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Toxicological information

Toxicity to reproduction

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Administrative data

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.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
other: read-across target
Reference
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
Reason / purpose for cross-reference:
reference to same study
Remarks:
7.8.2
Reference
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).

Data source

Reference
Reference Type:
other: FDA review
Title:
Centre for drug evaluation and Research Appoval Package For Application Number 21-468
Author:
FDA
Year:
2004
Bibliographic source:
US FDA online data base

Materials and methods

Test guideline
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

Test material

Constituent 1
Reference substance name:
Dilanthanum tricarbonate
EC Number:
209-599-5
EC Name:
Dilanthanum tricarbonate
Cas Number:
587-26-8
IUPAC Name:
dilanthanum tricarbonate

Test animals

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

Administration / exposure

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.
Doses / concentrationsopen allclose all
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

Examinations

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

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

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 / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed

Details on results (P0)

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.

Effect levels (P0)

open allclose all
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

Target system / organ toxicity (P0)

Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

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

Details on results (F1)

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.

Effect levels (F1)

open allclose all
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

Target system / organ toxicity (F1)

Critical effects observed:
no

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

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).