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EC number: 248-227-6
CAS number: 27107-89-7
Table 1: Absolute and Relative maternal Thymus weights
Dose Group (mg/kg diet)
Terminal body weight (g)
Thymus weight (g)
Relative thymus weight (%)
Table 12: Foetal and Placental Weights
Foetus weight (g)
Foetus weight - male foetuses (g)
Foetus weight - female foetuses (g)
Placenta weight (g)
Placenta weight - male foetuses (g)
Placenta weight - female foetuses (g)
A developmental toxicity study was carried out with the test material
under GLP conditions and in accordance with the standardised guidelines
OECD 414 and EU Method B.31.
The objective was to provide data on the possible effects of the test
material on pregnant female Wistar rats and the development of the
embryo and foetus consequent to continuous oral administration in the
diet from gestation day (GD) 6 until GD 19.
Rationale for dose-level selection:
In a dose range finding study with MOTE (TNO report V20347, 2014) in
pregnant females, dose-levels were 500, 1250 and 3000 ppm. Decreased in
thymus weight (known organotin target organ) were observed at all
dose-levels but due to low number of pregnant animals (3 -5 per group),
the effect was not dose-related but important (-48%, -19%, -37%, in the
low, mid and high-dose level, respectively). In the main study the same
dose-levels were selected (see below) as based on the range finding
study the observed decreased in thymus weight at all dose-levels was a
suficient indicator of maternal toxicity.
The test material was given at constant concentrations of 0 (control),
500 mg/kg diet (low-dose), 1250 mg/kg diet (mid-dose), and 3000 mg/kg
diet (high-dose). During the in-life phase clinical signs, maternal body
weight and food consumption were recorded. At Caesarean section, females
and foetuses of all groups were macroscopically examined. Foetuses,
placentas and reproductive organs were weighed. Foetuses were further
processed for visceral and skeletal examination.
It was determined that the test material was homogeneously distributed
at all dose levels and was stable in the diet after storage in the
animal room for four days or in a freezer (<-18 °C) for four weeks. The
content of the test material was close to intended at all levels.
Administration via the diet did not result in mortalities or
morbidities. No effect on food consumption and body weight was observed
in the low and mid-dose levels. Maternal toxicity was susbtanciated
by a transient decrease in body weight gain (-40 %, p <0.01) and food
consumption on days 6 to 10 (10 %, p <0.01) and 10 to 14 (7 %, p <0.01)
were observed in the high dose group as compared to the control group
during the first week of the treatment period.
Mean test material intake was 36, 89 and 208 mg/kg body weight/day for
the animals fed 500, 1250, and 3000 mg/kg diet, respectively.
No differences were observed on reproductive performance. The mean
number of implantation sites, resorptions and live foetuses were
comparable in all groups.
No adverse effect on thymus weight was observed at the low dose level. The
mean absolute and relative thymus weights were decreased (>10 %) in the
mid and high dose group. Immunotoxic compounds containing octyltin
are known to affect thymus weight in pregnant/lactating females.
Therefore, although the decrease in thymus weight in the mid and high
dose group did not reach statistical significance, it was considered to
be an adverse and test material-related effect.
Statistically significant decreased mean foetal weight in both sexes at
the mid and high dose levels were considered to be related to a
relatively high mean pup weight in the control group and were therefore
not considered treatment related. Foetal external, visceral, and
skeletal examinations did not reveal any treatment-related effects.
Daily administration of the test material at dose levels of 0, 500, 1250
or 3000 mg/kg diet to pregnant rats from gestation day 6 up to and
including gestation day 19, resulted in slight maternal toxicity as
evidenced by transient decreases in body weight gain and food
consumption at 3000 mg/kg diet, and a decreased thymus weight at 1250
and 3000 mg/kg diet. No developmental toxicity was observed.
The NOAEL for maternal toxicity was therefore 500 mg/kg diet
(corresponding to a daily mean test material intake of 36 mg/kg body
weight). In the absence of developmental effects the NOAEL for prenatal
developmental toxicity in the rat was 3000 mg/kg in diet (corresponding
to a daily mean test material intake of 208 mg/kg body weight).
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