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EC number: 267-956-0
CAS number: 67953-76-8
OBSERVATIONS, FOOD CONSUMPTION AND BODYWEIGHT
rats showed the same normal accepting behaviour with regard to the
food compared to the controls.
complete study was proceeded without any abnormalities.
animals of the controls and the respective dosing groups survived the
28 day period of the study. No substance-related symptoms could be
recorded during that time.
mean food intake (g/kg bw/d)
mean HEDP intake (mg/kg bw/d)
mean bodyweight increase (g)
general, the mean food consumption especially in males was slightly
decreased compared to the controls.
the HEDP dosing groups, a slightly higher mean bodyweight increase was
observed compared to the controls.
differential blood count was examined microscopically.
male individual of group 2 (500 ppm) exhibited a high increase of
banded neutrophil granulocytes, in 1 male individual of group 4 (10000
ppm) a moderate increase of banded neutrophil granulocytes was
all dosing groups, including control, hydronephrosis of the kidneys
was observed to variant degrees. In some females, the presence of
hydrometra was found. Beside that, all other organs only showed
species-typical individual results independent from dosing and without
any noticeable accumulations.
the highest dosing group (10000 ppm) an enlargement of the tibiae
could be observed to a low degree.
HEDP application, an increase of the absolute and relative weights of
the tibiae compared to the controls was found. This observation was
relevant for all HEDP dosing groups and not dependent on the amount
applied and could be interpreted as an inhibitory effect on the bone
resorption. This result was more obvious for males than for females.
bones of controls and dosing groups were without any findings in the
weights of the tibiae
Mean weight (g)
weights of the tibiae
Mean weight (%)
In a 28-day feeding study, rats received
doses of 0/500/2000/10000 ppm of HEDP in the diet (corresponding to
appr. 0/48.5-50/203.9-190.5/965 -1135.2 mg/kg bw/d). Besides the
evaluation of mortality, symptoms of intoxication, body weights, food
consumption, haematology and (histo-)pathology, specific examinations of
the three bone types (tibia, metatarsus, calcaneus) were conducted.
In the highest dose group, the application
of HEDP led to a low-degree enlargement of the tibiae. Dose-independent
increases in the absolute and relative weight of the tibiae, but not of
the other examinated bones, were found at all dose levels. However, the
findings did not correspond to the x-ray examinations, that did not
exhibit any alterations. No adverse effects were observed with regard to
any other of the investigated parameters. The study directors concluded
that the changed in tibia weights might be interpreted as inhibitory
effect on bone resorption.
The study focused on medical aspects rather
than on toxicological assessment. With regard to the latter, the study
supports the presumption that HEDP can act as a complexing agent. This
mode of action was also observed in toxicological studies summarized in
chapter 7.5 (repeated dose toxicity). At the lowest dose of 48.5-50
mg/kg bw/day, which corresponds to the NOAEL derived in the repeated
dose toxicity key study, marginal effects on the tibia weights were
observed. However, it remains unclear, whether these effects could be
interpreted as adverse effect, or as a positive impact on the prevention
of bone resorption. The study directors did not deduce a NOAEL, which
was probably not in the scope of the study.
Two studies with pharmaceutical
background, focusing on the effects on bones, revealed marginal increase
in bone growth. These effects are in line with the postulated effect
that HEDP acts as a complexing agent for metals such as calcium.
However, in the absence of an adverse effect and the limited number of
organs examined, the studies do not allow the derivation of a NOAEL
abstracts/citations addressing the potential use of HEDP in cancer
therapy, osteoporosis, Paget disease, nuclear imaging, and
hypercalcaemia associated with malignancy, and other disorders of
calcium and phosphorus balance have been publishedin
the pharmaceutical literature.
Two rat studies with
medical background conducted with sodium salts of HEDP, for which
complete study reports are available, are described in more detail in
the endpoint study records of this chapter. Both studies investigated
medical rather than toxicological parameters in rats after oral
application of 28 days or 2 years. The reliability with regard to the
toxicological impact was not assignable (Klimisch 4), allowing no
deduction of a NOAEL.
In the study with
subacute application, the high dose of approx. 965-1135 mg/kg bw/d led
to low-degree enlargement of the tibiae. In the absence of morphological
changes, only dose-independent increases in the absolute and relative
weights of the tibiae, but not of other examined bones, were found at
all dose levels. All other investigated parameters including X-ray
analyses were not affected.
In the 24 month-study,
groups of rats (150 per group) were treated with either 14C-HEDP (3.3
ppm) or NaF (3.3 ppm) in their drinking water, controls (2 groups of 75
animals per group) received untreated drinking water. The mean daily
intake of HEDP was 0.184 mg/kg bw. Only a minimal amount of HEDP was
found in the bone, and compared to NaF, the accumulation of HEDP was
significantly less. Numerous additional evaluations including
biochemical parameters of bone metabolism, X-ray studies and
bone-morphometry showed no treatment-related adverse effects of HEDP.
Both studies focused on
the effects on bones as target organs. The marginal effects observed are
in line with the postulated effect that HEDP acts as a complexing agent
for metals such as calcium. However, in the absence of an adverse effect
and the limited number of organs examined, the studies do not allow the
derivation of a NOAEL value.
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