Sodium Salts of (1-Hydroxyethylidene)bisphosphonic acid (1-2:1)

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. Uptake and elimination of disodium HEDP (CAS No 7414-83-7) by humans is generally consistent with that seen in animals. The toxicokinetics behaviour of the sodium and potassium salts of HEDP is not expected to be different to that of the parent acid, as the salts are well water soluble and the dissociation is mainly dependent on the ambient pH in the gastrointestinal tract.

During in vivo toxicity studies the local pH and ionic conditions within the stomach, GI tract etc. dominate the speciation of the phosphonate, irrespective of the form originally dosed. At a defined pH, a salt will behave no differently to the parent acid, at identical concentration of the particular speciated form present, and will be fully dissociated to yield HEDP acid and salt. Hence some properties for a salt (in contact with water or in aqueous media) can be directly read across (with suitable mass correction) to the parent acid and vice versa (see CSR Section 1 for mass correction values). In the present context the effect of the alkaline metal counter-ion (sodium/potassium) will not be significant and has been extensively discussed in the public literature. In biological systems and the environment, polyvalent metal ions will be present, and the phosphonate ions show very strong affinity to them. Therefore, read-across within the HEDP category is considered appropriate.

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, suggest 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.

In a long-term investigation, 10% of a daily dose of disodium HEDP (20 mg/kg bwt/d for 6 - 12 mo) was absorbed from the gastrointestinal tract of osteoporotic female patients with around 2% of the dose eliminated in urine (Heaney and Saville, 1976). Limited information from Gural (1984; quoted in IUCLID data sheet for CAS No. 2809-21-4) noted that the oral bioavailability of 1000 mg 14C-disodium etidronate in human volunteers was 2%. Continuous oral intake of HEDP via drinking water is absorbed in the intestinal tract and reaches the bones (0.0065%) (Bartnik et al, 1986). This amount in the skeleton decreases after administration ceases.

For the derivation of DNEL, an oral absorption of 5% matches best animal and human data.

 

Dermal

HEDP is too hydrophilic to be absorbed through the skin. This is supported by a dermal absorption study in rats which resulted in a dermal absorption of 0.46% of the administered dose of sodium HEDP (Henkel, 1982). For the calculation of the dermal DNEL, a dermal absorption of 0.5% can be assumed.

Inhalation

The vapour pressure of HEDP is extremely low (<10E-08 Pa). Consequently, inhalation of HEDP vapour is not possible. It is possible that a dust (from solid) or aerosol (from aqueous solution) of HEDP could be inhaled. The potential particle size distributions that workers and consumers could be exposed to for these forms of HEDP are not currently known. However, the very high water solubility of this substance suggests that absorption will be low. In case of aerosol formation (spraying applications), droplets of water are typically in the range of 50 -100 µm, which is higher than the respirable fraction (5 -7 µm) or the inhalable fraction (10 -15 µm). Conservatively, an inhalative uptake of 5% is taken into account and used for the derivation of an inhalation DNEL.

Distribution

Bone distribution studies (Mőnkkőnen et al., 1989) demonstrate that the concentration of HEDP in mouse tibia and femur is maximal 2 hr following a single i.v. injection of 25 mg/kg bwt (approx. 13% of dose present in long bones; bone:plasma ratio equals 93), with detectable amounts of¹⁴C still present 12 months post-dose (5% of dose). Whole body autoradiography (Larsson and Rohlin, 1980) confirms deposition of¹⁴C on peripheral bone surfaces and in epiphyseal cartilage from long bones of rats within 30 min of HEDP treatment (single or 4 consecutive i.p. doses, 50 mg/kg bwt; 21.4 μCi/kg bwt). The overall pattern of distribution was similar irrespective of the age of the animals (1 d, 4 d, 25 d) or pre-conditioning with HEDP for up to 16 d. Studies in rats (Micheal et al., 1972) given 0.5 - 1000 mg/kg bwt¹⁴C disodium HEDP (CAS No 7414-83-7; supporting substance) revealed a dose-dependent increase in the amount of radiolabel present in tibia (0.02 - 580 μequiv./g tissue) and mandible (0.01 - 350 μequiv./g tissue) (time post-exposure not stated).

Metabolism

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

Excretion

Mean urinary recovery was 1.8% for 4 volunteers given 5 mg/kg bwt 14C-labelled disodium HEDP (specific activity unknown) after 2-3 wk pre-conditioning with unlabelled material (30 mg/kg bwt/d) (Recker and Saville, 1973). Faecal recovery of label over 5 d was 90%, with 3% of the dose excreted in urine over 24 hr, in another 5 human subjects given 30 mg/kg disodium HEDP (pre-treated as above) (Recker and Saville, 1973). Mean intestinal uptake of disodium HEDP was estimated as 3% in the first group (dose = 5 mg/kg bwt) and 7% in the second group (dose = 30 mg/kg bwt). Broadly similar faecal recoveries of 70 - 90% over 6 d were reported by Caniggia and Gennari (1977) in volunteers given an oral dose of 100 mg disodium HEDP containing 20 μCi³²P, although only limited experimental details are available for this study.

In a distribution and elimination study, male mice were given HEDP (25 mg/kg bwt; 49.5 μCi/kg bwt) by i.v. injection, and selected tissues analysed for¹⁴C for up to 360 d post-treatment (Mőnkkőnen et al., 1989).¹⁴C-HEDP disappeared rapidly from plasma, with 91% of the dose removed within 5 min and 99.8% by 2 hr (none present at 12 hr time-point). Levels in kidney were maximal 5 min post-treatment (approx. 32% of dose) and decreased thereafter (1-2% at 2 hr; trace at 12 hr; undetectable at 48 hr), consistent with rapid urinary elimination of the administered material.

Faecal excretion over 72 hr accounted for 80-95% of the dose eliminated by rat, monkey or rabbit, with <4% present in urine, small amounts present in carcass (up to 7% of dose) and trace amounts detected in soft tissues (up to 0.5% of dose). Less than 0.2% of the dose was exhaled as¹⁴C-carbon dioxide by the rat. Intestinal absorption appeared greater in the dog, with 9-10% of the dose eliminated in urine over 72 hr and 60-80% present in faeces. Soft tissues from the dog accounted for up to 1.5% of the dose, however carcass values were highly variable (<1% or 12%). Preconditioning of rats (0.5% unlabelled disodium HEDP in diet for 30 d prior to gavage administration of label) did not have any obvious influence on elimination (Michael et al., 1972).

Faecal elimination of labelled disodium HEDP (50 mg/kg bwt; 225 μCi/kg bwt) by the rat was greater following gavage administration (47% of dose) than after i.p. injection (4%) (Michael et al., 1972). Urinary excretion (33% versus 6%) and retention in carcass (51% versus 11%) were greater after parenteral administration. Trace amounts of label were present in rat bile irrespective of the route of exposure (0.1% after i.p. treatment, <0.01% after gavage) indicating negligible enterohepatic recirculation.

Reference

Bartnik, F; Potoker M; Pittermann, W (1986) HEDP Prüfung an Ratten nach Dauerangebot im Trinkwasser über zwei Jahre (Testing in rats after continuous supply over two years).Caniggia, A and Gennari, C (1977) Kinetics and intestinal absorption of 32P-HEDP in man. Calc Tissue Res 22, 428 - 429.

Gural, PG (1984) Pharmacokinetics and gastrointestinal absorption behaviour of etidronate. Dissertation, University of Kentucky, Lexington. Cited in European Chemicals Bureau IUCLID Data Sheet for CAS No 2809-21-4.

Heaney, RP and Saville, MD (1976) Etridonate disodium in postmenopausal osteoporosis. Clin Pharmacol Therap, 20, 593 - 604.

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

Larsson, SE and Ahlgren, O. (1992) Effects of disodium ethane-1-hydroxy-1,1-diphosphonate (HEDP) in adult normal and selectively parathyroidectomized rats. 1. Effects on plasma calcium, bone tissue and adrenal glands at low or normal calcium intake. Metab Bone Dis and Rel Res 4, 121 - 127.

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.

Mőnkkőnen, J, Koponen, H-M and Ylitalo, P (1989) Comparison of the distribution of three bisphosphonates in mice. Pharmacol. Toxicol. 65, 294 - 298.

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.

Recker, RR and Saville, PD (1973) Intestinal absorption of disodium ethane-1-hydroxy-1,1-diphosphonate (disodium etidronate) using a deconvolution technique. Toxicol Appl Pharmacol, 24, 580 - 589.