Registration Dossier

Administrative data

Description of key information

No data are available with the registered substance BHMT-H. However data are available with the structurally analogous substance DTPMP-xNa (CTL 1998). In a good quality 90-day feeding study (CTL, 1998) conducted to OECD 408 and GLP, groups of 12 male and 12 female Wistar-derived rats were fed diets containing 0 (control), 100, 1000 or 10000 ppm (equivalent to 8.2, 82.5 and 841.9 mg/kg bw/day in males and 9.2, 92.3 and 902.6 mg/kg for females) test material (sodium salt of DTPMP, xNa) for 90 consecutive days. There were no deaths and the majority of parameters were unaffected by the treatment. Minor changes in certain haematological parameters (red blood cell count was significantly increased, mean cell volume and mean cell haemoglobin concentration were significantly decreased) were noted at the highest dose. There was also a decreased incidence in Perls' staining of the spleen. Bone density was significantly increased in both sexes in the highest dose group, and the incidence of microlithiasis in the kidney was reduced at all dose levels. These changes are indicative of the influence of the test material on calcium homeostasis, however, without causing any changes in calcium plasma levels. Therefore, the changes were not considered to be of toxicological significance, and the NOAEL was 10000 ppm (equivalent to to 841.9 and 902.6 mg/kg bw/day of the salt in males and female, respectively). However, it is the opinion of the author of this study summary that anaemia in humans is of concern, and therefore the NOAEL is reduced to 1000 ppm (equivalent to 82.5 and 92.3 mg active acid/kg bw/day for males and females, respectively). The test material contained 46.9% active acid. According to the study report the administered test substance had been corrected for purity.

The registrants propose to conduct further investigations to validate the basis for read-across by conducting some in vitro testing before doing further long-term toxicity testing

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available
Study duration:
subchronic
Species:
rat

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

Structural similarity has also been investigated quantitatively with specific toxicological properties in mind (PFA, 2012). Aminomethylenephosphonates are known to bind to bonein vivoand to hydroxyapatitein vitro, and some toxicological effects could potentially be mediated through this property. Sub-chronic and chronic repeated dose effects and developmental toxicity in particular have been identified in this context. The Tanimoto method has been applied to evaluate structural similarity with regard to potential to complex or bind to a single metal (especially calcium) ion. The ring sizes for different binding configurations were defined as pharmacophores for a range of aminomethylenephosphonates (please refer to Section 1.4 for additional details on the substances assessed).The Tanimoto score represents a simple way to quantify the number of shared pharmacophores on a scale from zero to one and was used as a measure of similarity. Using this method, the phosphonate ions of BHMT and HMDTMP were found to have a similarity score of 1, and the highest similarity scores of either substance with any otheraminomethylenephosphonates were 0.67 or less. A threshold value of approximately 0.85 has been defined as a predictor of high similarity. Therefore read across between BHMT and HMDTMP categories is well justified for properties in which binding to calcium is critical, and specifically repeated dose and developmental toxicity, but read across to or from other categories of aminomethylenephosphonates such as DTPMP requires further investigation.

Justification for classification or non-classification