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EC number: 259-952-2 | CAS number: 56038-13-2
- 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
- Study period:
- 1998-1999
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 999
- Report date:
- 1999
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other: ICH Harmonised Tripartite Guideline
- Version / remarks:
- 24 June 1993
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 1,6-dichloro-1,6-dideoxy-β-D-fructofuranosyl 4-chloro-4-deoxy-α-D-galactose
- EC Number:
- 259-952-2
- EC Name:
- 1,6-dichloro-1,6-dideoxy-β-D-fructofuranosyl 4-chloro-4-deoxy-α-D-galactose
- Cas Number:
- 56038-13-2
- Molecular formula:
- C12H19Cl3O8
- IUPAC Name:
- 1,6-dichloro-1,6-dideoxy-β-D-fructofuranosyl 4-chloro-4-deoxy-α-D-galactose
- Test material form:
- solid: crystalline
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Provided by sponsor, Batch B041997SCM, 99.2% purity
- Purity test date: 21 September 1998
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: refrigerated at 1-10 degrees C
- Stability under test conditions: stable in aqueous solution for at least one year when stored below 21 degrees C
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: No reactivity - vehicle was water
TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: For each dose group, the test article was dissolved in a small quantity of the measured vehicle (water). Additional vehicle was added to make up the required concentration before stirring until homogeneous.
FORM AS APPLIED IN THE TEST (if different from that of starting material) : Dissolved in water.
Test animals
- Species:
- rabbit
- Strain:
- New Zealand White
- Remarks:
- Crl.NZW/Kbl BR
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River UK
- Age at study initiation: 4-5 months
- Weight at study initiation: at least 2.5kg
- Housing: individually in floor pens with soft wood chips
- Diet: ad libitum
- Water: ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16-22 degrees C
- Humidity (%): 40-80%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light):10/14
IN-LIFE DATES: From: 22 November 1998 To: 23 December 1998
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
For each dose group, the test article was dissolved in a small quantity of the measured vehicle. Additional vehicle was added to make up the required concentration before stirring until homogeneous. The solutions were stored refrigerated (1-10 degrees C) until dispensed to the animal house. Solutions were prepared weekly and dispensed as daily aliquots.
VEHICLE
- Justification for use and choice of vehicle (if other than water): Purified Water - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Achieved concentration of test article formulation tested before the start of treatment and for the last week of dosing. The concentrations of the analysed formulations ranged between 98 and 104% of nominal.
- Details on mating procedure:
- Mating occured at the suppliers facility 3 days prior to delivery of animals to Covance.
Purchased timed pregnant - Duration of treatment / exposure:
- Day 7 to Day 19 of gestation (inclusive)
- Frequency of treatment:
- Daily
- Duration of test:
- 12 days
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day
- Dose / conc.:
- 175 mg/kg bw/day (nominal)
- Dose / conc.:
- 350 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 24 females
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The high dose level was selected on the basis of the results of a range-finding study of embryo-foaetal development in the rabbit and the limit dose recommendations of the ICH and OECD guidelines. The low and intermediate dose levels were comparable to the dosages evaluated in a previous rabbit embryo-foetal development study. Individual dose volumes were adjusted according to the latest recorded body weight.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily & one hour after dosing.
- Cage side observations: observable signs of ill health or toxicity.
BODY WEIGHT: Yes
- Time schedule for examinations: Days 4, 7, 9,12,15,19, 24 and 29 of gestation.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
Food consumption was recorded daily from Day 4 to 29 of gestation and reported on the body weight intervals.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation Day 29
- Organs examined: Macroscopic examination - 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 - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: [all per litter]
- Skeletal examinations: Yes: [all per litter]
- Head examinations: Yes: [half per litter] - Statistics:
- Data were processed, where appropriate, to give litter mean values, group mean values and standard deviations.
Body weight, body weight gain, and food consumption were analysed using one-way analysis of variance (ANOVA). Pairwise comparisons with control were made using Dunnett's test. A regression test was performed to determine whether there was a linear relationship between increasing dose and response. Levene's test for equality of variances among the groups was also performed, and in all cases this showed no evidence of heterogeneity.
The numbers of corpea lutea, implantations, number of foetuses per female, percentage of male foetuses, litter weight, placental weight and foetal weight were analysed using non-parametric methods.
Gravid uterus weight was analysed using Analysis of Covariance and Dunnett's test using the corrected body weight on Day 29 as covariate.
The proportions of females having pre-and post-implantation loss, early and late intrauterine deaths and the number of litters having malformations and variations were analysed using the Cochran-Armitage test for dose-response and the Fisher exact test for pairwise comparisons. The tests were interpreted with one-sided risk for increased incidence with increasing dose.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Soft faeces were seen in 6 high dose animals, 2 intermediate dose, and one control animal, one high dose animal had coloured faeces. These findings were observed on single days during late gestation and were considered to be indicitive of treatment. At necropsy three high dose animals had a moderately distended caecum or colon - an occurance observed in other studies where high doses of a poorly absorbed substance are administered through gavage. One other animal had a mottled liver and a moderately distended gall bladder.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- One low dose animal was found dead on day 13 of gestation, necropsy findings indicate that this was due to a dosing error.
One high dose animal was killed for humane reasons on day 10 of gestation due to an injury to the thoratic area of its back. - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- No effects on bodyweight occured in the low or intermediate dose groups.
Marked body weight losses (ranging up to 710 grams) were observed in four of the high dose animals which aborted their litter and in one high dose animal that suffered total litter loss in utero. Two other high dose animals with a high incidence of interuterine deaths also had a significantly lower body weight. The mean body weight of the high dose animals with live foetuses on day 29 of gestation was slightly less than controls during the treatment period and this difference remained evident until termination. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Periods of low food intake (0-17 g/day) were observed in five high dose animals that lost litters and two animals with a high incidence of late interuterine deaths. In animals with live litters at day 29 of gestation, the mean food intale during the treatment period was slightly lower than that of the controls in all treatment groups, but there was no dose response relationship observed. The slightly lower intakes observed between days 19 and 24 may have been associated with the slight gastro-intestinal disturbance seen during this period.
- Food efficiency:
- not examined
- 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:
- not specified
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Three high dose animals were observed to have a moderately distended caecum or colon and further animals was seen to have a mottled liver and a moderately distended gall bladder.
- 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:
- effects observed, treatment-related
- Description (incidence and severity):
- In the high dose group four animals aborted, no abortions were observed in the low and intermediate dosing groups.
- Pre- and post-implantation loss:
- effects observed, treatment-related
- Description (incidence and severity):
- Two high dose animals had a high incidence of late resorptions and one had total early resorptions. The mean post-implantation loss of the remaining high dose animals was lower than that of the controls. In the intermediate dose group post implantation loss was slightly higher than the controls but the difference was not statistically significant and the incidence was similar to controls from other recent studies. In the low dose group post-implantation loss was less than that of the controls.
The incidence of pre-implantation loss showed no dose related trends. - Total litter losses by resorption:
- effects observed, treatment-related
- Description (incidence and severity):
- One animal from the high group suffered total early resorptions and two had a high incidence of late resorbtions.
- Early or late resorptions:
- effects observed, treatment-related
- Description (incidence and severity):
- One animal from the high group suffered total early resorptions and two had a high incidence of late resorptions.
- Dead fetuses:
- not specified
- Changes in pregnancy duration:
- not specified
- Changes in number of pregnant:
- not specified
- Other effects:
- no effects observed
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 350 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
- gross pathology
- number of abortions
Maternal abnormalities
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- other:
- Description (incidence and severity):
- Three high dose animals had a moderately distended caecum or colon.
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- No dose related trends and no significant differences from control animals, and the historical control range.
- Reduction in number of live offspring:
- not specified
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- No significant difference in the distrubution of sex.
- Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- Mean litter weight reflected the lower mean number of foetuses per female with the difference from control being statistically significant in the low and high dose levels but were withint the control range for historical controls.
- Changes in postnatal survival:
- not specified
- External malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Externals and visceral malformations were observed in 7 controls, 3 low dose, 7 intermediate dose and 4 high dose foetuses.
One high dose foetus had marked lenticular lesions, as did one low dose and 4 control animals. Further eye malformations were observed in one low dose and two intermediate dose animals.
In view of the isolated nature of the malformations, their distribution within the groups and the presence of similar malformations in control foetuses, they were considered to be unrelated to treatment. - Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Skeletal malformations occured in 4 control, 6 low, 5 intermediate, and 2 high dose foetuses. High dose malformations were extra and branched ribs and fused thoracic vertebral centra. Similar effects were observed in three low dose and one intermediate and one control animal. There was no dose response relationship.
- Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Externals and visceral malformations were observed in 7 controls, 3 low dose, 7 intermediate dose and 4 high dose foetuses. Three high dose foetuses, two intermediate dose and two control animals exhibited cardiovascular malformations. In view of the isolated nature of the malformations, their distribution within the groups and the presence of similar malformations in control foetuses, they were considered to be unrelated to treatment.
- Other effects:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- The numbers of external, visceral and skeletal variations showed no dose-related trends and the differences from the controls were not statistically significant.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- > 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- not specified
- Basis for effect level:
- other:
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Fetal abnormalities
- Key result
- Abnormalities:
- effects observed, non-treatment-related
- Localisation:
- external: eye
- skeletal: rib
- skeletal: vertebra
- visceral/soft tissue: cardiovascular
- visceral/soft tissue: eye
- Description (incidence and severity):
- The numbers of external, visceral and skeletal variations showed no dose-related trends and the differences from the controls were not statistically significant.
Overall developmental toxicity
- Developmental effects observed:
- yes
- Lowest effective dose / conc.:
- 1 000 mg/kg bw/day
- Treatment related:
- yes
- Relation to maternal toxicity:
- developmental effects as a secondary non-specific consequence of maternal toxicity effects
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
Any other information on results incl. tables
Table 1. Group mean body weight (kg)
Days of Gestation |
Control |
175 mg/kg/day |
350 mg/kg/day |
1000 mg/kg/day |
4 |
3.58 |
3.54 |
3.53 |
3.50 |
7 |
3.64 |
3.57 |
3.58 |
3.55 |
8 |
3.67 |
3.57 |
3.60 |
3.54 |
9 |
3.68 |
3.57 |
3.58 |
3.54 |
12 |
3.66 |
3.54 |
3.54 |
3.55 |
15 |
3.62 |
3.49 |
3.54 |
3.53 |
19 |
3.63 |
3.57 |
3.59 |
3.51 |
24 |
3.74 |
3.74 |
3.76 |
3.58 |
29 |
3.91 |
3.85 |
3.86 |
3.71 |
% body weight change Days 4-29 |
9.2 |
8.8 |
9.3 |
6.0 |
% body weight change Days 7-19 |
-0.3 |
0 |
0.3 |
-1.1 |
% body weight change Days 19-29 |
7.7 |
7.8 |
7.5 |
5.7 |
Table 2. Group mean food intake
Days of Gestation |
Control |
175 mg/kg/day |
350 mg/kg/day |
1000 mg/kg/day |
4-7 |
181 |
172 |
173 |
166 |
7-8 |
165 |
92 |
117 |
117 |
8-9 |
151 |
124 |
111 |
113 |
9-12 |
124 |
109 |
113 |
118 |
12-15 |
69 |
70 |
77 |
81 |
15-19 |
81 |
93 |
98 |
74 |
19-24 |
153 |
159 |
166 |
114 |
24-29 |
140 |
161 |
157 |
146 |
Mean intake (g/day) Days 4-29 |
129 |
130 |
133 |
117 |
Mean intake (g/day) Days 7-19 |
102 |
94 |
99 |
94 |
Mean Intake (g/day) Days 19-29 |
147 |
160 |
162 |
130 |
Table 3. Group mean caesarian data
Uterine/Implantation Data |
Control |
175 mg/kg/day |
350 mg/kg/day |
1000 mg/kg/day |
Number of females with live fetuses at Day 29 gestation |
22 |
20 |
21 |
15 |
Mean # of corpora lutea per female |
13.3 |
12.0 |
12.8 |
11.7 |
Pre-implantation loss |
|
|
|
|
Mean % |
11.8 |
15.0 |
18.2 |
15.7 |
# dams affected |
15 |
13 |
10 |
9 |
Early intrauterine deaths |
|
|
|
|
Mean # |
0.5 |
0.2 |
0.5 |
0.0 |
# dams affected |
8 |
4 |
7 |
0 |
Late intrauterine deaths |
|
|
|
|
Mean # |
0.4 |
0.7 |
0.8 |
1.3 |
# dams affected |
7 |
8 |
8 |
6 |
Dead fetuses |
|
|
|
|
Mean # |
0.1 |
0.0 |
0.0 |
0.1 |
# dams affected |
2 |
0 |
0 |
1 |
Post-implantation loss |
|
|
|
|
Mean # |
8.1 |
7.5 |
11.2 |
12.3 |
# dams affected |
12 |
10 |
13 |
6 |
Mean # of fetuses per female |
10.7 |
9.5 |
9.3 |
8.6 |
Fetal Data-Females with Live Fetuses |
Control |
175 mg/kg/day |
350 mg/kg/day |
1000 mg/kg/day |
# of male fetuses |
117 |
94 |
107 |
67 |
# of female fetuses |
119 |
96 |
89 |
62 |
% male fetuses |
50.0 |
47.8 |
53.3 |
55.4 |
Mean litter weight (g) |
394.7 |
360.0 * |
345.6 |
308.8 ** |
Mean placental weight (g) |
4.83 |
4.96 |
5.01 |
5.08 |
Mean fetal weight (g) |
37.4 |
38.4 |
38.5 |
36.1 |
Mean fetal weight (g)-males |
37.1 |
39.1 |
39.0 |
37.5 |
Mean fetal weight (g)-females |
37.4 |
37.8 |
37.9 |
34.7 |
*p<0.05; **p<0.01
Table 4. Fetal Defect Data
Endpoint |
Control |
175 mg/kg/day |
350 mg/kg/day |
1000 mg/kg/day |
# of fetuses examined |
236 |
190 |
196 |
129 |
# of litters examined |
22 |
20 |
21 |
15 |
External and Visceral Defects |
|
|
|
|
# showing malformations |
7 |
3 |
7 |
4 |
-Mean % of fetuses affected |
2.8 |
1.7 |
3.7 |
3.0 |
-Number of litters affected |
5 |
3 |
6 |
4 |
# showing variations |
45 |
70 |
55 |
46 |
-Mean % of fetuses affected |
17.3 |
37.5 |
30.9 |
36.6 |
-Number of litters affected |
16 |
19 |
19 |
15 |
Skeletal Defects |
|
|
|
|
# showing malformations |
4 |
6 |
5 |
2 |
-Mean % of fetuses affected |
2.2 |
3.4 |
2.8 |
1.5 |
-Number of litters affected |
4 |
4 |
3 |
2 |
# showing variations |
210 |
169 |
188 |
116 |
-Mean % of fetuses affected |
89.3 |
89.1 |
96.8 |
90.8 |
-Number of litters affected |
22 |
20 |
21 |
15 |
Total # of fetuses showing malformations |
10 |
8 |
11 |
6 |
% of fetuses examined |
4.2 |
4.2 |
5.6 |
4.7 |
# of litters affected |
8 |
6 |
8 |
5 |
Applicant's summary and conclusion
- Conclusions:
- The developmental toxicity of the test item on rabbits was determined in a GLP study according to ICH harmonized tripartite guideline similar to OECD guidelines. Oral gavage treatment with sucralose at a limit dose of 1,000 mg/kg/day produced maternal toxicity, abortion, and increased numbers of interuterine deaths, but no teratogenicity. No maternal or embryo-foetal effects were seen at 350 or 175 mg/kg/day. Thus, this study indicates that sucralose is not teratogenic in rabbits.
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