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EC number: 238-510-2 | CAS number: 14507-19-8
- 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
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
In a study equivalent to OECD Guideline 415 (One-Generation Reproduction Toxicity Study) no treatment related effects on male and female fertility and mating performance and no clearly treatment related effect on fetal development was observed in this study up to the highest dose tested (2000 mg/kg bw). This data has been read-across from lanthanum carbonate.
Link to relevant study records
- Endpoint:
- one-generation reproductive toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: FDA peer reviewed summary of study data conducted according to an approved test guideline.
- Reason / purpose for cross-reference:
- other: read-across target
- Reason / purpose for cross-reference:
- reference to same study
- Remarks:
- 7.8.2
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
- GLP compliance:
- not specified
- Remarks:
- published data
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: males: 42-44 d, females 25-28 d
- Weight at study initiation: (P) Males: 188-199 g; Females: 60-79 g
- Acclimation period: 8 weeks - Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Remarks:
- 0.5 % in water
- Duration of treatment / exposure:
- Males: at least 63 days prior to mating and throughout the mating period.
Females: 14 days before mating until day 17 of pregnancy - Frequency of treatment:
- Once daily
- Details on study schedule:
- Males were killed after the end of the mating period, females on day 20 of pregnancy.
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 200 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 600 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 2 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 25
- Control animals:
- yes, concurrent vehicle
- Parental animals: Observations and examinations:
- CLINICAL OBSERVATIONS: daily
MORTALITY: twice daily
BODY WEIGHT: twice weekly for males and females during premating period, females daily during pregnancy
FOOD CONSUMPTION: weekly, pregnancy d 0-6, 6-12, 12-17, 17-20. - Sperm parameters (parental animals):
- Parameters examined:
testis weight, epididymis weight - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals after the end of the mating period
- Maternal animals: All surviving animals at day 20 of pregnancy.
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
- Fmales: pregnancy status, number of corpora lutea, implantation sites, resorptions, dead and live fetuses, fetal and placental weight, fetal sex, external fetal anomalies.
HISTOPATHOLOGY / ORGAN WEIGHTS
Males: testes and epididymis weights were taken. Testes were fixed in Bouins fluid followed by formaldehyde, epididymis fixed in neutral buffered formaldehyde.
Females: uterus and ovaries were fixed in neutral buffered formaldehyde. - Postmortem examinations (offspring):
- Half of the life fetuses were fixed in Bouins fluid for examination for visceral abnormalities. The other half was briefly fixed in alcohol, vicera examined and exviscerated, carcasses cleared in Alizarin red S for examination of skeletal variants and malformations.
- Statistics:
- Analysis of variance on all parameters, residuals for heterogenity of variance with Levene's test, if significant at the 1% level, non-parametric analysis was perfomed. William's test for comparison of high dose and control at two sided 5% level. If this was significant the other dose levels were compared at one sided 5% level. Kruskal-Wallis ANOVA test for non-parametric analysis or in case of significant differences in treatment group variances in Levene's test, followed by Shirley's non-parametric version of William's test . Nominal data were analysed by Fisher's exact test.
- Reproductive indices:
- Copulation index
Fertility indices - Offspring viability indices:
- Pre- and postnatal implantation losses
- Clinical signs:
- no effects observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- not examined
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 2 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Fertility was not impaired
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 220 mg/kg bw/day (actual dose received)
- Based on:
- element
- Sex:
- male/female
- Basis for effect level:
- other: Paental toxicity Recalculated as La3+
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 220 mg/kg bw/day (actual dose received)
- Based on:
- element
- Sex:
- male/female
- Basis for effect level:
- other: Fertility was not impaired. Recalculated as La3+
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 407 mg/kg bw/day (actual dose received)
- Based on:
- other: Lanthanum oxide
- Sex:
- male/female
- Basis for effect level:
- other: Parental toxicity. Recalculated as lanthanum oxide
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 407 mg/kg bw/day (actual dose received)
- Based on:
- other: lanthanum oxide
- Sex:
- male/female
- Basis for effect level:
- other: Fertility was not impaired. Recalculated as lanthanum oxide
- Critical effects observed:
- no
- Clinical signs:
- not specified
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Histopathological findings:
- not specified
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 2 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: parental toxicity
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 2 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No clear treatment related effects on fetal development
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- >= 1 220 mg/kg bw/day (actual dose received)
- Based on:
- element
- Sex:
- male/female
- Basis for effect level:
- other: No clear treatment related effects on fetal development Recalculated as La3+
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- >= 1 407 mg/kg bw/day (actual dose received)
- Based on:
- other: Lanthanum oxide
- Sex:
- male/female
- Basis for effect level:
- other: No clear treatment related effects on fetal development. Recalculated as Lanthanum oxide
- Critical effects observed:
- no
- Reproductive effects observed:
- not specified
- Conclusions:
- No treatment related effects on male and female fertility and mating performance and no clearly treatment related effect on fetal development was observed in this study up to the highest dose tested (2000 mg/kg bw of lanthanum carbonate).
- Endpoint:
- one-generation reproductive toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Study conducted on read-across material
- Justification for type of information:
- Read-across to structurally similar substance, lanthanum tricarbonate, is justified on the basis that toxicological effects will be driven by the metal cation species (La3+) which is analogous to the registered substance and the read-across substance.
- Reason / purpose for cross-reference:
- read-across source
- Dose descriptor:
- NOAEL
- Effect level:
- 2 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Fertility was not impaired
- Critical effects observed:
- no
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 2 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No clear treatment related effects on fetal development
- Critical effects observed:
- no
- Endpoint:
- screening for reproductive / developmental toxicity
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- the study does not need to be conducted because a pre-natal developmental toxicity study is available
- Justification for type of information:
- JUSTIFICATION FOR DATA WAIVING
In accordance with column 2 of REACH Annex VIII, a screening study for reproductive/ developmental toxicity (information requirement 8.7.1) does not need to be conducted because a pre-natal developmental toxicity study (Annex IX, 8.7.2) is available. Additionally, an oral study conducted to OECD Guideline 415 (One-Generation Reproduction Toxicity Study) already sufficiently addresses the reproductive toxicity data requirement and is considered the most relevant route of exposure. - Endpoint:
- extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- other:
- Justification for type of information:
- JUSTIFICATION FOR DATA WAIVING
In accordance with section 1 of REACH Annex XI, the Extended One-Generation Reproductive Toxicity Study with the extension of cohort 1B to include the F2 generation (required in section 8.7.3 of Annex IX does not need to be conducted since the study does not appear to be scientifically necessary. An oral study conducted to OECD Guideline 415 (One-Generation Reproduction Toxicity Study) already sufficiently addresses the reproductive toxicity data requirement and is considered the most relevant route of exposure. Additionally, in accordance with column 2 of REACH Annex IX, information requirement 8.7.3 is not necesarry since the substance has no uses leading to significant exposure of consumers or professionals. Indeed, the substance has no professional or consumer uses and no article service life uses. Furthermore, the substance is not classified as a mutagen, there are no indications that the internal dose for the substance and/or any of its metabolites will reach a steady state in the test animals only after an extended exposure, and there are no indications of one or more relevant modes of action related to endocrine disruption from available data. - Reproductive effects observed:
- not specified
Referenceopen allclose all
No test substance related changes were observed for the mean numbers of corpora lutea, implantations, live fetuses, pre- and postimplantation losses. Although the percent of male fetuses was singnificantly higher compared to the concurrent controls in the high dose group, the number was in the historical control range of the laboratory. There was no statistically significant increase in the incidence of any major abnormality. The overal number of major fetal abnormalities was inreased in the mid and high dose group, but there was no dose response and the incidence was within the historical control range of the laboratory. Some statisitcally significant increased incidences of variations were observed as follows: increased incidence of cervical rib (minor skeletal malformation) in the low and high dose group, but not in the mid dose group. As there was no dose response relationship this findign was considered incidental and not treatment related. An increase of incidences of increased pelvic caviation in the kidneys (a variation) was statistically significant in the high dose group compared to concurrent controls, but the incidence was within the historical control rate and not considered treatment related.
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
In accordance with column 2 of REACH Annex VIII, a screening study for reproductive/ developmental toxicity (information requirement 8.7.1) does not need to be conducted because a pre-natal developmental toxicity study (Annex IX, 8.7.2) is available. Additionally, an oral study conducted to OECD Guideline 415 (One-Generation Reproduction Toxicity Study) already sufficiently addresses the reproductive toxicity data requirement and is considered the most relevant route of exposure.
In accordance with section 1 of REACH Annex XI, the Extended One-Generation Reproductive Toxicity Study with the extension of cohort 1B to include the F2 generation (required in section 8.7.3 of Annex IX does not need to be conducted since the study does not appear to be scientifically necessary. An oral study conducted to OECD Guideline 415 (One-Generation Reproduction Toxicity Study) already sufficiently addresses the reproductive toxicity data requirement and is considered the most relevant route of exposure. Additionally, in accordance with column 2 of REACH Annex IX, information requirement 8.7.3 is not necesarry since the substance has no uses leading to significant exposure of consumers or professionals. Indeed, the substance has no professional or consumer uses and no article service life uses. Furthermore, the substance is not classified as a mutagen, there are no indications that the internal dose for the substance and/or any of its metabolites will reach a steady state in the test animals only after an extended exposure, and there are no indications of one or more relevant modes of action related to endocrine disruption from available data.
In the one generation reproductive toxicity study, conducted with the read across substance (dilanthanum tricarbonate), no treatment related effects on male and female fertility and mating performance and no clearly treatment related effect on fetal development was observed in this study up to the highest dose tested (2000 mg/kg bw of lanthanum carbonate). Read-across to structurally similar substance, lanthanum tricarbonate, is justified on the basis that toxicological effects will be driven by the metal cation species (La3+) which is analogous to the registered substance and the read-across substance.
Effects on developmental toxicity
Description of key information
Three relevant studies are used in a weight of evidence approach.
1) In a study equivalent to OECD Guideline 415 (One-Generation Reproduction Toxicity Study) no treatment related effects on male and female fertility and mating performance and no clearly treatment related effect on fetal development was observed in this study up to the highest dose tested (2000 mg/kg bw). This data has been read-across from lanthanum carbonate.
2) In an OECD Guideline 414 (Prenatal Developmental Toxicity Study) maternal toxicity with reduced body weight gain and food consumption was observed at the highest dose group. All findings related to a possible developmental toxicity were confined to the high dose group and were all within the historical control range. Therefore no treatment related adverse developmental toxicity 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. This data was read-across from lanthanum carbonate.
3) In a pre- and postnatal developmental toxicity after administration of 200, 600 or 2000 mg/k bw/day of lanthanum carbonate to pregnant rats from implantation to the end of lactation the only findings were reduced body weights and body weight gains in the F1 generation with concomitant delays in preputial separation and vaginal opening. No other treatment related effects were observed and mating behaviour and pregnancy parameters were not impaired in the F1 generation. The observed effects were however slight and no comparison to historical control values was provided.
Read-across to this structurally similar substance, lanthanum tricarbonate, is justified on the basis that toxicological effects will be driven by the metal cation species (La3+) which is analogous to the registered substance and the read-across substance.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: FDA peer reviewed summary of study data conducted according to an approved test guideline.
- Reason / purpose for cross-reference:
- other: read-across target
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- not specified
- Remarks:
- Data are publicly available from FDA review of a pharamaceutical
- 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 - 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:
- Sacrifica on day 28 of pregnancy
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- 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
- 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.
- 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. - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 750 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 500 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: developmental 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:
- 915 mg/kg bw/day (actual dose received)
- Based on:
- element
- Basis for effect level:
- other: developmental 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
- Dose descriptor:
- NOAEL
- Effect level:
- 1 073 mg/kg bw/day (actual dose received)
- Based on:
- other: lanthanum oxide
- Basis for effect level:
- other: developmental toxicity
- Key result
- Abnormalities:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- Details on embryotoxic / teratogenic effects:
At 1500 mg/kg bw/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 trends in 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 at the mid and low dose group, the findings were not considered treatement related. - 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: Developmental toxicity
- Key result
- Abnormalities:
- effects observed, non-treatment-related
- Key result
- Developmental effects observed:
- no
- Conclusions:
- Maternal toxicity with reduced body weight gain and food consumption was oberved at the highst dose group. All findigns related to a possible developmental toxicity were confined to the high dose group and 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.
- Endpoint:
- developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Study conducted on read-across material
- Justification for type of information:
- Read-across to structurally similar substance, lanthanum tricarbonate, is justified on the basis that toxicological effects will be driven by the metal cation species (La3+) which is analogous to the registered substance and the read-across substance.
- Reason / purpose for cross-reference:
- read-across source
- 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:
- 1 500 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
- Abnormalities:
- no effects observed
- Description (incidence and severity):
- maternal (developmental)
- 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: Developmental toxicity
- Abnormalities:
- effects observed, non-treatment-related
- Developmental effects observed:
- no
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: FDA peer reviewed summary of study data conducted according to a method equivalent to an approved test guideline.
- Reason / purpose for cross-reference:
- reference to same study
- Remarks:
- 7.8.1
- Reason / purpose for cross-reference:
- other: read-across target
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: OECD 415 one generation
- GLP compliance:
- not specified
- Remarks:
- Data are publicly available from FDA review of a pharamaceutical
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: males: 42-44 d, females 25-28 d
- Weight at study initiation: (P) Males: 188-199 g; Females: 60-79 g
- Acclimation period: 8 weeks - Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Remarks:
- 0.5 % in water
- Duration of treatment / exposure:
- Males: at least 63 days prior to mating and throughout the mating period.
Females: 14 days before mating until day 17 of pregnancy - Frequency of treatment:
- once daily
- Duration of test:
- Males were killed after the end of the mating period, females on day 20 of pregnancy.
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 200 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 600 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 2 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 25
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- CLNICAL OBSERVATIONS: daily
MORTALITY: twice daily
BODY WEIGHT: twice weekly for males and females during premating period, females daily during pregnancy
FOOD CONSUMPTION: weekly, pregnancy d 0-6, 6-12, 12-17, 17-20. - Maternal examinations:
- Pregnancy status
Number of corpora lutea, iplantation sites, resorptions, dead and live fetuses. Placental weights - Ovaries and uterine content:
- not applicable
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes - Fetal examinations:
- dead and live fetuses
fetal weights
fetal sex
Half of the life fetuses were fixed in Bouins fluid for examination for visceral abnormalities. The other half was briefly fixed in alcohol, vicera examined and exviscerated, carcasses cleared in Alizarin red S for examination of skeletal variants and malformations.
external abnormalities - Statistics:
- Analysis of variance on all parameters, residuals for heterogenity of variance with Levene's test, if significant at the 1% level, non-parametric analysis was perfomed. William's test for comparison of high dose and control at two sided 5% level. If this was significant the other dose levels were compared at one sided 5% level. Kruskal-Wallis ANOVA test for non-parametric analysis or in case of significant differences in treatment group variances in Levene's test, followed by Shirley's non-parametric version of William's test . Nominal data were analysed by Fisher's exact test.
- Indices:
- Copulation and fertility index, pre- and post-implantation loss
- Historical control data:
- Included in the analysis of the results
- Details on maternal toxic effects:
- Maternal toxic effects:no effects
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 2 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 2 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 220 mg/kg bw/day (actual dose received)
- Based on:
- element
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 220 mg/kg bw/day (actual dose received)
- Based on:
- element
- Basis for effect level:
- other: developmental toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 407 mg/kg bw/day (actual dose received)
- Based on:
- other: lanthanum oxide
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 407 mg/kg bw/day (actual dose received)
- Based on:
- other: lanthanum oxide
- Basis for effect level:
- other: developmental toxicity
- Abnormalities:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
Developmental toxicity results:
No test substance related changes were observed for the mean numbers of corpora lutea, implantations, live fetuses, pre- and postimplantation losses. Although the percent of male fetuses was singnificantly higher compared to the concurrent controls in the high dose group, the number was in the historical control range of the laboratory. There was no statistically significant increase in the incidence of any major abnormality. The overal number of major fetal abnormalities was inreased in the mid and high dose group, but there was no dose response and the incidence was within the historical control range of the laboratory. Some statisitcally significant increased incidences of variations were observed as follows: increased incidence of cervical rib (minor skeletal malformation) in the low and high dose group, but not in the mid dose group. As there was no dose response relationship this finding was considered incidental and not treatment related. An increase of incidences of increased pelvic caviation in the kidneys (a variation) was statistically significant in the high dose group compared to concurrent controls, but the incidence was within the historical control rate and not considered treatment related. - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 2 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No treatment-related effects observed
- Key result
- Abnormalities:
- effects observed, non-treatment-related
- Key result
- Developmental effects observed:
- no
- Conclusions:
- No treatment related effects on male and female fertility and mating performance and no clearly treatment related effect on fetal development was observed in this study up to the highest dose tested (2000 mg/kg bw of lanthanum carbonate).
- Endpoint:
- developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Study conducted on read-across material
- Justification for type of information:
- Read-across to structurally similar substance, lanthanum tricarbonate, is justified on the basis that toxicological effects will be driven by the metal cation species (La3+) which is analogous to the registered substance and the read-across substance.
- Reason / purpose for cross-reference:
- read-across source
- Dose descriptor:
- NOAEL
- Effect level:
- 2 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- 2 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Abnormalities:
- no effects observed
- Dose descriptor:
- NOAEL
- Effect level:
- 2 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No treatment-related effects observed
- Abnormalities:
- effects observed, non-treatment-related
- Developmental effects observed:
- no
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: FDA peer reviewed summary of study data conducted according to a method equivalent to an approved test guideline.
- Reason / purpose for cross-reference:
- other: read-across target
- Qualifier:
- according to guideline
- Guideline:
- other: Pre and postnatal developmental toxicity
- GLP compliance:
- not specified
- Remarks:
- Data are publicly available from FDA review of a pharamaceutical
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: 10 weeks
- Weight at study initiation: 265 to 364 g
- Time mated day 4 of pregnancy
- Housing: propylene cages, sawdust betting
- Diet ad libitum
- Water ad libitum - Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Remarks:
- 0.5% in water
- Analytical verification of doses or concentrations:
- yes
- Details on mating procedure:
- not applicable, time mated females used
- Duration of treatment / exposure:
- from day 6 of pregnancy to day 20 post partum
- Frequency of treatment:
- once daily
- Duration of test:
- All dams of the F0 generationm were killed on PND 21 after weaning their offspring.
Females of the F1 generation were killed on day 13 after mating, males of the F1 generation about 14 days after mating. - Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 200 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 600 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 2 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 25
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- F0 dams were allowed to raise their pups to PND 21.
After weaning 20 F1 pups/sex/per group were randomly selsected for post weaning examinations and rearing to sexual maturity. - Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- mortality: twice daily
beginning on day 21 of pregnancy all females were observed at 30 min intervals for signs of parturition.
BODY WEIGHT: Yes
- Time schedule for examinations: daily from day 5 of pregnancy to necropsy on PND 21
FOOD CONSUMPTION: during pregnancy and on PND 4 to 14
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on PND 21
- Organs examined: all major organs
- Organ weights: ovaries, pituitary, adrenals. - Ovaries and uterine content:
- not applicable
- Fetal examinations:
- not applicable
- 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. The nominal data were analysed using Fisher's exact test.
- Indices:
- Gestation, live birth, vialbility
- Details on maternal toxic effects:
- Details on maternal toxic effects:
Pale and reduced quatities of feces were observed in treated groups during late pregnancy and early lactation. No other clinical signs were observed.
No treatment related effect on mternal body weight, body weight gain or food consumption during pregnancy and lactation was observed with the exeption of a lower foood intake in the high dose group (signifcantly lower than cotnrols) during day 7 to 14 of lactation. - Dose descriptor:
- NOAEL
- Effect level:
- 2 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- 600 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: other:
- Abnormalities:
- not specified
- Remarks on result:
- not measured/tested
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Conclusions:
- After adminstraiton of 200, 600 or 2000 mg/k bw/day of lanthanum carbonate to pregnant rats from implantation to the end of lactiation the only findings were reduced body weights and body weight gains in the F1 generation with concomitant delays in preputial separation and vaginal opening. No other treatment related effects were observed and mating behaviour and pregnancy parameters were not impaired in the F1 generation. The obseved effects were however slight and no comparison to historical contol values was provided.
- Endpoint:
- developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Study conducted on read-across material
- Justification for type of information:
- Read-across to structurally similar substance, lanthanum tricarbonate, is justified on the basis that toxicological effects will be driven by the metal cation species (La3+) which is analogous to the registered substance and the read-across substance.
- Reason / purpose for cross-reference:
- read-across source
- Dose descriptor:
- NOAEL
- Effect level:
- 2 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- 600 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: Reductions in body weights and concomitant delays in preputial separation and vaginal opening. Effects were slight.
- Abnormalities:
- not specified
- Remarks on result:
- not measured/tested
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
Referenceopen allclose all
One high dose female littered only one dead pup. All other females produced live litters. The gestation index was 100, 100, 100 and 95.5% for the control, 200, 600 and 2000 mg/kg bw/day dose groups respectively. There was no difference between treated and control animals with regard to the mean duration of gestation and parturition.
Six females failed to rear their offspring: 2 from the control, 3 from the 600 mg/kg /day dose group and one in the 2000 mg/kg/day dose group. As there was no dose relationship and no effect was observed on pup survival in the remaining litters, this finding was not regarded as treatment related.
Necropsy findings in F0 females were unremarkable, no treatment related effects on absolute and relative body weights, or weights of ovaries, pituitary or adrenals were observed.
F1 generation
No effects on the mean number of pups born, mean live birth index, sex ratio of pups or vialbility indices were observed.
Pup body weights on PND0 were all comparable to controls.
From PND 7 (PND 7, 14, 21) pup body weights at 2000 mg/kg/day were significantly lower than that of controls in both sexes. In females a reduction in bw was observed at PND4 only in all treatment groups. Overall body weight gain was reduced in the high dose group in both sexes from PND0 to 21. significantly reduced body weight gain was also observed in the mid dose females.
The poercentage of pups with eyes open on PND16 was significantly reduced in the high dose group compered to controls. (7 of 21 litters of the high dose groups had 50% or more pups with delayed eye opening on PND16. The times of eye opening in the other dose groups were similar to controls. The time of eye opening may be related to the reduced body weights of the pups of the high dose group. No effects were observed in all does groups on the time of eye opening, presence of righting reflex, startle response or pupillary light reflex.
No clinical signs were observed in F1 animals except at the hgih dose group pale body and piloerection immediately after weaning.
The body weights of the high dose F1 males were lower than controls throughout the study with statisitcally significance from week 5 to 14 (except for week 12). Body weights in F1 females of the high dose group were also lower than controls reaching statisitical significance from week 5 to 8. No treatment related effects on body weights were observed in the lower dose groups. The body weights during pregnancy in the F1 generation were coparable to controls in all dose groups.
No treatment related effects were observed on E-maze learning, auditory function or ophthalmoscopy.
In the high dose males preputial separation was significantly delayed conmpared to controls. A dose related delay in vaginal opening was observed in females from all treated groups compared to controls. However the delays in the low and mid dose groups were in the range of one standard derivation of the controls.
No treatment related differenced to controls were observed in the mean number of days taken for mating, the copulation and fertility indices, pregnancy rates, nuber of corpora lutea, implantations and live embryos, pre- and post implantation losses. Necropsy of F1 offspring did not show any treatment related findings. No effect of F0 maternal treatment on F1 organ weights was reported. The mean absolute pituitary weight was lower in high dose males than in controls, but no significant effects on relative pituitary weights were observed.
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Additional information
One generation study
No treatment related effects on male and female fertility and mating performance and no clearly treatment related effect on fetal development was observed in this study up to the highest dose tested (2000 mg/kg bw of lanthanum carbonate).
Developmental (rabbit)
Maternal toxicity with reduced body weight gain and food consumption was oberved at the highst dose group. All findigns related to a possible developmental toxicity were confined to the high dose group and 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.
Pre-postnatal
After adminstraiton of 200, 600 or 2000 mg/k bw/day of lanthanum carbonate to pregnant rats from implantation to the end of lactiation the only findings were reduced body weights and body weight gains in the F1 generation with concomitant delays in preputial separation and vaginal opening. No other treatment related effects were observed and mating behaviour and pregnancy parameters were not impaired in the F1 generation. The obseved effects were however slight and no comparison to historical contol values was provided.
Read-across to this structurally similar substance, lanthanum tricarbonate, is justified on the basis that toxicological effects will be driven by the metal cation species (La3+) which is analogous to the registered substance and the read-across substance.
Justification for classification or non-classification
The available data (read-across from lanthanum carbonate) suggest an absence of reproductive and developmental toxicity and hence classification is not required.
Additional information
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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.