Strontium neodecanoate

Toxicity to reproduction

Administrative data

Endpoint:

fertility, other

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

- animals were not mated, therefore no examination of gestation/pregnancy and offspring could be conducted - mortality was checked once only - detailed clinical observation and neurobehavioural examination were missing - food consumption was not measured weekly, but in week 2, 5, 9 and 12. - epididymes was not examined - housing conditions were not described - acclimatisation period was not stated

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Short-term toxicity of strontium chloride in rats

Author:

Kroes, R. et al.

Year:

1977

Bibliographic source:

Toxicology 7: 11 - 21.

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: OECD 408

Deviations:

yes

Remarks:

see section 7.5.1

Principles of method if other than guideline:

A subchronic study was conducted with strontium chloride hexahydrate using groups of 10 male and 10 female Wistar rats. The rats were given the test substance at dose levels of 0, 75, 300, 1200 or 4800 ppm (0, 7.5, 30, 120, or 480 mg/kg/day, resepctively) ad libitum via diet for a duration of 90 days. The following parameters were investigated: clinical signs/mortality, body weight, food consumption/food efficiency, organ weights, and histopathology. Additional males were used for the determination of the strontium levels in bone and muscle, which were examined at different times during the study.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

strontium chloride hexahydrate

IUPAC Name:

strontium chloride hexahydrate

Constituent 2

Reference substance name:

Strontium chloride

EC Number:

233-971-6

EC Name:

Strontium chloride

Cas Number:

10476-85-4

IUPAC Name:

strontium dichloride

Constituent 3

Reference substance name:

10025-70-4

Cas Number:

10025-70-4

IUPAC Name:

10025-70-4

Test material form:

not specified

Details on test material:

- Name of test material (as cited in study report): strontium chloride hexahydrate (from Mallinckrodt, St. Louis, Missouri, U.S.A.)
- Molecular formula: SrCl2 6H2O
- Composition of test material, percentage of components: barium content less than 0.02 %

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS - SPF Wistar rats
- Source: National Institute of Public Health
- Weight: 40 - 60 g
- Housing: housed under conventional conditions, littermate-divided in wire cages, two in a cage according to sex
- Diet (ad libitum): semi-purified diet (Muracon SSP-tox, Trouw Ltd., Putten, The Netherlands); diet contained 0.05 % Mg, 0.75 % P, 0.85 % Ca and 1.8 I.U. Vit. D.3 per gram
- Water (ad libitum): tap water

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

no data

Details on mating procedure:

no data

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

no data

Duration of treatment / exposure:

90 days

Frequency of treatment:

ad libitum

Details on study schedule:

no data

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0, 75, 300, 1200 or 4800 ppm strontium chloride hexahydrate
Basis:
nominal in diet

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0, 7.5, 30, 120 or 480 mg/kg bw/day strontium chloride hexahydrate (calculated from ppm values)
Basis:
nominal in diet

No. of animals per sex per dose:

Treatment group: 10 males / 10 females
Control group: 10 males / 10 females

Control animals:

yes, plain diet

Details on study design:

- Range-finding experiment:
Rats with an initial body weight of 130-170 g were divided into 5 groups each consisting of 3 females and 3 males, receiving 0, 3, 30, 300 and 3000 ppm strontium chloride hexahydrate in the diets respectively during two weeks.
The animals were weighed at the beginning of the experiment and after 1 and 2 weeks. Food intake was recorded during the experimental period and was measured per cage (two rats) and expressed as the average intake per day per rat. Food conversion was calculated, blood samples were taken at the end of the experiment and hematological investigation was restricted to haemoglobin, hematocrit and the number of erythrocytes and leucocytes. The mean cell volume, mean cell haemoglobin concentration, and mean cell haemoglobin were calculated.
At the end of the 2 weeks X-ray photographs were made of all animals. Strontium concentration was measured in blood, bone and muscle. Liver and kidneys were weighed and examined histopathologically by preparing paraffin sections (5 µm) stained with haemalum and eosin.

Results:
Behaviour, growth, food intake and food efficiency were not affected in the range-finding experiment. Haematological investigation revealed only a slight elevation of the total number of erythrocytes in males and females and a slight increase of the white cell count in the males at the highest dose level. No differences were found in liver and kidney weights and histopathological examination revealed no abnormalities. Strontium in blood and muscle were only noted at the highest dose level whereas from 300 ppm onwards increased concentrations were found in bone.

Positive control:

no data

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked: behaviour and mortality

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- food intake was measured in week 2, 5, 9 and 12.
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE: No data

Oestrous cyclicity (parental animals):

no data

Sperm parameters (parental animals):

no data

Litter observations:

not examined

Postmortem examinations (parental animals):

SACRIFICE / GROSS NECROPSY / HISTOPATHOLOGY / ORGAN WEIGHTS
In the ninth and the twelfth week of the experiment X-ray photographs were prepared from 2 females and 2 males of the control group and from 5 females and 5 males of the 4800 ppm dose group.

After 12 weeks the remaining animals were killed and the weight of brain, pituitary, heart, thyroid, liver, kidneys, spleen, adrenals, ovaries or testes, uterus or prostate was determined.
Histopathology of these organs and also of lungs, thymus, pancreas, mesenterial lymph nodes, stomach, duodenum, ileum, jejunum, coecum, colon, rectum, urinary bladder, nervus ischiadicus, musculus quadriceps and femur was carried out by preparing paraffin sections (5 µm) stained by haemalum and eosin.

The glycogen content in the liver was determined in 5 males after 8 weeks and in 6 females and 6 males after 12 weeks.

Determination of strontium in bone and muscle was conducted by X-ray spectrometry.

Postmortem examinations (offspring):

not examined

Statistics:

Student's t-test was used in order to observe differences between separate treatment groups and corresponding controls.

Reproductive indices:

no data

Offspring viability indices:

no data

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Other effects:

not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

not examined

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
- behaviour was not affected.
- after more than 11 weeks one control female died during bleeding procedure.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
- growth was not affected.
- food intake and food efficiency were not affected.

ORGAN WEIGHTS (PARENTAL ANIMALS)
- significant increase of the relative thyroid weights was found for the males at the 1200 ppm (control group: 0.0054 %; treatment group: 0.0072 %; P < 0.01) and 4800 ppm dose levels (control group: 0.0054 %; treatment group: 0.0068 %; P < 0.001).
- relative pituitary weights of the females at 300 ppm dose level (control group: 0.0074 %; treatment group: 0.0062 %; P < 0.05) and at 4800 ppm dose level (control group: 0.0074 %; treatment group: 0.0056 %; P < 0.01) were significantly decreased.
- relative prostate weights were significantly decreased at 75 ppm (control group: 0.128 %; treatment group: 0.092 %; P < 0.01) and 1200 ppm dose levels (control group: 0.128 %; treatment group: 0.101 %; P < 0.05).

Please also refer to table 1 in the field "Any other information on results inc. tables" below.
Please also refer to the field "Attached background material" below.

GROSS PATHOLOGY (PARENTAL ANIMALS)
- neither after 9 nor after 12 weeks changes could be noticed in the X-ray photographs of the animals.

HISTOPATHOLOGY (PARENTAL ANIMALS)
- slight changes in the liver and thyroid after blind examination.
- changes consisted of a loss of glycogen in the liver at the 4800 ppm dose group and a slightly increased activity in the thyroid of the males of the 4800 ppm dose group
- detectable amounts of strontium in muscle were only noticed at the 4800 ppm dose level
- detectable amounts of strontium in bone were elevated at all dose levels.
- glycogen concentration in the liver after 12 weeks showed a dose-related decrease, which was only significant in the females in the 4800 ppm dose group (control group: 22.4 ± 6.1 in mg/g liver; treatment group: 7.8 ± 3.7 in mg/g liver; P < 0.001).

Effect levels (P0)

1

Dose descriptor:

NOAEL

Remarks:

(fertility)

Effect level:

4 800 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: The authors did not report any histological changes for uterus, overies, testes and prostate.

2

Dose descriptor:

NOAEL

Remarks:

(fertility)

Effect level:

480 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: NOAEL for strontium chloride hexahydrate calculated from ppm value.

3

Dose descriptor:

NOAEL

Remarks:

(fertility)

Effect level:

157.7 mg/kg bw/day (nominal)

Based on:

element

Remarks:

strontium

Sex:

male/female

Basis for effect level:

other: NOAEL calculated for strontium from data obtained for strontium chloride hexahydrate.

Results: F1 generation

General toxicity (F1)

Clinical signs:

not examined

Mortality / viability:

not examined

Body weight and weight changes:

not examined

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

Details on results (F1)

not examined

Effect levels (F1)

Remarks on result:

not measured/tested

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

NOAEL (fertility; males/females): 4800 ppm strontium chloride hexahydrate (nominal)
NOAEL (fertility; males/females): 480 mg/kg bw/day strontium chloride hexahydrate (nominal; calculated from ppm value)
NOAEL (fertility; males/females): 157.7 mg/kg bw/day strontium (nominal; calculated from data of strontium chloride hexahydrate)
The authors did not report any histological changes for uterus, overies, testes and prostate after the administration of up to and including 4800 ppm strontium chloride hexahydrate.