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Category Amidoamines/imidazolines (AAI):

Amidoamine/imidazolines are made from fatty acid and polyethyleneamines. The manufacturing process is a one-step process with formation of amide and imidazoline structures. To promote imidazoline formation from the amide, the reaction mixture is heated to temperatures above 180ºC. The resulting product therefore is a mixture of the amide structure of the fatty acid and the polyethyleneamine and its imidazoline. Also is possible that two fatty acid molecules bind at each end of the polyethyleneamine resulting in di-substituted amine or imidazoline. This can be influenced by the ratio of fatty acids (FA) and ethyleneamines (EA) in the reaction. The final product is a mixture of these substances, containing amine-, amide-, and imidazoline functional groups.

 The members of this category can be characterised by their starting materials: the hydrophobic part from fatty acids and the hydrophilic part from the polyethyleneamines:

 - Fatty acids (FA):

The difference in alkyl chain length distribution is limited among the members of this category. The sources are indicated as tall oil, vegetable oil, rape oil, C12-18 and C18-unsaturated fatty acids and tallow. All of these consist of predominantly C16 and C18 alkyl chain lengths.

The majority is derived from tall oil, basically consisting of C18unsaturated and some C16. Some of the substances refer to another source in their name as vegetable oil or tallow, but even then the actual composition show the same chain length distribution as tall oil.

Upon harmonization of the use of names and CAS numbers within this category this has lead to some renaming and use of different CAS numbers compared to what was reported in earlier study reports for those substances.

 Within a specific structure, the variability of the alkyl chain length is considered to have a possible modifying activity, which is related to modification of the physiological properties of the molecule with increase or shortening of the apolar alkyl chain part. This is suspected to influence aspects related to bioavailability, but not aspects of chemical reactivity and route of metabolisation, aspects that influence specific mechanisms of toxicity such as sensitisation and genotoxicity and are more related to the hydrophilic part. As the differences in chain lengths are only very minimal as all substances basically contain C16 and C18 alkyl chains, it seems justified from a toxicological point of view to consider the fatty acid part as similar for all AAI substances.

- Polyethyleneamines (EA):

The chain length of the polyethyleneamines used for the production of the various Amidoamines/imidazolines in this category can vary. In order of increasing EA length, ranging from DETA (diethylenetriamine), TETA (triethylenetetramine), TEPA (tetraethylenepentamine), PEHA (pentaethylenehexamine) and higher, generally denoted as polyethyleneamines (PolyEA). Although some products are derived from the use of basically one specific ethyleneamine, often a mixture of ethyleneamines of different lengths are used.

Upon the binding of the fatty acids with the amines of the EA, this results to a mixture of these substances, containing amine-, amide-, and imidazoline functional groups. These groups determine chemical reactivity and route of metabolisation, and relate to toxicity.

All substances within the AAI group show the same reactive groups, show similar composition of amide, imidazoline, and some dimer structures of both, with the length of original EA amines used for production as biggest difference. The range of molecular weights among the AAI substance are very similar, with a range from about 100 to 600 (for Tall oil + DETA) up to 100 to 900 (for Tall oil + polyamines) in case of use of larger ethyleneamines. Other physico-chemical properties also show very little variation: They are all (somewhat viscous) liquids, with a melting point below  -30 ºC, a boiling point above 300 ºC, and a very low vapour pressure (0.00017 mPa at 25°C for C18 unsaturated + DETA).

They are surface active with surface tension about 30-35 mN/m for aqueous concentrations above CMC. For DETA, TETA and HEPA based AAI, the CMC is resp. 99, 19 and 15 mg/L.

The Pow for Tall oil + DETA is 2.2, which representing the substance with relatively the smallest hydrophilic part and thus highest Pow value within the group of AAI substance.

Toxicological profile

As indicated above, the substances within the group of AAI are all very much alike, and show the same reactive groups. The major difference is related to the length of the ethyleneamines used for the production. Available data from repeated dose studies performed on various representative substances over the group of AAI indicates that toxicity decreases with increasing length of EA groups. The level of formed imidazoline compared to imidazoline seems to be of no consequence for the toxicity. Data from study on a substance consisting of only Amidoamine and no imidazoline resulted to the same level 

The level of free EA can be of impact, but as EA are not much more toxic compared to the NOAELs obtained for these AAI products, it cannot have a large impact.

All substances show similar acute oral toxicity, all with a LD50 > 2000 mg/kg bw. There is possibly a small tendency of decreased toxicity with increasing size of the EA. All AAI are corrosive to skin Cat. 1C, and sensitizing to skin. (The presence of some free EA in teh products could also have some influence here)

Several AAI substances were tested for genotoxicity, and all that were tested were not mutagenic in bacterial mutagenicity study (Ames test), induced no chromosomal aberrations in human lymphocytes, and were not mutagenic in mouse lymphoma cells. AAI substances in general therefore need not be classified for genotoxicity

 

Repeated dose studies (combined repeated dose/reproduction toxicity screening studies or standard 28-day studies) show the lowest NOAEL of 30 mg/kg bw/day for TO+DETA, based on an increased incidence/severity of macrophage foci in the mesenteric lymph node. This could be related to the route of application and to the irritant effect of the test item after uptake.

Both Tall oil + TEPA and Tall oil + PolyEA (containing higher EA) show a NOAEL of 300 mg/kg bw/day (showing some small effects, not considered toxicologically relevant).

No reproductive or developmental toxicity was observed in an OECD 422 screening study with Tall oil diethylenetriamine imidazoline. Similar OECD 422 studies have been performed on AAI based on TEPA and PolyEA, and have also shown no indication of concern for reproductive or developmental toxicity up to the highest dose tested.

In conclusion: It seems that lower EA results to higher toxicity, and that the forming of imidazoline itself does not play a significant role. For cross-reading in general use is made with data of same or lower EA-length where available, and that of Tall oil + DETA representing the worst case.

For next phase testing, results from studies with TO + DETA can be regarded as the worst case assumption for all others substances in the AAI category. Consequently, only studies on Tall oil + DETA are proposed for the next phase, and include a 90-day study, and a developmental toxicity study. In view of the total lack of effects on reproduction in all three of the performed reproduction toxicity screening studies, a 2-generation study is not considered to provide useful additional information. In addition the low likelihood of exposure can be considered as these substances are only applied in professional or industrial setting applying adequate PPE, due to corrosive properties, and with low potential of exposure via inhalation due to very low vapour pressure.

 

Toxicokinetics, metabolism and distribution

Alkyl amidoamine/imidazolines are mainly protonated under environmental conditions. The protonated fraction will behave as salt in water. AAI are surface active and have a low solubility in the form of CMC. For DETA, TETA and HEPA based AAI, the observed CMC were resp. 99, 19 and 15 mg/L. The actual dissolved concentration in water will be extremely low as alkyl amidoamines/imidazolines will sorb strongly to sorbents. As a consequence, absorption from gastro-intestinal system is likely to be slow.

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 all corrosive to skin, and toxicity following dermal exposure is characterised by local tissue damage, rather than the result of percutaneously absorbed material.

Physical-chemical properties of AAI indicate a low likelihood for exposure via inhalation, with a boiling point > 300 °C and very low vapour pressure (0.00017 mPa at 25°C for DETA based AAI).