[[(phosphonomethyl)imino]bis[hexamethylenenitrilobis(methylene)]]tetrakisphosphonic acid

Endpoint summary

Additional information

Based on the available data, no major differences appear to exist between animals and humans with regard to the absorption, distribution and elimination of phosphonic acid compounds in vivo. There are no actual toxicokinetics data for BHMT-H, therefore toxicokinetics data are read across from studies of related phosphonic acids and salts.

Absorption

Oral

The physicochemical properties of phosphonic acid compounds, notably their high polarity, charge and complexing power, suggests that they will not be readily absorbed from the gastrointestinal tract. This is supported by experimental data on DTPMP-H and ATMP-H which confirm that absorption after oral exposure is low, averaging 2-7% in animals and 2-10% in humans. In a study by Procter and Gamble (1978) approximately 2% of a dose of sodium hydroxyde-neutralised DTPMP-H was absorbed from a gavage dose, and 98% of the dose was excreted in faeces within 72 hours of dosing. In a well conducted and reported toxicokinetics study, approximately 2.2 % of ATMP was absorbed and 84% was rapidly eliminated in faeces after single oral administration in rats (Monsanto, 1995).

 

Gastrointestinal pH is a major determinant influencing uptake following oral exposure of phosphonates. It is extremely acidic in the stomach (range: pH 1-4) and alkaline in the small intestine (pH 4-7). The number of ionisations of the phosphonic acid moiety increases with increasing pH, rising from 1-2 at low pH (i.e. stomach) to 4-6 at more neutral pH (reflective of conditions in the small intestine). The negative charge on each molecule also increases with each ionisation, further reducing the already low potential for uptake. Stability constants for the interaction of phosphonic acids with divalent metal ions are high, and indicate strong binding, especially at lower pH. Complexation of a metal with a phosphonic acid would produce an ion pair of charge close to neutral which might favour absorption; however, the overall polarity of the complex would remain high thereby counteracting this potential. Overall, these considerations indicate that ingested phosphonic acid compounds will be retained within the gut lumen.

Dermal

BMHT-H is too hydrophilic to be absorbed through the skin. Using read across data from a dermal absorption study with sodium salt of DTPMP (Procter and Gamble, 1978, Reliability 2), 89% of the applied radioactivity (0.6 mg/kg bw) was recovered from the test site 72 hrours after application to rat skin, with negligible amounts in faeces (< 0.01%) and minor amounts in urine (< 2% ) and carcass (<1.5%).

Inhalation

The vapour pressure of BHMT-H is extremely low (2.7E-09 Pa). Consequently, inhalation of BHMT-H vapour is not possible. It is possible that aerosol (from aqueous solution) of BHMT-H could be inhaled; however the very high water solubility of this substance suggests that any absorption would be low.

Distribution

Based on studies on other phosphonic acids, ATMP, bone appears to be a specific site for deposition of phosphonic acids in vivo. Blood/tissue ratios demonstrate an approximate 80 to 200 fold increase in the concentration of phosphonic acids in rat sternum, tibia and femur after gavage exposure compared to that present in blood (Monsanto, 1995), with whole body radiography indicating preferential deposition in the epiphyseal plate of the long bones (Monsanto, 1995). A dose-dependent increase in radiolabel was observed in tibia and mandible in rats following gavage administration of 0.5 to 1000 mg/kg bw phosphonic acid.

Metabolism

There are no data on the metabolism of BHMT-H. However read across data from ATMP indicates that metabolism of ATMP in vivo is limited. Of the proportion of an oral dose excreted in urine, 25% is present as parent substance, approx. 50% as N-methyl derivative and the remainder as an unidentified product (Monsanto, 1995). Conversion of orally administered PACs to carbon dioxide by the rat has been variously reported as 0% (Monsanto, 1995), 0.2% (Michael et al., 1972) or 10% (Henkel, 1983), with 0.4% conversion described in humans (Procter and Gamble, 1978).

Excretion

There are no data on the excretion of BHMT-H. However information is available on the elimination of ¹⁴C-DTPMP (neutralised sodium salt) following oral or dermal administration to Sprague Dawley rats. Following gavage administration (10 mg/kg bw, 7 μCi/kg bw), faecal excretion over 72 hr accounted for 98% of the dose (94% eliminated during the first 24 hr). Trace amounts of radioactivity were detected in urine (1.3% of dose), with negligible quantities present as exhaled carbon dioxide (0.4%). The total recovery for this study was 101% (Procter and Gamble, 1978).

In addition, a dermal absorption study, 89% of a dose of¹⁴C-DTPMP (0.6 mg/kg bw; 2.3 μCi/kg bw) was recovered from the application site, with < 0.01% present in faeces, 0.02 - 2% eliminated via urine and 0.0 - 1.5% retained in the carcass after 72 hr (Procter and Gamble, 1978). No total recovery is reported for this study (but would appear to be >90%).

Reference

Michael, WR, King, WR and Wakim, JM (1972) Metabolism of disodium ethane-1-hydroxy-1,1-diphosphonate (disodium etidronate) in the rat, rabbit, dog and monkey. Toxicol Appl Pharmacol, 21, 503 - 515.