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EC number: 629-732-4
CAS number: 1224966-13-5
Tall oil fatty acids, reaction products with
polyethylenepolyamines was administered by daily oral gavage to male and
female Wistar Han rats at dose levels of 30, 100 and 300 mg/kg/day. The
males were exposed for 2 weeks prior to mating, during mating, and up to
termination (for 28 days). A total of 5 animals each of Groups 1 and 4
were allowed a 2-week recovery period. The females were exposed for at
least 42 days, i.e. 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, were homogeneous and were stable
for at least 6 hours at room temperature.
Treatment up to 300 mg/kg/day was well
tolerated and did not result in toxicologically relevant clinical signs
or changes in body weight and food intake. A higher motor activity was
recorded for females at 300 mg/kg/day, although this was not accompanied
by supportive clinical signs (e.g. hyperactivity) or changes in
functional observation battery parameters. Therefore, this change was
not considered to be of toxicological relevance.
Clinical biochemistry measurements at the
end of treatment at 300 mg/kg/day showed notably higher alanine and
aspartate aminotransferase activity in both sexes (but without
corroborative histopathological findings, e.g. liver damage), along with
lower total protein and higher total bilirubin levels in males (within
normal range for rats of this age and strain) and higher inorganic
phosphate level in females. These changes had resolved to values
comparable to controls at the end of the recovery period for males. No
(further) changes were noted in clinical biochemistry and haematology
parameters at any dose level.
Macroscopic examination at the end of
treatment revealed a lower absolute and relative heart weight for both
sexes at 300 mg/kg/day. No histopathological correlate was found and no
such change was apparent at the end of the recovery period for males. No
(further) macroscopic abnormalities or organ weight changes were
observed at any dose level.
Histopathology showed a slight,
statistically non-significant, increase in incidence and severity of
multifocal vacuolation of the zona glomerulosa of the adrenal glands in
both sexes at 300 mg/kg/day. Following the recovery period this finding
had reverted to background incidence and severity.
No signs of parental toxicity were observed
at 30 and 100 mg/kg/day.
No reproductive/developmental toxicity was
observed at any dose level.
Overall, all parental findings observed at
the end of treatment at 300 mg/kg/day were not considered to be adverse
since these changes were generally slight and reversible in nature, and
occurred in the absence of supportive histopathological lesions.
Therefore, the parental, reproductive and developmental No Observed
Adverse Effect Level (NOAEL) of 300 mg/kg/day was derived.
The available data available for the
group of Amidoamines/imidazolines (AAI) substances indicate that
cross-reading between substances in this group is justified. (See
document in support of category justification). The data shows that for
AAI substances based on shorter polyethyleneamines (EA), relatively
higher toxicity is observed compared to AAI based on longer EA. The
forming of imidazoline itself does not seem to play a significant role.
No reproductive/developmental toxicity
was observed at any of the dose levels in an OECD 422 study with Fatty
acid reaction product with pentaethylene-hexamine (AAI-PEHA), and thus a
reproduction/developmental NOAEL of 300 mg/kg/day was determined.
Similar OECD 422 studies have been performed on other substances from
the group of AAI: on Fatty acid reaction product with
diethylene-triamine (AAI-DETA) and on Fatty acid reaction product with
tetraethylene-pentamine (AAI-TEPA). No indication of concern for
reproductive or developmental toxicity was observed in these studies up
to the highest dose tested. Also an OECD 414 developmental toxicity in
rat on a similar substance showed no concern for developmental effects.
All already available data from the
group of AAI substances, including 90-day studies in rats and dogs on a
similar substance, suggest low toxicity and have shown no adverse
effects on reproductive organs. (See also document in support of
Also the low likelihood of exposure
can be considered as its use is limited to industrial and professional
users where following its severe corrosive properties will provide for
sufficient protection measures to prevent exposure. The 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) and use
applications that do not involve the forming of aerosols, particles or
droplets of an inhalable size.
In view of low potential of exposures
in combination with an overall low level of toxicity, and a total lack
of effects observed in reproductive parameters from developmental
toxicity and reproduction screening studies within the group of AAI, and
no effects on reproductive organs observed in available repeated dose
studies, a 2-generation study is not considered necessary.
No developmental toxicity was observed in an OECD 422 screening study with atty acids C18 unsat, reaction products with pentaethylenehexamine (AAI-PEHA); No developmental toxicity was observed in a developmental toxicity study (OECD 414) study on a similar substance.
The objective of this study was to
evaluate the potential of the test substance to produce developmental
toxicity when administered by a gavage to pregnant CD® rats during
organogenesis. Maternal toxicity was also evaluated. Timed-pregnant rats
were administered the test substance by gavage on gestation days (gd) 6
through 15. Twentyfive copulation plug-positive females per group were
dosed with undiluted test substance at dose levels corresponding to 100,
300 and 1000 mg active ingredient/kg/day. An additional 25 females,
assigned to the control group, received Milli-Q water at a dose volume
equivalent to that used in the high dose group. Clinical observations
were made daily (twice daily during dosing), and maternal body weights
were measured on gd 0, 6, 9, 12, 15, 18 and 21. At scheduled sacrifice
on gd 21, the dams were evaluated for liver and gravid uterine weights,
number of corpora lutea and number and status of implantation sites
(including early and late resorptions, dead fetuses and live fetuses).
Approximately one-half of the live fetuses in each litter were examined
for visceral and craniofacial malformations and variations. The
remaining one-half of the fetuses were stained with alizarin red S and
were examined for skeletal malformations and variations.
Maternal: The pregnancy rate was
equivalent across groups and ranged from 88 - 100%. No females aborted
or delivered early. At scheduled sacrifice, three females in the control
group, two females in the 100 mg/kg/day group and one female in the 300
mg/kg/day group were found to be nonpregnant. One female from the
control group and one female from the 300 mg/kg/day group contained no
viable fetuses at scheduled sacrifice. Twenty-one to 25 live litters
were available for evaluation from each group. One female in the 300
mg/kg/day treatment group became moribund and was sacrificed on gd 10.
Two to three dams in the 300 and 1000 mg/kg/day treatment groups
exhibited audible respiration during or subsequent to the treatment
period. None of these observations were considered to be test substance
related. There were no treatment-related effects on food consumption,
gestational body weight and body weight gain, corrected body weight,
corrected body weight gain, and gravid uterine weight. No
treatmentrelated differences in gestational parameters including total
number of implantations, number of viable implants, and number of
nonviable implants, were observed in any dose group.
Fetal: Fetal body weights per litter
were not affected by treatment.
No treatment-related malformations or
variations were observed in this study.
Maternal toxicity NOEL: > 1000
Developmental toxicity NOEL: > 1000
Similar OECD 422 studies have been
performed on other substances from the group of AAI: on Fatty acid
reaction product with diethylene-triamine (AAI-DETA) and on Fatty acid
reaction product with tetraethylene-pentamine (AAI-TEPA). No indication
of concern for reproductive or developmental toxicity was observed in
these studies up to the highest dose tested. Also an OECD 414
developmental toxicity in rat on a similar substance showed no concern
for developmental effects.
To strengthen the data for the group
of AAI, a full prenatal developmental toxicity study in rats according
to OECD 414 is therefore intended to perform on FA reaction product with
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