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EC number: 908-700-6 | CAS number: 64519-82-0
- 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:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
Data source
Referenceopen allclose all
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 982
- Report date:
- 1982
- Reference Type:
- publication
- Title:
- Embryotoxicity/Teratogenicity Of Isomalt In Rats And Rabbits
- Author:
- Waalkens-Berendsen, D.H., et al.
- Year:
- 1 990
- Bibliographic source:
- Fd Chem. Toxic. 28: 1-9
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- adopted in 2001
- GLP compliance:
- yes
Test material
- Reference substance name:
- Reaction mass of 1-O-α-D-glucopyranosyl-D-mannitol and 6-O-α-D-glucopyranosyl-D-glucitol
- EC Number:
- 908-700-6
- Cas Number:
- 64519-82-0
- Molecular formula:
- 6-O-alpha-D-Glucopyranosyl-D-sorbitol: C12H24O11 1-O-alpha-D-Glucopyranosyl-D-mannitol: C12H24O11
- IUPAC Name:
- Reaction mass of 1-O-α-D-glucopyranosyl-D-mannitol and 6-O-α-D-glucopyranosyl-D-glucitol
- Test material form:
- solid: crystalline
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Remarks:
- Cpb:WU (Wistar, random)
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Central Institute for the Breeding of Laboratory Animals TNO, Zeist, The Netherlands
- Weight at study initiation: 153 to 204 g
- Fasting period before study: no
- Housing: in supsended steel cages fitted with wire-mesh floors (4 females/cage during acclimatization, individually during pregnancy)
- Diet: stock diet for rats, modified with casein, d1-methionine and 10% maize food starch. The modification allowed the incorporation of up to 10% test item at the expense of maize starch (see Table 1). Food was offered ad libitum, to the control and all test item groups. A restricted feeding control group received 80% of the amount consumed by the control group animals from day 1 onwards.
- Water: source not specified (ad libitum)
- Acclimation period: 14 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 2
- Humidity (%): ≥ 40
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 19 Oct 1981 To: 25 Nov 1981
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- not specified
- Details on exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): not specified
- Mixing appropriate amounts with (Type of food): not specified
- Storage temperature of food: not specified
TEST ITEM INTAKE
- Test item intake was not specified in the report.
- Test item intake was calculated retrospectively based on mean body weights and food consumption at the end of the period of organogenesis. The calculation of test item intake is detailed in Table 3. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The actual levels of test item in the diet were analysed once during the study and were found to equal or close to the target concentrations (see Table 2).
- Details on mating procedure:
- - Impregnation procedure: co-housed
- If co-housed:
- M/F ratio per cage: 1/2
- Length of cohabitation: overnight
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy - Duration of treatment / exposure:
- from gestation day 0 to 21
- Frequency of treatment:
- daily, 7 days/week
- Duration of test:
- throughout pregnancy (day 0 to 21)
Doses / concentrationsopen allclose all
- Dose / conc.:
- 2.5 other: %
- Remarks:
- corresponding to 25 000 ppm (ca. 1970 mg/kg bw/day, calculated from mean bw and food consumption)
- Dose / conc.:
- 5 other: %
- Remarks:
- corresponding to 50 000 ppm (ca. 4120 mg/kg bw/day, calculated from mean bw and food consumption)
- Dose / conc.:
- 10 other: %
- Remarks:
- corresponding to 100 000 ppm (ca. 7970 mg/kg bw/day, calculated from mean bw and food consumption)
- No. of animals per sex per dose:
- 22 - 23 females/dose
- Control animals:
- yes
- yes, plain diet
- Details on study design:
- - Dose selection rationale: not specified
- Rationale for animal assignment: Mated fermales were assigned to each group in rotation. The sequence was continued from where it ended on the previous day until each group contained the desired number of mated females.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations: general condition and behaviour were checked
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations: daily from day 0 until day 21 of gestation
FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/animal/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION: No
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21 - 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: Ovaries and empty uteri as well as placentas of live fetuses were weighed - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter
Both soft tissue and skeletal examinations were carried out on the foetuses of the control and high dose group as well as of foetuses of the restricetd feeding group. - Statistics:
- For the statistical analyses of differences in degree of ossification between the test and control groups the Student t-test was applied to transformed ossification values (DgOt) expressed in degrees and calculated by the formula:
DgOt = arcsine √DgO°
Statistical analysis of differences in body weight, food consumption, organ weights, litter data, foetus weights and lengths and placenta weights was carried out by applying analysis of co-variance, followed by Dunnett's multiple comparison tes, whereas skeletal and visceral anomalies were evaluated by the Chi-square test. - Indices:
- Percentage pre-implantation loss (PRIL) was calculatde for each litter by the formula:
PRIL = number of corpora lutea - number of implantation sites / number of corpora lutea x 100%
Percentage post-implantation loss (POIL) was calculated for each litter by the formula:
POIL = number of implantation sites - number of live young / number of implantation sites x 100%
The degree of ossification of foetus skeletons (DgO) was calculated for each litter by the formula:
DgO = number of bones without ossification (or with incomplete ossification) / numbers of bones examined - Historical control data:
- Historical control data on reproduction data and on fetal malformations and variations (external, skeletal and visceral) are provided in the report.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Some females in each of the groups showed focal baldness. No signs of ill-health nor any reaction to the treatment were observed.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Mean maternal body weights and weight gain during pregnancy were similar for both the controls and all test item-fed females. The body weights of pregnant females which had access only to restricted amounts of food stayed significantly behind as compared with the controls. During the full gestation period these animals gained only 60% of the mean weight gain of control animals.
Corrected body weight gains were similar in all groups with diet offered ad libitum. In the restricted feeding group corrected body weight gain was only 16% of that of the control group. - Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Mean food intake was similar in all test item groups and the controls.
Since, the animals of the restricted-feeding group were provided daily with only 80% of the food consumed by the controls during the preceeding day, these animals consumed practically all the food offered. However, since the amounts of food were calculated on the basis of body weights, the actual food intake per animal in this group appeared to be even less than 80% of the food consumed by controls. - Food efficiency:
- no effects observed
- Description (incidence and severity):
- There were no consistent or dose-related differences in food efficiency between the test item groups and the controls.
The grand means of the restricted-feeding group were lower than the control value. - Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- Gravid and empty uterus weights were significantly decreased in the restricted feeding group only.
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- At autopsy a minor degree of haemorrhagic nasal discharge was noticed in one dam of the 5.0% test item and in two dams of the restricted-feeding group. One female of the 10.0% test item group showed diarrhoea and one control animal exhibited a periocular haemorrhage. Focal baldness was observed in several dams in all groups.
No gross maternal organ changes were seen in in dams of any of the groups. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- The numbers of early and late resorptions were similar in the test item groups and the control. A slight increase of the number of resorptions and through that of post-implantation loss was observed in the restricted feeding group.
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- not examined
- Changes in number of pregnant:
- no effects observed
- Details on maternal toxic effects:
- The feeding of restricted amounts of stock diet to pregnant females resulted in decreased maternal weight gain and consequently, in lower uterus weights. The effects on foetuses were principally of an embryotoxic nature as expressed by increased numbers of resorptions, smaller foetuses, decreased foetus weights and retardation in bone development. It is therefore concluded that restriction of the diet of pregnant rats during gestation induces embryotoxic effects.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 7 970 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: no adverse effects noted up to and including the highest dose tested
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- Foetal weights as well as foetal rump lengths were significantly decreased in the restricted-feeding group only.
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- not examined
- External malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Spina bifida was observed in 3 foetuses of one litter in the high dose group. Further, one foetus of the high dose group and one foetus of the restricted-feeding group showed a ringtail. No other externally visible malformations were observed.
External variants were seen in several foetuses; subcutaneous haemorrhages or petechia occurred in one or a few foetuses in all groups, while one dismature foetus was observed in the high dose group. None of these findings were considered to be related to the treatment.
Although spina bifida occurred in 3 foetuses of the top-dose group only, the total number of foetuses with skeletal or visceral malformations in this group was similar to the number of affected control foetuses. In addition, the percentage of litters with one or more foetuses showing malformations was even higher in the control (4 out of 17) than in the high dose group (3 out of 19). Therefore, and since all 3 spina bifida foetuses originated from the same litter, no significance is attached to these findings. - Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Skeletal malformations were observed in 5 foetuses: in 2 foetuses from the control, in 2 from the high dose, and in 1 foetus from the restricted feeding group. Neither the type nor the incidence of the observed malformations indicated any treatment-relationship.
Minor skeletal anomalies and skeletal variants were observed in several foetuses in all groups or occasionally in one or a few foetuses.
The number of foetuses showing dislocation of one or several sternebrae was increased in both the high dose and the restricted-feeding group. Further, the incidences of supernumerary ribs and skull bones was increased in the restricted-feeding group only.
A slightly higher number of incompletely ossified cervical vertebral bodies in the high dose group was considered an incidental finding and reflects the variation in ossification normally found in skeletons of foetuses of the strain of rats used. For the remaining data on ossification degrees no differences were observed between the control and high dose group.
In the restricted-feeding group however decreased degrees of ossification were observed in several bones such as metacarpals, metatarsals and cervical thoracic vertebral bodies.
The somewhat higher number of dislocated sternebrae in the high dose group as compared with the control group, is not considered of significance since, firstly no other indications were noticed that might point to a skeletal effect of the test substance and secondly, the observed control values were rather low in comparison with those of historical control series. - Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Visceral malformations were observed in 7 foetuses: the control group revealed 2 foetuses with microphthalmia and 1 foetus with anophthalmia. They originated all three from different litters. In the high dose group spina bifida was observed in 2 foetuses from one litter. One of these foetuses also showed microdactyly of a hindlimb. Further, a double kidney was observed in one foetus from a different litter. The restricted-feeding group revealed only one foetus with visceral malformations consisting of right-sided testicular cryptorchism and left-sided testis atrophy.
The other observations listed,were either minor anomalies or visceral variants.
Neither meningial haemorrhages nor dilated brain ventricles were observed in the control group. However, since these anomalies are regularly being observed in our control series, these findings were considered to reflect the variation normally found, rather than to be related to the treatment. The other minor anomalies were about equally spread among the high dose, restricted-feeding and the control animals or occurred occasionally in one or a few foetuses.
No differences were noted in the nature of the observed visceral variants. Although the number of foetuses with unilaterally increased renal pelvic cavitation was slightly higher in the high dose group as compared with controls, the observed incidence is fully comparable with values observed in historical control series. Moreover, there were no other indications of a treatment-related soft tissue effect. Therefore, no significance was attached to the somewhat higher incidence of minor kidney variants.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 7 970 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no adverse effects noted up to and including the highest dose tested
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Any other information on results incl. tables
Table 2. Analytical results of test substance concentration in diet
Nominal concentration (%) |
Actual concentration (%) |
2.5 |
2.5 |
5.0 |
5.0 |
10.0 |
9.6 |
Table 3. Achieved test item intake
Nominal concentration of test item in diet (%) | ||||
0.0 | 2.5 | 5.0 | 10.0 | |
Body weights (g, mean bw at end of organogenesis, day 16) |
238.4 | 241.7 | 240.1 | 240.9 |
Food consumption (g/food/animal/day, mean food consumption at end of organogenesis, day 16) |
18.5 | 19.0 | 19.8 | 19.2 |
Food consumption (g/food/kg bw/day, mean of means) |
77.6 | 78.6 | 82.5 | 79.7 |
Test item intake (g/kg bw/day) |
0.0 | 2.0 | 4.1 | 8.0 |
Test item intake (mg/kg bw/day) |
0.0 | 1965.2 | 4123.3 | 7970.1 |
Applicant's summary and conclusion
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.