Pentasodium pentahydrogen [[(phosphonatomethyl)imino]bis[ethane-2,1-diylnitrilobis(methylene)]]tetrakisphosphonate

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. The toxicokinetics of the sodium salts of DTPMP are not expected to be different to those of the parent acid. Therefore the following information and predictions are applicable to the acid and sodium 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 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 DTPMP was absorbed from a gavage dose, and 98% of the dose was excreted in feces within 72 hours of dosing.

Gastrointestinal pH is a major determinant influencing uptake, and is relatively acidic in the stomach (range: pH 1 - 4) and slightly more alkaline in the 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 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 pHs. 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

DTPMP is too hydrophilic to be absorbed through the skin. In an in vivo dermal kinetics study (Procter and Gamble, 1978) it was shown that less than 1% of a dose of sodium DTPMP was absorbed over a 72 hour exposure period.

Inhalation

The vapour pressure of DTPMP is extremely low (<10E-08 Pa). Consequently, inhalation of DTPMP vapour is not possible. It is possible that a dust (from solid) or aerosol (from aqueous solution) of DTPMP could be inhaled. However, particle size distribution studies on the sodium salt of DTPMP indicate that any dust generated would be non-inhalable. In addition, the very high water solubility of this substance suggests that absorption will be low. 

Distribution

In oral and dermal studies conducted by Procter and Gamble (1978) the concentrations of DTPMP in all tissues was extremely low, due the low absorption. In the oral study it was shown that most test substance was distributed to the bone, and this tissue had nine times more DTPMP than any other organ or tissue. In studies on other phosphonic acids, ATMP and HEDP, 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 (Hotz et al., 1995), with whole body radiography indicating preferential deposition in the epiphyseal plate of the long bones (Hotz et al., 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 DTPMP. Metabolism of ATMP in vivo appears 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 (Hotz et al., 1995). Conversion of orally administered PACs to carbon dioxide by the rat has been variously reported as 0% (Hotz et al., 1995), 0.2% (Michael et al., 1972).

Excretion

In an oral toxicokinetics study (Procter and Gamble, 1978), 98% of a gavage dose was excreted in the feces within 72 hours. Of the remaining dose 1.3% was found in urine (majority within 24 hours) and 0.4% in expired CO₂. Faecal elimination of unabsorbed material predominates after ingestion (up to 90% of dose). Following a dermal application (Procter and Gamble, 1978) the majority of the absorbed dose was excreted in urine within 24 hours of the start of exposure. For ATMP, renal clearance of any material absorbed from the gut is rapid, with urinary half-lives of 5 hr and 70 hr reported. This second phase of excretion may represent mobilisation of material initially sequestered by bone, since deposition studies have shown preferential accumulation of these substances in the epiphyseal plate and other regions of the long bones in vivo. 

In a well designed and reported study, Hotz et al. (1995) demonstrated that faecal excretion was the principal route of elimination following gavage administration of¹⁴C-ATMP to male rats (150 mg/kg bw; 28.76 μCi/kg bw); 74% of the dose eliminated in 24 hr, 83% at 48 hr, up to a maximum 84% at 10 d. Trace amounts of radioactivity were present in urine (approx. 1% of dose) and blood, tissues and carcass (total approx. 0.3%) but not in exhaled air. Overall mean recovery from all sources was 85.9%. In contrast, renal clearance predominated after i.v. injection (15 mg/kg bw; 1.93 μCi/kg bw), with 46% of the dose recovered in urine 6 hr post-dosing, rising to 50% after 24 hr (maximum 53% accounted for over 10 d). Overall mean recovery was 88.9%. Approx. 4 to 5% of the dose was eliminated via faeces, while blood, tissues and carcass contained a total of 23% of the dose. Based upon relative urinary excretion after gavage and i.v. administration, gastrointestinal uptake was calculated as 2.15%. Kinetic analyses indicate that ATMP is excreted in a biexponential manner by the rat, with urinary half-lives of 5 hr or 70 hr after oral exposure, and 2 hr or 127 hr after i.v. treatment (Hotz et al., 1995).

Reference

Hotz, KJ, Warren, JA, Kinnett, ML and Wilson, AGE (1995) Study of the pharmacokinetics of absorption, tissue distribution and excretion of ATMP in Sprague-Dawley rats. Unpublished report, Ceregen (a unit of Monsanto Company Environmental Health Laboratory) St Louis, MO, Report Number MSL 14475, 6 December 1995.

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.

Procter and Gamble (1978) Metabolic Screen (rats, oral, dermal) E8218. Unpublished report dated 29.11.1978