Amides, coco, N-[3-(dimethylamino)propyl], N-oxides

Endpoint summary

Description of key information

No experimental toxicokinetic data are available and thus, predictions were made using information on physico-chemical properties.

Thus, oral absorption is assumed to be highly likely as well as absorption by inhalation when the test substance is present as a finely divided powder or dust. Estimated absorption for the dermal route is 40%.

The test substance is suggested to distribute throughout the body. Metabolites are assumed to be aldehydes interacting with proteins, primary amines, and carboxylic acid groups. The main excretion pathway is assumed to be via urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

40

Absorption rate - inhalation (%):

100

Additional information

There were no studies available generating results on toxicokinetic properties of the test substance.

The expected toxicokinetic behavior was derived from the physico-chemical properties, the results of the available toxicological studies and the ECHA guidance document part 7c.

The test subtance has a molecular weight of~240 g/mol is a solid with a water solubility of 430.0 g/l (20°C). It has a low volatility of ≤4.5 hPa (20°C) and is hydrophilic (log Pow 2.11 at 23°C). It has a surface tension of 33.0 mN/m at 20°C. The structure shows unsaturated carbonhydrate bonds and an amine oxide group making the molecule highly polarizable and ionizable.

 

Absorption:

Oral:The test substance is assumed to be easily soluble in GI fluids and favorable for absorption by passive diffusion. It may be hydrolyzed in GI fluids. In addition, absorption may be enhanced because of damage to cell membranes as the test substance is a surfactant. Absorption in the stomach is not considered likely and it is assumed that most of the test substance is absorbed in the intestine. Signs of toxicity (clinical signs and death) were observed in an oral toxicity study in rats at 2000 mg/kg bw/day and thus, oral bioavailability was confirmed. In addition, a 28-day repeated dose oral toxicity study in rats was conducted, also showing signs of toxicity. No absorption rate has been reported and thus, an absorption rate of 100% has to be assumed.   

Inhalation: The test substance is suggested not to be a volatile substance. However, finely divided powder or dust may enter the respiratory tract. It is assumed that the test substance is favorable for absorption, but that it is removed from the air in the upper respiratory tract. It is suggested that the rate of the inhalation uptake is limited by the rate at which it dissolves into aqueous fluids (mucus) and then partition into blood. In addition, it is likely to be swallowed with the mucus or may pass across the respiratory epithelium via aqueous membrane pores. No data of experimental animals, epidemiological data or data obtained from accidental exposure are available. No absorption rate has been reported and thus, an absorption rate of 100% has to be assumed.

Dermal:The physico-chemical properties of the test substance are ambiguous to make an appropriate assumption on dermal absorption. The test substance first need to be dissolved into the surface moisture of the skin before uptake can be initiated. Penetration through the stratum corneum is reduced due to hydrophilicity. However, water solubility, surface tension, and the log P value, which is in the optimal range, suggest dermal absorption. In addition, the low vapor pressure would also suggest favorable dermal absorption. The test substance has an irritating potential to the skin but it is not a skin sensitizer. No signs of systemic toxicity and no deaths occurred in an acute dermal toxicity study conducted in rats. In addition, Kroes et al. (2007) used physico-chemical properties proposing dermal absorption of cosmetics. Herein, the potential to be absorbed across the skin (expressed in percent) corresponded to the maximum flux. Based on the results established by Kroes et al. (2007), the test substance is suggested to have a dermal absorption of 40%.

Distribution:From experimental studies conducted it is concluded that the test substance is distributed throughout the body, because effects were observed in various organs, such as liver and kidney. In addition, the log P value, the molecular weight and the water solubility of the test substance may indicate distribution into cells.

Accumulative potential:With the log P value being <4, it is not assumed that the test substance has an accumulative potential.

 

Metabolism:The chemical structure is similar to the coconut oil but the test substance contents unsaturated hydrogen bonds which may undergo electrophilic addition and be transformed into an alcohol. The reactive N-oxide group is proposed to undergo enzymatic transformation by liver microsomal cytochrome P-450 and be reduced to -N(CH3)2 (tertiary amine). The tertiary amine group is further on transformed in a three-step oxidation to an aldehyde whereas the first step may lead to a -CH2-NH-CH2-structure by oxidative N-demethylation. In another step of oxidative N-demethylation, the aforementioned structure is oxidized to H2N-CH2, and, as a final step, oxidized by oxidative N-deamination reactions to an aldehyde. The resulting aldehyde may interact directly with proteins. Protein interaction is assumed to arise at higher concentrations of the test substance or after long term exposure since the transformation to aldehyde requires numerous metabolic steps.   

The amide group is suggested to be hydrolyzed by amidohydrolases and be transformed into primary amines and a carboxylic acid group.

 

Excretion:It is suggested that the test substance is mainly excreted via urine based on the low molecular weight (<300 g/mol), good water solubility, and ionization of the molecule at the pH of urine. In addition, exfoliation is also likely to occur.