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EC number: 701-390-1
CAS number: -
A NOAEL for reproduction/developmental
toxicity of 100 mg/kg/day was established from a combined repeated
dose/reproduction toxicity study with Tallow tripropylenetetraamine.
Tallow Tripropylenetetramine was
administered by daily oral gavage to male and female Wistar Han rats at
dose levels of 0, 30, 100 or 300 mg/kg/day. The males were exposed for 2
weeks prior to mating, during mating, and up to termination (for at
least 28 days). The females were exposed for 42-54 days, i.e. 2 weeks
prior to mating, during mating, during post-coitum, and at least 4 days
Formulation analysis showed that the
formulations were prepared accurately, were homogeneous and were stable
for at least 6 hours at room temperature.
All animals at 300 mg/kg were killed in
extremis on Day 10 of treatment. Microscopic findings in the stomach
(including ulcers and erosions, corresponding to irregular surface of
the forestomach at necropsy) were considered to have contributed to the
moribundity. Prior to death these animals primarily showed hunched
posture and piloerection, along with notable weight loss (up to 13%) and
reduced food intake. At necropsy, all sacrificed animals showed
yellowish contents of the gastro-intestinal tract, irregular surface of
the forestomach, dilation of the small intestines or caecum and reduced
size of the thymus. Histopathological changes other than stomach effects
noted at 300 mg/kg/day included hypertrophy of the epithelium of the
duodenum, jejunum, ileum and caecum with or without foamy macrophages in
the villi, foamy macrophages in the mesenteric lymph nodes, and lymphoid
atrophy of the thymus, corresponding to dilation of the small intestines
or caecum and reduced size of the thymus at necropsy.
At 100 mg/kg, one male and one female were
killed in extremis on Day 27 and 38 of treatment, respectively. For one
of these animals findings in the stomach (including an ulcer) were
considered to have contributed to the moribundity, whilst for the other
animal no clear cause of moribundity was established
histopathologically. Clinical signs at 100 mg/kg/day primarily consisted
of piloerection among females. In addition, lower absolute body weights
and body weight gain were recorded during the Repro period for males and
females, and for females also during post-coitum and lactation. Also,
absolute and relative food consumption of females was lower than
controls during the premating phase, and remained lower during the
post-coitum period, but not during lactation. Clinical biochemistry
changes in males and/or females consisted of higher alanine and
aspartate aminotransferase activity, lower total protein and albumin
levels, and higher total bilirubin, urea, cholesterol and bile acid
levels. Haematological changes were confined to a higher relative and/or
absolute neutrophil count, and higher platelet counts. Necropsy revealed
lower liver, spleen, prostate, heart and thymus weight in males and/or
females, which may at least in part be explained by the lower terminal
body weights. Histopathological changes among the surviving animals
consisted of hypertrophy of the epithelium and/or foamy macrophages in
the villi of the duodenum, jejunum, ileum and caecum, lymphoid atrophy
of the thymus and macrophage foci in the mesenteric lymph node.
At 30 mg/kg/day, a lower body weight gain
was recorded for males during the Repro period without changes in food
intake. Haematology showed a higher relative neutrophil count in
females, but absolute neutrophil counts remained similar to controls.
Clinical biochemistry parameters remained unaffected. Histopathological
changes consisted of foamy macrophages in the villi of the ileum and
jejunum, hypertrophy of the epithelium of the caecum and macrophage foci
in the mesenteric lymph node.
No treatment-related changes were noted
during functional observation tests at any dose level.
No toxicologically relevant differences in
reproductive/developmental parameters occurred up to 100 mg/kg/day. No
potential effect on reproductive/developmental parameters could be
determined at 300 mg/kg since all animals were sacrificed at this dose
Since all animals were sacrificed at 300
mg/kg/day, and hence no potential effect on reproductive/developmental
parameters could be determined at this dose level, the reproductive and
developmental NOAEL was established to be 100 mg/kg/day.
A combined repeated dose/reproduction screening toxicity study according to OECD 422 has been performed with Tallow tripropylenetetraamine in rats. Dose levels consisted of 0, 30, 100 and 300 mg/kgbw/day. The highest dose group of 300 mg/kgbw/day was terminated on day 10 due to high toxicity (Ulceration of the stomach). Parental effects for this study are summarised in the chapter on repeated dose toxicity. Since all animals were sacrificed at 300 mg/kg/day, and hence no potential effect on reproductive/developmental parameters could be determined at this dose level, the reproductive and developmental NOAEL was established to be 100 mg/kg/day.
Cross-reading and category approach:
Within the category of the Polyamine there are further studies available that clearly demonstrate thesame toxicological profile for the various substances over this category, and a clear lack for concern for reproduction toxicity from the range of available relevant studies.
(See the document for the category justification for the polyamines that is attached to this dossier).
A combined repeated dose/reproduction screening toxicity study according to OECD 422 has been performed with Coco dipropylene triamine. Dose levels consisted of 0, 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). 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).
At 100 mg/kg/day, five males died spontaneously or were sacrificed over Days 6-9 of treatment; the remaining animals of both sexes (including the recovery animals) were euthanized in extremis on Day 9. Toxicologically-relevant clinical signs that were noted among the majority of animals of both sexes included hunched posture and piloerection, and at a lower incidence, lethargy, laboured respiration, rales, ptosis, pale appearance and diarrhoea with brown staining of the genital region. Significant weight loss was observed among these animals (up to 15%) along with notably lower food intake levels. Several macroscopic findings were noted in both sexes, and most commonly included irregular surface of the forestomach, and gelatinous/yellowish contents and dilation of the small intestines. The most prominent histopathological finding seen in most animals at 100 mg/kg/day consisted of ulceration of the stomach which was considered to be the most likely cause of death/moribundity for these animals. Other histopathological changes noted among all animals of this dose group included inflammation and diffuse hyperkeratosis of the stomach, hyperplasia of the squamous epithelium of the forestomach, and foamy macrophage infiltrate of the jejunum, ileum and mesenteric lymph nodes.
At 30 mg/kg/day, one female was found dead on Day 20 of treatment. Prior to death this female showed hunched posture, piloerection and salivation. Histopathological examination did not reveal an apparent cause of death. However, given that all animals at 100 mg/kg/day were found dead or sacrificed, it could not be excluded that this death was related to treatment. Motor activity at this dose level appeared slightly reduced but there were no supportive clinical signs (such as lethargy). Toxicologically relevant findings at 30 mg/kg/day included higher absolute and relative neutrophil counts and higher absolute white blood cell counts, and lower lymphocyte counts (males and/or females) along with a corresponding reduction in absolute and relative thymus weights (males). These lower thymus weights were not correlated histopathologically. Microscopic findings noted in most animals of this dose group included foamy macrophage infiltration of the jejunum and ileum and foamy macrophage foci in the mesenteric lymph node.
At 10 mg/kg, treatment-related findings were confined to microscopic findings that included foamy macrophage infiltration in the ileum and jejunum and foamy macrophage foci found in the mesenteric lymph nodes of most animals.
Reproductive/Developmental findings: No reproductive/developmental toxicity was observed at any dose level.
Based on the presence of foamy macrophage infiltration in the ileum and jejunum and foamy macrophage foci in the mesenteric lymph nodes at 10 mg/kg/day, a parental NOAEL could not be determined.
A reproduction/developmental NOAEL of 30 mg/kg/day was determined.
A full two-generation study on C12-Y-triamine has also shown no indication of concern for reproductive toxicity:
An oral two-generation reproductive toxicity study with rats, performed in accordance with OECD Guideline 416 (version of 1983) and under GLP is available (Inveresk, 1995). Parental animals received the test substance by gavage at dose levels of 0, 3, 9 and 27 mg/kg bw/day pure substance 10 weeks prior to mating until weaning of the F1 generation. The treatment of F1 animals commenced from day 25 after birth and continued to weaning of the F2 generation. The F1 animals were mated 11 weeks after weaning.
At the high dose level most animals of both generations showed signs of reaction to treatment, consisting of dyspnea, piloerection and hunched posture, and many animals also had episodes of post-dosing salivation. For occasional animals, the outline of the spine was prominent. A total of 8 animals died or were killed after showing marked signs of reaction, and a 9th death may also have been related to treatment. In both generations, at the highest dose level, mean weight gain was markedly lower than controls; this effect was apparent for males, and for females in the premating period and during gestation. Food consumption at the high dose level in both generations was slightly lower than in controls. Mating performance, fertility, duration of gestation, litter size and pup survival were considered to be similar in all groups.
Mean seminal vesicle weights in the high dose groups of both generations were significantly lower than controls, however, it was considered that this reduction was an indirect effect of the lower body weights, rather than a direct effect on the seminal vesicles. Mean absolute epidymides and testes weights in the same groups were lower than control, with the value for epidymides for F0 animals and the value for testis for F1 animals attaining statistical significance. However, after adjustment for bodyweight (covariance analysis) these effects were not apparent. Mean prostate weights were essentially similar in all groups of both generations.
In the F2 generation, slightly reduced pup and litter weights and observed clinical signs (2 pups with body tremors) were observed at 27 mg/kg bw/day.
In the current version of the OECD 416 guideline, histopathology of the pups is part of the standard procedure. This study was performed in accordance with the 1983 version of the guideline in which these investigations were not required. However in the subchronic 90-day study in rats histopathological examinations were performed. The lack of effects on reproduction in the 2-generation study along with the supporting data from the 90-day study confidently allows the conclusion that the substance is not a selective reproductive toxicant. The NOAEL for systemic toxicity was set at 9 mg/kg bw/day, while the NOAEL for reproductive toxicity was considered to exceed 27 mg/kg bw/day.
Available data from reproduction toxicity studies in rat on Polyamines:
Results NOAEL (in mg/kg bw/d)
No effects on pre/post implantation rate, late/early resorptions, corpora lutea or number of live fetuses were seen in this study.
There was a slight increase in visceral and skeletal variations. No malformations were observed.
NOAEL development: 1.25 mg
NOAEL reproduction and development: 30 mg (highest dose since all animals were sacrificed at 100 mg/kg/day, and hence no potential effect on reproductive/developmental parameters could be determined at this dose level.)
NOAEL maternal = 30 mg/kg based on signs of toxicity and lower BW seen from 60 mg/kg.
NOAEL maternal = 7.5 mg
NOAEL teratology > 60 mgNOAEL development = 22.5 mg, based on secondary effects due to maternal toxicity observed in the foetuses (increase in incidence of early embryonic deaths and slightly decreased mean foetal weight).
NOAEL maternal, F1 and F2: 9 mg. Based on reduced body weight gain, clinical signs of reaction to treatment at higher levels. There were no obvious adverse effects on mating and littering performance at any of the levels tested.
NOAEL reproduction and development: 100 mg (highest dose since all animals were sacrificed at 300 mg/kg/day, and hence no potential effect on reproductive/developmental parameters could be determined at this dose level.)
Additionally, no adverse effects on reproductive organs were identified in any of the available repeated dose studies on Polyamines.
In addition the low likelihood of exposure can be considered as these substances are only used in an industrial setting, applying adequate PPE. Consumers/general population will not be exposed. For corrosive substances, the use of protective gloves and other equipment, such as face shields, aprons and good work practices are mandatory. As a result, direct dermal contact occurs only occasionally. Therefore, repeated substantial daily dermal exposure is unlikely. Likelihood of exposures via inhalation is also low considering the high boiling point (> 300 °C) and very low vapour pressure (< 4.7 x 10-5 Pa at 20°C).
Conclusion: In view of the total lack of effects on reproduction in all these reproduction toxicity studies, a further 2-generation study is not considered to provide useful additional information for the evaluation of reproduction toxcity Tallow tripropylenetetraamine.
Cross-reading to a prenatal
developmental toxicity study on Tallow dipropylenetriamine resulted to a
maternal NOAEL of 30 mg/kg. Based on the observation of pale adrenals,
and signs of retarded skeletal ossification seen at 60 and 120 mg/kg, a
developmental NOAEL of 30 mg/kg was selected.
female Wistar Han rats were assigned to four dose groups, each
containing twenty-two animals. The test item was administered once daily
by gavage from Day 6 to 19 post-coitum at doses of 30, 60 and 120 mg/kg
(Groups 2, 3 and 4 respectively). The rats of the control group received
the vehicle, propylene glycol, alone. Accuracy, homogeneity and
stability of formulations were demonstrated by analyses.
toxicity was evident in both the 60 and 120 mg/kg groups and included
mortality, adverse clinical signs (hunched posture, rales, piloerection,
salivation and lean appearance, among others), reduced food consumption,
and substantially lower body weights and body weight loss compared to
controls: 7% lower for 60 mg/kg and 25% lower BW for 120 mg/kg treated
animals. Treatment related macroscopic findings (emaciated appearance,
enlarged adrenal glands, small and large intestines thickened and
distended with gas, among others) were also seen for mid- and high-dose
animals as well.
toxicologically relevant maternal findings were noted with treatment up
to 30 mg/kg.
significant differences were observed between control and treated groups
regarding the number of corpora lutea, implantation sites, viable or
dead fetuses, early or late resorptions, or pre- and postimplantation
loss. The percentage of early resorptions, total resorptions and
post-implantation loss was relatively higher (not statistically
significant) for females at 120 mg/kg than controls. This was
attributable to two females who both had 100% post-implantation loss,
consisting of early resorptions.
effects were observed on litter size and sex-ratio.
body weights were significantly lower at 120 mg/kg (2.8 g) compared to
controls (3.4 g), which was secondary to the lower gains/maternal weight
loss at this dose level.
malformations and variations:
external malformations and developmental variations were observed in any
of the fetuses.
malformations and variations:
malformations were observed in 4(3), 0(0), 4(4) and 1(1) fetuses
(litters) in the control, 30, 60 and 120 mg/kg groups, respectively.
None of the malformations noted at 60 and 120 were considered to be
variations included a dose related increase of yellow-white discolored
(anaemic?) adrenal glands in the 60 and 120 mg/kg groups in 7(2) and
48(5) fetuses (litters), whereas none occurred in the control and 30
mg/kg groups. The physiological effects of this variation are unknown,
but the discoloration could not be ignored and was considered to be
Other variations noted in test
substance treated groups were small supernumerary liver lobes, liver
appendix, partially undescended thymus horns, convoluted ureter, dilated
ureter and right subclavian originating from the aortic arch. These
variations were not considered to be treatment related, because they
occurred at similar frequencies in the control group, occurred
infrequently, occurred without dose-relationship and/or occurred at
frequencies within the historical control range.
Malformations and Variations:
evaluations included the observation of effects that that were
interpreted as polydactyly and malpositioned metatarsals. This finding
is further discussed below.
incidences of bent limb bones in the 30 and 60 mg/kg groups (2.9% and
3.0% per litter, respectively) were higher than the historical control
data range (0.0%-1.6% per litter) and concurrent control value (1.5% per
litter), but as no cases occurred in the high dose group, a relation to
treatment could not be established.
Remaining skeletal malformations
observed in fetuses of test substance treated groups were sternoschisis
(nos. A045-03 and -07) and vertebral anomaly with or without associated
rib anomaly (no. A065-06). Because these findings occurred at a low
incidence, were seen in historical controls and, in the case of
vertebral anomaly with or without associated rib anomaly, occurred in a
concurrent control fetus (no. A018-01) they were not considered to be
treatment related. The only other skeletal malformation in this study
was a vertebral centra anomaly, noted in a control fetus.
variations were observed in 87.7%, 84.1%, 83.3% and 80.1% of fetuses per
litter in the control, 30, 60 and 120 mg/kg groups, respectively.
skeletal ossification was evidenced at 120 mg/kg by the variations of
unossified sternebrae nos. 5 and/or 6, unossified sternebrae nos. 1, 2,
3 and/or 4, entire sternum unossified, reduced ossification of
sternebrae, unossified vertebral centra, reduced ossification of
vertebral centra, reduced ossification of vertebral arches, unossified
hyoid, unossified metacarpals and/or metatarsals, unossified or reduced
ossification of pubis and unossified or reduced ossification of ischium.
This delayed skeletal ossification was in line with the reduced fetal
weights at 120 mg/kg; these were all secondary to the maternal toxicity
at this dose level.
of retarded skeletal ossification were also present at 60 mg/kg, and
were demonstrated by higher incidences of unossified sternebrae nos. 1,
2, 3 and/or 4, reduced ossification of sternebrae, reduced ossification
of vertebral arches, unossified or reduced ossification of pubis and
unossified or reduced ossification of ischium.
reported skeletal malformations
Number examined skeletally
no. of fetuses (litters)
% per litter
polydactyly of a total number of 712 fetuses from treated groups there
are 10 (1.40%) affected.
Control: (2008-2012; Crl:WI(Han; outbred, SPF-Quality)
studies; fetuses/litters examined externally 4557 / 384, skeletal 3122 /
(external examination): 1 fetus
Malpositioned (skeletal examination): 3 fetuses
obvious dose relation could be established for these separate
malformations, but they were considered to be related findings because
both malformations were localized in the same region and result from
patterning errors during limb development. These incidences of hindpaw
malformations show an increase at 30, 60 and 120 mg/kg when compared to
the control group and therefore were considered to be a result of
polydactyly generally has a genetic background, the parentage of the
affected fetuses and their mothers were checked. Affected litters are
not all derived from the same
fathers, and the supplied females
were not siblings.
request of the Sponsor, an independent external consultant examined the
affected fetuses. This expert concluded that these findings were not
true malformations but were attributable to tissue mechanical damage or
processing artefacts and subsequent displacement of the digits, which
could give the appearance of extra hind paw structures. One case of
polydactyly could not be discounted, though for the other fetuses no
agreement could be established. (See attached review and discussion
the skeletal examinations in the main study, skeletal exams of the paws
were performed for all fetuses (all dose groups). At 150 mg/kg, an extra
metatarsal on the hind paw was seen for a single fetus. (See attached
RF-extra metatarsal.pdf) However, the description “extra metatarsal” is
rather dubious. The photograph shows no clear evidence of a
supernumerary structure. The small brown area could be anything; the
colouration certainly does not indicate ossified bone. Such
areas can be often seen if the soft tissue clearing is not good. When
ossification is less than optimal, it can sometimes appear to be
fragmented. A reason for the unclear picture could be that long alcohol
fixation of almost a year adversely affects
the staining process. After about three months, the results of the
staining procedure are usually less than optimal. The soft tissue
clearing tends to be poor.
the polydactyly findings are not considered a genuine, test substance
related finding. Supportive arguments for artefact are:
conclusion, based on the results in this prenatal developmental toxicity
study the maternal NOAEL for C16-18, C18-unsaturated-alkyl dipropylene
triamine was established as being 30 mg/kg. Based on the observation of
pale adrenals in 7 fetuses, and signs of retarded skeletal ossification
seen at 60 and 120 mg/kg, a developmental NOAEL of 30 mg/kg was selected.
No developmental toxicity was observed in an OECD 422 screening study with Tallow tripropylenetetraamine.
Cross-reading and category approach:
Within the category of the Polyamine there are further studies available that clearly demonstrate the same toxicological profile for the various substances over this category, and a clear lack for concern for developmental (Foetal toxicity and teratogenicity) toxicity from the range of available relevant studies.
(See the document for the category justification for the polyamines that is attached to this dossier).
A similar OECD 422 study on Coco dipropylenetrimine, and a two generation study C12 -Y-triamine are available. These reproduction studies have also shown no indication of concern for developmental toxicity:
To strengthen the cross-reading approach with this category of Polyamines, an additional OECD 414 study was performed on Tallow dipropylenetriamine. This substance contains the same alkyl chain length as Tallow tripropylenetetraamine, but contains one diaminepropane (DP) less. Results from Tallow dipropylenetriamine can be considered a worst case situation for Tallow tripropylenetetraamine:
Tallow dipropylenetriamine was administered once daily by gavage from day 6 to 19 post-coitum at doses of 30, 60 and 120 mg/kg. Maternal toxicity was evident in both 60 and 120 mg/kg groups and included mortality, adverse clinical signs (hunched posture, rales, piloerection, salivation and lean appearance, among others), reduced food consumption, and substantially lower body weights and body weight loss compared to controls: 7% lower for 60 mg/kg and 25% lower BW for 120 mg/kg treated animals. Treatment related macroscopic findings (emaciated appearance, enlarged adrenal glands, small and large intestines thickened and distended with gas, among others) were also seen for mid- and high-dose animals as well. No toxicologically relevant maternal findings were noted with treatment up to 30 mg/kg. No significant differences were observed between control and treated groups regarding the number of corpora lutea, implantation sites, viable or dead foetuses, early or late resorptions, or pre- and post implantation loss. The percentage of early resorptions, total resorptions and post-implantation loss was relatively higher (not statistically significant) for females at 120 mg/kg than controls. This was attributable to two females who both had 100% post-implantation loss, consisting of early resorptions. No effects were observed on litter size and sex-ratio. Foetal body weights were significantly lower at 120 mg/kg (2.8 g) compared to controls (3.4 g), which was secondary to the lower gains/maternal weight loss at this dose level. Also signs of retarded skeletal ossification were observed at 60 and 120 mg/kg. Visceral variations included a dose related increase of yellow-white discoloured (anaemic?) adrenal glands in the 60 and 120 mg/kg groups in 7(2) and 48(5) foetuses (litters), whereas none occurred in the control and 30 mg/kg groups. Based on these effects a developmental NOAEL of 30 mg/kg was selected.
Additionally, there is a low likelihood of exposure to these substances as they are only used in an industrial setting. Consumers/general population will not be exposed. Because of corrosive properties adequate use of protective gloves and other equipment, such as face shields, aprons and good work practices are mandatory. Likelihood of exposures via inhalation is also low considering the high boiling point (> 300 °C) and very low vapour pressure (< 4.7 x 10-5 Pa at 20°C).
No further studies available.
All available data from studies involving the evaluation of reproduction and developmental parameters have not shown any indication of reproductive or developmental effects. Therefore no classification is required for this endpoint.
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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