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Description of key information

The available toxicokinetic studies on the structurally similar lauric acid diethanolamine condensate (LDEA, CAS No.120-40-1) demonstrated rapid and effective metabolism by P450 enzymes, with the metabolites mostly excreted via urine. Amides, C8-18 and C18-unsatd., N,N-bis(hydroxyethyl) is expected to have a similar toxicokinetic profile, with no significant bioaccumulation potential.
Short description of key information on absorption rate:
The available studies on the structurally similar lauric acid diethanolamine condensate (LDEA, CAS No.120-40-1) demonstrate that absorption through rat skin is slower than through mouse skin. In rats, 25 to 30% of the dose penetrated the skin during the first 72 hours, whereas in mice, 50 to 70% of the applied dose was absorbed in the first 72 hours. Therefore amides, C8-18 and C18-unsatd., N,N-bis(hydroxyethyl) is expected to have a similar dermal absorption profile. It is also important to consider that the degree of dermal absorption through human skin is expected to be less than that of animal skin since human skin is less permeable (factor of 3-7) and therefore the absorption rate through human skin can be expected to be less than 30%, therefore 10% absorption can be assumed.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - dermal (%):
10

Additional information

In vitro and in vivo animal studies have been conducted to elucidate the absorption, distribution, metabolism and elimination of the structurally similar lauric acid diethanolamine condensate (LDEA, CAS No.120-40-1), which has been adopted for read-across to amides, C8-18 and C18-unsatd., N,N-bis(hydroxyethyl).

Oral administration of LDEA to mice and rats has shown it to be well absorbed and rapidly eliminated in the urine (> 60% eliminated in urine in the first 24 hours and 80% after 72 hours) as two major metabolites - the half acid amides of succinic and adipic acid - with no evidence of the parent compound, free diethanolamine (DEA) or DEA derivatives present in the urine.

Dermal application of LDEA has demonstrated that absorption through rat skin was slower compared to the skin of mice. Less than approximately 29% of the dose penetrated through rat skin during the first 72 hours whereas in the mouse, 50 to 70% of the applied dose was absorbed by the skin during the first 72 hours.

Toxicokinetic studies in mice and rats have shown that the total retention of LDEA was low and a total of 3% was recovered from all tissues collected. The highest tissue to blood ratios (TBR) appeared to be in adipose and liver tissues.

Based on LDEA, the metabolism of amides, C8-18 and C18-unsatd., N,N-bis(hydroxyethyl) is expected to follow a pathway in which the first step is hydroxylation on the carbon 12 (ω-hydroxylation) by an inducible form of P450 enzyme. The ω hydroxyl group is then oxidised to a ω-carboxyl group by cytosolic alcohol and aldehydehydrogenases and the resulting fatty acid diethanolamine condensate is degraded by β-oxidation with successive removal of two carbon (acteyl) fragments from the carboxy terminal end of the molecule. Following analysis of the urine, two major polar metabolites were identified – the half acid amide of succinic and adipic acid - and no evidence of free DEA, DEA metabolites or unchanged LDEA which suggests that the amide linkage to DEA is not cleaved during metabolism.

Excretion of LDEA appears to be rapid with most of the administered dose excreted in urine, and less than 1% excreted in faeces and CO2.

In conclusion, based on the available toxicokinetics data, amides, C8-18 and C18-unsatd., N,N-bis(hydroxyethyl) is not expected to bioaccumulate due to rapid and effective metabolism by P450 enzymes into innocuous polar metabolites which are rapidly excreted (primarily) in urine.

Basic toxicokinetics

Merdink et al. (1996) investigated the in vitro metabolism of lauric acid diethanolamine condensate (LDEA, CAS No.120-40-1) in liver and kidney microsomes of rats to determine the extent of its hydroxylation, to identify the products formed and to examine whether treatment with an agent that induces P450 enzymes would affect hydroxylation rates. Liver and kidney microsomes treated with bis(2-ethylhexyl) phthalate (DEHP) and incubated with LDEA were analysed from which 97% of the hydroxylated products were identified as two major products, 11-hydroxyl and 12-hydroxy derivatives of LDEA. Treatment of rats with the cytochrome P4504A inducer and peroxisome proliferator, DEHP, increased the LDEA 12-hydroxylation rate by 5-fold, whereas the LDEA 11-hydroxylase activity remained unchanged. Incubating liver microsomes from DEHP-treated rats with a polyclonal anti-rat 4A inhibited the formation of 12-hydroxyl LDEA by 80%, compared to no inhibitory effect on the rate of 11-hydroxyl LDEA formation. Rat kidney microsomes also resulted in hydroxylation of LDEA at its 11- and 12-carbon atoms. These results suggest that LDEA in the presence of rat liver and kidney microsomes is rapidly converted into 11- and 12-hydroxyl derivatives.

Studies conducted by Mathews et al. (1996) to investigate the toxicokinetics of lauric acid diethanolamine condensate (LDEA, CAS No.120-40-1) demonstrated that oral administration to rats (1,000 mg/kg bw) resulted in LDEA being well absorbed and rapidly eliminated; more than 60% of the dose was eliminated in urine and 4% in faeces in the first 24 hours and 80% was eliminated in the urine and 9% in faeces after 72 hours. Following oral administration to mice, LDEA was rapidly distributed to tissues, metabolised and excreted as approximately 95% of the dose was excreted in the first 24 hours, of which 90% appeared in urine. Analysis of the urine revealed the presence of two major metabolites, thehalf-acid amides of succinic and of adipic acid. No parent compound, diethanolamine (DEA) or DEA-derived metabolites were detected. Tissue blood ratios were found to be highest in the adipose and liver tissues.