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Administrative data

Link to relevant study record(s)

Description of key information

Short description of key information on bioaccumulation potential result: 
In accordance with REACh (Regulation (EC) No 1907/2006) Annex VIII section 8.8.1, a toxicokinetics study is not required as assessment of the toxicokinetic behaviour of the substance has been derived from the relevant available information. This assessment is located within the endpoint summary for toxicokinetics, metabolism and distribution.

Key value for chemical safety assessment

Additional information

Metabolic data demonstrate that the notifiable substance [identified under the brand name Lycasin® 80/55, a commercial hydrogenated glucose syrup which is mainly composed of maltitol (~52.5%), hydrogenated oligosaccharides (~40.5%), and sorbitol (~7%)],as well as the read-across substances (maltose, maltitol, and sorbitol) share a common metabolic pathway, as they are all converted to D-glucose and/or sorbitol via hydrolysis of their glycosidic linkages by the intestinal brush border carbohydrases. On the basis of their common mono- and disaccharide metabolites, the properties of the notifiable substance are expected to be similar to the read-across substances maltose, maltitol, and sorbitol.  Considering this, it is anticipated that exposure to any of the aforementioned saccharides would ultimately result in the formation of D-glucose and/or sorbitol.  As such, maltose, sorbitol, maltitol, and Lycasin® 80/55 may be used as appropriate surrogates for one another. The absorption, distribution, metabolism, and excretion of the notifiable substance were assessed based on the studies available for the notifiable substance, as well as the read-across substances sorbitol and maltitol. 

Although the high water solubility of the notifiable substance is not expected to favour its absorption from the gastrointestinal tract, absorption into the systemic circulation following oral exposure has been demonstrated with Lycasin® 80/55 and with the read-across substances sorbitol and maltitol. Detection of sorbitol and/or maltitol at levels significantly greater than baseline and/or control levels in the blood of rats, dogs, and humans following acute or repeated oral exposures to sorbitol, maltitol, or Lycasin® 80/55 indicates that the aforementioned compounds were absorbed via the oral route of exposure [1, 2, 3, 4, 5, 6, 7]. The recovery of the administered substance, its metabolites, or radioactivity (in studies in which radiolabeled test compounds were used) in the urine and/or breath of humans or rats also suggests that the compounds were absorbed following oral exposure [1, 3, 4, 5, 6]. In addition, the observation of mortality following acute oral doses of 12 to 30 g sorbitol/kg body weight in rats and rabbits suggests that sorbitol is absorbed into the systemic circulation, although death may have been caused by dehydration due to the presence of very large amounts of poorly-digestible carbohydrates in the gastrointestinal tract [8, 9]. 

The distribution of the notifiable substance to different tissues was supported by a study which demonstrated the distribution of sorbitol to the liver and spleen in rats administered 3165 to 4549 mg Lycasin® 80/55/day for 10 days [5]. The observation of similar amounts of sorbitol in the liver and spleen of treated and control rats suggests that exposure to sorbitol at levels above those normally found in the diet does not lead to bioaccumulation in these organs. No sorbitol was detected in the kidneys of animals in either group, and no maltitol was detected in the liver, spleen, or kidneys of either group [5]. Although the results of this study suggest that sorbitol and maltitol are not distributed to the kidneys following oral exposure, the excretion of sorbitol and/or maltitol in the urine of rats, dogs, and humans, following oral or intravenous exposure, has been reported in several studies [1, 3, 4, 5, 6]. Since the animals in the study by Verwaerde and Dupas (1982) [5] were killed following an 8 to 12-hour washout period, it is possible that the distribution of sorbitol to the kidney may be transient and proportional to circulating levels of sorbitol and/or maltitol, which have been demonstrated to peak and decrease rapidly following oral exposure [1, 3, 6]. The distribution of sorbitol and/or maltitol to the liver and kidney is supported by the observation of hepatic and renal effects in toxicity studies in which dogs and rats were exposed to sorbitol (up to 18% in the diet) or Lycasin® 80/55 (up to 18% in the diet, or 5 g/kg body weight/day) for 6 to 24 months [10, 11, 12]. 

The observation of increased urinary and/or blood sorbitol levels following oral or intravenous exposures to maltitol suggests that maltitol is at least partially hydrolyzed by the intestinal mucosa and microbiota to sorbitol and glucose [2, 3, 4, 5, 6]. In addition, the observation of gastrointestinal distress in human and animal studies suggests that the hydrolysis of maltitol is slow compared to readily digestible sugars such as maltose [1, 2, 3, 4, 6]. Sorbitol can undergo dehydrogenation by sorbitol dehydrogenase to form fructose, which is used in the glycolytic production of ATP. It is therefore expected that ingested maltitol, sorbitol, or Lycasin® 80/55 will be excreted as intact polyols, converted to VFA (Volatile Fatty Acids) by the intestinal microbiota, or hydrolyzed to glucose and/or converted to fructose, which will enter normal glycolytic pathways and be used for the generation of ATP. 

The high water solubility of the notifiable substance favours its excretion via the urine. However, reported urinary recoveries of sorbitol and/or maltitol following oral exposure of rats, dogs, and humans to maltitol or Lycasin® 80/55 are variable, and suggest a rapid (i.e., within 24 hours of exposure) but low (i.e., ≤10% of the administered dose) level of urinary excretion [1, 3, 4, 5, 6]. In animal studies in which maltitol was administered intravenously, greater proportions of the administered dose of intact maltitol (i.e.,84 to 88%) were detected in the urine [3, 4]. This discrepancy, along with the observation of increased urinary excretion of polyols in germ-free versus conventional rats and the disappearance of symptoms of gastrointestinal distress following several days of maltitol or Lycasin® 80/55 supplementation, may suggest the contribution of the intestinal microbiota to their hydrolysis.   

Reported fecal recovery of sorbitol and/or maltitol following oral exposure of rats, dogs, and humans to sorbitol, maltitol, or Lycasin® 80/55 also is variable, and has been reported to range from 0 to 14.3%, with peak excretion occurring between 24 and 48 hours of exposure [1, 3, 4, 5, 6, 7]. Fecal polyol excretion has been reported to be reduced in conventional versus germ-free rats, further supporting the role of the intestinal microbiota in the hydrolysis of maltitol [3, 4]. Recovery of radioactivity from ingested radiolabeled maltitol in the breath of humans and rats was reported to be between 45.5% and 56% [1, 6], and was reported to peak within 3 hours of exposure [6]. However, the recovery of radioactivity in the breath does not demonstrate absorption and caloric utilization, since microbial production of VFA may also contribute to the presence of exhaled radioactive compounds. 

The low vapour pressure, high boiling point, and high water solubility of the notifiable substance do not favour its absorption via inhalation. Likewise, the high water solubility of the notifiable substance would likely limit its absorption following dermal exposure. However, since no dermal or inhalation studies on the notifiable substance or any of the read-across substances were available, the absorption of the notifiable substance via dermal or inhalation routes is unknown. In addition, 2 reproductive and 4 developmental studies in which the toxicity of sorbitol or Lycasin® 80/55 were investigated were available; however, none reported any maternal or fetal effects, and therefore did not provide any pertinent toxicokinetic information [12, 13, 14]. Given the high water solubility of the notifiable substance, the low plasma half life (i.e., 2.1 hours) of maltitol [1], and observed rapid excretion of maltitol and Lycasin® 80/55 following oral or intravenous exposures, the potential for bioaccumulation of the notifiable substance is low. 



[1]       Rennhard HH, Bianchine JR (1976) Metabolism and caloric utilization of orally administered maltitol-14C in rat, dog, and man. J Agric Food Chem, 24(2):287-291

[2]       Zunft HJ, Schulze J, Gärtner H & Grütte FK (1983) Digestion of Maltitol in Man, Rat, and Rabbit. Ann Nutr Metab, 27:470-476

[3]       Kearsley MW, Birch, GG, Lian-Loh RHP (1982) The metabolic fate of hydrogenated glucose syrups.  Starch/Starke, 34(8): 279-283

[4]       Lian-Loh R, Birch GG, Coates ME (1982) The metabolism of maltitol in the rat.  Br J Nutr, 48: 477-481

[5]     Verwaerde F, Dupas H (1982) A study of the urinary excretion and risks of accumulation of maltitol in certain organs of rats fed with Lycasin®.  Institut Francais de Recherches et Essais Biologiques, Roquette Freres. 

[6]     Oku T, Akiba M, Lee MH, Moon SJ, Hosoya N (1991) Metabolic fate of ingested [14C]-maltitol in man.  J Nutr Sci Vitaminol, 37: 529-544. 

[7]     Beaugerie L, Flourie B, Marteau P, Pellier P, Franchisseur C, Rambaud JC (1990) Digestion and absorption in the human intestine of three sugar alcohols.  Gastroenterology, 99:717-723. 

[8]     Tanaka S, Gomi T (1972) Acute toxicological test of sorbitol. Omiya Research Laboratory, Nikken Chemicals Co., Ltd, Nikken Chemicals Co., Ltd.

[9]     Okumura, Kojima (1972) A study of toxicity using sorbitol. Nikken Chemical Co.

[10]     Coquet B (1982) 6-Month Oral Toxicity in the Beagle Dog. Institut Francais de Recherches et Essais Biologiques, Roquette Freres, Report no. 005224; Genoux P (1982) Sorbitol 6-Month Toxicity Study in the Beagle Dog Complementary Biochemical Examinations. Institut Francais de Recherches et Essais Biologiques, Roquette Freres, Report no. 201232

[11]     Virat M (1982) A 13 week toxicity study of per os administered product in dogs. I.F.R.E.B./IPLT, Les Oncins BP 109, 69210 L-Arbresle., Roquette Freres; Report no. 202212.

[12]     Modderman JP (1993) Safety Assessment of Hydrogenated Starch Hydrolysates. Regul Toxicol Pharm, 18:80-114

[13]     Morgareidge K, 1972, Teratologic Evaluation of FDA 71-31 (Sorbitol), Food and Drug Research Laboratories, Inc. 60 Evergreen Place, East Orange, New Jersey 07018, U.S. Food and Drug Administration, Report no. PB-221 806

[14]     Leroy P & Dupas H, 1983, Lycasin® 80/55 Three Generation Reproduction Toxicity Studies, Roquette Freres, 62136 Lestrem, France, Roquette Freres

Discussion on bioaccumulation potential result:

Studies identified which address portions of the basic toxicokinetics.

1. Verwaerde, F. & Dupas, H. (1982) Study of the in vivo digestion of Lycasin(R) 80/55 in the rat. Unpublished report from Roquette Freres, Lestrem, France. Submitted to WHO by Roquette Freres.

2. Lian-Loy, R., Birch, G.G., & Coates, M.E. (1982). The metabolism of maltitol in the rat. Br. J. Nutr., 48, 477-481.

3. Verwaerde, F. & Dupas, H. (1982). Study of the in vivo digestion of Lycasin(R) 80/55 in the rat. Unpublished report from Roquette Freres, Lestrem, France. Submitted to WHO by Roquette Freres.

4. Verwaerde, F. & Dupas, H. (1984). Study of the in vivo digestion of Lycasin(R) 80/55 in the rat. Volume III. A comparative study on fed and fasting rats. Unpublished report from Roquette Freres, Lestrem, France. Submitted to WHO by Roquette Freres.

5. Verwaerde, F. (1982). Digestion in vitro by enzymes of the intestinal mucosa of rat and man of Lycasin(R) 80/55 and of its main fractions with a comparison with several di- and polysaccharides. Unpublished report from Roquette Freres, Lestrem, France. Submitted to WHO by Roquette Freres.