1,3-Propanediamine, N-[3-((C11-14, C13-rich)oxy)propyl]- branched acetate

Endpoint summary

Description of key information

Etherdiamines/acetates are protonated under ambient conditions. The substance has a cationic surfactant structure which leads to high adsorptive properties to negatively charged surfaces as cellular membranes which are easily disrupted by its surfactant structure. Cytotoxicity at the local site of contact through disruption of cell membrane is considered the most prominent mechanism of action for toxic effects. The substance has high corrosive properties on skin and shows gastro-intestinal irritation following oral ingestion. Uptake is expected to be slow. Uptake and metabolisation is indicated by metabolic adaption of the liver. The log Pow was found to be -0.4 which indicates that the substance will not bioaccumulate.

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

The common name for the substance “Reaction mass of 1,3-Propanediamine, N-[3-(tridecyloxy)propyl]-, branched and 1,3-Propanediamine, N-[3-(tridecyloxy)propyl]-, branched acetate” used in this dossier is Etherdiamine C13i/acetate.

 

The manufacturing process is a multi-step process. In the first step fatty alcohol is reacted with acrylonitrile at elevated temperature to form an ethernitrile. In the second step the ethernitrile is hydrogenated to the corresponding primary etheramine. This process is repeated for the conversion of the etheramine into an etherdiamine: The etheramine is reacted with acrylonitrile and the resulting nitrile is again hydrogenated to the corresponding primary amine of the resulting etherdiamine. In the final step the etherdiamine is partially neutralised with acetic acid to form a cationic-amine acetate salt. The final product Etherdiamine C13i/acetate contains for about half the etherdiamine acetate, and half etherdiamine without acetate.

 

Physical-chemical properties

Etherdiamines/acetates are protonated under ambient conditions. This means that they will sorb strongly to negatively charges substances like glassware, soil and sediment constituents and also organisms.

Etherdiamine C13i has a molecular weight of 314 (as acetate salt 374), and has a calculated logP of 5.2 (KOWWIN). But under environmental and physiological conditions at pH around 7, the logD is about 0.5, and from pH 5 and lower -1 (http://www.chemicalize.org), which is related to the protonation of the primary amine. This is confirmed by a measured Pow at pH 6 of -0.4 (OECD 123 slow stirring at 1% of CMC, at 25 °C).

As the substance forms micelles in water the water solubility is expressed as the critical micelle concentration (CMC). For this substance the CMC has been determined to be between 1300 – 2200 mg/L (pH 7, 23 – 25°C)

In physiological circumstances both nitrogens are positively charged, resulting to a cationic surfactant structure which leads to high adsorptive properties to negatively charged surfaces as cellular membranes. The apolar tails easily dissolve in the membranes, whereas the polar head causes disruption and leakage of the membranes leading to cell damage or lysis of the cell content. As a consequence, the whole molecule will not easily pass membrane structures. Cytotoxicity at the local site of contact through disruption of cell membrane is considered the most prominent mechanism of action for toxic effects.

 

The substance is a clear light-yellow liquid, with a melting point below -30ºC and boiling point > 300ºC and has a measured vapour pressure of 0.005 Pa at 25°C, which represents a maximum vapour concentration in the air of about 0.6 mg/m3 or 0.05 ppm. Evaporation rate is expected to be low.

 

Toxicological profile

As Etherdiamine C13i/acetate is used in industrial settingsas flotation agent in mining, involving potential exposures of only a limited number of people working in industrial setting under controlled conditions. In view of its corrosive properties, handling takes place under controlled conditions, minimising likelihood of exposures.

 

Etherdiamine C13i was tested both with and without the acetate for dermal irritation/corrosion in in vivo studies on rabbit skin. Both were found to be corrosive to rabbit skin following 3 minutes exposure. Consequently it is concluded that the presence of acetic acid does not impact corrosive properties of the etherdiamine.

There are two studies that evaluated the acute oral toxicity of Etherdiamine C13i showing that its LD50 is within the range of 300-2000 mg/kg bw, with LD50 cut-off value of 500 mg/kg body weight. Although both studies have been performed on etherdiamine C13i without acetate, they are considered to be relevant for the evaluation of etherdiamine C13i with acetate as well. Dermal corrosion studies have shown that the presence of acetate does not impact the corrosive properties of the compound. Additionally, the conversion of about half of the etherdiamine to etherdiamine-acetate salt, as is the case for the Etherdiamine /acetate product mixture, is not considered to have a large impact as it will probably be dissociated again in stomach and intestinal fluids.

Due to its corrosive properties, further acut ein vivo testing via dermal and inhalation route is not justified.

As the substance is corrosive, symptoms of local respiratory irritation are expected, which should limit the systemic uptake of amount needed for systemic toxicity.

Also for acute dermal toxicity, effects will be characterised by local tissue damage. Systemic uptake via skin is likely to be very limited, in view of the use of protective measure related to the handling of corrosive material.

 

There is no information on possible skin sensitisation available from testing. Cross reading with primary alkylamines indicates that the substance would not be sensitising to skin. Testing is in view of its corrosive properties and only industrial use not required.

 

There are no concerns for genotoxicity. Etherdiamine C13i/acetate is not mutagenic in the Salmonella typhimurium reverse mutation assay, is not clastogenic in human lymphocytes, and not mutagenic in the HPRT mutation test with Chinese hamster V79 cells.

 

All information combined from a 14-day (OECD 414 developmental toxicity study), 28-day (OECD 407) and 90-day (OECD 408) repeated dose study show all a comparable picture with respect to the inflammatory responses observed: The macroscopic findings (thickened intestinal wall and enlarged mesenteric lymph nodes) and the microscopic correlate (foamy) macrophages in the lamina propria or granulocytic (necrotizing) inflammation and granuloma(s) with or without central necrosis in the lymph nodes) and the increase of neutrophils all point to a generalised inflammatory response that is both increasing with dose and duration. Actual systemic inflammatory responses extending to organs outside the gastro-intestinal tract do occur after longer duration of dosing at lower dose levels.

A LOAEL of 0.5 mg/kg bw/day was established from the 90-day study in rat by oral gavage, at which level leukocytosis was seen, inflammatory responses in mesenteric lymph nodes and lungs, and effects in the hindlegs and/or tail of few animals that were histopathologically supported by occurrence of arthritis with or without hyperostosis.

For MoA this is considered to be related to phospholipidosis effect, resulting to the high partitioning into phospholipids and subsequent accumulation of these phospholipids in mesenteric macrophages.

 

Possible relevance to other routes of exposure:

- Inhalation: Effects are mainly local lymph nodes. It is uncertain whether similar effects in lung are to be expected. Based on the available data and progression of effects from mesenteric lymph nodes to lungs, similar sensitivity is assumed.

- Dermal: Effects are mainly on local lymph nodes following absorption. On skin local corrosive/irritant effects and lower absorption are to be expected. However, based on local irritant effects that are possibly inflammatory mediated, same sensitivity is assumed.

Available repeated dose studies on Etherdiamine C13i/acetate do not indicate adverse effects on reproductive organs, including oestrous cycle evaluation and histopathological examination of the male and female reproductive organs. Study of Etherdiamine C13i/acetate in a prenatal developmental toxicity study in rats has not shown reproductive or teratogenic effects. Developmental effects characterised as increased incidence of delayed ossification were only visible at maternal toxic dose levels and are considered secondary to that. Also comparable fatty amine-like substances lack of effects on reproduction.

 

 

Toxicokinetics, metabolism and distribution

Etherdiamine C13i is mainly protonated under environmental conditions. The protonated fraction will behave as salt in water. Etherdiamine C13i is surface active and has a low solubility in the form of CMC (1.3 – 2.2 g/L at pH 7).

Similarly to other cationic fatty nitrile derivatives, Etherdiamine C13i is expected to sorb strongly to sorbents and patitionates strongly into phospholipid membranes. As a consequence, absorption from gastro-intestinal system is likely to be slow.

 

With a vapour pressure of 0.005 Pa at 25°C and expected low evaporation rate, potential for inhalation is limited. The substance is very corrosive and itsuse is limited to industrial settings under controlled conditions which further limits the likelihood of exposure.

 

The mode of action of Etherdiamine follows from its structure, consisting of an apolar fatty acid chain and a polar end of a primary amine from the ether part with primary amine. The structure can disrupt the cytoplasmatic membrane, leading to lyses of the cell content and consequently the death of the cell.

Etherdiamine C13i is corrosive to skin, and toxicity following dermal exposure is characterised by local tissue damage, rather than the result of percutaneously absorbed material. It is not expected to easily pass the skin in view of its ionised form at physiological conditions. However, as this is not quantitatively evaluated, 100% dermal absorption is considered as worst case assumption.

 

The log Pow was found to be -0.4 which indicates that the substance not will bioaccumulate.

 

Attached document provide results from profiling. Etherdiamine C13i does not trigger any alert for mechanistic or endpoint toxicity. The only alert triggered Class III (high) Toxic hazard classification by Cramer. Class III is described as: “Substances with chemical structures that permit no strong initial presumption of safety or may even suggest significant toxicity or have reactive functional groups.” Just the presence of an aliphatic secondary amine causes this response.

QSAR Toolbox metabolism profilers, MetaPrint2D and BioTransformer indicate that a large range of human relevant phase I liver metabolism is possible.