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EC number: 267-956-0
CAS number: 67953-76-8
X ray studies showed that there was no
influence of HEDP on morphology and length of bones.
Food consumption and body weight increased
slightly in comparison with the control group.
No treatment related effects were observed
in the following evaluations:
macroscopical and microscopical examinations
blood chemistry (including determination of
magnesium, iron and zinc in serum)
bone marrow smears
organ weight determination
determination of calcium and phosphor in
trachaea and tibia
Table 1 Distribution of ¹⁴C after 2 year exposure to 3.3 ppm ¹⁴C-HEDP
in drinking water
¹⁴C-activity in % overall intake
¹⁴C-activity, relative distribution (%)
5.7 ± 5.4 x 10ˉ³
7.6 ± 1.2 x 10ˉ³
1.3 ± 0.2 x 10ˉ⁵
1.0 ± 0.7 x 10ˉ⁴
4.2 ± 1.2 x 10ˉ⁵
2.6 ± 1.1 x 10ˉ⁴
2.1 ± 0.5 x 10ˉ⁵
4.7 ± 4.7 x 10ˉ⁶
3.1 ± 0.1 x 10ˉ⁵
4.0 ± 1.7 x 10ˉ⁵
2.8 ± 1.9 x 10ˉ⁶
2.2 ± 0.5 x 10ˉ⁵*
6.6 ± 0.9 x 10ˉ⁶
2.3 ± 0.8 x 10ˉ⁵
1.0 ± 0.6 x 10ˉ⁵
5.6 ± 1.9 x 10ˉ⁶
1.7 ± 1.3 x 10ˉ⁵*
Sum without stomach and intestine
8.0 ± 1.1 x 10ˉ³
1.4 ± 0.7 x 10ˉ²
* Tissue weight not known
There is no toxicokinetic data available
for HEDP potassium salt, therefore all data were read-across from HEDP
sodium salt. 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 potassium HEDP (CAS No 67953 -76 -8) by humans
is generally consistent with that seen in animals. The toxicokinetics of
the sodium and potassium salts of HEDP are not expected to be different
to those of the parent acid, as the salts are well water soluble and the
dissociation is mainly dependent on the ambient pH in the
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
Therefore the following information and predictions are applicable to
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.
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.
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
Bone distribution studies (Mőnkkőnen et al., 1989) demonstrate that the
concentration of HEDP in mouse tibia and femur is maximal 2 hours
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 bw; 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
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).
Mean urinary recovery was 1.8% for 4 volunteers given 5 mg/kg bwt
14C-labelled disodium HEDP (specific activity unknown) after 2-3 week
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 minutes and 99.8% by 2 hours (none present at 12 hour
time-point). Levels in kidney were maximal 5 minutes post-treatment
(approx. 32% of dose) and decreased thereafter (1-2% at 2 hours; trace
at 12 hours; undetectable at 48 hours), consistent with rapid urinary
elimination of the administered material.
Faecal excretion over 72 hours 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
hours 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
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
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
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.
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