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Toxicity to terrestrial plants

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One long-term study conducted with the earthworm Eisenia fetida, according to the OECD Guideline 222, is available for the subcategory 2 member Fatty acids, C18-unsaturated, dimers, “Dimer” (CAS No. 61788-89-4). As no effects occurred in this study, the members of the subcategory 2 predominantly oligomers, are considered as not harmful to terrestrial organisms and no further testing on terrestrial plants is needed. According to Article 13 "General Requirements for Generation of Information on Intrinsic Properties of substances", Information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Having regard 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, whereby substances may be considered as a category provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity. The long term toxicity on soil macroorganisms in accordance to Regulation (EC) No 1907/2006, Annex IX 9.4, Effects on terrestrial organisms, was tested on the read across substance, Fatty acids, C18-unsaturated, dimers (CAS No. 61788-89-4). As UVCB substances derived from natural sources, both Fatty acids, C18-unsaturated, dimers (CAS No. 61788-89-4) and Fatty acids, C18-unsaturated, dimers, hydrogenated (CAS No. 68783-41-5), as all members of this category are chemically similar, as they are all essentially a complex mixture of C16 - C18 or C18 unsaturated and saturated, branched and linear fatty acids with varying structural geometric isomers C16 -C18 unsaturated fatty acids. The key points that the members share are:

• Common origin of C16-18 unsaturated fatty acids

• Similar/overlapping structural features (no hydrolysable groups, all members have a homologous composition of fatty acids with a C16 - C18 carbon chain in diverse forms, that are susceptible to oxidation of metabolic process)

• Similar metabolic pathways (same ADME pathways of fatty acids, Absorbed fatty acids undergo rapid metabolisation (via ß- or ω-oxidation) and excretion either in the expired CO2 or as a hydroxylated or conjugated metabolite in the urine in the case of cyclic fatty acids)

• Similar physico-chemical properties (log Koc >5, the log Kow is judged to be > 4, the insolubility in water)

• Common properties for environmental fate & eco-toxicologcial profile of the two sub-categories (not readily biodegradable, no toxicological effects up to the water solubility limit for aquatic organisms)

• Common levels and mode of human health related effects

Please refer to IUCLID Chapter 6.3 for more details on the category justification for terrestrial toxicity and to section 13 for the complete category justification. The selection of fatty acids, C18-unsaturated, dimers (CAS No. 61788-89-4) as representative test substance for the sub-category “predominantly oligomers” was an iterative process of combination of different aspects: CAS No.71808-39-4 crude dimer, Fatty Acids, C16-18 & C-18 unsaturated, dimerised also contains monomers, which are acknowledged as being readily biodegradable. This is also reflected in the screening test for biodegradation (OECD 301B test) where CAS No. 71808-39-4 had a degradation value of 29.3 %. Thus, this substance is regarded as not suitable as a representative for the sub-category Dimerised Fatty Acids and its Derivatives “predominantly oligomers” which comprises of substances that reveal a potential persistence due to their lack of readily and inherent biodegradability. Trimers are expected to have a lower bioavailability when compared with dimers based on the molecular size (Lipinski rule of 5). They are also expected to have higher potential to adsorb to soil due to the increasing carbon chain length. Therefore, Fatty acids, C18-unsaturated, trimers (CAS No. 68937-90-6) was evaluated not to be the most suitable representative test substance for the sub-category “predominantly oligomers”. The only difference between the two remaining dimerized fatty acids, namely Fatty acids, C-18 unsaturated, dimers (CAS No. 61788-89-4) and Fatty acids, C-18 unsaturated, dimers, hydrogenated (CAS No. 68783-41-5) is there degree of saturation or hydrogenation, respectively. In fact, all substances are closely similar. Based on an evaluation conducted using the OECD Toolbox, the degree of saturation is estimated to not have any effect on the toxicity profile of C18 fatty acids. The profiles for C18 fatty acids containing 0, 1 or 2 double bonds are the same in terms of lack of structural alerts, toxic hazard classification by Cramer, aquatic toxicity mode of action by OASIS, aquatic toxicity classification by ECOSAR, etc. For the unsaturated fatty acids additional organic functional groups are indicated (allyl, alkene), but these are not coupled to any structural alerts for protein binding. Experimental data on the long-term toxicity of 16/18C fatty acids to daphnia seem to indicate that unsaturated fatty acids even have slightly higher toxic potential compared to the corresponding saturated fatty acids (MOE, 2008; MOE 2003, entered under IUCLID section 5.1). This observation could possibly be explained by the fact that additional steps are required for the β-oxidation process, when double bonds are present, and more energy is thus needed for the metabolism of unsaturated fatty acids (Berg, Tymoczko and Stryer, 2002). Based on this information, Fatty Acids, C16-18 and C-18, Unsaturated, Branched and Linear can be considered as a worst case read-across substance. Additionally, the production volume of the unsaturated form is much higher than the other members. Therefore, one can assume that the risk of any exposure would be highest here due to large production volumes. Based on all aspects discussed above, Fatty acids, C18-unsaturated, dimers, hydrogenated (CAS No. 68783-41-5) is considered as representative member of the sub-category 2 “predominantly oligomer”.

References:

Berg, J.M., Tymoczko, J.L. and Stryer, L. (2002) Biochemistry, 5th edition, W.H. Freeman and Company Lipinski et al. (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Adv. Drug Del. Rev., 2001, 46, 3-26. Ministry of the Environment, Government of Japan (2003). Daphnia magna, reproduction test by oleic acid. Food Research Laboratories. Report No. 14053. 2003-03-31 Ministry of the Environment, Government of Japan (2008). Daphnia, reproduction toxicity test for palmitic acid. Mitsubishi Chemical Safety Institute Ltd.,Laboratory. Report No. A050381. 2008-02-14.