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EC number: 629-725-6 | CAS number: 1226892-45-0
A combined repeated dose/reproduction screening toxicity study according to OECD 422 with Fatty acid reaction products with tetraethylene-pentamine (FA-TEPA) resulted to a NOAEL of 300 mg/kg bw/day being the highest tested dose level. All already available data from the group of Amidoamine/imidazolines (AAI) substances, including 90-day studies in rat and dogs on similar substances, also indicate low repeated dose toxicity.
Tall oil reaction products with tetraethylene-pentamine (Amidoamine/Imidazoline) was administered by daily oral gavage to male and female Wistar Han rats at dose levels of 30, 100 and 300 mg/kg/day. 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 2 weeks prior to mating, during mating, during post-coitum, and at least 4 days of lactation (for 41-48 days).
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 at the end of treatment were generally slight in nature and had normalized at the end of the recovery period. These changes consisted of higher alanine and aspartate aminotransferase activity in both sexes at 300 mg/kg/day, higher aspartate aminotransferase activity in males at 100 mg/kg/day, higher inorganic phosphate level in males at 300 mg/kg/day, and higher chloride level in females at 300 mg/kg/day. No macroscopic or histopathological lesions were observed that would support these variations. Therefore, these variations in clinical biochemistry parameters were considered to be of no toxicological relevance.
The lower (relative) heart weight in both sexes at 300 mg/kg/day, and lower (relative) seminal vesicle and prostate weight at 300 mg/kg/day generally remained within the range considered normal for rats of this age and strain. Moreover, these changes had resolved at the end of the recovery phase and no histopathological correlates were found. Also, the lower seminal vesicle weight was not reflective of reproductive toxicity. Therefore, these organ weight changes were considered to be of no toxicological relevance.
No treatment-related changes were noted in any of the remaining parental parameters investigated in this study (i.e. clinical appearance, functional observations, haematology, macroscopic and microscopic examination).
No reproductive/developmental toxicity was observed at any dose level.
Based on these results, a parental, reproductive and developmental No Observed Adverse Effect Level (NOAEL) of 300 mg/kg/day was determined.
No adverse effects have been observed up to 300 mg/kg bw/day. In a 9-day RF the following effects have been observed at 500 mg: lethargy, hunched posture, uncoordinated movements and piloerection (all animals); lower BW and food consumption, increased ALAT and slightly reduced
Albumin, and lower (relative) thymus weight. No histopathology has been performed.
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.
FA-TEPA is corrosive to skin, which leads to the assumption that effects seen at high dose level of 500 mg/kg bw/day in the range finding study might be related to local irritation of the gastro-intestinal tract. Unfortunately, no such effects have been observed in the main study, and no signs of local irritation have been reported with histopathological examination. The data suggest that the threshold for the local effects are at 300 mg/kg bw/day (dosing concentration 60 mg/mL in PG).
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 (FA+DETA) therefore represents the worst case. In series of 28-day and combined repeated dose/reproduction screening toxicity studies (OECD 422) FA+DETA has shown the highest level of toxicity. (See also document in support of category justification and results of studies described below). Consequently, use can be made of read-across from FA+DETA to FA+TEPA.
A combined repeated dose/reproduction screening toxicity study according to OECD 422 has been performed with Fatty acid reaction product with tetraethylene-pentamine (FA+TEPA). A rangefinder study concluded that a dose level of 500 mg/kg/day is probably too toxic, whereas 150 mg/kg/day showed insufficient toxicity. In the subsequent full study, AAI-TEPA was administered by daily oral gavage to male and female Wistar Han rats at dose levels of 30, 100 and 300 mg/kg/day. 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 2 weeks prior to mating, during mating, during post-coitum, and at least 4 days of lactation (for 41-48 days).
On FA+DETA the following data is available:
A combined repeated dose/reproduction screening toxicity study according to OECD 422 has been performed with FA+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.
Histopathology revealedan 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).
A subsequent 90-day (OECD 408, GLP) study was performed applying the same dose levels of 0, 10, 30 and 100 mg/kg/day FA+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.
Otherwise, no specific toxic effects have been observed.
Other available data from the group of AAI substances, including 90-day studies in rat and dogs on a similar substance, indicate low toxicity. (NOAEL of 730 mg/kg bw in rat based on increased organ weights seen at 2200 mg/kg, and a NOAEL in dogs of about 1635 mg/kg bw/day.)
The available data show that substances of the AAI group are of low toxicity, and an increase in the duration from 28 days to 90-days does not results to increased toxicity. The only difference between FA+DETA and the other AAI with longer polyethyleneamine groups, is the occurrence of foamy macrophages in mesenteric lymph nodes which is only observed in studies with FA+DETA, but not with the higher polyethyleneamines. Consequently, this effect from FA+DETA cannot be used to set NOAEL for FA+TEPA. Otherwise, the 90-day study with FA+DETA was without significant toxicity. Therefore it was decided to take the NOAEL from the OECD 422 study involving exposures up to around 45 days is selected as starting point for DNEL derivation, with application of the full assessment factors for extrapolation from sub-acute to chronic exposures.
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 for DETA based AAI, which is considered to have the highest vapour pressure within the AAI).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
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.
A combined repeated dose/reproduction screening toxicity study according to OECD 422 with AAI-TEPA resulted to a NOAEL of 300 mg/kg bw/day, the highest dose tested. Also available data from the group of Amidoamine/Imidazoline (AAI) substances, including 90-day studies in rat and dogs on similar substances, confirm very low systemic toxicity.
Consequently, serious toxicity is not observed at levels requiring consideration classification for STOTS-RE.
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