Reaction mass of Fatty acids, montan-wax and Fatty acids, montan-wax, ethylene esters and Fatty acids, montan wax, mixed esters with fatty acids C16-18 and ethylene glycol and Fatty acids, montan-wax, stearyl esters and Montan wax

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

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

Adequacy of study:

supporting study

Justification for type of information:

For details on endpoint specific justification please see read-across report in section 13 or find a link in cross-reference “assessment report”.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Conclusions:

After oral application of rats octacosanol, which is a structural analogue of the submission substance, was excreted mostly in faeces, lower amounts in urine and expired air. The substance was distributed throughout the whole body. Only low amonuts of radioacitivity were retained in the individual organs or tissues at day 7 after dosing (highest amount per gram in adipose tissue; overall low bioaccumulation potential for such types of substances based on study results).

Executive summary:

The study used as source investigated the distribution and excretion of octacosanol after single oral exposure to rats.The study results of the source compound were considered applicable to the target compound. Justification and applicability of the read-across approach (structural analogue) is outlined in the read-across report in section 13 or find a link in cross reference “assessment report”.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

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

Adequacy of study:

supporting study

Justification for type of information:

For details on endpoint specific justification please see read-across report in section 13 or find a link in cross-reference “assessment report”.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Details on distribution in tissues:

The rapid formation of octacosanoic acid from octacosanol was shown in the plasma of rats and monkeys. This primary metabolite was detected at the first time point of measurement (15 min after dosing in rats, 30 min in monkeys).

Metabolites identified:

yes

Details on metabolites:

The rapid formation of octacosanoic acid from octacosanol was shown in the plasma of rats and monkeys. This metabolite was detected at the first time point of measurement (15 min after dosing).
The liver peak concentration of octacosanoic acid in the rat was about six times the concentration of octacosanol.
In monkeys further metabolites were examined (fatty saturated and unsaturated acids with shorter chain lengths): palmitic acid, oleic acid, stearic acid, myristic acid and palmitoleic acid. All examined metabolites were detected within 3 h after dosing.

Conclusions:

After oral exposure of policosanol, which is a structural analogue of the submission substance, to rats or monkeys the main component octacosanol is rapidly and efficiently metabolised to octacosanoic acid and shorter fatty acids (overall low bioaccumulation potential for such types of substances based on study results).

Executive summary:

The study used as source investigated bioavailability and metabolism of policosanol after single oral exposure of rats or monkeys.The study results of the source compound were considered applicable to the target compound. Justification and applicability of the read-across approach (structural analogue) is outlined in the read-across report in section 13 or find a link in cross reference “assessment report”.

Reference 3

Endpoint:

basic toxicokinetics in vivo

Type of information:

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

Adequacy of study:

supporting study

Justification for type of information:

For details on endpoint specific justification please see read-across report in section 13 or find a link in cross-reference “assessment report”.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Conclusions:

CD36 is a specific transport system in the mouse intestine, facilitating the uptake of very long chain fatty acids (VLCA).

Executive summary:

The study used as source investigated gastrointestinal uptake of long chain fatty acids (C16 -C26) after single oral exposure to mice.The study results of the source compound were considered applicable to the target compound. Justification and applicability of the read-across approach (structural analogue) is outlined in the read-across report in section 13 or find a link in cross reference “assessment report”.

Reference 4

Endpoint:

basic toxicokinetics, other

Remarks:

compilation of data on toxicokinetics and metabolism of very long chain fatty esters, acids and alcohols

Type of information:

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

Adequacy of study:

supporting study

Justification for type of information:

For details on endpoint specific justification please see read-across report in section 13 or find a link in cross-reference “assessment report”.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Conclusions:

The very long chain fatty waxes can be absorbed in the gut only after cleavage into alcohols and acids. The formed alcohols are oxidised to the corresponding fatty acids, but within a fatty acid cycle there is also a reverse reaction possible (reduction of the acid to the alcohol).

Executive summary:

The study used as source reviewed data on toxicokinetics and metabolism of very long chain fatty esters, acids and alcohols.The study results of the source compound were considered applicable to the target compound. Justification and applicability of the read-across approach (structural analogue) is outlined in the read-across report in section 13 or find a link in cross reference “assessment report”.

Reference 5

Endpoint:

basic toxicokinetics, other

Remarks:

compilation of data on toxicokinetics and metabolism of very long chain fatty acids

Type of information:

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

Adequacy of study:

supporting study

Justification for type of information:

For details on endpoint specific justification please see read-across report in section 13 or find a link in cross-reference “assessment report”.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Conclusions:

Fatty acids are synthesised by fatty acid synthases in the cytosol of mammalian cells and elongated into very long chain fatty acdids (VLCFA, stuctural analogues of the submission substance) by several membrane-bound enzymes in the endoplasmatic reticulum. VLCFA mostly occur as esters or amides linked to a broad variety of different lipids.

Executive summary:

The study used as source reviewed data on toxicokinetics and metabolism of very long chain fatty acids.

The study results of the source compound were considered applicable to the target compound. Justification and applicability of the read-across approach (structural analogue) is outlined in the read-across report in section 13 or find a link in cross reference “assessment report”.

Reference 6

Endpoint:

basic toxicokinetics, other

Remarks:

compilation of data on the metabolism of very long chain fatty acids

Type of information:

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

Adequacy of study:

supporting study

Justification for type of information:

For details on endpoint specific justification please see read-across report in section 13 or find a link in cross-reference “assessment report”.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Conclusions:

Very long chain fatty acids (VLCFA) with chain lengths up to C34 (which are structural analogues of the submission substance) are endogenous substances, which are synthesised and degradated within in the organism.

Executive summary:

The study used as source reviewed metabolic pathways of very long chain fatty acids (VLCFA). The study results of the source compound were considered applicable to the target compound. Justification and applicability of the read-across approach (structural analogue) is outlined in the read-across report in section 13 or find a link in cross reference “assessment report”.

Description of key information

No data on toxicokinetics are available for the members of the Montan waxes category. The following information is based on structurally related very long chain fatty esters, alcohols and acids (VLCFA), which originate from other natural sources.

In analogy to structurally related very long chain fatty esters, alcohols and acids (VLCFA) the Montan waxes are expected to be absorbed via the oral route. Wax esters are absorbed only after cleavage to the corresponding alcohols and acids. Due to their molecular size, dermal exposure is unlikely. Inhalation exposure is not expected due to their negligible volatility.The presence of labelled CO₂in the expired air after VLCFA exposure indicates the oxidation of the alcohols to the corresponding acids and their β-oxidation, with fatty acids of shorter chain lengths as metabolic intermediates. No bioaccumulation was observed with VLCFA.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The uptake of VLCFA (C22:0 to C28:0) from a VLCFA-unrestricted diet totals to about 450 mg/day VLCFA in common foods.

Synthesis of VLCFA with chain lengths up to 34 carbon atoms has been observed in the mammalian organism. They are present in small amounts in most tissues and body fluids with highest concentrations in brain and meibomian glands. They occur also as alpha-hydroxy derivates in brain, kidney and stomach. Endogenous VLCFA are degraded by several acyl CoA oxidases to shorter acids and finally to acetate and CO₂.

Fatty acids are synthesised by fatty acid synthases in the cytosol of mammalian cells and elongated into VLCFA by several membrane-bound enzymes in the endoplasmatic reticulum. β-Hydroxy and β-keto acids are intermediates of the chain elongation steps.

Very long chain fatty esters cannot be absorbed in the gut after oral uptake, but a systemic uptake (10 -40%) occurs after cleavage into the corresponding alcohols and acids. There are specific transport mechanisms for VLCFA in the intestine. The alcohols are oxidised to the corresponding fatty acids, which are either incorporated into phospholipids or undergo β-oxidation. This is suggested to be the major pathway of metabolism. However, in some tissues the fatty acids can be reduced at least partially to the corresponding alcohols (fatty acid cycle). Therefore, the metabolites of the ester cleavage may be converted (at least partially) into each other.

After oral exposure of rats or monkeys to octacosanol or Policosanol, the substances or metabolites were distributed in the whole organism and eliminated in feces, expired air and (in traces) in urine. Only minor amounts of radioactivity were retained in tissues after 7 days. The presence of labelled CO₂in the expired air indicates the oxidation of the alcohol to octacosanoic acid and their β-oxidation, yielding fatty acids of shorter chain lenghts as metabolic intermediates (palmitic acid, oleic acid, stearic acid, myristic acid and palmitoleic acid).

No information is available with respect to absorption after dermal or inhalation exposure, but considering the high molecular size and low vapour pressure no significant dermal absorption respective inhalation exposure has to be expected.

The above mentioned pathways are expected to apply also for the Montan wax group.