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EC number: 900-501-2
CAS number: -
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.
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
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
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
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
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 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
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).
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
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
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:
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:
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.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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