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EC number: 203-468-6
CAS number: 107-15-3
reduction in parental body weight gain of female rats in the
intermediate and high dose group of the F0 generation, in the high dose
group of the F1 generation and of male rats in the high dose group of
both F0 and F1 generations.
substance-related parental deaths in the F0 or F1 generation.
decrease of absolute liver weight in male rats of the high dose F1
macroscopic or histopathologic findings except a significant higher
incidence of hepatocellular pleomorphism in both sexes of the high dose
group of the F1 generation (6/10 male, 10/10 female; control: 0/20 each)
and a significant decreased prevalence of kidney tubular mineralization
in female rats of the high dose group of the F1 generation (0/10 female;
conclusion there was no evidence of fertility impairment or embryotoxic
effect at dose levels that show maternal or paternal toxicity.
In a two-generation study, male and female Fischer 344 rats were fed
diets containing 0, 50, 150 or 500 mg/kg/day of EDA*2HCl. At each dose
level 13 male and 26 female rats were mated in both F0 and F1
generation. In the high dose group effects noted were decreased body
weight gain in both F0 and F1 generations, a higher incidence of
hepatocellular pleomorphism in F1 generation, and decreased liver
weights in male rats in F1 generation. In the intermediate dose group
female rats of F0 generation showed a decreased body weight gain. No
evidence of impaired fertility or embryotoxicity was seen at any dose
level. NOAEL parental was 50 mg/kg (23 mg/kg calculated as
Ethylenediamine base) and NOAEL F1 offspring was 500 mg/kg (227mg/kg
calculated as ethylenediamine base).
In a two-generation reproduction study (Yang
et al., 1984a) there was no reproductive effect noted in any dose group
as regards fertility, pup survival, number of pups born alive and number
of pups weaned per litter
Growth retardation was observed in fetuses from dams receiving 1000 mg/kg/day, levels which resulted in maternal toxicity. However there was no evidence of a teratogenic effect.
reduction in maternal body weight gain in the intermediate dose group
during gestation day 6 - 15 and in the high dose group during gestation
day 6 - 21; significant decreased diet consumption in the intermediate
and high dose group during gestation day 6 - 15; significant increased
number of resorptions/litter and significant decreased mean fetal body
weight and reduced fetal crown-rump length in the high dose group;
significant higher incidence of a shortened mandible, edematous eye
bulge, shortened or missing innominate artery, unossified sternebrae in
fetuses of the high dose group.
F = fetuses
L = litters
artery to branch off of the aorta is the brachiocephalic which becomes
the innominate after the left carotid branches off. The
innominate then branches into the right subclavian and right carotid
the authors stated it was missing, they really mean that the right and
left carotid branch off of the brachiocephalic artery at the same time.
there is no innominate. However,
this would not affect blood supply to areas served by these arteries.
Fischer 344 rats were fed EDA*2HCl on
gestation day 6-15. Groups of 20 rats were fed doses 50, 250, or 1000
mg/kg. Two control groups were used. Standard endpoints for
teratogenicity were evaluated.
Reduction in maternal body weight gain was noted in the high and
intermediate dose group. Reduced diet consumption was also noted in
those groups. In the high dose group there was an increased number of
resorptions/litter, decreased mean fetal weight and length, higher
incidence of shortened mandible, edematous eye bulge, shortened or
missing sternebrae, delayed ossification and missing, or shortened
There are both rat and rabbit
pre-natal developmental toxicity (teratology)studies. The rabbit study
consisted of New Zealand White rabbits, which were dosed by gavage with
Ethylenediamine dihydrochoride (EDA*2HCL) on gestation days 6-19. The
dose levels were 0, 10, 40 and 80mg/kg bw, calculated as Ethylenediamine
base. The top dose was selected due to 20% mortality in a dose ranging
study at 100mg/kg bw/day. There were no adverse effect on the maternal
females and no indication of any developmental toxicity/teratogenicity
on the foetuses.
In a rat teratology study
Ethylenediamine dihydrochoride was administered in the diet at 0, 50,
250 and 1000mg/kg bw/day for days 6-15 of gestation. These doses were
25, 114 and 454 mg/kg bw/day calculated as ethylenediamine base. There
was significantly reduced body weight gain in the intermediate and high
dose groups together with reduced food consumption. There were several
findings in the offspring at the high dose, such as reduced
ossification, increased resorptions, decreased foetal weight and
length. The most important finding was an increased incidence of missing
and shortened innominate artery. By missing the authors meant that the
right and left carotid branched off the brachiocephalic artery, rather
than it becoming the innominate after the left carotid branches. So
there is no innominate but this would not affect blood supply. As
missing innominate artery has been observed in offspring of rats on
diets deficient in folic acid, further studies were performed to
determine if this effect was due to malnutrition due to decreased diet
consumption. A first step was to establish if the reduced food
consumption was due to unpalatability of the diet, 10 pregnant rats were
dosed by gavage from days 6-15 of gestation at 1000mg/kg Ethylenediamine
dihydrochloride (454mg/kg bw/day calculated as Ethylenediamine
base).These rats showed reduced bodyweight gain and food consumption,
even though there was no ethylenediamine dihydrochoride in the diet. The
foetuses were not examine internally, but there was a decrease in live
foetuses/litter and increase in resorptions.
NOAEL for developmental toxicity was 250mg/kg EDA*2HCL (114mg/k bw/day
calculated as Ethylenediamine base.
This demonstrated that the reduced
food consumption seen in the dietary study was not due to unpalatability
of the diet. This study was followed by a paired feeding study where a
group of pregnant females were fed the same amount of control diet aswas
consumed by the rats who were receiving 1000mg/kg EDA*2HCL (454mg/kg
Ethylenediamine base). The paired fed controls had the same incidence of
missing innominate arteries as those fed Ethylenediamine. This indicated
that this effect was as suspected due to a folic acid deficiency caused
by reduced food consumption The ethylenediamine dosed rat did however
still show shortened innominate arteries, the authors concluded that
this shortening was not a teratogenic effect as it would not result in a
functional deficit and may not be irreversible but rather a result of
the growth retardation seen together with reduced foetal weights which
only occurred in the presence of maternal toxicity.
The two generation study in rats
showed clearly that there were no adverse effects on reproduction either
on fertility or embryotoxicity from Ethylenediamine, administered in the
diet up to 500mg/kg bw/day od EDA*2HCL, (227mg/kg bw/day calculated as
Ethylenediamine base) the highest dose group.
There were no indications of any
developmental toxicity / teratogenicity seen in rabbits at a maximal
dose of 80mg/kg bw/day of Ethylenediamine by gavage.
In the rat teratogenicity study there
were some findings interpreted as being due to malnutrition (low folic
acid) which was the case for the missing innominate arteries, due to
reduced maternal food consumption, caused by the ethylene diamine but
not due to unpalatability of the diet. Other findings of shortened
innominate arteries, delayed ossification etc. were considered to be due
to delayed development linked to reduced foetal weight at a maternally
toxic dose level. The NOAEL for effects in the foetuses was 250mg/kg
EDA*2HCL (114mg/k bw/day calculated as
Based on these findings it is
concluded that ethylene diamine does not require any classification
under the EU CLP(GHS) criteria for adverse effects on reproduction or
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