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Endpoint summary

Additional information

Hypothesis for the analogue approach

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 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 fatty acid amides. Most of the components of the target substance have alkyl chain ranging between C16 and C18, while the source substance is predominantly C22.

·                    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 (<0.0191 mg/L), high partition coefficient (log Pow >6.62) 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 ammonia as well as free long-chain, saturated or unsaturated fatty acids (C16, C18 and C22). 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.

·                    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 available results demonstrate no acute or chronic toxicity of the substances up to the limit of water solubility. Based on the study results both substances are considered not toxic to aquatic organisms. Experimental data evaluating the toxicity of the target and source substance to soil/sediment organisms are not available. Since the substances are poorly water soluble an exposure of sediment organisms is considered unlikely.The Guidance on information requirements and chemical safety assessment, Chapter R7.b (ECHA, 2014) 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, 2014). Thus, discharged concentrations of this substance (if at all) into the aqueous/sediment and soil compartment are likely to be low. Based on the available information, toxicity to soil and sediment organisms is expected to be low. Evaporation into air and the transport through the atmospheric compartment are not expected since the target substance and the source substance are not volatile based on the low vapour pressure. Moreover, bioaccumulation is assumed to be low based on the results of the bioaccumulation assessment; the substances are not expected to bioaccumulate. Available data for the target and the source substance showed that the substances are not toxic 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). The target 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 substance 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 substance are not mutagenic or clastogenic and have no toxic effects on reproduction or intrauterine development.

Target and source chemicals

The target substance, Amides, C18, branched and linear, is a UVCB chemical containing predominantly amides of stearic acid (stearamide) and isostearic acid (isostearamide). In the fatty acid nomenclature these fatty acids are both denoted C18 due to the length of their carbon chains.

Possible analogues are amides of long chain fatty acids. One example of such a substance is erucamide (amide of erucic acid), CAS No. 112-84-5. Erucic acid is a mono-unsaturated fatty acid with a carbon chain consisting of 22 carbon atoms with a double bond at position 13 (omega-9) of the carbon chain (cis-docos-13-enoic acid). Comparable to the target substance it is not classified in Annex I of Directive 67/548/EEC, and does not have to be self-classified according to the available experimental data. Erucic acid is also present in various oils and fats which are part of human diets (20-40% in oils from mustard seeds and up to 50% in original high erucic rapeseed oil, <2% in low erucic acid rapeseed oil) and will also be broken down into shorter-chain fatty acids in the process of beta-oxidation. The existence of the double bond does not interfere with the anticipation of a common metabolism for saturated and unsaturated fatty acids, as dehydrogenation and introduction of atransdouble bond into the saturated fatty acid chain is the first step of beta-oxidation. Acisbond as present in erucic acid will be converted by an endogenous isomerase to the correspondingtransbond; the resulting fatty acid will then share the same metabolic fate as saturated ones.

The target substance and the potential source substance are solid at ambient conditions. They demonstrate physico-chemical characteristics in a comparable range of magnitude. Amides of long-chain fatty acids follow the same metabolic pathways after systemic uptake.

All fatty acids in question are abundantly available in human daily nutrition and are utilised by fat metabolism.

List of endpoints covered by analogue approach

Source chemical: Erucamide, CAS No. 112-84-5

- 8.6.2. Sub-chronic toxicity (90 days) (IX)

- 8.7.2. Prenatal developmental toxicity (IX)

Analogue approach justification

Physico-chemical properties

The target substance and the source substance are amides of fatty acids, saturated (target substance) and unsaturated (source substance). The substances are solids at ambient conditions.

Melting point

The melting point of the target substance is 77 °C. The melting point of the source substance is in the range of 64 °C to 83 °C. It is a known fact that the melting temperatures of non-monoconstituent substances (e.g. target substance) as well as those of unsaturated substances (e.g. source substance) are expected to be lower than the melting temperatures of saturated mono-constituents of a similar chain length.  

Boiling point

Stearamide was reported to boil at 250 – 251 °C at reduced pressure. This is in agreement with the measured value for the target substance at ambient pressure, > 250 °C. Reliable QSAR data is available for the source substance; as expected the calculated boiling point at 1013 hPa (460 - 488 °C) is high.

Density

The target substance has a measured density of 0.87 g/cm³ at 20 °C, which compares well with the measured value of 0.908 g/cm³ at 20 °C for the source substance.

Vapour pressure

The vapour pressures of both target and sources substances are very low. Valid calculations (EPISUITE v4.11) show values of2.83E-04 Pa and 1.91E-04 Paat 25 °Crespectivelyfor theC18 iso and C18 linear components of the target substance. SPARC v4.6 calculated values are of order of magnitude 1E-07. The calculated value for the source substance (< 5.0E-07 Pa. ACD Labs) is comparable.

Octanol-water partition coefficient

The partition coefficient log Kow exceeds 3 for the target substance and the source substance. The calculated values for theC18 iso and C18 linear components of the target substance(log Kow of 6.62 and 6.7, respectively) agree well with the experimental value for the source substance (log Kow = 8).

Water solubility

As expected, both target and source substances are characterised by very low water solubility i.e. below 0.1 mg/L. These low values correlate with the high log Kow; water solubility is expected to be inversely related to the log Kow.

Table: Data matrix physico-chemical data Target and Source Chemical

	Target Chemical	Source Chemical
Name/CAS #	Amide, C18, branched and linear	Erucamide/112-84-5
Molecular weight, g/mol	283.5	337.6
Appearance / physical state	Solid, off-white	Solid, off white powder
Melting point / Freezing point	Experimental result: 77 °C	Experimental result: 64 – 83 °C/94 °C Lide
Boiling point	Experimental result: > 250 °C at 1013 hPa.	(Q)SAR: 460 – 488 °C at 1013 hPa (ACD Labs)
Density	Experimental result: 0.87 g/cm³ at 20 °C	Experimental result: 0.908 g/cm³ at 20 °C
Vapour pressure	(Q)SAR: C18 iso component: 2.83E-04 Pa at 25 °C (MPBPWIN) C18 linear component: 1.91E-04 Pa at 25 °C (MPBPWIN)	(Q)SAR: < 5.0E-07 Pa at 25 °C (ACD Labs)
Partition coefficient (log KOW)	(Q)SAR: C18 iso component: 6.62 (KOWWIN) C18 linear component: 6.70 (KOWWIN)	Experimental result: 8.00 (HPLC method)
Water solubility	Experimental result: 1.91E-02 mg/L at 20 °C, pH 5.4 - 5.6	Experimental result: < 0.1 mg/L at 20 °C