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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
1 407 mg/kg bw/day
Additional information

Studies on lanthanum oxide itself are not available. Studies with other lanthanum compounds, in particular mixtures of oxides and lanthanum carbonate which has a comparable solubility to lanthanum oxide and is regarded to be very similar with regard to its toxicokinetics are considered relevant for read across to lanthanum oxide. Some studies performed with lanthanum chloride are considered as well, although the bioavailability of the chloride may be higher.

Hutcheson et al. (1975) fed a diet containing 0.4, 4, 40 and 400 ppm Lanthanum oxide and other metal oxides 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.

No effects on male and female reproductive organs were observed in a subchronic oral toxicity study with lanthanum carbonate (Reißmüller, 2006) in rats at doses up to and including 974 mg/kg bw/d for males and 1480.4 mg/kg bw for females (corresponding to 525 mg/kg bw and 799 mg/kg bw of lanthanum oxide).

Moreover, the applicant is aware of recent guideline studies on reproductive and developmental toxicity of Lanthanum carbonate tetrahydrate that are quoted in a publicly accessible data base of the US FDA (2004). The applicant has made all efforts to obtain access to the original studies for use in the REACH registration , but it was denied. As the studies were made in the framework of a drug approval they do not fall under the data sharing obligations of REACH. However, as summaries of the studies are publicly accessible and provide the most valid information for the endpoint fertility, the applicant finds it appropriate to use the available information for the assessment rather than to propose further studies for animal protection reasons.

A reliable one generation fertility and embryonic development study was conducted similar to OECD 415 in male and female Sprague-Dawley rats (SD IOPS-Caw strain) with Lanthanum carbonate administered orally by gavage at doses of 200, 600 or 2000 mg/kg bw/d. In this study 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 from 14 days before mating until study termination on gestational day 20. Clinical signs were evaluated daily, mortality twice daily, body weights for males and females during the pre-mating period twice weekly. During pregnancy female bodyweights 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.

In males testes and epididymis were removed, testes weighed and both fixed.

In females pregnancy status, numbers of corpora lutea, implantation sites, resorptions, dead and live fetuses were recorded. Fetal and placental weights, fetal sex and external abnormalities were recorded and copulation index, fertility index, pre- and post-implantation losses were calculated. After fixation, one half of the live fetuses were examined for visceral abnormalities, the other half was examined for skeletal abnormalities.

Two males of two treatment groups were found dead during the pre-mating period. One death could be attributed to a dosing error, the other could not be attributed due to cannibalism.

No treatment related effects were observed on clinical signs, body weight gain, food consumption, mean number of days for mating, copulation and fertility indices for males, number of females pregnant (pregnancy rates 92, 96, 100 and 92% at 0, 200, 600, 2000 mg/kg bw/day). No treatment-related macroscopic findings were observed at necropsy. Testes weights (absolute and relative) of treated animals did not differ from those of controls. It can therefore be concluded that the NOAEL for fertility/reproductive toxicity was 2000 mg/kg bw, the highest dose tested in this study.This corresponds to a dose of 1407 mg/kg bw of lanthanum oxide.

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.

Short description of key information:
Taking into account all available information on the effects of various lanthanum salts on reproduction parameters, it can be concluded that Lanthanum oxide neither affect fertility nor mating performance in rats of both sexes at doses up to and including 1407 mg/kg bw/day of lanthanum oxide, the highest dose (recalculated as lanthanum oxide) tested in the respective study.

Effects on developmental toxicity

Description of key information
No effects were observed on embryo and fetal development of rats in a one generation study with lanthanum tricarbonate administered by oral gavage up to the highest dose level tested (2000 mg/kg bw/day). This would correspond to a NOAEL for both parental and developmental toxicity of 1407 mg/kg bw/day of lanthanum oxide. A guideline conform oral (gavage) developmental toxicity study with lanthanum tricarbonate in rabbits did not show any clearly treatment-related effects on developmental toxicity up to the highest dose tested 1500 mg/kg bw/day. At this dose level signs of maternal toxicity as reduced body weight gain and food intake, reduced fecal output and loose feces were observed. The NOAEL for maternal toxicity was 750 mg/kg bw/day, while for developmental toxicity a NOAEL of 1500 mg/kg day can be derived. This would correspond to a NOAEL for maternal toxicity of 537 mg/kg bw of lanthanum oxide and a NOAEL for developmental toxicity  915 mg/kg bw of Lanthanum oxide. A prenatal-postnatal development  study in female rats was performed with  lanthanum tricarbonate by oral gavage at dose levels  of 200, 600 and 2000 mg/kg bw from day 6 of pregnancy until day 20 post partum. The only findings that could possibly be related to maternal treatment with Lanthanum carbonate during pregnancy and lactation were observed in the high dose group and consisted of reduced body weight gain and delayed eye opening, preputial separation and vaginal opening in the F1 generation. The observed effects are often related to body weight and can probably be considered as secondary to the lower body weights in this dose group. No other landmarks of development or behavioral parameters were changed. Mating and sexual performance of the F1 generation was unaffected by the treatment. In the absence of single animal data, historical control data of the findings and of a litter based statistical analysis of the F1 generation findings no firm canclusions on effects can be drawn.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
1 073 mg/kg bw/day
Additional information

Studies on lanthanum oxide itself are not available. Studies with other lanthanum compounds, in particular lanthanum carbonate which has a comparable solubility to lanthanum oxide and is regarded to be very similar with regard to its toxicokinetics are considered relevant for read across to lanthanum oxide. Some studies performed with lanthanum chloride are considered as well, although the bioavailability of the chloride may be higher

The applicant is aware of recent guideline studies on reproductive and developmental toxicity of Lanthanum carbonate tetrahydrate that are quoted in a publicly accessible data base of the US FDA (2004). The applicant has made all efforts to obtain access to the original studies for use in the REACH registration , but it was denied. As the studies were made in the framework of a drug approval they do not fall under the data sharing obligations of REACH. However, as summaries of the studies are publicly accessible and provide the most valid information for the endpoint fertility, the applicant finds it appropriate to use the available information for the assessment rather than to propose further studies for animal protection reasons.  

A reliable one generation fertility and embryonic development study was conducted similar to OECD 415 in male and female Sprague-Dawley rats (SD IOPS-Caw strain) with lanthanum carbonate administered orally at doses of 200, 600 or 2000 mg/kg bw/d. In this study 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 from 14 days before mating until study termination on gestational day 20. Clinical signs were evaluated daily, mortality twice daily, body weights for males and females during the pre-mating period twice weekly. During pregnancy female bodyweights 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. In males testes and epididymis were removed, testes weighed and both fixed.In females pregnancy status, numbers of corpora lutea, implantation sites, resorptions, dead and live fetuses were recorded. Fetal and placental weights, fetal sex and external abnormalities were recorded and copulation index, fertility index, pre- and post-implantation losses were calculated. After fixation, one half of the live fetuses were examined for visceral abnormalities, the other half was examined for skeletal abnormalities.

Two males of two treatment groups were found dead during the pre-mating period. One death could be attributed to a dosing error, the other could not be attributed due to cannibalism.

No treatment-related effects on clinical signs, body weight gain or food consumption, were observed. No treatment-related macroscopic findings were observed at necropsy. The mean number of corpora lutea, implantations, live fetuses and mean percent of pre- and post-implantation losses, mean litter weights, mean fetal and placental weights were similar between groups and not affected by treatment. The percentage of male fetuses was significantly higher in the high dose group compared to controls, but the level was within the historical control levels of the performing institute and therefore this was not considered a treatment-related effect. No statistically significant increase of any major abnormality was observed between dosed and controls. 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 a by chance finding and not treatment-related. Some statistically significant differences in minor skeletal malformations were reported, but there was no dose relationship. A dose-related increase in one variation (increased pelvic cavitation of kidneys) was noted , but the incidences in the treated groups were within the historical control range which showed a high variability. It can therefore be concluded that no treatment related developmental toxicity or teratogenicity was observed in this study and the NOAEL for developmental toxicity was 2000 mg/kg bw, the highest dose tested in this study. This corresponds to 1407 mg/kg bw of lanthanum oxide.

In addition to this study, two other studies are reported in the document by FDA (2004), a developmental toxicity study in rabbits and a pre- and postnatal development study in rats. These studies are briefly summarized below.

 

In a GLP-compliant rabbit developmental toxicity study according to OECD 414, groups of time-mated female New Zealand White rabbits received daily doses of 0 (vehicle control), 250, 750 and 1500 mg/kg bw/day of Lanthanum carbonate by oral gavage from day 6 to 18 of pregnancy. Surviving animals were killed on day 28 of pregnancy. 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.

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

Pregnancy status, 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. The brain was examined and thereafter the fetuses were treated with potassium hydroxide and stained for examination of skeletal and visceral malformations and variations.

One female of the high dose group showed clinical signs as reduced fecal output (liquid/loose feces), reduced body weight, presence of mucus on the tray. Necropsy findings included red stained fur, distended stomach with dark fluid and empty colon. This female aborted 7 fetuses on day 25 of pregnancy.

A higher incidence of reduced fecal output with liquid loose feces was observed in the high dose group. 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. No remarkable findings were observed at necropsy. 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 were comparable between groups. At the highest dose group the numbers of pre- and post- implantation losses were significantly higher than control values (16.7 versus 8.8% and 10% versus 4.7%), but well within the historical control values of the performing institute (pre-implantation loss 2.5 to 26.7%; post-implantation loss 3.8 to 15.9%). No effect on these or other 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 controls in the mid and high does groups, but no dose dependency was observed. No treatment-related effects were observed on the overall incidences of external, visceral or skeletal malformations or variation. The incidence of single endpoint of minor skeletal malformations was increased compared to concurrent control 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, no clearly treatment-related effects on developmental toxicity were observed up to the highest dose tested that was clearly maternally toxic. The NOAEL for maternal toxicity was 750 mg/kg bw/day, while for developmental toxicity a NOAEL of 1500 mg/kg day can be derived. This corresponds to a maternal NOAEL of 537 mg/kg bw as lanthanum oxide and a developmental NOAEL of 1073 mg/kg bw as lanthanum oxide.

 

In a pre-postnatal study performed according to OECD 426, time-mated female Sprague-Dawley rats were orally (gavage) exposed to Lanthanum carbonate from implantation (GD 6) throughout lactation (PND 20) at doses of 200, 600, 1000 or 2000 mg/kg bw/d. 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 F0 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. In the F1 generation, litter size and sex were recorded and pups were examined for gross malformations, clinical signs and body weight gain. In this study also neurological parameters were investigated in the F1 generation, including auditory function and E-maze learning.

At 13 weeks of age each F1 female was mated with a male from the same group (mating period up to 7 days). F1 females with no evidence of pregnancy were necropsied. F1 males were killed about 2 weeks after the end of the mating period, major organs were examined and testes, epididymes and adrenals were weighed and the testes , epididymes and organs with gross changes were preserved. Body weights of F1 pregnant females were recorded on GD 0, 7 and 13. The females were necropsied on GD 13 and all major organs examined for macroscopic changes. Ovaries, pituitary and adrenals were weighed. All organs or tissues with gross abnormalities were fixed. Pregnancy status, numbers of corpora lutea, implantation sites, early and late resorptions and life fetuses were recorded. Gestation, live birth index and viability index were calculated.

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.

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 95% for the 0, 200, 600 and 2000 mg/kg bw groups, respectively. There was no difference between groups with regard to duration of gestation and parturition. 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. Necropsy findings of F0 females were unremarkable and no treatment related effects on absolute or relative body weights, pituitary, ovary and adrenal weights were observed.

In the F1 generation, the mean number of pups born, mean live birth index, sex ratio and viability index were comparable to controls in all treatment groups. PND 0 body weights were comparable between groups. On PND 7, 14 and 21 pup weights of the high dose group were significantly lower than controls. On PND 4 a reduced body weight was noted in females of all dosed groups. The overall body weight gain for the high dose group between PND 0 and 21 was reduced in males and females. Significantly reduced body weight gain was also noted in mid dose females. At the high dose the percentage of pups with eyes open was significantly lower (50%) compared to controls on PND 16. The times of eye opening were similar to controls in all other dose groups. No treatment related effects were observed on the time of ear opening, presence of righting startle or papillary light reflex reactions.

No clinical signs were reported in the F1 animals except for pale body and piloerection of high dose animals directly after weaning. Body weights of high dose F1 males 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. Body weights during pregnancy of F1 females were all similar to controls. Preputial separation was significantly delayed in high dose males compared to controls. A dose related delay in vaginal opening was noted in the treated females.

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 F1 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 were observed in the number of corpora lutea, implantations and live embryos, pre- and post implantation losses. Necropsy of F1 offspring did not show any treatment related findings. Organ weights were comparable to controls in all treatment groups, with the exception of the absolute pituitary weight in high dose males that was lower than controls, but the relative weight of the pituitary was not significantly different from that of controls.

In conclusion the only findings that could possibly be related to maternal treatment with Lanthanum carbonate during pregnancy and lactation were observed in the high dose group and consisted of reduced body weight gain and delayed eye opening, preputial separation and vaginal opening in the F1 generation. The observed effects are often related to body weight and can probably be considered as secondary to the lower body weights in this dose group. No other landmarks of development or behavioral parameters were changed. Mating and sexual performance of the F1 generation was unaffected by the treatment. In the absence of single animal data, historical control data of the findings and of a litter based statistical analysis of the F1 generation findings no firm conclusion on the relevance of the reported effects with regard to the treatment can be drawn. A tentative NOAEL of 600 mg/kg bw/day can be derived from this study. This would correspond to ca. 429 mg/kg bw/day of Lanthanum oxide.

 

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/d was derived, which corresponds to the highest dose tested.

Justification for classification or non-classification

Based on the available studies with lanthanum carbonate that did not show treatment related effects on fertility in and developmental toxicity in a one generation study in rats and a developmental toxicity study in rabbits up to the highest dose tested, no classification for fertility or developmental toxicity is proposed for lanthanum oxide based on the analogue approach.