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

Endpoint summary

Additional information

No experimental data on the aquatic toxicity of Isomalt are available. Thus, for all trophic levels effect values are either derived by QSAR predictions for the components of Isomalt or read-across from the analogue substance Isomaltulose. No toxic effects towards aquatic freshwater organisms of all three trophic levels (fish, invertebrates, algae) were identified.

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 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. Therefore long-term exposure is 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.

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 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