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EC number: 900-501-2 | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- 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: Comparable to guideline study with acceptable restrictions.
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 997
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 6-O-α-D-glucopyranosyl-D-fructose
- EC Number:
- 237-282-1
- EC Name:
- 6-O-α-D-glucopyranosyl-D-fructose
- Cas Number:
- 13718-94-0
- Molecular formula:
- C12H22O11
- IUPAC Name:
- 6-O-alpha-D-glucopyranosyl-D-fructose
- Details on test material:
- - Name of test material (as cited in study report): Isomaltulose (6-O(α-D-glucopyranosyl)-D-fructofuranose)
- Physical state: white crystalline powder
- Analytical purity: 98.5%
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Wistar (Hsd/Cpb:WU)
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Harlan-CPB, Zeist, The Netherlands
- Age at study initiation (at mating): 13 weeks
- Housing: mated females were housed individually in suspended stainless-steel wire-screen cages
- Diet: institute's cereal-based powdered stock diet (during treatment period supplemented with 2.5% casein, 0.1% DL-methionine and 0-10% maize starch), ad libitum
- Water: ad libitum
- Acclimation period: 5 days before mating
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-24
- Humidity (%): 50-60
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- DIET PREPARATION
- Mixing appropriate amounts with (Type of food): institute's cereal-based powdered stock diet supplemented with 2.5% casein, 0.1% DL-methionine and 10% maize starch; 0, 2.5, 5 or 10% test substance was incorporated at the expense of maize starch.
- Storage temperature of food: freezer
Fresh portions of diet were provided to the rats every 4-6 days. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- All diets were analysed for test substance content by HPLC. The adequacy of the mixing procedure was investigated by analysis of 5 samples of each test diet from the first batch. The stability of the test substance in this batch of diets was examined after storage for 7 days at room temperature.
The test substance was found to be stable in the diet under the experimental conditions applied.
The actual levels of the test substance were as follows:
low-dose diet: 87-96% of the intended level
mid-dose diet: 98-102% of the intended level
high-dose diet: 98-103% of the intended level
The analyses of the 5 samples of each of the diets from the first batch showed coefficients of variation of 4% or less, indicating satisfactory homogeneity. - Details on mating procedure:
- - Impregnation procedure: cohoused
- M/F ratio per cage: 1:2
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy - Duration of treatment / exposure:
- Day 0 - 21 of gestation
- Frequency of treatment:
- continuously
- Duration of test:
- 21 days of gestation
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
2.5, 5 and 10%
Basis:
nominal in diet
- Remarks:
- Doses / Concentrations:
1760, 3520 and 6930 mg/kg bw/day
Basis:
other: overall means of periodical calculations from data on body weight, food intake and nominal levels of test substance
- No. of animals per sex per dose:
- 24 females
- Control animals:
- yes, plain diet
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
BODY WEIGHT: Yes
- Body weight gain during days 0-6, 6-16 and 16-21 of gestation was determined.
FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Water intake (g/rat/day) during days 0-6, 6-16 and 16-21 of gestation was determined.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: major abdominal and thoracic maternal organs - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: Number of live and dead foetuses; sex of live foetuses; foetal and placental weights; foetal length; - Fetal examinations:
- - External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [half per litter]
- Skeletal examinations: Yes: [half per litter]
- Head examinations: No - Statistics:
- Body weight gain, food and water intake were evaluated by ANOVA/Dunnett's test (P < 0.05). Maternal survival and pregnancy status, maternal and foetal external macroscopic observations, and skeletal and visceral examinations were evaluated by Fisher's exact probability test. The percentages of pre- and post-implantation loss were subjected to Kruskal-Wallis one-way ANOVA followed by the Mann-Whitney U test.
- Indices:
- Fertility index (%) = (No. of pregnant females/No. of mated females) x 100
Preimplantation loss (%) = [(No of corpora lutea-No. of implantation sites)/No. of corpora lutea] x 100
Postimplantation loss (%) = [(No of implantation sites-No. of live foetuses)/No. of implantation sites] x 100
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:no effects
Details on maternal toxic effects:
No mortality occured and no clinical signs attributabe to the treatment were noted. Body weight gain, food and water consumption did not reveal treatment-related differences during pregnany. There were no severe macroscopic abnormalities at gross pathology of the maternal organs and tissues.
No significant differences in fertility and gestation indices, the numbers of corpura lutea and implantations, live and dead foetuses, foetal sex ratios and early and late resorptions were noted. There were no differences in ovaries, gravid and empty uterus weights in any of the dose groups compared to control animals.
Effect levels (maternal animals)
- Dose descriptor:
- NOAEL
- Effect level:
- >= 6 930 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: No adverse effects were noted up to the highest dose tested.
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
Placental weight, foetal weight and foetal length were comparable between treatment and control groups.
Examination of foetal soft tissues did not reveal treatment related changes. There were no visceral malformations in any of the groups. The few visceral anomalies or visceral variations (Table 1) were spread about equally among the treatment and control groups or occurred occationally in one or a few foetuses. No significant differences between treated and control animals were found at examination of the placentas during foetal screening.
No foetal skeletal malformations occurred. Among skeletal variations, the incidence of foetuses with a supernumerary rudimentary 14th rib was higher in the controls than in any of the treatment groups (Table 2). The incidence of crooked toes varied among the treatment groups and was slightly increased in foetuses of the top-dose group. Similar variations have been noted regularly in control rats in previous studies and therefore the occurence of crooked toes in the present study is considered to reflect a processing artefact rather than a treatment-related effect. A statistically significant increased incidence of foetuses showing incomplete ossification of the skull bones was found in the low-dose group and was considered to be accidental, since it was not confirmed in the higher dose groups (table 2). Almost every foetus, including those in the control group, showed delayed ossification of the phalanges (Table 2). The delayed ossification was more prominent in the treatment groups. However, there was no dose-response relationship and no relevant effects on ossification of other bones were observed. Thus, the delayed ossification of the phalanges was not considered treatment-related.
Effect levels (fetuses)
- Dose descriptor:
- NOAEL
- Effect level:
- >= 6 930 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects were noted up to the highest dose tested.
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Any other information on results incl. tables
Table 1: Visceral alterations in foetuses
Parameters |
Dose groups (dietary levels) |
|||
0 |
2.5% |
5% |
10% |
|
No of foetuses examined |
126 |
120 |
119 |
130 |
Visceral anomalies |
||||
Eyes: folded retin |
1 |
0 |
0 |
1 |
Brain: meningeal haemorrhage |
3 |
1 |
1 |
2 |
Heart: pericard filled with haemorrhagic fluid |
3 |
2 |
2 |
3 |
Spleen: heamorrhage |
0 |
1 |
0 |
0 |
Stomach: heamorrhage |
2 |
2 |
5 |
5 |
Thoracic activity: filled with haemorrhagic fluid |
0 |
0 |
0 |
1 |
Abdominal cavity: containing haemorrhagic fluid |
1 |
2 |
0 |
1 |
Extremeties: flexure of one limb |
0 |
0 |
0 |
1 |
Pancreas: haemorrhage |
5 |
10 |
7 |
11 |
Skin subcutaneous haemorrhage |
0 |
0 |
1 |
0 |
Total incidence of visceral anomalies |
13 |
16 |
15 |
21 |
Visceral variations |
||||
Oesophagus: oesophagectasia |
7 |
8 |
9 |
3 |
Thymus: small haemorrhage(s), petechiae |
3 |
1 |
0 |
0 |
Stomach: hypertrophy |
13 |
5 |
5 |
12 |
Stomach: hypotrophy |
0 |
1 |
0 |
0 |
Kidneys: increased renal pelvic cavitation |
11 |
11 |
19 |
14 |
Urether: hydrourether |
1 |
2 |
0 |
4 |
Urether: bent urether |
0 |
1 |
0 |
0 |
Tail: crooked |
3 |
5 |
4 |
2 |
Tail: curly |
1 |
2 |
2 |
1 |
Tail: ringtail |
0 |
1 |
0 |
0 |
Extremeties: crooked |
0 |
2 |
0 |
0 |
Extremeties: bent |
0 |
1 |
0 |
0 |
Salivary gland: haemorrhage |
0 |
0 |
0 |
2 |
Total incidence of visceral variations |
30 |
34 |
31 |
32 |
Table 2: Skeletal alterations in foetuses
Parameters |
Dose groups (dietary levels) |
|||
0 |
2.5% |
5% |
10% |
|
No of foetuses examined |
137 |
134 |
137 |
145 |
Skeletal variations |
||||
Sternum: dislocated sternebra(e) |
37 |
31 |
30 |
51 |
Sternum: supernumerary sternebra(e) |
0 |
1 |
1 |
1 |
Sternum: absent |
0 |
0 |
1 |
0 |
Ribs: 14th rib present |
9 |
3 |
4 |
1* |
Ribs: irregular shaped ribs |
0 |
1 |
0 |
0 |
Ribs: wavy rib(s) |
1 |
0 |
0 |
1 |
Ribs: 13th rib rudimentary |
0 |
0 |
1 |
0 |
Forelimbs: crooked fingers |
1 |
2 |
1 |
2 |
Hindlimbs: crooked toes |
1 |
7 |
4 |
10* |
Total skeletal variations |
44 |
43 |
38 |
61 |
Skeletal ossification |
||||
Skull bones: two or more bones incompletely ossified |
36 |
58*** |
48 |
49 |
Skull bones: hyoid bone absent |
0 |
1 |
0 |
2 |
Sternum: sternebra(e) reduced or incompletely ossified |
59 |
70 |
63 |
63 |
Phalanges front: 10-20 digits incompletely ossified |
4 |
1 |
3 |
5 |
Phalanges front: 10-20 digits not ossified |
136 |
118*** |
132 |
133** |
Phalanges front: more than 20 digits not ossified |
1 |
15*** |
4 |
10* |
Phalanges hind: 10-20 digits incompletely ossified |
3 |
1 |
2 |
0 |
Phalanges hind: 10-20 digits not ossified |
136 |
111 |
129* |
127*** |
Phalanges hind: more than 20 digits not ossified |
1 |
19** |
8* |
18*** |
Total skeletal retardations |
137 |
134 |
137 |
145 |
*/**/***: values differ significantly from the corresponding control value (* P<0.05; ** P<0.01; *** P<0.001) using Fisher's exact probability test
Applicant's summary and conclusion
- Conclusions:
- No maternal toxicity occurred and no effects on reproductive performance, nor on embryonic or foetal development including visceral and skeletal examination were noted up to and including a dietary level of 10% isomaltulose equivalent to 6930 mg/kg bw/day.
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