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EC number: 215-200-5 | CAS number: 1312-81-8
- 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
- Study period:
- July 10, 1996 to August 8, 1996
- Reliability:
- other: Data are publicly available from FDA review of a pharamaceutical, but the applicant was allowed by the owner to use the published information on the FDA web-page
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
- Remarks:
- the documentation is regarded sufficient, but some details are missing
Data source
Reference
- Reference Type:
- other: FDA review
- Title:
- Unnamed
- Year:
- 2 004
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- yes (incl. QA statement)
Test material
- Reference substance name:
- Dilanthanum tricarbonate
- EC Number:
- 209-599-5
- EC Name:
- Dilanthanum tricarbonate
- Cas Number:
- 587-26-8
- Molecular formula:
- CH2O3.2/3La
- IUPAC Name:
- Dilanthanum tricarbonate
Constituent 1
Test animals
- Species:
- rabbit
- Strain:
- New Zealand White
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: 4 months
- Weight at study initiation: 3 to 4 kg
- Housing: individually grid-bottom metal cges
- Diet ad libitum
- Water ad libitum
- Acclimation period: 4 to 5 days
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Remarks:
- 0.5 % in water
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Animals were time-mated, day 2 of pregnancy at study initiation
- Details on mating procedure:
- not applicable
- Duration of treatment / exposure:
- Day 6 to day 18 of of pregnancy
- Frequency of treatment:
- daily
- Duration of test:
- Sacrifice on day 28 of pregnancy
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Remarks:
- Vehicle Control
- Dose / conc.:
- 250 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 750 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 500 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 20
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
Th edoses were selected based on a range finding study in pregnant rabbits dosed from day 6 to 18 of pregnancy with 0, 250, 500, 1000 and 1500 mg/kg bw/d. In this study the 1500 mg/kg bw dose produced maternal toxiciy (reduced bw gain, reduced food consumption, reduced feces production. Reduction of fetal body weight was observed at this dose level as well.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Mortality and clinical signs of toxicity: daily
BODY WEIGHT: Yes
- Time schedule for examinations: day 0, 3, 6, 18, 22, 25, 28 of pregnancy.
FOOD CONSUMPTION: Yes
daily from days 3 to 6 of pregnancy and every 2 days thereafter.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 28
- All major organs were examined. Organs and tissues with macroscopic changes were preserved in neutral buffered formaldehyde. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- dead an live fetuses
- placental weight
- pre and post implantation losses - Fetal examinations:
- -n Number of ead and live fetuses
- fetal weights
- sex determination
External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head and brain examinations: Yes: all per litter - Statistics:
- Analysis of variance on all parameters. Residuals examined for heterogeneity of variance with Levene's test. If the latter was significant on the 1% level,the respective variable was analysed with non=parametric analysis: Kruskal-Wallis ANOVA followed by Shirley's non parametric version of Williams test. If Lenvene's test was not significant on the 1% level, Williams test for comparison of treated and control groups.
- Historical control data:
- Historical control data were included in the evaluation.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- At 1500 mg/kg bw: reduced fecal output, reduction in bw, presence of mucus in tray liner. This female aborted 7 fetuses on day 25 of pregnancy.
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- In the high dose group reduction of body weight gain during days 6 to 10 of p[regnancy was observed. Overall Body weight gain in the high dose group was significantly lower than that of controls.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- In the high dose group food consumption was reduced throughout the dosing period and statistically significant between day 6 and 10 of pregnancy.
- 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
- 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
- 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:
- effects observed, treatment-related
- Description (incidence and severity):
- One high dose female aborted 7 fetuses on day 25 of pregnancy.
- Pre- and post-implantation loss:
- effects observed, treatment-related
- Description (incidence and severity):
- At 1500 mg/kg bw/day the mean pre-implantation loss and the mean postimplantation loss were higher then the cocurrent control values: 16.7% and 10% compared to 8.8 abd 4.7%. Historical controi values were 12.8% (2.5 to 26.7%) and 9.6 % (3.8 to 15.9%) respectively.
No effects were observed in the other dose groups. - 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
- Changes in number of pregnant:
- no effects observed
- Other effects:
- no effects observed
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
One high dose female that aborted 7 fetuses on day 25 had reduced fecal output, reduction in body weight and mucus on the tray liner. Necropsy findings showed red staining of the fur, distended stomach with dark fluid and empty colon.
A higher incidence of reduced fecal output and liquid/loose feces was observed in the high dose group.
Reduction in bw gain during days 6 to 10 of pregnancy, with an overall weight gain significantly lower than controls.
Food consumption was lower in the high dose group throughout the dosing period, with the difference being statisitically different from controls on day 6 to 10 of pregnancy.
No effects were observed in the other dose groups.
No macroscopic organ changes were observed in any of the dose groups.
Pregnancy rates were 90, 90, 95 and 95% for the control, 250, 750 and 1500 mg/kg bw/day dose groups respectively.
Effect levels (maternal animals)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 750 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- 458 mg/kg bw/day (actual dose received)
- Based on:
- element
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- 537 mg/kg bw/day (actual dose received)
- Based on:
- other: as lanthanum oxide
- Basis for effect level:
- other: maternal toxicity
Results (fetuses)
- Fetal body weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Mean litter weights and mean fetal weights were were lower in the high dose group than in the control group, but not statisitcally significant,
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Mean litter weights and mean fetal weights were were lower in the high dose group than in the control group, but not statisitcally significant,
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Description (incidence and severity):
- There were no significant treatm,ent related effects on the overall incidences of external, skeletal or visceral malformations.
- Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- There were no significant treatm,ent related effects on the overall incidences of external, skeletal or visceral malformations.
- Visceral malformations:
- no effects observed
- Description (incidence and severity):
- There were no significant treatm,ent related effects on the overall incidences of external, skeletal or visceral malformations.
- Other effects:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Increased in single incidences of minor skeletal malformations (incomplete or absence of ossification of the parietal bone, one or more metacarpal or astrahgalus or variations (incomplete ossification of one or more phalanges of the hind limbs) were observed in treated groups. Thery did with 4 exceptions not reach statistical significance, were mostly not dose related and were well within the historical control variation of the test institute.
- Details on embryotoxic / teratogenic effects:
- Details on embryotoxic / teratogenic effects:
At 1500 mg/k gb /day the mean preimplantation and post-implantation loss values were higher than the respective control values (16.7 and 10% versus 8.8 and 4.7%). Howevr the values were well within the historical control ranges of the institute performing the study (2.5 to 26.7% and 3.8 to 15.9%).
No differences from controls were observed in the other dose groups.
No treatement related effects were observed on sex ratio.
Althoug the mean litter weights and mean fetal weigths were lower in the high dose gropu than in the concurrent control, the difference did not reach statistical significance. Fetal weights in the other dose groups were comparable to those of controls.
Placental weights were lower than concurrent controls in all dose groups (statistically significant at the mid and high dose group), but there was no dose response relationship.
The fetal and litter incidences of external, visceral or skeletal malformations or variations were all comparable to the controls.
Increased single incidences of minor skeletal malformations (incomplete and absence of ossification of the parietal bone, one or more metacarpel (forelimb) or atragalus (hindlimb) or variations (incomplete ossification of one or more phalanges of the hind limbs) were observed in treated groups. All those incedences were however within the historical control incidences of the peforming institute.
As all incidences of findings were within the hsitorical control ranges, and did not occur in a dose related manner the findings were not considered treatement related.
Effect levels (fetuses)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 500 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no clearly treatment related effects, all in the range of historical control incidences. No effects in the absence of maternal toxicity
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 915 mg/kg bw/day (actual dose received)
- Based on:
- element
- Sex:
- male/female
- Basis for effect level:
- other: no clearly treatment related effects, all in the range of historical control incidences. No effects in the absence of maternal toxicity
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 1 073 mg/kg bw/day (actual dose received)
- Based on:
- other: calculated as La2O3
- Sex:
- male/female
- Basis for effect level:
- other: no clearly treatment related effects, all in the range of historical control incidences. No effects in the absence of maternal toxicity
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- Maternal toxicity with reduced body weight gain and food consumption was oberved at the highest dose group. All findigns related to a possible developmental toxicity were confined to the high dose group, very minor and likely secondary to the maternal toxicity if at all treatment related. They were all within the historical control range. Therefore no treatmen related adverse developmental toxicty was observed. The NOAEL for maternal toxicity is 750 mg/kg bw /day and for developmental toxicity it is 1500 mg/kg bw day, the highest dose tested in this study.
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