Registration Dossier

Administrative data

Description of key information

- skin sensitisation study, OECD 406, GLP, RL1, not sensitizing, read-across from Isostearic acid, esters with methyl- α-D-glucoside

- QSAR prediction, Toxtree decision tree approach, no reactivity domain found, suspected non-sensitizer

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2008-05-14 to 2008-08-13
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
July 17th, 1992
Deviations:
no
GLP compliance:
yes (incl. certificate)
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
A valid GPMT conducted according to guideline is available, which is reliable without restrictions and adequate for classification and labelling purposes. Potency estimation is not mandatory when existing guideline and GLP conforming data are available, which were conducted before the new annex of the REACH Regulation entered into force. Moreover, no indication for skin sensitisation was observed in this study, thus, no dose response information is needed. For this reason and for reasons of animal welfare no additional LLNA was conducted.
Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Kissleg, Germany
- Age at study initiation: approximately 4 weeks
- Weight at study initiation: 360.6 ± 22.8 9 (test group) and 355.7 ± 15.4 9 (control group) at start of the main experiment
- Housing: with 2 or 3 animals in Makrolon-cages No. IV
- Diet: ad libitum, type "3023" from Altromin International, Lage, Gerrnany as pelleted diet (Batch No.: 0638; expiry date: 2008-11-19)
- Water: ad libitum, tap water
- Acclimation period: 14 d


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 30 -70
- Air changes (per hr): 8 times/hour
- Photoperiod (hrs dark / hrs light): 12/12

Route:
intradermal
Vehicle:
other: sesame oil
Concentration / amount:
Intradermal: 0.5 % (w/w) solution of the test substance in sesame oil
Day(s)/duration:
day 0
Route:
epicutaneous, occlusive
Vehicle:
other: sesame oil
Concentration / amount:
Dermal: 75 % (w/w) solution of the test substance in sesame oil
Day(s)/duration:
day 7
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
other: sesame oil
Concentration / amount:
15 % (w/w) solution in sesame oil
Day(s)/duration:
day 21
No. of animals per dose:
19 (test group 10, control group 5, pilot experiment 4)
Details on study design:
RANGE FINDING TESTS:
Intradermal: 0.1 ml of 5 %, 3.5 %, 2 % and 0.5 % (w/w) solution in sesame oil.
Dermal: soaked patch with 100 % and 75 % (w/w) solution in sesame oil.
Challenge: soaked patch with Duhring chamber with 50 %, 25 %, 15 % and 5 % (w/w) in sesame oil

-- Intradermal application:
- 1 animal was shorn on the right and left flank over an area of approximately 4 cm x 6 cm.
- Animals received 0.1 ml of various concentrations by disposable syringe.
- Observation: after 24 h

-- Dermal application:
- Soaked patches of 2 cm x 2 cm size with various concentrations of the test substance in sesame oil were applied to the right and left flank.
- Dressing: The patches were covered with Blenderm (3 M company, St. Paul, USA) and bandaged on with Acrylastic (Beiersdorf AG, Hamburg, Germany) which was fixed by Leukoplast (Beiersdorf AG, Hamburg, Germany).
- Observation: after 24 h

-- Challenge application:
- Duhring chambers (diameter 4 cm) were filled with a soaked patch of 2 cm x 2 cm size with various concentrations of the test substance in sesame oil and applied to the skin. 24 hours before the flanks of the animals had been shorn.
- Dressing: The gauze patch and the Duhring chamber were applied each to one flank of a guinea pig, covered with
Micrapore (3 M company, St. Paul, USA) and bandaged on with Acrylastic (Beiersdorf AG, Hamburg, Germany) which was fixed by Leukoplast (Beiersdorf AG, Hamburg, Germany).
- Observation: after 24 hours

MAIN STUDY
Based on the results of the pilot experiment the following concentrations were chosen for the main experiment:
Intradermal: 0.1 ml of 0.5 % (w/w) solution of the test substance in sesame oil.
Dermal: soaked patch with 75 % (w/w) solution of the test substance in sesame oil.
Challenge: soaked patch with Duhring chamber with 15 % (w/w) solution in sesame oil

A. INTRADERMAL INDUCTION (day 0)
- Exposure period: 24 h
- Test groups:
(1) 0.1 ml per side FCA (mixed at a ratio of 1:1 in vehicle)
(2) 0.1 ml per side of the 0.5 % (w/w) solution of the test substance found to be slightly irritant in the pilot experiment.
(3) 0.1 ml per side of the 0.5 % (w/w) solution of the test substance found to be slightly irritant in the pilot experiment in FCA (mixed at a ratio of 1:1 in vehicle).
- Control group: treated similarly - with the exception that they received only the diluting vehicle agent
- Site: on the back over an area of 4 cm x 6 cm below the shoulder blade
- Concentrations: 0.5 % (w/w)

B. DERMAL INDUCTION (day 7)
- Exposure period: 48 h
- Site: same part of the skin was dermally treated
- A soaked patch (2 cm x 4 cm) with the 75 % (w/w) solution of the test substance was placed over the injection area and fixed in the way described in the pilot experiment.
- Concentration: 75 % (w/w)
C. CHALLENGE EXPOSURE (day 21)
- Exposure period: 24 h
- Site: Areas of 5 cm x 5 cm on the flanks of the animals. Left flank: test substance, right flank: control with vehicle
- Duhring chambers (0 4 cm) were filled with soaked patches (2 cm x 2 cm) with the 15 % (w/w) solution of the test substance in sesame oil
- Evaluation (hr after challenge): 24 h, 48 h (After 24 hours the plaster was removed. After a further 21 hours after removal of the plaster the skin was shorn. Three hours later the skin reaction was assessed. This assessment was repeated after a further 24 hours.)
- Concentration: 15 % (w/w)

SCORING SYSTEM
erythema and scurf formation:
- no reddening: 0
- slight reddening (difficult to detect): 1
- easily detectable (erythema): 2
- medium (erythema): 3
- strong (erythema) (dark red) to slight formation of scurf (damage deep down): 4
edema formation:
- no swelling: 0
- slight swelling (hardly detectable): 1
- easily recognizable swelling (clearly marked by elevation): 2
- medium edema (swelling of approx. 1 mm): 3
- strong edema (swelling over 1 mm and clearly stretching beyond the treated area): 4
Positive control substance(s):
yes
Remarks:
2-Mercaptobenzothiazole 98 %, Sigma-Aldrich, Germany, Batch No. 04718CC-264 in sesame oil
Positive control results:
A validation experiment was performed according to the method of Magnusson and Kligman with 2-Mercaptobenzothiazole 98 % in sesame oil and produced a sensitisation rate of 90 % showing the sensitivity of the test system. (2008-02-25 to 2008-03-28)
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
15% (w/w)
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
15 % (w/w)
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
15 % (w/w)
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
15 % (w/w)
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
2-Mercaptobenzothiazole 98%
No. with + reactions:
9
Total no. in group:
10
Remarks on result:
positive indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
2-Mercaptobenzothiazole 98%
No. with + reactions:
9
Total no. in group:
10
Remarks on result:
positive indication of skin sensitisation

Pilot experiment:

- The intradermal application of the 5 %, 3.5 % and 2 % (w/w) test substance in sesame oil showed medium reactions, but the 0.5 % (w/w) solution of the test substance in sesame oil elicited a slight reaction.

- Dermal application without Duhring Chambers of 100 % and 75 % (w/w) solutions of the test substance in sesame oil showed slight reactions. Dermal application of 50 % and 25 % (w/w) test substance in sesame oil with Duhring Chambers provoked a medium or slight reaction, respectively, whereas the 15 % and 5 % (w/w) test substance in sesame oil with Duhring Chambers showed no reaction.

- Control group: no reactions

Main study

Induction:

- The intradermal and the epicutaneous induction resulted in slight skin reactions in a various number of animals indicating that the chosen test substance concentrations led to slight irritation. In the control group animals no skin reaction was observed after the application of the vehicle sesame oil.

- Additional observations: Crust formation (diameter: 6 mm) was observed at the injection sites with FCA in the test group and the control group animals 1-2 weeks following the intradermal injection.

Challenge:

- No visible changes of the treated skin sites were observed in the test group animals 24 h and 48 h after patch removal (= grading "0").

- In the control group animals also no visible signs of skin reactions were observed (= grading "0") indicating that the chosen concentration of the test substance was a subirritative dose.

Interpretation of results:
GHS criteria not met
Conclusions:
In this study the test substance is not a dermal sensitizer.
Executive summary:

In a dermal sensitization study according to OECD guideline 406 with Isostearic acid, esters with methyl α-D-glucoside (100% UVCB substance), Dunkin-Hartley guinea pigs were tested using the method of Magnusson and Kligman. Positive control substance was 2-Mercaptobenzothiazole.

Based on the results of the pilot study, for the intradermal and epicutaneous induction procedure test substance concentrations of 0.5 % and 75 % in sesame oil were used, respectively. The test article concentration for the challenge procedure was 15 % in sesame oil.

Slight skin reactions were observed after induction, whereas at challenge no visible changes of the treated skin sites (no erythema and no edema) were observed in test or control animals at any time point. 

In this study Isostearic acid, esters with methyl α-D-glucoside is not a dermal sensitizer.

Endpoint:
skin sensitisation: in vivo (non-LLNA)
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 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-a-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
Justification for non-LLNA method:
A valid GPMT conducted according to guideline is available, which is reliable without restrictions and adequate for classification and labelling purposes. Potency estimation is not mandatory when existing guideline and GLP conforming data are available, which were conducted before the new annex of the REACH Regulation entered into force. Moreover, no indication for skin sensitisation was observed in this study, thus, no dose response information is needed. For this reason and for reasons of animal welfare no additional LLNA was conducted.
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
15 % (w/w)
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
15 % (w/w)
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
15 % (w/w)
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
15 % (w/w)
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
2-Mercaptobenzothiazole 98%
No. with + reactions:
9
Total no. in group:
10
Remarks on result:
positive indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
2-Mercaptobenzothiazole 98%
No. with + reactions:
9
Total no. in group:
10
Remarks on result:
positive indication of skin sensitisation

Pilot experiment:

- The intradermal application of the 5 %, 3.5 % and 2 % (w/w) test substance in sesame oil showed medium reactions, but the 0.5 % (w/w) solution of the test substance in sesame oil elicited a slight reaction.

- Dermal application without Duhring Chambers of 100 % and 75 % (w/w) solutions of the test substance in sesame oil showed slight reactions. Dermal application of 50 % and 25 % (w/w) test substance in sesame oil with Duhring Chambers provoked a medium or slight reaction, respectively, whereas the 15 % and 5 % (w/w) test substance in sesame oil with Duhring Chambers showed no reaction.

- Control group: no reactions

Main study

Induction:

- The intradermal and the epicutaneous induction resulted in slight skin reactions in a various number of animals indicating that the chosen test substance concentrations led to slight irritation. In the control group animals no skin reaction was observed after the application of the vehicle sesame oil.

- Additional observations: Crust formation (diameter: 6 mm) was observed at the injection sites with FCA in the test group and the control group animals 1-2 weeks following the intradermal injection.

Challenge:

- No visible changes of the treated skin sites were observed in the test group animals 24 h and 48 h after patch removal (= grading "0").

- In the control group animals also no visible signs of skin reactions were observed (= grading "0") indicating that the chosen concentration of the test substance was a subirritative dose.

Interpretation of results:
GHS criteria not met
Conclusions:
In a studyconducted according to OECD guideline 406 with the source substance Isostearic acid, esters with methyl α-D-glucoside the source substance is not a dermal sensitizer. Additionally the sensitizing potential of the target substance alpha methyl glucoside was estimated using the Toxtree decision tree approach. There were no alerts found for alpha methyl glucoside, thus, the target substance is also considered not to be a skin sensitizer.
Executive summary:

In a dermal sensitization study according to OECD guideline 406 with the source substance Isostearic acid, esters with methyl α-D-glucoside (100% UVCB substance), Dunkin-Hartley guinea pigs were tested using the method of Magnusson and Kligman. Positive control substance was 2-Mercaptobenzothiazole.

Based on the results of the pilot study, for the intradermal and epicutaneous induction procedure test substance concentrations of 0.5 % and 75 % in sesame oil were used, respectively. The test article concentration for the challenge procedure was 15 % in sesame oil.

Slight skin reactions were observed after induction, whereas at challenge no visible changes of the treated skin sites (no erythema and no edema) were observed in test or control animals at any time point. 

In this study Isostearic acid, esters with methyl α-D-glucoside is not a dermal sensitizer.

Endpoint:
skin sensitisation, other
Remarks:
in silico prediction
Type of information:
(Q)SAR
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification
Justification for type of information:
1. SOFTWARE
Toxtree (Estimation of Toxic Hazard - A Decision Tree Approach) version 2.6.13

2. MODEL (incl. version number)
2.6.13

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
CAS: 97-30-3

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
Toxtree predicts the skin sensitization according to decision rules based on the identification of Structural Alerts (SA) for skin sensitizationas defined by Enoch SJ et al. (Enoch SJ, Madden JC, Cronin MT, Identification of mechanisms of toxic action for skin sensitisation using a SMARTS pattern based approach, SAR QSAR Environ Res. 2008; 19(5-6):555-78).As one or more SAs embedded in a molecular structure are recognised, the system flags the potential skin sensitization activity of the chemical. The methodology used to capture this information is based on series of SMARTS (Smiles ARbitary Target Specification) patterns (www.daylight.com) defining the rules. Thus, chemicals which contain a given reactive fragment are then assigned to the reactivity domain that the fragment belongs to. It is important to realize that a chemical may be assigned to one of the electrophilic reactivity domains even if it is a non-sensitizer. The SMARTS rules aim to identify potential electrophilic fragments and therefore identify a potential hazard associated with a compound. However, the best approach is to firstly classify the chemicals into potential reactivity domains and then perform further analysis within the domains in order to be able to predict skin sensitization.

5. APPLICABILITY DOMAIN
- Descriptor domain: structural properties
Currently there is no universally accepted definition of model domain. However, users may wish to consider the possibility that property estimates are less accurate for compounds that contain certain electrophilic reactivity domains. It is also possible that a compound may have a functional group(s) or other structural features not represented in the training set, and for which no fragment coefficient was developed. These points should be taken into consideration when interpreting model results. The training set is proprietary to Ideaconsult Ltd.


6. ADEQUACY OF THE RESULT
QSAR predictions were performed with Toxtree and VEGA. Since the VEGA program stated that the substance is outside the applicability domain, predictions with this specific software were considered not reliable. However, the Toxtree estimation revealed that there are no structural fragments associated with skin sensitisation reactivity domains, thus, based on structure the substance is considered not to be a sensitizer.
Qualifier:
no guideline followed
Principles of method if other than guideline:
QSAR prediction with Toxtree decision tree approach.
GLP compliance:
no
Key result
Parameter:
other: in silico prediction
Vehicle controls validity:
not applicable
Negative controls validity:
not applicable
Positive controls validity:
not applicable
Remarks on result:
other: Based on structure there are no skin sensitisation reactivity alerts

Skin sensitisation reactivity domains:

QSNAR.SNAr-Nucleophilic Aromatic Substitution No   97-30-3

QSB.Schiff Base Formation No   97-30-3  

QMA.Michael Acceptor No   97-30-3  

Qacyl.Acyl Transfer Agents No   97-30-3  

QSN2.SN2-Nucleophilic Aliphatic Substitution No   97-30-3

Q6.At least one alert for skin sensitisation? No Class No skin sensitisation reactivity domains alerts identified. 97-30-3


Interpretation of results:
GHS criteria not met
Conclusions:
Based on a reliable prediction performed with the Toxtree software, alpha methyl glucoside is not considered to be a skin sensitizer.
Executive summary:

The sensitising potential of alpha methyl glucoside was estimated using the Toxtree decision tree approach. This QSAR software predicts the sensitising potential via skin sensitisation reactivity domains. No structural alert was found for alpha methyl glucoside. The test item is therefore considered to be a non-sensitizer.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

No experimental data on skin sensitisation are available for the target substance alpha methyl glucoside. However, reliable data from an skin sensitisation study conducted with the closely related source substance Isostearic acid, esters with methylα-D-glucoside is available.A justification for read-across is given below.

 

Skin Sensitisation:

In a skin sensitisation study conducted according to OECD guideline 406, 15 Dunkin-Hartley guinea pigs were exposed to Isostearic acid, esters with methylα-D-glucoside (100% UVCB substance, 10 animals) using the method of Magnusson and Kligman. Further 5 animals were used for the control group. Positive control substance was 2-Mercaptobenzothiazole. The animals were exposed intrdermally and epicutaneously to 0.5 % (w/w), single exposure, or 75 % (w/w) solution of the test substance, exposure period of 48 h, respectively. 14 days after the induction procedure the animals were challenged for 24 h with 15 % (w/w) solution of the test substance applied epicutaneously. The reading timepoints were 24 h and 48 h after end of the exposure. None of the animals showed any indication of sensitisation.

Isostearic acid, esters with methylα-D-glucoside is not considered to be a sensitizer.

Toxtree (decision tree approach)

The sensitising potential of alpha methyl glucoside was estimated using the Toxtree decision tree approach. This QSAR software predicts the sensitising potential via skin sensitisation reactivity domains. No structural alert was found for alpha methyl glucoside. The test item is therefore considered to be a non-sensitizer.

 

Respiratory sensitisation:

No data are available for alpha methyl glucoside or for Isostearic acid, esters with methylα-D-glucoside. Since the target substance showed no indication for skin or eye irritation in reliable studies conducted according to OECD guidelines 439 and 437, respectively, and no sensitizing potential was detected with the Toxtree estimation approach and because Isostearic acid, esters with methylα-D-glucoside exhibited no indication for sensitisation of the skin, alpha methyl glucoside is considered to non sensitizing to the respiratory tract.

Based on the available information, the sensitizing potential of alpha methyl glucoside is considered to be low. There are no data gaps for sensitisation. Even though there is no information on sensitizing potential in humans, there is no reason to believe that the results 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.

 

 

Structural similarity

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 sensitisation data

Endpoint

Target substance

Source substance

 

Alpha methyl glucoside

 

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

 

skin sensitisation

 

No data, read-across

 

OECD 406, guinea pig RL 1, GLP

not sensitizing

 

 

QSAR Calculation with Toxtree decision tree approach

 

no alert for sensitisation

 

 

Skin sensitisation – no classification according to Regulation (EC) No 1272/2008 (CLP) and the Globally Harmonized System for Classification and Labelling of Chemicals (GHS).

 

No experimental data are available for the target substance. However, the sensitising potential of alpha methyl glucoside was estimated using the Toxtree decision tree approach. This QSAR software predicts the skin sensitization according to decision rules based on the identification of Structural Alerts (SA) for skin sensitizationas defined by Enoch SJ et al. (Enoch SJ, Madden JC, Cronin MT, Identification of mechanisms of toxic action for skin sensitisation using a SMARTS pattern based approach, SAR QSAR Environ Res. 2008; 19(5-6):555-78). As one or more SAs embedded in a molecular structure are recognised, the system flags the potential skin sensitization activity of the chemical. The methodology used to capture this information is based on series of SMARTS (Smiles ARbitary Target Specification) patterns (www.daylight.com) defining the rules. Thus, chemicals which contain a given reactive fragment are then assigned to the reactivity domain that the fragment belongs to. It is important to realize that a chemical may be assigned to one of the electrophilic reactivity domains even if it is a non-sensitizer. The SMARTS rules aim to identify potential electrophilic fragments and therefore identify a potential hazard associated with a compound.

No structural alert was found for alpha methyl glucoside. The test item is therefore considered to be a non-sensitizer.

Additionally, the closely related source substance Isostearic acid, esters with methyl-alpha-D-glucoside was not sensitizing in guinea pigs.

Quality of the experimental data of the analogues:

The source substance Isostearic acid, esters with methyl-α-D-glucoside has been tested in a reliable study according to OECD TG 406. The tests have been conducted according to GLP criteria. The Toxtree decision tree approach is a validated and accepted in silico method for the prediction of the reaction capacity of a test item. It predicts with sufficient reliability the reaction of the test item with intracellular proteins, which is a prerequisite for the activation of the AOP of sensitization. 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 target substance and the degradation products of the source substance have similar toxicity profiles under the experimental conditions in the considered studies for the endpoint skin sensitisation. Furthermore, there are data from the Toxtree decision tree estimation which support the read-across hypothesis.

Thus, the results obtained with the source substance Isostearic acid, esters with methyl-α-D-glucoside and the QSAR estimation performed with the Toxtree decision tree approach are considered to be also relevant for the target substance alpha methyl glucoside.

 

References:

Lee, Y. J., & Han, H. J. (2007). Regulatory mechanisms of Na+/glucose cotransporters in renal proximal tubule cells.Kidney International,72, S27-S35.

Segal, S., Genel, M., Holtzapple, P., & Rea, C. (1973). Transport of alpha-methyl-D-glucoside by human kidney cortex.Metabolism,22(1), 67-76.

Prieto, R. M., Ferrer, M., & Tur, J. A. (1996). Changes in intestinal alpha-methyl-D-glucoside uptake due to pregnancy and lactation in rats.Digestion,57(1), 16-21.

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.

Enoch, S. J., Madden, J. C., & Cronin, M. T. D. (2008). Identification of mechanisms of toxic action for skin sensitisation using a SMARTS pattern based approach.SAR and QSAR in Environmental Research,19(5-6), 555-578.

Koser, S. A., & Saunders, F. (1932). The Fermentation of Alpha-Methyl-D-Glucoside by Members of the Coli-areogenes Group.Journal of bacteriology,24(4), 267.

Tittsler, R. P., & Sandholzer, L. A. (1935). The fermentation of alpha-methylglucoside by bacteria.Journal of bacteriology,29(4), 363.

Devriese, L. A., Pot, B., & Collins, M. D. (1993). Phenotypic identification of the genus Enterococcus and differentiation of phylogenetically distinct enterococcal species and species groups.Journal of Applied Microbiology,75(5), 399-408.

 

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available
Additional information:

Respiratory sensitisation:

No data are available for alpha methyl glucoside or for Isostearic acid, esters with methyl α-D-glucoside. Since the target substance showed no indication for skin or eye irritation in reliable studies conducted according to OECD guidelines 439 and 437, respectively, and no sensitizing potential was detected with the Toxtree estimation approach and because the source substance Isostearic acid, esters with methyl α-D-glucoside exhibited no indication for sensitisation of the skin, alpha methyl glucoside is considered to non sensitizing to the respiratory tract.

Based on the available information, the sensitizing potential of alpha methyl glucoside is considered to be low. There are no data gaps for sensitisation. Even though there is no information on sensitizing potential in humans, there is no reason to believe that the results observed in experimental animals would not be relevant for human health.

Justification for classification or non-classification

Based on reliable and relevant data from an adequate QSAR prediction and data from the source substance Isotearic acid, esters with methyl-α-D-glucose, 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) with respect to skin sensitisation.