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EC number: 701-116-0
CAS number: 2156592-45-7
NOAEL (systemic, development and reproduction) = 400 mg/kg bw/day (RTC,
effects on rats after repeated oral dosing with (Z)-4-[C11-13
(branched) alkylamino]-4-oxo-2-butenoic acid,
as well as any effects of the test item on male and female reproductive
performance, such as gonadal function, conception, parturition and early
lactation of the offspring were investigated. The study was conducted
according to OECD 422 guideline and GLP (RTC, 2013).
was corn oil. All doses were administered at a constant volume of 4
mL/kg body weight. The dose levels were 0, 40, 125 and 400 mg/kg bw/day.
treated for 2 weeks prior to pairing and during pairing with females
until the day before necropsy, for a total of 31 or 32 days.
treated for 2 weeks prior to pairing, during pairing and throughout the
gestation and lactation periods until Day 3 post partum.
following investigations were performed: body weight, clinical signs
(including neurotoxicity assessment, motor activity and sensory reaction
to stimuli), food consumption, oestrous cycle, mating performance,
clinical pathology investigations (haematology and clinical chemistry),
litter data, macroscopic observations, organ weights and
and fate of females
Two cases of
premature death occurred during the study. One male of the control group
was found dead on Day 2 of treatment but the cause of death could not be
determined. One female of the high dose group was found dead on Day 3 of
treatment and the cause of death was considered as a consequence of
were found not pregnant: one in the control and one in the mid-dose
one high dose female was sacrificed for total litter loss on Day 2 post
of females with live pups on Day 4 post partum was: 9 in each of
the control and mid-dose groups, 10 in the low dose group and 8 in the
high dose group.
clinical observations (Functional Observation Battery Tests)
and decreased muscle tone were the main clinical sign observed in all
high dose males throughout the study and in all high dose females during post
coitum and post partum periods.Decreased
muscle tone was considered not to be of toxicological relevance, since
no effects were seen in the functional observation battery tests,
especially in the grip strength and foot splay tests.
assessment (removal of animals from the home cage and open arena)
of animals at removal from the cage and in an open arena (neurotoxicity
assessment) did not reveal changes attributable to the test item.
weight and body weight gain
Males of the
high dose showed a slight body weight loss during the first week of the
study, and body weights remained slightly decreased compared to the
other groups throughout the study. However, these changes were mainly
attributable to one male, which was probably mis-dosed. No differences
of toxicological significance in body weights were recorded in animals
of both sexes compared to the control group, throughout the study.
on food consumption were observed in either males or females.
activity and sensory reactivity to stimuli
differences were noted in all parameters investigated between control
and treated groups.
of toxicological significance were observed in haematology parameters
and coagulation tests.
to the absence of related histopathological changes, the recorded
alterations were considered of no toxicological relevance.
cycle, reproductive parameters, pairing combination and mating
differences were observed for these parameters between treated and
mated both in the control and treated groups.
cycle, copulatory index and fertility index did not show intergroup
pre-implantation loss data, pre-birth loss data and gestation length of
data at birth, on Day 1 and on Day 4 post partum of females and
sex ratio of pups
significant differences were observed on litter data parameters and sex
ratios at birth, on Day 1 and Day 4 post partum.
signs of pups
signs noted in pups throughout the study were considered unrelated to
findings in decedent pups and in pups sacrificed on Day 4 post partum
findings in decedent pups and in pups sacrificed on Day 4 post partum did
not reveal any treatment-related effect.
body weight and organ weights
body weight was slightly decreased in high dose males, while no
differences were observed in females.
noted in absolute and relative organ weights between treated and control
animals were not accompanied by histological findings. Therefore, they
were considered of no toxicological importance.
Two cases of
premature death occurred during the study. Onecontrol
male for whichthe cause of death
could not be determined and one high dose female for which the cause of
death is considered as related to mis-dosing of the test item.
treatment-related changes were noted.
treatment-related findings were noted.
In a single
male rat from the high dose, the bronchi and the alveoli in the
centriacinar areas contained mucus-like fluid. This change was
associated with goblet-cell metaplasia of the epithelium lining the
bronchi, peribronchial fibrosis, presence of polymorphonuclear cells and
histiocytes within the mucus.
changes are suggested to be related to mis-dosing of the test item.
tubules were evaluated with respect to their stage in the spermatogenic
cycle and no alterations were noted.
On the basis
of the results obtained in the study, the NOAEL (No Observed Adverse
Effect Level) for both systemic toxicity and reproduction/developmental
toxicity was considered 400 mg/kg/day for males and females.
Based on the available data, the test
substance is not classified with regard to toxicity to reproduction
according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008
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