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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
fertility, other
Remarks:
based on a 90 day repeated dose oral toxicity study
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

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
Molecular formula:
Cl2Sr
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 / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 75, 300, 1200 or 4800 ppm strontium chloride hexahydrate
Basis:
nominal in diet
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)

open allclose all
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.
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.
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.