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EC number: 931-295-2
CAS number: -
Available repeated dose studies on
Etherdiamine C13i/acetate do not indicate adverse effects on
reproductive organs, including oestrous cycle evaluation and
histopathological examination of the male and female reproductive
organs. Prenatal developmental toxicity study onEtherdiamine
C13i/acetateshowed no indications reproductive effects. Also comparable
fatty amine-like substances lack of effects on reproduction.
There is no information available from
a specific reproduction toxicity study on Etherdiamine C13i/acetate.
A 28-day study on Etherdiamine
C13i/acetate included the evaluation of reproductive organs. The
following organs were weighted and microscopically examined:
Epididymides, prostate and seminal vesicles incl. coagulating glands,
testis, ovaries and uterus. Dose levels were 0, 3, 9, and 25 mg/kg
bw/day dosed by gavage. In the high dose group, 2/5 males and 1/5 males
from the recovery group showed reduced size seminal vesicles upon gross
examination, and of prostate gland in one of these high dose group
animals. Organ weights showed a dose dependent reduced weight, which was
significant in the high dose males for prostate (with seminal vesicles
incl. coagulating glands) (44%) and Epididymides (18%). Only for the
high dose group for prostate effects remained when based on body weight
ratio’s. The recovery groups showed no differences for these organ
weights, indicating that observed effects are reversible and likely
secondary to the general weight loss. The organ weights for ovaries and
uterus showed no significant changes in females. Histopathology only
indicated minimal reduced secretion in the prostate gland and minimal
reduced colloid in the seminal vesicles in high dose group males. Only
minimal reduced colloid in the seminal vesicles was still present in one
Considering that the lowest dose of 3
mg/kg bw represented a LOAEL rather than a NOAEL, the effects on
prostate and seminal vesicles in the high dosed males at 25 mg/kg which
was resolved after a 14-day recovery period are not indicative for a
specific reproductive organ toxicity.
In a 90-days study Wistar rats were
administered 0, 0.5, 2.2 or 8.8 mg/kg bw/d of Etherdiamine C13i/acetate.
Examinations were performed according to OECD 408 with additionally
oestrous cycle determination. There were no indications of possible
reproductive toxicity based on the parameters determined in this study.
Estrous cycle length/regularity appeared unaffected during the period in
which estrous cycle length was determined (Day 76-91), and
histopathological examination of the male and female reproductive organs
did not show lesions that were directly related to treatment.
Inactive uterus (cervix) epithelium
was observed in 4/10 females at 2 mg/kg. In general, this finding is
probably related to poor health condition. Atrophy/mucification of the
vagina epithelium was seen in 1/1 females at 0.5 mg/kg and in 1/10
females a 2 mg/kg.
Also in this study, the lowest dose of
0.5 mg/kg represented a LOAEL rather than a NOAEL, and the effects
observed on the uterus epithelium (‘inactive uterus’) observed at 2
mg/kg are not indicative for a specific reproductive organ toxicity.
Also the study ofEtherdiamine
C13i/acetate in a prenatal developmental toxicity study in rats
has not shown reproductive effects.
Literature does not provide additional
information. Comparable fatty nitrile derivatives (like diamines) have
not shown a concern for reproduction toxicity.
The likelihood of exposures to Etherdiamine
C13i/acetate is low considering use and physical properties: The
substance is very corrosive and its use is limited to industrial
settings under controlled conditions. Also the high boiling point (> 300
°C) and low vapour pressure (0.005 Pa at 25°C) indicate that the
potential for inhalation is not significant to justify this study.
In view of limited exposures, lack of
effects on reproductive organs observed in repeated dose studies in
contrast to severe systemic toxicity observed in these studies, and lack
of effects on reproduction seen in reproduction and developmental
toxicity studies on comparable fatty amine-like substances and
MoA considerations, there are no concerns for reproduction
toxic effects by Etherdiamine C13i/acetate that would warrant further
studies for reproduction toxicity.
Likelihood of exposures toEtherdiamine
C13i/acetateis low considering use and physical properties:
Exposures are limited based on its use
as flotation agent in mining, involving potential exposures of only a
limited number of people working in industrial setting under controlled
conditions. The high boiling point (> 300 °C) and low vapour pressure
(0.005 Pa at 25°C) indicate that the potential for inhalation is not
significant. Evaluation of concentrations in the air generally showed
levels below detection limit (i.e. less than 0.17 to 0.19 µg/m3).
Only one area showed levels of Lilaflot D817M above the DNEL of 3.5 µg/m3,
but this did not involve long time presence of people.
Substance is corrosive. Effects will
be characterized by local corrosive effects that are related to
duration, quantity and concentration, rather than by systemic toxicity
due to dermal uptake. Related to corrosive properties, exposures are
likely to be limited in view of protective measures taken.
an oral OECD 414 prenatal developmental toxicity study in rats with
Etherdiamine C13i/acetate, no maternal NOAEL was determined based on
observation of granulocytic (necrotizing) inflammation in the ileum and
granulomas with or without necrosis in the mesenteric lymph nodes in
females starting at the lowest dose of 3 mg/kg. The developmental NOAEL
can be set at 7 mg/kg bw, based on adecreased
fetal BW at 15 mg/kg bw correlated with a trend towards a higher
incidence of unossified metatarsal #1. Metatarsals of digit #1 is the
last one that will ossify (starts on gestation Day 21). No
teratogenic effects were observed.
In a prenatal developmental toxicity study
rats were exposed to 0, 3, 7 or 15 mg/kg bw/d of the test substance once
daily by oral gavage from days 6 to 20 post-coitum inclusive. The
control group received the vehicle propylene glycol. Examinations were
according to OECD 414 (2001) with additional histopathology of the
stomach, small intestine and mesenteric lymph nodes.
Two high dose
females at 15 mg/kg were euthanized moribund on Days 15 and 17
post-coitum, respectively. Toxicologically
relevant clinical signs (lethargy, hunched posture, piloerection, and
lean appearance) were noted at 15 mg/kg only. Treatment at 7 and
15 mg/kg resulted in reduced body weights, body weight
gains, body weight corrected for uterine weight, and food consumption.
Treatment related adverse
morphological alterations were present in the small intestine and the
draining mesenteric lymph node of animals in all treated groups. At
necropsy, a thickened wall of the duodenum, ileum and/or jejunum was
noted which at the microscopic level correlated with (foamy) macrophages
in the lamina propria and/or granulocytic (necrotizing) inflammation of
the duodenum, jejunum and ileum. In general, these changes were dose
related with the highest incidence and severity seen in the ileum.
Enlarged mesenteric lymph nodes recorded at necropsy correlated with
granulomas with or without necrosis (up to marked), extranodal
inflammation with or without peritonitis, increased incidence, severity
of increased macrophage foci, increased cellularity of cortex and/or
medullary cords. Some of these findings were also noted in the 2 high
dose females sacrificed moribund after 9 or 12 treatment days.
on the morphological data it is most likely that the (necrotizing)
inflammation in the intestine caused by exposure to the test substance
spreads to the draining mesenteric lymph nodes with possible
breakthrough of granulomas into the abdominal cavity.
at 15 mg/kg resulted in significantly lower fetal body weights (both
sexes).This is most likely related to the reduced food
consumption and body weight loss seen in the mothers.
A higher incidence of unossified
metatarsal #1 was noted for all treated groups. The mean litter
proportion was 8.6%, 10.2% and 18.9% in the 3, 7 and 15 mg/kg groups,
respectively, as compared to 2.9% in the control group. None of these
changes was statistically significant. It should, however, be noted that
the litter proportion for the high dose group was in actuality even
higher, since the 7 dead fetuses from litter 77 were not included in the
group mean count.
There was also a trend towards a
higher incidence of unossified sternebae in the 7 and 15 mg/kg groups.
The mean litter proportion of unossified sternebra #5 was 1.6%, 4.5% and
4.6% in the 3, 7 and 15 mg/kg groups, respectively, as compared to 2.4%
in the control group. In addition, unossified sternebra #2 with or
without unossified vertebral centra and reduced ossification of the
pubis was noted for 3 fetuses from the same litter.
It should be noted that necropsy was
performed on Day 21 post-coitum. At this time point, ossification of the
skeleton should be almost complete. As such the higher incidence of
unossified metatarsals and/or unossified sternebrae noted in all treated
groups was regarded as treatment related. The exact cause of the delayed
ossification is unknown. The (necrotizing) inflammation of the small
intestine seen in the mothers may have resulted in impaired absorption
of nutrition factors necessary for bone calcification. However, there
were no data (like blood parameters) available from this study to
substantiate this hypothesis.
toxicologically significant changes were noted in any of the remaining
developmental parameters investigated in this study (i.e. litter size,
visceral and skeletal developmental malformations, external and visceral
NOAEL maternal toxicity:
Based on the Granulocytic (necrotizing)
inflammation in the ileum and granulomas with or without necrosis in the
mesenteric lymph nodes in females starting at 3 mg/kg, no NOAEL for
maternal toxicity could be derived. These findings are in agreement with
the results obtained in other repeated dose studies for this substance.
NOAEL developmental toxicity:
The study report concluded that on the basis
of the observed incidence of unossified metatarsal #1 also at the lowest
dose of 3 mg/kg, no developmental NOAEL for Etherdiamine C13i/acetate
could be derived. However, there are some additional comments that can
be made to this:
- None of these increased incidences of
delayed ossifications was statistically significant.
- The effects as such is not severe
(classified as variation) and are also commonly seen in control groups.
Higer incidences of such delayed ossifications are often seen at levels
that result to maternal toxicity, and these delays are considered to be
rapidly catching up after birth under normal feeding conditions.
- When a delayed development is noted
(secondary to maternal toxicity), which is plausible considering the
lower fetal body weights observed in the high dose fetuses, the
evaluation for skeletal variation in principal shows a pattern of
delayed ossifications. It seems that the data in this study point a
narrow impact on the ossification of metatarsal #1 alone which is also
visible at lower dose levels, but do not indicate a delayed ossification
of other structures that would also be expected. For
example, the reported proportion of unossified sternebrae was even lower
in the 3 mg/kg group than in the control.
Looking at the total picture, there is
a clear dose related effects on maternal health and nutritional status,
already visible from the lowest dose, that clearly has a dose related
effect on fetal development as shown by decreased fetal BW and delayed
fetal growth. For both a dose effect relation is visible, and effects
are certainly clear at the highest dose level.
However, for the low and mid-dose
levels the effects seem to show increased incidence of delayed
ossification as observed compared to control specifically of the
metatarsalis, however not so clear as for the high dose, and adversity
Based on the arguments above, we
consider the reported small, statistically non-significant, increased
incidence of unossified metatarsal #1 as observed at 3 and 7 mg/kg bw,
as not adverse.
The NOAEL for developmental toxicity
therefore is set at 7 mg/kg bw., based on adecreased fetal BW at 15
mg/kg bw correlated with a trend towards a higher incidence of
unossified metatarsal #1. Metatarsals of digit #1 is the last one that
will ossify (starts on gestation Day 21).No teratogenic effects were
In a prenatal developmental toxicity
study rats were exposed to 0, 3, 7 or 15 mg/kg bw/d of the test
substance once daily by oral gavage from days 6 to 20 post-coitum
inclusive. The control group received the vehicle propylene glycol.
Examinations were according to OECD 414 (2001) with additional
histopathology of the stomach, small intestine and mesenteric lymph
Based on the Granulocytic
(necrotizing) inflammation in the ileum and granulomas with or without
necrosis in the mesenteric lymph nodes in females starting at 3 mg/kg,
no NOAEL for maternal toxicity could be derived. These findings are in
agreement with the results obtained in other repeated dose studies for
There is a clear dose related effects
on maternal health and nutritional status that clearly has a dose
related effect on fetal development as shown by decreased fetal BW and
delayed fetal growth.
Mean fetal body weights (sexes
combined) were 5.1, 5.1, 5.0 and 4.6 for the control, 3, 7 and 15 mg/kg
groups, respectively.The mean litter proportion of unossified metatarsal
#1 was 2.9%, 8.6%, 10.2% and 18.9% in the control, 3, 7 and 15 mg/kg
groups. The levels at 3 and 7 mg/kg groups were small and not
statistically different from control, and of similar magnitude therefore
not indicative for a dose-response relationship and therefore likely not
substance related. At 15 mg/kg there is a clear increase, which is also
associated with clear lower BW pups, and lower BW and food intake of the
mothers. In that respect, the lower proportion is control compared to
the 3 and 7 mg/kg groups is most likely incidental.
Based on structure and mechanism of
cytotoxicity, reproduction toxicity is not expected.
Etherdiamine C13i/acetate has a
cationic surfactant.Under physiological conditions, the cationic
surfactant structure leads to high adsorption at negatively charged
surfaces such as cellular membranes. The cationic surfactant molecules
then partition into the membranes in such a way that part of the
molecule is associated to the polar head groups of the phospholipid
while the non-polar alkyl chain partitions into hydrophobic environment
of the membrane interior. A solute molecule partitioning in this way is,
like the phospholipid molecules of which the membrane is composed, able
to move freely in two dimensions only, but it cannot easily pass through
the membrane to the intracellular environment. Noteworthy in this
respect is that recent research shows that the log distribution
coefficients for cationic surfactants between water and phospholipids
are several orders of magnitude higher than between water and oil (Niels
Timmer, Steven Droge, 2017). Consequently, the primary activity of
cationic surfactants is disruption and leakage of cell membranes leading
to damage or lysis of the cell content(s). Cytotoxicity through
disruption of cell membrane at exposure site will occur rather than
absorption over the cell membrane. Consequently, significant uptake
followed by placental transfer is not expected to occur. This generic
behaviour provides for a common mode of action for cationic surfactants
that is not subject to species differences. Although these substances
show similar effects with respect to occurrence of foamy macrophages in
mesenteric lymph nodes, with inflammatory reactions at higher dose
levels and longer duration, between the various structures the actual
potency of the effects can vary enormously and cannot be predicted.
Available reproduction data on all these substances combined however,
indicate that these effects do not lead to, or are linked to, effects on
reproduction or development.
Study of Etherdiamine
C13i/acetate in a prenatal developmental toxicity study in rats
has not shown reproductive or teratogenic effects. Developmental effects
characterised as increased incidence of delayed ossification were only
visible at maternal toxic dose levels and are considered secondary to
in view of limited exposures, lack of effects on reproductive organs
observed in repeated dose studies, and lack of effects on reproduction
seen in reproduction and developmental toxicity studies on comparable
fatty amine-like substances and MoA considerations, there are no
concerns for reproduction toxic effects by Etherdiamine C13i/acetate,
and no classification for reproduction toxicity is required.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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