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Administrative data

Description of key information

A LOAEL of 0.411 mg/kg bw/day was derived from chronic studies in rat and dog, based upon effects on

retention in the primary spongiosa of the bones examined (ribs and femurs) at all doses tested.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The read-across is based upon a common functional group - the target and source substances will both ionise to produce the same species in the digestive tract.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Source : sodium alendronate; target: alendronic acid

3. ANALOGUE APPROACH JUSTIFICATION
The ionisation of the two substances in the digestive tract will yield identical species and will present the same toxicokinetic profile.

4. DATA MATRIX
The read-across is based upon the oral repeat dose study for the rat (source), adjsuted for the difference in molecular weights observed between the target and source chemical
Reason / purpose:
read-across source
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
The main clinical signs observed before sacrifice in the
mid-dose male 88-0172 and in the high-dose female 88-0227
were body weight loss, anorexia, coughing (88-0l72M), dyspnea
(88-0227F) and vomiting (both dogs). These clinical signs
suggested a possible faulty intubation;
this was subsequently confirmed by the gross and histopathological
findings
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Two dogs, one mid-dose male (88-0172) and one high-dose female(88-0227).
showing severe signs of respiratory distress, were sacrificed in Drug Weeks 48 and 5O, respectively.
Both animals presented gross and microscopical evidence of severe inhalation bronchopneumonia

(faulty intubation).
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
throughout the study, a lower body weight gain was observed
in the high-dose female group (8 mg/kg/day) when compared to
the control female group (see Figure 1). The time-response
analyses for body weight in female groups during the 0-52 week
period was statistically significant (P ~ 0.05) for quadratic
effect only through the high-dose female group.
At the end of the study, the decrease in mean body weight
gain observed in the high-dose female group was about 33 percent
when compared to control females while in the female
groupin recovery, treated for 13 weeks at the high dosage
(8mg/kg/day), the mean body weight gain was roughly similar
(-7%) to that of the female control group.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
There were no drug-related changes:
the time-response analyses for food consumption in female groups during the
0-52 week period was not statistically significant (P > 0.05)
for average, linear, and quadratic effect
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Before sacrifice, the mid-dose male 88-0172 and the high-dose
female 88-0227 had increased leukocyte counts (19.5 x lo3;mm3
and 30.1 x 103/mm3, respectively) due to increased segmented
neutrophil counts (17 ,062/mm3 and 25,585/mm3, respectively).
These increases were thought to be the reflection of the
inflammatory process observed histologically in the lungs and
consequence of a bronchopneumonia.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
All the transient (from Drug Week 5 to Drug Week 13) drugr elated
changes observed reflected the pharmacological activity of the compound.
In Drug Weeks 5, 8, and 13, a statistically significant
(P ,{ 0.05) decrease in serum total calcium mean values was
observed in both groups treated at the dosage level of 8 mg/kg/day.
'From Drug Week 26 onwards, these mean values returned to control mean values.
In Drug Weeks 5 and 8, a statistically significant (P ~ 0.05)
decrease in serum phosphorus mean values was observed in all
MK-0217-treated groups. In Drug Week 13,all the group mean values (sexes
combined) were lower (10.9 -21. 7%) when compared to
concurrent control; From Drug Week 26 onwards, these
values returned to control values.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
All the transient (from Drug Week 5 to Drug Week 13) drugr elated
changes observed reflected the pharmacological activity of the compound.
In Drug Weeks 5, 8, and 13, a statistically significant
(P ,{ 0.05) decrease in serum total calcium mean values was
observed in both groups treated at the dosage level of 8 mg/kg/day.
'From Drug Week 26 onwards, these mean values returned to control mean values.
In Drug Weeks 5 and 8, a statistically significant (P ~ 0.05)
decrease in serum phosphorus mean values was observed in all
MK-0217-treated groups. In Drug Week 13,all the group mean values (sexes
combined) were lower (10.9 -21. 7%) when compared to
concurrent control; From Drug Week 26 onwards, these
values returned to control values.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Bone: Histologically, retention of primary spongiosa was observed
in the ribs of the majority of treated dogs. These changes
were more prominent in the 8 mg/kg/ day group. The severity
of the change ranged from very slight to severe.
Retention of primary spongiosa was also present in the
femurs of the majority of treated dogs (except three dogs of
the 0.5 mg/kg/day group). The extent of the change ranged
from very slight to marked, and the femurs appeared less
affected than the ribs with a larger number of animals within
the range of slight to moderate severity.
Mineralization of the renal papilla accompanied by chronic
focal nephritis was present in one dog of the 8 mg/kg/day
group (88-0129F) and in a second dog of the recovery group
(88-0188M).
Key result
Dose descriptor:
LOAEL
Effect level:
ca. 0.411 mg/kg bw/day (actual dose received)
Based on:
other: calculated from source result based on differential molecular weight
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
0.411 mg/kg bw/day (actual dose received)
System:
musculoskeletal system
Organ:
bone
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
6.572 mg/kg bw/day (actual dose received)
System:
urinary
Organ:
kidney
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes
Conclusions:
The oral administration of the source substance for 53 weeks at doses
ranging from 0.5-8 mg/kg/day induced retention in the primary
spongiosa of the bones examined (ribs and femurs) at all
doses. A trend towards restoration of bone remodelling was
observed in the group kept in recovery for 40 weeks after
receiving the high dose level for 13 weeks.
In addition, the administration of 8 mg/kg/day induced
chronic focal nephritis and mineralization of the papilla. A LOAEL of 0.411 mg/kg bw/day has been
derived for the target substance from the effects noted above. For the readacross, the LOAEL has been calculated from the results obtained with the source material based upon the differential molecular weight (267.1/325.13)
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
0.411 mg/kg bw/day
Study duration:
chronic
Species:
dog
Quality of whole database:
Two studies are available, both conducted in accordance with accepted methodologies of the time and in accrodance with GLP.
System:
musculoskeletal system
Organ:
bone
bone marrow

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

Dose dependent effects on bone homeostasis are observed in two separate species following chronic exposure to the substance; the retention in the primary spongiosa representing a morphological change in the bone which, although reversible, is clear evidence of organ/tissue dysfunction. Classification for STOT repeat dose category 2 is justified based upon the effects observed in two species at doses upto 6.572 mg/kg bw/day.