Oleic acid, compound with (Z)-N-octadec-9-enylpropane-1,3-diamine (2:1)

Endpoint summary

Description of key information

There are no specific studies available that study absorption, distribution, metabolism or excretion of Oleyl-diamine dioleate.

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, it is considered that no significant difference in absorption occurs between oral, dermal and inhalation route. Very likely this means an overestimation of the dermal absorption compared to oral route. Available studies do not indicate a concern for bioaccumulation. An ADME study applying radio-labelled Hydrogenated tallow diamine by oral route indicates slow absorption, with highest concentrations of radioactivity seen in the intestinal mucosa, abdominal lymph nodes, liver, spleen, adrenal cortex, myocardium and brown fat. All other tissues showed low or very low levels of radioactivity.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

The hazard evaluation of Oleyl diamine/Oleyl diamine dioleate includes highly reliable GLP studies performed over the category of alkyl-diamines. Cross-reading to data available on other diamines and polyamines is acceptable on the basis of identical alkyl-diamine structure, resulting to the same functional groups with similar properties leading to common biological activity, and common metabolic degradation. Further information on the applicability of the read-across from various diamines to Oleyl-diamine can be obtained from the document "Category polyamines - 20170518.pdf".

 

1. Physical-chemical properties

(Z)-N-9-octadecenyl-1,3-diaminopropane (Oleyl diamine) CAS 7173-62-8, has a molecular weight of 324.67 g/mole and is at room temperature a white-grey liquid with solid parts as being in semi melted stage. The substance has a melting point of 3°C, a boiling point of > 150°C at 1013 hPa and a vapour pressure less than 0.0015 Pa at 20°C (worst case, as based on read-across from shorter chain C12-14-diamine). Solubility and Pow are pH dependent. The octanol-water partition coefficient (log Pow) is 0.0 at 25.7 °C and as the substance forms micelles in water the water solubility is expressed as the critical micelle concentration (CMC, a solubility limit) at 36 mg/L at pH 7 and 23°C.

Physical-chemical properties of the salt, Oleyl diamine dioleate CAS 34140-91-5 are close, except for the molecular weight (i.e. 889.5 g/mole).

In physiological circumstances, both nitrogens are positively charged, resulting to a cationic surfactant structure which leads to high adsorptive properties to negatively charged surfaces such as cell 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 will is considered the most prominent mechanism of action for toxic effects.

 

2. Data from acute toxicity studies and irritation studies

Data more relevant for the classification for acute toxicity is derived from series of highly reliable GLP (Acute Toxic Class, OECD 423) studies performed together over the category of alkyl-diamines. LD50 for Oleyl diamine ranges between 500 and 1000 mg/kg bw.

Oleyl diamine is corrosive to the skin while Oleyl diamine is mildly irritating to skin. Both are not expected to easily pass the skin in view of their ionised form at physiological conditions. Testing via dermal route for is therefore not a preferred route. However, as dermal absorption is not quantitatively evaluated, 100% is assumed as worst case assumption.

 

3. Data from repeated dose toxicity studies

Oral:

Several repeated toxicity studies by oral route are available among the polyamines category. The similarity of the findings in these studies supports the acceptability of grouping and the cross-reading and also indicated that the shorter chain diamines results to the lowest NOAEL.

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. A mode of action has not been established but it is possible to suspect the known corrosivity to be at least partially involved. 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 generally considered to be non-adverse. 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. Consequently, the whole molecule will not easily pass membrane structures. Noteworthy in this respect is that recent research shows that the log distribution coefficient for cationic surfactants between water and phospholipid are possibly several orders of magnitude higher than between water and oil. The complex of cationic surfactant and phospholipids are difficult to digest by the macrophages, and they accumulate with the lysosomes. Recent (unpublished) studies have shown that these cationic surfactants, are all lysosomotropic, and scored positive for phospholipidosis in in vitro studies with HepG2 cells.

When taking into consideration the relatively strong corrosive effects 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.

 

Inhalation:

Oleyl diamine or Oleyl diamine dioleate are liquid/paste with a vapour pressure less than 0.0015 Pa at 20°C (value is an overestimation as it is based on read-across from shorter chain C12-14-diamine). Also the use of these substances will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalation route will be unlikely to occur.

 

Dermal:

No data from repeated dose studies via dermal route. Oleyl diamine is corrosive to the skin while Oleyl diamine dioleate is mildly irritating to skin.The polyamines are on overall corrosive to the skin. For these corrosive effects to the skin, a trend can be observed, with higher corrosion for shorter chain lengths (C12-14-diamine vs C16-18-diamine) and for higher levels of unsaturation (Oley-diamine vs HT-diamine). This could be related to the physical state of the substance: The more liquid the better the contact to the skin and penetration to the viable cell layers however, polyamines are not expected to easily pass the skin in view of their ionised form at physiological conditions. The dermal route is therefore not a preferred route for dosing when evaluating repeated dose toxicity.

 

4. Absorption, distribution, metabolism, excretion

A well performed study (Active Biotech research, 2009) withN-C16-18-alkyl (evennumbered)-1,3-diaminepropane with14C-labelled C18-diamine, gives some information on the tissue distribution of the category. The highest tissue concentrations of radioactivity were registered in the intestinal mucosa, abdominal lymph nodes, liver, spleen, adrenal cortex, myocardium and brown fat. All other tissues showed low or very low levels of radioactivity. The labelled diamine seemed to be quite slowly absorbed from the gastrointestinal tract. The blood radioactivity was low and slightly above LOQ . Furthermore, for almost all tissues the highest concentration of radioactivity was obtained at 24 hours after the administration. However, due to lack of quantitative data, the absorption rate following oral dosing is considered to be 100%.

The findings in the toxicokinetics study are in agreement with the toxicological results from the repeated dosing studies by oral gavage. Octadecyl diamines when administered orally are not extensively absorbed, probably due to its low solubility and CMC formation. The effects of the diamines on which the NOAEL’s are based in the 28 and 90-day repeated dose toxicity studies, effects in the small intestinal and mesenteric lymph node lesions intestines, indicate local effects, and can probably be considered local NOAEL’s.

 

Dermal absorption

At this stage no data are available on dermal absorption. In physiological circumstances, both nitrogens are positively charged, resulting to a cationic surfactant structure which leads to high adsorptive properties to negatively charged surfaces such as cell 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 through membrane structures.

Based on the corrosive properties of most di-amines, facilitated dermal absorption as a consequence of facilitated penetration through damaged skin can be anticipated. The existing EU risk assessment on primary alkylamines considered that absorption could be dependent on the solvent and concentration, and decided that up to 60% dermal absorption may be taken as a worst case for assessment purposes.

On the other hand however, there is information that these substances adsorb into the str. corneum, but do not penetrate skin. Data from in vitro testing on comparable cationic surfactants show that the rate of absorption is extremely low.

Due to the lack of quantitative absorption data for comparison between oral and dermal absorption, 100% absorption is taken as a conservative approach.