Lanthanum

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

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.

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

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.

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

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.

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: Parental 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

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

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

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).

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

Short 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.
In accordance with section 1 of REACH Annex XI, the two-generation reproductive toxicity study (required in section 8.7.3 of Annex IX does not need to be conducted if 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.

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/kg 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.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

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

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. Study conducted on a read-across substance.

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

not specified

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

Remarks:

Doses / Concentrations:
0, 250, 750, 1500 mg/kg bw/day
Basis:
actual ingested

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 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.

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.

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

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%). 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 weights 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 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 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.

Abnormalities:

not specified

Developmental effects observed:

not specified

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.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

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.