Diisopropyl adipate

Endpoint summary

Additional information

Justification for grouping of substances and read-across

The PFAE Linear (Polyfunctional Aliphatic Ester) category consists of 16 substances, well-defined mono-constituent substances as well as related UVCB substances, respectively with varying fatty alcohol chain lengths and branching. The distinguishing feature of this category of chemicals is that they are diester derivatives of common dicarboxylic acids: namely adipic (C6), azelaic (C9) and sebacic (C10) acids. The alcohol portion of the diesters generally falls in the C3-C20 carbon number range, including linear and branched, even and odd numbered alcohols. 

Carboxylic acid esters are generally produced by chemical reaction of an alcohol with an organic 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). Diesters are the final products of esterification of alcohols (e.g. octanol) with a dicarboxylic organic acid (e.g. adipic acid).

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 linear.

List of category members including CAS and molecular weight (range)

ID#	CAS	Chemical name	Molecular weight	Carbon number in alcohol	Carbon number in acid	Substance type
1	6938-94-9 (a)	Diisopropyl adipate	230.3	C3 iso	C6	M
2	105-99-7	Dibutyl adipate	258.35	C4	C6	M
3	110-33-8	Dihexyl adipate	314.46	C6	C6	M
4	1330-86-5	Diisooctyl adipate	370.57	C8 iso	C6	M
5	123-79-5 (b)	Dioctyl adipate	370.57	C8	C6	M
6	103-23-1	Bis(2-ethylhexyl) adipate / DEHA	370.64	C8 branched	C6	M
7	68515-75-3	Hexanedioic acid, di-C7-9-branched and linear alkyl esters	342.52-398.63	C7-C9 linear and branched	C6	UCVB
8	33703-08-1	Diisononyl adipate	398.63	C9 iso	C6	UVCB
9	16958-92-2	Bis(tridecyl) adipate	454.73-566.94	C11-C15	C6	UVCB
10	85117-94-8	Bis(2-octyldodecyl) adipate	707.2	C20 branched	C6	M
11	103-24-2	Bis(2-ethylhexyl) azelate	412.65	C8 branched	C9	M
12	897626-46-9	Bis(2-octyldodecyl) azelate	749.28	C20 branched	C9	M
13	7491-02-3	Diisopropyl sebacate	286.41	C3 iso	C10	M
14	109-43-3	Dibutyl sebacate	314.47	C4	C10	M
15	122-62-3	Bis(2-ethylhexyl) sebacate	426.69	C8 branched	C10	M
16	69275-01-0	Bis(2-octyldodecyl) sebacate	763.34	C20 branched	C10	M

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

(b) Substances that are either already registered under REACh or not subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in normal font.

Category specific similarities/trends:

Grouping of substances into this category is based on:

(1) common functional groups: all members of the category PFAE linear are diester derivatives of the common saturated diacids: namely adipic (C6), azelaic (C9) and sebacic (C10) acid. The alcohol portion of the diesters generally falls in the C3-C20 carbon number range, including linear and branched alcohols; 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 dicarboxylic acid. Esterification is, in principle, a reversible reaction (hydrolysis). Thus, the fatty alcohol and dicarboxylic acid moieties are simultaneously precursors and breakdown products of the category members. For the purpose of grouping of substances, enzymatic hydrolysis in the gastrointestinal tract and/or liver is identified as the biological process, by which the breakdown of the category members result in structurally similar chemicals (Takahashi et al., 1981). Following hydrolysis, the fatty alcohol is, in general, enzymatically oxidized to the corresponding carboxylic acid, which can be further degraded by β-oxidation. Alternative oxidation pathways (alpha- and omega-oxidation) are available and are relevant for degradation of branched fatty acids (for further information please see chapter 7.1 of the technical dossier); 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 (a) physicochemical, (b) environmental fate, ecotoxicological and (c) toxicological properties. For those individual endpoints showing a trend (d), the pattern in the changing of potency is clearly and expectedly related to the carbon chain length of the dicarboxylic acid and the carbon chain length and/or branching of the alcohol.

a) Physicochemical properties:

The molecular weight of the category members ranges from 230 g/mol (CAS 6938-94-9, Diisopropyl adipate) to 763 g/mol (CAS 69275-01-0, Bis(2-octyldodecyl) azelate). Category substances are characterized with low melting points: they are liquid under ambient conditions. All category substances decompose before boiling and they are non-volatile. Calculated vapour pressures exceed 0.01 Pa (at 20 °C) only for two compounds with the lowest molecular weight: Diisopropyl adipate (MW = 230 g/mol, VP = 0.26 Pa) and Dibutyl adipate (MW = 258 g/mol, VP = 0.02 Pa – both experimental and calculated). The same two compounds are soluble in amounts exceeding 10 mg/L (i.e: 180 mg/L and 35 mg/L, respectively). The remaining substances with <10 mg/L are very poorly soluble or insoluble in water. The calculated octanol/water partition coefficient increases with molecular weight accordingly: from log Pow = 3.2 (Diisopropyl adipate) to log Pow = 21.4 (Bis(2-octyldodecyl) azelate).

b) Environmental fate and ecotoxicological properties:

All members of the category are readily biodegradable according to the OECD criteria. Therefore, the category members will not be persistent in the environment. The abiotic degradation via hydrolysis is not considered to be a relevant degradation pathway in the environment. Relatively good water soluble (approximately > 10 mg/L) members of the category exhibit log Kow values < 5. Substances with log Kow < 5 are expected to distribute in the aquatic, sediment and soil compartment. In contrast, substances with log Kow values > 5, will mainly distribute into soil and sediment exclusively. Nevertheless, since all members of the category are readily biodegradable, they will not be persistent in the terrestrial environment. Based on the rapid environmental biodegradation and metabolisation via enzymatic hydrolysis, relevant uptake and bioaccumulation in aquatic organisms is not expected. Enzymatic breakdown will initially lead to the free dicarboxylic acid and the free alcohol. From literature it is well known, that these hydrolysis products will be metabolised and excreted in fish effectively (see expert statement on bioaccumulation chapter 5.3 of the technical dossier). This is supported by low calculated BCF values calculated for all category members (BCF < 1 - 29 L/kg ww; BCFBAF v3.01; Arnot-Gobas, including biotransformation, upper trophic).

Based on the experimental data, the majority of category members exhibit no acute or chronic toxicity to aquatic organisms. Only two “water soluble” esters with Adipic acid (C6) as dicarboxylic acid component and short chain alcohols, exhibit toxic or harmful effects (CAS 105-99-7, Dibutyl adipate and CAS 6938-94-9, Diisopropyl adipate). Due to their rapid biodegradability and rapid metabolization, no adverse effects are anticipated in sediment and soil organisms. This assumption is supported by three short term tests to earthworm for Bis(2-ethylhexyl) adipate (CAS 103-23-1), Dibutyl adipate (CAS 105-99-7) and Bis(tridecyl) adipate (CAS 16958-92-2) showing LC50 values above 800 mg/kg soil dw.

c) Toxicological properties:

The toxicological properties show that all category members have similar toxicokinetic behaviour (enzymatic hydrolysis of the ester bond leading to the corresponding dicarboxylic acid and alcohol, then absorption and further metabolism to polar products that are excreted in the urine or exhalation as CO2).  There is consistently low toxicity among the category members which can be explained by the common metabolic fate of all aliphatic diesters, independent of the lengths of the dicarboxylic acid backbone (C6, C9 or C10) or the alcohol side chains (C3 to C20). Thus, considering all available evidence and expert judgement the category members showed no acute oral, dermal or inhalation toxicity, no skin irritation, eye irritation or sensitizing properties, no human hazard for systemic toxicity after repeated oral, inhalative and dermal exposure and are not mutagenic or clastogenic and have shown no relevant reproduction toxicity and have no effect on intrauterine development.

In order to avoid the need to test every substance for every endpoint, the category concept is applied for the assessment of environmental fate and environmental and human health hazards. Thus where applicable, environmental and human health effects are predicted from adequate and reliable data for source substance(s) within the group by interpolation to the target substances in the group (read-across approach) applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. In particular, for each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across.

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

Environmental fate parameter of the PFAE linear category

ID#	CAS	Biodegradation: screening tests	BCF/BAF [L/kg]	Adsorption [log Koc]
1	6938-94-9 (a)	RA: CAS 105-99-7	6.3/6.3 (Arnot-Gobas)	1.87 (MCI)
2	105-99-7	readily biodegradable	12.6/12.6 (Arnot-Gobas)	2.54 (MCI)
3	110-33-8	readily biodegradable	28.7/28.7 (Arnot-Gobas)	3.58 (MCI)
4	1330-86-5	readily biodegradable	4.8/5.8 (Arnot-Gobas)	4.48 (MCI)
5	123-79-5 (b)	readily biodegradable	--	4.63 (MCI)
6	103-23-1	readily biodegradable	27/-- (Experimental result)	--
7	68515-75-3	--	--	--
8	33703-08-1	--	--	--
9	16958-92-2	readily biodegradable	0.9/0.9 (Arnot-Gobas)	> 5 (MCI)
10	85117-94-8	--	--	--
11	103-24-2	readily biodegradable	1.3/1.9 (Arnot-Gobas)	> 5 (MCI)
12	897626-46-9	readily biodegradable	0.9/0.9 (Arnot-Gobas)	> 5 (MCI)
13	7491-02-3	readily biodegradable	16.9/16.9 (Arnot-Gobas)	2.91 (MCI)
14	109-43-3	RA: CAS 122-62-3 RA: CAS 7491-02-3	28.7/28.7 (Arnot-Gobas)	3.59 (MCI)
15	122-62-3	readily biodegradable	6.7/6.7 (Arnot-Gobas)	5.6 (MCI)
16	69275-01-0	readily biodegradable	--	--

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

(b) Substances that are either already registered under REACh or not subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in normal font.

Discussion

Partitioning of substances into the different environmental compartments depends mainly on their physico-chemical properties. All members of the category are readily biodegradable according to the OECD criteria; hence they will not be persistent in the environment. Similarly since all substances are not likely to be present in the atmosphere due to their low vapour pressure (<1 Pa), indirect photolysis is not to be expected. Abiotic hydrolysis is not relevant, since all members of the PFAE linear category are readily biodegradable and thus expected to be eliminated through rapid biodegradation in natural waters. Additionally, estimated rates of hydrolysis are very low.

The varying chain-lengths of the acid backbone/ alcohol side chains, will ultimately influence environmental distribution of the category member within the environment compartment. The lower chain length members are more water soluble and exhibit log Pow values <5. These substances are expected to distribute in the aquatic, sediment and soil compartment. In contrast, substances with longer chain lengths and a corresponding high log Pow value (>5), will mainly distribute into soil and sediment exclusively. However, due to their ready biodegradability, all members of the category will not be persistent in the environment. Based on the rapid environmental biodegradation and metabolisation via enzymatic hydrolysis, relevant uptake and bioaccumulation in aquatic organisms is not expected. Enzymatic breakdown will initially lead to the free dicarboxylic acid and the free alcohol. From literature it is well known, that these hydrolysis products will be metabolised and excreted in fish effectively (for detailed information please see chapter 5.3 of technical dossiers). This is supported by low calculated BCF values calculated for all category members (BCF <1 - 29 L/kg ww; BCFBAF v3.01; Arnot-Gobas, including biotransformation, upper trophic).

Evaporation into air and the transport through the atmospheric compartment is not expected since the category members are not volatile based on the low vapour pressure (VP: <1 Pa).

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