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EC number: 202-338-6
CAS number: 94-49-5
combined OECD 422/408 study at 1000 mg/kg bw/d decreased T4 levels (for
females in combination with increased incidence of follicular cell
hypertrophy in the thyroid) at 1000 mg/kg, of which adversity could not
be excluded was observed.
treated at 1000 mg/kg bw/d microscopic examination revealed an increased
incidence of follicular cell hypertrophy (minimal or slight) in the
thyroid. This was accompanied by a decrease of thyroid hormone T4 (on
average 19%). In males treated at 1000 mg/kg serum levels of thyroid
hormone T4 were also decreased (on average by 57%), unaccompanied by
treatment related changes in thyroid weight or morphology. For both
males and females no corroborative findings were observed in TSH levels.
findings, referring to Draft Guidance for the identification of
endocrine disruptors in the context of Regulations (EU) No 16 528/2012
and (EC) No 1107/2009 (December 2017), may indicate a hazard for human
thyroid insufficiency in adults as well as pre- and post-natal
neurological development of offspring. An OECD 426 is proposed as a
follow up study to further evaluate the potential neurodevelopmental
Wistar Han rats were treated with Ethylene glycol dibenzoate by
daily oral gavage at dose levels of 100, 300 and 1000 mg/kg (10
rats/sex/dose level). Concurrent controls (10 rats/sex) received the
vehicle, polyethylene glycol 400, alone. Males were treated for 8 weeks
prior to mating, during mating, and up to termination (for 92
days). Females that delivered offspring were treated for 8 weeks prior
to mating, during mating, duringpost-coitum, and 14-15 days of lactation
(for 93-98 days). Females without offspring were treated for 85 days
(two non-pregnant females) or 96 days (one female without evidence of
Formulation analysis showed that the formulations were prepared
accurately and homogeneously.
In females treated at 1000 mg/kgmicroscopic examination revealed
an increased incidence of follicular cell hypertrophy (minimal or
slight) in the thyroid. This was accompanied by a decrease of thyroid
hormone T4 (on average 19%). In males treated at 1000 mg/kg serum levels
of thyroid hormone T4 were also decreased (on average by 57%),
unaccompanied by treatment related changes in thyroid weight or
morphology. For both males and females no corroborative findings were
observed in TSH levels. Based on the minimal or slight increase in
follicular cell hypertrophy in combination with a decrease in T4 levels
in 1000 mg/kg treated femalesand the magnitude of decreased T4 levels in
1000 mg/kg treated males, adversity could not be excluded.
Exposure to the test item up to 1000 mg/kg was not associated with
obvious toxicity in the remaining parental parameters examined in this
study (i.e. mortality, clinical appearance, functional tests,
ophthalmoscopy, body weight, food consumption, clinical pathology,
macroscopic examination and organ weights). Other changes noted in
treated rats, mostly at 1000 mg/kg, were considered non-adverse as
Slight salivation observed after dosing among treated animals (all
dose levels) was considered a physiological response rather than a sign
of systemic toxicity.
Male rats administered the test item showed reduced body weight
gain from start treatment onwards, which was not accompanied by reduced
food consumption. This occurred to a similar degree at 300 and 1000
mg/kg, and to a lesser degree at 100 mg/kg. The resulting reduction in
mean body weights was modest (about 10% from Day 36 onwards at 300 and
1000 mg/kg) and the growth rate of treated males had returned to control
levels after five weeks of treatment. Therefore, the decreased body
weights of treated male rats were regarded as non-adverse within the
context of this study.
A further treatment-related morphological change observed in
females treated at 1000 mg/kg consisted of anincreased incidence of
minimal hyperplasia/hypertrophy of the urothelium of the urinary
bladder. There was no inflammation or cell death involved in this
process. Therefore, this minimal change was considered as non-adverse.
Clinical pathology showed several changes in males treated at 1000
mg/kg: higher values for aspartate aminotransferase (ASAT), alkaline
phosphatase (ALP), total bilirubin and albumin; and lower values for
cholesterol. Additionally, the increased prothrombin time (PT) for males
at 1000 mg/kg could be related to the decrease in the number of
platelets. These changes were not accompanied byadverse anatomic
pathology alterations and the mean values for these parameters in 1000
mg/kg males generally remainedwithin the range considered normal for
rats of this strain and age (see results section). As such, these
clinical pathology changes were regarded as non-adverse.
Based on decreased T4 levels (for females in combination with increased
incidence of follicular cell hypertrophy in the thyroid) at 1000 mg/kg,
of which adversity could not be excluded, a NOAEL of 300 mg/kg bw/day is
derived for parental toxicity.
Based on the available information the
substance is not classified as for repeated dose toxicity.
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