reaction products of Fatty acids, C16-18 and C18-unsatd (2 moles) with tetraethylenepentamine (1 mole)

Endpoint summary

Description of key information

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.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

10 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Consistent results from all studies within the whole group of Amidoamine/imidazolines (AAI). Available studies are OECD Guidline compliant and performed under GLP.

System:

gastrointestinal tract

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Oral route

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 justification).

 

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.

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).

 

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.

 

Dermal route

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.

 

Inhalation:

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 duration.

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 dermal exposure.

Justification for classification or non-classification

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.