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EC number: 233-634-3
CAS number: 10287-53-3
Table 1: Summary of Female Fertility and Reproductive
Unscheduled Deaths Prior to Cohabitation
Unscheduled Deaths During Cohabitation
Non Pregnant Females
Matings Per Day Periods Of Cohabitation
Mating Index %
Fecundity Index %
Fertility Index %
Mating index % = Mated females/females cohabited
(excluding females sacrificed during Cohabitation) x 100
Fecundity Index % = Pregnant females/mated females
(excluding females with an undetermined pregnancy status) x 100
Fertility Index % = Pregnant females/females cohabited
(excluding females sacrificed during Cohabitation or with an
undetermined pregnancy status) x 100
#Fisher 1-tail Descending Test significant at the 0.001
Table 2: Parturition and Litter Data Summary
Number of females with live pups at Day 13 post-partum
Mean duration of gestation (days)
Mean number of implantation sites
Mean number of pups born
Mean number of pups alive Day 1
Mean % male pups Day 1
Mean number of pups alive Day 4 before culling
Mean number of pups culled Day 4
Mean number of pups alive Day 4 after culling
Mean number of pups alive Day 7
Mean number of pups alive Day 13
W = Wilcoxon rank sum test
X = not analysed
Table 3: Summary of Pup Survival
Post-implantation survival index %
Live birth index %
Survival index 1-4 %
Survival index 4-7 %
Survival index 7-13 %
X = not analysed
Once daily oral gavage administration of 50, 175, or 600 mg/kg/day of
test material to male rats for up to 54 consecutive days and to female
rats for up to 64 days (pre-pairing, throughout gestation and during the
first 2 weeks of lactation) resulted in adverse effects on male
fertility following 600 or 175 mg/kg/day administration.
Although no scheduled deaths or clinically observable signs of toxicity
were evident, and there was no effect on mating performance, no
pregnancies were achieved following administration of 600 or 175
Following seminology assessments, sperm count and sperm motility were
greatly reduced at these dose levels, and organ weights for the
reproductive tissues were greatly reduced for males administered 600
mg/kg/day compared with controls. The reproductive tract of females
administered 600 mg/kg/day demonstrated normal oestrous cycling
microscopically, whereas the reproductive tracts from control females
all confirmed previous pregnancy/parturition. This correlated with the
low sperm counts in males and suggests that the failure to achieve
pregnancy in females administered 600 mg/kg/day was attributable to
effects on the male reproductive systems rather than an effect on the
female reproductive system. Based on sperm count and sperm motility data
for males administered 175 mg/kg/day, the same effects on the male
reproductive systems rather than an effect on the female reproductive
system can be inferred for females treated at 175 mg/kg/day.
Overall, the findings in the tissues examined were suggestive of
endocrine effects of the test material involving the male reproductive
tract and pituitary-thyroid gland axis. The thyroid/parathyroid weights
were variable, not dose-dependent and inconsistent between sexes.
Microscopically, colloid depletion/follicular cell hypertrophy was
present in males from all dose groups. Independently, colloid depletion
causes an overall decrease in thyroid weight and follicular cell
hypertrophy causes an increase in thyroid weight, hence no consistent
effect on these organ weights can be determined and the
thyroid/parathyroid weights cannot be directly correlated
microscopically, although the microscopic changes in the thyroid
correspond with the increases in TSH.
Due to the findings in this study, dose levels of 600 or 175 mg/kg/day
were considered to cause adverse effects on male fertility. No adverse
effects were noted following administration of 50 mg/kg/day to males, or
the resultant offspring.
The omission of T4 data from this study do not affect the conclusion or
the no observed adverse effects level (NOAEL) based on the adverse
effects on male fertility.
The toxicity of the test material to reproduction was investigated in
accordance with the standardised guideline OECD 421 under GLP
conditions. The study was to screen for effects of the test material on
male and female reproductive performance (i.e. gonadal function, mating
behaviour, conception, development of the conceptus and parturition) and
offspring growth post-partum.
Four groups of 10 male and 10 female Crl:CD(SD) rats were administered
0, 50, 175 or 600 mg/kg/day test material orally by gavage, at a
constant dose volume of 5 mL/kg. The control material (vehicle) was corn
oil. Formulations prepared for use during Weeks 1 and 6 were analysed
for achieved concentration and mean values were within the specified
Before the start of dosing, all females were screened for regular
oestrous cycles; only females showing regular oestrous cycles were
included in the study. Males were dosed once daily for up to
54 consecutive days (two weeks prior to pairing, during the pairing
phase and until the day before necropsy) and were sent to necropsy in
Week 7. Females were dosed for up to 64 days (two weeks prior to
pairing, during the pairing phase, throughout gestation and up to
Lactation Day [LD] 13, 25 days post-coitum or after the completion of
the pairing phase for any non-mated
females, where applicable) and sent to necropsy on LD 14, 26 days post‑coitum
for females which did not achieve a pregnancy. Any female which failed
to mate was also sent to necropsy at the end of the pairing phase.
Following 2 weeks of dosing, animals were paired for mating on a one
male: one female basis within each dose group. Once mating was
confirmed, females were individually housed and males were returned to
their home cage.
Assessment of toxicity in adults was based on clinical observations,
body weights, food consumption, oestrous cycling, mating, fertility and
pregnancy indices and offspring parameters. Pup clinical observations,
litter size, sex and body weights were recorded. Ano-genital distance
was recorded on Postnatal Day (PND) 4 and nipple retention was also
recorded for male pups on PND 13. One pup/sex/litter was selected from
each dose group for thyroid weight recording and processing for
Complete necropsies were performed on all animals, and any macroscopic
abnormalities were noted. Blood samples were collected at necropsy from
all adult animals for haematology assessments and from all adults and
selected PND 4 and PND 13 pups for thyroid hormone assessments. Selected
organ weights were recorded for all adult males and anatomic
(microscopic) pathology assessments were conducted on selected tissues
from adults and on the thyroid for PND 13 pups.
No unscheduled deaths occurred, and no toxicologically significant
clinical or post-dose observations were observed.
Administration of 600 mg/kg/day resulted in lower body weight gains for
males, compared with controls and initial reductions in food
consumption. Slight reductions in body weight gain were also noted for
females during the first 2 weeks of dosing. Mating performance was not
affected; however, no pregnancies were evident for any female following
administration of 600 mg/kg/day. Significant reductions in sperm counts
and lower sperm motility were noted in males administered 600 mg/kg/day,
compared with controls. Macroscopic examinations revealed small testis
and epididymis and lower reproductive organ weights (testis, epididymis,
prostate, levator ani muscle / bulbocavernosus complex and right
bulbo-urethral gland) were noted at this dose level, compared with
controls. Microscopic examinations revealed colloid depletion/follicular
cell hypertrophy of the thyroid gland for all males and an increased
incidence in vacuolation of the pituitary gland was also present for
most males administered 600 mg/kg/day, compared with concurrent
controls. Thyroid stimulating hormone (TSH) levels were elevated for
males administered 600 mg/kg/day, compared with controls. Haematology
assessments also revealed lower haemoglobin, red blood cell, packed cell
volume, mean cell volume, mean cell haemoglobin concentration,
haemoglobin distribution width, platelets, platelet crit and eosinophils
for males, compared with controls. Reticulocyte (counts and percentage)
and large unstained cells were increased, compared with controls. Due to
different physiological status, control data could not be accurately
compared with data obtained from females administered 600 mg/kg/day.
Similar findings were noted following 175 mg/kg/day administration.
Slightly lower body weights were observed for both sexes during the
first 2 weeks of dosing, compared with controls. Mating performance was
not affected although no pregnancies were evident for any female at this
dose level. Reductions in sperm count and lower sperm motility were
noted for males administered 175 mg/kg/day, compared with controls and
small testis and small epididymis were recorded macroscopically.
Microscopic examination of tissues from 175 mg/kg/day males revealed
colloid depletion/follicular cell hypertrophy of the thyroid glands and
an increased incidence in vacuolation of the pituitary in some males.
Increases in TSH were evident for males administered 175 mg/kg/day
compared with controls and haematology assessments also showed a slight
reduction in haemoglobin and increase in % reticulocytes, compared with
controls. Due to different physiological status, control data could not
be accurately compared with data obtained for females administered 175
Animals administered 50 mg/kg/day showed no adverse effect on body
weight, food consumption, mating performance, fecundity or fertility,
with all females of this group becoming pregnant and bearing live pups.
Seminology assessments revealed slight reductions in sperm counts
although sperm motility and morphology was not affected, and no test
material-related microscopic findings were noted in the testis or
epididymis of males administered 50 mg/kg/day. Microscopic changes in
the thyroid consisted of colloid depletion/follicular cell hypertrophy
of the thyroid gland present in some males administered 50 mg/kg/day.
For the pups delivered from females administered 50 mg/kg/day, no test
differences in litter size or survival indices were noted. Furthermore,
no test material-related clinical observations, pup deaths, adverse
effects on body weight or ano-genital distance were noted from 50
mg/kg/day litters and there was no evidence of nipple retention. Thyroid
stimulating hormone (TSH) was slightly increased for the PND 4 pups from
the 50 mg/kg/day litters, compared with controls, and was also higher
for PND 13 male and females, however, there were no correlating
microscopic changes in the pup thyroid gland from this dose level.
Under the conditions of this study, dosing of the test material resulted
in adverse effects on male fertility following administration of 600 or
175 mg/kg/day. Fertility was not affected following administration of 50
mg/kg/day, therefore a ‘no observed adverse effect level’ (NOAEL) for
male reproductive toxicity was established as 50 mg/kg/day.
No adverse effects were noted for females administered 600 or 175
mg/kg/day. The absence of pregnancies at these dose levels was
considered to have resulted from an adverse effect on the male
reproductive system. As such, a NOAEL for reproductive toxicity was
established as 600 mg/kg/day for females.
The NOAEL for offspring development was considered to be 50 mg/kg/day in
the absence of any adverse effects noted at this dose level.
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