Lanthanum trihydroxide

Endpoint summary

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

Reference

Reference 1

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

No treatment related effects on clinical signs, body weight gain, food consumption, mean number of days taken to mate, fertility, and mating performance were observed. Copulation and fertility inidices were comparable to controls. No effect on the pregnancy rates was observed (92, 96, 100, 92% at 0, 200, 600, 2000 mg/kg bw). No treatment related macroscopic findings were observed at necropsy.

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

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 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.

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).

Reference 2

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

Reference 3

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.

Reference 4

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

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

Reference

Reference 1

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.

Reference 2

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

Reference 3

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).

Reference 4

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

Reference 5

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

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.

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.

Reference 6

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

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.