Sodium salts of [hexane-1,6-diylbis[nitrilobis(methylene)]]tetrakisphosphonic acid (4-7 Na:1)

Endpoint summary

Description of key information

No toxicokinetics studies are available for either HMDTMP (4-7K). An assessment has been made with reference to relevant chemical properties and read-across evidence.

Additional information

No toxicokinetics studies are available for either HMDTMP (4-7Na) or other forms of HMDTMP. An assessment has been made with reference to relevant chemical properties and read-across evidence.

​

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 HMDTMP (4-7Na), therefore toxicokinetics data are read across from related phosphonic acids and salts. It is not anticipated that the toxicokinetics of the HMDTMP salt will differ from the corresponding parent acid.

 

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 other phosphonates such as DTPMP and ATMP, which are also members of the aminomethylenephosphonates analogue group. The data confirm that absorption after oral exposure is low, averaging 2-7% in animals and 2-10% in humans. 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 faeces within 72 hours of dosing.

 

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

Based on the very low log K_owvalue (-4) HMDTMP (4-7Na) would be too hydrophilic to cross the stratum corneum. Dermal absorption is therefore likely to be very low. No systemic effects were observed in an acute toxicity study by dermal route for HMDTMP-xNa (CAS 56744-47-9).

 

Inhalation

The vapour pressure of HMDTMP (4-7Na) is extremely low. Consequently, inhalation of vapour is not possible. It is possible that an aerosol (from aqueous solution) could be inhaled. The potential aerosol droplet sizes that workers and consumers could be exposed to for these forms of HMDTMP (4-7Na) are not currently known. However, the very high water solubility of these substances suggests that absorption by this route would be low. Any inhaled material would be expected to partition readily to mucus in the lungs, and hence be expectorated or ingested.

 

Distribution

There are no data on the distribution of HMDTMP (4-7Na) or other forms of HMDTMP. Due to the hydrophilic nature of these two substances, it is expected that the rate of diffusion across the membranes would limit their distribution. However, based on studies on other similar phosphonic acids such as EDTMP and ATMP, bone appears to be a specific site for deposition of phosphonic acids in vivo. In a reliable study where two groups of male rats and mice were orally dosed with¹⁴C-labelled EDTMP (15 and 150 mg/kg bw respectively). The autoradiographs indicated that after one and fourteen days of dosing, radioactivity was localised mainly in the bone for both species and dose levels (Wilson A.G.E, 1989). The binding strength among phosphonates varies and it is reversible to different degrees.

 

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.

 

Based on the very low lipophilicity, distribution into fatty tissues is unlikely.

Metabolism

There are no data on the metabolism of HMDTMP (4-7Na) or other forms of HMDTMP. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation for these substances.

 

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 HMDTMP (4-7Na) or other forms of HMDTMP.

 

In a well conducted (reliability 2) study in rats where ¹⁴C-labelled EDTMP was dosed by gavage, 77% was excreted in faeces (i.e. gut absorption is poor). Small quantities were absorbed as indicated by 1% of dose in expired air, in urine (1%) and carcass contained less than 0.2%. (ESL, 1983) In a Toxicokinetics screening study (Rel. 4 due to limited reporting) where 3.97 mg/kg¹⁴C-labelled EDTMP was orally dosed to rats. 92.9% of the dose was found in the faeces. Most (83.8%) of this was in the 0-24-hour fraction. Approximately 1% of the dosed radioactivity was contained in the carcass and tissues at sacrifice (72 hours). The urine contained 1.78% of the dose and the CO2 contained 2.03% after 72 hours. These data suggest minimal absorption of the test material (Gibson W.B, 1979).

 

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 hours 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 of ¹⁴C-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 hours (Procter and Gamble, 1978). No total recovery is reported for this study (but would appear to be >90%).