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

Short-term toxicity to aquatic invertebrates

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

short-term toxicity to aquatic invertebrates

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

Please refer to the analogue approach justification provided in IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Duration:

48 h

Dose descriptor:

EC50

Effect conc.:

> 100 mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

mobility

Conclusions:

No effects observed up to 100 mg/L. Therefore the EC50 (48h) was above 100 mg/L and will be reported as >100 mg/L (Daphnia magna, OECD 202, nominal, read-across).

Executive summary:

One experimental study is available investigating the toxicity to aquatic invertebrates. The study was conducted with the read-across source substance isomaltulose (CAS 13718-94-0) according to OECD 202 (GLP) using Daphnia magna under static conditions. The study was performed as limit test. The absence of any mortality or visible signs of abnormalities of daphnids at 100 mg/L indicates no toxicity towards aquatic invertebrates. The EC50 (48 h) of the test item was determined to be > 100 mg/L test item (nominal).

Reference 2

Endpoint:

short-term toxicity to aquatic invertebrates

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. SOFTWARE
Vega version 1.1.4

2. MODEL (incl. version number)
Daphnia Magna LC50 48h (EPA) v1.0.7

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. Further information on the OECD criteria as outlined by the applicant is provided below under "Any other information of materials and methods incl. tables"

5. APPLICABILITY DOMAIN
See attached information and information as provided in "Any other information on results 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: Vega v1.1.4
- Model(s) used: Daphnia Magna LC50 48h (EPA) v1.0.7
Full reference and details of the used formulas can be found in:
R. Todeschini and V. Consonni, 2009. Molecular Descriptors for Chemoinformatics, Wiley-VCH
U.S. Environmental Protection Agency, 2016. User’s Guide for T.E.S.T. (version 4.2) (Toxicity Estimation Software Tool), 2016
- 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

Analytical monitoring:

no

Vehicle:

no

Test organisms (species):

Daphnia magna

Water media type:

freshwater

Total exposure duration:

48 h

Reference substance (positive control):

no

Duration:

48 h

Dose descriptor:

LC50

Effect conc.:

288 822 438 g/L

Conc. based on:

test mat.

Basis for effect:

mobility

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

Validity criteria fulfilled:

not applicable

Reference 3

Endpoint:

short-term toxicity to aquatic invertebrates

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

Justification for type of information:

1. SOFTWARE
Vega version 1.1.4

2. MODEL (incl. version number)
Daphnia Magna LC50 48h (EPA) v1.0.7

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. Further information on the OECD criteria as outlined by the applicant is provided below under "Any other information of materials and methods incl. tables"

5. APPLICABILITY DOMAIN
See attached information and information as provided in "Any other information on results 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: Vega v1.1.4
- Model(s) used: Daphnia Magna LC50 48h (EPA) v1.0.7
Full reference and details of the used formulas can be found in:
R. Todeschini and V. Consonni, 2009. Molecular Descriptors for Chemoinformatics, Wiley-VCH U.S. Environmental Protection Agency, 2016. User’s Guide for T.E.S.T. (version 4.2) (Toxicity Estimation Software Tool)
- 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

Analytical monitoring:

no

Vehicle:

no

Test organisms (species):

Daphnia magna

Water media type:

freshwater

Total exposure duration:

48 h

Reference substance (positive control):

no

Duration:

48 h

Dose descriptor:

LC50

Effect conc.:

288 822 438 g/L

Conc. based on:

test mat.

Basis for effect:

mobility

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

Validity criteria fulfilled:

not applicable

Description of key information

EC50 (48 h) > 100 mg/L (nominal, Daphnia magna, OECD 202; read-across from Isomaltulose (CAS 13718-94-0))

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, to aquatic invertebrates. 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 (48 h) of 288822438 g/L. The very high LC50 value indicates that Isomalt is not toxic to aquatic invertebrates. 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.

Further evidence for the non-toxicity to aquatic organisms is provided by data available from a read-across substance and general knowledge on sugars as detailed below.

The calculated high LC50 value is corroborated by the findings of a 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. In this study conducted according to the OECD guideline 202 and GLP no effects were observed towards Daphnia magna up to the highest concentration tested resulting in an EC50 (48 h) of >100 mg/L.

In general, based on the molecular structure of the constituents of Isomalt, and their natural occurrence and role in common metabolic pathways, toxic effects on aquatic organisms are not to be expected.

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.

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.

Furthermore, the target substance has been evaluated using the OECD QSAR Toolbox v4.2 by means of the set of profilers relevant for aquatic toxicity endpoints in order to support the QSAR and literature data used for this dossier. The chemical structure (smile codes) was used as input parameter for the evaluation. The OECD QSAR Toolbox output did not give any critical alerts rising concerns regarding toxicity by the substance. A summary of the relevant profilers and the OECD QSAR Toolbox output for aquatic toxicity related endpoints is given in Table 1.

Table 1: OECD QSAR Toolbox profiling for Environmental toxicity relevant endpoints.

Endpoint	Relevant Profilers	OECD QSAR Toolbox Output
Environmental Toxicity	Protein binding by OASIS	No alert found
	Protein binding by OECD	No alert found
	Protein binding potency GSH	Not possible to classify according to these rules (GSH)
	Acute aquatic toxicity classification by Verhaar (Modified)	Class 5 (Not possible to classify according to these rules)
	Acute aquatic toxicity MOA by OASIS	Basesurface narcotics
	Aquatic toxicity classification by ECOSAR	Neutral Organics

 

No positive structural alerts in the profiling outcomes were identified for the protein binding profilers: “Protein binding by OASIS” and “Protein binding by OECD”. Furthermore, no specific mode of action besides baseline toxicity was identified by the profilers “Aquatic toxicity classification by ECOSAR” or “Acute aquatic toxicity MOA by OASIS”. Since the log Kow is very low (-4.2 to -3.7, experimentally determined) no baseline toxicity is expected either. These information support the literature data and the attained QSAR results leading to the conclusion that the substance does not pose a hazard for the environment.

In conclusion, with all the information available as detailed above, and for reasons of animal welfare, further testing on aquatic invertebrates 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