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Administrative data

Link to relevant study record(s)

Description of key information

Short description of key information on bioaccumulation potential result:

The available toxicokinetic studies on the structurally similar amides, C12, N, N-bis(2-hydroxyethyl), demonstrated rapid and effective metabolism by P450 enzymes with the metabolites mostly excreted in the urine. There is some indication of bioaccumulation in adipose and liver tissue. However, based on the overall available information, amides, C16-18 (even-numbered) and C18-unsatd., N,N-bis(hydroxyethyl) is expected to have a similar toxicokinetic profile including no significant bioaccumulation potential.

Short description of key information on absorption rate:

The available studies on the structurally similar amides, C12, N, N-bis(2-hydroxyethyl) 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, C16-18 (even-numbered) 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%. A 10% absorption can therefore assumed.

Key value for chemical safety assessment

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

Additional information

Molecular transformations imitating liver metabolism of amides, C12, N,N-bis(2-hydroxyethyl) as well as structurally similar amides, C12-18(even-numbered) and C18-unsatd., N,N-bis(hydroxyethyl) and amides, C12-18(even-numbered) and C18-unsatd., N,N-bis(hydroxyethyl) were modelled using OECD (Q)SAR application toolbox v.2.3. The simulated liver metabolism data indicate the same result.

The simulated GI metabolism data for structurally similar amides, C12-18(even-numbered) and C18-unsatd., N,N-bis(hydroxyethyl) and amides, C8-18 and C18-unsatd., N,N-bis(hydroxyethyl) indicates that it is predominantly metabolised by dealkylation, hydroxylation and oxidation transformation reactions. The simulated metabolism data further justifies the read-across approach used in this chemical safety report.

Reliablein vitroandin vivoanimal studies have been conducted to elucidate the absorption, distribution, metabolism and elimination of LDEA. Oral administration of LDEA at 1,000 mg/kg bw to 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 – half amides of succinic and adipic acid. No evidence of the parent compound, free DEA or DEA derivatives were present in the urine.

Dermal application of LDEA to mice and rats 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 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 tissue and liver tissue.

The metabolism of LDEA appears to have followed a degradation pathway in which first step is the 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 aldehyde dehydrogenases 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 - half 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. Further, the excretion of LDEA is expected to be rapid with most of the administered substance excreted in urine, and less than 1% excreted in faeces and CO2.

In conclusion based on the available read across toxicokinetics data, amides, C16-18(even-numbered) and C18-unsatd., N,N-bis(hydroxyethyl) is expected not to significantly bioaccumulate given the rapid and effective metabolism by P450 enzymes into innocuous polar metabolites which are then rapidly excreted (primarily) in urine. Consequently it is reasonable to assume no significant risk from bioaccumulation is expected to occur following oral or dermal exposure.

Discussion on bioaccumulation potential result:

Molecular transformations imitating liver metabolism of amides, C16-18 (even-numbered) and C18-unsatd., N,N-bis(hydroxyethyl) was modelled using OECD (Q)SAR application toolbox v.2.3. The model was conducted for the C18 alkyl chain containing test substance using CAS as the input parameter. The results of the simulated liver metabolism indicate that the test substance is predominantly metabolised by either epoxidation, aliphatic C-oxidation, N-dealkylation, C-hydroxylation or amide hydrolysis Phase I transformation reactions.

Merdinket al.(1996) investigated thein vitrometabolism of LDEA in liver and kidney microsomes of rats to determine the extent of its hydroxylation, identify the products formed and 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: 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 induced 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.

Mathewset al.(1996) investigated the toxicokinetics of LDEA in rats and mice following oral and dermal administration. Oral administration (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. 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, DEA or DEA-derived metabolites were detected. Tissue blood ratios were found to be highest in the adipose and liver tissues.

Discussion on absorption rate:

Mathewset al.(1996) studied the absorption and excretion of radiolabelled (14C) LDEA in F344 rats in which five male rats were exposed dermal to 25 mg/kg, 5 days a week for 3 weeks. The authors concluded that 70-85% was dermally absorbed ,with only metabolised LDEA present in urine.

Mathewset al.(1996) also conducted dermal absorption studies to evaluate the absorption of radiolabelled (14C) LDEA 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 animal 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 clearly state that availablein vivoandin vitrodata demonstrate that animal skin is more permeable than human skin and in particular rat skin is much more permeable than human skin by a factor 3-7. For dermal exposure assessment, a penetration of 10% can therefore be assumed.