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EC number: 202-338-6
CAS number: 94-49-5
In a combined OECD 422/408 study no
reproduction toxicity was observed up to the highest dose level tested
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
(Frazieret al., 20121).
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 (Palazziet al.,
No reproduction toxicity was observed up to the highest dose level
tested (1000 mg/kg).
No treatment-related changes were noted in any of the reproductive
parameters investigated in this study (i.e. mating and fertility
indices, precoital time, number of implantation sites, estrous cycle,
spermatogenic profiling and histopathological examination of
A skewed sex ratio towards females was noted at 1000 mg/kg: 66%
female pups versus 43% in the control group (the difference was
statistically significant). With such a high proportion of female pups
it could not be excluded that the skewed sex ratio was related to
treatment. This was strengthened by the finding that the percentage of
female pups was about 70-80% in 5/8 litters of normal size at 1000 mg/kg
versus 1/9 in the control group. There were no treatment-related changes
in nipple retention in male pups, anogenital distances in male and
female pups, or reproductive organs of parental animals. Therefore, it
was considered unlikely that the skewed sex ratio resulted from an
endocrine mediated (antiandrogenic) effect. An alternative explanation
for the skewed sex ratio could be selective loss of male embryos due to
a sex difference in sensitivity to toxic effects of the test item. The
slightly increased number of unaccounted for implantation sites noted at
1000 mg/kg (resulting in a slightly lower live litter size) might
reflect higher sensitivity of male embryos but does not constitute
conclusive evidence of selective loss of male embryos.
Live birth index at 1000 mg/kg was lower compared to controls (91%
versus 100%). In total, 9 pups of the 1000 mg/kg group were found dead
at first litter check: 7/9 of one litter (2 male and 5 female pups) and
one male pup in two other litters. Additionally, a slight increase in
postnatal loss was noted: 4 pups in three litters died between PND 1 and
4. Furthermore, decreased mean pup weights were noted at 1000 mg/kg on
PND 1 (statistically significant for combined mean weights, relative to
control 11%). Mean pup weights at 1000 mg/kg remained slightly lower at
PND 4 and 7, but were close to control values at PND 13. Based on the
combination of a decreased live birth index, a slight increase in
postnatal loss and decrease mean pup weights at PND 1, a
treatment-related effect on the early viability of the pups could not be
No treatment-related relevant changes were noted in any of the
other developmental parameters investigated in this study (i.e.
gestation index and duration, lactation indices, parturition, maternal
care and the postnatal pup parameters clinical signs, anogenital
distance (PND 1), areola/nipple retention (PND 13 males), serum
concentration of thyroid hormone T4 (PND 13-15) and macroscopy).
In a combined OECD 422/408 study at 1000
mg/kg bw/d a skewed sex ratio towards females, a reduced live birth
index, increased postnatal loss and decreased body weights at 1000 mg/kg are
observed which was possibly related to treatment. Therefore, and in line
with the REACH annex IX testing requirements a testing proposal for an
OECD 414 is included in the dossier.
Based on the available information the
substance is not classified as reprotoxic.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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