Registration Dossier

Administrative data

Description of key information

- acute oral toxicity study, OECD 423, GLP, RL1, LD50 > 2000 mg/kg bw for Isostearic acid, esters with methyl α-D-glucoside in 1% aq. carboxymethyl cellulose, read-across

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2008-08-01 to 2008-08-26
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
2001
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
2004
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Version / remarks:
2002
Qualifier:
according to
Guideline:
other: JMAFF, Notification No. 8147, Nov. 2000
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: young adult animals (approx. 9-12 weeks old)
- Weight at study initiation: 165 - 200 g
- Fasting period before study: max 20 h, 3- 4 hours after administration
- Housing: group housing of 3 animals per cage in labeled Macrolon cages (MIV type; height 18 cm.)
- Diet: ad libitum, pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water: ad libitum, tap water
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.0 ±3.0°C (actual range: 19.7 - 21.5°C)
- Humidity (%):30-70% (actual range: 47 - 82%)
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12


Route of administration:
oral: gavage
Vehicle:
other: 1% aq. carboxymethyl cellulose and water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 1 % aqueous carboxymethyl cellulose
- Justification for choice of vehicle: The vehicle was selected based on trial formulations performed at NOTOX and on test substance data supplied by the sponsor.

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg bw


Doses:
300 and 2000 mg/kg bw
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
- The toxicity of the test substance was assessed by stepwise treatment of groups of 3 females. The first group was treated at a dose level of 300 mg/kg bw. In a stepwise procedure additional groups of females were dosed at 300 and 2000 mg/kg bw.
- Frequency of dosage: single dosage, on day 1
- Duration of observation period following administration: 15 days
- Frequency of observations (mortaliity/viability): twice daily
- Frequency of weighing: day 1 (pre-administration), 8 and 15
- Frequency of observation (clinical signs): at periodic intervals on the day of dosing (day 1) and once daily thereafter, until day 15
- Necropsy of survivors performed: yes
- Clinical signs: The symptoms were graded according to fixed scales and the time of onset, degree and duration were recorded:
Maximum grade 4: grading slight (1) to very severe (4)
Maximum grade 3: grading slight (1) to severe (3)
Maximum grade 1: presence is scored (1).
Statistics:
- No statistical analysis was performed (The method used is not intended to allow the calculation of a precise LD50 value).
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Remarks on result:
other: no mortality
Mortality:
- No mortality occurred.
Clinical signs:
- Hunched posture and/or piloerection were noted in all animals on day 1 and in the first set of animals at 300 mg/kg bw on day 2.
Body weight:
- The body weight gain shown by the animals over the study period was considered to be similar to that expected of normal untreated animals of the same age and strain.
Gross pathology:
- No abnormalities were found at macroscopic post mortem examination of the animals.
Interpretation of results:
GHS criteria not met
Conclusions:
The oral LD50 value of test substance in Wistar rats was established to exceed 2000 mg/kg body weight.
Executive summary:

In an acute oral toxicity study according to OECD TG 423, groups of fasted, young adult female Wistar rats were given a single oral dose of test substance Isostearic acid, esters with methyl α-D-glucoside in 1% aq. carboxymethyl cellulose and water. The substance was administered by oral gavage at 300 mg/kg bw. In a stepwise procedure additional groups of females were dosed at 300 and 2000 mg/kg body weight. All animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice on day 15.

Oral LD50 Females > 2000 mg/kg bw

No mortality occurred. Hunched posture and/or piloerection were noted in all animals on day 1 and in the first set of animals at 300 mg/kg bw on day 2. The body weight gain shown by the animals over the study period was considered to be normal. No abnormalities were found at macroscopic post mortem examination of the animals.

In this study Isostearic acid, esters with methyl α-D-glucoside in 1% aq. carboxymethyl cellulose and water is practically non-toxic based on LD50 in female rats.

Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source substance is constituted of the target substance (alpha methyl glucoside) esterified to Isostearic acid and therefore exhibit partially similar toxicological behaviour due to similarity in their structure. During synthesis of Isostearic acid esters with methyl-α-D-glucose the four OH-groups of the methyl glucose are partially esterified with isostearate groups. The molar ratio of methyl glucose and isostearic acid is chosen close to 1:2 which means that the products may be a mixture of non reacted methyl glucose and its 4 monostearates, 6 distearates, 4 tristearates and 1 tetrastearate isomers. These numbers will increase accordingly, if the cyclic form of glucose is in equilibrium with its linear form and the other anomer (hemiacetalic carbon). A possible hydrolysis results in alpha methyl glucoside and excess Isostearic acid.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The target substance alpha methyl glucoside is a monoconstituent substance composed of a methyl-group which is o-glycosidic bound to the α-D-glucose core structure.
The source substance Isostearic acid esters with Methyl-α-D-glucose is an UVCB with a composition of 80% alpha methyl glucoside isostearate esters (mainly di-), 16% isostearic acid and 4% alpha methyl glucoside.


3. ANALOGUE APPROACH JUSTIFICATION
For detailed information please refer to the attached justification

4. DATA MATRIX
For detailed information please refer to the attached justification
Reason / purpose:
read-across source
Key result
Sex:
male/female
Dose descriptor:
LD50
Remarks:
in rats
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Results found for Isostearic acid esters with methyl-d-glucose
Mortality:
- No mortality occurred. (Isostearic acid esters with methyl-a-D-glucoside)
Clinical signs:
- Hunched posture and/or piloerection were noted in all animals on day 1 and in the first set of animals at 300 mg/kg bw on day 2. (Isostearic acid esters with methyl-a-D-glucoside)
Body weight:
- The body weight gain shown by the animals over the study period was considered to be similar to that expected of normal untreated animals of the same age and strain. (Isostearic acid esters with methyl-a-D-glucoside)
Gross pathology:
- No abnormalities were found at macroscopic post mortem examination of the animals. (Isostearic acid esters with methyl-a-D-glucoside)
Interpretation of results:
GHS criteria not met
Conclusions:
The oral LD50 of Isostearic acid esters with methyl-D-glucose in female rats is above 2000 mg/kg bw. Based on the different molecular weights of source and target substance the LD50 value of > 2000 mg/kg bw for Isostearic acid esters with methyl-D-glucose was adjusted to 733.8 mg/kg bw for alpha methyl glucoside.
Executive summary:

In an acute oral toxicity study according to OECD TG 423, groups offasted, young adult female Wistar rats were given a single oral dose of test substanceIsostearic acid, esterswith methyl α-D-glucosidein 1% aq. carboxymethyl cellulose and water. The substancewas administered by oral gavage at 300 mg/kg bw. In a stepwise procedure additional groups of females were dosed at 300 and 2000 mg/kg body weight. All animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice on day 15.

Oral LD50Females > 2000 mg/kg bw

No mortality occurred. Hunched posture and/orpiloerection were noted in all animals on day 1 and in the first set of animals at 300 mg/kg bw on day 2.The body weight gain shown by the animals over the study period was considered to be normal.No abnormalities were found at macroscopic post mortem examination of the animals.

In this studyIsostearic acid, esterswith methyl α-D-glucoside in 1% aq. carboxymethyl cellulose and water is of low toxicity based on LD50in female rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
2 000 mg/kg bw
Quality of whole database:
The key study was conducted according to OECD guideline 423 and GLP, thus, the study is of high quality.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

There are no data for alpha methyl glucoside regarding acute oral toxicity, however, there are reliable and relevant data for the structurally similar Isostearic acid, esters with methyl α-D-glucoside indicating a very low oral toxicity for the target substance.

In an acute oral toxicity study according to OECD TG 423, groups of fasted, young adult female Wistar rats were given a single oral dose of test substance Isostearic acid, esters with methyl α-D-glucoside in 1% aq. carboxymethyl cellulose and water. The substance was administered by oral gavage at 300 mg/kg bw. In a stepwise procedure additional groups of females were dosed at 300 and 2000 mg/kg body weight. All animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice on day 15. No mortality occurred. Hunched posture and/orpiloerection were noted in all animals on day 1 and in the first set of animals at 300 mg/kg bw on day 2.The body weight gain shown by the animals over the study period was considered to be normal. No abnormalities were found at macroscopic post mortem examination of the animals. In this study Isostearic acid, esters with methyl α-D-glucoside in 1% aq. carboxymethyl cellulose and water exhibits a low acute oral toxicity based on LD50 in female.

Oral LD50 Females > 2000 mg/kg bw

Acute inhalation toxicity

Given that inhalation is not a relevant route of exposure, testing by the inhalation route is not necessary according to REACH Regulation Annex VIII 8.5.2 Column 2. Inhalation is not a relevant route of exposure to alpha methyl glucoside. This applies to both workers and the general population and is due to the physicochemical properties of the substance. Alpha methyl glucoside is a granular solid, and the particles exhibit a mean diameter of D50= 100 µm, thus the particles are considered to be not inhalable. Generation of inhalable particles such as dust is therefore not to be expected. Vaporisation needs not to be considered due to the substance’s very low vapour pressure of6.532E-4 Pa at 25°C. The generation of aerosols is excluded by technical means or product design. The substance is not used in spray applications. The most likely route of human exposure for workers and consumers is the dermal route. Results of laboratory animal studies show a low acute toxicity after oral exposure. Therefore the acute intrinsic toxic activity alpha methyl glucoside is considered to be low. The occurrence of a systemic toxicity relevant to humans after inhalation is unlikely and therefore the conduct of an acute inhalation toxicity study is unjustified.

 

Acute dermal toxicity

The testing of acute dermal toxicity of alpha methyl glucoside is scientifically not justified based on retrospective data analyses undertaken by Creton et al. (2010) and Seidle et al. (2010) to ascertain the value of regulatory requirements prescribing multiroute testing for acute systemic toxicity. These analyses have examined the concordance among regulatory classifications for acute oral, dermal, and/ or inhalation toxicity for ~500 agrochemical and biocidal active substances and nearly 2000 industrial chemicals. The findings from these two independent reviews have revealed that acute dermal studies of pure substances do not add value above and beyond oral data for hazard classification of pesticides, biocides, or chemicals.

 According to the COMMISSION REGULATION (EU) 2016/863 of 31 May 2016 amending Annexes VII and VIII to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) as regards skin corrosion/irritation, serious eye damage/eye irritation, skin sensitisation and acute toxicity, recent “scientific analysis of available data fromin vivo acute toxicity studies have shown that substances that are not toxic via the oral route may be expected with high certainty to be also non-toxic via the dermal route. Therefore, testing those substances via the dermal route does not provide essential information for their safety assessment.”

 

References

Creton S. et al.: Acute toxicity testing of chemicals—Opportunities to avoid redundant testing and use alternative approaches, Critical Reviews in Toxicology, 2010; 40(1): 50–83

Seidle T. et al.: Cross-Sector Review of Drivers and Available 3Rs Approaches for Acute Systemic Toxicity Testing, TOXICOLOGICAL SCIENCES 116(2), 382–396 (2010).

Based on the available information, the acute toxicity of methyl-alpha-D-glucopyranoside is low. There are no data gaps in acute toxicity. Even though there is no information on acute toxicity in humans, there is no reason to believe that the low acute toxicity observed in experimental animals would not be relevant for human health.

Justification for read-across

For details on substance identity, toxicokinetics and detailed toxicological profiles, please refer also to the general justification for read-across attached as pdf document to section 13 of the IUCLID file. ´

Analogue approach justification

The read-across hypothesis is based on similar break down products of target and source substance, i.e. the target substance (alpha methyl glucoside) is one of two break down products of the source substance (Isostearic acid, esters with Methyl-α-D-glucose). According to scenario 1 of the Read-across Assessment Framework (RAAF) this analogue approach is based on the (bio) transformation of the source substance to common compounds, i.e. the target substance alpha methyl glucoside and Isostearic acid. Based on the available experimental data, including genotoxicity studies, the read-across strategy is supported by a similar toxicological behaviour of the two substances and their break-down products, respectively. Although there is a difference in absorption, for both substances a very low acute toxicity and mutagenicity was shown. However, in accordance with ECHA guidance on information requirements chapter R 7.c absorption of Isostearic acid, esters with methyl-α-D-glucose in the GI-tract is considered unlikely due to its size. The main metabolism pathway of the unchanged source substance would then be biotransformation by xenobiotic metabolism, i.e. functionalisation, conjugation and subsequent biliary excretion. However, unspecific hydrolysis of the source substance (Isostearic acid, esters with methyl-α-D-glucose) during GI-tract passage is more likely to occur resulting in its breakdown products, namely alpha methyl glucoside and Isostearic acid.

Alpha methyl glucoside (target substance) is a non-metabolisable glucose analogue which is used in several published studies to investigate cellular glucose uptake (Segal et al., 1973; Lee et al., 2007; Prieto et al., 1996; Genel et al., 1970). Alpha methyl glucoside enters the cell via the ubiquitously occurring SGLT transporter. Recovery of nearly 100% of labelled alpha methyl glucoside revealed a full absorption in various tissues. Due to reabsorption by the kidney, its concentration is elevated in the renal brush border membrane (Lee et al., 2007). This increase of alpha methyl glucoside is only limited by the ion gradient resulting from sodium symport. Alpha methyl-glucoside is considered to be mainly renally excreted. The other remaining break down product Isotearic acid is metabolised via β-oxidation and is thereby eliminated by the intermediary metabolism and thus, indistinguishable from fatty acids from other sources including diet.

The respective toxicological data (RL 1 or 2) are summarised in the table below; robust study summaries are included in the Technical Dossier in the respective sections.

Toxicological data are summarised in the data matrix.

 

a. Structural similarity and functional groups

The target substance, alpha methyl glucoside, consists of alpha-D-glucose which forms an o-glycosidic bond with a methyl-group at C1. Since several studies confirm that alpha methyl glucoside should be regarded to as a non-metabolizable sugar in mammalian cells, it can be concluded that the substance is renally excreted without transformation (Segal et al., 1973; Lee et al., 2007; Prieto et al., 1996; Genel et al., 1970). Although not metabolisable by mammalian cells it was shown that alpha methyl glucoside is metabolised by several bacteria except these ones occurring most frequently in the GI flora (Devriese et al., 1996, Tittsler & Sandholzer, 1935, Koser & Saunders, 1932).

The source substance, Isostearic acid esters with methyl-α-D-glucose, consists of one to four C18 aliphatic chains which are esterified to alpha methyl glucoside. Although this substance has a very lipophilic character (logKow > 6.5, water solubility < 5E-004 g/L and a high molecular weight (weighted mean) 690.31 g/mol) it cannot be excluded that it is absorbed to little extent. Subsequent to uptake unhydrolysed Isostearic acid, esters with methyl-α-D-glucose will to some extent undergo biotransformation by xenobiotic metabolism and subsequently biliary excreted, on the other hand unspecific hydrolysis is likely to occur and two fragments will emerge of which one is readily metabolised by fatty acid metabolism, i.e. β-oxidation of the aliphatic chain and the other one, alpha methyl glucoside (= target substance), is excreted unchanged. However, since Isostearic acid, esters with methyl-α-D-glucose is an UVCB consisting of an estimated amount of 4% of methyl-α-D-glucose, it must be assumed that studies conducted with the source substance are also performed with 4% of the target substance.

However, there are some differences between the target substance and the source substance regarding their physicochemical properties and consequently their toxicological effects.

 

b. Common breakdown products:

The metabolism expected to occur in the unhydrolysed source substance Isostearic acid, esters with methyl-α-D-glucose due to its size is functionalisation, conjugation and excretion. On the other hand hydrolysis of the isostearic acid moeity is likely to occur. The rate of hydrolysis is assumed to be enzyme-mediated and may thus be limited. Further degradation may be the metabolism of the fatty acid chain via β-oxidation. However, since the source substance is considered to be highly lipophilic, intestinal absorption may be limited for the unhydrolysed substance. However, the source substance is considered to be unspecifically hydrolysed in the GI-tract and subsequently absorbed and further metabolised. In case of alpha methyl glucoside (one of two breakdown products), a known non-metabolisable molecule, distribution preferentially to the kidney and in tissues exhibiting the SGLT1 and SGLT2 transporter occurs. This uptake and transient increase of concentration is also driven by renal reabsorption and slow excretion but this increase is limited by sodium symport. Finally, alpha methyl glucoside is considered to be renally excreted.

c. Differences

As described above alpha methyl glucoside and Isostearic acid, esters with methyl-α-D-glucose are distinguished by the presence or absence of the C18 alkyl-chains.Associated with the presence of these alkyl chains also differences in the physicochemical properties of both substances occur, i.e. differences in water solubility, partition coefficient, molecular weight etc. These physicochemical characteristics are also decisive for absorption of the source substance either oral (via GI-tract), dermal or by inhalation. Exposure to the source substance via inhalation route can be excluded due to its waxy appearance and its low vapour pressure. Due to its high molecular weight and log Kow the absorption of the unhydrolysed source substance is also limited via the dermal and the oral route. However, as explained above the composition of the source substance substantiates an exposure to the target substance as well. In contrast, dermal absorption of alpha methyl glucoside is likely due to its small molecular weight. Respiratory absorption of alpha methyl glucoside cannot be fully excluded due to its granular form although its median particle size is 100 µm, thus, it is considered that the substance is not inhalable according to ECHA guidance on information requirements Chapter R.7.c.

Since alpha methyl glucoside is produced and handled only as an intermediate consumer exposure is assumed to be marginal, thus, exposure via the oral route is not expected.

Dermal absorption of alpha methyl glucoside is also considered to be low due to its low log Kow (-2.5) it is presumably to hydrophilic to cross the stratum corneum.

 

Comparison of acute oral toxicity data

Endpoint

Target substance

Source substance

 

Alpha methyl glucoside

 

Isostearic acid, esters with methyl-α-D-glucoside

 

Acute oral toxicity

 

No data, read-across

 

OECD 423, rat, RL 1, GLP

LD50 females > 2000 mg/kg bw

 

 

Acute toxicity: According to Regulation (EC) No 1272/2008 (CLP) and the Globally Harmonized System for Classification and Labelling of Chemicals (GHS) Alpha methyl glucoside does not need to be classified.

 

No experimental data are available for the target substance.

The oral LD50 of the closely related source substance Isostearic acid, esters with methyl-alpha-D-glucoside in female rats was > 2000 mg/kg bw. 

Quality of the experimental data of the analogues:

The source substance Isostearic acid, esters with methyl-alpha-D-glucoside has been tested in a reliable study according to OECD TG 423. The tests have been conducted according to GLP criteria. Therefore, these data have no uncertainties and can be used in an analogue approach. The available data from the source chemical is sufficiently reliable to justify the read-across approach.

 

Conclusion for read-across

The structural similarities between the breakdown products of the source substance and the target substance as presented above support the read-across hypothesis. Adequate and reliable scientific information indicates that the source substances and their subsequent degradation products have similar toxicity profiles compared with alpha methyl glucoside.

Thus, the results obtained with the source substance Isostearic acid, esters with methyl-alpha-D-glucoside are considered to be also relevant for the target substance alpha methyl glucoside. 

 

In general, based on the diverging molecular weight of the target and the source substance a LD50 value obtained from the source substance has to be adjusted. However, due to supporting information from varying sources adjustment of the LD50 value is scientifically not justified. A justification is given below.

Alpha methyl glucoside is not only the core structure of the source substance Isostearic acid, esters withα-methyl glucoside, it is also structurally almost identical to alpha D-glucopyranoside. Alpha D-glucopyranoside is the major carbon source and an indispensable part of the intermediary metabolism in many organisms including rodents and humans (common textbooks of Biochemistry). It was shown that both compounds are absorbed by the same transporter system and both, alpha D-glucopyranoside and alpha methyl glucoside are known to be renally excreted. There are published information that indicate that higher doses (3000 mg/kg bw) of alpha methyl glucoside administered to rats via oral gavage do not result in adverse effects within 2 h after administration (Demarest, K et al., 2012). Due to the structural similarity to alpha D-glucopyranoside, whose LD50 is > 20000 mg/kg bw in rabbits (Spector, 1955), the LD50 of alpha methyl glucoside, although non-metabolisable, is considered to be in the same order of magnitude. Data about the acute oral toxicity ofα-D-glucopyranoside is mainly provided by studies conducted prior to implementation of GLP and/or OECD test-guidelines, i.e. collection of data/handbook data, thus, a detailed documentation of the occurring effects after administration of high doses of alpha D-glucopyranoside is lacking. The exceptional high doses of alpha D-glucopyranoside which are required to mediate a toxic effect (deterioration of physiological functions/mortality) suggest that toxicity results mainly from deterioration of cell functions mediated by dehydration. Based on the structural similarity it can be assumed that despite its non-metabolisable nature, alpha methyl glucoside causes the same dehydration symptoms at high doses. Furthermore, it is highly unlikely that other adverse effects occur at low doses of alpha methyl glucoside because it is considered to be renally excreted unchanged. Local effects were not detected during reliable and relevant irritation studies conducted according to OECD test guideline 439 and 437 with the target substance alpha methyl glucoside, thus, based on all available information an increased risk even during the intermittent workers exposure patterns or due to peak exposures during work is not expected.

Moreover, although alpha methyl glucoside is a non-metabolisable compound, information from other regulatory institutions like US EPA confirm a low toxicity. At the US EPA alpha methyl glucoside is listed on the ‘Safer Chemical Ingredients list’ as chemical that has been verified to be of low concern based on experimental and modeled data (www.epa.gov/saferchoice/safer-ingredients). Additionally, the FDA states that alpha methyl glucoside is considered to be safe in certain substances which are polyester resins and are safely used as articles which are intended for repeated use in contact with food (21CFR177.2420).

In summary, the available information provides evidence that alpha methyl glucoside exhibits a low toxicity, thus, adjustment of the descriptor starting point is scientifically not justified.

 

References:

1)    Spector, W. S. (1955).HANDBOOK OF TOXICOLOGY. VOLUME 1. NATIONAL ACADEMY OF SCIENCES-NATIONAL RESEARCH COUNCIL WASHINGTON DC.

2)    Brot-Laroche, Edith, et al. "Characterization of the d-glucose/Na+ cotransport system in the intestinal brush-border membrane by using the specific substrate, methyl α-d-glucopyranoside."Biochimica et Biophysica Acta (BBA)-Biomembranes904.1 (1987): 71-80.

3)    Kimmich GA, Randles J: alpha-Methylglucoside satisfies only Na+-dependent transport system of intestinal epithelium.Am J Physiol 241:C227–C232, 1981

4)    Genel, M., London, D., Holtzapple, P. G., & Segal, S. (1971). Uptake of alpha-methylglucoside by normal and diabetic human jejunal mucosa.Translational Research,77(5), 743-750.

5)    Lostao, M. P., et al. "On the multiplicity of glucose analogues transport systems in rat intestine."Revista espanola de fisiologia47.4 (1991): 209-216.

6)    Segal, Stanton, et al. "Transport of alpha-methyl-D-glucoside by human kidney cortex."Metabolism22.1 (1973): 67-76.

7)    Demarest, Keith T., et al. "Methods of using alpha-methylglucoside (AMG) as an indicator for glucose absorption and excretion." U.S. Patent No. 8,147,801. 3 Apr. 2012.

8)    FDA: 21CFR177.2420; TITLE 21--FOOD AND DRUGS; FOOD AND DRUG ADMINISTRATION; DEPARTMENT OF HEALTH AND HUMAN SERVICES; SUBCHAPTER B--FOOD FOR HUMAN CONSUMPTION (CONTINUED); PART 177 -- INDIRECT FOOD ADDITIVES: POLYMERS; Subpart C--Substances for Use Only as Components of Articles Intended for Repeated Use

Justification for classification or non-classification

Experimental data for acute oral toxicity of alpha methyl glucoside are not available. Isostearic acid, esters with methyl-glucoside serves as source substance in order to provide data for several toxicological endpoints required for registration according to Regulation (EC) No 1907/2006 (REACH) Annex VII.

This read-across is based on ECHAs read-across assessment frame scenario 1: ‘The analogue approach for which the read-across hypothesis is based on (bio) transformation to common compounds’. Isostearic acid, esters with α-methyl-glucoside contains alpha methyl glucoside as core structure and it is assumed to be hydrolysed or transformed during passage through the GI-tract, resulting in Isostearic acid and alpha methyl glucoside. Both are considered to be absorbed from the GI-tract (Genel M. et al., 1971, Lostao M. P et al., 1991). The latter one is known to be absorbed via the SGLT transporter (Brot-Laroche, E, et al.1987;Kimmich GA, et al., 1981). This absorption leads to a transient increase of alpha methyl glucoside in these cells which is most likely limited by the mode of absorption (sodium symport/ion gradient) (Segal et al., 1973). Thus, the dose descriptors obtained from the existing acute oral toxicity study conducted according to OECD test guideline 423 and the combined repeated dose and reproduction/developmental screening study according to OECD 422 with the source substance were considered as an appropriate starting point for deriving a DNEL. In general, based on the diverging molecular weight of the target and the source substance this dose descriptor has to be adjusted. However, due to supporting information from varying sources adjustment of the dose descriptor is scientifically not justified. A justification is given below.

Although alpha methyl glucoside is the core structure of the source substance Isostearic acid, esters with α-methyl glucoside, it is also structurally almost identical to α-D-glucopyranoside. Alpha D-glucopyranoside is the major carbon source and an indispensable part of the intermediary metabolism in many organisms including rodents and humans (common textbooks of Biochemistry). It was shown that both compounds are absorbed by the same transporter and both, alpha D-glucopyranoside and alpha methyl glucoside are known to be renally excreted. There are published information that indicate that higher doses (3000 mg/kg bw) of alpha methyl glucoside administered to rats via oral gavage do not result in adverse effects within 2h after administration (Demarest, K et al., 2012). Due to the structural similarity to a-D glucose, whose LD50 is > 20000 mg/kg bw in rabbits (Spector, 1955), the LD50 of alpha methyl glucoside, although non-metabolisable, is considered to be in the same order of magnitude. Data about the acute oral toxicity of α-D-glucopyranoside is mainly provided by studies conducted prior to implementation of GLP and/or OECD test-guidelines, i.e. collection of data/handbook data, thus, a detailed documentation of the occurring effects after administration of high doses of α-D-glucopyranoside is lacking. The exceptional high doses of glucose which are required to mediate a toxic effect (deterioration of physiological functions/mortality) suggest that toxicity results mainly from deterioration of cell functions mediated by dehydration. Based on the structural similarity it can be assumed that despite its non-metabolisable nature, alpha methyl glucoside causes the same dehydration symptoms at high doses. Furthermore, it is highly unlikely that other adverse effects occur at low doses of alpha methyl glucoside because it is considered to be excreted unchanged. Local effects were not detected during reliable and relevant irritation studies conducted according to OECD test guideline 439 and 437 with the target substance alpha methyl glucoside, thus, based on all available information an increased risk even during the intermittent workers exposure patterns or due to peak exposures during work is not expected.

Moreover, although alpha methyl glucoside is a non-metabolisable compound, information from other regulatory institutions like US EPA confirm a low toxicity. At the US EPA alpha methyl glucoside is listed on the ‘Safer Chemical Ingredients list’ as chemical that has been verified to be of low concern based on experimental and modeled data. Additionally, the FDA states that alpha methyl glucoside is considered to be safe in certain substances which are polyester resins and are safely used as articles which are intended for repeated use in contact with food.

In summary, the available information provides evidence that alpha methyl glucoside exhibits a low toxicity, thus, adjustment of the descriptor starting point is scientifically not justified.


 

References:

1)   Spector, W. S. (1955).HANDBOOK OF TOXICOLOGY. VOLUME 1. NATIONAL ACADEMY OF SCIENCES-NATIONAL RESEARCH COUNCIL WASHINGTON DC.

2)   Brot-Laroche, Edith, et al. "Characterization of the d-glucose/Na+ cotransport system in the intestinal brush-border membrane by using the specific substrate, methyl α-d-glucopyranoside."Biochimica et Biophysica Acta (BBA)-Biomembranes904.1 (1987): 71-80.

3)   Kimmich GA, Randles J: alpha-Methylglucoside satisfies only Na+-dependent transport system of intestinal epithelium. Am J Physiol 241:C227–C232, 1981

4)   Genel, M., London, D., Holtzapple, P. G., & Segal, S. (1971). Uptake of alpha-methylglucoside by normal and diabetic human jejunal mucosa.Translational Research,77(5), 743-750.

5)   Lostao, M. P., et al. "On the multiplicity of glucose analogues transport systems in rat intestine."Revista espanola de fisiologia47.4 (1991): 209-216.

6)   Segal, Stanton, et al. "Transport of alpha-methyl-D-glucoside by human kidney cortex."Metabolism22.1 (1973): 67-76.

7)   Demarest, Keith T., et al. "Methods of using alpha-methylglucoside (AMG) as an indicator for glucose absorption and excretion." U.S. Patent No. 8,147,801. 3 Apr. 2012.

Based on the available, reliable and relevant data alpha methyl glucoside does not need to be classified according to Regulation (EC) No 1272/2008 (CLP) and the globally Harmonized System for Classification and Labelling of Chemicals (GHS).