Rape oil, reaction products with diethanolamine

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
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 in the urine. There is some indication of bioaccumulation in adipose and liver tissue. However, based on the overall available information, the toxicokinetics of HE Rape Oil, reaction product with diethanolamine are expected to have a similar  profile including 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 HE Rape Oil, reaction product with diethanolamine 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 - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

Simulators of molecular transformations imitating liver of the structurally similar amides, C18 -unsatd., N,N-bis(hydroxyethyl), as well as amides, C16-18 (even-numbered) and C18-unsatd., N, N-bis(hydroxyethyl), amides, C12, N,N-bis(2-hydroxyethyl), amides, C12-18(even-numbered) and C18-unsatd., N,N-bis(hydroxyethyl) and amides, C8-18 and C18-unsatd., N,N-bis(hydroxyethyl) were modelled using OECD (Q)SAR application toolbox v.2.2 or 2.3. The results of the simulated liver metabolism indicate that all four substances are predominantly metabolised by either C-oxidation transformation reactions.

Furthermore, 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. Therefore, the simulated metabolism data further justifies the read-across approach used in this chemical safety report.

Reliable in vitro and in vivo animal studies have been conducted to elucidate the absorption, distribution, metabolism, and elimination of structurally similar lauric acid diethanolamine condensate (LDEA), which has been adopted for read-across to HE Rape Oil, reaction product with diethanolamine.

Oral administration of LDEA at 1,000 mg/kg bw doses to rats have shown LDEA to be well absorbed and rapidly eliminated in the urine (>60% eliminated in urine in the first 24 hrs and 80% after 72 hrs) as two major metabolites – half amides of succinic and adipic acid. No evidence of the parent compound, free diethanolamine (DEA) or diethanolamine derivatives were present in the urine.

Dermal applications of LDEA to mice and rats have demonstrated that absorption of LDEA 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 where as 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 tissue and liver tissue.

The metabolism of LDEA appears to have followed a degradation pathway in which the 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 aldehydehydrogenases and the resulting fatty acid diethanolamine condensate is degraded by β-oxidation with successive removal of two carbon (acetyl) 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 toxicokinetics data, HE Rape Oil, reaction product with diethanolamine is expected not to significantly bioaccumulate based on 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 to HE Rape Oil, reaction product with diethanolamine.

 

Discussion on bioaccumulation potential result:

Simulators of molecular transformations imitating liver metabolism of the structurally similar amides, C18 -unsatd., N,N-bis(hydroxyethyl) was modelled using OECD (Q)SAR application toolbox v.2.3. The modelling was conducted using CAS as the input parameter. The results of the simulated liver metabolism indicate that the test substance is predominantly metabolised by either epoxidation at the site of unsaturation or aliphatic-C-oxidation Phase I transformation reactions. The Phase I reactions suggest that the lipophilic compound, C18-unsatd., DEA would become more polar and water-soluble by insertion of oxygen. The resulting new hydrophilic molecules as a whole can easily be excreted from the body following a likely subsequent phase II transformation reactions. Moreover, the resulting increased hydrophilicity will also further reduce or eliminate the possible re-absorption of the chemical.

Merdink et al., (1996) investigated the in vitro metabolism of structurally similar 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 hydroxy derivatives.

Studies conducted by Mathews et al., (1996) to investigate the toxicokinetics of structurally similar 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.

 

Discussion on absorption rate:

Mathews et al., (1996) studied the absorption and excretion of radiolabelled (14C) lauric acid diethanolamine condensate, (LDEA, CAS No.120-40-1) in F344 rats in which five male rats were exposed dermal 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) also conducted dermal absorption studies to evaluate the absorption of radiolabelled (14C) 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 clearly 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.