Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Key studies on oral repeated dose toxicity are available for the following read-across analogues:

Subchronic (90 days, rat): NOAEL oral (female) ≥ 8100 mg/kg bw/day; CAS 13718-94-0, isomaltulose (Jonker et al., 2002)

Subchronic (90 days, rat): NOAEL oral (male) ≥ 7000 mg/kg bw/day; CAS 13718-94-0, isomaltulose (Jonker et al., 2002)

Subchronic (26 weeks, rat): NOAEL oral ≥ 4500 mg/kg bw/day; CAS 13718-94-0, isomaltulose (Yamaguchi et al., 1986)

Subchronic (26 weeks, rat): NOAEL oral ≥ 4500 mg/kg bw/day; palatinose syrup (Yamaguchi et al., 1987)

No data are available for repeated dose toxicity after dermal exposure and inhalation, respectively.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptabel well documented publication which meets basic scientific principles
Principles of method if other than guideline:
Rats were exposed daily to isomaltulose over a time period of 26 weeks to evaluate the subchronic toxic potential.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
other: Sprague-Dawley SPF (Crj: CD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: approx. 5 weeks
- Weight at study initiation: females: 94-118 g; males: 111-130 g
- Housing: individually in metal cages
- Diet: commercial solid feed CE-2 (Japan CLEA), ad libitum
- Water: tap water, ad libitum
- Acclimation period: one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ± 1
- Humidity (%): 55 ± 5
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
The amount of sample needed daily was weighed out and completely dissolved by adding an appropriate amount of distilled water and stirring in a approx. 60 °C water bath. Concentrations of 20, 40 and 60% (w/v) were then prepared by adding distilled water. The solutions were cooled to room temperature for use and applied within 4 hours after preparation.

VEHICLE
- Concentration in vehicle: 20, 40 and 60% (w/v)
- Amount of vehicle (if gavage): 0.5 mL/100 g bw
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
26 weeks (183 days for females; 184 days for males)
Frequency of treatment:
once daily
Remarks:
Doses / Concentrations:
1500, 3000 and 4500 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
15
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The maximum dose of the test substance was set at 7.5 mL/kg of 60% (w/v) aqueous solution using the results of acute toxicity tests previously conducted by the authors and sample dissolution preliminary experiments.

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: once a week up to week 13 of administration and once every two weeks thereafter for each animal

FOOD CONSUMPTION: Yes
- Time schedule for examinations: once a week up to week 13 of administration and once every two weeks thereafter for each individual

WATER INTAKE (if drinking water study): Yes
- Time schedule for examinations: The water intake was measured as amount per animal per day by randomly selecting five animals from each group in week, 1, 4, 13 and 26 after start of test substance administration.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: in week 5 and 26
- Dose groups that were examined: all dose groups (5 randomly selected animals from each dose group)

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood samples were collected in week 26 on the day before the final test substance administration
- How many animals: each animal
- Parameters examined: erythrocyte count, hemoglobin concentration, hematocrit value, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean cospuscular hemoglobin concentration (MCHC), leukocyte count, platelet count and leukocyte differentials

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the time of autopsy
- How many animals: each animal
- Parameters examined: total protein, albumin, total cholesterol, calcium, glucose, urea nitrogen, uric acid, creatinine, alkaline phosphatase, LDH, GPT, GOT, total bilirubin and inorganic phosphorus

URINALYSIS: Yes
- Time schedule for collection of urine: samples were collected in week 1, 4, 13 and 26 from five randomly selected animals from each group
- Metabolism cages used for collection of urine: Yes
- Parameters examined: specific gravity, pH, occult blood, total protein, glucose, ketones, urobilinogen and bilirubin

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
The following organs were weighed: brain, heart, lungs, liver, kidneys, spleen, thyroid, pituitary, adrenals, thymus, submaxillary glands, ovaries, uterus, prostate, testes, seminalvesicles.

HISTOPATHOLOGY: Yes (control and high dose group)
The following orans and tissues were stained with hematoxylin-eosin and examined histopathologically: site of the lesion, brain, heart, aorta, lungs, liver, spleen, pancreas, kidneys, urinary bladder, stomach, esophagus, duodenom, ileum, colon, testes, seminal vesicles, epididides, prostate, ovaries, uterus, mammary glands, submaxillary gland, pituitary, thyroid, adrenals, femoral bone marrow, thymus, mesenteric lymph nodes, eyeballs (including lacrimal glands) and skin
Statistics:
Mean and standard deviations; Student t-test (P <0.05)
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
3000 mg/kg bw/day, females: slightly accelerated weight gain (non adverse)
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
all dose groups: reduced food intake (non adverse)
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
changes in hemoglobin concentration, platelet count, hematocrit value, MCH (not dose-dependent, non adverse)
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
changes in Ca, alkaline phosphatase activity, LDH, urea nitrogen, uric acid, creatinine, bilirubin, GOT, glucose, inorganic phosphorus; changes either not dose-dependent or do not markedly exceed the range of physiological fluctuations (non adverse)
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
all doses, females: decrease in relative heart weight; 4500 mg/kg bw, males: increased liver weight; 3000 mg/kg bw: decreased relative lung, uterus and submaxillary gland weights in females and increased relative thyroid weight in males (non adverse)
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
Two females and males of the control group, one male of the 1500 mg/kg bw/day group, two females of the 3000 mg/kg bw/day group and one female and three males of the 4500 mg/kg bw/day group died of rupture of the esophagus showing pulmonary congestion, edema or hemorrhages, due to an erroneous manipulation during administration. There were no other deaths and no test-substance related symptoms could be found in any of the animals.

BODY WEIGHT AND WEIGHT GAIN
Other than slightly accelerated weight gain in females of the 3000 mg/kg bw/day group compared to the control animals in week 9, 11 and 13, no acceleration or inhibition of weight gain could be found in either males or females during the 26 weeks of the test substance administration.

FEED INTAKE
Decreased feed intake was noted from week 23 and from week 13 in males receiving 1500 and 3000 mg/kg bw/day, respectively. In the 4500 mg/kg bw/day group decreased feed intake was observed for females in week 19 and 23 and for males starting at week 11.
The reduced feed intake might be due to the intake of additional energy by daily gavage of the test item.

WATER INTAKE
There were no changes in water intake in any of the dose groups.

OPHTHALMOSCOPIC EXAMINATION
No changes could be observed in the cornea, iris or conjunctivae in any dose group. The ocular fundus findings did not reveal any changes considered to be test substance-related.

HAEMATOLOGY
Increases in hemoglobin concentration were noted in in females receiving 4500 mg/kg bw/day and in males receiving 3000 mg/kg bw/day. A decrease in platelet count was noted in females of the 1500 mg/kg bw/day group and in males of the 3000 mg/kg bw/day group. Hematocrit values were increased in males of the 3000 mg/kg bw/day group. A tendency to increase in mean corpuscular hemoglobin (MCH) in males administered 4500 mg/kg bw/day was found. However, these findings were not considered test substance-related.

CLINICAL CHEMISTRY
Calcium concentration, alkaline phosphatase activity and LDH activity of females and urea nitrogen concentration of males tended to decrease dose-dependently. In addition a dose-dependent decrease in uric acid and creatinine concentration was noted in males and females exposed to the test substance. Decreases in urea nitrogen and bilirubin concentrations in females of the 1500 mg/kg bw/day group, decreases in GOT activity of females of the 4500 mg/kg bw/day group, increases in alkaline phosphatase activity of males receiving 3000 mg/kg bw/day and increases in glucose and inorganic phosphorus concentration of males administered 4500 mg/kg bw/day were determined. However none of these changes markedly exceeded the range of physiological fluctuation.

URINALYSIS
Ketones became positive in week 4, 13, 26 in males of each group, including the control animals. Animals with positive results for bilirubin were found sporadically from week 1 of administration. However, no dose-response relationship was observed for the positive findings in ketones and bilirubin. No further abnormalities in examined parameters could be found in any of the dose groups.

ORGAN WEIGHTS
Slight decreases were noted in the relative weight of heart in females exposed to the test substance compared to the control animals. In females of the 3000 mg/kg bw/day group relative weight of lungs, uterus and submaxillary glands was slightly decreased. Slight sporadic increases were determined in the relative weight of the thyroid in males of the 3000 mg/kg bw/day group and in the relative weight of the liver and absolute weight of the adrenals in males administered 4500 mg/kg bw/day.

GROSS PATHOLOGY and HISTOPATHOLOGY: NON-NEOPLASTIC
Histopathology was restricted to animals of the control and high dose group.
Tiny fatty droplets were seen primarily in the peripheral hepatocyte of the lobules in male and female rats. Rarely, slight hyperplasia of the bile duct was noted. In the kidney, formation of vacuoles in the epithelial cells of the straight part of the proximal tubules was observed occasionally in females and rarely in males, respectively. Occasionally small grouping of foam cells in the alveoli were noted. Calcification was seen in the tunica media of the arteries in the lung. In the pancreas, fibrosis of the islet of Langerhans and deposition of hemosiderin were seen in males. However, no differences between the administration and control group was determined regarding the histopathological findings in liver, kidney, lungs and pancreas. In addition, although there was slight myocardial fibrosis in males of the administration groups, there was not great difference from the control goup.

In general, there were no abnormal findings believed to have been caused by the test substance administration in the pathological examination.
Dose descriptor:
NOAEL
Effect level:
>= 4 500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects were noted up to the highest dose tested.
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 2) and consistent studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on common functional group(s), common breakdown products, similarities in PC/ECO/TOX properties (refer to endpoint discussion for further details).
The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Repeated dose toxicity

Justification for read-across

There are no data available on the repeated dose toxicity of Reaction mass of 1-O-α-D-glucopyranosyl-D-fructose and 6-O-α-D-glucopyranosyl-D-fructose and fructose and glucose and sucrose. In accordance with Regulation (EC) No 1907/2006, Annex XI, 1.5, read-across from structurally related substances is conducted to fulfill the standard information requirements set out in Regulation (EC) No 1907/2006, Annex IX, 8.6.

According to Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across) “to avoid the need to test every substance for every endpoint”.

All substances contained in Reaction mass of 1-O-α-D-glucopyranosyl-D-fructose and 6-O-α-D-glucopyranosyl-D-fructose and fructose and glucose and sucrose represent mono- or disaccharides which all consist of glucose and/or fructose. Reaction mass of 1-O-α-D-glucopyranosyl-D-fructose and 6-O-α-D-glucopyranosyl-D-fructose and fructose and glucose and sucrose is the aqueous solution (syrup) of the reaction mass of isomaltulose (CAS 13718-94-0), trehalulose (CAS 51411-23-5), fructose (CAS 57-48-7), glucose (CAS 50-99-7), sucrose (CAS 57-50-1), isomaltose (CAS 499-40-1) and oligosaccharides.

All ingredients are substances naturally occurring in fruits, vegetables and other crops or honey.

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006, whereby physicochemical, toxicological and ecotoxicological properties may be predicted from data for reference substance(s) by interpolation to other substances on the basis of structural similarity, isomaltulose (CAS 13718-94-0) and Palatinose syrup are selected as source substances for assessment of repeated dose toxicity.

The read-across is based on the presence of common functional groups and common breakdown products via biological processes, which result in structurally similar chemicals. In general, disaccharides like isomaltulose, trehalulose and sucrose are enzymatically hydrolysed at the glycosidic bond between the monosaccharide units to equal parts in glucose and fructose (Cheetham, 1982; Goda and Hosoya, 1983; MacDonald and Daniel, 1983; Yamada et al., 1985; Ziesenitz, 1986; Goda et al., 1991; Würsch, 1991; Günther and Heymann, 1998), which subsequently enter well-characterized carbohydrate metabolic pathways (Lina et al ., 2002) as essential energy substrate or they are converted to storable glycogen (see Toxicokinetics). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Repeated dose toxicity: oral

Subchronic toxicity

Isomaltulose (CAS 13718-94-0)

Subchronic toxicity of isomaltulose was tested in groups of 40 Wistar rats (20/sex) in a study equivalent to OECD guideline 408 (Jonker et al., 2002).Test animals received diets supplemented with 2.5, 5, or 10% isomaltulose corresponding to 1 700, 3 500, and 7 000 mg isomaltulose/kg body weight/day for males, and 2 000, 4 000, and 8 100 mg/kg body weight/day for females.The respective control group was fed basal diet supplemented with 10% sucrose. No clinical signs, early deaths, or compound-induced adverse effects, including neurotoxic or immunotoxic effects were reported in the treatment groups. Body and organ weights, including the liver, food and water consumption, as well as food conversion efficiency were reported to remain unaffected by isomaltulose. Further, no inter-group variability was reported with respect to haematological or clinical chemistry values, which were obtained at necropsy, and both ophthalmoscopic evaluations and urinalyses conducted in week 13 were unremarkable. Furthermore, the concentrating ability of the kidneys was unaffected as evidenced by a lack of variations reported in the urinary output and density. 10 animals/sex and dose group were necropsied at the end of the study period, and with the exception of strain and age related lesions, neither gross nor microscopic examinations revealed compound-induced abnormalities in any of the rats examined. In addition, no alterations were evident in the liver. Consequently, isomaltulose did not elicit any signs of adverse effects in rats at dietary concentrations of up to 10% thereby leading to NOAELs ≥ 7 000 or 8 100 mg isomaltulose/kg body weight/day in males and females, respectively.

Two further studies were conducted specifically to investigate the effect of isomaltulose on the tissue mineral content. In the first study, groups of 6 Wistar rats received diets supplemented with 30% sucrose (control) or 30% isomaltulose corresponding to approx. 15 000 mg/kg body weight/day for 8 weeks (Kashimura et al., 1990). Clinical observations revealed no treatment-related effects or early deaths and body weight gain was comparable among the groups. Slight decreases in the absolute liver, spleen and kidney weight reaching statistically significance for the absolute kidney weight have been reported. As the relative organ weight referred to body weight revealed no significance, this alteration is not interpreted as adverse. Other organs including the adrenal gland, brain, caecum, spleen and testis revealed no statistically significant variations. Furthermore, haemocratic values were reported to be similar between the control and treatment groups. Analyses on the tissue mineral content revealed a non-significant decrease in calcium concentrations in the heart and a non-significant increase in the testis and whole blood samples. A slight but non-significantly increased phosphorous level was determined in the blood plasma whereas magnesium concentrations were not affected. Based on these findings, a NOAEL ≥ 15 000 mg isomaltuose/kg bw/day was determined.

In a subsequent feeding study, rats received diets containing 30 % sucrose (control), 7.5 or 15% isomaltulose (corresponding to approx.15 000 mg sucrose/kg body weight/day, 3 750 and 7 500 mg isomaltulose/kg body weight/day, respectively) for 13-weeks (Kashimura et al., 1992). Average weight gain and haemocratic levels were unremarkable in all groups. Regarding the tissue mineral content, dose-dependent but not statistically significant increases were observed in the brain for zinc and copper whereas a significant but slight increase was determined for manganese. Moreover, whole blood samples revealed a dose-dependent, significant decrease in the zinc content. As alterations in the mineral status of zinc, copper and manganese do not clearly represent adverse effects and no signs of systemic toxicity or mortalities were noted, a NOAEL ≥ 7 500 mg isomaltulose/kg bw/day was defined. Further, exposures to 5% isomaltulose corresponding to approx. 2 500 mg/kg body weight/day over a period of 16 days did not cause alterations in body weight gain, organ weights or mineral uptake of calcium, magnesium, phosphorous or iron thereby supporting non-hazardous properties of isomaltulose after repeated exposures (Kashimura et al., 1996).

Palatinose syrup

Palatinose syrup was administered to 14 rats/sex/group at dose levels of 1 500, 3 000, or 4 500 mg/kg body weight/day via gavage over 26 weeks (Yamaguchi et al., 1987). No compound-related adverse effects were observed on survival rate, body weight and clinical signs of toxicity.Statistically significant reduction in food consumption reported in high-dose animals was not accompanied by body weight alterations and might be attributed to the high dosage volume of 4.663 mL/kg bw. Furthermore, water consumption was unaffected except a decrease in high-dose males only in the 4th week of the treatment. Haematological alterations including increased haemoglobin and haematocrit values in high-dose females and increased number of white blood cells and blood platelets in mid-dose females were interpreted as incidental as no dose-dependency was observed. Furthermore, blood chemistry did not reveal effects of biological relevance. A decrease in uric acid and glucose was found in females of the low-dose group whereas total bilirubin increased in females of the mid- and high-dose groups. In males, a decrease in total protein, albumin and calcium was observed in the low-dose group, a decrease in total protein, creatinine, albumin, uric acid, calcium, chlolesterol and LDH activity in the mid-dose group as well as a decrease of uric acid and an increase of inorganic phosphours in the high-dose group. In 3/12 males of the high-dose group an extremely high activity of GPT and GOT was determined. Organ weights were comparable among the groups except non-dose related and gender-specific alterations on the thyroid, brain, spleen, lung and liver weight. Histopathology of high-dose animals showed slight alterations in the liver including fat modification and increased Kupfer cells. Moreover, 4/14 males revealed signs of kidney illness, eosinophilic body on the kidney and fibrosis of the islets of Langerhans cells in the pancreas. Furthermore, a small number of male animals showed modifications on the heart muscle. As the observed effects did not follow any dose-relationship and no consistency between the gender was observed, a NOAEL ≥ 4 500 mg Palatinose® syrup/kg body weight/day was defined under the conditions of this study (Yamaguchi et al., 1987).

Chronic toxicity

Isomaltulose (CAS 13718-94-0)

One chronic toxicity studies has been performed in Sprague Dawley rats (Yamaguchi et al., 1986). 15 male and 15 female rats /group were exposed to 1 500, 3 000 and 4 500 mg isomaltulose/kg body weight/day via oral gavage (Yamaguchi et al., 1986; Lina et al., 2002). No compound-related adverse effects were reported with respect to clinical signs of toxicity, mortality, water consumption and ophthalmoscopy. Additionally, no variations in urinalysis were reported compared to controls. Slightly accelerated body weight gain was observed in females of the mid-dose group in week 9, 11 and 13. In contrast, low- and mid-dose males showed a slight reduction in food consumption starting at week 23 or 13, respectively. In the high dose-group, a decreased feed intake was observed for females and males in week 19 and 23 or week 11, respectively. As the reduced food intake might be due to the intake of additional energy by daily gavage of the test item and signs of systemic toxicity are missing, these effects are not interpreted as adverse. Increases in haemoglobin concentration were noted in high-dose females and males. Moreover, a decrease in platelet count was noted in low-dose females and mid-dose males whereas haematocrit values were increased in mid-dose males. A tendency in increased mean corpuscular haemoglobin (MCH) was found in high-dose males. These findings were considered as incidental as no dose-response relationship was present.The results of biochemistry analyses revealed slight, but statistically significant decreases in levels of uric acid (reported in males of the two highest-dose groups and in all groups of treated females), urea (reported in males of the two highest dose groups and in low-dose females) and creatinine (reported in both sexes in all treatment groups), as well as in levels of alkaline phosphatase, lactate dehydrogenase (LDH) and cystolic glutamic-oxaloacetic transaminase (S-GOT) (reported in high-dose females).Increases in levels of serum phosphorus and glucose were reported in high-dose males, whereas only elevated phosphorus levels were reported in high-dose females. These observations are likely physiological changes associated with the high sugar load imposed on the animals as none of the alterations markedly exceeded the range of physiological fluctuations. It must therefore be reinforced that variations on blood biochemistry values are not representative for adverse effects, but rather may be indicative of physiological adaptations. Furthermore, variations observed in the clinical chemistry were within the ranges of historical control data, or otherwise did not demonstrate a dose-related response. Slight decreases in relative organ weights of the heart, lungs, uterus and submaxillary glands in females and sporadic increases in the relative weight of the thyroid and liver in mid- and high-dose males, respectively, were not correlated to pathological alterations and are hence not considered as adverse. Therefore, a NOAEL ≥ 4 500 mg isomaltulose/kg body weight/day was defined (Yamaguchi et al., 1986, Lina et al., 2002).

 

Human evidence

Tolerability of isomaltulose was shown in several epidemiological studies for doses ranging from 5 – 48 g /day as no gastrointestinal symptoms e.g. diarrhoea, flatulence or abdominal pain were observed human volunteers (Spengler and Sommerauer, 1989 [unpublished], Kashimura 1990b, Tamura et al., 2004).

Fructose, glucose and sucrose are not further described in the present dossier as sufficient information is known about the intrinsic properties to consider them as non-hazardous which resulted in inclusion on Annex IV of Regulation (EC) 1907/2006. This has been recently verified by the Comission as reviewed by Blainey et al. (2010). Isomaltose occurs naturally at branch sites within amylopectin in starches and is thus present in commercially available starch hydrolysates and maltodextrines, which are both included in Annex IV.

Based on the available data, the surrogate substances isomaltulose and Palatinose® syrup are considered to exhibit low hazardous potential after short- and long-term exposures. Further, reliable data prove tolerability of isomaltulose in humans. Thus, Reaction mass of 1-O-α-D-glucopyranosyl-D-fructose and 6-O-α-D-glucopyranosyl-D-fructose and fructose and glucose and sucrose is considered as safe in regard to repeated dose exposures.

 

References not included in IUCLID:

Blainey M, Avila Cd, van der Zandt P. Review of REACH Annex IV--establishing the minimum risk of a substance based on its intrinsic properties. Regul Toxicol Pharmacol. 2010 Feb;56(1):111-20.

Cheetham, P.S.J. 1982. The human sucrase-isomaltase complex: Physiological, biochemical, nutritional and medical aspects. In: Lee, C.K.; Lindley, M.G. (Eds.). Developments in Food Carbohydrate - 3. Disaccharidases. Applied Science Publishers; London, Engl./Englewood, New Jersey, pp. 107-140.

Goda, T.; Hoyosa, N. 1983. Hydrolysis of palatinose by rat intestinal sucrase-isomaltase complex. Nihon Eiyo Shokuryo Gakkaishi 36:169-173. Cited In: Würsch, 1991.

Goda, T.; Takase, S.; Hosoya, N. 1991. Hydrolysis of palatinose condens ates by rat intestinal disaccharidases. Nihon Eiyo Shokuryo Gakkaishi 44(5):395-398.

Günther, S.; Heymann, H. 1998. Di- and oligosaccharide substrate specificities and subsite binding engergies of pig intestinal glycoamylase-maltase.Arch Biochem Biophys 354(1):111-116.

Kashimura, J.; Nakajima, Y.; Benno, Y.; Misuoka, T. 1990.Comparison of faecal microflora among subjects

Lina, B.A.R.; Jonker, D.; Kozianowski, G. 2002.Isomaltulose (Palatinose®): A review of biological and toxicological studies. Food Chem Toxicol 40(10):1375-1381

MacDonald, I.; Daniel, J.W. 1983. The bioavailability of isomaltulose in man and rat. Nutr Rep Int 28(5):1083-1090.

Spengler M, Sommerauer B (1989). Toleranz und Akzeptanz von Isomaltulose (Palatinose®) im Vergleich zu Saccharose bei 12 wöchiger oraler Gabe von aufsteigenden Dosen (12-48 g) an gesunde Probanden.[Tolerance and acceptance of Isomaltulose (Palatinose®) compared to sucrose in a 12 week study with healthy volunteers and increasing oral doses (12-48 g). (Isomalulose-Studie Nr. 101). Bayer AG. [unpublished study dated 7.3.1989].

Tamura  A, Shiomi T, Tamaki N, Shigematsu N, Tomita F, Hara H (2004). Comparative effect of repeated ingestion of difructose anhydride III and palatinose on the induction of gastrointestinal symptoms in humans. Biosci Biotechnol Biochem 68(9):1882-1887.

Würsch, P. 1991. Metabolism and tolerance of sugarless sweeteners. In: Rugg-Gunn, A.J.(Ed.). Sugarless: The Way Forward. Else vier Applied Science; New York, pp. 32-51.

Yamada, K.; Shinohara, H.; Hosoya, N. 1985. Hydrolysis of 1-O-α-D-glucopyranosyl-D-fructofuranose (Trehalulose) by rat intestinal surcrase-isomaltase complex. Nutrition Reports International 32 (5): 1211 - 1220

Ziesenitz, S.C. 1986. Carbohydrasen aus jejunalmucosa des Menschen = [Carbohydrases from the human jejunal mucosa]. Z Ernährungswiss 25(4):253-258. Cited In: Würsch, 1991.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

Hazard assessment is conducted by means of read-across from a structural surrogate. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:

No study required since exposure of humans via inhalation is unlikely taking into account the physicochemical properties of the substances and the lack of exposure to aerosols, particles or droplets of inhalable size under normal conditions of use.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:

No study required since exposure of humans via inhalation is unlikely taking into account the physicochemical properties of the substances and the lack of exposure to aerosols, particles or droplets of inhalable size under normal conditions of use.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:

No study required since sufficient weight of evidence is available to exclude that Reaction mass of 1-O-α-D-glucopyranosyl-D-fructose and 6-O-α-D-glucopyranosyl-D-fructose and fructose and glucose and sucrose is toxic after acute dermal exposure considering the available data on read-across to the main components, which have been shown not to be irritating, sensitising or toxic after acute or repeated oral exposure. Moreover, sufficient information is known for the ingredients glucose, fructose and sucrose to consider them as non-hazardous and to include them in Annex IV of Regulation (EC) No. 987/2008.  Therefore, in accordance with Annex XI, Section 1.2 of Regulation (EC) 1907/2006 further testing on vertebrate animals for that property shall be omitted and further testing not involving vertebrate animals may be omitted.  

Justification for selection of repeated dose toxicity dermal - local effects endpoint:

No study required since sufficient weight of evidence is available to exclude that Reaction mass of 1-O-α-D-glucopyranosyl-D-fructose and 6-O-α-D-glucopyranosyl-D-fructose and fructose and glucose and sucrose is toxic after acute dermal exposure considering the available data on read-across to the main components, which have been shown not to be irritating, sensitising or toxic after acute or repeated oral exposure. Moreover, sufficient information is known for the ingredients glucose, fructose and sucrose to consider them as non-hazardous and to include them in Annex IV of Regulation (EC) No. 987/2008.  Therefore, in accordance with Annex XI, Section 1.2 of Regulation (EC) 1907/2006 further testing on vertebrate animals for that property shall be omitted and further testing not involving vertebrate animals may be omitted.  

Justification for classification or non-classification

Based on read-across, the available data on repeated dose toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.