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Administrative data

Description of key information

According to Annex VIII, column 2, a 28-day study is not required as a suitable (sub-)chronic study is available. 
In a key 13-week gavage study conducted with Lycasin 80/55, a NOAEL value of 4.95 g/kg body weight/day (limit test, actual ingested) was derived for male and female dogs (Virat, 1982).
One (1) key study and 1 supporting study for long term repeated dose toxicity (>=12 months) were identified. In a 52-week repeated dose toxicity study with Malbit® (87% maltitol, 5% sorbitol, 6% maltotriitol, dry substance), the NOAEL of 4.5 g/kg body weight/day was identified for male and female rats (Conz and Fumero, 1989).
In a 24-month drinking water study conducted with Lycasin 80/55 (7.0% sorbitol, 52.5% maltitol, 22.5% tri- to hexasaccharides, and 17.5% higher-order hydrogenated saccharides), a NOAEL value of 18% in drinking water (limit test, nominal) was derived for male and female rats (Modderman, 1993; Leroy and Dupas, 1984).
Exposure by inhalation or dermal routes are not considered the most relevant route of exposure; no inhalation or dermal studies were identified.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
4 500 mg/kg bw/day

Additional information

Metabolic data demonstrate that the notifiable substance (Lycasin® 80/55), as well as the read-across substances (maltose, maltitol, sorbitol, wheat glucose syrup (WGS), and dextrin) share a common metabolic pathway as they are 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, Lycasin® 80/55 is expected to be similar to the read-across substances maltose, sorbitol, maltitol, WGS, and dextrin. 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, WGS, and dextrin may be used as appropriate surrogates for the notifiable substance, considering their common metabolic products.

 

According to Annex VIII, column 2, a 28-day study is not required as a suitable (sub-)chronic study is available.

 

One key sub-chronic toxicity study was identified. In this study, which was similar in design to OECD testing guideline 409, Lycasin 80/55 at 0 (control), or 4.95 g/kg body weight/day (actual ingested) was administered by gavage to Beagle dogs for a period of 13 weeks (Virat, 1982). Four (4) animals per sex were included in each group. Endpoints assessed included clinical signs, body weight, food consumption, ophthalmoscopic examination, haematology, clinical chemistry, urinalysis, gross pathology, and histopathology. The occurrence of diarrhea, a slight increase in the level of circulating triglycerides in 3 female dogs, and a minimal ectasia in the renal tubules were reported. The authors considered these observations to be physiological, in relation to the high amount of hydrogenated sugar provided by the treatment. NOAEL values were not reported by the study authors. Review of the study data suggested that a NOAEL of 4.95 g/kg body weight/day (actual ingested) can be considered in both male and female dogs based on a lack of toxicity. 

 

One (1) key study and 1 supporting study for long term repeated dose toxicity (>=12 months) were identified. In the key long term repeated dose toxicity study, Malbit® (87% maltitol, 5% sorbitol, 6% maltotriitol, dry substance) was evaluated in a 52-week study in rats (Conz and Fumero, 1989). This GLP study was similar in design to OECD test guideline 453. Malbit® was administered via the diet at 0 (control), 0.5, 1.5, or 4.5 g/kg body weight/day to Sprague-Dawley rats (20 rats/sex/group) for 52 weeks. Endpoints assessed included clinical signs, body weight, food consumption, ophthalmoscopic examination, haematology, clinical chemistry, urinalysis, gross pathology, and histopathology. There were no differences in mortality, ophthalmoscopical examination, body weight, food consumption, behaviour, hematology, or urinalysis. At blood chemistry only, a few minor functional modifications emerged mainly in males at 26 and/or 51 weeks of treatment, without morphological-related changes. These were a slight increase, not dosage-related, in mean creatinine values in all treated male groups (51 weeks) with individual values within the norm, a slight reduction in the highest dosage treated males, of total, free and esterified cholesterol accompanied by a reduction in the NEFA values (26 and 51 weeks); a slight increase in the highest dosage group of females, in the alpha lipoprotein fraction (serum lipoprotein electrophoresis) was also seen at 51 weeks when this examination was performed. At post-mortem examinations, no modifications related to treatment were seen in particular, no compound-related dilatations of cecum and colon diameter were seen, and no compound-related morphological changes of the gastrointestinal tract were found. In conclusion, under the experimental conditions applied, the test substance was well tolerated when administered into the diet for 52 weeks to Sprague Dawley CD (SD) BR rats up to and including the highest dose level tested of 4.5 g/kg body weight/day. Based on the results, a NOAEL of 4.5 g/kg body weight/day was derived. 

 

The supporting study was similar in design to OECD testing guideline 452 (Modderman, 1993; Leroy and Dupas, 1984). Lycasin® 80/55 (7.0% sorbitol, 52.5% maltitol, 22.5% tri- to hexasaccharides, and 17.5% higher-order hydrogenated saccharides) at 0 (control) or 18% in water was administered in drinking water to Sprague-Dawley rats for a period of 24 months. Fifty (50) animals per sex were included in each group. Endpoints assessed included clinical signs, body weight, water consumption, haematology, clinical chemistry, urinalysis, gross pathology, and histopathology. Diarrhea was observed in early stages in dosed group, which disappeared by the fourth week and mean body weight was significantly lower in the dosed group in the early stage of dosing period. In addition, food consumption was significantly lower and beverage consumption was higher in the dosed group. A significant decrease in the concentration of electrolytes in the urinalysis parameter and a significant increase in the relative cecum weight of the dosed group were observed. The authors commented that these observations have been observed commonly in feeding studies involving slowly digestible carbohydrates and polyols and have been correlated with adaptive responses to the low digestibility of the test substances. The authors further commented that these changes have been not correlated to any other specific toxicological characteristic of these substances. NOAEL values were not reported by the study authors. Review of the study data suggested that a NOAEL value of 18% in drinking water can be considered in male and female rats, based on the lack of toxicological effects.

Justification for classification or non-classification

The notifiable substance did not exhibit significant toxic effects arising from a repeated exposure. As a result, the substance does not meet the criteria for classification according to Regulation (EC) No 1272/2008, Annex I section 3.9.