[[(phosphonomethyl)imino]bis[ethylenenitrilobis(methylene)]]tetrakisphosphonic acid, potassium salt

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 and potassium and ammonium salts of DTPMP are not expected to be different to those of the parent acid. Therefore the following information and predictions are applicable to these 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.

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.

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

There are no data on the distribution of DTPMP. Based on 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 ATMPin 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) or 10% (Henkel KgaA, 1983a), with 0.4% conversion described in humans (Procter and Gamble, 1978).

Excretion

Limited information is available on the elimination of ¹⁴C-DTPMP following oral or dermal administration to SD rats. This is derived from the IUCLID data sheet for CAS No 15827-60-8 however, since the test substance is described as a neutralised sodium salt, CAS No 22042-96-2 may be a more reliable indicator of the substance under investigation.

In the gavage investigation (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, 1987; quoted in IUCLID data sheet).

In the 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, 1987; quoted in IUCLID datasheet). No total recovery is reported for this study (but would appear to be >90%).

 

Reference

Henkel KgaA (1983a) Unpublished data, Archive No 830091. Cited in European Chemicals Bureau IUCLID Data Sheet for CAS No 6419-19-8.

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) Unpublished data, Report ECM BTS 476, E-8218, MVL-YE 205, European Chemicals Bureau IUCLID Data Sheet for CAS No 15827-60-8.