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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated 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: FDA peer reviewed summary of study data conducted according to an approved test guideline. Study conducted on read-across substance lanthanum carbonate.

Data source

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

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 4 months
- Weight at study initiation: 3 to 4 kg
- Housing: individually grid-bottom metal cages
- Diet ad libitum
- Water ad libitum
- Acclimation period: 4 to 5 days

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.5 % in water
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Animals were time-mated, day 2 of pregnancy at study initiation
Details on mating procedure:
not applicable
Duration of treatment / exposure:
Day 6 to day 18 of of pregnancy
Frequency of treatment:
daily
Duration of test:
Sacrifice on day 28 of pregnancy
No. of animals per sex per dose:
20
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Mortality and clinical signs of toxicity: daily
BODY WEIGHT: Yes
- Time schedule for examinations: day 0, 3, 6, 18, 22, 25, 28 of pregnancy.

FOOD CONSUMPTION: Yes
daily from days 3 to 6 of pregnancy and every 2 days thereafter.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 28
- All major organs were examined. Organs and tissues with macroscopic changes were preserved in neutral buffered formaldehyde.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- dead an live fetuses
- placental weight
- pre and post implantation losses
Fetal examinations:
-n Number of dead 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 Levene's test was not significant on the 1% level, Williams test for comparison of treated and control groups.
Historical control data:
Historical control data were included in the evaluation.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

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 statistically different from controls on day 6 to 10 of pregnancy.
No effects were observed in the other dose groups.
No macroscopic organ changes were observed in any of the dose groups.
Pregnancy rates were 90, 90, 95 and 95% for the control, 250, 750 and 1500 mg/kg bw/day dose groups respectively.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
750 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
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

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
At 1500 mg/k gb /day the mean preimplantation and post-implantation loss values were higher than the respective control values (16.7 and 10% versus 8.8 and 4.7%). However 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 treatment related effects were observed on sex ratio.
Although the mean litter weights and mean fetal weigths were lower in the high dose group 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 metacarpal (forelimb) or atragalus (hindlimb) or variations (incomplete ossification of one or more phalanges of the hind limbs) were observed in treated groups. All those incidences were however within the historical control incidences of the performing institute.
As all incidences of findings were within the historical control ranges, and did not occur at the mid and low dose group, the findings were not considered treatment related.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Maternal toxicity with reduced body weight gain and food consumption was 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.