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EC number: 237-864-5
CAS number: 14025-15-1
One well performed and reported subchronic
oral toxicity study was available.
In this study, the possible
effects of EDTA-CuNa2 on reproductive performance and development,
and its sub-chronic toxicity were examined in groups of 12 male
and 12 female Wistar rats. EDTA-CuNa2was administered
daily by gavage during a premating period of 10 weeks and during
mating, gestation and lactation until postnatal day 4. The dose
levels were 0 (tap water only), 150, 500 and 1500 mg/kg bw/day.
Due to mortality, the high-dose level was reduced to 1050 mg/kg
bw/day from day 9 of the study.
The content and homogeneity of
the test substance in the carrier were confirmed by analysis.
All male and female rats of the
high-dose group were found dead or killed in moribund condition
before the start of the mating period. Three males of the mid-dose
group were killed in moribund condition during or at the end of
the mating period.
Clinical signs observed in rats
of the high-dose group and, to a lesser extent, in the mid-dose
group included thin appearance, hunched posture, piloerection,
blepharospasm, swollen abdomen, soft faeces and green watery
discharge around perineum.
and motor activity assessment did not indicate specific neurotoxic
effects of the test substance. Ophthalmoscopic examination did not
reveal any treatment-related changes.
Body weights were decreased in
males of the high-dose group, and, from the end of the premating
period, in males of the mid-dose group. During lactation, female
body weights were increased in the remaining treatment groups.
Feed intake was reduced in males of the high-dose group.
and clinical chemistry was conductedin
females on day 65 (at the end of the premating period), and in
males on day 85 (a few days prior to necropsy). At these time
points, all males and most females of the high-dose group had died
or had been killed.
following changes in haematology were noted in the mid-dose group
(now representing the highest dose level):
time was decreased in both sexes.
blood cell count was increased and MCV and MCH were decreased in
white blood cell counts and absolute neutrophils and monocytes
counts were increased in males.
following changes in clinical chemistry were noted:
ASAT, ALAT and GGT activity were increased in males of the
mid-dose group. In females ALP activity (mid-dose group) and ALAT
activity (low- and mid-dose group) were decreased.
was increased in males of the mid-dose group
was increased in the mid-dose group in both sexes
inorganic phosphate and calcium were increased in mid-dose males
was increased in males of the low- and mid-dose group. Potassium
was increased in females of the mid-dose group.
The surviving rats (control,
low- and mid-dose group) were killed on day 90 (males) or on day 4
of lactation (females).
body weights were decreased in males and increased in females of
the mid-dose group.
absolute and the relative weights of the heart were decreased in
the mid-dose group in both sexes.
relative weight of the kidneys was increased in males of the
mid-dose group. In females of this group, the absolute kidney
weight was increased.
absolute and the relative weights of the spleen were increased in
the mid-dose females.
absolute and the relative weights of the ovaries were decreased in
females of the mid-dose group.
absolute weight of the testis was decreased in mid-dose males.
The main gross finding in
animals of the mid-dose group (and in intercurrently killed
animals of the high-dose group) were enlarged intestines with
green/watery contents, a pale and/or green appearance of the liver
and kidneys, small epididymides and seminal vesicles, enlarged
dark spleen, small thymus and a variety of changes in the stomach.
Microscopic examination revealed
histopathological changes in the kidneys, the liver and the
histopathological changes in the kidneys were characterised by
tubular necrosis and degeneration, tubular epithelial cell
karyomegaly and accumulation of brown pigment. These changes were
mainly present in the mid-dose animals. However, tubular
epithelial brown pigment was also noted in the kidneys of 6/10
changes in the liver were accumulation of periportal macrophages,
especially in the mid-dose males, hepatocellular karyomegaly,
brown pigment accumulation, bile duct hyperplasia and (multi)focal
infiltration of mononuclear inflammatory cells. These changes were
mainly present in the mid-dose animals. However, mononuclear cell
infiltrate was also noted in the liver of 6/10 low-dose males and
3/10 low-dose females.
changes in the spleen were accumulation of brown pigment and
accumulation of macrophages in the white pulp in animals of the
The decedent high-dose animals
were subjected to microscopical examination only on the basis of
macroscopic observations. The microscopic observations in this
group confirmed the above histopathological changes.
Based on the histopathological
effects in liver and kidneys noted in animals of the low-dose
group, the no-observed-adverse-effect level (NOAEL) for parental
toxicity was close to 150 mg/kg bw/day.
When comparing the results of this study
with EDTA-CuNa2 with repeated dose studies of other metal chelates (see
read across document in section 13), it was concluded that EDTA-CuNa2
was slightly more toxic (NOAEL of ca. 150 mg/kg bw) than the other metal
chelates (NOAELs >= 500 mg/kg bw).
Because in this subchronic study effects
were limited at a dose level of 150 mg/kg bw, no classification is
needed for STOT repeated exposure.
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