Fatty acids, C16-18, 2-butyloctyl esters

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

other: publication

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Preliminary studies:

The target substance Fatty acids, C16-18, 2-butyloctyl esters is an alkyl ester with a linear C16/C18-acid moiety and a branched C12-alcohol moiety.
Alkyl esters have a common metabolic fate that involves a stepwise hydrolysis of the ester bonds by carboxylesterases by which the breakdown of the esters results in structurally similar chemicals, the fatty acid component and the respective alcohol (Fukami and Yokoi, 2012; Long, 1958; Lehninger, 1970; Mattson and Volpenhein, 1972). Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different places in the organism: After oral ingestion, esters of alcohols and fatty acids undergo enzymatic hydrolysis already in the gastro-intestinal fluids. In contrast, substances that are absorbed through the pulmonary alveolar membrane or through the skin enter the systemic circulation directly before entering the liver where hydrolysis will basically take place.
The target substance and source substances have molecular weights between 256.42 and 452.81 g/mol, the water solubility is 1 mg/L and the Pow values are > 6.68. Thus, absorption in the gastrointestinal (GI) tract may be expected and will mainly take place via micellar solubilisation because of the high lipophilicity (ECHA, 2008 ). The esters are expected to mainly undergo enzymatic hydrolysis in the gastrointestinal fluids,whereby the respective alcohol as well as the fatty acid is formed (Mattson and Volpenhein, 1972). For both cleavage products absorption from the GI-tract is anticipated. The highly lipophilic fatty acid is absorbed by micellar solubilisation (Ramirez et al., 2001), whereas the water soluble alcohol is readily dissolved into the GI-fluids and absorbed. The breakdown products of ester hydrolysis are free alcohols (2-ethylhexanol, 2-butyloctanol, butanol and ethanol) and the respective free fatty acids with carbon chain length from C8-C18, mainly saturated but also monounsaturated C18-chain length.
Due to the hydrolysis, not only the predictions based on the physico-chemical characteristics of the intact fatty esters will apply, but the physico-chemical characteristics of the breakdown products of the ester should also be considered. Following absorption, the ester and its cleavage products can be distributed within the body. The alcohols have low molecular weights and moderate water solubility and will therefore be widely distributed within the body (ECHA, 2012; HSDB, 2011). The high log Pow value of the esters implies that they have the potential to accumulate in adipose tissue. However, as they undergo esterase-catalysed hydrolysis, the accumulation potential of the cleavage products is considered to be most relevant. In contrast, accumulation of the fatty acids as triglycerides stored in adipose tissue or the incorporation into cell membranes is possible. At the same time, fatty acids are also required as a source for energy generation. Overall, the available information indicates that no significant bioaccumulation of the esters, acids or alcohols in adipose tissue is anticipated.
Following hydrolysis , the alcohols and acids may be metabolised further. The first cleavage product, the alcohol, is oxidized in several steps by the nonspecific alcohol dehydrogenase and the aldehyde dehydrogenase to the corresponding aldehyde and acid. Glucuronidation may also take place at all steps; thereby facilitating urinary excretion (HSDB, 2011). The second cleavage product, the fatty acid, is stepwise degraded by beta-oxidation based on enzymatic removal of C2 units in the matrix of mitochondria in most vertebrate tissues. The C2 units are cleaved as acyl-CoA, the entry molecular for the citric acid cycle. The omega- and alpha-oxidation pathways, alternative pathways for oxidation, can be found in the liver and the brain, respectively (Lehninger, 1970; Stryer, 1996). Based on the metabolism described above, the fatty esters and the breakdown products are expected to be metabolised in the body to a high extent. The fatty acid components will be metabolised for energy generation or stored as lipid in adipose tissue or used for further physiological properties e. g. incorporation into cell membranes (Lehninger, 1970; Stryer, 1996). Therefore, the fatty acid component is not expected to be excreted to a significant degree via the urine or faeces but excreted via exhaled air as CO2 or stored as described above. The second route of excretion is expected to be by biliary excretion with the faeces . For the fraction of alcohol that is not matabolised to the corresponding acid, the main route of excretion is via the urine. Due to the low molecular weight and the high water solubility the alcohol is readily conjugated with e.g. glutathione and excreted (HSDB, 2011).

Conclusions:

Interpretation of results: no bioaccumulation potential based on study results

Executive summary:

The target substance Fatty acids, C16-18, 2-butyloctyl esters is an alkyl ester with a linear C16/C18-acid moiety and a branched C12-alcohol moiety. Alkyl esters have a common metabolic fate that involves a stepwise hydrolysis of the ester bonds by carboxylesterases by which the breakdown of the esters results in structurally similar chemicals, the fatty acid component and the respective alcohol (Fukami and Yokoi, 2012; Long, 1958; Lehninger, 1970; Mattson and Volpenhein, 1972). Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different places in the organism: After oral ingestion, esters of alcohols and fatty acids undergo enzymatic hydrolysis already in the gastro-intestinal fluids. In contrast, substances that are absorbed through the pulmonary alveolar membrane or through the skin enter the systemic circulation directly before entering the liver where hydrolysis will basically take place. The target substance and source substances have molecular weights between 256.42 and 452.81 g/mol, the water solubility is 1 mg/L and the Pow values are > 6.68. Thus, absorption in the gastrointestinal (GI) tract may be expected and will mainly take place via micellar solubilisation because of the high lipophilicity (ECHA, 2008 ). The esters are expected to mainly undergo enzymatic hydrolysis in the gastrointestinal fluids,whereby the respective alcohol as well as the fatty acid is formed (Mattson and Volpenhein, 1972). For both cleavage products absorption from the GI-tract is anticipated. The highly lipophilic fatty acid is absorbed by micellar solubilisation (Ramirez et al., 2001), whereas the water soluble alcohol is readily dissolved into the GI-fluids and absorbed. The breakdown products of ester hydrolysis are free alcohols (2-ethylhexanol, 2-butyloctanol, butanol and ethanol) and the respective free fatty acids with carbon chain length from C8-C18, mainly saturated but also monounsaturated C18-chain length. Due to the hydrolysis, not only the predictions based on the physico-chemical characteristics of the intact fatty esters will apply, but the physico-chemical characteristics of the breakdown products of the ester should also be considered. Following absorption, the ester and its cleavage products can be distributed within the body. The alcohols have low molecular weights and moderate water solubility and will therefore be widely distributed within the body (ECHA, 2012; HSDB, 2011). The high log Pow value of the esters implies that they have the potential to accumulate in adipose tissue. However, as they undergo esterase-catalysed hydrolysis, the accumulation potential of the cleavage products is considered to be most relevant. In contrast, accumulation of the fatty acids as triglycerides stored in adipose tissue or the incorporation into cell membranes is possible. At the same time, fatty acids are also required as a source for energy generation. Overall, the available information indicates that no significant bioaccumulation of the esters, acids or alcohols in adipose tissue is anticipated. Following hydrolysis , the alcohols and acids may be metabolised further. The first cleavage product, the alcohol, is oxidized in several steps by the nonspecific alcohol dehydrogenase and the aldehyde dehydrogenase to the corresponding aldehyde and acid. Glucuronidation may also take place at all steps; thereby facilitating urinary excretion (HSDB, 2011). The second cleavage product, the fatty acid, is stepwise degraded by beta-oxidation based on enzymatic removal of C2 units in the matrix of mitochondria in most vertebrate tissues. The C2 units are cleaved as acyl-CoA, the entry molecular for the citric acid cycle. The omega- and alpha-oxidation pathways, alternative pathways for oxidation, can be found in the liver and the brain, respectively (Lehninger, 1970; Stryer, 1996). Based on the metabolism described above, the fatty esters and the breakdown products are expected to be metabolised in the body to a high extent. The fatty acid components will be metabolised for energy generation or stored as lipid in adipose tissue or used for further physiological properties e. g. incorporation into cell membranes (Lehninger, 1970; Stryer, 1996). Therefore, the fatty acid component is not expected to be excreted to a significant degree via the urine or faeces but excreted via exhaled air as CO2 or stored as described above. The second route of excretion is expected to be by biliary excretion with the faeces . For the fraction of alcohol that is not matabolised to the corresponding acid, the main route of excretion is via the urine. Due to the low molecular weight and the high water solubility the alcohol is readily conjugated with e.g. glutathione and excreted (HSDB, 2011).

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

The target substance Fatty acids, C16-18, 2-butyloctyl esters is an alkyl ester with a linear C16/C18-acid moiety and a branched C12-alcohol moiety. Alkyl esters have a common metabolic fate that involves a stepwise hydrolysis of the ester bonds by carboxylesterases by which the breakdown of the esters results in structurally similar chemicals, the fatty acid component and the respective alcohol (Fukami and Yokoi, 2012; Long, 1958; Lehninger, 1970; Mattson and Volpenhein, 1972). Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different places in the organism: After oral ingestion, esters of alcohols and fatty acids undergo enzymatic hydrolysis already in the gastro-intestinal fluids. In contrast, substances that are absorbed through the pulmonary alveolar membrane or through the skin enter the systemic circulation directly before entering the liver where hydrolysis will basically take place. The target substance and source substances have molecular weights between 256.42 and 452.81 g/mol, the water solubility is 1 mg/L and the Pow values are > 6.68. Thus, absorption in the gastrointestinal (GI) tract may be expected and will mainly take place via micellar solubilisation because of the high lipophilicity (ECHA, 2008 ). The esters are expected to mainly undergo enzymatic hydrolysis in the gastrointestinal fluids,whereby the respective alcohol as well as the fatty acid is formed (Mattson and Volpenhein, 1972). For both cleavage products absorption from the GI-tract is anticipated. The highly lipophilic fatty acid is absorbed by micellar solubilisation (Ramirez et al., 2001), whereas the water soluble alcohol is readily dissolved into the GI-fluids and absorbed. The breakdown products of ester hydrolysis are free alcohols (2-ethylhexanol, 2-butyloctanol, butanol and ethanol) and the respective free fatty acids with carbon chain length from C8-C18, mainly saturated but also monounsaturated C18-chain length. Due to the hydrolysis, not only the predictions based on the physico-chemical characteristics of the intact fatty esters will apply, but the physico-chemical characteristics of the breakdown products of the ester should also be considered. Following absorption, the ester and its cleavage products can be distributed within the body. The alcohols have low molecular weights and moderate water solubility and will therefore be widely distributed within the body (ECHA, 2012; HSDB, 2011). The high log Pow value of the esters implies that they have the potential to accumulate in adipose tissue. However, as they undergo esterase-catalysed hydrolysis, the accumulation potential of the cleavage products is considered to be most relevant. In contrast, accumulation of the fatty acids as triglycerides stored in adipose tissue or the incorporation into cell membranes is possible. At the same time, fatty acids are also required as a source for energy generation. Overall, the available information indicates that no significant bioaccumulation of the esters, acids or alcohols in adipose tissue is anticipated. Following hydrolysis , the alcohols and acids may be metabolised further. The first cleavage product, the alcohol, is oxidized in several steps by the nonspecific alcohol dehydrogenase and the aldehyde dehydrogenase to the corresponding aldehyde and acid. Glucuronidation may also take place at all steps; thereby facilitating urinary excretion (HSDB, 2011). The second cleavage product, the fatty acid, is stepwise degraded by beta-oxidation based on enzymatic removal of C2 units in the matrix of mitochondria in most vertebrate tissues. The C2 units are cleaved as acyl-CoA, the entry molecular for the citric acid cycle. The omega- and alpha-oxidation pathways, alternative pathways for oxidation, can be found in the liver and the brain, respectively (Lehninger, 1970; Stryer, 1996). Based on the metabolism described above, the fatty esters and the breakdown products are expected to be metabolised in the body to a high extent. The fatty acid components will be metabolised for energy generation or stored as lipid in adipose tissue or used for further physiological properties e. g. incorporation into cell membranes (Lehninger, 1970; Stryer, 1996). Therefore, the fatty acid component is not expected to be excreted to a significant degree via the urine or faeces but excreted via exhaled air as CO2 or stored as described above. The second route of excretion is expected to be by biliary excretion with the faeces . For the fraction of alcohol that is not matabolised to the corresponding acid, the main route of excretion is via the urine. Due to the low molecular weight and the high water solubility the alcohol is readily conjugated with e.g. glutathione and excreted (HSDB, 2011).