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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Basic data given, but critical details for the evaluation of the study,as standard devialtion and variation in effects and their relation to historical control data are missing. Statisitcal analysis for some endpoints did not take into account litter effects.

Data source

Reference
Reference Type:
publication
Title:
Neurodevelopmental effects of lanthanum in mice
Author:
Briner, W. et al.
Year:
2000
Bibliographic source:
Neurotoxicology and Teratology 22: 573-581

Materials and methods

Principles of method if other than guideline:
No guideline mentioned: Mice were exposed to Lanthanum chloride in drinking water at 0, 125, 250, and 500 mg/L concentration prior to conception, during gestation, and until 30 days postnatally.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Lanthanum chloride
- Molecular formula (if other than submission substance): LaCl3·7H2O
- Analytical purity: no data

Test animals

Species:
mouse
Strain:
Swiss Webster
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 4-6 weeks
- Housing: 10 per cage
- Access to food and water: ad libitum

ENVIRONMENTAL CONDITIONS
- Photoperiod: 14 h:10 h (light:dark cycle)

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on exposure:
The female mice were exposed to lanthanum chloride in distilled drinking water under one of four doses (0, 125, 250, and 500 mg/L corresponding to 0, 0.34, 0.67, and 1.35 mM respectively).
Details on mating procedure:
Impregnation procedure: cohoused, no further information available

Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
The mice were exposed for 14 days and then mated with males of the same age and strain. Exposure to lanthanum continued through gestation, parturition, and the postnatal period until day 30. The day of birth was designated postnatal day 0.
Frequency of treatment:
Drinking water ad libitum
Details on study schedule:
Mice were exposed for 14 days and then mated with males of the same age and strain. Exposure to lanthanum continued through gestation, parturition, and the postnatal period for the dams and pups until day 30. The day of birth was designated postnatal day 0.
For all the assessments the experimenter was blind to the treatment group of the animals. All experimenters were trained to criterion. Testing was done during the same time each day and the order of testing was random.
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 125, 250, and 500 mg/L; 0, 0.34, 0.67, and 1.35 mM, respectively
Basis:
nominal in water
No. of animals per sex per dose:
Dams: Control: 10; 125 and 250 mg/L: 7; 500 mg/L: 12
Control animals:
yes, concurrent no treatment
Positive control:
no data

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: no data
Sperm parameters (parental animals):
no males exposed
Litter observations:
STANDARDISATION OF LITTERS: no data

PARAMETERS EXAMINED
1) Developmental assessment:
Behavioral and neurologic assessments were made from age 4 to 20 days including the development of
- swimming behavior (every day)
- ear and eye opening (every day)
- weight gain (at 4, 8, 12, and 16 days of age).

Swimming was scored by dropping the animals into a pool of warm water (approx. 33° C) from a height of 6 inches.
Swimming behavior was scored within 10 s to avoid fatigue.
- a score of 0 was assigned if the animal was not able to keep its nose out of the water
- a score of 1 was assigned if the nose was out of the water
- a score of 2 was assigned if the nose and half of the head to the middle of the ear was out of the water
- a score of 3 was assigned if more than half of the head was out of the water
- a score of 4 was assigned if the animals exhibited adult swimming behavior by kicking with the hind limbs while keeping the forelimbs extended forward.

2) Neurological assessment
Between 30 and 32 days of age the animals were assessed with a modified version of a functional observational battery according to O´Donoghue (1996). Modifications consisted of the omission of the open-field component because pilot work did not suggest an effect of lanthanum exposure.

Postmortem examinations (parental animals):
no data
Postmortem examinations (offspring):
Brain chemistry
At 59 to 60 days of age the animals were killed with chloroform and weighed, and brains were removed, which were weighed and frozen. Lipid, protein, and lanthanum content of the brains were determined.
Statistics:
The litter was the unit of analysis for only part of the data derived from this study. For continuous variables (weights, swimming, lanthanum content, protein content) data were collapsed across litters and analyzed as by analysis of variance (ANOVA). For categorical data one subject was selected at random from each litter and analyzed with the chi-squared test. Gender was not used as an independent variable because pilot studies found no differences between the sexes. Follow-up analytic comparisons were done to determine group differences from control when appropriate.
Reproductive indices:
no data
Offspring viability indices:
no data

Results and discussion

Results: P0 (first parental animals)

Details on results (P0)

Overall, lanthanum exposure did not appear to have a noticeable effect on the health of the dams (no further information available).

Effect levels (P0)

Dose descriptor:
NOAEL
Remarks:
reproduction
Effect level:
40 mg/kg bw/day (nominal)
Sex:
female
Basis for effect level:
other: recalculated value from 500 mg/L drinking water based on a daily water consumption of 200 mL/kg bw/d no effects up to and including the highest dose tested

Results: F1 generation

Details on results (F1)

VIABILITY (OFFSPRING)
Litter size did not differ significantly between the groups [F(3, 32) = 0.33, p = 0.8 nor did the mortality rate of the pups due to cannibalism or
death of unknown cause [F(3, 32) = 0.77, p = 0.52].

CLINICAL SIGNS (OFFSPRING)
The general health and constitution of the offspring did not differ between the groups.
Eye opening:
The eye opening was delayed for the 125- and 250-mg/L groups, when compared to control. This was apparent at 14 days of age for both the 125- and 250-mg/L groups with a trend toward significance at 15 days postnatally for the 250-mg/L group. The 500-mg/L group were more similar to the
control group with regard to eye opening. Prior to and after those ages variance in eye opening was negligible. As there was no dose response and the high dose animals were comparable to controls, the effects are not considered treatment related.
Ear opening:
There was a trend for ear opening to be delayed for the 125- and 250-mg/L lanthanum groups at 13 days of age. Follow-up analysis found a significant difference between the control and 250-mg/L group. The 500-mg/L group appeared to behave more similarly to control. Prior to and after those ages differences in ear development were not significant. As there was no dose response and the high dose animals were comparable to controls, the effects are not considered treatment related.

BODY WEIGHT (OFFSPRING)
Weight gain did not differ in a statistically significant manner among the treatment groups although there was a nonsignificant trend for the 250- and 500-mg/L lanthanum-exposed groups to gain weight less readily than the other groups.

SEXUAL MATURATION (OFFSPRING)
No data given

ORGAN WEIGHTS (OFFSPRING)
The brain weight of the litters did differ between groups with the 500-mg/L group being statistically significantly different from the control group [F(3, 31) = 5.11, p = 0.006]. The brain-to-body-weight ratios did not differ between groups. Brain lanthanum, protein, and lipid content did not differ between treatment groups. However, there was a statistically significant correlation between brain lanthanum and protein content [r(19) = 0.49, p < 0.05]. Although being statistically significant, the effects described above are not of toxicological significance.

GROSS PATHOLOGY (OFFSPRING)
no data given

HISTOPATHOLOGY (OFFSPRING)
no data given

OTHER FINDINGS (OFFSPRING)
Emergence of walking behaviour
The emergence of walking behavior was delayed at 5 and 6 days postnatally for the 250-mg/kg group for both 5 and 6 days postnatally. The other
groups did not differ from control. After this age there was not a statistically significant difference between any of the groups. The authors did not analyse the relation to body weight of this effect. As the effect was only observed in the mid dose group and not in the low and high dose group, the findings are not considered treatment related.

Swimming development
A trend for swimming development to be delayed was reported by the authors for postnatal days 6 through 14 with statistically significant effects for the 250-mg/L and 500-mg/L groups. However, the graph depicted in the publication did not indicate a significant effect at the 500 mg/L dose level. According to the graph there was no dose response as well with regard to effect size. Furthermore the statisitcal analysis for this endpoint did not take into account the litter and may therfore not be appropriate. The reported effects on swimming behavior can therefore not be regarded as treatment related effects in the opinion of the applicant.

Neurological assessment (30-32 days of age)
Touch Response performance was characterized by the 125- and 250-mg/L lanthanum-exposed groups scoring more frequently for jerking toward the object (score 3) than the control group. However, according to the graphical depiction more animals inthe controls had a score 4 (agressive or violent reaction with or without vocalization. The 250-mg/L group also exhibited more freezing or turning to the opposite side (score 2). The
500-mg/L group reacted in a manner more similar to the control group (turning toward object or walking away). The variation in the responses is and standard deviation as well as historicall control data are also not given. As there was again no dose response and the low and high dose group were similar to controls, this effect cannot be regarded as treatment related.
Visual Placing Response performance was characterized by proportionately more mice in the 500-mg/L group scoring 1 for early vigorous extension or placing before vibrissae contact. The 125- and 250-mg/L groups scored 2 more frequently (placing after slight vibrissae contact), but according to the grpahical depiction the control group animals also scored 1 and 2, but in a slightly different proportion. No indication of the varialtionand standard deviation of the responses are given and also no indications of the historical control values. In the absence of this infomation the reported effects remain of questionable toxicological significance. As also no dose response in the pattern of reaction was observed, the applicant is of the opinion that the reported effects cannot be clearly related to the treatment.

The neurological effects described above usually occured at the low and medium dose level. Usually, high dose animals appeared to behave similar to controls. No clear dose response was observed for any of the reported effects. It can therfore be concluded that no clearly test substance related effects were observed in this study.

Effect levels (F1)

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Dose descriptor:
NOAEL
Remarks:
developmental
Generation:
F1
Effect level:
40 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: recalculated value from 500 mg/L drinking water based on a daily water consumption of 200 mL/kg bw/d
Dose descriptor:
NOAEL
Remarks:
neurotoxicity
Generation:
F1
Effect level:
40 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: recalculated value from 500 mg/L drinking water based on a daily water consumption of 200 mL/kg bw/d no clearly test substance related effect on neurobehavioral endpoints. (Original data: test substance was LaCl3*7H2O)
Dose descriptor:
NOAEL
Remarks:
neurotoxicity
Generation:
F1
Effect level:
500 mg/L drinking water
Sex:
male/female
Basis for effect level:
other: Converted to lanthanum trichloride anhydrous!

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Exposure of female and offspring mice to up to 500 mg/L of lanthanum chloride in drinking water from 14 days premating throughout the postnatal period did not result in any clearly treatment related effects. Female mating behavoir and outcome was reportedly not affected by the treatment. Although the authors have reported some behavioral changes in some dose groups, the reported effects did not show a dose response and the effects as reported cannot be attributed to the treatment.