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EC number: 629-765-4
CAS number: 1226892-44-9
No data on acute toxicity is available for"Fatty acids C18 unsat,
reaction products with triethylenetetramine" (or TO + TETA). Read-across
is performed with "Fatty acids C18 unsat, reaction products with
diethylenetetramine" (or TO + DETA).
A combined repeated dose/reproduction screening toxicity study
according to OECD 422 with Fatty acids, C18 unsat, reaction products
with diethylenetriamine (AAI-DETA) resulted to a NOAEL of 10 mg/kg
bw/day based on the increased incidence/severity of macrophage foci in
the mesenteric lymph node observed at 30 or 100 mg/kg bw/day, the
highest dose tested. All already available data from the group of AAI
substances, including 90 -day studies in rat and dogs on a similar
substance, also indicate low repeated dose toxicity.
The 90-day NOAEL with AAI-DETA is considered to be 10 mg/kg bw/d.
At higher dose levels an increase of the presence of foamy macrophages
in the lamina propria of the small intestines and mesenteric lymph nodes
is observed, as well as lower mean body weight and body weight gain,
especially in the males, with lower food intake, essentially during the
second half of the treatment period.
Accuracy of preparation: The
concentrations analysed in the formulations for the 10, 30 and 100 mg/kg dose
groups were in agreement with target concentrations (i.e. mean
accuracies between 90% and 110%). A small response at the retention time
of the test substance was observed in the chromatograms of the control formulations.
It was considered to derive from carry over since a similar response was
obtained in the analytical blanks.
Homogeneity: The formulations
of Group 2 and Group 4 were homogeneous (i.e. coefficient of variation = 10%).
Stability: Formulations at the
entire range were stable when stored under nitrogen in a refrigerator
for at least 8 days.
Tall oil diethylenetriamine imidazoline was
administered by daily oral gavage to groups of 10 male and 10 female
Wistar Han rats for 90 days at dose levels of 0, 10, 30 and 100
mg/kg/day. The study was performed under GLP and based
on OECD TG 408.
Chemical analyses of formulations
preparations; clinical signs daily; functional observation tests in Week
12; body weight and food consumption weekly; ophthalmoscopy at pretest
and in Week 13; estrous cycle determination; clinical pathology and
macroscopy at termination; organ weights and histopathology (including
spermatogenesis staging) on a selection of tissues.
Formulation analyses confirmed that
formulations of test substance in propylene glycol were prepared
accurately and homogenously, and were stable over at least 8 days.
All animals survived up until scheduled
termination. No toxicologically significant clinical signs were noted
during the observation period.
The treatment-related lower motor activity
of males at 100 mg/kg, and a trend towards lower motor activity for
females at 30 and 100 mg/kg were considered not to represent an adverse
effect on neurobehaviour. These results were not supported by clinical
observations or other functional observation tests, were slight in
nature (within the normal range for rats of this age and strain), and
had no supportive morphological correlates in examined neuronal tissues.
Males at 30 and 100 mg/kg showed a lower
mean body weight and body weight gain with lower food intake,
essentially during the second half of the treatment period, with a
slightly lower body weight and body weight gain of females at 100 mg/kg
during the last week of treatment.
No treatment-related ophthalmology findings,
changes in haematological parameters or macroscopic findings were noted.
Test item-related microscopic findings
foamy macrophages in the lamina propria of the small intestines (males
and females starting at 10 mg/kg/day),
- foamy macrophages in the mesenteric lymph
nodes (females starting at 10 mg/kg/day, males starting at 30
- increased incidence and severity of
pigmented macrophage foci in the mesenteric lymph nodes (males and
females starting at 30 mg/kg/day),
- increased incidence and severity of
alveolar (mainly foamy) macrophage aggregations in the lung (females at
macrophages in the glomeruli of the kidneys (males and females at 100
The findings in the lamina propria of the
small intestines were considered to have caused reduced protein uptake,
and to correlate with lower total protein and albumin levels in males
and females at 100 mg/kg.
Other treatment-related changes in clinical
biochemistry parameters at 100 mg/kg consisted of higher alanine and
aspartate aminotransferase activity in males and females, higher total
bilirubin and glucose levels in males, lower urea levels in males (with
a trend towards an increase among female dose groups), higher bile acid
levels in females, and lower calcium levels in females at 100 mg/kg
(possibly secondary to the lower albumin levels).
The lower liver, thymus and spleen weights
in males at 100 mg/kg (with a decreasing trend across other male groups)
had no histopathological correlates, and were therefore ascribed to the
lower terminal body weights for these males. As such, these changes were
considered to be of no toxicological relevance.
One male at 100 mg/kg showed various
microscopic (and correlating macroscopic and organ weight) changes in
reproductive organs including undeveloped testes (correlating to absence
of all spermatogenesis stages) with reduced sperm content in the
epididymides and immature prostate, and a difference in cell size in the
periportal-centrilobular area of the liver. In addition, this animal
showed a lower weight gain during treatment, and blood analyses showed a
lower glucose value and a higher bile acid and inorganic phosphate
level. Since these findings were confined to this single animal, these
were considered unrelated to treatment with the test substance.
There were no indications of possible
reproductive toxicity based on the parameters determined in this study.
No treatment related changes in estrous cycle length were noted across
the dose groups during the period in which estrous cycle length was
determined (Day 72 up to and including Day 92), and histopathological
examination of the male and female reproductive organs (including
spermatogenesis staging) did not show treatment-related lesions.
The first effects to occur is the presence
of foamy macrophages in the lamina propria of the small intestines and
mesenteric lymph nodes. These effects are considered to represent a
local, porte d’entrée related effect due to the route of application,
rather than a systemic effect.
The study evaluated the subchronic
oral toxicity of Varisoft 475 (75%) in a 13-week study in dogs. Four
male and four female beagle dogs were offered the test substance in the
diet at concentrations of 0, 4000, 12000 and 4000 ppm active ingredient
for 13 weeks. Diet and water were available ad libitum, except prior to
clinical pathology testing and necropsy, when diet and/or water were
withheld overnight. Male animals weighed between 9.1 to 11.6 kg and
females weighed 6.5 to 8.8 kg. Observations were conducted at least
twice daily for mortality and overt toxicity. Detailed observations,
body weights and food consumption were recorded weekly. Ophthalmological
examinations were performed on all animals prior to study initiation and
at study termination. Physical examinations, as well as hematological
clinical chemistry and urological evaluations were conducted on all
animals prior to study initiation and at monthly intervals during the
study. At study termination, a thorough post-mortem examination was
conducted on all dogs. A complete set of all major tissues and organs
was harvested and selected organs were weight. The saved tissues were
processed histologically and microscopic examination was conducted.
Actual dose received: 142, 366 and
1322 mg/kg/day for males; 144, 632 and 1948 mg/kg/day for females
During the 13-week treatment period,
one male and one female dog administered diets containing 40,000 ppm
test substance lost 1.4 and 1.1 kg of body weight, respectively. The
body weight gains of all other male and female dogs administered test
substance in their diet were considered to be comparable to the body
weight gains of the respective control animals in this study. During the
first week of the study, there was a clear reduction in food
consumption, indicating an aversion to the treated diets, in both the
male and female dogs administered diets containing 40,000 ppm test
substance. Thereafter, there continued to be evidence of aversion to the
treated diets. In males, this was evidenced by a slight reduction in
food consumption in all treatment groups. In females, the aversion was
evidenced by an apparent increase in food spillage, which was considered
to at least partially account for the difference in actual received
dosages between males and females. All dogs survived to study
termination. No changes noted in physical condition or appearance were
considered to be related to treatment with the test substance. At
termination, body weights appeared to be reduced for males and females
receiving 40,000 ppm of the test substance in the diet. However, the
reduction was due to the body weight loss of the one male and one female
dog noted above. Small reductions in mean values for erythrocyte,
hemoglobin and hematocrit were observed in both male and female dogs in
the 40,000 ppm treatment group relative to the corresponding mean
control values at one or more intervals of analysis. The differences
were slight, a slight difference was also observed in the pre-study
measurements, and the values were within historical control range.
Therefore, the toxicological significance of the changes in hematology
measurements was unclear. At all analysis intervals during the treatment
period, mean cholesterol values for male and female dogs in the 40,000
ppm treatment group were reduced relative to the corresponding control
group. The mean cholesterol values for the male dogs in the 12,000 ppm
treatment group were also reduced relative to the corresponding
controls. No treatment-related changes in urinalysis measurements were
observed. No treatment related ophthalmologic changes or clinical
observations, organ weight changes, or gross necropsy observations were
seen at termination. A small number of macroscopic lesions were seen in
both male and female animals across dietary concentrations. These
lesions were considered to be spontaneous and not related to the
administration of the test article. The ratio of the weight of the
pituitary gland to the body weight of males at the 12,000 ppm dietary
concentration was significantly decreased relative to the control group.
The ratio of the weight of the pituitary gland to the body weight of
females in the 4,000 ppm dietary concentration also was significantly
decreased compared to the control group. The ratio of the weight of the
right adrenal gland to the brain weight of the females was significantly
increased at the 4,000 ppm dietary concentration compared to the control
group. These findings were not consistent, could not be correlated with
microscopic findings and were considered to be either spurious or due to
biological variation, and not related to the administration of the test
article. A small number of non-neoplastic findings were evident in this
study. Many of them occurred in single animals. Some of the more common
lesions included interstitial pneumonia, parathyroid cysts, pituitary
cysts, thymic atrophy, c-cell hyperplasia of the thyroid gland and
mineralization of the kidneys. Multifocal mineralization of the renal
medulla of the kidneys was present in both male (16/16) and female
(15/16) dogs of all dietary concentrations. The above lesions are
considered to be common spontaneous findings in a 13-week beagle dog
study, and none of the microscopic findings were considered to be
related to the administration of the test article. Reproductive organs
were examined meeting the requirements for SIDS/HPV reproductive
NOEL = 4,000 ppm (143 mg/kg/day)
LOAEL (LOEL) 12,000 ppm (366 and 632
mg/kg/day for males and females, respectively)
Evaluation by EPA concluded that:
Decreased food consumption observed in
all treatment groups, most likely reflects decreased palatability in the
treated diet. A significant decrease in body weight was observed in one
male and one female at the highest dose. Study authors attributed
observed decreases in mean cholesterol levels at or above 366
mg/kg-bw/day to decreased food intake. Macroscopic lesions (type not
specified) were observed in all treatment groups; however, these lesions
were not dose-related. Other findings reported in this study include
significantly increased relative adrenal gland weight in females treated
at 144 mg/kgbw/ day and significantly decreased relative pituitary gland
weight in males and females at 1322 and 144 mg/kg-bw/day, respectively
(level of significance not specified). These effects most likely reflect
biological variation. No treatment- related histopathology was observed.
NOAEL ~ 1635 mg/kg-bw/day (males and
Tall oil diethylenetriamine imidazoline was
administered by daily oral gavage to male and female Wistar Han rats at
dose levels of 10, 30 and 100 mg/kg/day. The males were exposed for 2
weeks prior to mating, during mating, and up to termination (for 28
days). There was a 2 week recovery period for 5 animals of Group 1 and
4. The females were exposed for 2 weeks prior to mating, during mating,
during post-coitum, and at least 4 days of lactation.
Formulation analysis showed that the
formulations were prepared accurately and homogeneously and were stable
for at least 6 hours at room temperature.
The changes in clinical biochemistry
parameters in animals at 100 mg/kg/day at the end of the treatment
period were generally slight in nature (i.e. mostly within the normal
range) and were fully reversible after a 14-day recovery period in
males. Moreover, no morphological changes were observed that would
support these changes which included higher alanine and aspartate
aminotransferase activity and creatinine level in males, and lower total
protein and urea level in males and females respectively. Therefore,
these changes were not considered to be of toxicological relevance.
The lower prostate and seminal vesicle
weight, and lower prostate to body weight ratio at the end of the
treatment period in males at 100 mg/kg/day were absent at the end of the
recovery period in males, and were not supported by any
histopathological lesions or reproductive toxicity. No toxicological
relevance was ascribed to these findings.
Histopathology revealed foamy macrophage
foci in the ileum of all selected males and females at 100 mg/kg/day, a
slightly increased incidence and degree of macrophage foci in the
mesenteric lymph node of both sexes at 100 mg/kg/day, and increased
incidence of lymphoid atrophy in the thymus of females at 100 mg/kg/day.
At the end of the 14-day recovery period for males, foamy macrophage
foci in the ileum had completely resolved, whilst macrophage foci in the
mesenteric lymph node persisted at higher severity than observed at the
end of treatment. Given the persistence of this finding it was
considered to be of an adverse nature.
No toxicologically significant changes were
noted in any of the remaining parental parameters investigated in this
study (i.e. clinical appearance, functional observations, body weight,
food consumption, haematology and macroscopic examination).
Based on the increased incidence/severity of
macrophage foci in the mesenteric lymph node at both the end of
treatment and recovery period in males, a parental No Observed Adverse
Effect Level (NOAEL) of 30 mg/kg/day was derived.
As explained in the category
justification, For cross-reading in general use is made with data of
same or lower EA-length where available, and that of Tall oil + DETA
representing the worst case.
This dossier is for the substance
"Fatty acids C18 unsat, reaction products with triethylenetetramine" (or
TO + TETA). As for the substance itself no toxicological information is
available, cross-reading has been applied to TO + DETA.
The available data available within
the group of Amidoamines/imidazolines (AAI) substances indicate that for
AAI substances based on shorter polyethyleneamines (EA), higher toxicity
is observed compared to AAI based on longer EA. The forming of
imidazoline itself does not seem to play a significant role. For
cross-reading purposes between substances of AAI, Fatty acid reaction
product with diethylene-triamine (AAI-DETA) therefore represents the
worst case. In series of 28-day and combined repeated dose/reproduction
screening toxicity studies (OECD 422) AAI-DETA has shown the highest
level of toxicity. (See also document in support of category
A combined repeated dose/reproduction
screening toxicity study according to OECD 422 has been performed with
AAI-DETA administered by daily oral gavage to rats at dose levels of 0,
10, 30 and 100 mg/kg/day. The males were exposed for 28 days. The
females were exposed for 2 weeks prior to mating, during mating, during
post-coitum, and at least 4 days of lactation (for 42-55 days). For the
male also 14-day recovery groups were added to the control and HD group.
Results: The changes in clinical
biochemistry parameters in animals at 100 mg/kg/day at the end of the
treatment period were slight in and were fully reversible after a 14-day
recovery period in males. Moreover, no morphological changes were
observed that would support these changes which included higher alanine
and aspartate aminotransferase activity and creatinine level in males,
and lower total protein and urea level in males and females respectively.
increased incidence and severity of foamy macrophage foci in the
mesenteric lymph node at the end of treatment, and in males also after
the after the recovery period.Also an increased incidence of
lymphoid atrophy in the thymus of females was seen at 100 mg/kg/day.
No toxicologically significant changes
were noted in any of the remaining parental parameters investigated in
this study (i.e. clinical appearance, functional observations, body
weight, food consumption, haematology and macroscopic examination).
The study report concludes to a parental
NOAEL of 30 mg/kg/day based on the increased incidence and severity of
foamy macrophage foci in the mesenteric lymph node at the end of
treatment, and in males also after the after the recovery period.
However, considering that the incidence and severity of macrophage as
observed at 30 mg is somewhat higher than at 10 mg and the control
group, the NOAEL could also have been set at 10 mg/kg bw.
A subsequent 90-day (OECD 408, GLP)
study was performed applying the same dose levels of 0, 10, 30 and 100
mg/kg/day AAI-DETA to groups of 10 animals/dose/sex.
The results from this study are comparable
to those obtained from the earlier OECD 422 study: The first effect to
occur is the presence of foamy macrophages in the lamina propria of the
small intestines and mesenteric lymph nodes. These effects are
considered to represent a local, porte d’entrée related effect due to
the route of application, rather than a systemic effect.
The magnitude of these effects as observed
at the lowest dose level of 10 mg/kg, is often also observed in control
groups in general, and was also seen in the control group of the OECD
422 study performed before on the same substance. These effects are
therefore not considered adverse. As no other effects were observed,
this dose level is considered to represent the NOAEL.
At higher dose levels an increase in foamy
macrophages is observed beyond levels that can occur in control groups,
as well as lower mean body weight and body weight gain, especially in
the males, with lower food intake, essentially during the second half of
the treatment period.
Comparing the effects of foamy macrophages
between the OECD 422 and the 90-day study, show that the NOAEL level
around 10 is rather comparable between the two studies, but that with
increase of the duration in the 90-day study, an increase in this
response is seen at 30 and 100 mg/kg bw/d.
Other available data from the group of
AAI substances, including 90-day studies in rat and dogs on a similar
substance, indicate low toxicity.
For dermal exposures, effects are
rather characterized by local corrosive effects that are related to
duration, quantity and concentration, than by systemic toxicity due to
dermal uptake. The mode of action of for AAI follows from its structure,
consisting of an apolar fatty acid chain and a polar end of a primary
amine from the polyethyleneamine. The structure can disrupt the
cytoplasmatic membrane, leading to lyses of the cell content and
consequently the death of the cell.
The AAI are protonated under
environmental conditions which causes them to strongly adsorb to organic
matter. This all leads to a low dermal absorption.
Physical-chemical properties of
polyamines indicate a low likelihood for exposure via inhalation, with a
boiling point > 300 °C and low vapour pressure (0.00017 mPa at 25°C).Any
inhalation exposures would therefore only be possible in the form of
aerosol, consisting of larger droplets depositing in upper airways which
could result to local irritation or corrosion
Justification for selection of repeated
dose toxicity via oral route - systemic effects endpoint:
Recent study of high quality and of longest
Justification for selection of repeated
dose toxicity inhalation - systemic effects endpoint:
Likelihood of exposures via inhalation is
low considering the high boiling point (> 300 °C) and very low vapour
pressure (0.00017 mPa at 25°C),as well as low possibility of exposure to
aerosols or droplets of an inhalable size. Furthermore, as the substance
is classified as corrosive, local effects will be dose-limiting and
preclude sufficient uptake for systemic effects to develop. The
potential for inhalation is not significant to justify this study.
Justification for selection of repeated
dose toxicity inhalation - local effects endpoint:
Lack of exposures
Justification for selection of repeated
dose toxicity dermal - systemic effects endpoint:
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. Because of the corrosive and sensitising properties,
exposures are likely to be limited.
Justification for selection of repeated
dose toxicity dermal - local effects endpoint:
Lack of exposures: use is limited to
industrial and professional users where because of its corrosive and
sensitising properties sufficient measures will be taken to prevent
Classification for STOT-RE Cat. 2 is
required in case of significant toxic effects at levels = 100 mg/kgbw/d
in case of standard 90-day study. In case of 28-day studies this can be
multiplied by 3.
The available 90 -day study on
AAI-DETA did not indicate severe toxicity at 100mg/kg/day.
Also other available data do not suggest severe toxicity at levelsrequiring
consideration for classification for STOTS-RE.
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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