Reaction mass of 1-O-α-D-glucopyranosyl-D-mannitol and 6-O-α-D-glucopyranosyl-D-glucitol

Toxicity to soil macroorganisms except arthropods

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

toxicity to soil macroorganisms except arthropods: short-term

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification

Remarks:

The substance is not fully compliant with the applicability domain of the model. However, this calculation is used in a weight of evidence approach, in accordance to the REACh Regulation (EC) No 1907/2006, Annex XI General rules for adaptation of the standard testing regime set out in Annexes VII to X, 1.2. It is adequately documented and justified. For more detail see field `overall remarks, attachments´.

Justification for type of information:

1. QSAR SOFTWARE

EPI Suite v4.11 Estimation Programs Interface Suite™ for Microsoft® Windows v 4.11. US EPA, United States Environmental Protection Agency, Washington, DC, USA.

2. MODEL (incl. version number)

ECOSAR v1.11

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL

See “Test material information”

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached information on the model provided by the developer.

5. APPLICABILITY DOMAIN
See attached information and information as provided in "Any other information on material and methods incl. tables".

6. ADEQUACY OF THE RESULT
See assessment of adequacy as outlined in the "Overall remarks, attachments" section.

Qualifier:

according to guideline

Guideline:

other: REACH Guidance on QSARs R.6

Principles of method if other than guideline:

- Software tool(s) used including version: EPI Suite v4.11
- Model(s) used: ECOSAR v1.11
Full reference and details of the used formulas can be found in:
Mayo-Beana, K., Morana, K., Meylan, B. & Ranslow, P. "Methodology document for the Ecological Structure-Activity Relationship Model (ECOSAR) class program. Estimating toxicity of industrial chemicals to aquatic organisms using the ECOSAR (Ecological Structure Activity Relationship) class program. MS-Windows Version 1.11". May, 2012.
- Model description: see field 'Justification for non-standard information', 'Attached justification' and 'any other information on material and methods'
- Justification of QSAR prediction: see field 'Justification for type of information', 'Attached justification' and/or 'overall remarks'

GLP compliance:

no

Test organisms (species):

other: earthworm

Total exposure duration:

14 d

Duration:

14 d

Dose descriptor:

LC50

Effect conc.:

3 932.315 other: mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

mortality

Remarks on result:

other: ECOSAR class Neutral organics

For detailed information on the results please refer to the attached report.

Validity criteria fulfilled:

not applicable

Reference 2

Endpoint:

toxicity to soil macroorganisms except arthropods: short-term

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification

Remarks:

The substance is not fully compliant with the applicability domain of the model. However, this calculation is used in a weight of evidence approach, in accordance to the REACh Regulation (EC) No 1907/2006, Annex XI General rules for adaptation of the standard testing regime set out in Annexes VII to X, 1.2. It is adequately documented and justified. For more detail see field `overall remarks, attachments´.

Justification for type of information:

1. QSAR SOFTWARE

EPI Suite v4.11 Estimation Programs Interface Suite™ for Microsoft® Windows v 4.11. US EPA, United States Environmental Protection Agency, Washington, DC, USA.

2. MODEL (incl. version number)

ECOSAR v1.11

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL

See “Test material information”

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached information on the model provided by the developer.

5. APPLICABILITY DOMAIN
See attached information and information as provided in "Any other information on material and methods incl. tables".

6. ADEQUACY OF THE RESULT
See assessment of adequacy as outlined in the "Overall remarks, attachments" section.

Qualifier:

according to guideline

Guideline:

other: REACH Guidance on QSARs R.6

Principles of method if other than guideline:

- Software tool(s) used including version: EPI Suite v4.11
- Model(s) used: ECOSAR v1.11
Full reference and details of the used formulas can be found in:
Mayo-Beana, K., Morana, K., Meylan, B. & Ranslow, P. "Methodology document for the Ecological Structure-Activity Relationship Model (ECOSAR) class program. Estimating toxicity of industrial chemicals to aquatic organisms using the ECOSAR (Ecological Structure Activity Relationship) class program. MS-Windows Version 1.11". May, 2012.
- Model description: see field 'Justification for non-standard information', 'Attached justification' and 'any other information on material and methods'
- Justification of QSAR prediction: see field 'Justification for type of information', 'Attached justification' and/or 'overall remarks'

GLP compliance:

no

Test organisms (species):

other: earthworm

Total exposure duration:

14 d

Duration:

14 d

Dose descriptor:

LC50

Effect conc.:

3 932.315 other: mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

mortality

Remarks on result:

other: ECOSAR class Neutral organics

For detailed information on the results please refer to the attached report.

Validity criteria fulfilled:

not applicable

Description of key information

LC50 (14 d) = 3932.315 mg/L (QSAR prediction for both components of Isomalt, i.e.1-O-α-D-glucopyranosyl-D-mannitol (1,1-GPM) and 6-O-α-D-glucopyranosyl-D-glucitol (=6-O-α-D-glucopyranosyl-D-sorbitol) (1,6-GPS))

Additional information

No studies are available on the short-term toxicity of Reaction mass of 1-O-α-D-glucopyranosyl-D-mannitol and 6-O-α-D-glucopyranosyl-D-glucitol, i.e. Isomalt, towards soil macroorganisms. Therefore, QSAR calculations were done for both of the main components, i.e. 1-O-α-D-glucopyranosyl-D-mannitol (1,1-GPM) and 6-O-α-D-glucopyranosyl-D-glucitol (=6-O-α-D-glucopyranosyl-D-sorbitol) (1,6-GPS). As the sugar alcohols in both of the disaccharides are isomers of each other the calculated effect value is the same for both components of Isomalt, i.e. a LC50 (14 d) of 3932.315 mg/L. The very high LC50 value indicates that Isomalt is not toxic to terrestrial macroorganisms. Both disaccharides are not fully compliant with the applicability domain of the model (see details in the attached QSAR reports). However, the result is used in a weight of evidence approach, in accordance to the REACh Regulation (EC) No 1907/2006, Annex XI General rules for adaptation of the standard testing regime set out in Annexes VII to X, 1.2.

Isomalt belongs to the group of polyols and is a mixture of hydrogenated mono- and disaccharides whose principal components are both the disaccharides 1-O-α-D-glucopyranosyl-D-mannitol (1,1-GPM) and 6-O-α-D-glucopyranosyl-D-glucitol (=6-O-α-D-glucopyranosyl-D-sorbitol) (1,6-GPS). These disaccharides are composed of a pyranose, i.e. a six membered ring with 5 carbon atoms and one oxygen atom, connected to glucitol (also known as sorbitol) or to mannitol. Glucitol and mannitol are sugar alcohols that are isomers of each other. Isomalt is manufactured in a two-stage process in which sucrose is first transformed into Isomaltulose, a reducing disaccharide (6-O-α-D-glucopyranosyl-D-fructose). The Isomaltulose is then hydrogenated to yield Isomalt, using a nickel catalyst.

Complete hydrolysis of Isomalt yields glucose, sorbitol, and mannitol (2:1:1) (JECFA, 1985). Glucose is a common monosaccharide that feeds into glycolysis. Glycolysis is a well described metabolic pathway used by virtually all cells, both eukaryotic and prokaryotic, to produce energy in form of ATP. Mannitol is known to be metabolically inert in humans and occurs naturally, as a sugar or sugar alcohol, in fruits and vegetables. It is rapidly excreted in the urine. Sorbitol also occurs naturally in fruits and will either be excreted in the urine by the kidneys, or metabolized to carbon dioxide and dextrose, the latter of which will feed into glycolysis again (Wishart et al., 2018). The monosacharides are metabolized following the classical route (Lina, Jonker and Kozianowski, 2002; and references therein).

Moreover, based on a ready biodegradability study available for Isomaltulose (=6-O-alpha-D-glucopyranosyl-D-fructose), used as source substance in a read-across approach as detailed in the analogue justification attached to IUCLID section 13, and QSAR calculations done for both of the main components, i.e. 1-O-α-D-glucopyranosyl-D-mannitol (1,1-GPM) and 6-O-α-D-glucopyranosyl-D-glucitol (=6-O-α-D-glucopyranosyl-D-sorbitol) (1,6-GPS), Isomalt is expected to be rapidly degraded in the environment. A long term exposure to the substance is therefore not expected.

Glucose, D-glucitol, and D-mannitol are included in Annex IV of Regulation (EC) No 1907/2006, as sufficient information is known about these substances, and they are considered to cause minimum risk because of their intrinsic properties.

All toxicological data available for Isomalt indicate that there is no toxicity at all and consequently the substance is not classified for any hazard. Isomalt is widely used as a food additive. It is produced in compliance with applicable German and European Food Law (e.g. Regulation (EC) No 178/2002, Regulation (EC) No 852/2004) as well as international quality standards including ISO 9001 and IFS Food. The specifications cover the requirements for Isomalt of Codex Alimentarius, Food Chemicals Codex (FCC) and Regulation (EU) No 231/2012. The product is an evaluated and as safe classified food additive (E953). By the responsible “Joint Expert Committee on Food Additives” (JECFA, an advisory body of WHO/FAO) an ADI (acceptable daily intake for man) for ISOMALT was not established (ADI: “not specified”). ADI „not specified“ means that, on the basis of the available data (chemical, biochemical, toxicological, and other) the intake of the substance arising from its use (at the levels necessary to achieve the desired effect) does not represent a hazard to health.

In conclusion, with all the information available as detailed above, and for reasons of animal welfare, further testing on terrestrial organisms is not considered justified.

References:

JECFA (1985) Isomalt. International Programme on Chemical Safety, World Health Organization. Toxicological Evaluation of Certain Food Additives and Contaminants. Who Food Additives Series 20. WHO, Geneva.

Wishart, D.S. et al. (2018) DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Research, 46: D1074–D1082, doi: 10.1093/nar/gkx1037.https://www.drugbank.ca/drugs/DB00742accessed for Mannitol,https://www.drugbank.ca/drugs/DB01638accessed for Sorbitol