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EC number: 266-037-1 | CAS number: 65997-01-5
- 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:
- No data
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 999
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- (3S,5S,8R,9S,10S,13R,14S,17R)-17-[(2R,5R)-5,6-dimethylheptan-2-yl]-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-ol
- Molecular formula:
- C28H50O
- IUPAC Name:
- (3S,5S,8R,9S,10S,13R,14S,17R)-17-[(2R,5R)-5,6-dimethylheptan-2-yl]-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-ol
- Test material form:
- other: waxy solid
- Details on test material:
- The purity of the test sample is approximately 99%
The test substance consisted of stanol fatty acid esters derived from wood (tall oil) or vegetable oil precursors obtained from Raision Tehaat OY AB, Raisio, Finland.
The sample identified as Sito-70 stanol ester contained 57.08% total stanols /l00g fat (68% sitostanol, 30% campestanol, 2% unsaturated sterol), 41.96% fatty acids, and, 2% unsaturated sterols and unknowns. Approximately 93.4% of the esterified groups was C-18 fatty acids, with 3.6% C-16, 2.1% C-20, and 0.9% other fatty acid esters.
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Harlan, Netherlands BV.
- Age at study initiation: At least 12 weeks
- Weight at study initiation: 241-248 g
- Fasting period before study: None
- Housing:
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 11 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 47-88
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light):12/12
IN-LIFE DATES: No data
Administration / exposure
- Route of administration:
- oral: feed
- Details on exposure:
- DIET PREPARATION
During the acclimatization period rats were fed a defined powdered diet obtained from Special Diets Services, Witham, England. The plant stanol ester product was fed to the rats in the same diet that was supplemented with rapeseed oil to equalize the energy contribution from the fatty acids in the diets with varying amounts of the stanol esters. A total of 3.68% total fatty acids from rapeseed oil and the test substance was maintained in all control and test diets with the assumption that both the test substance-derived fatty acids and rapeseed oil provide 9 kcal/g.
- Storage temperature of food: 2-10°C - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The fortified test diets were analyzed for stability, content, and homogeneity of the test substance. The analytical procedure involved acid hydrolysis, extraction
into petroleum ether, alkaline hydrolysis of the dried ether extracts, derivatization, and quantification by GC/FID. Recovery of the stanol from fortified diets varied within a range of 96.7 to 97.9% for the three test diets. The test substance was found to be stable in the diet for at least 7 days at room temperature and for at
least 39 days refrigerated at 2-10oC. Analyses showed that the stanol ester was homogeneously distributed in the diets with a coefficient of variation of <4% for five samples of each diet. The actual versus intended content of total stanols in the three test diets varied from 91.8 to 97.5%. - Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1 male to 2 females
- Length of cohabitation: until evidence of mating
- Further matings after two unsuccessful attempts: no data
- 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:
- Day 0 to 21 of gestation
- Frequency of treatment:
- Daily
- Duration of test:
- 22 days
Doses / concentrationsopen allclose all
- Dose / conc.:
- 1 other: % total stanols
- Remarks:
- Equivalent to 1.75% plant stanol esters
- Dose / conc.:
- 2.5 other: % total stanols
- Remarks:
- Equivalent to 4.38% plant stanol esters
- Dose / conc.:
- 5 other: % total stanols
- Remarks:
- Equivalent to 8.76% plant stanol esters
- No. of animals per sex per dose:
- 28 females
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: No data
- Rationale for animal assignment (if not random): The mated females were distributed over the control and treatment groups such that the rats that became pregnant on the same day were equally distributed over all groups. Females impregnated by the same male were placed in different treatment groups.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: From the details in the publication, the exact nature of the observations is not clear.
BODY WEIGHT: Yes
- Time schedule for examinations: Day 0, 7, 14 and 21 of gestation.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes, food intake was measured for gestation days 0-7, 7-14 and 14-21.
- 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: No
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: Details of examination not provided. - 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 fetuses, sex of fetuses, weights of ovaries, empty uteri, fetuses and placentas. - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No data - Statistics:
- Statistical evaluations of the equality of means for body weights, body weight gain, organ weights, and food consumption data were performed by a one-way
analysis of variance (ANOVA) followed by Dunnett's multiple-comparison test. Clinical findings and fetopathological data were evaluated by Fisher's exact
probability test. Differences in the number of pregnant females and females with live fetuses were evaluated using Fisher's exact probability test. Numbers of corpora lutea, implantations, live and dead fetuses, and early and late resorptions were evaluated by Kruskal-Wallis nonparametric analysis followed by the Mann-
Whitney U test.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- Daily clinical observations during the gestation period did not reveal any adverse findings in the rats' appearance, general condition, or behaviour in any of the groups.
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Mean body weights and body weight gain of pregnant females during gestation were not significantly different from the control values throughout the study in the groups fed 1 and 2.5 % total stanols. In the group fed 5% stanols a significant reduction in mean body weight relative to controls was observed at gestation days 7 and 14 but not at day 21. Body weight gains were not significantly different from control values for any group throughout gestation except for a small but
statistically significant decrease at days 0-7 for the high-dose group. - Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Food consumption (expressed as g/animal/day) showed no significant differences from controls. A small but statistically significant increase in food consumption
(expressed as g/kg bw/day) was observed in the mid dose group during gestation days 7-14 and in the high dose group during gestations days 7-14 and 14-21. - 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 examined
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Gross examinations of the maternal organs and tissues did not reveal any significant or treatment-related differences among the stanol-ester-treated and control groups.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- no effects observed
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed - Changes in number of pregnant:
- no effects observed
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 6 200 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: No adverse effects observed in maternal animals.
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined - Reduction in number of live offspring:
- not examined
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- A total of 682 live fetuses from 104 litters were examined for skeletal malformations, abnormalities, and variations. In 3 fetuses of 2 litters of the low dose group, missing ribs were observed. No other skeletal malformations were observed in the control or high dose groups. No significant increases in skeletal
anomalies were observed in the stanol-ester-treated groups. Skeletal anomalies were observed in 1 fetus in the low dose group that had wavy ribs, 1 fetus that had separated sternebrae, and 1 fetus that had a few ribs with reduced size. No significant differences were found in skeletal variations in any of the treated groups and the variations noted were considered to be typical observations in rat studies.
Variations in ossification were significantly greater than controls in the high dose group that had a higher incidence of fetuses with incompletely ossified frontalis and extra caudal bodies. Significant differences were also seen in the mid dose group for increased incidence of incompletely ossified frontalis and a decreased incidence of ossification of proximal phalanges of the front legs. The low dose group had a reduced incidence of fetuses with an incompletely ossified interparietalis and incidence of five to eight proximal phalanges on the hind legs but an increased incidence of incompletely ossified 0-2 metatarsals. No statistically significant differences were noted in skeletal variations when the data were analyzed on a litter basis and the incidence of variations showed no apparent relationship with increasing dose. Because of the apparent lack of a treatment-related effect, the incidence in variations in ossification were not considered to be biologically
significant. - Visceral malformations:
- no effects observed
- Description (incidence and severity):
- No increases in visceral malformations were observed in the fetuses of groups fed with stanol esters. The incidence of visceral anomalies showed a
statistically significant decrease in the total number of fetuses with anomalies due to a decrease in the incidence of fetuses with dilated urinary bladders in the mid- and high dose groups in comparison to the controls. There was also a dose-related decrease in the incidence of fetuses with hydroureter that was significantly lower than the control at the high dose level. Although these results showed a dose-related decrease between the concentration of rapeseed oil in the diet
and dilated urinary bladder and hydroureter, there are no reports in the literature that describe a relationship between fetal developmental abnormalities and high
concentrations of rapeseed oil. Also, the incidence of dilated urinary bladder and hydroureter in the control and low dose groups was outside the upper limits of the historical control range of the testing facility. The number and type of visceral variations seen were considered to be typical for rats and no significant differences were noted among the control and treated groups.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 6 200 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects observed.
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Any other information on results incl. tables
Table 2 Reproductive Performance during Gestation Days 0 -21.
Dietary percentage of plant stanols (percentage stanol esters) | ||||
Parameter | 0 | 1 (1.75) | 2.5 (4.38) | 5 (8.76) |
Females mated | 28 | 28 | 28 | 28 |
Delivered prematurely (n) | 0 | 0 | 0 | 0 |
Pregnant at necropsy (n) | 25 | 28 | 26 | 25 |
With live fetuses (n) | 25 | 28 | 26 | 25 |
With no viable fetuses | 0 | 0 | 0 | 0 |
Corpora lutea (n/rat)* | 14.28 ± 0.35 | 14.14 ± 0.32 | 13.73 ± 0.34 | 13.36 ± 0.29 |
Implantation sites (n/rat)* | 13.36 ± 0.37 | 13.11 ± 0.42 | 12.65 ± 0.35 | 12.28 ± 0.50 |
Preimplantation loss (%/rat)* | 6.29 ± 1.62 | 7.57 ± 1.73 | 7.71 ± 1.58 | 8.40 ± 3.14 |
Live fetuses (n/rats)* | 13.04 ± 0.36 | 12.75 ± 0.46 | 12.35 ± 0.36 | 12.12 ± 0.51 |
Postimplantation loss (%/rat)* | 2.21 ± 0.97 | 2.83 ± 1.39 | 2.56 ± 0.80 | 1.30 ± 0.91 |
Dead fetuses (n/rat) | 0 | 0 | 0 | 0 |
Resorptions total (n/rat)* | 0.32 ± 0.14 | 0.36 ± 0.19 | 0.31 ± 0.09 | 0.16 ± 0.11 |
Resorptions early (n/rat)* | 0.32 ± 0.14 | 0.32 ± 0.19 | 0.31 ± 0.09 | 0.16 ± 0.11 |
Resorptions late (n/rat)* | 0.00 | 0.04 ± 0.04 | 0.00 | 0.00 |
Total number of fetuses (n) | 326 | 357 | 321 | 303 |
Male fetuses (%) | 57 | 47a | 49 | 56 |
Female fetuses (%) | 43 | 53a | 51 | 44 |
Gravid uterus (g)* | 76.95 ± 1.72 | 75.29 ± 2.05 | 73.40 ± 1.77 | 71.92 ± 2.31 |
Empty uterus (g)* | 5.12 ± 0.16 | 4.91 ± 0.15 | 4.85 ± 0.14 | 4.81 ± 0.14 |
Ovaries (g)* | 0.11 ± 0.006 | 0.11 ± 0.004 | 0.11 ± 0.004 | 0.11 ± 0.004 |
Placenta weight: all fetuses (g)* | 0.54 ± 0.01 | 0.53 ± 0.01 | 0.56 ± 0.01 | 0.55 ± 0.01 |
Body weight of viable fetuses (g)* | 4.29 ± 0.06 | 4.33 ± 0.08 | 4.37 ± 0.07 | 4.34 ± 0.09 |
Male fetuses (g)* | 4.38 ± 0.06 | 4.43 ± 0.09 | 4.49 ± 0.07 | 4.45 ± 0.10 |
Female fetuses (g)* | 4.18 ± 0.06 | 4.24 ± 0.08 | 4.26 ± 0.07 | 4.21 ± 0.08 |
* values are means ±SE
a P<0.05, Fisher's exact test
Table 3 Visceral Malformations, Anomalies and Variations
|
Dietary Percentage of Plant Stanols (% stanol esters) | |||
Parametera | 0 | 1 (1.75) | 2.5 (4.38) | 5 (8.76) |
Fetuses (litters) examined | 157 (25) | 170 (28) | 152 (26) | 146 (25) |
Malformations total | 4 (2) | 0 (0) | 0 (0) | 0 (0) |
Brain: hydrocephaly | 1 (1) | 0 (0) | 0 (0) | 0 (0) |
Kidneys: hydronephrosis | 3 (1) | 0 (0) | 0 (0) | 0 (0) |
Anomalies total | 30 (13) | 28 (12) | 7*** (5)* | 8*** (5)* |
Dilated oesophagus | 0 (0) | 0 (0) | 0 (0) | 1 (1) |
Dilated urinary bladder | 24 (10) | 24 (11) | 4*** (3)* | 6** (4) |
Ureters, hydroureter | 10 (5) | 5 (2) | 3 (2) | 2* (2) |
Variations total | 26 (14) | 32 (16) | 23 (11) | 15 (8) |
Stomach distended | 1 (1) | 0 (0) | 0 (0) | 0 (0) |
Stomach with haemorrhagic fluid | 9 (6) | 6 (4) | 7 (5) | 7 (5) |
Kidney: increased renal pelvic cavitation | 13 (8) | 20 (11) | 12 (7) | 5 (4) |
Ureters: bent | 6 (5) | 10 (6) | 12 (7) | 4 (4) |
a Values are incidences in fetuses (litters)
* P<0.05, **P<0.01, ***P<0.001
Table 4 Skeletal Malformations, Anomalies and Variations
Dietary Percentage of Plant Stanols (% stanol esters) | ||||
Parametera | 0 | 1 (1.75) | 2.5 (4.38) | 5 (8.76) |
Fetuses (litters) examined | 169 (25) | 187 (28) | 169 (26) | 157 (25) |
Skeletal malformations (total) | 0 (0) | 3 (2) | 0 (0) | 0 (0) |
- Ribs, missing | 0 (0) | 3 (2) | 0 (0) | 0 (0) |
Skeletal anomalies (total): | 1 (1) | 3 (2) | 0 (0) | 0 (0) |
- Ribs, 2 or more wavy | 0 (0) | 1 (1) | 0 (0) | 0 (0) |
- Ribs, 2 or more reduced size | 0 (0) | 1 (1) | 0 (0) | 0 (0) |
- Sternabrae, separated | 1 (1) | 1 (1) | 0 (0) | 0 (0) |
Skeletal variations (total): | 41 (18) | 58 (23) | 51 (21) | 43 (21) |
- Ribs, accessory lumbar ribs | 2 (1) | 9 (6) | 6 (5) | 7 (5) |
- Sternebrae, irregular shape of one | 12 (10) | 17 (12) | 16 (13) | 18 (12) |
- Sternebrae, irregular shape of 2 or more |
27 (13) |
37 (19) |
27 (14) |
19 (12) |
- Sternebrae, one supernumerary |
1 (1) |
0 (0) |
5 (1) |
1 (1) |
a Values are incidences in fetuses (litters)
Applicant's summary and conclusion
- Conclusions:
- In a prenatal developmental toxicity study conducted to OECD 414 and in compliance with GLP (reliability 1) administration of stanol fatty acid esters in the diet of Wistar rats throughout gestation days 0-21 did not cause any general adverse effects on maternal animals or developmental toxicity in maternal animals or fetuses. The NOAEL from this study was at least 6200 mg/kg bw/day (the highest dose tested).
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