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Description of key information

Short description of key information on bioaccumulation potential result:
The predicted metabolism of amides, C12-18(even-numbered) and C18(unsatd.), N-hydroxyethyl and the structurally similar fatty acid alkanolamides as well as the toxicokinetics data conducted in vitro and in vivo suggests that the fatty acid alkanolamides share a common toxicokinetics profile resulting in a low 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), demonstrates 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, C12-18(even numbered) and C18(unsatd.), N-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

Simulators of molecular transformations imitating liver and gastro-intestinal (GI) metabolism of amides, C12-18 (even-numbered) and C18-unsatd., N-hydroxyethyl were modelled using OECD (Q)SAR application toolbox. The model was conducted for the major alkyl chain of amides, C12-18 (even-numbered) and C18-unsatd., N-hydroxyethyl using SMILES notation as the input parameter. The predicted metabolites from the GI simulator included: acetic acid (ca2+); 2-decenoic acid; dodec-2-enoic acid; dodecanoic acid; decanoic acid; octanoic acid; 3-hydroxy/keto dodecanoic acid; 3-hydroxy decanoic acid; 3-keto decanoic acid; glycine; acetic acid, mercapto-, compd. with 2-aminoethanol. The predicted metabolites from the liver metabolism simulator included: acetic acid (ca2+); N-(hydroxyethyl) dodecanoic acid); N-(hydroxyethyl) decanoic acid; N-(hydroxyethyl) octanoic acid; N-(hydroxyethyl) 11-hydroxy dodecane; N-(hydroxyethyl) dodecanol; N- (hydroxyethyl) dodecanal; lauramide; N-(hydroxyethyl) 11-hydroxy dodecanoic acid; N-(hydroxyethyl) 11-hydroxy/keto/aldehyde dodecanamide; 12-hydroxy dodecanamide. The results of the simulated GI and liver metabolism indicate that amides, C12-18 (even-numbered) and C18-unsatd., N-hydroxyethyl is predominantly metabolised by hydrolysis, dealkylation, hydroxylation, carbonylation and oxidation transformation reactions.

Liver and gastro-intestinal metabolism of structurally similar amides, C8-18 (even numbered) and C18-unsatd., N-(hydroxyethyl) (“MEA-FAA”) was also simulated using OECD (Q)SAR application toolbox. The results showed the same or similar metabolites as those predicted for amides, C12 -18, C18(unsatd.), N-hydroxyethyl. Hence the metabolism data derived from the QSAR application toolbox supports the read-across approach adopted since both fatty acid alkanolamides are predominantly metabolised by hydrolysis, dealkylation and oxidation transformation reactions as evidenced by the common metabolites predicted.

Furthermore, liver and gastro-intestinal metabolism of other structurally similar alkanolamides with differing alkyl chain lengths was also simulated using OECD (Q)SAR application toolbox. The results showed the same or similar metabolites as those predicted for amides, C12-18 (even-numbered) and C18-unsatd., N-hydroxyethyl (“MEA-FAA”). Hence the metabolism data derived from the OECD (Q)SAR application toolbox supports the read-across approach adopted since it evident that fatty acid alkanolamides are predominantly metabolised by hydrolysis, dealkylation and oxidation transformation reactions as evidenced by the common metabolites predicted.

Furthermore, reliable in vitro and in vivo animal studies conducted to elucidate the absorption, distribution, metabolism and elimination of structurally similar fatty acid alkanolamide-lauric acid diethanolamine (LDEA, CAS No.120-40-1) revealed rapid absorption and elimination in the urine (i.e., > 60% eliminated in urine in the first 24 hours and 80% after 72 hours) following oral administration.

Dermal applications of LDEA to mice and rats have demonstrated that absorption of LDEA through rat skin was slower compared to that of mouse skin. 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 (i.e., 3% recovered from all tissues collected).

In conclusion, amides, C12-18 (even-numbered) and C18-unsatd., N-hydroxyethyl is not expected to bioaccumulate due to its rapid and effective metabolism by P450 enzymes into innocuous polar metabolites which are then rapidly excreted in urine. It is therefore reasonable to assume no significant risk from bioaccumulation of amides, C12-18 (even-numbered) and C18-unsatd., N-hydroxyethyl following oral or dermal exposure.

Metabolism

Simulators of molecular transformations imitating liver and gastro-intestinal (GI) metabolism of amides, C12-18 (even-numbered) and C18-unsatd., N-hydroxyethyl, was modelled using the OECD (Q)SAR application toolbox (v1.1.02). The modelling was conducted for the major alkyl chain of amides,C12 -18 and C18-unsatd., N-hydroxyethyl. The GI and liver metabolism simulator resulted in a number of metabolites which were either the same or similar to the metabolites predicted for the metabolism of the structurally similar amides, C8-18 (even numbered) and C18-unsatd., N-(hydroxyethyl). The simulated GI and liver metabolism data for both fatty acid alkanolamide indicates that both are predominantly metabolised by hydrolysis, dealkylation and oxidation transformation reactions.

Merdink et al. (1996) investigated the in vitro metabolism of lauric acid diethanolamine (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-hydroxy derivatives.

Studies conducted by Mathews et al. (1996) to investigate the toxicokinetics of lauric acid diethanolamine (LDEA, CAS No.120-40 -1) in rats and mice following oral and dermal administration demonstrated that oral administration of LDEA (1,000 mg/kg bw) to rats 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 the half-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.

Dermal absorption

Mathews et al. (1996) studied the dermal absorption and excretion of radiolabelled (14C) lauric acid diethanolamine (LDEA, CAS No.120-40-1) in F344 rats in which five male rats were exposed to 25 mg/kg of LDEA, 5 days a week for 3 weeks. The authors concluded that 70-85 % LDEA was dermally absorbed with only metabolised LDEA present in urine.

 

Mathews et al. (1996) further conducted dermal absorption studies to evaluate the absorption of radiolabelled (14C) lauric acid diethanolamine (LDEA, CAS No.120-40-1) in B6C3F1 mice and Fischer 344 rats. These studies showed that absorption through rat skin was slow with less than 30% of the dose absorbed during the first 72 hours, compared to mice, in which 50 to 70% of the applied dose was absorbed in the first 72 hours. There were no statistically significant differences in absorption across the range of doses. The disposition of LDEA in the tissues was also similar across the four dose levels.The difference in absorption rates between animals and human skin has been investigated and reported by The European Center for Ecotoxicology and Toxicology of Chemicals (ECETOC monograph 20) as well as by the European Commission DG Sanco (Sanco/222/2000 rev. 72004). Both reports state that available in vivo and in vitro data demonstrate that all animal skin are more permeable than human skin and in particular rat skin is much more permeable than human skin by a factor 3-7 and hence for dermal exposure assessment a penetration of 10% can be assumed.