Lanthanum chloride, anhydrous

Toxicity to reproduction

Administrative data

Endpoint:

three-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:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well documented publication/study report which meets basic scientific principles

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1975

Materials and methods

Principles of method if other than guideline:

Lanthanum oxide was fed at various doses to mice for three generations. Survival, hematology, morphological development, maturation, reproduction and lactational performance were analysed.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Details on test material:

- Name of test material (as cited in study report): Lanthanum oxide
- Analytical purity: no data
- Stability under test conditions: not verified, but considered stable due to inorganic nature

Test animals

Species:

mouse

Strain:

CF-1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: weanlings in each generation
- Weight prior to mating (means of groups): (P) 26.61 to 28.74 g; (F1): 26.21 to 30.2 g; (F3): 28.55 to 37.04 g
- Housing: standard polycarbonate mouse cages; Until initation of breeding: groups of 4 females and 2 males respectively were housed together
Mating period: 2 males with 4 females for 17 days. Pregnant females individually, after birth of the young with their respective litters.
- Diet (e.g. ad libitum): ground commercial stock diet


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 3
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: diet

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:


DIET PREPARATION
- Rate of preparation of diet (frequency): Each diet was prepared in sufficient quantities to last the entire experiment.
- Mixing appropriate amounts with (Type of food): ground stock diet (Laboratory chow, Relston Purina, St. Louis Mo)
- Storage temperature of food: The diet was pelleted and stored until feeding.

Details on mating procedure:

- M/F ratio per cage: 2/4
- Length of cohabitation: 17 days
- After successful mating each pregnant female was caged (how): individually

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Neutron activation analysis was used to determine 1, 10 and 100 times the use amount in the diets.

Duration of treatment / exposure:

continuously for three generations

Frequency of treatment:

continuous

Details on study schedule:

- Each generation began at the same time (weanlings; no further details given).

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0.4, 4, 40 and 400 ppm
Basis:
nominal in diet
given as Lanthanum

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0.69 (basal diet), 1.16 ± 0.22, 6.08 ± 1.02 and 62.5 ± 1.20 µg/g
Basis:
analytical conc.
given as Lanthanum

No. of animals per sex per dose:

16 females, 8 males

Control animals:

yes, plain diet

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: Mice were individually weighed at 3-weeks intervals until the breeding period. The dams were weighes again when the pups were weaned at 21 days.

OTHER:
Haematology/clinical chemistry: For each generation, five 3-month-old dams from the control group and five from the high-dose group were beld via the tail.
- Parameters examined: erythrocyte and leukocyte count, hemoglobin concentration, packed cell volume, serum protein, albumin, alpha-globulin, beta-globulin, gamma-globulin. Serum proteins were determined using microzone electrophoresis.

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 2 postpartum: to 6 +1 per litter

PARAMETERS EXAMINED
The following parameters were examined in [F1 / F2 / F3] offspring:
number and sex of pups, postnatal mortality, presence of gross anomalies, weight gain, physical abnormalities

Postmortem examinations (parental animals):

GROSS NECROPSY
- Gross necropsy consisted of integumentary, cardiovascular system, respiratory tract, gastro-intestinal tract, genital organs, urinary tract, endocrine and hematopoetic system, nervous and musculoskeleton system observations in control and high-dose animals.

Lanthanum content was determined in whole carcass of second generation control and high-dose animals.

Postmortem examinations (offspring):

The same as stated for parental animals.

Reproductive indices:

Females with litters
Average litter size per generation

Results and discussion

Results: P0 (first parental generation)

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
No test test substance related clincal signs were reported. The general appearance of all mice in all dose groups was good. Morbidity and mortality were less than 0.5 % in all dose groups and controls.

BODY WEIGHT (PARENTAL ANIMALS)
Body weights at mating and body weights of dams after weaning were comparable with controls for all dose groups.
Average daily body weight gains were significantly higher in the controls and the highest dose group than in the other groups. As there was no dose response relationship this is not considered a treatment related effect.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
The reproductive performance was reported to be comparable between controls and all dose groups.

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

>= 91.8 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: recalculated value for Lanthanum chloride, corresponding to 400 ppm Lanthanum oxide (= 52 mg La/kg/d) no effects up to and including the highest dose tested

Remarks on result:

other: Generation: P, F1, F2 and F3 (migrated information)

Results: F1 generation

Details on results (F1)

VIABILITY (OFFSPRING)
Viability was reported comparable in all generations and all dose groups with controls. Overall mortality and morbidity was less than 0.5% .

CLINICAL SIGNS (OFFSPRING)
There were reportedly no test substance related clincial signs in all generations and all dose groups. The general appearance of all mice in all dose groups was good.

BODY WEIGHT (OFFSPRING)
Average body weights after birth were comparable to controls in all dose groups in all three generations.
The average daily body weight gains in the second generation were singificantly higher than controls for the two lower dose groups and significantly lower than controls for the two higher dose groups. In the third generation the second highest dose group had a significantly lower daily body weight gain than all other groups. However the authors report that the differences detected in average daily body weight gains at different times were not related to the levels of minerals added to the diet.
No singificant differences were observed prior to mating or after weaning of the dams in all 3 generations.

GROSS PATHOLOGY (OFFSPRING)
Gross pathology of the third generation adult mice of the second highest dose group was performed and reportedly revealed no abnormal findings.

OTHER FINDINGS (OFFSPRING)
Haematology and serum protein investigations of the third generation second highest dose group animals were comparable to controls and all parameters were within normal limits.

Rare earth analysis in the second generation carcasses of the second highest dose group did not reveal any increases in levels that could clearly be related to the diet. All levels detected in controls and treated animals were at or below the lowest standards used in the analytical procedure.

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

The general appearance of all mice in all groups was good. No morphological anomalies were seen. Necropsy examinations of third generation adult mice fed the basal or 40 ppm diet did not reveal any abnormalities. No differences were detected in the number of females having litters within generations for the different groups. No significant differences were detected in average litter size. Hematology and serum proteins did not differ between animals in the same generation irrespective of whether they were fed the control or high dose diet.

Tables on reproductive/developmental parameters 1. Females with litters Dose group 1. Generation 2. Generation 3. Generation control 14/16 14/16 14/16 low 13/16 16/16 12/16 second 12/16 16/16 12/16 third 14/16 14/16 14/16 high 12/16 16/16 14/16 2. Average litter size (± standard error of mean (SEM)) Dose group 1. Generation 2. Generation 3. Generation control 6.4 ± 0.61 8.7 ± 0.60 7.0 ± 0.3 low 7.6 ± 0.70 9.06 ± 0.5 6.83 ±0.9 second 6.6 ± 0.6 8.2± 0.6 8.67 ± 1.0 third 8.1 ± 0.7 8.36 ±0.6 8.17 ± 0.7 high 6.90 ± 0.9 10.45 ± 0.5 7.17 ± 1.1 3. Average weight at birth in g (± SEM) Dose group 1. Generation 2. Generation 3. Generation control 7.58± 0.21 7.31 ± 0.31 7.73 ± 0.26 low 7.49 ± 0.28 7.00 ± 0.28 8.88 ± 0.39 second 7.61 ± 0.26 7.14± 0.21 8.09 ± 2.0 third 7.14 ± 0.22 7.8± 0.22 8.81 ± 0.39 high 7.33 ± 0.26 7.2± 0.18 8.36 ± 0.29