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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:
key study
Study period:
July 10, 1996 to August 8, 1996
Reliability:
other: Data are publicly available from FDA review of a pharamaceutical, but the applicant was allowed by the owner to use the published information on the FDA web-page
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
the documentation is regarded sufficient, but some details are missing

Data source

Reference
Reference Type:
other: FDA review
Title:
Unnamed
Year:
2004

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Chemical structure
Reference substance name:
Dilanthanum tricarbonate
EC Number:
209-599-5
EC Name:
Dilanthanum tricarbonate
Cas Number:
587-26-8
Molecular formula:
CH2O3.2/3La
IUPAC Name:
Dilanthanum tricarbonate

Test animals

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

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.5 % in water
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Animals were time-mated, day 2 of pregnancy at study initiation
Details on mating procedure:
not applicable
Duration of treatment / exposure:
Day 6 to day 18 of of pregnancy
Frequency of treatment:
daily
Duration of test:
Sacrifice on day 28 of pregnancy
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
Vehicle Control
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Dose / conc.:
750 mg/kg bw/day (actual dose received)
Dose / conc.:
1 500 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
20
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
Th edoses were selected based on a range finding study in pregnant rabbits dosed from day 6 to 18 of pregnancy with 0, 250, 500, 1000 and 1500 mg/kg bw/d. In this study the 1500 mg/kg bw dose produced maternal toxiciy (reduced bw gain, reduced food consumption, reduced feces production. Reduction of fetal body weight was observed at this dose level as well.

Examinations

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

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

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 28
- All major organs were examined. Organs and tissues with macroscopic changes were preserved in neutral buffered formaldehyde.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- dead an live fetuses
- placental weight
- pre and post implantation losses
Fetal examinations:
-n Number of ead and live fetuses
- fetal weights
- sex determination
External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head and brain examinations: Yes: all per litter
Statistics:
Analysis of variance on all parameters. Residuals examined for heterogeneity of variance with Levene's test. If the latter was significant on the 1% level,the respective variable was analysed with non=parametric analysis: Kruskal-Wallis ANOVA followed by Shirley's non parametric version of Williams test. If Lenvene's test was not significant on the 1% level, Williams test for comparison of treated and control groups.
Historical control data:
Historical control data were included in the evaluation.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
At 1500 mg/kg bw: reduced fecal output, reduction in bw, presence of mucus in tray liner. This female aborted 7 fetuses on day 25 of pregnancy.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
In the high dose group reduction of body weight gain during days 6 to 10 of p[regnancy was observed. Overall Body weight gain in the high dose group was significantly lower than that of controls.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
In the high dose group food consumption was reduced throughout the dosing period and statistically significant between day 6 and 10 of pregnancy.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed

Maternal developmental toxicity

Number of abortions:
effects observed, treatment-related
Description (incidence and severity):
One high dose female aborted 7 fetuses on day 25 of pregnancy.
Pre- and post-implantation loss:
effects observed, treatment-related
Description (incidence and severity):
At 1500 mg/kg bw/day the mean pre-implantation loss and the mean postimplantation loss were higher then the cocurrent control values: 16.7% and 10% compared to 8.8 abd 4.7%. Historical controi values were 12.8% (2.5 to 26.7%) and 9.6 % (3.8 to 15.9%) respectively.
No effects were observed in the other dose groups.
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
no effects observed
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
One high dose female that aborted 7 fetuses on day 25 had reduced fecal output, reduction in body weight and mucus on the tray liner. Necropsy findings showed red staining of the fur, distended stomach with dark fluid and empty colon.
A higher incidence of reduced fecal output and liquid/loose feces was observed in the high dose group.
Reduction in bw gain during days 6 to 10 of pregnancy, with an overall weight gain significantly lower than controls.
Food consumption was lower in the high dose group throughout the dosing period, with the difference being statisitically different from controls on day 6 to 10 of pregnancy.
No effects were observed in the other dose groups.
No macroscopic organ changes were observed in any of the dose groups.
Pregnancy rates were 90, 90, 95 and 95% for the control, 250, 750 and 1500 mg/kg bw/day dose groups respectively.

Effect levels (maternal animals)

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

Results (fetuses)

Fetal body weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Mean litter weights and mean fetal weights were were lower in the high dose group than in the control group, but not statisitcally significant,
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
effects observed, non-treatment-related
Description (incidence and severity):
Mean litter weights and mean fetal weights were were lower in the high dose group than in the control group, but not statisitcally significant,
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
There were no significant treatm,ent related effects on the overall incidences of external, skeletal or visceral malformations.
Skeletal malformations:
no effects observed
Description (incidence and severity):
There were no significant treatm,ent related effects on the overall incidences of external, skeletal or visceral malformations.
Visceral malformations:
no effects observed
Description (incidence and severity):
There were no significant treatm,ent related effects on the overall incidences of external, skeletal or visceral malformations.
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
Increased in single incidences of minor skeletal malformations (incomplete or absence of ossification of the parietal bone, one or more metacarpal or astrahgalus or variations (incomplete ossification of one or more phalanges of the hind limbs) were observed in treated groups. Thery did with 4 exceptions not reach statistical significance, were mostly not dose related and were well within the historical control variation of the test institute.
Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
At 1500 mg/k gb /day the mean preimplantation and post-implantation loss values were higher than the respective control values (16.7 and 10% versus 8.8 and 4.7%). Howevr the values were well within the historical control ranges of the institute performing the study (2.5 to 26.7% and 3.8 to 15.9%).
No differences from controls were observed in the other dose groups.
No treatement related effects were observed on sex ratio.
Althoug the mean litter weights and mean fetal weigths were lower in the high dose gropu than in the concurrent control, the difference did not reach statistical significance. Fetal weights in the other dose groups were comparable to those of controls.
Placental weights were lower than concurrent controls in all dose groups (statistically significant at the mid and high dose group), but there was no dose response relationship.
The fetal and litter incidences of external, visceral or skeletal malformations or variations were all comparable to the controls.
Increased single incidences of minor skeletal malformations (incomplete and absence of ossification of the parietal bone, one or more metacarpel (forelimb) or atragalus (hindlimb) or variations (incomplete ossification of one or more phalanges of the hind limbs) were observed in treated groups. All those incedences were however within the historical control incidences of the peforming institute.
As all incidences of findings were within the hsitorical control ranges, and did not occur in a dose related manner the findings were not considered treatement related.

Effect levels (fetuses)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
1 500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no clearly treatment related effects, all in the range of historical control incidences. No effects in the absence of maternal toxicity
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 915 mg/kg bw/day (actual dose received)
Based on:
element
Sex:
male/female
Basis for effect level:
other: no clearly treatment related effects, all in the range of historical control incidences. No effects in the absence of maternal toxicity
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 1 073 mg/kg bw/day (actual dose received)
Based on:
other: calculated as La2O3
Sex:
male/female
Basis for effect level:
other: no clearly treatment related effects, all in the range of historical control incidences. No effects in the absence of maternal toxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Maternal toxicity with reduced body weight gain and food consumption was oberved at the highest dose group. All findigns related to a possible developmental toxicity were confined to the high dose group, very minor and likely secondary to the maternal toxicity if at all treatment related. They were all within the historical control range. Therefore no treatmen related adverse developmental toxicty was observed. The NOAEL for maternal toxicity is 750 mg/kg bw /day and for developmental toxicity it is 1500 mg/kg bw day, the highest dose tested in this study.