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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).

Aquatic toxicity of the PFAE linear category

CAS

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

6938-94-9 (a)

RA: CAS 105-99-7

LC50 = 37.4 mg/L (RL3)*

Waiving

RA: CAS 105-99-7

EC50 = 31 mg/L (RL3)*

Waiving

RA: CAS 105-99-7

EC50 = 41 mg/L (RL3)*

RA: CAS 105-99-7

105-99-7

LC50 (96h) = 3.64 mg/L (measured)

Waiving

EC50 = 16.6 mg/L**

(Q)SAR = 1.61 mg/L

Waiving

EC50 (72h) = 5.16 mg/L (measured)

EC10 > 10000 mg/L

110-33-8

LC50 (96h) > 1000 mg/L*

Waiving

EC50 (48h) > 0.099 mg/L (measured)*

Waiving

EC50(72h) > 0.0094 mg/L (measured)*

RA: CAS 105-99-7

1330-86-5

RA: CAS 103-23-1

RA: CAS 123-79-5

RA: 33703-08-1

Waiving

RA: CAS 103-23-1

RA: 33703-08-1

RA: CAS 103-23-1

RA: 33703-08-1

RA: CAS 103-23-1

RA: 33703-08-1

Waiving

123-79-5 (b)

LC50 (96h) = 5500 mg/L*

-

-

-

-

EC10 (16h) > 1000 mg/L*

103-23-1

LC50 (96h) > 45 mg/L*

-

EC50 (48h) > 48 mg/L (measured)*

NOEC (21d) = 14 mg/L*

EC50 (72h) > 46 mg/L (measured)*

NOEC > 350 mg/L*

68515-75-3

-

-

-

-

-

-

33703-08-1

LC50 (96h) > 500 mg/L*

-

EC50 (48h) > 100 mg/L*

NOEC (21d) ≥ 0.1008 mg/L (measured)*

EC50 (72h) > 100 mg/L*

EC20 (0.5h) > 1000 mg/L*

16958-92-2

LC50 (96h) > 5000 mg/L

Waiving

Experimental study ongoing

Experimental study ongoing

EL10 (72h) > 13 g/L*

EC10 (3h) > 13 g/L*

85117-94-8

-

-

-

-

-

-

103-24-2

LC50 (96h) > 10000 mg/L*

Waiving

EC50 (48h) > 0.0931 mg/L (measured)*

NOEC (21d) ≥ 0.0637 mg/L (measured)*

EC50 (72h) > 0.0845 mg/L (measured)*

EC10 (16h) > 10000 mg/L *

897626-46-9

RA: CAS 69275-01-0
RA: CAS 103-24-2

Waiving

EC50 (48h) > 100 mg/L*

RA: CAS 103-24-2

EC50 (72h) > 100 mg/L*

EC50 (3h) > 1000 mg/L*

7491-02-3

RA: CAS 109-43-3

Waiving

EC50 (48h) > 8 mg/L*

Waiving

EC50 (72h) > 15.8 mg/L*

Waiving

109-43-3

LC50 (96h) > 10000 mg/L*

Waiving

RA: CAS 122-62-3

Waiving

RA: CAS 122-62-3

Waiving

122-62-3

LC50 (96h) > 1000 mg/L*

Waiving

EC50 (48h) > 1000 mg/L*

Waiving

EC50 (72h) > 1000 mg/L*

Waiving

69275-01-0

LC50 (96h) > 100 mg/L

-

-

-

-

-

*indicates that no effects are observed up the limit of water solubility of this substance

(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

The PFAE linear is a robust category with sufficient experimental data collectively covering acid carbon numbers from C6 to C10 and total carbon numbers ranging from C10 to C38. Short-term aquatic toxicity data is available for all trophic levels within the PFAE linear category. Long-term data is available for aquatic invertebrates and algae. The read across approach used for the aquatic toxicity is performed under consideration for the acid chain length in particular, i.e. read across is only performed within the Adipic acid ester (C6), the Azelaic acid ester (C9) and Sebaic acid ester (C10). Furthermore, since only the structurally closest source substance to the target substance is/are chosen for read across, the PFAE linear category presents the most profound overview on the aquatic toxicity of linear polyfunctional aliphatic esters so far.

Based on the experimental data, the majority of category members exhibit no acute and chronic toxicity to aquatic organisms, up to the limit of water solubility. Only two “water soluble” esters with Adipic acid (C6) as dicarboxylic acid component and short chain alcohols, exhibit ecotoxicolgical effects (CAS 105-99-7, Dibutyl adipate and CAS 6938-94-9, Diisopropyl adipate). Nevertheless, based on the current data, which is considered adequate for an accurate chemical safety assessment of the category, no category member is currently classified for environmental effects according to the 2nd ATP of the Regulation (EC) No.1272/2008 (CLP).

No effect on microbial respiration or growth occurred for any member of the category. Thus disturbances in sewage treatment plants are not anticipated for any member of the category.

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