Amines, N-(C16-18 and C18-unsatd. alkyl)trimethylenedi-, dioleates

Endpoint summary

Description of key information

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

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 “N-C16-C18-alkyl-(evennumbered, C18 unsaturated) propane-1,3-diaminium di[(9Z)-octadec-9-enoate]” CAS 1307863-78-0 (Formerly also CAS number 61791-53-5 was used for this substance), further referred to as Tallow-diamine dioleate.

 

Much of the available data for evaluation of the hazards of Tallow-diamine dioleate is obtained from cross-reading from Oleyl-diamine dioleate.Cross-reading betweenfrom Oleyl-diamine dioleate to Tallow-diamine dioleateis acceptable on the basis ofidentical chemicalstructures. The only differences between the two substances are related to the alkyl-chains linked to the diamine.Contrary to oleyl do tallow-alkyl chains also contain some C16-chains next to the C18-alkyl chains.The toxicological relevance of this difference is expected to be negligible as it leads to a difference in (average) molecular weight for the Tallow-diamine dioleate of less than 2% lower than that of Oleyl-diamine diolate. The higher level of unsaturation in oleyl-alkyl chainscompared to tallow-alkyl chainscan be considered a worst case representationwith respect to possible toxicity whencompared to tallowalthough the actual toxicological impact is very limited. Due to this very great similarity between these two substances, all results obtained from Oleyl-diamine dioleatearefully applicable for the evaluation of Tallow-diamine dioleate as well.

 

Tallow-diamine dioleate and Oleyl-diamine dioleate are salts of an alkyl-diamine and oleic acid, in a molar ratio of 1:2. Absorption and subsequent possible toxicity follows the dissociation of the salt. The diamine structure is much more toxic than the oleic acid part, and therefore it is considered that toxicity profile of alkyl-diamine dioleate will be fully driven by its alkyl-diamine content.

 

The available repeated dose data allows for the comparison of a 28-day study on Oleyl-diamine dioleate with an available 28-day study on Oleyl-diamine done at a different time in a different lab. The outcome of both studies show an almost exact match between the two observed toxicity profiles and levels when based on Oleyl-diamine content. This demonstrates that the toxicity of the alkyl-diamine dioleate salts is indeed driven by their alkyl-diamine content. For further evaluation of toxicity of alkyll-diamine dioleate, including reproduction toxicity, therefore cross-reading can be done to the data available on alkyl-diamine.

 

 

1. Physical-chemical properties

Tallow-diamine dioleatehas a molecular weight of approx.876g/mol and is an amber coloured pasteat 20°C.The substance has a measured melting point of38 °C, a measured boiling point of 184°C at 1013 hPa and a vapour pressure expected to be below 0.0015 Pa at 20°C (as this is based on read-across from shorter chain C_12-14-diamine and not being a dioleic-acid salt). The octanol-water partition coefficient (log Pow) could not be measured due to its very low water solubility of less than 0.005 mg/L at 20°C. Besides, the substance is a salt, making it not suitable for testing. As sated, being a salt, the toxicological properties can be expected to be derived from its Tallow-diamine content.

In physiological circumstances both nitrogens in the alkyl-diamine 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 will is considered the most prominent mechanism of action for toxic effects.

 

2. Data from acute toxicity studies and irritation studies

Acute oral toxicity ofTallow-diamine dioleatewas evaluated in an acute limit dose study, indicating an LD50 is > 5000 mg/kg bw. Also an acute dermal toxicity study resulted to an LD50 > 2000 mg/kg (based on cross-reading to Oleyl-diamine dioleate), although the dermal exposure lead to skin corrosion.

Again based on cross-reading from Oleyl-diamine dioleate, also Tallow-diamine dioleate is considered to be irritating to both skin and eye. Following a negative GPMT study on Oleyl-diamine dioleate, no classification is needed for skin sensitisation.

 

3. Data from repeated dose toxicity studies

Oral:

Oleyl-diamine dioleatehas been evaluated for repeated dose toxicity ina 28-day repeated dose toxicity study(OECD 407). For further information use is made of cross-reading to various results obtained onthe alkyl-diamines, specifically Oleyl-diamine and C12-14-diamine.

The results from the 28-day study with Oleyl-diamine dioleate forms an excellent match with the results from the 28-day on Oleyl-diamine. This makes clear that the toxicological profile of Oleyl-diamine dioleate is fully determined by its Oleyl diamine content.Further evaluation for repeated dose toxicity of Oleyl-diamine involving sub-chronic studies is based on read-across from C12-14-diamine,whichwith the shorter chain-lengthcan be regarded to be the worst case representative for the group of alkyl-diamines with longer chain lengths.

 

The most significant treatment-related changes in all studies areincreased WBC (neutrophils) at higher dose levels combined with changes in body weight gain. The critical effects are histopathological test item-related effects on the small intestine and mesenteric lymph nodes, which only partially regressed during the recovery period. A relatively strong inflammatory reaction is also observed. These effects have consistently been observed with these sort of substances (Fatty amine derived substances), which support the current approach of grouping of substances and read-across of data. When taking into consideration the relatively strong corrosive effects of these substances and the route of administration, it cannot be excluded that the overall toxicity reflects a point-of-first-contact effect. 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 of foamy macrophages are local and are by some interpreted as phospholipidosis (PLDsis), something which is commonly observed following treatment with cationic amphiphiolic drugs and considered to be non-adverse.

 

All findings observed in the 90-day repeated dose toxicity study are comparable with the 28-day repeated dose toxicity study performed with C12-14-diamine, which indicates that duration has no great impact on the NOEAL.

Small intestinal and mesenteric lymph node lesions show only slowly reversible. The effects were not reversible during the 28-day recovery period, but had partially regressed after the 90-day recovery period. Other effects seen at higher dose levels as spleen, bone marrow and tracheal changes had completely regressed after the 28-day and 90-day recovery period.

 

Inhalation:

Tallow-diamine dioleate is a solid at 20°C with a melting point of 38 °C. It has a vapour pressure less than 0.0015 Pa at 20°C (value is an overestimation as it is based on read-across from C12-14-diamine rather than a dioleic acid salt of an alkyl diamine as Tallow-diamine dioleate salt) and the indicated use patterns also does not give rise to a high concern for specific exposures via inhalation.

 

Dermal:

No data from repeated dose studies via dermal route.Tallow-diamine dioleateis irritating to the skin and eyes, and under the conditions of the in the acute dermal toxicity test, it was corrosive. Tallow-diamine is not expected to easily pass the skin from the dioleate salt form, in view of its ionised form at physiological conditions.Testing via dermal route is therefore not a preferred route.

 

4. Absorption, distribution, metabolism, excretion

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

It is expectedTallow-diamine dioleatewhen administered orally is not extensively absorbed, due to its low solubility.The data from repeated dose studies comparingOleyl-diamine dioleateresults with those on Oleyl-diamine, indicates that the salt becomes dissociated after which the alkyl-diamine becomes available.The effects of the diamines on which the NOAEL’s are based in the 28 and 90-day repeated dose toxicity studies, concerneffects in the small intestinesand mesenteric lymph node lesions. As these indicate local effects they can probably be considered local NOAEL’s.

The available repeated dose studies show that the NOAEL does not change with increasing study duration from 28-day to 90-days. This is an indication for lack of bioaccumulating potential.

 

Dermal absorption:

At this stage no data are available on dermal absorption.Tallow-diamineis not expected to easily pass the skinfrom the dioleate salt form, inview of its ionised form at physiological conditions.Dependent on the solvent and concentration, up to 60% dermal absorption may be taken as a worst case for assessment purposesfor the Tallow-diamine(value taken from the existing EU risk assessment on primary alkylamines).

However, due to the lack of quantitative absorption data, 100% absorption is taken as a conservative approach in this dossier.