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Description of key information

A combined repeated dose/reproduction screening toxicity study according to OECD 422 with Fatty acid reaction products with tetraethylene-pentamine (AAI-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 a similar substance, also indicate low repeated dose toxicity.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Consistent results from all studies within the whole group of Amidoamine/imidazolines (AAI), indicating a low level of toxicity. (See also document in support of category justification).

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

A combined repeated dose/reproduction screening toxicity study according to OECD 422 has been performed with Fatty acid reaction product with tetraethylene-pentamine (AAI-TEPA). A rangefinder study concluded that a dose level of 500 mg/kg/day is probably too toxic, whereas 150 mg/kg/day only resulted to a slightly increased ALAT and a hunched posture and piloerection on one day in all animals.

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).

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).

Based on these results, a parental, reproductive and developmental No Observed Adverse Effect Level (NOAEL) of 300 mg/kg/day was determined.

 

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 in general 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).

To set the NOAEL for repeated dose more accurately, read across to a planned full 90-day study (OECD 408) is proposed for AAI-DETA.

 

All 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 exposure no good overall NOAEL can be established as 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 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).

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

Although not the study of longest duration, it is the study of highest reliability

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). The potential for inhalation is not significant to justify this study. Furthermore, as the substance is classified as corrosive, such testing should normally not be conducted.

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:

All substances from the group of Amidoamine/imidazolines (AAI) are corrosive to the skin and are not expected to easily pass the skin. The skin is therefore not a preferred route when studying repeated dose systemic toxicity.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:

Lack of exposures: use is limited to industrial and professional users where following its severe corrosive properties will provide for sufficient protection measures to prevent dermal exposure.

Besides, being corrosive to the skin, local effects of irritation or corrosion are to be expected and no further studies are indicated.

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.

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 from the group of Amidoamine/Imidazoline (AAI) substances, including 90-day studies in rat and dogs on a similar substance, indicate very low toxicity.

Consequently, serious toxicity is not observed at levels requiring consideration classification for STOTS-RE.