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EC number: 253-575-7
CAS number: 37640-57-6
Table 1: Body
weights and changes [g] in pregnant dams
dams died on GD 9 due to severe intoxication; two other dams were not
are presented as means±SD
weight on GD 20−gravid
difference at p<0.05
level compared with the control group.
difference at p<0.01
level compared with the control group.
Table 2: Maternal kidney toxicity parameters
are presented as means±SD.
level compared with the control group
Table 3: External
and visceral vlterations in the fetuses
In a developmental toxicity similar to OECD
414 (Kim et al., 2013), groups of pregnant female rats were treated by
oral gavage with a 1:1 mixture of melamine (MEL) and cyanuric acid (CYA)
in 1% aqueous CMC at 6, 20 or 60 mg/kg bw/d from GD 6 through GD 19 and
necropsied on GD 20. The dose of 6 mg/kg bw/d MEL and CYA (1:1)
corresponded to 3 mg/kg bw/d MEL plus 3 mg/kg bw/d CYA. Concurrent
control animals were treated with the vehicle only. Maternal assessments
included mortality, clinical observations, body weight, food
consumption, clinical chemistry parameters (BUN, creatinine), gross
pathology and examinations of ovaries and uterine contents. Fetal
examinations included determination of body weight, sex and assessment
of morphological abnormalities (external, visceral, skeletal).
Histopathological examinations were conducted on the kidneys of the dams
and their fetuses. At 20 mg/kg bw/d MEL and CYA (1:1) and above there
were treatment-related clinical signs and histopathological changes in
the kidneys including crystal deposition. Fetal kidney did not show any
histopathological changes. At the maternal toxic dose of 60 mg/kg bw/d
MEL and CYA (1:1), fetal body weight was statistically significantly
reduced as compared to control, and there was delayed fetal
ossification. Under the conditions of this study, the NOAEL for maternal
toxicity was 6 mg/kg bw/d MEL and CYA (1:1) and the NOAEL for
developmental effects and fetotoxicity was 20 mg/kg bw/d MEL and CYA
(1:1). MEL and CYA (1:1) was not teratogenic.
In this study, there was another separate group of pregnant rats treated
with 1000 mg/kg bw of melamine. These results are not presented since 7
of the 13 animals were sacrificed in moribund condition and the criteria
for a maximum tolerated dose are clearly exceeded.
Melamine was tested
for its prenatal toxicity in Wistar rats. The test substance was
administered as a constant homogeneous addition to the food to 23 – 24
pregnant female Wistar rats/group at concentrations of 1,500 ; 4,500 and
15,000 ppm on day 6 through day 16 post coitum (p.c.). The control
group, consisting of 23 dams, was dosed with the food only. Food
consumption and body weights of the animals were recorded regularly
throughout the study period.The state of health of the animals was
checked each day. On day 20 post coitum, all females were sacrificed and
assessed by gross pathology (including weight determination of the
terminal body weight, the unopened uterus, the liver and the kidneys).
The fetuses were removed from the uterus, sexed, weighed and further
investigated for any external, soft tissue and/or skeletal findings. The
following findings were obtained and assessed as substance-related:
Test group 3 (15000ppm
= about 1060 mg/kgbody weight/day):
significantly decreased food consumption between days 6 and 16 p.c.
(about 26% less than the concurrent control group )
significantly reduced body weights from day 10 to day 17 p .c .
significant body weight loss between days 6-10 p.c. and significantly
decreased body weight
gain between days 10 and 15 p.c.
significantly lower carcass weight and decreased corrected body weight
gain (about 53
% less than in the concurrent control group )
-hematuria in nearly
all and indrawn flanks in 7 out of 25 animals between days 8 and 17
p.c.; piloerection in one female between days 8 and 15 p.c.
Test group 2 (4500ppm
= about 400 mg/kg body weight/day):
effects on dams, gestational parameters or fetuses.
Test group 1 (1500ppm=
about 136 mg/kg body weight/day) :
Thus, under the
conditions of this study, the administration of MELAMINE to pregnant
female Wistar rats during organogenesis elicited signs of maternal
toxicity at 15000 ppm, but induced no substance related effects in the
dams at 1500 or 4500 ppm. Maternal toxicity was substantiated in this
full scale prenatal toxicity study by reduced food consumption,
impairments in body weight / body weight gain, decreased corrected body
weight gain and clinical symptoms like hematuria, indrawn flanks and
piloerection at 15000 ppm (about 1060 mg/kg body weight/day) .
Nearly all signs of
maternal toxicity proved to be fully reversible after cessation of the
test substance administration. The carcass weight and the corrected body
weight gain, however, showed still some impairments at terminal
There were no
substance-related findings on the gestational parameters and no signs of
developmental toxicity up to and including the highest dose level
(15000ppm). Especially no indications of teratogenicity were found.
Based on the results
of this full-scale prenatal toxicity study in Wistar rats, the no
observed adverse effect level (NOAEL) for the dams is 4500 ppm(about 400
mg/kg body weight/day), but 15000 ppm (about 1060 mg/kg body weight/day)
for the fetal organism.
using the oral route:
The chosen oral route in this study is
considered to be appropriate, even if it is not the most likely route of
human exposure. Justifications are: There is apparently no metabolism of
melamine in the organism and by this no first pass effect. A rapid and
near to complete absorption was found after the oral route in rats. The
same can be assumed for the inhalation route, whereas a low dermal
absorption was estimated for melamine. Effects after oral exposure can
stand therefore for effects after inhalation exposure and are on the
worst case side of effects after dermal exposure.
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