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EC number: 270-877-4
CAS number: 68479-98-1
developmental toxicity study was conducted with Diethylmethylbenzene
diamine (DEDTA) accoring to OECD TG 414 (2001) and Council Regulation EC
No. 440/2008 B.31 (2008). Groups of 24 pregnant rats received DEDTA by
continuous oral administration in the diet from gestation day (GD) 0
until GD 20. The test substance was given at constant dietary nominal
concentrations of 0 (control), 50
(low-dose), 150 (mid-dose) and 500 mg/kg diet (high-dose). These doses
corresponded to 0, 2.63, 7.83 and 20.45 mg/kg bw per day. During the
in-life phase clinical signs, maternal body weight and food consumption
were recorded. Ophthalmoscopic examination was performed pre-treatment
and at gestation day 20. At Caesarean section, females and fetuses of
all groups were macroscopically examined and blood was collected for
haematology and clinical chemistry. Fetuses, placentas and reproductive
organs were weighed. Histopathology of the pancreas as the primary
target organ for DEDTA toxicity was performed in the dams. Fetuses were
further processed for fetopathological examination.
analysis of the experimental diets, DETDA was found to be homogeneously
distributed at all dose levels and stable in diets after storage in a
freezer (≤ - 18ºC). However, the initial measured content of DETDA was
10-16% lower than intended, and storage in the animal room for 5 days
(in an open container) resulted in 32-41% loss. Although
the measured concentrations were lower than the intended nominal
concentrations in diets, the achieved exposure levels did result in
maternal toxicity at the high dose level. Therefore the guideline
requirements of maternal toxicity at the high dose level were met and
the study was considered valid at relevant dose levels.
In the high
dose group maternal toxicity was observed as represented by a body
weight loss during the first three days of gestation, followed by a
decreased mean body weight gain and decreased food consumption during
gestation, reduced ovary weight and induction
of acinar cell apoptosis and mononuclear cell inflammation in the
pancreas in most of the animals of the high dose group (13 animals with
minimal to moderate apoptosis of the pancreatic acinar cells, 15 animals
with minimal to mild mononuclear cell inflammation). In the mid dose
group minimal induction of acinar cell apoptosis was observed in two
animals and minimal mononuclear cell inflammation in one animal.
Although this finding was of low incidence and severity in
this group, it could be
regarded as a first indication of an effect
on the target organ. Consequently,
the low dose level was considered a No Observed Effect Level (NOEL) for
toxicity was observed in the high dose group, as evidenced by a
decreased number of implantation sites and live fetuses. In addition
mean placenta weight and mean fetus weight were decreased, which was
confirmed by an increase in incidence of small fetuses. A slight
retardation in ossification in the fetuses of the high dose group was
related to the lower fetus weight.
observations with single incidences including one foetus showing a
hernia ventralis, one fetus being too small and one fetus showing
dilated ventricles of the brain were considered not treatement related
based on the low (single) incidence and the absence of dose relationship.
of developmental effects in the mid-dose group, the NOAEL for
developmental toxicity was placed at the mid-dose level of 7.83 mg/kg
fetus weight, placenta weight and ossification are considered to be
related to maternal toxicity as outlined in Waalkens-Berendsen et al.,
2002 and 2004, Wolterbeek et al., 2004 and Meiling et al., 2004.
In this study overt maternal toxicity was observed at the high dose
level. An onset of the target organ effects in the dams was already
observed in some animals of the mid dose group, but not accompanied by
the effects on embryo-fetal development that were observed at the high
dose level were considered to be secondary to maternal toxicity
D.H., Kuilman-Wahls M.E.M., Wolterbeek A.P.M. Maternal toxicity and
fetal development: effects of decreased food intake.
Toxicology 16, 425, 2002.
APM, Tegelenbosch-Schouten MM, Waalkens-Berendsen DH and Dijkstra A.
of maternal toxicity on pre- and postnatal development of rats.
Toxicology 18, 753, 2004.
J, Wolterbeek APM, Waalkens-Berendsen DH, Tegelenbosch-Schouten MM
and Dijkstra A. Impact of maternal toxicity on pre- and postnatal
development of rats.
and Applied Pharmacology 197, 211, 2004.
ID, Tegelenbosch-Schouten MM, Dijkstra A and Wolterbeek APM.
Toxicologist 78, Suppl. 1, 221, 2004
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