Methyl α-D-glucoside

Endpoint summary

Description of key information

There are no experimental toxicokinetic data available for alpha methyl glucoside, thus, the toxicokinetic behaviour of the test item was evaluated according to ECHA endpoint specific guidance Chapter 7c based on its physico-chemical properties. A detailed description is given below.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

Toxicokinetic expert statement Alpha methyl glucoside

Data from in vitro or in vivo studies, which were designed to identify the toxicokinetic properties of alpha methyl glucoside, are not available. But there are published results substantiating the assumed toxicokinetic behaviour which is in line with the physico-chemical properties of alpha methyl glucoside.

Parameter	Value used for CSR
Molecular Weight	194.183 g/mol
Melting Point	167-168°C at 1013 hPa
Boiling Point	200°C at 26.57 Pa
Density	1.46 g/cm^3
Vapour Pressure	1.89E-006 Pa at 25°C
Partition coefficient n-octanol/water (log Kow)	-2.35
Dissociation constant	13.71 at 25°C
Water solubility	1080 g/L at 25°C
Particle size	D50 = 100 µm

 

Oral absorption

Alpha methyl glucoside has a molecular weight of less than 500 g/mol (194.183 g/mol), a water solubility of 1080 g/L at 25°C and a log Kow of -2.35 which indicates that the substance is hydrophilic.

The small size and the water solubility of the molecule are in general a prerequisite for absorption, because water-soluble substances will readily dissolve into the gastrointestinal fluids. However, absorption of very hydrophilic substances, i.e. substances with a log Kow below -1, by passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid.

Alpha methyl glucoside core structure is a-D-glucose which is a ubiquitously occurring carbon source for many organisms. Alpha-D-glucose as well as alpha methyl glucoside are known to be taken up by the intestine not only by passive transport mechanisms but also by transporters (Bormans et al., 2003; Lee et al., 2007). However, although readily taken up alpha methyl glucoside is not considered to be a substrate for phosphorylation by hexokinase, the initial reaction of glucose catabolism (Ghosh et al., 2018). According to ECHA endpoint specific guidance Chapter 7c and Chapter 8 in case of route-to-route extrapolation and in the absence of any route-specific information on the starting route a factor of 2 should be included resulting in a default oral absorption rate for alpha methyl glucoside of 50 % and as a worst case default value for respiratory absorption 100%.

 

Respiratory absorption

Alpha methyl glucoside is a solid at room temperature and its boiling temperature was determined at 200°C together with a low vapour pressure of1.89E-006 Pa at 25°Csubstance evaporation and uptake by inhalation is unlikely. The uptake after direct inhalation of substance dust particles and aerosols is also very unlikely because alpha methyl glucoside is only handled as an intermediate in a granular form with a median diameter of 100 µm. Nevertheless, since a median diameter of the granular particles of ≥ 100 µm is considered to be the inspirable particle size (according to ECHA endpoint specific guidance Chapter 7.c) an inhalation of particles cannot be excluded. However, after inhalation alpha methyl glucoside, it will be readily absorbed due to its physicochemical properties, i.e. its high water solubility (1080 g/L) or its low log Kow (-2.35) and is therefore unlikely to be coughed or sneezed out of the body. Irrespective of its physico-chemical properties the main absorption occurs via SGLT transporters. Alpha methyl glucoside is slowly excreted via the urine in its unchanged form. Due to its particles size deposition into lymphoid tissues is also rather unlikely.

Because of its granular form accidental exposure to dusts cannot be excluded. Thus, for precautionary reasons the estimated absorption of alpha methyl glucoside via the respiratory tract is 100%.

 

Dermal absorption

Due to its low molecular weight (194.18 g/mol) and its high water solubility (1080 g/L), alpha methyl glucoside may be dermally absorbed. However, since alpha methyl glucoside possesses a very low log Kow the substance may be to hydrophilic to penetrate the stratum corneum, thus, it is not expected to be dermally absorbed. However, the exact absorption rate cannot be predicted. Thus, according to the ECHA guidance on information requirements Chapter R.7.c and Chapter 8 a for precautionary reasons a value of 50% absorption is considered appropriate because dermal absorption is not expected to be higher than the oral absorption.

 

Distribution

Alpha methyl glucoside is mainly absorbed by SGLT transporter which are present in almost all tissues (Bormans et al., 2003).

As a small molecule a wide distribution can be expected. It was reported that alpha methyl glucoside was detected in the whole carcass, blood, the brain, the kidneys, the spleen or the intestine (Bormans et al., 2003, Dameto et al., 1994; Wright et al., 2011). However, there are studies reporting that alpha methyl glucoside is accumulated especially in the intestinal and renal brush border membrane, most likely due to the slow excretion from other cells and its uptake from the glomerular filtrate (Lee et al., 2007).

 

Metabolism

Alpha methyl glucoside is known to be non-metabolisable (Richter et al., 2015). Due to substrate specificity of the human hexokinase the catabolism of alpha methyl glucoside is not possible. However, alpha methyl glucoside is readily fermented by some bacteria or yeast indicating that these organisms are capable of utilising alpha methyl glucoside (Constantino et al., 1991;Reider et al. 1979;Erni et al., 1982). It was shown that although some bacteria are capable of metabolising alpha methyl glucoside for bacteria randomly occurring in the intestine alpha methyl glucoside remains unmetabolisable (Koser & Saunders, 1932). Hence, after oral administration alpha methyl glucoside can be considered to be absorbed from the intestine in cells containing SGLT transporter. Excretion from other tissues/cells seems to be rather slow (Bormans et al., 2003) but is triggered by the administration of D-glucose (Segal et al., 1973).

 

Elimination

The major routes of excretion for substances from the systemic circulation are the urine and/or the faeces. As depicted above, excretion by exhalation does not seem to be relevant as demonstrated by Bormans et al.(2003) because the substance is a non-volatile, non-metabolisable solid. Renal excretion is considered to be slow, because there are studies indicating that alpha methyl glucoside is reabsorbed by the kidney from the glomerular filtrate, thus, the concentration of alpha methyl glucoside is increased especially in the renal brush border membrane (proximal tubule cells; Lee & Han, 2006; Lee et al., 2007; Lee, Park & Han, 2005; Gatley, 2003). Due to its structure functionalisation of the substance by phase I or phase II metabolism is not necessary.

 

Bioaccumulation

Although alpha methyl glucoside is considered to be non-metabolisable and its concentration may be increased in cells capable of alpha methyl glucoside absorption, it is considered to be mainly renally excreted without further functionalisation. Additionally, the responsible transporter is a Na⁺/ glucose symporter; the increased concentration of alpha methyl glucoside is limited by an ion-gradient. Since alpha methyl glucoside is only manufactured and handled as an intermediate oral exposure can be excluded. The main exposure occurs by the inhalation and dermal route, thus, alpha methyl glucoside is unlikely to accumulate with the repeated intermittent exposure patterns normally encountered in the workplace due to the very low log Kow of -2.5.

 

 

 

 

References

Bormans, Guy M., et al. "Synthesis and biologic evaluation of 11C-methyl-D-glucoside, a tracer of the sodium-dependent glucose transporters."Journal of Nuclear Medicine44.7 (2003): 1075-1081. 

Dameto, M. C., et al. "Effect of cafeteria diet onα-MG intestinal absorption in rats."Comparative Biochemistry and Physiology Part A: Physiology108.2-3 (1994): 467-470. 

Wright, Ernest M., Donald DF Loo, and Bruce A. Hirayama. "Biology of human sodium glucose transporters."Physiological reviews91.2 (2011): 733-794.

Costantino, HENRY R., STEPHEN H. Brown, and R. M. Kelly. "Purification and characterization of an alpha-glucosidase from a hyperthermophilic archaebacterium, Pyrococcus furiosus, exhibiting a temperature optimum of 105 to 115 degrees C."Journal of bacteriology172.7 (1990): 3654-3660.

Erni, B., et al. "Bacterial phosphotransferase system. Solubilization and purification of the glucose-specific enzyme II from membranes of Salmonella typhimurium."Journal of Biological Chemistry257.22 (1982): 13726-13730.

Gatley, S. John. "Labeled glucose analogs in the genomic era."Journal of Nuclear Medicine44.7 (2003): 1082-1086.

Reider, Edith, Erwin F. Wagner, and Manfred Schweiger. "Control of phosphoenolpyruvate-dependent phosphotransferase-mediated sugar transport in Escherichia coli by energization of the cell membrane."Proceedings of the National Academy of Sciences76.11 (1979): 5529-5533.

Richter, Jan P., et al. "The structural and functional characterization of mammalian ADP-dependent glucokinase."Journal of Biological Chemistry291.8 (2016): 3694-3704.

Ghosh, B. K. (2018).Organization of prokaryotic cell membranes(Vol. 1).Crc Press.