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EC number: 451-530-8
CAS number: 736150-63-3
Reproducttive toxicity of TS-ED 532 was investigated in a preliminary
reproduction study and subsequently in a combined 2 -generation
reprodution/developmental neurotoxicity study. The preliminary study was
performed to establish a relevant dosing regime for the combined study.
There were no findings considered to be of toxicological significance
and the lowest identified NOAEL in the preliminary reproduction toxicity
study was ≥ 1105 mg/kg bw/day (F0 male) at exposure level 20000 ppm.
The combined two-generation reproduction/developmental neurotoxicity
study formed represents a combination study design specifically taking
into consideration the requirements of the OECD guideline 416 and 426. A
combination study design was chosen based on the requirements of using
the minimum number of test animals. The study was performed to
investigate the effects of TS-ED 532 on reproduction, pre-natal
development and post-natal development of the rat when administered to
two successive generations. Measurement of antiandrogen endpoints
(nipple retention at PND 12-15 and anogenital distance at PND 1) was
included to evaluate a possible endocrine disrupting effect. The study
also investigated the potential of TS-ED 532 to cause developmental
neurotoxicity in the offspring, including assessment of neurobehavior.
The assessment of pre-weaning offspring, adolescent and young adult
animals in a programme of neurobehavioural tests was validated in
advance of the study. The study incorporated a positive control group
for endocrine disruption endpoints (ano-genital distance and nipple
retention), which were validated in advance of the combined study.
TS-ED 532 was administered orally by dietary admixture continuously over
each generation, including a maturation period of at least 10 weeks,
mating, gestation and lactation. Control animals were handled in an
identical manner to those receiving TS-ED 532 and were given laboratory
diet treated with amounts of Arachis oil equivalent to the amount of
TS-ED 532 added to the high dose group dietary admixtures to ensure
comparable calorific intake. In order to achieve a high dose level that
approximated a TS-ED 532 intake equivalent to 1000 mg/kg bw/day, the
dietary concentration of TS-ED 532 in diet for this group was reviewed
and periodically adjusted during maturation.
In preliminary prenatal studies performed in rats and rabbits using oral gavage dosing with TS-ED 532, the preliminary NOEL for maternal and developmental toxicity was established at 1000 mg/kg bw/day. In the main prenatal studies studies performed in rats and rabbits using oral gavage dosing with TS-ED 532 at dose levels of 100, 300 and 1000 mg/kg bw/day, no significant toxicological maternal effects were observed at any dose level. The NOEL was therefore, considered to be 1000 mg/kg bw/day. No significant toxicological changes were detected in the offspring parameters studied. The NOEL for developmental toxicity was therefore considered to be 1000 mg/kg bw/day. A NOAEL > 1000 mg/kg bw/day for developmental toxicity was established in rats and rabbits.
Preliminary prenatal studies were performed in rats and rabbits to
establish relevant dose levels for main prenatal studies. A dosing
regimen of 0, 250, 500 and 1000 mg/kg bw/ day was used. In these
studies, a preliminary NOEL for maternal and developmental toxicity was
established at1000 mg/kg bw/day.
Main prenatal studies studies were performed in rats and rabbits. The
oral administration of TS-ED 532 to pregnant rats and rabbits by oral
gavage during organogenesis at dose levels of 100, 300 and 1000
mg/kg/day did not result in any toxicological significant maternal
effects at any dose level. The NOEL was therefore, considered to be 1000
mg/kg/day. No toxicological significant changes were detected in the
offspring parameters measured. The NOEL for developmental toxicity was
therefore considered to be 1000 mg/kg/day.
A NOAEL > 1000 mg/kg bw/day for developmental toxicity usnig rat and
rabbit was established.
TS-ED 532 did not show any evidence of developmental and reproductive
effects, including endocrine disrupting effects, at maximum recommended
dose levels in accordance with guideline. The identified NOAEL was >
1000 mg/kg bw/day for developmental toxicity in rats and rabbits, and
NOAEL ≥ 1159 mg/kg bw/day for reproductive and developmental
neurotoxicity in rats.
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