N,N'-ethane-1,2-diylbisoleamide

Endpoint summary

Additional information

In accordance with Article 13 (1) of Regulation (EC) No. 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met. In particular, information shall be generated whenever possible by means other than vertebrate animal tests, through the use of alternative methods, for example, in vitro methods or qualitative or quantitative structure-activity relationship models or from information from structurally related substances (grouping or read-across).” According to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No. 1907/2006, substances may be considered as a group provided that their physicochemical and toxicological are likely to be similar or follow a regular pattern as a result of structural similarity. The substances within the analogue approach (listed inTable1) are considered to apply to these general rules and the similarity is justified on basis of scope of variability and overlapping of composition, representative molecular structure, physico-chemical properties and toxicological profiles. There is convincing evidence that these chemicals lie in the overall common profile of this analogue approach. The key points that the target and source substances share are:

Common functional groups:

Both, source and target are mixtures of long-chain alkyl N,N’-bisamides of ethylenediamine. Most of the components of both substances have alkyl chain ranging between C16 and C18.

Similar physico-chemical properties:

For the purpose of read-across of (eco)toxicity data, the most relevant physico-chemical parameters are physical state (appearance), vapour pressure, octanol/water partition coefficient and water solubility. Both substances are solid and have in common a low water solubility (<0.01 mg/L), high partition coefficient (log Pow >10) and a low vapour pressure (< 3 Pa at 25 °C).

Similar metabolic pathways:

The target and source substance are anticipated to be hydrolysed in the gastrointestinal tract and/or liver, resulting in the generation of free ethylenediamine as well as free long-chain, saturated or unsaturated fatty acids (C16, C18 or C18:1). Hydrolysis represents the first chemical step in the absorption, distribution, metabolism and excretion pathways assumed to be similar between the target substance and the source substance. Following hydrolysis of fatty acid amides, fatty acids are readily absorbed by the intestinal mucosa and distribute systemically in the organism. They are either re-esterified into triacylglycerols and stored in adipose tissue, or enzymatically degraded in order to generate energy, primarily via β-oxidation and the subsequent catabolic pathways citric acid cycle and oxidative phosphorylation. Unsaturated fatty acids require additional isomerization prior to entering the β-oxidation cycle. Ethylenediamine, a further potential metabolite resulting from the hydrolysis of both the source and target substance, is likewise readily absorbed and distributed within the body, especially in liver and kidney. Rapid and major excretion of ethylenediamine occurs via urine, with N-acetylethylenediamine being identified as main urinary metabolite. To a minor extent, ethylenediamine is also exhaled as CO₂and excreted via faces.

Common properties for environmental fate & eco-toxicological profile of the target and source substance:

Considering the low water solubility and the high potential for adsorption to organic soil and sediment particles, the main compartment for environmental distribution is expected to be soil and sediment. The Guidance on information requirements and chemical safety assessment, Chapter R7.b (ECHA, 2012) states that once insoluble chemicals enter a standard STP, they will be extensively removed in the primary settling tank and fat trap and thus, only limited amounts will get in contact with activated sludge organisms. Nevertheless, once this contact takes place, these substances are expected to be removed from the water column to a significant degree by adsorption to sewage sludge (Guidance on information requirements and chemical safety assessment, Chapter R.7a, (ECHA, 2012). Thus, discharged concentrations of this substance (if at all) into the aqueous/sediment and soil compartment are likely to be low. Evaporation into air and the transport through the atmospheric compartment is not expected since the target substance and the source substances are not volatile based on the low vapor pressure. Moreover, bioaccumulation is assumed to be low based on the results of the bioaccumulation study. Available data for the target and the source substance showed that the substances are of low toxicity to aquatic organisms as no effects were observed in acute and chronic studies up to the limit of water solubility (fish, aquatic invertebrates and algae). Target and source substance did not exhibit any effects on aquatic microorganisms. Therefore, effects on the microorganism community and the degradation process in sewage treatment plants are not anticipated.

Common levels and mode of human health related effects:

The available data indicate that the target and source substances have similar toxicokinetic behaviour (low bioavailability of the parent substance; anticipated hydrolysis of the amide bond followed by absorption, distribution, metabolism and excretion of the breakdown products) and that the constant pattern consists in a lack of potency change of properties. Thus, based on the available data, the target and the source substance of the analogue approach show a low acute oral, dermal and inhalation toxicity and no potential for skin or eye irritation and skin sensitisation. Furthermore, the target and source substances are not mutagenic or clastogenic and have no toxic effects on reproduction or intrauterine development.

Physico-chemical properties – data matrix

	Target	Source
Chemical name	Amides, C16-C18 (even numbered, C18 unsaturated) N,N'-ethylenebis	Amides, C16-C18 (even) , N,N'-ethylenebis
CAS No.	--	--
EC No.	--	--
Physical state / Appearance	Experimental result: solid	Experimental result: solid
Melting Point	Experimental result: 120.9 ‑124.1 °C	Experimental result: 144.35 °C
Boiling Point	Experimental result: > 300 °C (decomposition)	Experimental result: > 200 °C (decomposition)
Density	Experimental result: 0.8929 g/mL (ca. 20 °C)	Experimental result: 1.0075 g/mL (23 °C)
Vapour Pressure	Experimental result (extrapolated value): 18 Pa at 20 °C (static method) QSAR: 0.0297 Pa (25 °C, Modified Grain method)	Experimental result (extrapolated value): 0.000023 Pa at 20 °C (effusion method) QSAR: 2.74 Pa (25 °C, Modified Grain method)
Partition Coefficient (log Kow)	QSAR: Log Pow > 10	QSAR: Log Pow > 10
Water solubility	QSAR: C18:1 ‑ C18:1 derivative WATERNT = 5.8E‑7 mg/L C16:0 ‑ C18:1 derivative WATERNT = 5.6E‑7 mg/L C16:0 ‑ C16:0 derivative WATERNT = 5.4E‑7 mg/L	QSAR: C18:0 ‑ C18:0 WATERNT = 5.9E‑7 mg/L C16:0 ‑ C18:0 WATERNT = 5.7E‑7 mg/L C16:0 ‑ C16:0 WATERNT = 5.4E‑7 mg/L

Common origin

All constituents of both the target substance and the source substance have a common structure, i.e. two long fatty acid chains bridged with an ethylene-diamide group.

In both cases, the correspondent fatty acid starting material (oleic acid and stearic acid, respectively, which are UVCB substances themselves) are widely available products of natural origin. They are typically obtained from the fat hydrolysis process.

Manufacturing and associated similar structure characteristics

The synthesis of bis-amides follows well known amide formation reactions. They involve reacting an amine (di-amine in this case) and a carboxylic acid, with or without solvent. Generally, there is a previous step to activate the carboxylic acid moiety.

Structural similarity

All identified constituents of both, target and source substance share common functional groups, namely, bis secondary amide with long aliphatic chains.

Physico-chemical properties

Physical state (appearance)

The target and the source substances are solid under ambient temperature and pressure.

Melting point

The melting point of the target substance ranges between 120.9 and 124.1 °C; the melting point of the source substance is 144.35.

Boiling point

The source substance decomposes before boiling above 200 °C.

The target substance decomposes before boiling above 300 °C.

Density

The density of the target substance is 0.8975 g/mL at room temperature. This is comparable to the source substance, 1.0075 g/mL at room temperature.

Vapour pressure

The experimentally measured values are different by several orders of magnitude. However, comparing these two values is meaningless since they have been obtained using different methods: the value of the source substance was obtained using the effusion method, which is an indirect method; on the other hand the value of the target substance measurement was obtained using the static method, which is a direct method.

Comparing calculated vapour pressure values is more suitable since they are based on the same method and parameters in all calculations.

The calculated vapour pressure of the source substance is 2.74 Pa at 25 °C using the modified Grain method. Using the same algorithm, the vapour pressure of the target substance is 0.0297 Pa at 25 °C. These two values represent the worst case and it would be reasonable to expect a variation of two orders of magnitude taking into account the boiling point is a cut off value.

Octanol / water partition coefficient

Calculated log Pow for the source as well as for the target substance is above 10.

Water solubility

An exact experimental measurement was not possible to obtain for target and source substance due to both having very poor solubility in water (< 0.01 mg/L). Calculations using the same algorithm provide comparable small values for both source and target substance. All the identified components of the source substance have a water solubility smaller than 6E-7 mg/L. Likewise, water solubilities of identified components of the target substance are also smaller than 6E-7 mg/L.