Reaction product of D-Glucopyranoside, methyl; esterified with oleic acid, methyl ester

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Type of information:

other: assessement of toxicokinetic behaviour based on physico-chemical properties and toxicological data

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: An assessment of the toxicokinetic behaviour of substance D-glucopyranoside methyl 2,6-dioleate was performed, taking into account the chemical structure, the available physico-chemical-data and the available toxicological data.

Reason / purpose for cross-reference:

other: Reference to same expert statement

Objective of study:

absorption

distribution

excretion

metabolism

Qualifier:

according to guideline

Guideline:

other: Technical guidance document, Part I, 2003; ECHA guidance R7C., 2014

Deviations:

no

GLP compliance:

no

Remarks:

not applicable

Details on study design:

The toxicokinetic profile of the UVCB substance D-glucopyranoside methyl 2,6-dioleate (the test substance in the following) was not determined by actual absorption, distribution, metabolism or excretion measurements. Rather, the physical chemical properties of the test substance and its toxicological data were used to predict toxicokinetic behaviour.

Type:

absorption

Results:

The substance is not favourable for absorption via all routes of exposure, due to its molecular weight (MW =723.07 – 1955.1 g/mol), water solubility (7.68 mg/L), vapour pressure (0.00627 Pa at 25°C) and logPow (6.79 - 10).

Type:

distribution

Results:

The distribution in tissues is expected to be limited based only on physico-chemical properties. The substance is not expected to cross biological membranes extensively.

Type:

excretion

Results:

The high molecular weight constituents are expected to be eliminated via the faeces whereby polar metabolites of fatty acids and glucopyranose can be excreted via the urine.

Details on absorption:

The test substance is not favourable for absorption, since the majority of constituents have very high molecular weight (MW = 723.07 – 1955.1 g/mol), low water solubility (7.68 mg/L) and high log Pow (>4). Such lipophilic low water soluble substances are hindered to be absorbed because the dissolving in the gastrointestinal fluids is impaired. On the other hand, any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for the test substance since it is again poorly soluble in water. The substance does bear, however, surface activity; therefore an enhancement of absorption is theoretically possible. The substance is however not irritating to skin and eyes so that an enhancement of absorption is not expected.

Details on distribution in tissues:

However, the amount of the test substance, which is absorbed following dermal exposure into the stratum corneum, is unlikely to be transferred into the epidermis. Although the substance shows characteristics of a surfactant, it is not irritating to skin, and therefore an enhancement of dermal absorption can be ruled out. In support of this hypothesis (the low dermal absorption), the systemic toxicity of the test substance via the skin is low (acute dermal toxicity, LD50 value of > 2000 mg/kg bw for rats).
In conclusion, the evaluation of all the available indicators and the results of toxicity studies allow the allocation of the chemical in question into the group of chemicals with a low dermal absorption.

Details on excretion:

For D-glucopyranoside methyl 2,6-dioleate no data is available concerning its elimination. Most of the constituents have high molecular weight so that absorption through intestinal mucosa will be hindered. These constituents are expected not to be absorbed but excreted in the faeces. Concerning the fate of the constituents which are passed through the walls of the GI tract and are systemically available, they can be eliminated via the bile by passing liver and if re-absorbed and metabolised (as predicted by the OECD QSAR Toolbox), polar metabolised can be filtered by the kidneys and excreted via the urine. The parent substance, if not absorbed into systemic circulation and does not undergo the first-pass metabolism, is expected to eliminate via the faeces.

Metabolites identified:

yes

Details on metabolites:

Hydrolysis does not apply for the test substance because it is hindered due to the long hydrophobic hydrocarbon chain of the carboxylic acids rests. However, in case if some minor amounts of the substance are absorbed into systemic circulation and the ester bond is hydrolysed it is expected to be extensively metabolised. Glycopyranose rest of the constituents of the test substance is involved into intermediary carbohydrate metabolism and carboxylic acids (i.e oleic, stearic, linoleic and palmitic) undergo fatty acids metabolism (Biochemistry book; ISBN: According to the modelling results by the OECD QSAR Toolbox (v4.1), 18 metabolites are predicted for the test substance (see attached Table 1).The predicted metabolites point to a cleavage of ester bond whereby mono-oleates of methyl glucopyranoside (metabolite 7-11) are formed. Their glycopyranose moiety is stepwise oxidised. Oleic acid moiety (metabolite 13) is either oxidised resulting in hydroxyl or carbonyl derivatives of the oleic acid (metabolites 1, 4, 17 and 18) or undergoes β-oxidation (metabolites 3, 5 and 6) producing acetate unit (metabolite 2). Methylated D-glucopyranose (metabolite 15) is de-methylated to D-glucopyranose (metabolite 17) producing methanol (metabolite 14). Glucopyranosode moiety can be de-methylated directly at D-glucopyranoside methyl 2,6-dioleate (metabolite 12).
The above mentioned hydroxylated metabolites can react in phase 2 of the biotransformation with different molecules, leading to the formation of conjugations. This might be necessary for the parent compound, as its water solubility is fairly low and it cannot be eliminated via the urine without further metabolism. Further metabolism is most likely the conjugation of the hydroxyl-groups with glucuronic acid, activated sulphate or activated methionine.
In conclusion, it is likely that the substance of interest will be subject to metabolism by cytochrome P450 enzymes, by cleavage of the ester bond followed by beta-oxidation of fatty acids.

Conclusions:

The toxicological profile for the D-glucopyranoside methyl 2,6-dioleate indicate that dermal and inhalation absorption is expected to be limited due to the physico-chemical properties of the substance that are rather not in favour of extensive absorption potential (high molecular weight, high hydrophobicity and low vapour pressure). Oral absorption, if any, is expected to occur by micellular solubilisation, pinocytosis or persorption. If absorbed, test substance is not expected to be widely distributed because of its limited absorption potential. The parent substance and its metabolites are not expected to accumulate in the body but can be metabolised by P450-enzymes, enzymes involved in carbohydrate metabolism or β-oxidation. The high molecular weight constituents are expected to be eliminated via the faeces whereby polar metabolites of fatty acids and glucopyranose can be excreted via the urine.

Executive summary:

The substance D-glucopyranoside methyl 2,6-dioleate is expected to be absorbed to a limited extent after oral exposure, based on its high molecular weight, its low water solubility, its high Log P_owand/or absence of toxicity in the oral acute toxicity study and in long-term studies by oral route of exposure. Concerning the absorption after exposure via inhalation, as the chemical has a low vapour pressure, is highly lipophilic, has a high Log P_ow, and has a rather high molecular weight, it is clear, that the substance is poorly available for inhalation and will not be absorbed significantly. The substance is also not expected to be absorbed following dermal exposure into the epidermis, due to its low water solubility and its fairly high molecular weight and its high Log P_ow. Concerning its distribution in the body the substance is expected to be distributed into the intravasal compartment and possibly also into the intracellular compartment. The substance does not indicate a significant potential for accumulation, when taking into account the predicted behaviour concerning absorption and metabolism. The substance is expected to be significantly extensively metabolised (metabolism by cytochrome P450 enzymes, followed by cleavage of ester bond and beta-oxidation of fatty acid moieties) and to be eliminated via the urine and also via the bile.

Description of key information

The substance D-glucopyranoside methyl 2,6 -dioleate is expected to be significantly extensively metabolised (metabolism by cytochrome P450 enzymes, followed by cleavage of ester bond and beta-oxidation of fatty acid moieties) and to be eliminated via the urine and also via the bile.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

Toxicokinetic behaviour of the D-glucopyranoside methyl 2,6-dioleate

The toxicokinetic profile of the UVCB substance D-glucopyranoside methyl 2,6-dioleate (the test substance in the following) was not determined by actual absorption, distribution, metabolism or excretion measurements. Rather, the physical chemical properties of the test substance and its toxicological data were used to predict toxicokinetic behaviour.

Toxicological profile of the test substance

The test substance is a yellow coloured liquid. The molecular weight of the constituents is in the range of 125.96 – 1955.1 g/mol. The substance has a melting point at -18°C (Fox, 2015c) and has been determined to decompose from approximately 200 °C (473 K) at 99 kPa. The substance has a low vapour pressure, 0.00627 Pa at 25°C (Tremain, 2015). Its relative density was reported to be 0.983 at 20 °C (Fox, 2015c). The test substance is slightly soluble in water (7.68 mg/L at 20 °C; Fox, 2015d). While the partition coefficient Log10 P_owof the test substance has been experimentally determined to be in the range of 6.79 to >10.0, a key value of 8.0 is used by the exposure assessment due to the applicability domain of the modelling tool for environmental risk assessment (CHESAR v3.0). For the EPIWIN calculations of some endpoints, logPow of 6.79 was used.

The test substance is not acutely toxic by oral and dermal exposure routes (LD50 > 2000 mg/kg bw; Weinberg, 2015a,b) and was not irritating to skin and eyes (Sanders, 2015a,b). The test substance was shown not to bear a potential to cause allergic skin reactions (Sanders, 2015c). In the long-term toxicity studies, the test substance was of low toxicological activity. In a 28-day repeated dose toxicity study, orally administered test substance did not produce clinical signs, alterations in body weight and food consumption in treated animals. There were no findings at necropsy. The NOAEL of 1000 mg/kg bw was established for rats (Haas, 2015). In a combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422), functional fertility parameters were not affected, nor developmental toxicity effects were observed (Herberth, 2016). NOAEL of 1000 mg/kg bw was established for reproductive and developmental toxicity. The test substance was negative in a chromosome aberration test in human lymphocytes (OECD 473; Bowles, 2015) and in a Mouse Lymphoma Assay (OECD 476; Brown, 2015). Ames test was negative in an experimental study (Thompson, 2017) and was in addition predicted to be negative by read-across from structurally similar chemicals with the same functional groups (the OECD QSAR Toolbox v4.0).

Absorption

In general, absorption of a chemical is possible, if the substance crosses biological membranes. This process requires a substance to be soluble, both in lipid and in water, and is also dependent on its molecular weight (substances with molecular weights below 500 are favourable for absorption). Generally, the absorption of chemicals which are surfactants or irritants may be enhanced, because of damage to cell membranes.

The test substance is not favourable for absorption, since the majority of constituents have very high molecular weight (MW = 723.07 – 1955.1 g/mol), low water solubility (7.68 mg/L) and high log P_ow(>4). Such lipophilic low water soluble substances are hindered to be absorbed because the dissolution in the gastrointestinal fluids is limited. On the other hand, any lipophilic compound may be taken up by micellular solubilisation and this mechanism may be of relevance for smaller MW-fractions of the test substance since it is again poorly soluble in water. The substance does bear, however, surface activity; therefore an enhancement of absorption is theoretically possible. The substance is however not irritating to skin and eyes so that an enhancement of absorption is not expected.

The above mentioned properties determine the absorption of the test substance to be, generally, rather limited, based on the absorption-hindering properties (high molecular weight, slight water solubility and high Log P_ow) and the absence of systemic effects in toxicological experiments.

Oral route

Regarding oral absorption, in the stomach, a substance will most likely be hydrolysed, because this is a favoured reaction in the acidic environment of the stomach. The constituents of the UVCB test substance may theoretically hydrolyse because they are glycosides which are known as esters of a sugar rest (pyranose in this particular case) and a carboxylic acid (oleic, stearic, linoleic and palmitic). There are also some ethers representatives in the composition of the UVCB substance. “Ethers do not usually hydrolyze within environmentally relevant pH and temperature. Although esters can hydrolyze, especially in alkaline conditions, the test item components are considered to have a significantly reduced hydrolytic rate due to them being essentially insoluble in water. This is especially the case with the larger products that would be highly hydrophobic. The smaller products may be more susceptible to hydrolysis as they would have the potential to emulsify in water” (Fox, 2015).

In the small intestine absorption occurs mainly via passive diffusion or lipophilic compounds may form micelles and be taken into the lymphatic system. Additionally, metabolism can occur by gut microflora or by enzymes in the gastrointestinal mucosa. However, the absorption of highly lipophilic substances (Log P_owof 4 or above) may be limited by the inability of such substances to dissolve into gastrointestinal fluids and hence make contact with the mucosal surface. The absorption of such substances will be enhanced if they undergo micellular solubilisation by bile salts. Substances absorbed as micelles enter the circulation via the lymphatic system, bypassing the liver.

The available toxicological data suggest that any orally administered test substance is of low toxicological activity (oral LD50 is greater than 2000 mg/kg bw; 28-day and OECD 422 NOAEL is 1000 mg/kg bw). This may be explained by a limited absorption fully through the walls of the gastrointestinal tract (even though micellular solubilisation, pinocytosis and persorption cannot be ruled out) or by low toxicological activity of the substance per se. Since the constituents of the test substance are glucopyranosides of long-chain carboxylic acids that are known to be naturally occurring constituents of plants, a low systemic toxicity can be also assumed.

Based on these data, 50 % oral absorption is considered appropriate for the purpose of DNEL derivation in case of route-to-route extrapolation (according to ECHA Guidance on information requirements and chemical safety assessment, Chapter R.8, 2012).

Inhalation route

Concerning absorption in the respiratory tract, any gas or vapour has to be sufficiently lipophilic to cross the alveolar and capillary membranes (moderate Log P_owvalues between 0-4 favourable for absorption). The rate of systemic uptake of very hydrophilic gases or vapours may be limited by the rate at which they partition out of the aqueous fluids (mucus) lining the respiratory tract and into the blood. Such substances may be transported out of the lungs with the mucus and swallowed or pass across the respiratory epithelium via aqueous membrane pores. Lipophilic substances (Log P_ow>0) have the potential to be absorbed directly across the respiratory tract epithelium. Very hydrophilic substances can be absorbed through aqueous pores (for substances with molecular weights below and around 200) or be retained in the mucus.

The test substance has a low vapour pressure (0.00627 Pa at 25°C), which indicates only low availability for inhalation. The high molecular weight and the high Log P_owalso indicate no possibility for absorption through aqueous pores. Absorption by micellular solubilisation may be of possible for such highly lipophilic constituents of the test substance. However, based on this data the potential for absorption directly across the respiratory tract epithelium is unlikely. Therefore, it can be expected that the test substance is marginally available in the air for inhalation and any inhaled substance is not expected to be absorbed through the lungs but rather be swallowed (aspiration). However, according to ECHA guidance R.8, in the absence of experimental data on absorption, worst case assumption should be used in case of route-route extrapolation (50 % for the starting route and 100% for the end route). Since no inhalation repeated dose toxicity study is available for the test substance, 100 % absorption is considered for inhalation route while 50% absorption is assumed for oral route (the starting route) (please see above).

Dermal route

In order to cross the skin, a compound must first penetrate into the stratum corneum and may subsequently reach the epidermis, the dermis and the vascular network. The stratum corneum provides its greatest barrier function against hydrophilic compounds, whereas the epidermis is most resistant to penetration by highly lipophilic compounds. Substances with a molecular weight above 500 are normally not able to penetrate the skin. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Therefore if the water solubility is below 1 mg/L, dermal uptake is likely to be low. Additionally Log P_owvalues between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal; TGD, Part I, Appendix IV; ECHA guidance R7. C, 2014). Above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into thestratum corneum will be high. Above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake into the stratum corneum itself may be slow. Vapours of substances with vapour pressures below 100 Pa are likely to have enough contact time to be absorbed and the amount absorbed dermally is most likely more than 10% and less than 100 % of the amount that would be absorbed by inhalation. If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration. During the whole absorption process into the skin, the compound can be subject to biotransformation.

In the case of the test substance the molecular weight in the range of 723.07 – 1955.1 g/mol indicates already a marginal potential to penetrate the skin. This is accompanied by a low hydrophilicity of the substance (log P_owof 6.79 - 10) and low water solubility (7.68 mg/L). Even though the stratum corneum is open for lipophilic substances, the epidermis is very resistant against penetration by highly lipophilic substances (log P_ow>4). However, the amount of the test substance, which is absorbed following dermal exposure into the stratum corneum, is unlikely to be transferred into the epidermis. Although the substance shows characteristics of a surfactant, it is not irritating to skin, and therefore an enhancement of dermal absorption can be ruled out.In support of this hypothesis (the low dermal absorption), the systemic toxicity of the test substance via the skin is low (acute dermal toxicity, LD₅₀value of > 2000 mg/kg bw for rats).

In conclusion, the evaluation of all the available indicators and the results of toxicity studies allow the allocation of the chemical in question into the group of chemicals with a low dermal absorption. In detail, due to it’s molecular weight, log P_owof 6.79-10, low water solubility (7.68 mg/L) and the results for the dermal acute toxicity, the use of a factor of 10 % for the estimation of dermal uptake for D-glucopyranoside methyl 2,6 -dioleate is justified (Schuhmacher –Wolz et al.,2003; TGD, Part I, 2003; ECHA guidance R.7C, 2014).

Distribution

In general, the following principle applies: the smaller the molecule, the wider the distribution. A lipophilic molecule (Log P_ow>0) is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues. It’s not possible to foresee an extent of protein binding, which can limit the amount of a substance available for distribution. Furthermore, if a substance undergoes extensive first-pass metabolism, predictions made on the basis of the physico-chemical characteristics of the parent substance may not be applicable.

In case of the test substance no data is available for distribution patterns. Often such information can be gathered from gross and histopathological findings in treated animals in long-term studies. In this case no findings were noted in the animals at necropsy and no microscopic lesions were observed in the 28-day an in the screening studies (Haas, 2015; Herberth, 2016). Based on these findings, no extensive distribution potential can be concluded for the test substance. Even though the high Log P_owwould indicate the possibility to reach the intracellular compartment, this seems to be unlikely as the molecular weight of the un-metabolised substance is so high. Therefore, the distribution is expected to be rather limited.

Accumulation

It is also important to consider the potential for a substance to accumulate or to be retained within the body. Lipophilic substances have the potential to accumulate within the body (mainly in the adipose tissue), if the dosing interval is shorter than 4 times the whole body half-life. Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, substances with high Log P_owvalues tend to have longer half-lives. On this basis, there is the potential for highly lipophilic substances (Log P_ow>4) to accumulate in biota which are frequently exposed. Highly lipophilic substances (Log P_owbetween 4 and 6) that come into contact with the skin can readily penetrate the lipid rich stratum corneum but are not well absorbed systemically. Although they may persist in the stratum corneum, they will eventually be cleared as the stratum corneum is sloughed off. A turnover time of 12 days has been quoted for skin epithelial cells

Accordingly, the high Log P_owof the test substance might indicate a certain potential for accumulation in the body. This, however, is limited as the absorption is expected to be low or even negligible via all routes of exposure and because metabolism and excretion of the test substance are expected to influence this initial prediction (please see below).

Metabolism

As specified above, hydrolysis does not apply for the test substance because it is hindered due to the long hydrophobic hydrocarbon chain of the carboxylic acids rests. However, in case if some minor amounts of the substance are absorbed into systemic circulation and the ester bond is hydrolysed it is expected to be extensively metabolised. Glycopyranose rest of the constituents of the test substance is involved into intermediary carbohydrate metabolism and carboxylic acids (i.e oleic, stearic, linoleic and palmitic) undergo fatty acids metabolism (Biochemistry book; ISBN: According to the modelling results by the OECD QSAR Toolbox (v4.1), 18 metabolites are predicted for the test substance (please see attached Table 1).

The predicted metabolites point to a cleavage of ester bond whereby mono-oleates of methyl glucopyranoside (metabolite 7-11) are formed. Their glycopyranose moiety is stepwise oxidised. Oleic acid moiety (metabolite 13) is either oxidised resulting in hydroxyl or carbonyl derivatives of the oleic acid (metabolites 1, 4, 17 and 18) or undergoes β-oxidation (metabolites 3, 5 and 6) producing acetate unit (metabolite 2). Methylated D-glucopyranose (metabolite 15) is de-methylated to D-glucopyranose (metabolite 17) producing methanol (metabolite 14). Glucopyranosode moiety can be de-methylated directly at D-glucopyranoside methyl 2,6-dioleate (metabolite 12).

The above mentioned hydroxylated metabolites can react in phase 2 of the biotransformation with different molecules, leading to the formation of conjugations. This might be necessary for the parent compound, as its water solubility is fairly low and it cannot be eliminated via the urine without further metabolism. Further metabolism is most likely the conjugation of the hydroxyl-groups with glucuronic acid, activated sulphate or activated methionine.

In conclusion, it is likely that the substance of interest will be subject to metabolism by cytochrome P450 enzymes, by cleavage of the ester bond followed by beta-oxidation of fatty acids.

Excretion

The major routes of excretion for substances from the systemic circulation are the urine and/or the faeces (via bile and directly from the gastrointestinal mucosa). For non-polar volatile substances and metabolites exhaled air is an important route of excretion. Substances that are excreted favourable in the urine tend to be water-soluble and of low molecular weight (below 300 in the rat) and be ionized at the pH of urine. Most will have been filtered out of the blood by the kidneys though a small amount may enter the urine directly by passive diffusion and there is the potential for reabsorption into the systemic circulation across the tubular epithelium. Substances that are excreted in the bile tend to be amphipathic (containing both polar and nonpolar regions), hydrophobic/strongly polar and have higher molecular weights and pass through the intestines before they are excreted in the faeces and as a result may undergo enterohepatic recycling which will prolong their biological half-life. This is particularly a problem for conjugated molecules that are hydrolysed by gastrointestinal bacteria to form smaller more lipid soluble molecules that can then be reabsorbed from the GI tract. Those substances less likely to recirculate are substances having strong polarity and high molecular weight of their own accord. Other substances excreted in the faeces are those that have diffused out of the systemic circulation into the GI tract directly, substances which have been removed from the gastrointestinal mucosa by efflux mechanisms and non-absorbed substances that have been ingested or inhaled and subsequently swallowed. Non-ionized and lipid soluble molecules may be excreted in the saliva (where they may be swallowed again) or in the sweat. Highly lipophilic substances that have penetrated the stratum corneum but not penetrated the viable epidermis may be sloughed off with or without metabolism with skin cells.

For D-glucopyranoside methyl 2,6-dioleate no data is available concerning its elimination. Most of the constituents have high molecular weight so that absorption through intestinal mucosa will be hindered. These constituents are expected not to be absorbed but excreted in the faeces. Concerning the fate of the constituents which are passed through the walls of the GI tract and are systemically available, they can be eliminated via the bile by passing liver and if re-absorbed and metabolised (as predicted by the OECD QSAR Toolbox), polar metabolites can be filtered by the kidneys and excreted via the urine. The parent substance, if not absorbed into systemic circulation and does not undergo the first-pass metabolism, is expected to eliminate via the faeces.

Conclusion:

The toxicological profile for the D-glucopyranoside methyl 2,6-dioleate indicate that dermal and inhalation absorption is expected to be limited due to the physico-chemical properties of the substance that are rather not in favour of extensive absorption potential (high molecular weight, high hydrophobicity and low vapour pressure). Oral absorption, if any, is expected to occur by micellular solubilisation, pinocytosis or persorption. if absorbed, the test substance is not expected to be widely distributed because of its limited absorption potential. The parent substance and its metabolites are not expected to accumulate in the body but can be metabolised by P450-enzymes, enzymes involved in carbohydrate metabolism or β-oxidation. The high molecular weight constituents are expected to be eliminated via the faeces whereby polar metabolites of fatty acids and glucopyranose can be excreted via the urine.

 

The following information is taken into account for any hazard / risk assessment:

The substance D-glucopyranoside methyl 2,6-dioleate is expected to be absorbed to a limited extent after oral exposure, based on its high molecular weight, its low water solubility, its high Log P_owand/or absence of toxicity in the oral acute toxicity study and in long-term studies by oral route of exposure. Concerning the absorption after exposure via inhalation, as the chemical has a low vapour pressure, is highly lipophilic, has a high Log P_ow, and has a rather high molecular weight, it is clear, that the substance is poorly available for inhalation and will not be absorbed significantly. The substance is also not expected to be absorbed following dermal exposure into the epidermis, due to its low water solubility and its fairly high molecular weight and its high Log P_ow. Concerning its distribution in the body the substance is expected to be distributed into the intravasal compartment and possibly also into the intracellular compartment. The substance does not indicate a significant potential for accumulation, when taking into account the predicted behaviour concerning absorption and metabolism. The substance is expected to be significantly extensively metabolised (metabolism by cytochrome P450 enzymes, followed by cleavage of ester bond and beta-oxidation of fatty acid moieties) and to be eliminated via the urine and also via the bile.