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EC number: 500-051-3
CAS number: 26780-96-1
No data available
For further data on the comprehensive chronic 2-year study (D. Stout,
1992), see chapter repeated dose toxicity.
Overall, fetal morphological effects were observed at high doses in the presence of pronounced maternal toxicity. In a reliable developmental toxicity study in rats a dose of 20 mg/kg was considered the NOEL for maternal toxicity and a dose of 120 mg/kg was considered the NOEL for developmental toxicity.
A reliable developmental toxicity study is available in SD rats.
Twenty-five mated rats per dose were orally dosed with 0, 20, 120 and
300 mg/kg/day from gestation day 6 to 15. All animals were euthanized on
gestation day 20 and subjected to a cesarean section. Fetuses were
individually weighted, sexed and examined for external, visceral and
Homogeneity and stability of the test material was analyzed and
considered to be appropriate. No effect on maternal survival and
pregnancy status was observed. Body weight gain was statistically
reduced during gestation days 6 -9 in the high dose group and food
consumption was reduced at some time points in the mid and high dose
group. Clinical signs were observed at the following doses:
120 mg/kg: slight increase in the incidence of dark material around the
nose and post-dose salvation; 300 mg/kg: increased incidence of reddish
vaginal discharge, soft stool, fecal stain, urine stain, dark material
around the nose and/or eye(s) and post-dose observation of salvation,
rubbing of chin on cage floor and dried red material around mouth.
Maternal necropsy observations were generally unremarkably. Maternal
liver weight was dose related and statistically significantly increased
in the 120 and 300 mg/kg groups. Cesarean section showed no effect on
Fetal morphological observations: In the high dose group the number of
litter with malformations was statistically increased with increased
number of litter with kinked tail, rib anomalies and vertebral
abnormalities with or without associated rib anomalies. In the same
group statistically significant increase in the number of litter with
various developmental variations were noted (malalingned sternegra(e),
14th rudimentary rib, 7th cervical rib and 27 presacral vertebrae).
Additional, observation in the high dose group, although not
statistically significant, were: descendent urethra(s), renal papilla(e)
not developed and 14th full rib.
In conclusion: Fetal morphological effects were observed at the high
dose group in the presence of pronounced maternal toxicity expressed as
reduced maternal body weight, reduced food consumption, clinical signs,
and liver toxicity.
Sitarek et al. 1996 investigated the developmental toxicity of TMQ in a
prenatal toxicity study with severe limitations. Animals were dosed with
170, 340 and 670 mg/kg/day from GD 6 to 15. Fetuses were investigated on
GD20. The authors concluded, that embryo toxic and fetotoxic effects
were observed at doses toxic to the dam. The authors selected the TMQ
doses based on acute toxicity data and concluded that 170, 340 and 670
mg/kg/day corresponds to 6, 13 and 25% LD50. Mortality was seen in the
mid dose group (4/16) and in the high dose group (1/15). Additional
systemic effects in the dams at 670 mg/kg included increased liver,
adrenal, ovary and spleen weight, decreased body weight gain (controls:
98 g; 670 mg/kg group 60 g).
Developmental effects were reported at 670 mg/kg and included increased
post-implantation losses, decreased fetal body weight and fetal
crown-rump length, increased number of fetuses with variations in
cranium, vertebrae, palatine bones and cleft plate (3 fetuses out of
65), unilateral renal pelvis, congenital defect internal hydrocephalus.
At 340 mg/kg and 670 mg/kg an increase in the number of fetuses with
delayed ossification and number of fetuses with variations in ribs was
The authors discuss that the disturbances in the prenatal development of
the offspring as the result of exposure to 670 mg TMQ/kg/day may result
from the toxic damage to the pregnant female organism. Exposure to TMQ
at a lower dose (340 mg/kg/day) still results in delayed fetal
development. However, the pathophysiological consequences of these
findings are not known.
Due to limitations in study design and documentation this study is not
reliable for risk assessment because: an in-house strain was used and no
historical data concerning the background incidence of external,
skeletal or visceral alterations is given, the number of dams is low
compared to guideline requirements, the authors used the individual
fetus as the base for the statistical evaluation but correct would be to
use the litter as statistical unit and the MTD was clearly exceeded in
this study because mortality was high in the mid dose group (4/16 dams;
25%) but not dose related since only 1/15 dams died in the high dose
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