very high boiling point (> 300°C) together with a low vapour pressure (7.1E-009 Pa) therefore substance evaporation and uptake by inhalation as vapour is unlikely.

The uptake after direct inhalation of substance dust particles and aerosols is also very unlikely because DIMAPDO is marketed and used in a granular form (flakes) or as waxy liquid.

After uptake the very poor water solubility < 0.1 mg/L of DIMAPDO will additionally limit the amount that can be absorbed directly. In general poorly water-soluble dusts depositing in the nasopharyngeal region could be coughed or sneezed out of the body or swallowed. Such dusts depositing in the tracheo-bronchial region would mainly be cleared from the lungs by the mucocilliary mechanism and swallowed. A small amount may be taken up by phagocytosis and transported to the blood via the lymphatic system.

Poorly water-soluble dusts depositing in the alveolar region would mainly be engulfed by alveolar macrophages. The macrophages will then either translocate particles to the ciliated airways or carry particles into the pulmonary interstitium and lymphoid tissues.

Because the substance is produced and marketed as granular flakes with low probability of inhalation and most of the inhaled DIMAPDO particles will be swallowed and then absorbed via GI tract with an estimated absorption rate of 50% for exposure assessments via inhalation a worst case assumption of 100% may be appropriate.

 

Dermal absorption

Based on above data the substance may be absorbed dermally. The molecular weight < 500 g/mol, a log Kowbetween -1 and 4 favour a dermal absorption. Taking in account the pKaof 9.2 ± 0.4 meaning at skin pH of 5.5 almost all DIMAPDO molecules will be ionised and the very low water solubility < 0.1 mg/L a high dermal absorption is nevertheless unlikely. This is supported by a dermal absorption calculation using the IH SkinPerm model (v1.21). The absorbed fractions have been estimated to be 0% after 8 and 24 h and the absorbed amounts 0.12 and 0.35 mg after 8 and 24 h, respectively.  The maximum dermal absorption rate has been calculated to be 3.60E-06 mg/cm²/h. Due to missing information about the applicability of the calculation model in respect to the substance under investigation the results should be treated with care.

Therefore for exposure assessments a value of 10 % of absorption after dermal exposure may be appropriate.

 

Distribution

As a small molecule a wide distribution can be expected. No information on potential target organs is available. However, as an ionised molecule, the substance is thought to not readily diffuse across biological membranes.

 

Metabolism

It is very difficult to predict the metabolic changes a substance may undergo on the basis of physico-chemical information alone. Based on the structure, the substance is likely to undergo hydrolysis by amidases. The hydrolysis of Behenic acid 3-(dimethylaminopropyl) amide would result in Behenic acid and 3-Aminopropyldimethylamine.

 

Absorbed behenic acid can either undergo oxidation for use as an energy source or follow an anabolic path to be re-esterified to wax esters, sphingolipids, glycolipids or acylglycerols (Bernhard & Vischer 1949, Nicolaides 1974, Max et al. 1978, Alexson & Cannon 1984). Alexson and Cannon (1984) reported very low oxidation rates for behenic acid and other very long (C20-C22) chain acids. In contrast, the finding that behenate oil feeding resulted in high concentrations of plasma triacylglycerol myristic, palmitic, and stearic acids suggests that behenic acid may be hydrolyzed shortly after absorption into shorter-chain saturated fatty acids. In support of this suggestion are the results of a study by Bernhard and Vischer (Bernhard & Vischer 1949) who determined that absorption was ≈40% in rats fed deuterium-labeled behenic acid. The label was absorbed mainly in shorter-chain saturated fatty acids, particularly stearic, palmitic, myristic, and lauric acids.

 

In general, lower primary aliphatic amines are metabolised to the corresponding carboxylic acid and urea. The tertiary site would be expected to undergo oxidation mediated by cytochrome P-450 or mixed function amine oxidases.

 

Elimination

The major routes of excretion for substances from the systemic circulation are the urine and/or the faeces. Excretion by exhalation does not seem to be relevant.

Behenic acid as one metabolite would enter the regular fatty acid metabolism and be indistinguishable from Behenic acid from other sources. Thus, further considerations are not considered necessary.

The amine metabolite is likely to be excreted via the urine. Favourable physicochemical properties for urinary excretion are good water-solubility and low molecular weight (< 300 g/mol; mostly anionic and cationic compounds).  

 

Bioaccumulation

Based on a log Kowof 2.85 the substance is unlikely to accumulate with the repeated intermittent exposure patterns normally encountered in the workplace.

 

References

 

Alexson, S.E.M., and Cannon, B. 1984. A direct comparison between peroxisomal and mitochondrial preferences for fatty-acyl β-oxidation predicts channelling of medium-chain and very-long-chain unsaturated fatty acids to peroxisomes. Biochimica et Biophysica Acta 796:1-10

 

Bernhard, K., and Vischer, E. 1949. Der abbau der behensäure im tierkörper.Helvetica Chimica Acta 29:929-93

 

Bezard J. and Sawadogo, K.A. 1983. The glyceride structure of perorenal fatty tissue in rats supplied with a peanut-oil-diet. Reprod Nutr Develop 23:65-80

 

Carroll, K.K. 1958. Digestibility of Individual Fatty Acids in the Rat. J Nutr 64:399-410

 

Jandacek RJ, Hollenbach EJ, Kuehlthau CM, Steimle AR.Effects of dietary behenate and a caprenin-like fat on lipids in the hamster. J Nutr Biochem 1993;4:243–9

 

Nicolaides N,. 1974. Skin lipids: Their biochemical uniqueness. Science 186(4158):19-26;

 

Mattson FH, Streck JA. Effect of the consumption of glycerides containing behenic acid on the lipid content of the heart of weanling rats.J Nutr1974;104:483–8.

 

Max, E.E., Goodman, D.B., and Rasmussen, H. 1978. Purification and characterization of chick intestine brush border membrane. Effects of 1 alpha(OH) vitamin D3 treatment. Biochimica et Biophysica, Acta 511:224-239

 

Nolen, G.A., 1981. Biological evaluation of hydrogenated rapeseed oil. Am Oil Chem Soc J 58(1):31-37

 

Peters JC, Holcombe BN, Hiller LK, Webb DR. Caprenin 3. Absorption and caloric value in adult humans. J Am Coll Toxicol 1991;10:357–67

 

Tso, P., Pinkson, G., Klurfeld, D.M., and Kritchevsky, D. 1984. The absorption and transport of dietary cholesterol in the presence of peanut oil or randomized peanut oil. Lipids 19:11-16

 

Webb, DR., Peters, J.C., Jandacek, R.J., and Fortier, N.E. 1991. Caprenin 2. Short-term safety and metabolism in rats and hamsters. J Am Coll Toxicol 10(3):341-35

 

Webb, D.R. and Saunders, R.S. 1991. Caprenin 1. Digestion, Absorption, and Rearrangement in Thoracic Duct-Cannulated Rats.J Am Coll Toxicol 10(3):325-340