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

Endpoint summary

Description of key information

There are no specific studies available that study Absorption, distribution, metabolism or excretion of Oleyl-diamine mono-oleate. Due to lack of comparative quantitative data, absorption rates of 100% are indicated for all three routes. This basically indicates that in the considerations of DNEL setting, 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. 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

The substance Oleyl-diamine mono-oleate is a salt of (Z)-N-9-octadecenylpropane-1,3-diamine (Oleyl-diamine, CAS 7173-62-8) andOleic acid (CAS 112-80-1) at a molar ratio of 1:1,which dissociates into its components in aqueous environment. It should be noted that also both components of the salt individually have surface active properties, and form micelles rather than clear aqueous solutions. Also, both the structures appear under physiological conditions in a charged form in water solution. The Oleyl-diamine will be present as a cationic charged structure under physiological pH (pKa = 10.7) and Oleic acid as anionic structure (pKa = 4,8). Following systemic absorption after oral dosing, no distinction can be made between Oleyl-diamine absorption from Oleyl-diamine mono-oleate or from dosing of Oleyl-diamine itself.Consequently, the evaluation of the individual components is just as relevant for the hazard evaluation as testing with the actual salt.

 

Oleic acid, like other natural fatty acids is considered to be of lower toxicity than Oleyl-diamine. Proof of this is found in the comparison of the results from comparably performed 28-day studies on Oleyl-diamine and Oleyl-diamine-dioleic acid, showing that the systemic toxicity from Oleyl-diamine dioleate is fully driven by its Oleyl-diamine content. Also comparison of cytotoxicity from in vitro genotoxicity testing of Oleyl-diamine and Oleyl-diamine dioleate indicate better correlation on the basis of the Oleyl-diamine content, but even when corrected for Oleyl-diamine content, the cytotoxicity of products with Oleic acid tend to show a somewhat lower cytotoxicity than expected. On the other hand, these studies are not fully comparable due to differences in cells involved, difference in duration of exposure, and difference in valuation of cytotoxicity.

 

As toxicity of Oleyl-diamine mono-oleate is driven by its Oleyl-diamine content, the hazard evaluation can be done by cross-reading to available data on Oleyl-diamine.

Oleyl-diamine mono-oleate has an average mw of 607.1, of which 53.5% consists diamine (mw = 324.67) and 46.5% fatty acid (oleic acid mw = 282.46). This means that effect levels for Oleyl-diamine can be multiplied by 1.87 to obtain the corresponding level for Oleyl-diamine mono-oleate (on weight basis).

 

The hazard evaluation of (Z)-N-9-octadecenyl-1,3-diaminopropane (Oleyl diamine) 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" added to IUCLID Ch. 13.

 

Oleyl-diamine is a fatty amine (long alkyl chains linked to a nitrogen), linked to a 1,3-diamine propane (DP) group. The mode of action for Oleyl-diamine follows from its structure, consisting of an apolar fatty acid chain and a polar end of a primary amine. The substance is completely protonated under environmental conditions which causes them to strongly adsorb to organic matter and to negatively charged cell membranes. The long apolar fatty acid chains easily dissolve in the cytoplasmic membrane whereas its function and structure is disrupted by the polar amine groups. The disruption of the cytoplasmic membrane causes cell damage or lyses of the cell content. Whether toxicological effects occur depends on whether local concentrations reach a level at which cellular integrity cannot be maintained. However, the whole molecule will not easily pass the membrane structure. The fraction of the diamine adsorbed does not easily get free in solution again and the substance bound in the stratum corneum is not mobile.

Its molecular chemical profile and estimated properties is listed in the attached profiling document, where it is compared to Oleic acid.

 

Physical-chemical properties

The test substance, Oleyl-diamine mono-oleate CAS 40027-38-1, has a molecular weight of 607.1 g/mole and is at room temperature a yellow paste . The substance has a melting point of 30-40°C. No boiling point was detected, but it decomposes from 145 to 400 °C. The vapour pressure was determined by isothermal TGA effusion method and found to be between 9.2 x 10^-5 and 8.7 x 10^-4 Pa.

The substance is a salt, which dissociates into its components Oleyl-diamine and Oleic acid under aqueous conditions.It should be noted that also both components of the salt individually have surface active properties, and form micelles rather than clear aqueous solutions. Also, both the structures appear under physiological conditions in a charged form in water solution: oleyl-diamine as cationic, and the oleic acid as anionic structure. This means that solubility and Pow are pH dependent.

For surface-active structures, the standard test methods for water solubility and octanol/water partitioning are generally not suitable. For the free water solubility in general the CMC (critical micelle concentration as approximation for the maximum concentration where the substance is still in free solution) is provided rather than the amount that can be added while still showing a clear solution. The CMC was found to be 0.080 g/L (pH 6.5, 20°C, at 1 g/L). For Pow of such substances, the separate solubility in water and in octanol can be used, where the use of the CMC for water solubility will result to the most conservative result (i.e. the highest Pow value). For Oleyl-diamine mono-oleate the octanol solubility was found to be 720 g/L, which results to a logPo/w of 3.95 (i.e. log(0.080/720) ). The meaning of this value is questionable in view of the dissociation in physiological conditions and absorption processes, and when comparing to the logPo/w determined for Oleyl-diamine itself of 0.0 (OECD 123 shake-flask, slow-stirring method).

 

Absorption:

As this substance has a positive charge under physiological conditions (+2), transport across biological membranes is low and most likely reduce oral absorption and bioavailability. However, due to lack of comparative quantitative data for absorption over different routes, the absorption level is set at 100% for all routes. Available data from a toxicokinetic study on hydrogenated-tallow(HT)-diamine applying radiolabelled material (not included in this dossier) showed the labelled diamine to be quite slowly absorbed from the gastrointestinal tract. The blood radioactivity was low and slightly above LOQ for the different doses and dose regimens. Furthermore, for almost all tissues the highest concentration of radioactivity was obtained at 24 hours after the administration.Diamines when administered orally are not extensively absorbed, probably due to its low solubility and CMC formation.

These findings agree withthe toxicological results from the repeated dosing studies by oral gavage. 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. Furthermore, the NOAEL is not really influenced by the duration of the study, which supports the lack of bio-accumulating potential of the diamines.

 

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, and in the skin, most will be trapped locally in the phospholipids.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.

Based on the corrosive properties of diamines, facilitated dermal absorption due to 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 fromin vitrotesting on comparable cationic surfactants show that therateof 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.

 

Also for inhalation no data are available on absorption. With a very low vapour pressure of ≤ 0.00087 Pa at 25 °C, the potential for inhalation is limited. Relevant (in view of possible systemic absorption) exposures are only possible as aerosol. If any inhalation from aerosols does occur, this can only be in the form of larger droplets, as the use does not include fine spraying. Droplets will deposit mainly on upper airways, and will be subsequently swallowed following mucociliary transportation to pharynx. This results to no principal difference in absorption compared oral route. Absorption via respiratory route is therefore as worst-case set at 100% (to indicate a similar rate as via oral route).

The substance is severely corrosive, and droplets depositing in upper airways would result to local irritation or corrosion. The long term systemic inhalation DNEL considered sufficient to ensure that these effects do not occur.

 

Distribution and excretion

Information from other cationic amines, including comparable monoalkyl polyamines, show very low oral absorption, low tissue distribution with most of the substance primarily associated with the intestinal mucosa, and excretion of any absorbed material mostly via urine.

Repeated dose studies have not shown accumulation or increased toxicity upon elongation of study duration. Low bioaccumulation potential for Oleyl-diamine is also shown by the low calculated BCF (70.8 L/kg wetweight estimated with EPIWIN) and low acute-to-chronic ratio of toxicity to aquatic species.

 

Metabolism

There is no specific information on metabolism of Oleyl-diamine. In view of available information on various other alkyl-amines, metabolism is expected to be very limited. In case of metabolism, oxidation of alkyl chains is expected via a process similar to beta-oxidation of fatty acids.

The attached profiling document includes metabolism profile from simulators in OECD Toolbox (v.4.2.1) and MetaPrint2D.