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EC number: 953-265-8 | 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:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- 2004
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 2 004
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 1981
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 1-[4-[[2-O-(6-deoxy-α-L-mannopyranosyl)-β-D-glucopyranosyl]oxy]-2,6-dihydroxyphenyl]-3-(3-hydroxy-4-methoxyphenyl)propan-1-one
- EC Number:
- 243-978-6
- EC Name:
- 1-[4-[[2-O-(6-deoxy-α-L-mannopyranosyl)-β-D-glucopyranosyl]oxy]-2,6-dihydroxyphenyl]-3-(3-hydroxy-4-methoxyphenyl)propan-1-one
- Cas Number:
- 20702-77-6
- Molecular formula:
- C28H36O15
- IUPAC Name:
- 3,5-dihydroxy-4-[3-(3-hydroxy-4-methoxyphenyl)propanoyl]phenyl 2-O-(6-deoxy-alpha-L-mannopyranosyl)-beta-D-glucopyranoside
- Test material form:
- solid
Constituent 1
- Specific details on test material used for the study:
- Source: Zoster S.A. (Zeneta–Murcia, Spain)
- Purity: 96.9% (by HPLC) on a dry matter basis (water content 9.3%)
Test animals
- Species:
- rat
- Strain:
- Wistar
- Remarks:
- Crl:(WI)WU BR
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Wiga (Sulzfeld, Germany)
- Age at study initiation: about 11–13 weeks
- Weight at study initiation:
- Fasting period before study:
- Housing: For mating, two females were placed together with one male in suspended stainless steel cages fitted with wire-mesh fronts and floors. During gestation, the dams were housed individually in suspended stainless steel cages with wire-mesh fronts and floors.
- Diet: commercial rodent diet was fed ad libitum (RM3 Diet, SDS Special Diets Services, Witham, UK).
- Water: unfluoridated tap water were provided ad libitum.
- Acclimation period: 2-day quarantine and a 10-day acclimatization period.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
- Starting from day 0 of gestation, the rats received the experimental diets which were prepared by adding NHDC at levels of 0 (control), 1.25, 2.5, and 5% to the powdered RM3 diet.
DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food): Starting from day 0 of gestation, the rats received the experimental diets which were prepared by adding test item to the powdered RM3 diet (RM3 Diet, SDS Special Diets Services, Witham, UK).
- Storage temperature of food: The experimental diets were stored in a refrigerator until use.
- The different test diets were provided ad libitum from day 0 up to and including day 21 of gestation. The test diets were offered as a meal mash in stainless steel cans which were covered by a perforated stainless steel plate to prevent spillage. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- HPLC analyses in duplicate of the test diets demonstrated that the actual and nominal NHDC levels were similar (deviations of -6, -5, and -5% were found in the food of the low-, mid-, and high-dose group, respectively). From an earlier study it was known that NHDC can be homogenously distributed in the test diet and is stable (Lina et al., 1990; see 'attached background material').
- Details on mating procedure:
- Two females were placed together with one male in suspended stainless steel cages fitted with wire-mesh fronts and floors. Females showing evidence of mating (vaginal plug or vaginal smears with sperm cells) were randomly assigned in rotation to each experimental group, up to the day when 28 positive females had been allotted to each group. The day on which there was evidence of mating was recorded as day 0 of gestation.
- Duration of treatment / exposure:
- 21 days.
- Frequency of treatment:
- No data.
- Duration of test:
- 21 days.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 other: %
- Remarks:
- control group
- Dose / conc.:
- 1.25 other: %
- Dose / conc.:
- 2.5 other: %
- Dose / conc.:
- 5 other: %
- No. of animals per sex per dose:
- 28 mated females per dose.
- Control animals:
- yes
- Details on study design:
- - Dose selection rationale: The high-dose level applied in this study corresponds to that which was tested in a 13-week subchronic toxicity study in rats and an earlier three-generation reproduction and teratogenicity study in rats (Booth, 1974, unpublished; Gumbmann et al., 1978; Lina et al., 1990; see 'attached bacground material'): In the study by Lina (1990), neohesperidin dihydrochalcone was administered to groups of 20 male and 20 female Wistar rats at dietary levels of 0, 0.2, 1.0 and 5.0% for 91 days. Treatment-related changes were only observed at the high-dose level, and they were considered adaptive responses rather than manifestations of toxicity. It was concluded that the NOEL was ca. 750 mg/kg bw.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily
BODY WEIGHT: Yes
- Time schedule for examinations: days 0, 7, 14, and 21 of gestation.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Time schedule: Food consumption was determined during three consecutive periods (days 0–7, 7–14, and 14–21 of gestation.
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
WATER CONSUMPTION AND COMPOUND INTAKE (not a drinking water study): No data
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #21
- Macroscopic abnormalities of major organs of the abdominal and thoracic cavity were recorded.
- Organs examined: The ovaries, uterus, and cecum were removed and weighed. - 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 (control and high-dose group only)
- Head examinations: No
- Anogenital distance of all live rodent pups: Yes (only to identify sex) - Statistics:
- Data on maternal body weights, food consumption, fetal weights, and placenta weights were subjected to one-way analysis of variance (ANOVA) followed by Dunnetts multiple comparison test. Litter data were analyzed by analysis of variance (Kruskal–Wallis) followed by the Mann–Whitney U test. Parental necropsy findings, the number of mated and pregnant females and females with live fetuses, as well as the data on skeletal and visceral anomalies were evaluated by Fishers exact probability test.
- Indices:
- Fertility index (%) = (no. of pregnant females/no. of mated females) x 100.
Gestation index (%) = (no. of females with live fetuses/no. of females pregnant at C-section) x 100.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No signs of ill health, abnormal behavior or intolerance were noted in any treatment group.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- None of the females died during the study.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Mean maternal body weights and body weight changes during gestation were similar in all groups.
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- Maternal food consumption, when expressed in g/kg bw/day, was slightly yet significantly increased in the mid and high-dose group during the last week of pregnancy. However, this increase was statistically significant only for the relative food intake (expressed in g/kg bw/day) but not the absolute food intake (g/animal/day).
Mean daily test item intake, calculated on basis of the nominal dietary levels, ranged during the three measurement periods from 0.8 to 0.9, 1.6 to 1.7, and 3.1 to 3.4 g/kg bw/day for the low-, mid-, and high-dose group, respectively. - Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Endocrine findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- At necropsy the absolute and relative weight of the full cecum was significantly increased in all treatment groups in a dose-dependent manner. The weight of the empty cecum was significantly increased in the high-dose group. Cecal enlargement in rats and mice is a fully reversible, adaptive phenomenon which lacks relevance for human safety. Its occurrence demonstrated that the test item is not readily digested and absorbed.
No statistically significant differences were observed in gravid and empty uterus weights, ovary weight and placenta weight. No other gross changes were observed that could be attributed to the treatment. - Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Description (incidence and severity):
- None of the females aborted during the study. Two rats (one of the low- and one of the high-dose group) delivered just before Cesarean section.
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- The mean numbers of corpora lutea and implantation sites, the pre-implantation loss and the post-implantation loss did not differ between any of the treated groups and the controls.
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- The mean number of early and late resorptions id not differ between any of the treated groups and the controls.
- Dead fetuses:
- effects observed, non-treatment-related
- Description (incidence and severity):
- One fetus of the mid-dose group was dead.
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- no effects observed
- Other effects:
- no effects observed
- Details on maternal toxic effects:
- The fertility and reproductive performance did not show any treatment-related effects.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 5 other: % in diet
- Based on:
- test mat.
- Basis for effect level:
- other: no significant effects observed
- Remarks on result:
- other: equivalent to 3300 mg/kg bw
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- Mean fetal body weights of the viable fetuses were similar in all groups. Large fetuses were found in the control group (2 fetuses from 2 litters), in the low-dose group (9/2) and high-dose group (2/2). Small fetuses were found in the low-dose group (2/2).
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- The sex ratio was, within normal limits, close to 1 in all groups.
- Changes in litter size and weights:
- no effects observed
- Anogenital distance of all rodent fetuses:
- not examined
- Changes in postnatal survival:
- no effects observed
- External malformations:
- no effects observed
- Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Skeletal malformations and anomalies were not observed. The few skeletal variations included mainly irregularly shaped sternebrae. However, the incidence was low and not different between the high-dose group and the controls.
Variations in ossification (incomplete or absent ossification) occurred at a high incidence. However, the incidence of incomplete ossification was significantly increased in the high-dose group only for the front and hind proximal phalanges but not any other part of the skeleton. For the high-dose group a significantly increased number of fetuses had 1–4 incompletely ossified digits and 3–6 unossified digits of the proximal hind phalanges. However, these differences are compensated when taking the categories 5–8 incompletely ossified digits and 7–10 unossified digits into account. Moreover, the differences were only observed at fetal incidence but not litter incidence. Therefore, the observed differences are considered to be fortuitous findings. - Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- None of the observed visceral anomalies and variations was considered to be treatment related.
- Other effects:
- effects observed, non-treatment-related
- Description (incidence and severity):
- One fetus of the mid-dose group showed a subcutaneous hemorrhagic area.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 5 other: % in diet
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no significant effects observed
- Remarks on result:
- other: equivalent to 3300 mg/kg bw
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- The test item, at a dietary level of up to 5% (ca. 3.3 g/kg bw/day) did not exhibit any maternal toxicity, fetotoxicity, embryotoxicity, or teratogenicity in female Wistar Crl:(WI)WU BR rats. Therefore, the NOAEL in rats was set at 3300 mg/kg bw/d.
- Executive summary:
A study was conducted to assess the embryotoxic, fetotoxic, and teratogenic potential of the oral administration of the test item in rats by a method according to OECD 414 (GLP study). Starting from day 0 of gestation, 28 mated female Wistar Crl:(WI)WU BR rats per group received experimental diets containing the analogue substance at levels of 0 (control), 1.25, 2.5, and 5%. The top dose was selected on the basis of previous studies conducted. Maternal examinations performed included detailed clinical observations, body weights, food consumption and compound intake, gross necropsy, and organ weights. The fetuses were removed from the uterus, dried of amniotic fluid, weighed, sexed by observing the anogenital distance, and examined for gross abnormalities. The placentas of the live fetuses were weighed and examined for macroscopic abnormalities. Early and late resorptions and dead fetuses were counted. Half of the fetuses randomly selected from each litter were eviscerated, partly skinned, fixed in 70% ethanol, cleared in potassium hydroxide, and stained with Alizarin Red S for examination of the skeleton. The remaining fetuses were fixed in Bouins fluid for subsequent visceral examination. All examinations for fetal abnormalities were performed microscopically. Skeletal and visceral examinations were conducted on fetuses of the control and high-dose group only. Based on the test results, the test item, at a dietary level of up to 5% (corresponding to an intake of about 3.3 g/kg bw/day) did not exhibit any maternal toxicity, fetotoxicity, embryotoxicity, or teratogenicity in Wistar Crl:(WI)WU BR rats. Therefore, the NOAEL of the test item in rats was set at 3300 mg/kg bw/d.
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