Sodium Salts of (1-Hydroxyethylidene)bisphosphonic acid (1-2:1)

Specific investigations: other studies

Description of key information

Two studies with pharmaceutical background, focusing on the effects on bones, revealed marginal increase in bone growth. These effects are in line with the postulated effect that HEDP acts as a complexing agent for metals such as calcium. However, in the absence of an adverse effect and the limited number of organs examined, the studies do not allow the derivation of a NOAEL value.

Additional information

Numerous abstracts/citations addressing the potential use of HEDP in cancer therapy, osteoporosis, Paget disease, nuclear imaging, and hypercalcaemia associated with malignancy, and other disorders of calcium and phosphorus balance have been publishedin the pharmaceutical literature.

Two rat studies with medical background conducted with sodium salts of HEDP, for which complete study reports are available, are described in more detail in the endpoint study records of this chapter. Both studies investigated medical rather than toxicological parameters in rats after oral application of 28 days or 2 years. The reliability with regard to the toxicological impact was not assignable (Klimisch 4), allowing no deduction of a NOAEL.

In the study with subacute application, the high dose of approx. 965-1135 mg/kg bw/d led to low-degree enlargement of the tibiae. In the absence of morphological changes, only dose-independent increases in the absolute and relative weights of the tibiae, but not of other examined bones, were found at all dose levels. All other investigated parameters including X-ray analyses were not affected.

In the 24 month-study, groups of rats (150 per group) were treated with either 14C-HEDP (3.3 ppm) or NaF (3.3 ppm) in their drinking water, controls (2 groups of 75 animals per group) received untreated drinking water. The mean daily intake of HEDP was 0.184 mg/kg bw. Only a minimal amount of HEDP was found in the bone, and compared to NaF, the accumulation of HEDP was significantly less. Numerous additional evaluations including biochemical parameters of bone metabolism, X-ray studies and bone-morphometry showed no treatment-related adverse effects of HEDP.

Both studies focused on the effects on bones as target organs. The marginal effects observed are in line with the postulated effect that HEDP acts as a complexing agent for metals such as calcium. However, in the absence of an adverse effect and the limited number of organs examined, the studies do not allow the derivation of a NOAEL value.