Fatty acids, C16 and C18-unsaturated, methyl esters, chlorinated

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

According to Annex VIII of Reg. (EU) 1907/2006, the toxicokinetic of substance must be assessed from the relevant available information.
No specific studies were available for Fatty acids, C16-C18(even numbered) methyl esters, chlorinated. However, read across of studies on Medium Chain Chlorinated Paraffins/Alkanes, C14-C17, chloro and on Ethyl oleate were carried out.
Based on chemical structure the Medium Chain Chlorinated Paraffins/Alkanes, C14-C17, chloro is produced from C14-C17 alkane via chlorination. The chlorination process will chlorinate C-H bonds more or less randomly, although it is known that the sequence would be to chlorinate each carbon atom in the chain with one chlorine atom before putting a second chlorine atom on a carbon atom which already carries one chlorine atom. The process produces numerous potential isomers and identification of individual isomers is not possible.
Fatty acids, C16-C18(even numbered) methyl esters, chlorinated is produced from C16-C18 methyl esters with a similar randomly chlorination. Fatty acid esters are generally produced by chemical reaction of an alcohol (e.g. methanol) with an fatty acid in the presence of an acid catalyst. Monoesters are the final products of esterification of fatty acids with methanol.
The study on Medium Chain Chlorinated Paraffins/Alkanes, C14-C17, chloro provides insight about how chlorinated products are metabolized into the body, while study on ethyl oleate covers the behavior of Fatty acids esters.

In the gastrointestinal tract and/or livers similar biological processes occurred, enzymatic hydrolysis is the process by which the fatty acids are enzymatically degraded primarily via beta-oxidation. Alternative oxidation pathways (alpha- and omega-oxidation) are available and are relevant for degradation of branched fatty acids. Unsaturated fatty acids require additional isomerization prior to enter the beta-oxidation cycle. The methanol is slowly oxidized in the liver by the enzyme alcohol dehydrogenase (ADH) to formaldehyde, which itself is oxidized very rapidly by the enzyme aldehyde dehydrogenase (ALDH) to formic acid. Finally, formic acid is slowly metabolised to CO2 and H2O.
Data on Medium Chain Chlorinated Paraffins/Alkanes, C14-C17, chloro provide insight about the absorption, tissue distribution and elimination of a14C-labelled C14 -17 chlorinated paraffin (52% chlorinated) after a single oral gavage administration at a dose level of 525 mg/kg bw in male rats.
Radioactivity in blood and plasma, urine and faeces, selected tissues (but not gastrointestinal tract) and residual carcass was determined for up to 89 days post dosing. In animals kept in metabolism cages until termination, the average total recovery of radioactivity from urine, faeces and those tissues and organs sampled was 83.6% of the administered dose. Approximately 70% of the dose was recovered in the faeces and approximately 6% in the urine in the first 4 days after administration. This suggests that only about 30% of the orally administered dose was absorbed by day 4. Radioactivity was still detectable in urine and faeces at the end of the study, suggesting mobilization and excretion from tissue depots. Distribution of radioactivity into the liver and kidney was rapid, with highest levels (1.6 and 0.07% of the dose respectively) seen 24 hours after dosing; whereas distribution into fat and skin-and-fur was slower with the highest levels (2.5 and 3.7% respectively) seen on day 12 post-dosing. After reaching a peak, elimination of radioactivity from the tissues occurred with a half-life of approximately 2-5 days (well perfused tissues such as the liver and kidneys) or approximately 2 weeks (poorly perfused tissues such as white adipose tissue). On completion of the study (88 days) approximately 2% of the administered radioactivity remained in the tissues, primarily in the skin and fur (Elcombe, 2005a).

Overall, chlorinated paraffins and fatty acids methyl esters are expected to show a different bioaccumulation behavior.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

In the gastrointestinal tract and/or livers similar biological processes occurred, enzymatic hydrolysis is the process by which the fatty acids are enzymatically degraded primarily via beta-oxidation. Alternative oxidation pathways (alpha- and omega-oxidation) are available and are relevant for degradation of branched fatty acids. Unsaturated fatty acids require additional isomerization prior to enter the beta-oxidation cycle. The methanol is slowly oxidized in the liver by the enzyme alcohol dehydrogenase (ADH) to formaldehyde, which itself is oxidized very rapidly by the enzyme aldehyde dehydrogenase (ALDH) to formic acid. Finally, formic acid is slowly metabolised to CO2 and H2O.
Data on Medium Chain Chlorinated Paraffins/Alkanes, C14-C17, chloro provide insight about the absorption, tissue distribution and elimination of a14C-labelled C14 -17 chlorinated paraffin (52% chlorinated) after a single oral gavage administration at a dose level of 525 mg/kg bw in male rats.
Radioactivity in blood and plasma, urine and faeces, selected tissues (but not gastrointestinal tract) and residual carcass was determined for up to 89 days post dosing. In animals kept in metabolism cages until termination, the average total recovery of radioactivity from urine, faeces and those tissues and organs sampled was 83.6% of the administered dose. Approximately 70% of the dose was recovered in the faeces and approximately 6% in the urine in the first 4 days after administration. This suggests that only about 30% of the orally administered dose was absorbed by day 4. Radioactivity was still detectable in urine and faeces at the end of the study, suggesting mobilization and excretion from tissue depots. Distribution of radioactivity into the liver and kidney was rapid, with highest levels (1.6 and 0.07% of the dose respectively) seen 24 hours after dosing; whereas distribution into fat and skin-and-fur was slower with the highest levels (2.5 and 3.7% respectively) seen on day 12 post-dosing. After reaching a peak, elimination of radioactivity from the tissues occurred with a half-life of approximately 2-5 days (well perfused tissues such as the liver and kidneys) or approximately 2 weeks (poorly perfused tissues such as white adipose tissue). On completion of the study (88 days) approximately 2% of the administered radioactivity remained in the tissues, primarily in the skin and fur.

Conclusions:

The study on Medium Chain Chlorinated Paraffins/Alkanes, C14-C17, chloro provides insight about how chlorinated products are metabolized into the body, while study on ethyl oleate covers the behavior of Fatty acids esters.
Overall, chlorinated paraffins and fatty acids methyl esters are expected to show a different bioaccumulation behavior.

Description of key information

Although several data on chlorinated paraffins are provided in this dossier, those data are used to evidence the absence of a significant increased toxicity due to chlorination process. Nevertheless, it should be pointed out that a significantly different bioaccumulation behavior is expected between fatty acids methyl esters and chlorinated paraffins.