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

Dermal absorption

Administrative data

Endpoint:

dermal absorption, other

Type of information:

other: assessement of dermal absorption potential 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 dermal absorption potential was performed, taking into account the chemical structure, the available physico-chemical-data and the available toxicological data.

Cross-reference

Reason / purpose for cross-reference:

other: Reference to same expert statement

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.

Data source

Reference

Reference Type:

other: Expert statement

Title:

Unnamed

Year:

2017

Report date:

2017

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

no

Remarks:

not applicable

Test material

Test material information

Constituent 1

Reference substance name:

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

EC Number:

946-364-2

Molecular formula:

C43H78O8

IUPAC Name:

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

Test material form:

liquid

Results and discussion

Percutaneous absorption

Key result

Parameter:

percentage

Absorption:

10 %

Remarks on result:

other: The substance is expected to be poorly absorbed following dermal exposure into the stratum corneum, due to its LogPow of 6.79 -10 and low water solubility (7.68 mg/L).

Any other information on results incl. tables

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 the stratum 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).

Applicant's summary and conclusion

Conclusions:

No significant dermal absorption is expected for the substance D-glucopyranoside methyl 2,6-dioleate.

Executive summary:

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 the stratum 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).