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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because a pre-natal developmental toxicity study is available
Justification for type of information:
Derogation statement is applicable, as a pre-natal developmental toxicity study is available on STRONTIUM RANELATE.
Cross-reference
Reason / purpose for cross-reference:
data waiving: supporting information
Reference
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1998-05-01 to 1998-08-26
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Justification for type of information:
As few data are available on the target substance, a research of the potential analogues has been carried out.
The hypothesis is that properties are likely to be similar or follow a similar pattern as a result of the presence of a common metal ion (or ion complex including a hydrated metal ion). This is a reasonable assumption for the majority of inorganic compounds and some organic compounds (e.g. metal salts of some organic acids).
The following points are be considered:
- Chemical speciation and valency,
- The water solubility, as it provides a first indication of the availability of the metal ion in the different compartments of interest. The most simplistic approach to hazard evaluation is to assume that the specific metal-containing compound to be evaluated shows the same hazards as the most water-soluble compounds.
- Counter ions: the assumption that the metal ion is responsible for the common property or effect implies that the toxicity of the counter ion present in the compound will be largely irrelevant in producing the effects to be assessed.
Based on these data, we have selected the analogue Strontium ranelate.
Strontium has also physiochemical properties similar to calcium and both appear mainly in ionic form in water.

Furthermore, it is foreseen that read-across from strontium ranelate to strontium di(acetate) is possible, since as a first surrogate for bioavailability, the solubility of a test substance may be used. In the gastrointestinal tract (pH ~ 1.5) solubilities at low pH are relevant. Both substances (strontium ranelate and strontium di(aceate)) are "soluble" to "very soluble" at low pH (pH in the gastrointestinal tract is ~1.5). Hence, it can be concluded that possible adverse effects observed with SrRanelate are certainly representative of possible similar effects to be expected in strontium di(acetate) exposure.

A detail description is provided as attached report of this endpoint in this Iuclid file.
Reason / purpose for cross-reference:
read-across source
Clinical signs:
no effects observed
Description (incidence and severity):
Administration of S 12911-2 to pregnant female New Zealand White rabbits did not provoke any changes in behaviour.
One control female found dead on gestation Day 13, had blood in the thoracic cavity and congestive left pulmonary lobe. One female of the 1500 mg/kg dose level group, found dead on Gestation Day 16, had perforation of the oesophagus and haemorrhagic lungs. Another female of the 1500 mg/kg dose level group, found dead on Gestation Day 15, showed mainly yellowish contents (probably test compound) in the thoracic cavity and partially haemorrhagic left pulmonary lobe. An intubation error is likely to be the origin of these three deaths.
Mortality:
no mortality observed
Description (incidence):
Administration of S 12911-2 to pregnant female New Zealand White rabbits did not provoke test substance-related mortality.
One control female found dead on gestation Day 13, had blood in the thoracic cavity and congestive left pulmonary lobe. One female of the 1500 mg/kg dose level group, found dead on Gestation Day 16, had perforation of the oesophagus and haemorrhagic lungs. Another female of the 1500 mg/kg dose level group, found dead on Gestation Day 15, showed mainly yellowish contents (probably test compound) in the thoracic cavity and partially haemorrhagic left pulmonary lobe. An intubation error is likely to be the origin of these three deaths.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Global mean body weight gain of F0 females during treatment, from Gestation Day 6 through Gestation Day 19, was reduced at 1500 mg/kg when compared with that of control females (+270, +249, +257 and +164 g at 0, 150, 500 and 1500 mg/kg respectively). The difference from the control group was statistically significant at 1500 mg/kg (p < 0.01). After the withdrawal of treatment on Gestation Day 19, the mean body weight gain until terminal sacrifice on Gestation Day 30 was similar for all groups (+253, +238, +237 and +241 g at 0, 150, 500 and 1500 mg/kg respectively).
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Mean feed consumption of females treated at 150 and 500 mg/kg, was similar to that of controls during the entire treatment period, whereas that of females treated at 1500 mg/kg was lower than that of controls during the first and second week of treatment (150, 154, 158, and 122 g/day at 0, 150, 500, and 1500 mg/kg respectively for the second week). The difference from the control group were statistically significant at 1500 mg/kg (p < 0.01). After the withdrawal of treatment, mean feed consumption showed a slight rebound effect at 1500 mg/kg and was similar for all groups (147, 156, 155 and 163 g/day at 0, 150, 500 and 1500 mg/kg respectively).
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
Mean water consumption of F0 females was similar for all groups during the whole gestation period. The differences between groups were not statistically significant.
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
Administration of S 12911-2 to pregnant female New Zealand White rabbits did not provoke any changes in behaviour.
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
One female of the 150 mg/kg dose level group killed prematurely on Gestation Day 4 in the lowest dose group had a sacro-lumbar desmorrhexia and also several localized losses of substance on the mucosa of the stomach fundus.
One aborted female of the 500 mg/kg dose level group, showed aerocoly, as well as dark spots on the lungs and white areas on the liver at autopsy.
Autopsy at termianl sacrifice on Gestation Day 30 of all remaining F0 females revealed congestive ovarian follicles in one non-pregnant female of the 500 mg/kg dose group, accentuated hepatic lobular pattern in one pregnant female of the same dose group, one localized loss of substance on the fundic mucosa in another pregnant female of the same dose group, and in two pregnant females of the 1500 mg/kg dose group one depressed, greyish area or congestive areas on the fundic mucosa respectively. As these macroscopic findings can be seen spontaneously, they were not attributed to an adverse effect of the test substance, and therefore not subjected to a histopathological examination.
Other effects:
no effects observed
Description (incidence and severity):
- Uterine content: treatment of pregnant females during organogenesis with S 12911-2 up to the top dose of 1500 mg/kg, had no impact on the uterine contents.
- Mean foetal and placental weights and sex ratio were also similar between all group.
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Fetal body weight changes:
no effects observed
Description (incidence and severity):
No impact on uterine contents, mean foetal and placental weights.
Reduction in number of live offspring:
effects observed, non-treatment-related
Description (incidence and severity):
A non dose- and treatment-related higher mean rate of pre-implanatation loss in all treated groups (0.13, 0.22, 0.25, 0.18 at 0, 150, 500 and 1500 mg/kg, respectively) resulting slightly lower mean no. of implantations and mean no. of live foetuses.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
No impact on sex ratio.
Changes in litter size and weights:
effects observed, non-treatment-related
Description (incidence and severity):
A non dose- and treatment-related higher mean rate of pre-implanatation loss in all treated groups (0.13, 0.22, 0.25, 0.18 at 0, 150, 500 and 1500 mg/kg, respectively) resulting slightly lower mean no. of implantations and mean no. of live foetuses.
Changes in postnatal survival:
no effects observed
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
- articular stiffness in 0.6 , 0.7 2.4 and 6.2% of foetuses at 0, 150, 500 and 1500 mg/kg, respectively (spontaneous finding, not test item-related)
- one live foetus of the 500 mg/kg dose group was small sized, with shortened limbs, head deformities and a protruding tongue. This foetus was examined for the skeleton by a double staining method instead of X-ray radiography used for all other live foetuses.
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
An increase in the frequency of delays in the ossification of several bones, mainly at 1500 mg/kg:
- skeletal anaomalies >/= 3 (retarded ossification/live foetuses): 3/17, 2/16, 3/15, 10/18 at 0, 150, 500 and 1500 mg/kg, respectively
- hyoid bone (8.3, 9.7, 8.9 and 22.8% at 0, 150, 500 and 1500 mg/kg respectively, historical control mean and maximum 6.4 and 17.2%, respectively)
- pubic bone (1.9, 0.0, 1.6 and 5.5% at 0, 150, 500, and 1500 mg/kg respectively, historical control mean and maximum 3.8 and 15.8%, respectively)
- talus (3.8, 3.0, 3.2 and 7.6% at 0, 150, 500, and 1500 mg/kg respectively, historical control mean and maximum 7.2 and 23.2%, respectively)
- phalanges (0.0, 0.0, 12.1 and 18.6% at 0, 150, 500 and 1500 mg/kg respectively, historical control mean and maximum 5.5 and 15.8%, respectively)

An increase in the incidence of skeletal variants, mainly at 1500 mg/kg:
- skeletal variations >/= 3 (live and dead foetuses): 6/17, 6/16, 7/15, 11/18 at 0, 150, 500 and 1500 mg/kg, respectively
- frequency of supernumerary ribs, mainly from 500 mg/kg (34.6, 36.6, 47.6 and 57.2% at 0, 150, 500, and 1500 mg/kg respectively, historical control mean and maximum 22.1 and 45.5% respectively)
- wavy ribs only at 1500 mg/kg (8.3%, unknown in this rabbit strain)
- two foetuses (1.4%) with one or two bent femurs at 1500 mg/kg (unknown in this rabbit strain)
- five cases of malformed foetuses: two in the control , one at 500 mg/kg and two at 1500 mg/kg

In sum, the substance interfered with the ossification process of the foetuses by inducing delays in the ossification of some bones, as well as skeletal variations in form of wavy ribs and bent femurs. The ossification process continues after birth and recovers the prenatal delay. The clinical relevance for the rib and femur anomalies appears slight, as the ossification status at birth is quite more advanced in man than in the rabbit.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
- shortened innominate artery in 5.2, 5.2, 8.1 and 13.8% of foetuses at 0, 150, 500 and 1500 mg/kg, respectively (historical control mean and maximum 12.7 and 37.3%, respectively)
- absence of truncus brachiocephalicus in 10.3, 16.4, 16.1 and 17.2% of feotuses at 0, 150, 500 and 1500 mg/kg, respectively (historical control mean and maximum 16.4 and 44.4%, respectively)
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: fetotoxicity
Dose descriptor:
NOAEL
Effect level:
1 500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: embryotoxicity
Dose descriptor:
NOAEL
Effect level:
1 500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
The susbtance did not provoke any teratogenic effect.
Under the conditions of this study, the NOAELs were 500 mg/kg for materno- and foetotoxicity, and 1500 mg/kg for embryotoxicity and teratogenicity.

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion

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