Sodium salts of [[(phosphonomethyl)imino]bis[ethane-2,1-diylnitrilobis(methylene)]]tetrakisphosphonic acid (1-3 Na:1)

Endpoint summary

Description of key information

The available information suggests that only minor amounts of sodium DTPMP are absorbed after ingestion (limited by physicochemical interactions within the gut) or skin contact (limited by hydrophilic nature). There are also not expected to be any major differences between animals and humans for these parameters.

Key value for chemical safety assessment

Absorption rate - oral (%):

2

Additional information

Based on the available data for phosphonic acids (DTPMP, HEDP and ATMP), no major differences are expected to exist between animals and humans with regard to the absorption, distribution and elimination of phosphonic acid compounds in vivo. Also, based on physicochemical properties, the toxicokinetics of the 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 salts.

 

Absorption

Oral

The physicochemical properties of DTPMP 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 which confirm that absorption after oral exposure is low, averaging 2-7% in animals. In a rat study by Procter and Gamble (1978) approximately 2% of a dose of DTPMP-H 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 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

Based on the very low log Kow value (-3.4) DTPMP would be too hydrophilic to cross the stratum corneum. Dermal absorption is therefore likely to be very low. In a dermal absorption study in rats with DTPMP-H (Procter and Gamble, 1978, Reliability 2), 89% of the applied radioactivity (0.6 mg/kg bw) was recovered from the test site 72 hours 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 DTPMP is extremely low (<10E-08 Pa). Consequently, inhalation of DTPMP (5-7 Na) vapour is not possible. It is possible that aerosol (from aqueous solution) of DTPMP could be inhaled. In addition, the very high water solubility of this substance suggests that absorption will be low. Any inhaled material would be expected to partition readily to mucus in the lungs, and hence be expectorated or ingested.

Distribution

In oral and dermal studies conducted by Procter and Gamble (1978) the concentrations of DTPMP in all tissues was extremely low, due to the low overall absorption (Table 1). 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.

Bone imaging following 2 and 4 hour intravenous administration of radiolabelled DTPMP-H in rabbits (Subramanian et al., 1975) and rats (Goeckeler et al., 1978) confirms that DTPMP is preferentially distributed to bone, but that concentrations in the bone marrow are low in comparison with the bone and comparable with other tissues such as muscle, kidney and liver (Table 5.1.2).

 

Table 5.1.2 Distribution of DTPMP in tissues

Tissue	Distribution following oral administration (μg/kg) Procter and Gamble (1978) (species: rat)	Distribution following 2h intravenous administration (% dose/g) (2h) Goeckeler (1987) (species: rat)	Distribution following 4h intravenous administration (% dose/1% body weight) Subramanian (1975) (species: rabbit)	Distribution following 4h intravenous administration (% dose/1% body weight) Subramanian (1975) (species: rabbit)
Radiolabel	carbon	153-Sm	85-Sr	113m-In
Blood	0.05 ± 0.05	74	0.7	0.4
Plasma	0.03 ± 0.02	Not determined	Not determined	Not determined
Average bone	2.9 ± 0.79	30	8.1	4.8
Marrow	Below limit of detection	Not determined	0.3	0.2
Muscle	Below limit of detection	0.9	0.2	0.04
Kidney	0.17 ± 0.03	0.4	0.9	2.3
Liver	0.11 ± 0.02	0.3	0.3	0.2
Testes	0.05 ± 0.007	Not determined	Not determined	Not determined

 

 

Metabolism

There are no data on the metabolism of DTPMP.

 

Excretion  

Information is available on the elimination of 14C-DTPMP (neutralised sodium salt) following oral or dermal administration to SD rats. In an oral toxicokinetics study using SD rats and with 14C-DTPMP-H (neutralised to pH 7 with sodium hydroxide), 98% of a gavage dose (10 mg/kg bw, 7 μCi/kg bw), was excreted in the faeces within 72 hours (Procter and Gamble, 1978). Of the remaining dose 1.3% was found in urine (the majority within 24 hours) and 0.4% in expired CO2. Faecal elimination of unabsorbed material predominates after ingestion (up to 90% of dose). Following dermal application, the majority of the absorbed dose was excreted in urine within 24 hours of the start of exposure.