Amines, N-(3-aminopropyl)-N’-[3-(C16-18 (even numbered) and C18 unsaturated alkyl amino)propyl]trimethylenedi- and amines, N-(3-aminopropyl)-N’-(C16-18 (even numbered) and C18 unsaturated alkyl)trimethylenedi-

Endpoint summary

Description of key information

Due to lack of quantitative data, absorption rates of 100% are indicated for all three routes. This basically indicates that, as conservative approach, no significant difference in absorption is assumed in the comparison of absorption via dermal and inhalation routes compared to the oral route by which the hazard evaluations are done. Available studies do not indicate a concern for bioaccumulation.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

Scope of the group of Polyamine (PPA):

(See also Category approach justification for polyamines, AkzoNobel, 20 Apr. 2012)

Polyamines are substances that basically contain multiple (1 or more) 1,3-diamine propane (DP) groups linked to a fatty amine. These can be linearly linked based on two DP and fatty amine (triamine structure: alkyl dipropylenetriamine) or 3 DP with a fatty amine (tetramine structure: alkyl tripropylenetetramine), or in a branched form of two DP and a fatty amine.

 

Production starts from the fatty amine that is reacted with equimolar amounts acrylonitrile and subsequent hydrogenation resulting to a diamineSubsequent additions with acrylonitrile result to linear triamine and then tetraminesHowever, reactions are not complete, and consequently tetramines also contain for a large part triamines and some diamines, and the triamines can contain a considerable amount of diamines and some tetramines. Consequently, there is some overlap in contents between these substances. Further purification can be obtained by distillation.

Branched triamines (Y-triamine) are produced from the single reaction of primary fatty amine with 2 equivalents of acrylonitrile and subsequent hydrogenation

 

The common structuresof the polyamines can be represented as:

 Linear triamine: R – NH – [CH₂]₃– NH – [CH₂]₃– NH₂

 Y-triamine: R – N [– [CH₂]₃– NH – [CH₂]₃– NH₂]₂and

 Linear tetramine: R – NH – [CH₂]₃– NH – [CH₂]₃– NH – [CH₂]₃– NH₂

respectively, where the R is an alkyl chain ranging from 10 (Decane) to 18 (Octadecane), depending on the source of the fatty amine. For alkyl chain lengths, largely the following ranges are implied in this group:

          Tallow C16   25-40%

                      C18   50-75 %

          Oleyl   C18   > 70 %

          Coco  C12   45-62%,

                      C14   15-25%

 

At first glance, the group of linear PPA seems to consist of two substructures, for which the similarity needs to be ascertained in order to obtain confidence for cross reading within the whole group. Structurally, both are very similar: a linear alkyl chain and a primary amine at the end, with 2 or 3 secondary amines in between. Consequently, they share the same chemical reactivity and their physico-chemical properties are very similar from which a comparable toxicological profile can be expected.

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 by the 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 metabolism, aspects that influence specific mechanisms of toxicity such as sensitisation and genotoxicity. For these reasons, many of the studies can best be performed on the substance with the shortest chain length within the sub-category, as this is considered to result to the lowest NOAEL or most likely able to show specific effects. The data obtained so far indicate that over the group of the Polyamines the following pattern emerges:

- Substances with shorter alkyl chain lengths show higher toxicity compared to substances with longer chain lengths

- Longer chain polyamines, i. e. increasing number of DP-groups, result to lower toxicity.

As a consequence, it seems reasonable that results from shorter alkyl chains can represent a worst case for the comparable polyamine of longer alkyl chain, and results from a triamine as worst case approach for a tetramine with same alkyl chain.

 

Toxicological profile

Acute toxicity

The acute oral toxicity of Tallow tripropylenetetramine (Tetraamine C16 -18, C18 -unsaturated) indicate a LD50 between 300 and 2000 mg/kgbw. Other polyamines show comparable results where those with on average shorter alkyl chains show a somewhat higher toxicity compared to those with longer alkyl chain lengths. The number of propylene groups (dipropylenetriamine or tripropylenetetramine) does not seem to be of influence.

Potential exposure to PPA is mainly dermal. As the active substance is corrosive to the skin, dermal irritation/corrosion is a major concern when dealing with PPA formulations. Effects following dermal exposures will be characterized by local corrosive effects that are related to duration, quantity and concentration of the substance, rather than by systemic toxicity due to dermal uptake.

As tallow tripropylenetetramine and oleyl tripropylenetetramine represent the substances with the highest number of propylene groups and longest alkyl chain-length in this group, they are expected within the group of polyamines to show the lowest corrosive properties. Asin vivoskin corrosion studies indicate that these substances are corrosive, it is expected that all other substances in this group are corrosive to skin as well, and furtherin vivotesting would not be ethical. Also following oral dosing ulcerations in gastro-intestinal system are observed at the higher dose levels indicating corrosive properties for these compounds.

Dermal corrosion of polyamines is a property that is common in all fatty acid structures with free primary amines: The primary fatty amines are generally corrosive, and the branched alkyl dipropylenetriamines are even very corrosive inin vivostudies (resulting to corrosion following 3 minutes exposure).

 

Sensitisation:

As the substance is corrosive to skin, there is no need forin vivoskin sensitisation study. However, the molecular structure of the polyamines does not contain toxicophores indicating a concern for sensitization. Polyamines show further low dermal penetration, and no reactivity and protein binding (processes needed for haptenisation). Data available from sensitisation studies on structurally related branched triamine (Dodecyl dipropylene triamine) and primary amines do in general not indicate a concern for sensitisation.

 

Repeated dose toxicity:

A combined repeated dose/reproduction toxicity screening (OECD 422) study on Tallow tripropylenetetramine indicated LOAEL of 30 mg/kgbw/day based on foamy macrophage infiltration in the ileum and jejunum and foamy macrophage foci found in the mesenteric lymph nodes observed at this dose level. This study further showed severe toxicity at 300 mg/kg, causing the early termination of this dose group on day 10 of the study. Ulceration of the stomach was considered to be the most likely cause of death/moribundity for these animals. These severe effects make classification for STOT-RE Cat.2 necessary.

As from this combined repeated dose/reproduction toxicity study no NOAEL could be derived, a subsequent 90-day study was performed on Tallow dipropylenetriamine to which cross-reading is done in order to derive a more reliable NOAEL.The NOAEL in this study was determined at 2.5 mg/kg bw/day, based on effects observed at 10 mg/kg bw/day. At this level changes in blood were confined to a higher inorganic phosphate level, and marginally higher neutrophil counts. Also at 10 mg/kg bw/day, adverse histopathological findings were observed in the jejunum/ileum (minimally to slight foamy macrophages in lamina propria), mesenteric lymph nodes (general minimal to moderate foamy macrophages, accompanied by incidental cases of granulomas with central necrosis, lymphoid hyperplasia, sinus ectasia), liver (granulomatous lesion with central necrosis in 2 males) and bone marrow (minimal myeloid hyperplasia in 7/40 animals).

The most significant treatment-related changes in all studies performed on polyamines are effects on the small intestine and mesenteric lymph nodes. A relatively strong inflammatory reaction is also observed at high dose levels. These effects in the gastro-intestinal tract have consistently been observed with these polyamines, and are considered local effects related to the corrosive nature of the substances.

A mode of action has not been established but it is possible to suspect the known corrosivity to be at least partially involved. It is indicative that the observed effects are local and they are by some interpreted as phospholipidosis, something commonly observed following treatment with cationic amphiphilic material, including marketed pharmaceuticals, and considered to be non-adverse. When taking into consideration the relatively strong corrosive effects of this substance, and for substances belonging to the same group of chemicals, and the route of administration, it cannot be excluded that the overall toxicity reflects a point-of-first-contact effect.In that respect, considering that macrophages in the mesenteric lymph nodes are a local, porte d’entrée related effect due to the route of application, and not a systemic effect per se, the level of 2.5 mg/kg bw/day could also be argued to represent a NOAEL for local effects, and that the NOAEL for systemic effects is higher.

The available data results to a classification of STOT-RE Cat.2.

 

Reproduction toxicity:

In the same OECD 422 study mentioned above on Tallow tripropylenetetramine, no reproductive/ developmental toxicity was observed at any of the other dose levels and thus a reproduction/ developmental NOAEL of 100 mg/kg/day was determined.

Other available studies on comparable polyamines include a similar OECD 422 study on Coco dipropylenetriamine and a full two-generation study and developmental toxicity studies in rat and rabbit on a structurally related dodecane dipropylene branched triamine. These studies also have also shown no indication of concern for reproductive or developmental toxicity.

However, as OECD screening studies do not allow for a full developmental hazard evaluation, a full prenatal developmental toxicity study in rats according to OECD 414 was done for Tallow dipropylenetriamine. Within the group of polyamines, results from Tallow dipropylenetriamine are considered to be predictive forTallow tripropylenetetramineand will thus be used for read-across.

Thisprenatal developmental toxicity study resulted to a maternal NOAEL for C16-18, C18-unsaturated-alkyl dipropylene triamine 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. This study also includes endpoints that are relevant to assessing an effect on fertility. No effects on pre/post implantation rate, late/early resorptions, corpora lutea or number of live fetuses were seen in this study.

Other available studies on comparable polyamines include an a full two-generation study and developmental toxicity studies in rat and rabbit on a structurally related dodecane dipropylene branched triamine have also shown no indication of concern for reproductive or developmental toxicity.

 

Genotoxicity:

Tallow tripropylenetetramine is not mutagenic in the Salmonella typhimurium reverse mutation assay and in the Escherichia coli reverse mutation assay, is not clastogenic in human lymphocytes, and not mutagenic in the TK mutation test with L5178Y mouse lymphoma cells. Also studies on other polyamines indicate no concerns for genotoxicity. Furthermore, polyamines do not react with DNA or react to protein.

 

In addition, there is no consumer exposure to C16-18, C18-unsaturated-alkyl dipropylene triamine, and manufacture and use are highly controlled, limiting the possibility of exposures.

Toxicokinetics, metabolism and distribution

The mode of action of for polyamines follows from its structure, consisting of an apolar fatty acid chain and a polar end of a primary amine linked to a secondary amine. The structure can disrupt the cytoplasmic membrane, leading to lyses of the cell content and consequently the death of the cell.

The very high water solubility can be explained by the fact that the terminal amine groups are completely protonated under environmental conditions. The water solubility of polyamines is strongly influenced by pH.

The polyamines are all corrosive to skin. This is probably related to their structure causing disruption of cytoplasmic membranes. Toxicity following dermal exposure is characterised by local tissue damage, rather than the result of percutaneously absorbed material. A dermal absorption study [IRI report No.: 204648, 2003, The In vitro percutaneous absorption of [14C]-N-(3-aminopropyl) -Ndodecylpropane-1,3-diamine through human skin] performed on a structurally related dodecane branched dipropylene triamine for 24 hours, resulted in a complete dermal penetration of less than 0.01% whereas 0.92% of the applied dose did pass the stratum corneum but remained further fixed in the skin. Further toxicokinetic studies with substance indicated that oral absorption is about 2-5%, considerably higher than the indicated dermal absorption, and that there is no significant entero-hepatic circulation.

Due to lack of quantitative data, absorption rates of 100% are indicated for all three routes. This basically indicates that, although the absorption is probably low, there is no significant difference taking into account in the comparison of absorption via dermal and inhalation routes compared to the oral route by which the hazard evaluations are done. Especially for the dermal route this approach therefore represents a worst case situation. Available studies do not indicate a concern for bioaccumulation.

 

Physical-chemical properties of tallow dipropylenetriamine indicate a low likelihood for exposure via inhalation, being a paste at room temperature with a boiling point > 300 °C and low vapour pressure (4.7 x 10-5 Pa at 20°C for the coco dipropylene triamine, with the shortest average alkyl chain length representing the highest vapour pressure for the group of polyamines).

 

These substances are almost completely protonated under ambient conditions and will therefore not easily transported over biological membranes. The ready biodegradability is a strong indication that these substances are also quickly metabolized. Due to the cationic surface-active PPA adsorb strongly onto organic material which could be a limiting factor for intestinal uptake.