Lanthanum

Toxicity to reproduction

Administrative data

Endpoint:

one-generation reproductive toxicity

Remarks:

based on test type (migrated information)

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

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 a method equivalent to an approved test guideline. Study conducted on a read-across substance.

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:

equivalent or similar to guideline

Guideline:

OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

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 / concentrations

Remarks:

Doses / Concentrations:
0, 200, 600, 2000 mg/kg bw
Basis:
actual ingested

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)

1

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

2

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: Parental toxicity Recalculated as La3+

3

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+

4

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

5

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

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)

1

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

2

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

3

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+

4

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

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).