Fatty acids, C8-10, mixed esters with adipic acid and trimethylolpropane

Endpoint summary

Additional information

Justification for grouping of substances and read-across

The category covers fatty acid polyesters of polyols (Trimethylolpropane (TMP) or Pentaerythritol (PE)) mixed with adipic acid. The category contains UVCB substances with fatty acid carbon chain lengths from C8-C18 (even-numbered, including linear saturated and unsaturated chains) building mono-, di-,tri- or higher esters with TMP or PE respectively in variable proportions.

Fatty acid esters are generally produced by chemical reaction of an alcohol (in this case Polyol e.g. Propylidynetrimethanol) with an organic fatty acid (e.g. oleic acid) in the presence of an acid catalyst (Radzi et al., 2005). The esterification reaction is started by the transfer of a proton from the acid catalyst to the acid to form an alkyloxonium ion. The carboxylic acid is protonated on its carbonyl oxygen followed by a nucleophilic addition of a molecule of the alcohol to the carbonyl carbon of the acid. An intermediate product is formed. This intermediate product loses a water molecule and proton to give an ester (Liu et al., 2006; Lilja et al., 2005; Gubicza et al., 2000; Zhao, 2000). The dicarboxylic acid adipic acid functions as a crosslinking agent forming diesters with polyols and this scaffold is esterified with fatty acids. Oligomeric structures with high molecular weights (MW>>500 g/mol) are thus built.

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, which includes the use of information from structurally related substances (grouping or read-across).

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 substances listed below are allocated to the category of PFAE mixed and branched.

PFAE mixed and branched category members include:

ID#	CAS	EC	Chemical Name	Fatty acids	Di-carboxylic acid (cross-link)	Polyol	MW
1	95912-89-3 (a)	306-085-3	Fatty acids, C8-10, mixed esters with adipic acid and trimethylol-propane	C8-C10	Adipic acid	TMP	512.78 – 995.46
2	91001-61-5	292-832-8	Fatty acids, C16-18 and C18-unsatd., mixed esters with adipic acid and trimethylol-propane	C16, C18, C18 unsatd,	Adipic acid	TMP	849.46 – 1444.31
3	-	921-836-0	Mixed esters of fatty acid C16 and C16-C18-unsatd. with adipic acid and pentaerythritol	C16, C16- C18 unsatd,	Adipic acid	PE	1081.72 – 1969.08
4	78-16-0 (b)	201-089-0	2-ethyl-2-[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate	C7	-	TMP	470.68

TMP = Propylidynetrimethanol / Trimethylolpropane; PE = Pentaerythritol

(a) Category members subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in bold font.

(b) Surrogate substances are either chemicals forming part of a related category of structurally similar fatty acid esters or precursors/breakdown products of category members (i.e. alcohol and fatty acid moieties). Available data on these substances are used for assessment of toxicological properties by read-across on the same basis of structural similarity and/or mechanistic reasoning as described below for the present category.

 

Category specific similarities/trends:

Grouping of substances into this category is based on:

(1) common functional groups: all members of the respective category are esters of a polyfunctional alcohol with one or more carboxylic fatty acid(s) chain(s) and adipic acid (cross-linking agent) resulting in oligomeric structures. The alcohol moiety is either TMP or PE, which only differ by one hydroxyl-group. The carboxylic acid moiety comprises on one hand fatty acids with carbon chain lengths from C8-C18 (even-numbered) including saturated and unsaturated chains and on the other hand the dicarboxylic acid adipic acid; both acid components are bound to the alcohol with the latter acting as cross-linking agent, resulting in polyol polyesters. These Polyol polyesters may have multiple ester linkages and may include mixed esters derived from different carbon-length fatty acid mixtures; and

(2) common precursors and the likelihood of common breakdown products via biological processes, which result in structurally similar chemicals: all members of the category result from esterification of the alcohol with the respective fatty acids and adipic acid. Esterification is, in principle, a reversible reaction (hydrolysis). Thus, in theory the alcohol, dicarboxylic acid and fatty acid moieties are simultaneously precursors and breakdown products of the category members. Taken into account the high MW resulting in a very complex structure, the high log Pow and the very limited water solubility absorption of the substance is highly unlikely for any category member. Enzymatic hydrolysis in the gastrointestinal tract and/or liver - usually identified as the biological process, by which the breakdown of esters takes place - is highly unlikely for PFAE mixed and branched category members. The category members have a complex structure consisting of mixed polyols linked with adipic acid that is not anticipated to fit into the binding pocket of e.g. pancreatic lipase which hydrolyses emulsified triacylglycerols in the diet. The ester bond is thus not available to catalytic center of the enzyme. (refer to Toxicokinetics for details);and

(3) constant pattern in the changing of the potency of the properties across the category: the available data show similarities and trends within the category in regard to physicochemical, environmental fate, ecotoxicological and toxicological properties. For those individual endpoints showing a trend, the pattern in the changing of potency is clearly and expectedly related to the length of the fatty acid chains and the degree of substitution of the polyol:

a) Physicochemical properties:

The molecular weight of the category members ranges from 512.77 to 1969.08 g/mol. This range represents structures completely esterified and cross linked with one adipic acid unit and is taken as the lower limit of molecular weight and size for the different substances. The physical appearance is related to the chain length of the fatty acid moiety, the degree of saturation and the number of ester bonds. All substances are liquid. All category members a non-volatile (vapour pressure: <0.01 Pa). The octanol/water partition coefficient increases with increasing fatty acid chain length and number of ester bonds, ranging from log Pow = 10.64 for the C8 TMP triester component for CAS 95912-89-3 to log Pow = 28.35 for the C16 PE tetraester component of EC 921-836-0 (calculated values). These are values for the smallest components of all substances in the category. As log Pow >10 exceeds the applicability domain for the (Q)SAR model, log Pow is >10 is given for all category members. The water solubility for all substances is <1 mg/L, for Fatty acids, C8-10, mixed esters with adipic acid and trimethylolpropane (CAS 95912‑89‑3) the water solubility is determined to be even lower (<0.05 mg/L).

b) Environmental fate and ecotoxicological properties:

Considering the low water solubility (<1 mg/L) and the potential for adsorption to organic soil and sediment particles (log Koc >5), the main compartments for environmental distribution are expected to be the soil and sediment. Nevertheless, persistency in these compartments is not expected since all members of the category are readily biodegradable and are thus expected to be eliminated in sewage treatment plants to a high extent. Release to surface waters, and thereby exposure of sediment, is very unlikely. Thus, the soil is expected to be the major compartment of concern. Nevertheless, the category members are expected to be metabolised by soil microorganisms. Evaporation into air and the transport through the atmosphere to other environmental compartments is not expected since the category members are not volatile based on the low vapour pressure (<0.01 Pa).

All members of the category did not show any effects on aquatic organisms in the available acute and chronic tests representing the category members up to the limit of water solubility. Moreover, bioaccumulation is assumed to be low since due to the molecular weight, size and structural complexity of the molecules of the category members absorption is not likely and ingested molecules will be excreted unchanged. 

c) Toxicological properties:

The toxicological properties show that all category members have similar toxicokinetic behaviour (very high MW, complex structure, limited water solubility, high log Pow) and that the constant pattern consists in a lack of potency change of properties across the category, explained by the very low potential for absorption and thus systemic availability of all mixed Polyol polyesters with adipic acid independently of the fatty acid chain length. Therefore, considering all available evidence and expert judgement no category member showed acute oral, dermal or inhalation toxicity, no skin irritation, eye irritation or sensitizing properties and are not mutagenic. Based on the very limited potential for absorption repeated dose toxicity, reproductive toxicity and developmental toxicity are not expected and further tests are not considered necessary.  

The available data allows for an accurate hazard and risk assessment of the category and the category concept is applied for the assessment of environmental fate, environmental and human health hazards. Thus where applicable, environmental and human health effects are predicted from adequate and reliable read across data within the group applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006.

A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Section 13).

Endpoint specific data matrix:

ID #	Identifier	Short term toxicity to fish	Long term toxicity to fish	Short term toxicity to aquatic invertebrates	Long term toxicity to aquatic invertebrates	Toxicity to aquatic algae	Toxicity to microorganisms
1	CAS 95912-89-3 (a)	Experimental result LL50 (96h) >1000 mg/L (nom., WAF)	waiving	Experimental result EL50 (48h) >100 mg/L (nom., WAF)	Experimental result NOEL (21d)    ≥1 mg/L(nom.)	Experimental result: EC50 (72h) >100 mg/L (nom., WAF) NOELR (72h) ≥100 mg/L(nom., WAF)	waiving RA: CAS EC 921-836-0
2	CAS 91001-61-5	Experimental result LL50 (48h) >110 mg/L (nom., WAF)	waiving	Experimental result EL50 (48h) >100 mg/L (nom., WAF)	Experimental result NOELR (21d)   ≥110 mg/L(nom., WAF)	Experimental result: EL50 (72h) >100 mg/L (nom. WAF) NOELR (72h) ≥100 mg/L (nom., WAF)	waiving RA: CAS EC 921-836-0
3	EC 921-836-0	Experimental result LC50 (96h) >100 mg/L (nom.)	waiving	Experimental result EC50 (48h) >100 mg/L (nom.)	RA: CAS 91001-61-5	Experimental result: EC50 (72h) >100 mg/L (nom.) NOEC (72h) ≥100 mg/L (nom.)	waiving Experimental result NOEC (14d) >19.94 mg/L (nom., toxicity control OECD 301B)

(a) Category members subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in bold font.

Only for these substances a full set of experimental results and/or read-across is given.

Aquatic toxicity

Short-term aquatic toxicity data is available for all trophic levels within the PFAE mixed and branched category. Long-term data is available for aquatic invertebrates and algae. Additionally, the exposure concentrations of aquatic organisms are very low, due to the low water solubility and the high potential of adsorption to organic soil and sediment particles (log Koc > 5). In both short and long term studies, generally, no effects occurred up to the water solubility limit.

Short term toxicity to fish for the PFAE mixed and branched category members

The assessment of short-term toxicity to fish is based on three valid, reliable studies available within the category. All members of the PFAE mixed and branched category show, no toxic effects up to the limit of water solubility. 

Long term toxicity to fish for the PFAE mixed and branched category members

There are no long-term fish studies available for the PFAE mixed and branched members. The chemical safety assessment according to Annex I of Regulation (EC) No 1907/2006 does not indicate the need to investigate further the long-term toxicity to fish. Thus, in accordance to Annex IX, column 2 no further long-term toxicity test to fish is proposed. Available short-term studies for fish, daphnia and algae, all indicate no potential for aquatic toxicity. Moreover, NOECs obtained from long-term aquatic invertebrates and algal growth studies are clearly above the limit of water solubility (< 1 mg/L).

Based on the short-term values, fish cannot be identified as the most sensitive taxonomic group. According to the “Guidance on information requirements and chemical safety assessment Chapter R.7b: Endpoint specific guidance, R.7.8.5.3” (ECHA, 2012), long-term testing of fish should only be conducted if it represents the most sensitive taxonomic group. The Guidance states that if invertebrates are likely to be more sensitive than fish and algae or the relative sensitivity of invertebrates cannot be predicted, long-term testing on Daphnia sp. should be preferred instead of fish.

Due to their ready biodegradability it is not likely that aquatic organisms will be exposed to the PFAE mixed and branched category members since they will be ultimately degraded in sewage treatment plants. Thus, based on the above mentioned results, it is unlikely that any substance within the category will exhibit chronic toxicity to fish up to the limit of water solubility. Hence, based on the information discussed and due to animal welfare reasons, no further long-term test with fish is proposed.

Short term toxicity to aquatic invertebrates for the PFAE mixed and branched category members

The assessment of short-term toxicity to aquatic invertebrates is based on six valid, reliable studies available for the category. All members of the PFAE mixed and branched category show, no toxic effects up to the limit of water solubility.

 

Long term toxicity to aquatic invertebrates for the PFAE mixed and branched category members

The assessment of long-term toxicity to aquatic invertebrates is based on two valid, reliable studies available for the category members Fatty acids, C8 -10, mixed esters with adipic acid and trimethylolpropane (CAS 95912-89-3) and Fatty acids, C16-18 and C18-unsatd., mixed esters with adipic acid and trimethylolpropane (CAS 91001 -61 -5). Based on these results all members of the PFAE mixed and branched category show, no toxic effects up to the limit of water solubility.

 

Toxicity to algae for the PFAE mixed and branched category members

The assessment of toxicity to algae is based on five valid, reliable studies available for the category. All members of the PFAE mixed and branched category show, no toxic effects up to the limit of water solubility.

 

Toxicity to microorganisms for the PFAE mixed and branched category members

There are no studies on toxicity to microorganisms available for the PFAE mixed and branched category members. However, in accordance with Annex VIII, column 2,9.1.4 of Regulation (EC) No. 1907/2006, activated sludge respiration inhibition testing is not required since the substance is highly insoluble in water.

Additionally, a substance can be assumed to be not inhibitory to aquatic microorganisms, if in the toxicity control of a ready biodegradation test, more than 35% degradation based on TOC removal occurred within 14 days (OECD guidance 301). For the category member Mixed esters of fatty acid C16 and C16-C18-unsatd. with adipic acid and pentaerythritol a biodegradation test according to OECD guideline 301B is available (Bizzaro and Limiroli, 2012), which includes a toxicity control containing of about 19.94 mg/L of test substance. The toxicity control attained 79% degradation after 14 days of incubation. Hence, the substance was not toxic to aquatic microorganisms in the toxicity control and the highest test concentration of 19.94 mg/L can be determined as NOEC.

This result combined with the ready biodegradability (69 – 84.7% biodegradation after 28 d) of all PFAE mixed and branched category members implies low toxicity to activated sludge microorganisms.

General conclusion

No effects on aquatic organisms were observed in the short-term studies available for three trophic levels (fish, daphnia, algae) or long-term studies available for aquatic invertebrates and algae, up to the limit of water solubility (< 1 mg/L) for the PFAE mixed and branched category members. The PFAE mixed and branched category is a robust category with reliable data which allows a conclusive overview about the overall ecotoxicity profile of all category members. In the case of read-across, the best suited read-across was chosen.

Nevertheless, as it can be seen in the data matrix of the category justification in IUCLID Section 13, all reliable data in the category support the hazard assessment of each category member by showing a consistent pattern of results.

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within CSR.