Dilanthanum tricarbonate

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Description of key information

No extended-one generation reproductive toxicity (EOGRT) study is available. However, lanthanum carbonate was tested for its reproductive properties in several studies, including a reliable one generation study (similar to OECD 415) and a combined reproductive and neurodevelopmental study. In light of the fact that a new conducted EOGRT study might probably not add new insights in the reproductive properties of Lanthanum carbonate and in regard to animal welfare, hazard assessment on reproductive toxicity is determined on the existing data on Lanthan carbonate supported by data on structural analogues.

NOAEL (one-generation toxicity study): 2000 mg/kg bw/day

NOAEL (reproductive/developmental study): 2000 mg/kg bw/day 

Link to relevant study records

Reference

Reference 1

Endpoint:

one-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

October 1996

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

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

Deviations:

yes

Remarks:

day of sacrifice was day 20 of pregnany, females were not allowed to deliver pups, examined parameters other than usual

Principles of method if other than guideline:

- Short description of test conditions:
In this study, males were dosed for at least 63 days before mating with treatment continued throughout the mating period until the day before necropsy. Females were dosed for 14 days before mating with treatment continued through the mating period till day 17 of pregnancy. Males were killed after the end of the mating period. Other to OECD Guideline 415, females were killed at day 20 of pregnancy and thus did not deliver and wean pups.
- Parameters analysed: Females and pups were subjected to complete necropsies after sacrifice at day 20 of pregnancy. For more details, please refer to section "examinations"

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Remarks:

(SD) IOPS-Caw strain

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: (P) males: 5-6 wks; females: 3-4 wks
- Weight at study initiation: (P) Males: 188-199 g; Females: 60-79
- Acclimation period: 1 week (males), 8 weeks (females)

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Lanthanum carbonate was daily suspended in 0.5% aqueous carboxymethyl cellulose.
Dose volume: 10 mL/kg bw

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

P0 males: 63 days before mating, during mating, until day before necropsy
P0 females: 14 days before mating, during mating, until day 17 of pregnancy

Frequency of treatment:

daily

Details on study schedule:

P0 males sacrificed after mating period
P0 females sacrificed at day 20 of pregnany

Dose / conc.:

200 mg/kg bw/day

Dose / conc.:

600 mg/kg bw/day

Dose / conc.:

2 000 mg/kg bw/day

No. of animals per sex per dose:

25

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The doses were selected based on existing toxicity data including a preliminary study in rats conducted at dose levels of 200, 600, 1000 or 2000 mg/kg bw/day. In that study, males (6/group) were dosed from 14 days prior to mating, through the mating period until the day before necropsy after the end of the mating period. Females were dosed from 14 days prior to mating, through mating and pregnancy, until the day before necropsy on day 7 post-partum. No significant treatment related effects were seen in the parental or F1 generations except that the F1 pup body weights were slightly reduced in the group treated at 2000 mg/kg bw/day. Based on these findings, 2000 mg/kg bw/day was selected as the high dose for the reproductive toxicity studies. A low dose level of 200 mg/kg bw/day was selected as the no-effect level, with an intermediate dose level of 600 mg/kg bw/day.

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily/ twice daily (mortality)
- Cage side observations checked: not further specified

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: twice weekly for males and females during the pre-mating period, daily during pregnancy

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes (not specified)
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
- Time schedule: weekly (during pregnancy over days 0 to 6, 6 to 12, 12 to 17 and 17 to 20)

WATER CONSUMPTION AND COMPOUND INTAKE: No

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no (pups were not delivered)

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: number and sex of fetuses, number of live fetuses, number of litters, fetal and litter weight and presence of gross anomalies.

GROSS EXAMINATION OF DEAD PUPS: yes, for external,visceral and skeletal abnormalities

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: after mating period.
- Maternal animals: day 20 of pregnancy.

GROSS NECROPSY
- Gross necropsy: Organs and tissues showing macroscopic abnormalities were fixed for further analysis (males, females), pregnancy status was determined, numbers of corpora lutea, implantation sites, resorptions, and dead and live fetuses were recorded. The implantations were numbered separately for the right and left horns. The live fetuses and their placenta were removed, and the uterus and ovaries were fixed for further analysis.
(Effects that relate to developmental toxicity are reported and considered in the study entry under 7.8.2)

HISTOPATHOLOGY / ORGAN WEIGHTS
The following tissues were prepared for microscopic examination: testis, epididymides, placenta, uterus, ovaries. Organ weights: testis, placenta.
(Effects that relate to developmental toxicity are reported and considered in the study entry under 7.8.2)

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring was sacrificed at day 20 of pregnancy

GROSS NECROPSY
- Gross necropsy consisted of visceral external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGTHS
External, visceral examinations (abnormalities: half of litters) and skeletal examinations (ossification of skeleton, skeletal abnormalities and variants: half of litters) were performed.

Remarks: Structural congenital abnormalities that impair or potentially impair the survival of the fetus were classified as major abnormalities. Other defects were classified as minor abnormalities. Commonly observed variations in the degree of ossification from that expected of a day 20 gestation fetus together with common variations in the extent of renal pelvic cavitation and ureter dilatation were recorded as variants.

Statistics:

Analysis of variance (ANOVA) was performed on all parameters. Residuals from this preliminary analysis were examined for heterogeneity of variance using Levene's test. If the Levene 's test was significant at the 1% level, than the particular variable concerned was subjected to a non-parametric analysis. Otherwise, William's test was performed to compare the high dose with control at the two-sided 5% level. If this test was statistically significant, then comparisons of the subsequent doses against control were performed at the one-sided 5% level until a non-significant difference was found. If Levene's test indicated that there were significant differences in the treatment group variances, or if a parametric analysis was deemed to be inappropriate, then a Kruskal-Wallis ANOVA was performed to assess overall differences between the treatment groups, followed by Shirley's non-parametric version of Williams' test, which is based on mean ranks rather than the arithmetic means. Nominal data were analyzed using the Fisher's Exact Test.

Reproductive indices:

Copulation and fertility indices and pre- and post-implantation losses were calculated.

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, non-treatment-related

Description (incidence):

600 mg/kg bw/day: 1/25 males died unscheduled on day 25
2000 mg/kg bw/day: 1/25 males died unscheduled on day 63 (since that animal was cannibalized and the remaining tissues were partly autolysed, thus the cause of death could not be determined)

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

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:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Description (incidence and severity):

Effects that relate to developmental toxicity are reported and considered in the study entry under 7.8.2.

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

No treatment-related effect on number of pregnant females per group was observed. Pregnancy rates were 92, 96, 100 and 92% in control, 200, 600 and 2000 mg/kg bw/day dose groups, respectively. Mean number of implantations per female, mean number of corpora lutea, number of early/late embryo/fetal deaths, number of dead fetuses and number of viable fetuses did not differ from controls.

Key result

Dose descriptor:

NOAEL

Remarks:

general toxicity

Effect level:

2 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Key result

Dose descriptor:

NOAEL

Remarks:

reproductive toxicity

Effect level:

2 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effect on reproduction parameters observed

Critical effects observed:

no

Clinical signs:

not examined

Dermal irritation (if dermal study):

not examined

Mortality:

not examined

Body weight and weight changes:

not examined

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

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:

not examined

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

not examined

Clinical signs:

not examined

Dermal irritation (if dermal study):

not examined

Mortality / viability:

not examined

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Sexual maturation:

not examined

Anogenital distance (AGD):

not examined

Nipple retention in male pups:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

no effects observed

Description (incidence and severity):

External, visceral and skeletal findings are reported and considered in the study entry under 7.8.2

Skeletal malformations:
200 and 2000 mg/kg bw/day: Statistically significant increased incidences of cervial rib (minor skeletal malformation), although incidences at low and high dose were out of the historical control data range, observations are not considered relevant, since a dose relationship was absent.
Incidences 0/175 (control group), 5/182 (low dose), 0/192 (mid dose), 6/172 (high dose)

Visceral malformations:
2000 mg/kg bw/day: Statistically significant increase in incidences of increased pelvic caviation of kidneys (variation). The incidences of increased pelvic cavitation observed in treated groups (5.9-11.5%) were within the historical control range of 0.0 to 41.5% and thus not considered biologically relevant.
Fetal incidences: 14/341 (control group), 22/352 (low dose), 30/371(mid dose), 40/336 (high dose)
Litter incidences: 18/32 (control group), 9/24 (low dose), 15/25 (mid dose), 15/23 (high dose)

Other effects:

not specified

Description (incidence and severity):

Effects that relate to developmental toxicity are reported and considerd in the study entry under 7.8.2

Changes in sex ratio:
2000 mg/kg bw/day: Statistically Significant increase in the number of males (53.3%). Due to the low difference to the control group, the biological relevance of this increase is questionable.

Behaviour (functional findings):

not examined

Developmental immunotoxicity:

not examined

Dose descriptor:

NOAEL

Effect level:

2 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Reproductive effects observed:

no

Table 1: Mean values intrauterine development

Dose (mg/kg bw/day)	control	200	600	2000
Maternal effects
Number of dams with implantations	23	24	25	23
Mean number of implantation per female	15.8	15.8	15.7	15.3
Mean number of corpora lutea per female	16.8	17.5	16.8	16.3
Mean number of implantations %	93.9	91.3	94.6	95.9
Mean pre-implantation loss %	5.7	8.9	6.3	6.9
Number of early embryo/fetal deaths (resorption)	21	28	21	14
Number of late embryo/fetal deaths (resorption)	1	0	1	2
Number of dead fetuses	0	0	0	0
Mean post-implantation loss %	6.1	8.7	5.4	4.1
Mean placental weight [g] per female	0.61	0.69	0.62	0.67
Fetal effects
Number of dams with viable fetuses	23	24	25	23
Number of viable fetuses per group	341	352	371	336
Mean number of viable fetuses per female	14.8	14.7	14.8	14.6
Number male fetuses	154	174	181	187
Number female fetuses	187	178	190	149
Mean number of male fetuses %	45.1	49.5	48.3	53.3*
Mean litter weight [g]	60.4	59.5	61.6	60.8
Mean fetal weight [g]	4.07	4.05	4.15	4.15

* p<0.05

 

Table 2: Malformations

Dose (mg/kg bw/day)	control	200	600	2000
Total number of litters examined	23	24	25	23
Total number of fetuses examined	341	352	371	336
External and visceral examination
Number with major abnormalities	1	1	7	3
Number with minor abnormalities	3	1	4	3
Number with variations	46	68	85	72
Skeletal examination
Number with major abnormalities	0	0	3	1
Number with minor abnormalities	9	19	17	21
Number with variations	169	178	187	167

Reference 2

Endpoint:

reproductive toxicity, other

Remarks:

Combined Developmental neurotoxicity/reproductive toxicity study

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

January - June 1997

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

Principles of method if other than guideline:

Timed-mated female rats were administered the test substance at 200, 600 or 2000 mg/kg bw/day from implantation to end of lactation. All dams were allowed to rear their pups up to post-natal day 21, afterwards they were sacrificed for post-mortem examinations.
After weaning, 20 F1 pups/sex/group were randomly selected for detailed post-weaning examinations and rearing to sexual maturity. The remaining pups were subjected to necropsy.
The selected pups were examined daily for clinical signs, and weighed weekly. Ophthalmoscopic examination (PND 28-35) and assessments of auditory function (PND 28-35) and E-maze learning potential (PND 28) were performed. All males were examined daily for balanopreputial separation from PND 35, and females were examined daily for vaginal opening from PND 28.
When the selected F1 animals reached 13 weeks of age, each female was mated with a male from the same group for up to 7 days. Vaginal smears were taken daily until sperm was found in the smear. The male was removed from the cage on the day of mating. If a female had not mated within seven days, the male wasremoved and another male that had previously mated was substituted. The F1 pregnant females were weighed on days 0, 7, and 13 of pregnancy, and were necropsied on day 13. All major organs were examined grossly; ovaries, pituitary and adrenals were weighed. Organs or tissues showing gross abnormalities were fixed. Pregnancy status and the numbers of corpora lutea, implantation sites, early and late resorptions, and live embryos were recorded. The F1 females that showed no evidence of mating after the second mating were necropsied 13 days after the end of the mating period. The F1 males were killed about 2 weeks after the end of the mating period, major organs were examined, and the testes, epididymides and adrenals were weighed. The testes, epididymides and any other organs or tissues showing gross lesions were preserved. Furthermore, gestation, live birth and viability indices were calculated.

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Remarks:

(SD) IOPS-Caw

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: about 10 weeks (females)
- Weight at study initiation: 265 - 364 g (females)
- Housing: animals were housed in solid-bottomed polypropylene cages, with sawdust as bedding.
- Diet: pelleted rat and mouse diet
- Water: tap water, ad libitum

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Lanthanum carbonate was daily suspended in 0.5% aqueous carboxymethyl cellulose.
Dose volume: 10 mL/kg bw

Details on mating procedure:

P0: Timed-mated female rats

F1 Matings
- M/F ratio per cage: 1/1
- Length of cohabitation:7 days
- Proof of pregnancy: sperm in vaginal smear
- After 7 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analyses of the samples of formulations (prepared on the first day of dosing and in weeks 3 and 5) revealed that the concentrations were within 87 to 97% of the nominal values.

Duration of treatment / exposure:

P0 day 6 of pregnancy to day 20 post-partum

Frequency of treatment:

daily

Details on study schedule:

- Selection of parents from F1 generation after weaning
- Age at mating of the mated animals in the study: 13 weeks

Dose / conc.:

200 mg/kg bw/day

Dose / conc.:

600 mg/kg bw/day

Dose / conc.:

2 000 mg/kg bw/day

No. of animals per sex per dose:

25 P0
20 F1 matings

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The doses were selected based on existing toxicity data including a preliminary study in rats conducted at dose levels of 200, 600, 1000 or 2000 mg/kg bw/day. In that study, males (6/group) were dosed from 14 days prior to mating, through the mating period until the day before necropsy after the end of the mating period. Females were dosed from 14 days prior to mating, through mating and pregnancy, until the day before necropsy on day 7 post-partum. No significant treatment related effects were seen in the parental or F1 generations except that the F1 pup body weights were slightly reduced in the group treated at 2000 mg/kg bw/day. Based on these findings, 2000 mg/kg bw/day was selected as the high dose for the reproductive toxicity studies. A low dose level of 200 mg/kg bw/day and an intermediate dose level of 600 mg/kg bw/day was selected.

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily/twice daily (mortality)
- Cage side observations checked: Not further specified

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: daily (from day 5 of pregnancy until necropsy on postnatal day (PND) 21. (Body weights recorded on days 5, 6, 7, 8, 9, 12, 15 and 20 of pregnancy and on post-natal days 0, 4, 7, 14 and 21 were the only body weights reported.)

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
- Time schedule for examinations: Food consumption was recorded during pregnancy and on PND 1 to 14. (Food consumptions over days 5 to 6, 6 to 9, 9 to 12, 12 to 15, and 15 to 20 of pregnancy and during pnd 1 to 7 and 7 to 14 were reported.)

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on PND day 21 (after weaning of offspring)
- Organs examined: All major organs were examined, and ovaries, pituitary and adrenals were weighed. Ovaries, uterus, cervix, vagina, pituitary, adrenals and any gross lesions were fixed in buffered formalin.

OTHER:
Parturition: Beginning on day 21 of pregnancy, all P0 females were observed at about 30-minute intervals between the hours of 0700 and 2400 for evidence of parturition; the times of onset and completion of parturition were recorded.

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 8 pups/litter (4/sex/litter as nearly as possible); excess pups were killed and discarded.

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring (selected pups)
- Examinations: Litter size, sex of the pups, gross malformations, clinical signs (daily), and body weight (after birth and on PND 4, 7, 14 and 21).
- Examinations during lactation: ear opening (daily from day 0 to day 4 ), eye opening (daily up to day 16), static righting reflex (on day 5), startle response (on day 15) and pupillary light reflex (on day 21 ), All males were examined daily for balanopreputial separation from PND 35, and females were examined daily for vaginal opening from PND 28.

GROSS EXAMINATION OF DEAD PUPS:
yes, not further specified

ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY:
- Examinations during lactation: ear opening (daily from day 0 to day 4 ), eye opening (daily up to day 16), static righting reflex (on day 5), startle response (on day 15) and pupillary light reflex (on day 21 )

Postmortem examinations (parental animals):

SACRIFICE

- Maternal animals: Sacrifice on PND day 21 (after weaning of offspring)

GROSS NECROPSY
- Gross necropsy consisted of examination of all major organs

HISTOPATHOLOGY / ORGAN WEIGHTS
- Organs examined: All major organs were examined, and ovaries, pituitary and adrenals were weighed. Ovaries, uterus, cervix, vagina, pituitary, adrenals and any gross lesions were fixed in buffered formalin.

OVARIES AND UTERINE CONTENT
P0
The ovaries and uterine content was examined after termination: No
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: No
- Number of implantations: No
- Number of early resorptions: No
- Number of late resorptions: No

F1 matings
The ovaries and uterine content was examined after termination: No
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring not selected as parental animals was sacrificed at PND 4 (litter size reduction) and after weaning
- These animals were subjected to postmortem examinations
- The F1 pregnant females were weighed on days 0, 7, and 13 of pregnancy, and were necropsied on day 13.
- The F1 females that showed no evidence of mating after the second mating were necropsied 13 days after the end of the mating period.
- The F1 males were killed about 2 weeks after the end of the mating period.

GROSS NECROPSY
- Gross necropsy consisted of [external and internal examinations]:
F1 pregnant females
- Examinations: All major organs were examined grossly. Organs or tissues showing gross abnormalities were fixed in neutral buffered formaldehyde. Pregnancy status and the numbers of corpora lutea, implantation sites, early and late resorptions, and live embryos were recorded.
F1 males after mating
Examinations: Major organs were examined.

HISTOPATHOLOGY / ORGAN WEIGTHS
F1 pregnant females
- Examinations: ovaries, pituitary and adrenals were weighed. Organs or tissues showing gross abnormalities were fixed in neutral buffered formaldehyde. Pregnancy status and the numbers of corpora lutea, implantation sites, early and late resorptions, and live embryos were recorded.
F1 males after mating
- Examinations: Testes, epididymides and adrenals were weighed. The testes were preserved in Bouin 's solution and the epididymides and any other organs or tissues showing gross lesions were preserved in neutral buffered formaldehyde.

Statistics:

Analysis of variance (ANOVA) was performed on all parameters. Residuals from this preliminary analysis were examined for heterogeneity of variance using Levene's test. If the Levene's test was significant at the 1% level, then the particular variable was subjected to non-parametric analyses using Kruskal-Wallis ANOVA test followed by Shirley's non-parametric version of Williams test. lf the Levene's test was not significant at the 1% level, then William's test was done to compare treated and control groups. The nominal data were analyzed using the Fisher's exact test.

Reproductive indices:

Gestation index

Offspring viability indices:

Live birth and viability indices and cumulative survival index were calculated.
Furthermore, mean duration of pregnancy,mean duration of parturition and mean number of pups born were determined.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

P0 Dose level unknown: Pale and reduced quantities of feces were observed in treated groups during the late pregnancy and early lactation periods.

Dermal irritation (if dermal study):

not examined

Description (incidence and severity):

P0

Mortality:

not specified

Description (incidence):

P0

Body weight and weight changes:

no effects observed

Description (incidence and severity):

P0

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

P0 2000 mg/kg bw/day: Significantly lower food consumption compared to controls (during days 7 to 14 of lactation). Evaluation of adversity not possible, due to missing detailed information on results.

Food efficiency:

not examined

Description (incidence and severity):

P0

Water consumption and compound intake (if drinking water study):

not examined

Description (incidence and severity):

P0

Ophthalmological findings:

not examined

Description (incidence and severity):

P0

Haematological findings:

not examined

Description (incidence and severity):

P0

Clinical biochemistry findings:

not examined

Description (incidence and severity):

P0

Urinalysis findings:

not examined

Description (incidence and severity):

P0

Behaviour (functional findings):

not examined

Description (incidence and severity):

P0

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

P0

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

P0 Not further specified in the review document.

Histopathological findings: neoplastic:

not examined

Description (incidence and severity):

P0

Other effects:

not examined

Description (incidence and severity):

P0

Reproductive function: oestrous cycle:

not examined

Description (incidence and severity):

P0

Reproductive function: sperm measures:

not examined

Description (incidence and severity):

P0

Reproductive performance:

no effects observed

Description (incidence and severity):

Gestation indices did not differ significantly. P0 Gestation indices: 100% (control), 100% (low dose) , 100% (mid dose), 95.5% (high dose) (not statistically significant)
Mean duration of gestation, mean duration of parturition, mean number of pups born, mean viability indices and cumulative survival index did not differ significantly netween treatment and control groups.

Effects observed in P0 animals:
P 0: 2000 mg/kg bw/day: One animal littered only one dead pup.
P0 control, 600 and 2000 mg/kg bw/day: 2 females from the control group, 3 females from the mid dose group and 1 female from the high dose group failed to rear their offspring. Since there was no dose relationship or any effect on pup survival in the remaining litters of these groups, these losses were considered to be unrelated to treatment.

Dose descriptor:

NOAEL

Remarks:

P0 (general toxicity)

Effect level:

2 000 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

other: no adverse effcts observed.

Remarks on result:

other:

Remarks:

Significantly lower food sonsumption compared to controls (during days 7 to 14 of lactation). Evaluation of adversity not possible, due to missing detailed information on results.

Dose descriptor:

NOAEL

Remarks:

(fertility)

Effect level:

2 000 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

other: no adverse effects observed on the evaluated parameters.

Critical effects observed:

no

Clinical signs:

not specified

Description (incidence and severity):

P1

Dermal irritation (if dermal study):

not examined

Description (incidence and severity):

P1

Mortality:

not specified

Description (incidence):

P1

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

P1 (pups reared to sexual maturation):
2000 mg/kg bw/day: Body weights of high dose P1 males were lower than that of controls throughout the study, the differences were statistically significant from week 5 to 14 (except for week 12). In high dose females, body weights were lower than that of controls, the differences were statistically significant from week 5 to 8.

Food consumption and compound intake (if feeding study):

not specified

Description (incidence and severity):

P1

Food efficiency:

not examined

Description (incidence and severity):

P1

Water consumption and compound intake (if drinking water study):

not examined

Description (incidence and severity):

P1

Ophthalmological findings:

not examined

Description (incidence and severity):

P1

Haematological findings:

not examined

Description (incidence and severity):

P1

Clinical biochemistry findings:

not examined

Description (incidence and severity):

P1

Urinalysis findings:

not examined

Description (incidence and severity):

P1

Behaviour (functional findings):

not examined

Description (incidence and severity):

P1

Immunological findings:

not examined

Description (incidence and severity):

P1

Organ weight findings including organ / body weight ratios:

not examined

Description (incidence and severity):

P1

Gross pathological findings:

not examined

Description (incidence and severity):

P1

Histopathological findings: non-neoplastic:

not examined

Description (incidence and severity):

P1

Histopathological findings: neoplastic:

not examined

Description (incidence and severity):

P1

Other effects:

not examined

Description (incidence and severity):

P1

Reproductive function: oestrous cycle:

not examined

Description (incidence and severity):

P1

Reproductive function: sperm measures:

not examined

Description (incidence and severity):

P1

Reproductive performance:

no effects observed

Description (incidence and severity):

The mean number of days taken for mating, and the copulation and fertility indices were similar across control and treated groups. The pregnancy rates for F1 females were 84.2, 94.7, 85.0 and 100% at 0, 200, 600 and 2000 mg/kg bw/day, respectively. There were no differences in the numbers of corpora lutea, implantations and live embryos, or on the extent of pre- and post-implantation losses that were considered to be related to F0 maternal treatment with the test substance. The body weights during pregnancy (F1) in all treatment groups were simlar to control.

Dose descriptor:

LOAEL

Remarks:

P1 (general toxicity)

Effect level:

2 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Dose descriptor:

NOAEL

Remarks:

(fertility)

Effect level:

2 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed on evaluated parameters (exposure via P0 maternal animals).

Critical effects observed:

no

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

2000 mg/kg bw/day: pale body and piloerection were noted immediately after weaning.

Dermal irritation (if dermal study):

not examined

Description (incidence and severity):

F1

Mortality / viability:

not specified

Description (incidence and severity):

F1

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

F1
2000 mg/kg bw/day: Beginning from PND day 7, 14 and 21, pup weights were significantly reduced (males); Beginning from post-natal day 4 onwards, pup weight were significantly reduced in high dosed females. The overall body weight gain for the high dose group was significantly reduced for both sexes for post-natal day 0 to 21.

200 and 600 mg/kg bw/day: At mid dose body weights of females were significantly reduced on PND day 4, 4 post-culling and 21 and at low dose on post-natal day 4 and 4 post-culling. The overall body weight gain for mid dose females was significantly reduced for PND day 0 to 21.
The pup body weights were similar across control and treatment groups at post-natal day 0.

Food consumption and compound intake (if feeding study):

not examined

Description (incidence and severity):

F1

Food efficiency:

not examined

Description (incidence and severity):

F1

Water consumption and compound intake (if drinking water study):

not examined

Description (incidence and severity):

F1

Ophthalmological findings:

not examined

Description (incidence and severity):

F1

Clinical biochemistry findings:

not examined

Description (incidence and severity):

F1

Urinalysis findings:

not examined

Description (incidence and severity):

F1

Sexual maturation:

effects observed, treatment-related

Description (incidence and severity):

F1 2000 mg/kg bw/day: Preputial seperation, a criterion for sexual development, was significantly delayed in high dose males.
F1 200, 600 and 2000 mg/kg bw/day: A dose-related delay in vaginal opening was noted in all treatment groups.
Delays in sexual devlopmental, may probably result form the reduced body weights that were observed at the same dose levels.

Anogenital distance (AGD):

not examined

Description (incidence and severity):

F1

Nipple retention in male pups:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

2000 mg/kg bw/day: mean absolute pituitary weight was lower than in control, with no significant effect on relative pituitary weight.

Gross pathological findings:

no effects observed

Description (incidence and severity):

F1

Histopathological findings:

no effects observed

Description (incidence and severity):

F1

Other effects:

not examined

Behaviour (functional findings):

effects observed, treatment-related

Description (incidence and severity):

2000 mg/kg bw/day: The percentage of pups with eyes open on post-natal day 16 was significantly reduced at the high dose compared to control. 7/21 litters of the high dose group had 50% or more of pups with delayed eye opening on day 16. The times of eye opening in other dose groups were similar to control.

Developmental immunotoxicity:

not examined

Description (incidence and severity):

F1

F1 pups:
The mean number of pups born, sex ratio, mean live birth index, mean viability index (2, 3 and 4) and the mean cumulative survival index did not differ significantly between treatment and control groups. There were no clinical signs observed in F1 generation animals, except that at the high dose, pale body and piloerection were noted immediately after weaning. Necropsy of F1 offspring (pups that died, or were killed at culling on PND 4, at weaning on PND day 21 or terminally) showed no treatment related findings. There was no effect of F0 maternal treatment on F1 organ weights except that the mean absolute pituitary weight was lower in the high dose male group than in control, with no significant effect on relative pituitary weight.

F1 progeny reared to sexual maturity:
Sexual development was significantlydelayed in high dose males and in all dose groups in females. The percentage of pups with eyes open on post-natal day 16 was significantly reduced at the high dose compared to control. 7/21 litters of the high dose group had 50% or more of pups with delayed eye opening on day 16. The times of eye opening in other dose groups were similar to control. Examinations of E-maze learning, auditory function and opthalmoscopy did not reveal any treatment-related effects. There were no effects of maternal treatment on the time of ear opening, or on the presence of righting, startle or pupillary light reflexes. The body weights of high dose F1 males were lower than of controls throughout the study, the differences being statistically significant from week 5 to 14 (except for week 12). In high dose females, body weights were lower than control, the differences were statistically significant from week 5 to 8. There were no treatment-related effects on body weights in lower dose groups. At 2000 mg/kg bw/day: mean absolute pituitary weight was lower than in control, with no significant effect on relative pituitary weight.

Dose descriptor:

LOAEL

Remarks:

(Developmental neurotoxicity)

Generation:

F1

Effect level:

2 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

developmental neurotoxicity

Dose descriptor:

LOAEL

Remarks:

(Developmental toxicity)

Generation:

F1

Effect level:

2 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: sexual development delayed

Dose descriptor:

LOAEL

Remarks:

(Developmental toxicity)

Generation:

F1

Effect level:

200 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: sexual development delayed

Reproductive effects observed:

no

Table 1: Group mean and litter data P0 and F1 generation litters

Dose (mg/kg bw/day)	control	200	600	2000	Analysis of variance	Kruskal Wallis test
Number littered (N)	21	22	20	22
Gestation index %	100	100	100	95.5	NS
Mean duration of pregnancy (days ± SD)	21.7 ± 0.2	21.8 ± 0.3	21.9 ± 0.4	21.8 ± 0.5	NS
Mean duration of parturition (hours ± SD)	2.2 ± 0.6 (18)	2.5 ± 1.6 (20)	2.3 ±0.7 (17)	2.2 ± 0.7 (18)	NS
Mean number of pups born ± SD	14.0 ± 3.7	14.4 ± 2.4	14.6 ± 2.4	12.9 ± 4.4	NS
% males	44.4 (20)	51.0	50.6 (17)	52.1	NS
Mean live birth index 1	93.6	98.0	88.6	95.2	NS
Mean viability index 1	87.6	100	76.8	97.5 (21)		p<0.01
Mean viability index 2	100 (19)	100	100 (17)	98.8 (21)	NS	NS
Mean viability index 3	100 (19)	99.4	100 (17)	100 (21)	NS
Mean viability index 4	100 (19)	99.4	100 (17)	99.4 (21)	NS
Mean cumulative survival index	82.7	96.9	75.5	90.1 (21)		NS

SD standard deviation

N = number of animals in mean

() = N, where N differs from original

Table 2: Body weights and body weight gains (g) ± Standard deviations: F1 generation litters

Dose (mg/kg bw/day)	control	200	600	2000	Analysis of variance
Males
N	21	22	19	21
Body weight (day postpartum)
0	6.3 ± 0.6	6.2 ± 0.3	6.4 ± 0.5	6.4 ± 0.5 (20)	NS
4	9.2 ± 1.1 (19)	8.5 ± 0.8	8.8 ± 1.0 (16)	8.6 ± 1.1	NS
4pc	9.3 ± 1.0 (19)	8.5 ± 0.8	8.9 ± 1.0 (16)	8.7 ± 1.1	NS
7	14.9 ± 1.6 (19)	14.3 ± 1.7	14.8 ± 1.8 (16)	13.3 ± 1.6 **	p<0.05
14	32.6 ± 2.8 (19)	31.9 ± 2.7	31.9 ± 7.8 (16)	27.5 ± 3.4	p<0.001
21	52.1 ± 3.6 (19)	51.5 ± 4.5	51.9 ± 4.3 (16)	43.2 ± 6.3 ***	p<0.001
Body weight gain (day 0-21)	45.8 ± 3.6 (19)	45.3 ± 4.4	46.3 ± 5.0 (16)	36.8 ± 6.0 (20) ***	p<0.001
Females
N	21	22	20	21
0	6.04 ± 0.5	5.9 ± 0.3	6.0 ± 0.5	6.1 ± 0.6 (20)	NS
4	9.0 ± 0.9 (19)	8.2 ± 1.0*	8.3 ± 0.8 (17)*	8.3 ± 1.1*	NS
4pc	9.1 ± 0.9 (19)	8.2 ± 0.9 (21)**	8.3 ±0.9 (17)**	8.3 ± 1.0*	p<0.05
7	14.6 ±1.4 (19)	13.9 ± 2.0	13.8 ± 1.5 (17)	12.7 ± 1.6**	p<0.01
14	32.0 ± 2.5 (19)	31.3 ± 3.0	30.2 ± 3.0 (17)	26.7 ± 3.6***	p<0.001
21	52.0 ±3.6 (19)	50.7 ± 4.6	48.4 ± 5.8 (17)*	42.2 ± 6.3***	p<0.001
Body weight gain (day 0-21)	45 ± 3.7 (19)	44.8 ± 4.5	42.4 ± 5.6 (17)*	36.14 ± 5.9 (20)***	p<0.001

N = Number of litters in mean, ()= N, where differs from original, pc = post culling

* p < 0.05; ** p < 0.01; *** p< 0.001 William’s test

  

Dose (mg/kg bw/day)	control	200	600	2000
N	20	20	20	20
Day of preputial separation observed	44.3 ± 1.5	44.6 ± 1.3	44.8 ± 2.2	46.7 ± 3.4**
Day vaginal perforation pbserved	33.6 ± 1.5	34.0 ± 2.2*	34.5 ± 1.5**	35.4 ± 2.3***

N = Number of litters in mean; * p < 0.05; ** p < 0.01; *** p< 0.001 William’s test

 

Table 4: Group mean (Mating of F1 animals)

	control	200	600	2000
Pregnancy rate F1 females %	84.2	94.7	85.0	100
Number of females with implantations at scheduled kill	16	18	17	20
Number of corpora lutea	261	281	275	299
Number of corpora lutea per female ± SD	16.3 ± 2.4	15.6 ± 2.5	16.2 ± 1.6	15.0 ± 3.8
Mean % pre-implantation loss	7.8	6.1	4.3	8.6
Number of early embryo deaths	15	14	10	17
Number of late embryo deaths	0	0	0	0
Number of dead embryos	2	1	1	1
Mean % post-implantation loss	6.3	5.5	3.9	5.5
Number of live embryos	244	266	264	281
Mean number of live embryos per female	15.3	14.8	15.5	14.1
Mean % of implantations	93.7	94.5	96.1	94.5

SD = Standard deviation

Reference 3

Endpoint:

extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)

Data waiving:

other justification

Justification for data waiving:

other:

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

Lanthanum carbonate was tested for its reproductive properties in several studies, includinga reliable one generation study (similar to OECD 415) and a combined reproductive and neurodevelopmental study. No extended one-generation reproductive toxicity study or a two-generation study is available to fulfil the data requirements according to Annex X of Regulation EC (no) 1907/2006. However, the available information on reproductive toxicity do not indicate hazardous properties of Lanthanum carbonate in regard to reproductive performance and fertility. In light of the fact that a new conducted extended one-generation reproductive toxicity study might probably not add new insights in the reproductive properties of Lanthanum carbonate and in regard to animal welfare, hazard assessment on reproductive toxicity is determined on the existing data on Lanthanum carbonate supported by data on structural analogues containing lanthanum. A summary of the available data is summarized below.

 

A reliable combined one generation reproductive toxicity study combined with an embryonic developmental study was conducted similar to OECD 415 in male and female Spraque-Dawley rats (SD IOPS-Caw strain) with Lanathanum carbonate administered orally at doses of 200, 600 or 2000 mg/kg bw/day (Shire, 1996a). Males were dosed for at least 63 days prior to mating with exposure continuing until sacrifice at the end of the mating period. Females were dosed continuously starting 14 days before mating, through the mating period till day 17 of pregnancy. Males were killed after the end of the mating period and females were sacrificed on day 20 of pregnancy.

 

Clinical signs were evaluated daily, mortality twice daily, body weights for males and females during the pre-mating period twice weekly. During pregnancy female body weights were determined daily. Food consumption was determined weekly and during pregnancy at the following intervals: day 0 to 6, 6 to 12, 12 to 17 and 17 to 20. All organs or tissues showing macroscopic abnormalities were fixed for further analysis. In males testes and epididymis were removed, testes weighed and both fixed. In females, live fetuses and their placenta were removed, and the uterus and ovaries were fixed in neutral buffered formaldehyde. In addition, pregnancy status, numbers of corpora lutea, implantation sites, resorptions and dead and live fetuses were recorded. Fetal/Litter and placental weights as well as fetal sex were recorded in addition to copulation index, fertility index, pre- and post-implantation losses. Fetuses were examined for external abnormalities. After fixation, one half of the live fetuses were examined for visceral abnormalities, the other half was examined for skeletal abnormalities.

Two males were found dead during the pre-mating period, one animal dosed at 600 and the other animal dosed at 2000 mg/kg bw/day. Since the dead animal in the high dose group was cannibalized and the remaining tissues were partly autolysed, the cause of death could not be determined.

No treatment-related effects on clinical signs, body weight gain or food consumption, were observed. In addition, no macroscopic findings or histopathological effects were observed at necropsy.

No treatment-related effect on the number of pregnant females per group was observed. Pregnancy rates were 92, 96, 100 and 92% in control, 200, 600 and 2000 mg/kg bw/day dose groups, respectively.

The mean number of corpora lutea, implantations, live fetuses and mean percent of pre- and post-implantation losses, number of early/late embryo/fetal deaths and placental weights were similar between groups and not affected by treatment. Mean litter weights, mean fetal and placental weights were similar between the groups. The percentage of male fetuses was significantly higher in the high dose group (53.3%) compared to controls (45.1%). However, as the number of males is still near to 50% the biological relevance of this increase is questionable.

Combined examination of external/visceral and skeletal findings, did not reveal any statistically significant increase of any major abnormalities between treated and control groups. Although the total number of major abnormalities was increased compared to concurrent controls in the mid and high dose groups, the increase was not dose-related (higher in mid than in high dose group) and was within the historical control range of the institute. This is therefore regarded as a rather as incidental finding and not as treatment-related. Some statistically significant differences in minor skeletal malformations were reported at low and high dose, but there was no dose-relationship.

A dose-related increase in a visceral variation (pelvic cavitation of kidneys) was noted in the high dose group, but the incidences in the treated groups were within the historical control range which showed a high variability (0.0 to 41.5%). It can therefore be concluded that no treatment related developmental toxicity or teratogenicity was observed in this study.

Based on the results of the conducted study, no effects on reproductive performance and fertility have been observed. Thus, the following effect levels have been derived: NOAEL (general toxicity): 2000 mg/kg bw/day; NOAEL (reproductive toxicity): 2000 mg/kg bw (for effect levels on developmental toxicity, please refer to “Effects on developmental toxicity”).

 

Further, a reliable combined developmental neurotoxicity/reproductive toxicity study similar to OECD 426 was peformed (Shire, 1996b). In this study time-mated female Sprague-Dawley rats were orally exposed to Lanthanum carbonate from implantation (GD 6) throughout lactation (PND 20) at doses of 200, 600, 1000 or 2000 mg/kg bw/day via gavage. All dams were allowed to rear their pups up to post-natal day 21, afterwards the dams were sacrificed for post-mortem examinations. Mortality was recorded twice daily and clinical signs daily. Body weights were recorded daily from GD 5 to PND 21. Food consumption was recorded during pregnancy and on PND 1 to 14. At final sacrifice of P0 animals, all major organs were examined for macroscopic changes and ovaries, pituitary and adrenals were weighed. Ovaries, uterus, cervix, vagina, pituitary, adrenals and any gross lesions were fixed. Beginning on day 21 of pregnancy, all P0 females were observed at about 30-minute intervals for evidence of parturition; the times of onset and completion of parturition were recorded. Furthermore, gestation, live birth and viability indices were calculated.

After weaning, 20 F1 pups/sex/group were randomly selected for detailed post-weaning examinations and rearing to sexual maturity. The remaining pups were subjected to necropsy. The selected pups were examined daily for clinical signs, and weighed weekly. Ophthalmoscopic examination (PND 28-35) and assessments of auditory function (PND 28-35) and E-maze learning potential (PND 28) were performed. All males were examined daily for preputial separation from PND 35, and females were examined daily for vaginal opening from PND 28.

When the selected F1 animals reached 13 weeks of age, each female was mated with a male from the same group for up to 7 days. Vaginal smears were taken daily until sperm was found in the smear. The male was removed from the cage on the day of mating. If a female had not mated within seven days, the male was removed and another male that had previously mated was substituted. The F1 pregnant females were weighed on days 0, 7, and 13 of pregnancy, and were necropsied on day 13. All major organs were examined grossly; ovaries, pituitary and adrenals were weighed. Organs or tissues showing gross abnormalities were fixed. Pregnancy status and the numbers of corpora lutea, implantation sites, early and late resorptions, and live embryos were recorded. The F1 females that showed no evidence of mating after the second mating were necropsied 13 days after the end of the mating period. The F1 males were killed about 2 weeks after the end of the mating period, major organs were examined, and the testes, epididymides and adrenals were weighed. The testes, epididymides and any other organs or tissues showing gross lesions were preserved.

 

In the P0 generation, during late pregnancy and the lactation period pale and reduced quantities of feces were observed in the treated maternal groups.

There was no effect of treatment on maternal body weight or bodyweight gain during pregnancy and lactation. Food consumption of the high dose group was significantly lower than that of controls on lactation days (LD) 4 to 7. An evaluation of adversity is not possible due to missing detailed information on results, including body weights for this special study period. Necropsy findings of P0 females were unremarkable and no treatment related effects on absolute or relative body weights, pituitary, ovary and adrenal weights were observed. One high dose female had a litter of only 1 pup that was dead. All other pregnant females produced live litters. The gestation index was 100, 100, 100 and 96% for the control, 200, 600 and 2000 mg/kg bw/day groups, respectively. There was no difference between groups with regard to duration of gestation, parturition, mean number of pups born, mean viability indices and cumulative survival index. Six females failed to rear their litters, 2 from control, 3 of the 600 mg/kg/day group and 1 at the 2000 mg/kg/day group. As there was no dose relation, this effect was not regarded as treatment-related.

 

In the F1 generation, no clinical signs were reported except for pale body and piloerection of high dose animals directly after weaning. There was no effect on F1 organ weights except that the mean absolute pituitary weight was lower in the high dose male group than in control, with no significant effect on relative pituitary weight.

At a dose of 2000 mg/kg bw/day, pup weights (F1) were significantly reduced in males, beginning from post-natal day 7, 14 and 21. In females pup weights were significantly reduced, beginning from post-natal day 4 onwards. The overall body weight gain for the high dose group was significantly reduced for both sexes for post-natal day 0 to 21. At mid dose body weight of females were significantly reduced on post-natal day day 4, post-natal day 4 post-culling and post-natal day 21 and at low dose on post-natal day day 4 and post-natal day 4 post-culling. The overall body weight gain for mid dose females was significantly reduced for post-natal day day 0 to 21. The pup body weights were similar across control and treatment groups at post-natal day 0.

At the high dose the percentage of pups with eyes open was significantly lower (50%) compared to controls on post-natal day 16. 7/21 litters of the high dose group had 50% or more of pups with delayed eye opening on day 16. The times of eye opening were similar to controls in all other dose groups. At the same dose body weights were significantly reduced. Thus the delay in eye opening is probably a consequence of the reduced body weight. Based on the available data a possible link to maternal effects (reduced food consumption during lactation period) cannot be assessed and an evaluation of adversity is currently not possible due to missing detailed information on results.

No treatment related effects were observed on the time of ear opening, presence of righting startle or papillary light reflex reactions.

Examination sexual developmental revealed that preputial separation was significantly delayed in high dose males compared to controls. Similarly, a dose-related delay in vaginal opening was noted in females at all dose levels. Since body weights were significantly reduced at the same doses at which effects on sexual development were observed, the delay in sexual development is probably a consequence of the reduced body weight. Based on the available data a possible link to maternal effects (reduced food consumption during lactation period) cannot be assessed and an evaluation of adversity is currently not possible due to missing detailed information on results

 

Body weights of high dose F1 males reared to sexual maturation were statistically significantly lower than that of controls from week 5 to 11 and 13-14 and that of high dose females from week 5 to 8. There were no effects on body weights in other treatment groups.

 

Following mating of the F1 generation (now also declared as P1 generation), the following observations were made: The mean number of days taken for mating, copulation and fertility indices were similar between treated and control groups. Pregnancy rates for females in the P1 generation were comparable between groups (84.2, 94.7, 85.0 and 100% in the 0, 200, 600 and 2000 mg/kg/day dose groups, respectively). No differences between groups of P1 mated rats were observed in the number of corpora lutea, implantations and live embryos, pre- and post-implantation losses. Body weights during pregnancy of P1 females were all similar to controls.

 

In conclusion, there were no adverse effects observed in maternal P0 animals except for reduced food consumption at high dose during days 7 to 14 of lactation. Evaluation of adversity of this effect is currently not possible, due to missing detailed information on results. A NOAEL for maternal general toxicity and fertility was derived at 2000 mg/kg bw/day.

In the P1 generation (exposure via P0 maternal animals only), a LOAEL of 2000 mg/kg bw/day was derived for general toxicity based on significantly reduced body weight and weight gain. Further, a NOAEL of 2000 mg/kg bw/day was derived for fertility due to the absence of adverse effects on the evaluated reproductive parameters. In the F1 generation (offspring from P0 until end of maturation), a LOAEL for developmental effects in males was determined at 2000 mg/kg bw/day based on significantly delayed preputial separation. Further, based on significantly delayed vaginal opening at all doses, a LOAEL for developmental effects was determined at 200 mg/kg bw/day in females. However, at the same doses body weights were significantly reduced in males and females. Thus the delay in sexual development is probably a consequence of the reduced body weight. Based on the available data a possible link to maternal effects (reduced food consumption during lactation period) cannot be assessed. Evaluation of adversity is currently not possible, due to missing detailed information on results

Based on the delayed eye opening at the high dose in males and females, a LOAEL for Developmental neurotoxicity was established at 2000 mg/kg bw/day. However, the delay in eye opening is probably a consequence of the reduced body weight. As discussed above, evaluation of adversity is currently not possible, due to missing detailed information on results.

 

Furthermore, the following supporting data on reproductive toxicity on analogue substances is available (for further information on the rationale for read-across, please refer to the Analogue Justification provided within the technical dossier): 

 

In a combined repeated dose toxicity study with a reproduction / developmental toxicity screening test according to OECD Guideline 422 Sprague-Dawley rats received 0, 150, 450 or 1000 mg/kg bw/day cerium carbonate (containing water) by gavage (Davies, 2008). Males were exposed 15 days before mating, during the mating period (up to 3 weeks) until sacrifice (at least 4 weeks in total). Females were treated 2 weeks before mating, during mating, during pregnancy, during lactation until day 5 post-partum inclusive.

There were no adverse effects of treatment at any dose level on mortality, clinical signs, body weight or food consumption. No microscopic treatment-related changes were observed in the testes and ovaries.

The results observed in mating, fertility and estrous cycle as well as in spermatogenesis did not reveal any effects attributable to the administration of Cerium carbonate. The fertility index (80-100%) and mating index (90 -100%) was comparable for all groups. Thus, the NOAEL for mating and fertility (P) was considered to be 1000 mg/kg bw/day.

There were no significant nor dose-dependent effects in any group on the mean numbers of corpora lutea, implantations or number of pups delivered. In addition, there were no significant nor dose-dependent effects on pup survival after birth or on pup sex. Mean pup body weight was higher at all dose-levels but the mean body weight gain was comparable to the controls. At pup necropsy no relevant macroscopic findings could be determined. Thus, the NOAEL was considered to be 1000 mg/kg bw/day for developmental toxicity and teratogenicity.

 

Furthermore read-across studies from the surrogate substance Lanthanum chloride and Lanthanum oxide are available and included in the dossier as supporting studies.

 

The effects of lanthanum salts on fertility of rats and mice were investigated in some studies.

Hutcheson et al. (1975) fed a diet containing 0.4, 4, 40 and 400 ppm Lanthanum to male and female CF-1 mice for three generations. In all generations, no exposure related effects on reproduction (pregnancy rate and average litter size as well as lactation) were observed.

 

In a study performed by Briner et al. (2000), female mice were exposed to Lanthanum chloride via drinking water (125, 250, and 500 mg/L) for 14 days prior to mating with unexposed males. The exposure to lanthanum did not have a noticeable effect on the dams, and the litter size did not differ significantly between the groups.

 

Furthermore, histopathological data on sexual organs from a repeated dose 90-day oral toxicity study with the test substance Lanthanum carbonate were used for assessment of toxicity to reproduction.

 

In a repeated dose toxicity study (Reißmüller, 2006) in Wistar rats no compound-related reproductive effects on sexual organs (seminal vesicles/prostate/testes/epididymides or ovaries/uterus/vagina) were found during histopathological examination of animals having received doses of 1400, 4200, 14000 ppm Lanthanum carbonate octahydrate nominal in diet for 13 weeks.

 

Taking into account all available data for evaluation of reproductive toxicity of Lanthanum carbonate, there were no indications for adverse effects on reproduction. Therefore a waiver for an extended one generation study (OECD 433) is considered justified and included in the dossier. The performance of new studies on reproduction is not considered to add new insights in reproductive properties of Lanthanum carbonat and hence, due to animal welfare reasons, a further reproduction/fertility study should be omitted

Effects on developmental toxicity

Description of key information

Developmental toxicity study (similar to OECD 414), rabbit:

LOAEL (maternal animals) general toxicity: 1500 mg/kg bw/day

NOAEL (maternal animals) general toxicity: 750 mg/kg bw/day

LOAEL (maternal animals) developmental: toxicity 1500 mg/kg bw/day

NOAEL (maternal animals) developmental: toxicity 750 mg/kg bw/day

NOAEL (fetuses) developmental toxicity: 1500 mg/kg bw/day

Developmental toxicity study rats:

LOAEL (maternal animals) general toxicity: 2000 mg/kg bw/day

NOAEL (maternal animals) general toxicity: 2000 mg/kg bw/day

NOAEL (fetuses) developmental toxicity: 2000 mg/kg bw/day

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

10 July - 8 August 1996

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

not specified

GLP compliance:

yes

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: about 4 months
- Weight at study initiation: 3 - 4 kg (females)
- Housing: individually in grid-bottom metal cages suspended over paper-lined trays
- Diet: pelleted standard rabbit diet, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 4 - 5 days

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Lanthanum carbonate was daily suspended in 0.5% aqueous carboxymethyl cellulose.
Dose volume: 5 mL/kg bw

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analyses of samples of the test substance formulation (prepared on the first day of dosing and on a day toward the end of the dosing period) showed that the lanthanum content were within the specification limits.

Details on mating procedure:

- Impregnation procedure: purchased timed pregnant

Duration of treatment / exposure:

Day 6 to 18 of pregancy

Frequency of treatment:

daily

Duration of test:

28 days (Day 0 -28 of pregnancy)

Dose / conc.:

250 mg/kg bw/day

Dose / conc.:

750 mg/kg bw/day

Dose / conc.:

1 500 mg/kg bw/day

No. of animals per sex per dose:

20

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Based on an oral administration range-finding study conducted in pregnant rabbits (dosed from days 6 to 18 of pregnancy) at dose levels of 250, 500, 1000 and 1500 mg/kg bw/day. In that study, 1500 mg/kg bw/day produced maternal toxicity (reduction in body weight gain and food consumption, and reduced fecal production) and reduction in fetal body weight. There were no significant treatment-related effects in lower dose groups. Hence, 1500 mg/kg bw/day, a dose that produced slight maternal toxicity, was selected as the high dose for the rabbit developmental toxicity study. 250 mg/kg bw/day was chosen as the low dose and 750 mg/kg bw/day was selected as the mid dose for the study.

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
- Cage side observations checked: Clinical signs, mortality

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: Days 0, 3, 6 to 18, 22, 25 and 28 of pregnancy.

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data
- Food consumption was recorded daily from days 3 to 6 of pregnancy and every two days thereafter

WATER CONSUMPTION AND COMPOUND INTAKE: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on day 28 of gestation
- Organs examined: All major organs

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: Total numbers of live fetuses per group, mean number of fetuses per dam, numbers of male and female fetuses, mean litter weight and mean fetal and placental weights. Pre- and post- implantation losses were determined.

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: all per litter (brain)

Statistics:

Analysis of variance was performed on all parameters. Residuals from this preliminary analysis were examined for heterogeneity of variance using Levene's test. If the Levene's test was significant at the 1% level, then the particular variable was subjected to non-parametric analyses using Kruskal-Wallis ANOVA test followed by Shirley's non-parametric version of Williams test. If the Levene's test was not significant at the 1 % level, then William's test was done to compare treated and control groups.

Historical control data:

In this study:
control group: mean pre-implantation loss: 8.8%
control group: mean post-implantation loss: 4.7%

Historical control values:
mean pre-implantation loss = 12.8% (range= 2.5 - 26.7%)
mean post-implantation loss = 9.6% (range = 3.8-15.9%)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

1500 mg/kg bw/day: A higher incidence of reduced fecal output, with liquid/loose feces was noted compared to controls. Reduced fecal output (liquid/loose feces), reduction in body weight and presence of mucus on the tray liner was observed in one animal before abortion (non treatment-related, single event).

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

1500 mg/kg bw/day: Significant reduction in body weight gain was noted during the dosing period (days 6 to 18 of pregnancy).

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

1500 mg/kg bw/day: Significant lower food consumption during the dosing period (days 6 to 10).

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

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:

effects observed, non-treatment-related

Description (incidence and severity):

1500 mg/kg bw/day: Necropsy findings included red stained fur, distended stomach with dark fluid and empty colon in one female which aborted 7 fetusses on day 25 of pregnancy.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Number of abortions:

effects observed, non-treatment-related

Description (incidence and severity):

1500 mg/kg bw/day: One abortion (7 fetuses) was observed at day 25 of pregnancy.

Pre- and post-implantation loss:

effects observed, treatment-related

Description (incidence and severity):

1500 mg/ kg bw/day: The mean pre- and post-implantation loss was higher compared to controls, but not statistically significant and within historical control data. Thus, the biological significance of this effect remains unclear.

Total litter losses by resorption:

no effects observed

Early or late resorptions:

effects observed, treatment-related

Description (incidence and severity):

1500 mg/kg bw/day: Higher number of early and late resorptions, but not statistically significant and within historical control data. Thus, the biological significance of this effect remains unclear.

Dead fetuses:

effects observed, non-treatment-related

Description (incidence and severity):

control group: One dead fetus observed.

Changes in pregnancy duration:

not examined

Changes in number of pregnant:

not examined

Other effects:

effects observed, treatment-related

Description (incidence and severity):

1500 and 750 mg/kg bw/day: Placental weights were significantly reduced.

Remark:
The
At 1500 mg/kg bw/day an increased tendency of pre- and post-implantation losses and a tendency for reduced in fetal weights were observed. The toxicological relevance of reduced placental weights dose at mid dose is unclear, in the absence of effects on fetal body weight.

Key result

Dose descriptor:

LOAEL

Remarks:

general toxicity

Effect level:

1 500 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

body weight and weight gain

clinical signs

food consumption and compound intake

Key result

Dose descriptor:

NOAEL

Remarks:

general toxicity

Effect level:

750 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: No adverse effect observed.

Key result

Dose descriptor:

LOAEL

Remarks:

maternal developmental toxicity

Effect level:

1 500 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: mean placental weights were reduced at 750 and 1500 mg/kg bw/day and above, Since tendency of increased pre- and post-implantation losses and reduction in fetal weights were only observed at 1500 mg/kg bw/day, the high dose was considered as LOAEL.

Remarks on result:

other:

Remarks:

The relevance of reduced placental weights at mid dose is not clear in the absence of effects on fetal body weight.

Key result

Dose descriptor:

NOAEL

Remarks:

maternal developmental toxicity

Effect level:

750 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: no adverse effect observed.

Key result

Abnormalities:

effects observed, treatment-related

Localisation:

other: clinical effects

Description (incidence and severity):

Significant reduction of body weight and food consumption and higher incidence of reduced fecal output, with liquid/loose feces was noted compared to controls at 1500 mg/kg bw/day

Key result

Abnormalities:

effects observed, treatment-related

Localisation:

placenta

Description (incidence and severity):

Placental weight reduced at 750 mg/kg bw/day and above.

Key result

Abnormalities:

effects observed, treatment-related

Localisation:

other: pre-and post implantation losses

Description (incidence and severity):

Tendency of increased pre-and post implantation losses

Fetal body weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

1500 mg/kg bw/day: mean fetal weights reduced (males, females) (not statistically significant, non-adverse)

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):

1500 mg/kg bw/day: mean litter weights reduced (males, females) (not statistically significant, non-adverse)

Changes in postnatal survival:

not examined

External malformations:

no effects observed

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

1500 mg/kg bw/day: Increased trends in the incidences of minor skeletal malfomations (incomplete or absence of ossification of the parietal bone, one or more metacarpel (forelimb) or astragalus (hindlimb)) or variations (incomplete ossification of one or more phalanges of the hind limbs) were observed in treated groups. The incidences were within historical control ranges (non-adverse).

750 mg/kg bw/day: Increased trends in the incidences of minor skeletal malfomations (incomplete ossification of the parietal bone) reaching statistical significance, the incidences were within historical control ranges and are thus not interpreted as advers.

Visceral malformations:

no effects observed

Other effects:

not examined

Key result

Dose descriptor:

NOAEL

Effect level:

1 500 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed on intrauterine development

Key result

Developmental effects observed:

no

Table 1: Mean values intrauterine development

Dose (mg/kg bw/day)	control	250	750	1500
Maternal effects
Number of dams with implantations	18	18	19	18
Mean number of implantation per female	9.2	9.6	9.7	8.9
Mean number of corpora lutea per female	10.1	11.2	10.5	10.6
Mean number of implantations %	95.3	92.7	97.3	90.0
Mean pre-implantation loss %	8.1	13.1	7.0	16.7
Number of early embryo/fetal deaths (resorption)	3	9	2	10
Number of late embryo/fetal deaths (resorption)	3	7	3	5
Number of dead fetuses	1	0	0	0
Mean post-implantation loss %	4.7	7.3	2.7	10.0
Mean placental weight [g] per female	4.8	4.44	4.26*	4.34*
Fetal l effects
Number of dams with viable fetuses	18	18	19	18
Number of live fetuses per group	158	156	179	143
Mean number of live fetuses per female	8.8	8.7	9.4	8.1
Number male fetuses	74	66	87	75
Number female fetuses	84	90	92	70
Mean number of male fetuses %	46.3	41.1	49.2	50.4
Mean litter weight [g]	320.1	311.5	340.6	276.1
Mean fetal weight [g]	36.9	36.3	36.7	34.9

* p<0.05

 

Table 2: Malformations

Dose (mg/kg bw/day)	control	250	750	1500
Total number of litters examined	18	18	19	19
Total number of fetuses examined	158	156	179	145
External and visceral examination
Number with major abnormalities	3	2	2	1
Number with minor abnormalities	50	52	69	43
Number with variations	0	0	0	0
Skeletal examination
Number with major abnormalities	3	3	0	2
Number with minor abnormalities	26	37	47	40
Number with variations	157	153	176	145

Table 3: Selected Skeletal Malformations

Dose (mg/kg bw/day)	Type	control	250	750	1500
Skull
Parietal: Incomplete ossification	Minor	0 (0.0)	2 (1.3)	8* (4.2)	5 (4.3)T*
Forelimb
One or more metacarpal: not ossified	Minor	1 (0.6)	3 (2.8)	9 (4.0)	7 (3.6 )T*
Hindlimb
Astragalus Uni- or bilateral: not ossified	Minor	0 (0.0)	0 (0.0)	2 (0.8)	3 (3.0)T*
One or more phalange: incomplete ossification	Variant	4 (3.0)	5 (3.0)	15 (7.3)	15 (10.5)T*

T: trend test; * p<0.05, **; p<0.01, ***; p<0.001

( ): group mean percent

Reference 2

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

October 1996

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

Principles of method if other than guideline:

A mixed reproductive/developmental toxicity study was performed in rats. In this study, males were dosed for at least 63 days before mating with treatment continued throughout the mating period until the day before necropsy. Females were dosed for 14 days before mating with treatment continued through the mating period till day 17 of pregnancy. Males were killed after the end of the mating period and females were sacrificed on day 20 of pregnancy. Animals were subjected to complete necropsies. Organs or tissues showing macroscopic abnormalities were fixed. Testes and epididymides were removed and fixed and the testes weights were determined. For females, pregnancy status, numbers of corpora lutea, implantation sites, resorptions, and dead and live fetuses were determined.
The live fetuses and their placenta were removed, and the uterus and ovaries were fixed. Fetal and placental weights, fetal sex and external fetal abnormalities were recorded. Copulation and fertility indices and pre- and post-implantation losses were calculated. One half of the live fetuses were examined for visceral abnormalities. The remaining fetuses were examined for ossification of the skeleton and skeletal variants and abnormalities.
Structural congenital abnormalities that impair or potentially impair the survival of the fetus were classified as major abnormalities. Other defects were classified as minor abnormalities. Commonly observed variations in the degree of ossification from that expected of a day 20 gestation fetus together with common variations in the extent of renal pelvic cavitation and ureter dilatation were recorded as variants.

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Remarks:

(SD) IOPS-Caw strain

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 5 - 6 weeks (males), 3 - 4 (females)
- Weight at study initiation: 188-199 g (males), 60-79 g (females)
- Acclimation period: 1 week (males), 8 weeks (females)

Route of administration:

oral: gavage

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Lanthanum carbonate was daily suspended in 0.5% aqueous carboxymethyl cellulose.
Dose volume: 10 mL/kg bw

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

- Impregnation procedure: cohoused

Duration of treatment / exposure:

P0 males: 63 days before mating, during mating, until day before necropsy
P0 females: 14 days before mating, during mating, until day 17 of pregnancy

Frequency of treatment:

daily

Duration of test:

P0 males: 63 day before mating until end of mating period
P0 females: 14 days before mating until day 20 of pregnancy

Dose / conc.:

200 mg/kg bw/day

Dose / conc.:

600 mg/kg bw/day

Dose / conc.:

2 000 mg/kg bw/day

No. of animals per sex per dose:

25

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The doses were selected based on existing toxicity data including a preliminary study in rats conducted at dose levels of 200, 600, 1000 or 2000 mg/kg bw/day. In that study, males (6/group) were dosed from 14 days prior to mating, through the mating period until the day before necropsy after the end of the mating period. Females were dosed from 14 days prior to mating, through mating and pregnancy, until the day before necropsy on day 7 post-partum. No significant treatment related effects were seen in the parental or F1 generations except that the F1 pup body weights were slightly reduced in the group treated at 2000 mg/kg bw/day. Based on these findings, 2000 mg/kg bw/day was selected as the high dose for the reproductive toxicity studies. A low dose level of 200 mg/kg bw/day was selected as the no-effect level, with an intermediate dose level of 600 mg/kg bw/day.

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily/ twice daily (mortality)
- Cage side observations checked: not further specified

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: females during the pre-mating period, daily during pregnancy

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes (not specified
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
- Time schedule: weekly (during pregnancy over days 0 to 6, 6 to 12, 12 to 17 and 17 to 20)

WATER CONSUMPTION AND COMPOUND INTAKE: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: all organs or tissues showing macroscopic abnormalities were fixed for further analysis. Females: uterus, ovaries and placenta

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: Total numbers of live fetuses per group, mean number of fetuses per dam, numbers of male and female fetuses, mean litter weight and mean fetal and placental weights. Pre- and post- implantation losses were determined.

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No
- Other: sex ratio

Statistics:

Analysis of variance (ANOVA) was performed on all parameters. Residuals from this preliminary analysis were examined for heterogeneity of variance using Levene's test. If the Levene 's test was significant at the 1% level, then the particular variable concerned was subjected to a non-parametric analysis. Otherwise, William's test was performed to compare the high dose with control at the two-sided 5% level. If this test was statistically significant, than comparisons of the subsequent doses against control were performed at the one-sided 5% level until a non-significant difference was found. If Levene's test indicated that there were significant differences in the treatment group variances, or if a parametric analysis was deemed to be inappropriate, then a Kruskal-Wallis ANOVA was performed to assess overall differences between the treatment groups, followed by Shirley's non-parametric version of Williams' test, which is based on mean ranks rather than the arithmetic means. Nominal data were analyzed using the Fisher's Exact Test.

Indices:

Copulation and fertility indices and pre- and post-implantation losses were calculated.

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, non-treatment-related

Description (incidence):

600 mg/kg bw/day: 1/25 males died unscheduled on day 25
2000 mg/kg bw/day: 1/25 males died unscheduled on day 63 (since that animal was cannibalized and the remaining tissues were partly autolysed, thus the cause of death could not be determined)

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

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:

no effects observed

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

no effects observed

Early or late resorptions:

no effects observed

Dead fetuses:

no effects observed

Changes in pregnancy duration:

not examined

Changes in number of pregnant:

no effects observed

Other effects:

not examined

Key result

Dose descriptor:

NOAEL

Remarks:

general toxicity

Effect level:

2 000 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: no adverse effects observed

Key result

Dose descriptor:

NOAEL

Remarks:

developmental toxicity

Effect level:

2 000 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: no adverse effects on developmental parameters observed

Abnormalities:

no effects observed

Fetal body weight changes:

no effects observed

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

effects observed, treatment-related

Description (incidence and severity):

2000 mg/kg bw/day: Statistically significant increase in the number of males (53.3%). Due to the low difference to the control group, the biological relevance is questionable.

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

not examined

External malformations:

no effects observed

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

200 and 2000 mg/kg bw/day: Statistically significant increased incidences of cervical rib (minor skeletal malformation), although incidences at low and high dose were out of the historical control data range, observations are not considered relevant, since a dose relationship was absent.
Incidences 0/175 (control group), 5/182 (low dose), 0/192 (mid dose), 6/172 (high dose)

Visceral malformations:

effects observed, non-treatment-related

Description (incidence and severity):

2000 mg/kg bw/day: Statistically significant increase in incidences of increased pelvic caviation of kidneys (variation). The incidences of increased pelvic cavitation observed in treated groups (5.9-11.5%) were within the historical control range of 0.0 to 41.5% and thus not considered biologically relevant.
Fetal incidences: 14/341 (control group), 22/352 (low dose), 30/371(mid dose), 40/336 (high dose)
Litter incidences: 18/32 (control group), 9/24 (low dose), 15/25 (mid dose), 15/23 (high dose)

Other effects:

not examined

Key result

Dose descriptor:

NOAEL

Effect level:

2 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effect on fetal development observed

Abnormalities:

no effects observed

Developmental effects observed:

no

Table 1: Mean values intrauterine development

Dose (mg/kg bw/day)	control	200	600	2000
Maternal effects
Number of dams with implantations	23	24	25	23
Mean number of implantation per female	15.8	15.8	15.7	15.3
Mean number of corpora lutea per female	16.8	17.5	16.8	16.3
Mean number of implantations %	93.9	91.3	94.6	95.9
Mean pre-implantation loss %	5.7	8.9	6.3	6.9
Number of early embryo/fetal deaths (resorption)	21	28	21	14
Number of late embryo/fetal deaths (resorption)	1	0	1	2
Number of dead fetuses	0	0	0	0
Mean post-implantation loss %	6.1	8.7	5.4	4.1
Mean placental weight [g] per female	0.61	0.69	0.62	0.67
Fetal effects
Number of dams with viable fetuses	23	24	25	23
Number of viable fetuses per group	341	352	371	336
Mean number of viable fetuses per female	14.8	14.7	14.8	14.6
Number male fetuses	154	174	181	187
Number female fetuses	187	178	190	149
Mean number of male fetuses %	45.1	49.5	48.3	53.3*
Mean litter weight [g]	60.4	59.5	61.6	60.8
Mean fetal weight [g]	4.07	4.05	4.15	4.15

* p<0.05

 

Table 2: Malformations

Dose (mg/kg bw/day)	control	200	600	2000
Total number of litters examined	23	24	25	23
Total number of fetuses examined	341	352	371	336
External and visceral examination
Number with major abnormalities	1	1	7	3
Number with minor abnormalities	3	1	4	3
Number with variations	46	68	85	72
Skeletal examination
Number with major abnormalities	0	0	3	1
Number with minor abnormalities	9	19	17	21
Number with variations	169	178	187	167

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Lanthanum carbonate was tested for its ability to interfere with in utero development in several studies in two species, includingreliable data on developmental toxicity in rabbits and rats. Furthermore, hazard assessment issupported by data on structural analogues (for further details on the rationale for read across, please refer to the Analogue Justification provided in the technical dossier). A summary of the available data is summarized below. 

 

In a GLP-compliant rabbit developmental toxicity study performed similar to OECD 414, groups of time-mated female New Zealand White rabbits (20 animals per dose group) received daily doses of 250, 750 and 1500 mg/kg bw/day of Lanthanum carbonate suspended in 0.5% carboxyymethyl cellulose by oral gavage from day 6 to 18 of pregnancy (Shire, 1996c). Controls received the vehicle 0.5% carboxyymethyl cellulose.

Clinical observations and mortality were recorded daily, body weights were recorded on days 0, 3, 6 to 18, 22, 25 and 28 of pregnancy. Food consumption was recorded daily from days 3 to 6 of pregnancy and every 2 days thereafter. On day 28 of pregnancy, animals were sacrificed.

All major organs were examined macroscopically and organs showing abnormalities were fixed and stored.

Pregnancy rates, number of corpora lutea, implantation sites, early and late resorptions, dead and live fetuses, fetal and placental weights and external abnormalities were recorded. Pre- and post-implantation losses were determined. All live fetuses were examined for sex and visceral malformations after euthanization and fixation. Further, the brain was examined and fetuses were prepared for skeletal and visceral examinations to evaluate malformations and variations.

A higher incidence of reduced fecal output, with liquid/loose feces was noted in dams of the high dose group compared to controls. Further, reduced fecal output (liquid/loose feces), reduction in body weight and presence of mucus on the tray liner was observed in one animal before abortion. Necropsy findings included red stained fur, distended stomach with dark fluid and empty colon. This female aborted 7 fetuses on day 25 of pregnancy.

Significantly reduced body weight gain compared to controls was observed in the high dose group between GD 6 and 18 and the overall body weight gain during the dosing period was significantly lower than that of controls. Food consumption of the high dose animals was lower than that of controls throughout the dosing period with statistically significantly reduced levels compared to controls on GD 6 to 10. No effects of body weight or food consumption were observed in the other treatment groups. At mid and high dose significantly reduced placental weights were observed. Pregnancy rates were comparable between dose groups and controls (90, 90, 95, 95% at 0, 250, 750 and 1500 mg/kg bw/day).

The numbers of corpora lutea, implantations and early and late fetal deaths did not differ between groups. At the highest dose group the numbers of pre- and post- implantation losses were significantly higher than in controls (16.7 versus 8.8% and 10% versus 4.7%, respectively), but the values were well within the historical control ranges of the performing institute (historical control ranges: pre-implantation loss 2.5 to 26.7%; post-implantation loss 3.8 to 15.9%). Thus, the biological significance of this effect remains unclear. No effect on the remaining pregnancy parameters were observed in any other treatment group. No treatment-related effect was observed on sex ratios. The mean litter weight and mean fetal weights were slightly lower in the high dose compared to the control group, but this difference was not statistically significant. Fetal weights of other groups were similar to those of controls. The placental weight was statistically significantly lower than that of controls in the mid and high dose groups, but no dose dependency was observed. At 1500 mg/kg bw/day reduced placental weight was accompanied by a tendency of increased pre- and post-implantation losses and a tendency of reduced fetal body weights. The toxicological relevance of reduced placental weight at the mid dose remains unclear due to the absence of effects on fetal body weight and pre- and post-implantation losses. In contrast, recued placental weight was in line with increased pre- and post-implantation losses thereby indicating maternal developmental toxicity.

No treatment-related effects were observed on the overall incidences of external, visceral or skeletal malformations or variation. The incidence of minor skeletal malformations was increased compared to the concurrent control animals in a few instances: incomplete ossification of the parietal bone (statistically significant in the mid dose only) or in one or more metacarpal bones (no statistical significance in any dose group), but positive trend test of variations (incomplete ossification of one or more phalanges of the hind limbs). However, the observed incidences were all within the historical control ranges.

 

In conclusion, a NOAEL for general maternal toxicity of 750 mg/kg bw/day is defined based on clinical findings (reduced fecal output, with liquid/loose feces) and significantly reduced body weight and food consumption at the next higher dose level (1500 mg/kg bw/day). For maternal developmental toxicity a LOAEL of 1500 mg/kg bw/day was derived. At this dose level placental weights were significantly reduced. Furthermore, at the same dose level, a tendency of increased pre- and post-implantation losses and a tendency of reduced fetal body weights were observed. Due to general toxicity in dams at the same dose level, maternal toxicity leading to maternal developmental toxicity can not be excluded. A NOAEL for developmental maternal toxicity of 750 mg/kg bw/day is derived. In Fetuses, no adverse effects on the evaluated parameters were observed up to the highest dose tested, thus a NOAEL of 1500 mg/kg bw/day can be derived for fetal developmental effects.

 

Further, a reliable combined one generation reproductive toxicity study combined with an embryonic developmental study was conducted similar to OECD 415 in male and female Spraque-Dawley rats (SD IOPS-Caw strain) with Lanathanum carbonate administered orally at doses of 200, 600 or 2000 mg/kg bw/day (Shire, 1996a). Males were dosed for at least 63 days prior to mating with exposure continuing until sacrifice at the end of the mating period. Females were dosed continuously starting 14 days before mating, through the mating period till day 17 of pregnancy. Males were killed after the end of the mating period and females were sacrificed on day 20 of pregnancy.

 

Clinical signs were evaluated daily, mortality twice daily, body weights for males and females during the pre-mating period twice weekly. During pregnancy female body weights were determined daily. Food consumption was determined weekly and during pregnancy at the following intervals: day 0 to 6, 6 to 12, 12 to 17 and 17 to 20. All organs or tissues showing macroscopic abnormalities were fixed for further analysis. In males testes and epididymis were removed, testes weighed and both fixed. In females, live fetuses and their placenta were removed, and the uterus and ovaries were fixed in neutral buffered formaldehyde. In addition, pregnancy status, numbers of corpora lutea, implantation sites, resorptions and dead and live fetuses were recorded. Fetal/Litter and placental weights as well as fetal sex were recorded in addition to copulation index, fertility index, pre- and post-implantation losses. Fetuses were examined for external abnormalities. After fixation, one half of the live fetuses were examined for visceral abnormalities, the other half was examined for skeletal abnormalities.

Two males were found dead during the pre-mating period, one animal dosed at 600 and the other animal dosed at 2000 mg/kg bw/day. Since the dead animal in the high dose group was cannibalized and the remaining tissues were partly autolysed, the cause of death could not be determined.

No treatment-related effects on clinical signs, body weight gain or food consumption, were observed. In addition, no macroscopic findings or histopathological effects were observed at necropsy.

No treatment-related effect on the number of pregnant females per group was observed. Pregnancy rates were 92, 96, 100 and 92% in control, 200, 600 and 2000 mg/kg bw/day dose groups, respectively.

The mean number of corpora lutea, implantations, live fetuses and mean percent of pre- and post-implantation losses, number of early/late embryo/fetal deaths and placental weights were similar between groups and not affected by treatment. Mean litter weights, mean fetal and placental weights were similar between the groups. The percentage of male fetuses was significantly higher in the high dose group (53.3%) compared to controls (45.1%). However, as the number of males is still near to 50% the biological relevance of this increase is questionable.

Combined examination of external/visceral and skeletal findings, did not reveal any statistically significant increase of any major abnormalities between treated and control groups. Although the total number of major abnormalities was increased compared to concurrent controls in the mid and high dose groups, the increase was not dose-related (higher in mid than in high dose group) and was within the historical control range of the institute. This is therefore regarded as a rather as incidental finding and not as treatment-related. Some statistically significant differences in minor skeletal malformations were reported at low and high dose, but there was no dose-relationship.

A dose-related increase in a visceral variation (pelvic cavitation of kidneys) was noted in the high dose group, but the incidences in the treated groups were within the historical control range which showed a high variability (0.0 to 41.5%). It can therefore be concluded that no treatment related developmental toxicity or teratogenicity was observed in this study.

Based on the results of the conducted study, no effects on fetal development due to in utero exposure have been observed. Thus, a NOAEL of 2000 mg/kg bw/day was derived for developmental toxicity (for effect levels on reproduction, please refer to “Effects on fertility”)

 

Moreover, in a reliable combined developmental neurotoxicity/reproductive toxicity study similar to OECD 426 was peformed (Shire, 1996b). In this study time-mated female Sprague-Dawley rats were orally exposed to Lanthanum carbonate from implantation (GD 6) throughout lactation (PND 20) at doses of 200, 600, 1000 or 2000 mg/kg bw/day via gavage. All dams were allowed to rear their pups up to post-natal day 21, afterwards the dams were sacrificed for post-mortem examinations. Mortality was recorded twice daily and clinical signs daily. Body weights were recorded daily from GD 5 to PND 21. Food consumption was recorded during pregnancy and on PND 1 to 14. At final sacrifice of P0 animals, all major organs were examined for macroscopic changes and ovaries, pituitary and adrenals were weighed. Ovaries, uterus, cervix, vagina, pituitary, adrenals and any gross lesions were fixed. Beginning on day 21 of pregnancy, all P0 females were observed at about 30-minute intervals for evidence of parturition; the times of onset and completion of parturition were recorded. Furthermore, gestation, live birth and viability indices were calculated.

After weaning, 20 F1 pups/sex/group were randomly selected for detailed post-weaning examinations and rearing to sexual maturity. The remaining pups were subjected to necropsy. The selected pups were examined daily for clinical signs, and weighed weekly. Ophthalmoscopic examination (PND 28-35) and assessments of auditory function (PND 28-35) and E-maze learning potential (PND 28) were performed. All males were examined daily for preputial separation from PND 35, and females were examined daily for vaginal opening from PND 28.

When the selected F1 animals reached 13 weeks of age, each female was mated with a male from the same group for up to 7 days. Vaginal smears were taken daily until sperm was found in the smear. The male was removed from the cage on the day of mating. If a female had not mated within seven days, the male was removed and another male that had previously mated was substituted. The F1 pregnant females were weighed on days 0, 7, and 13 of pregnancy, and were necropsied on day 13. All major organs were examined grossly; ovaries, pituitary and adrenals were weighed. Organs or tissues showing gross abnormalities were fixed. Pregnancy status and the numbers of corpora lutea, implantation sites, early and late resorptions, and live embryos were recorded. The F1 females that showed no evidence of mating after the second mating were necropsied 13 days after the end of the mating period. The F1 males were killed about 2 weeks after the end of the mating period, major organs were examined, and the testes, epididymides and adrenals were weighed. The testes, epididymides and any other organs or tissues showing gross lesions were preserved.

 

In the P0 generation, during late pregnancy and the lactation period pale and reduced quantities of feces were observed in the treated maternal groups.

There was no effect of treatment on maternal body weight or bodyweight gain during pregnancy and lactation. Food consumption of the high dose group was significantly lower than that of controls on lactation days (LD) 4 to 7. An evaluation of adversity is not possible due to missing detailed information on results, including body weights for this special study period. Necropsy findings of P0 females were unremarkable and no treatment related effects on absolute or relative body weights, pituitary, ovary and adrenal weights were observed. One high dose female had a litter of only 1 pup that was dead. All other pregnant females produced live litters. The gestation index was 100, 100, 100 and 96% for the control, 200, 600 and 2000 mg/kg bw/day groups, respectively. There was no difference between groups with regard to duration of gestation, parturition, mean number of pups born, mean viability indices and cumulative survival index. Six females failed to rear their litters, 2 from control, 3 of the 600 mg/kg/day group and 1 at the 2000 mg/kg/day group. As there was no dose relation, this effect was not regarded as treatment-related.

 

In the F1 generation, no clinical signs were reported except for pale body and piloerection of high dose animals directly after weaning. There was no effect on F1 organ weights except that the mean absolute pituitary weight was lower in the high dose male group than in control, with no significant effect on relative pituitary weight.

At a dose of 2000 mg/kg bw/day, pup weights (F1) were significantly reduced in males, beginning from post-natal day 7, 14 and 21. In females pup weights were significantly reduced, beginning from post-natal day 4 onwards. The overall body weight gain for the high dose group was significantly reduced for both sexes for post-natal day 0 to 21. At mid dose body weight of females were significantly reduced on post-natal day day 4, post-natal day 4 post-culling and post-natal day 21 and at low dose on post-natal day day 4 and post-natal day 4 post-culling. The overall body weight gain for mid dose females was significantly reduced for post-natal day day 0 to 21. The pup body weights were similar across control and treatment groups at post-natal day 0.

At the high dose the percentage of pups with eyes open was significantly lower (50%) compared to controls on post-natal day 16. 7/21 litters of the high dose group had 50% or more of pups with delayed eye opening on day 16. The times of eye opening were similar to controls in all other dose groups. At the same dose body weights were significantly reduced. Thus the delay in eye opening is probably a consequence of the reduced body weight. Based on the available data a possible link to maternal effects (reduced food consumption during lactation period) cannot be assessed and an evaluation of adversity is currently not possible due to missing detailed information on results.

No treatment related effects were observed on the time of ear opening, presence of righting startle or papillary light reflex reactions.

Examination sexual developmental revealed that preputial separation was significantly delayed in high dose males compared to controls. Similarly, , a dose-related delay in vaginal opening was noted in females at all dose levels. Since body weights were significantly reduced at the same doses at which effects on sexual development were observed, the delay in sexual development is probably a consequence of the reduced body weight. Based on the available data a possible link to maternal effects (reduced food consumption during lactation period) cannot be assessed and an evaluation of adversity is currently not possible due to missing detailed information on results

 

Body weights of high dose F1 males reared to sexual maturation were statistically significantly lower than that of controls from week 5 to 11 and 13-14 and that of high dose females from week 5 to 8. There were no effects on body weights in other treatment groups.

 

Following mating of the F1 generation (now also declared as P1 generation), the following observations were made: The mean number of days taken for mating, copulation and fertility indices were similar between treated and control groups. Pregnancy rates for females in the P1 generation were comparable between groups (84.2, 94.7, 85.0 and 100% in the 0, 200, 600 and 2000 mg/kg/day dose groups, respectively). No differences between groups of P1 mated rats were observed in the number of corpora lutea, implantations and live embryos, pre- and post-implantation losses. Body weights during pregnancy of P1 females were all similar to controls.

 

In conclusion, there were no adverse effects observed in maternal P0 animals except for reduced food consumption at high dose during days 7 to 14 of lactation. Evaluation of adversity of this effect is currently not possible, due to missing detailed information on results. A NOAEL for maternal general toxicity and fertility was derived at 2000 mg/kg bw/day.

In the P1 generation (exposure via P0 maternal animals only), a LOAEL of 2000 mg/kg bw/day was derived for general toxicity based on significantly reduced body weight and weight gain. Further, a NOAEL of 2000 mg/kg bw/day was derived for fertility due to the absence of adverse effects on the evaluated reproductive parameters. In the F1 generation (offspring from P0 until end of maturation), a LOAEL for developmental effects in males was determined at 2000 mg/kg bw/day based on significantly delayed preputial separation. Further, based on significantly delayed vaginal opening at all doses, a LOAEL for developmental effects was determined at 200 mg/kg bw/day in females. However, at the same doses body weights were significantly reduced in males and females. Thus the delay in sexual development is probably a consequence of the reduced body weight. Based on the available data a possible link to maternal effects (reduced food consumption during lactation period) cannot be assessed. Evaluation of adversity is currently not possible, due to missing detailed information on results

Based on the delayed eye opening at the high dose in males and females, a LOAEL for Developmental neurotoxicity was established at 2000 mg/kg bw/day. However, the delay in eye opening is probably a consequence of the reduced body weight. As discussed above, evaluation of adversity is currently not possible, due to missing detailed information on results.

 

The same studies on Lanthanum carbonate were furthermore available as a short abstract (Läkemedelsverket 2006) and are included in the dossier as supporting studies.

 

Furthermore read-across studies from the surrogate substance Lanthanum chloride are available and included in the dossier as supporting studies (for further information on the rationale for read-across, please refer to the Analogue Justification provided within the technical dossier):

 

Lanthanum chloride was evaluated for effects on embryofetal development in rats and mice following oral administration.

 

In a non-guideline one-generation study, groups of 10 Swiss webster mice were exposed to Lanthanum chloride via drinking water at concentrations of 0, 125, 250, and 500 mg/L (corresponding to 0, 10, 20 and 40 mg/kg bw/d based on an average daily water consumption of 200 mL) 14 days prior to conception, during gestation, and until 30 days postnatally (Briner et al., 2000). Overall, litter size as well as general health and constitution including weight gain and relative brain weight did not differ significantly between the groups. However, there was a non-significant trend for delayed ear development and eye opening within exposed groups. Therefore, the NOAEL for developmental effects in this study is estimated to be 40 mg/kg bw/d, the highest dose tested.

 

In a non-standard study, maternal rats were exposed Lanthanum chloride from gestation day 0 through postnatal day 20 (Feng et al., 2006). From postnatal day 20, the pups were exposed to Lanthanum chloride until postnatal day 150. Among other parameters, physical and neurobehavioural development of the pups was recorded. In this study, Lanthanum chloride was not embryotoxic or teratogenic including the highest dose tested (40 mg/kg bw/d). Furthermore, there were no significant differences in body weight within all groups and no differences in pinna detachment and eye opening between groups. Thus, a NOAEL of 40 mg/kg bw/day was derived, which corresponds to the highest dose tested.

Justification for classification or non-classification

Based on the available data on reproductive toxicity, Lanthanum carbonate is not considered to exhibit hazardous properties on reproduction and fertility. The data are conclusive but not sufficient for classification according to the criteria 1272/2008/EC (CLP).