Docosanamide

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 characteristics are likely to be similar or follow a regular pattern as a result of structural similarity. The substances within the analogue approach 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:

The target substance and the source substances areprimary amides of saturated or unsaturated fatty acids, containing only one or no double bonds. Their structures contain a linear carbon chain (i.e. not branched) and the number of carbon atoms generally fall within the range of > C14 and < C24.

Similar physico-chemical properties:

For the purpose of read-across of (eco)toxicity data, the most relevant physico-chemical parameters are physical state (appearance), melting point, vapour pressure, octanol/water partition coefficient and water solubility. Each of the substances are solid in form and have in common a low water solubility (<0.1 mg/L), high log P_ow(> 5) and low vapour pressure (< 0.1 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 ammonia as well as the structurally closely related long-chain fatty acids behenic acid (C22) and erucic acid (C22:1ω9). 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. The resulting long-chain fatty acids are primarily degraded via peroxisomal β-oxidation and the breakdown products are finally metabolised for energy generation after transport to the mitochondria. Unsaturated fatty acids like erucic acid (C22:1ω9) require additional isomerization prior to entering the β-oxidation cycle. Alternative pathways for (very) long chain fatty acids (≥C22) may also involve omega-oxidation in the endoplasmic reticulum at high concentrations, resulting in the formation of long-chain dicarboxylic acids that are further degraded to short-chain dicarboxylic acids and finally excreted via urine. Ammonia, 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, where it is detoxified via the urea cycle. The resulting urea is transported to the kidneys, where it will either be re-absorbed and fed into physiological pathways, or directly excreted via urine.

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

Considering the low water solubility and the potential for adsorption to organic soil and sediment particles, the main compartment for environmental distribution is expected to be soil and sediment. Nevertheless, once this contact takes place, these substances are expected to be removed from the water column to a significant degree due to the readily biodegradability. Thus, discharged concentrations of these 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 vapour pressure. Moreover, bioaccumulation is assumed to be low based on the insolubility of amides of saturated and unsaturated fatty acids and the characteristics that the substances were readily biodegradable. It is not likely that they can be found in the aquatic environment in high concentrations. Additionally, a bioaccumulation test is technically hardly feasible due to the high insolubility of the substances and is not necessary due to the non-hazardous character of the substances. 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 no skin sensitisation properties. Furthermore, the target and source substances are not mutagenic or clastogenic and indicate no potential for systemic toxicity after repeated oral exposure and indicate no potential for systemic toxicity after repeated oral exposure.

Physico-chemical properties

ID No.	Target	Source 1	Source 2
CAS No.	3061-75-4	/	112-84-5
Substance name	Docosanamide	/	(Z)-Docos-13-enamide
Common name	Behenamide	Amides, C16-C18 (even numbered)	Erucamide
SMILES code	CCCCCCCCCCCCCCCCCCCCCC(=O)N	UVCB substance   Main component 1, Stearamide: CCCCCCCCCCCCCCCCCC(=O)N   Main component 2, Palmitamide: CCCCCCCCCCCCCCCC(=O)N	CCCCCCCC\C=C/CCCCCCCCCCCC(=O)N
Molecular weight [g/mol]	339.6	255.5 – 283.5	337.6
Physical state	Solid, Gardner 1.0	Solid, white to off-white powder	Solid, off white powder
Melting Point [°C]	Experimental result: 108.1°C	Experimental result: 97.5°C	Experimental result: 64 – 83°C
Boiling Point [°C]	Experimental result:ca. 279 °C at 1007 hPa	Experimental result: 235 – 251°C at 12 mm Hg; (Q)SAR: 388 – 411 °C at 1013 mBar (MPBPWIN)	(Q)SAR: 460 – 488°C at 1013 mBar (ACD Labs)
Relative density at 20 °C	Experimental result(Relative density): 0.99 at 20°C	Q)SAR: 0.87 g/cm³ at 20°C (SPARC)	Experimental result: 0.908 g/cm³ at 20°C
Vapour pressure at 20 °C	Experimental result:9.2E-02 Pa at 20 °C	(Q)SAR: 8.9E-5 – 3.4E-4 (MPBPWIN)	(Q)SAR: < 0.0000005 Pa at 25°C (ACD Labs)
Partition Coefficient (log Pow)	Experimental result:> 5.7 at 23°C	Experimental result: > 6.5 at 40°C	Experimental result: 8
Water solubility at 20 °C [g/L]	Experimental result:< 0.05 mg/L at 20°C	Experimental result: < 0.102 mg/L at 20°C	Experimental result: < 0.1 mg/L at 20°C

Common origin

Manufacturing and associated similar structure characteristics

The target substance, Docosanamide, and the source substances, Amides, C16-C18 (even numbered) and (Z)-docos-13-enamide, are primary alkyl amides produced from the reaction between an appropriate fatty acid and ammonia, commonly using a coupling agent (March, 1992). The fatty acids used are derived from natural fats and oils, and are of primarily plant origin; commercial material is, therefore, a variable mixture with a general composition ordinarily lying in the range C14-C24. They are either fully saturated or with a single C=C double bond, predominantly have an even number of C atoms, and are without any significant levels of branching in the alkyl chain.

Docosanamide is prepared from docosanoic acid [behenic acid; CAS No. 112-85-6]; Amides, C16-C18 (even numbered) is prepared from commercial stearic acid, being more accurately a mixture of stearic (octadecanoic) and palmitic (hexadecanoic) acids; and (Z)-docos-13-enamide is prepared from (Z)-docos-13-enoic acid (erucic acid; CAS No. 112-86-7).  

The natural variability of the raw material, the fatty acid, means that the final product, the fatty amide, has a composition that itself varies from batch to batch. Indeed, the variability in composition of the fatty acid means that some final products are considered as UVCB, e.g., Amides, C16-C18 (even numbered); whereas others, such as docosanamide or (Z)-docos-13-enamide, contain >80% of a single C chain length (C22 in both cases) and may be considered as monoconstituent substances.

Structural similarity

The target substance and the source substances belong to the chemical class ofAmides of Saturated and Unsaturated Fatty Acids. More specifically each of the substances is a primary amide of saturated or unsaturated fatty acids, containing only one or no double bonds. Their structures contain a linear carbon chain (i.e. not branched) and the number of carbon atoms generally fall within the range of > C14 and < C24. For details, see Analogue Justification in Section 13.

Physico-chemical properties

Physical state and melting point

The target and the source substances are solid under ambient temperature and pressure. The measured melting point of the target substance is 108.1°C. The measured melting point of the source substances (Z)-docos-13-enamide (erucamide, CAS 112-84-5) and Amides, C16-C18 (even numbered) are 64 - 83°C and 97.5°C, respectively.

Boiling point

The target substance exhibits boiling and/or thermal decomposition with evaporation of the decomposition products from 279°C. The predicted boiling point of the source substance (Z)-docos-13-enamide (erucamide, CAS 112-84-5) is 460 - 488°C. The measured boiling point of the source substance Amides, C16-C18 (even numbered) is 235 -251°C at 12 mmHg, and the predicted boiling point is 388 - 411°C at 1013 mmHg.

Density

The relative density of the target substance is 0.99 at 20°C. This is comparable to the densities of the source substances (Z)-docos-13-enamide (erucamide, CAS 112-84-5) and Amides, C16-C18 (even numbered), which are 0.908 g/cm³ (measured) and 0.87 g/cm³ (predicted), respectively.

Vapour pressure

The measured vapour pressure of the target substance is 9.2E-2 Pa at 20°C. The predicted vapour pressures of the source substances (Z)-docos-13-anamide (erucamide, CAS 112-84-5) and Amides, C16-C18 (even numbered) are < 5.0E-7 Pa at 25°C and < 3.4E-4 Pa at 25°C, respectively. The experimentally measured values for the target substance is different by several orders of magnitude from the predicted values for the source substances. This could be due to the degree of error introduced by comparing measred values with predicted values. However, all the reported values are very low (< 0.1 Pa); therefore, differences between the values become irrelevant.

Octanol-water partition coefficient (log P_ow)

The measured log K_ow value of the target substance is >5.7 at 23°C. This is comparable to the measured log K_ow values of the source substances (Z)-docos-13-enamide (erucamide, CAS 112-84-5) and Amides, C16-C18 (even numbered), which are 8 and 6.5, respectively.

Water solubility

A measured water solubility value of the target substance is < 0.05 mg/L at 20°C. This is comparable to the measured water solubility values of the source substances (Z)-docos-13 enamide (erucamide, CAS 112-84-5) and Amides, C16-C18 (even numbered), which are both < 0.1 mg/L at 20°C.

Surface tension

The surface tension of the target substance does not need to be conducted as the water solubility is below 1 mg/L at 20°C. The water solubility of the source substances (Z)-docos-13-enamide (erucamide, CAS 112-84-5) and Amides, C16-C18 (even numbered) is also below 1 mg/L at 20°C; therefore, surface tension can also be waived for these substances.

Flammability

The target substance is non-flammable, and pyrophoricity and flammability on contact with water are not expected. The source substances (Z)-docos-13-enamide (erucamide, CAS 112-84-5) and Amides, C16-C18 (even numbered) are also non flammable, and pyrophoricity and flammability on contact with water are not expected.