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EC number: 223-267-7
CAS number: 3794-83-0
A NOAEL for HEDP-4Na of 48 mg/kg bw/d was derived based on the lowest
NOAEL for HEDP-2Na of 41 mg/kg bw/d for anaemic effects described in the
interim report of a combined chronic toxicity / carcinogenicity study
with disodium etidronate. The NOAEL takes into consideration the most
susceptible life span (juvenile animals).
order to reduce the number of animals used, a combined
dietary chronic toxicity and carcinogenicity study in
rats has been carried out using a protocol similar to
OECD 453. Four satellite groups of 10 animals of each
sex (dose and control groups) were fed diets
containing 0-10000 ppm disodium etidronate and used to
provide blood and urine samples during the first 26
weeks of the study. After the first 26 weeks of the
study all surviving rats in the satellite groups were
killed for interim examination. The results of the
interim report for the satellite groups are reported
separately because juvenile rats during their growth
phase seem to be more susceptible to effects of HEDP
related to perturbations of iron homeostasis
than adult rats. The doses quoted in the interim
report (0, 500, 2000, and 10000 ppm corresponding to
0, 41, 169, 817 mg/kg bw/d for males and 0, 50, 195
and 1000 mg/kg bw/d for females) take into account the higher
feed intake as a function of bodyweight during the
first few weeks of the study. A decrease in red blood
cell parameters was seen in the top dose group for
both sexes, and for males at 169 mg/kg by week 12
although some improvement was noted from the week 7
values. Blood smears indicated prolonged anaemia in
both sexes at the top dose, with a slight retardation
of bone marrow development. Severe pallor of the skin
of the top dose group animals and slight pallor in the
mid dose rats was seen. A pale color was also noted
for organs well supplied with blood (spleen and
kidneys). These observations are consistent with
perturbation of iron homeostasis. During week 25,
values relating to red cell parameters among rats
receiving 2000 ppm were similar to control values. For
rats receiving 10000 ppm the packed cell volume and
haemoglobin concentrations were only marginally lower
than control values although the differences attained
a level of statistical significance. The NOAEL for
juvenile rats is assigned to the lowest dose group
(500 ppm) where no indication of anaemia was seen.
In order to reduce the number of animals used, a combined dietary
chronic toxicity and carcinogenicity study in rats was carried out
(Huntingdon Research Centre, 1979). With the main exception of the
number of animals (40 instead of 50 rats of each sex per dose group) the
study meets the criteria of the OECD guideline No. 453. Sprague-Dawley
rats were fed diets containing 0-10000 ppm disodium etidronate for 104
weeks. The mean doses for the whole two-year study are equivalent to 0,
19, 78 and 384 mg/kg in males and 0, 24, 96 and 493 mg/kg in females.
During the study, animals were observed for clinical signs of toxicity
and mortality. Observations included body weight, food and water
consumption, ophthalmoscopic examination, hematology, clinical chemistry
and urine analysis. During the study and at study terminations all
animals underwent necropsies and histopathological examinations. No
mortality or treatment-related effects were observed on ophthalmoscopy,
clinical chemistry or gross pathology. No histopathological changes were
found at study termination. A pale colour of the spleen was seen in the
mid and high dose group at 26 weeks, indicating a lack of iron.
Concordantly, haematological disturbances associated with anaemia were
observed in the high and mid-dose groups at the earlier analysis times.
All haematological effects had resolved by the study termination, thus
indicating reversibility of the effect. There were no treatment related
changes in incidence or types of neoplastic change observed.
As part of the combined dietary chronic toxicity and carcinogenicity
study, additional four satellite groups of ten animals of each sex (dose
and control groups) were included for evaluation of toxicity and
non-neoplastic pathology at 6 months. The results obtained in the first
twelve weeks (haematology, biochemistry, urinalysis) were reported
separately in a 90 day interim report (Huntingdon Research Centre,
1977). In general, the protocol was similar to the OECD guideline No.
408 (Repeated Dose 90-Day Oral Toxicity in Rodents).
Though the disodium etidronate content of the diet was identical
(0-10.000 ppm), the
doses in mg/kg bodyweight/day quoted in the 90 day interim report are
higher than those in the chronic study report. (top dose of 817 mg/kg in
males and 1000 mg/kg in females c.f. 384 and 493 mg/kg for the 2 year
study). This can be explained by the higher feed intake as a function of
bodyweight. The doses corresponded to 0, 41, 169, 817 mg/kg bw/d for
males and 0, 50, 195 and 1000 mg/kg bw/d for females.
A decrease in red blood cell parameters was seen in the top dose group
for both sexes, and for males at 2000 ppm by week 12. There was evidence
of prolonged anaemia in both sexes at 10000 ppm. Severe pallor of the
skin of the top dose group animals and slight pallor in rats receiving
2000 ppm was seen. These observations are consistent with perturbation
of iron homeostasis.
The effects are consistent with the chelating properties
its salts causing a reduction in
bioavailability of iron. In principle, two NOAEL values – one for adult
(78 mg/kg bw/d), one for juvenile animals during their growth phase (41
mg/kg bw/d) – can be derived on the basis of the results (anaemia) of
the two key studies. A NOAEL of 41 mg/kg bw/d already takes into account
the most susceptible subgroup (adolescent animals).
The NOAEL value can then be adjusted for the molecular weight of the
tetrasodium salt resulting in 48 mg/kg/day.
Acute and short-term inhalation studies of questionable reliability in
rats indicate local irritating effects in the nasopharyngeal zone after
exposure to aerosols of unknown particle range containing unknown
compositions of HEDP and its salts. The pH values were not stated in the
reports. As an example, the pH values of aqueous solutions at around 1%
can vary between < 2 for the parent polyprotic etidronic acid and 11-12
for the tetrasodium etidronate salt (see pKa values in the chapter
“dissociation constant”). Acidic or basic pH conditions significantly
determine the induction of local effects and thus could explain the
Justification for grouping:
See CSR Annex I or IUCLID section 13.
Based on the available data, adverse effects
on iron homeostasis were not considered to be severe enough to trigger
classification. Therefore a classification for STOT-RE is not proposed
for sodium salts of HEDP.
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