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Key value for chemical safety assessment

Additional information

Justification for grouping of substances and read-across

There are no data available on toxicity after repeated exposure of Fatty acids, C18-unsatd., dimers, 2-ethylhexyl esters (CAS 68334-05-4). In order to fulfil the standard information requirements set out in Annex X, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances was conducted.

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 for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances and/or common chemical precursors or similar hydrolysis/breakdown products (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 predicted as similar provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity and/or common chemical precursors or similar hydrolysis/breakdown products.

The read-across is either based on structural similarity or on the metabolism of Fatty acids, C18-unsatd., dimers, 2-ethylhexyl esters (CAS 68334-05-4), in particular on the fact that the substance undergoes enzymatic ester hydrolysis resulting in the formation of Fatty acids, C18-unsatd., dimers and 2-ethylhexanol. A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Overview of genetic toxicity

CAS

Chemical name

Genetic Toxicity in vitro: gene mutation in bacteria

Genetic Toxicity in vitro: cytogenicity in mammalian cells

Genetic Toxicity in vitro: gene mutation in mammalian cells

Genetic toxicity in vivo

68334-05-4 (a)

Fatty acids, C18-unsatd., dimers, 2-ethylhexyl esters

RA: CAS 68783-41-5

RA: CAS 104-76-7

RA: CAS 68783-41-5

RA: CAS 68783-41-5

RA: CAS 104-76-7

RA: CAS 104-76-7

61788-89-4

Fatty acids, C18-

unsatd., dimers

Experimental result:
not mutagenic

Experimental result:
not clastogenic

Experimental result:
not mutagenic

--

104-76-7 (b)

2-ethylhexanol

Experimental result:
not mutagenic

--

Experimental result:
not mutagenic

Experimental result:
not clastogenic

(a) The substance subject to registration is indicated in bold font.

(b) Reference (read-across) substances are indicated in normal font. Lack of data for a given endpoint is indicated by “--“.

The above mentioned substances are considered to be similar on the basis of structural similarity and common chemical precursors and common hydrolysis/breakdown products. The available endpoint information is used to predict the same endpoints for Fatty acids, C18-unsatd., dimers, 2-ethylhexyl esters (CAS 68334-05-4). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

 

Discussion

Genetic toxicity (mutagenicity) in bacteria in vitro

CAS 61788-89-4

An Ames test was performed with the read across substance fatty acids, C18 unsatd., dimers (CAS No. 61788-89-4) equivalent to OECD guideline 471 in S. typhimurium strains TA 1535, TA 1537, TA 98 and TA 100 with and without metabolic activation by rat liver S9-mix (, 1993). The cells were treated with 50, 150, 500, 1500, 5000 µg and 1000, 2000, 3000, 4000, 5000 µg of the test substance/plate. No cytotoxicity was observed and as some significant increases seen in revertant colonies were irreproducible, it is concluded that under the conditions of this study fatty acids, C18 unsatd., dimers did not induce mutations in Salmonella typhimurium strains TA1535, TA1537, TA100 and TA98.

CAS 104-76-7

A Salmonella/mammalian microsome plate incorporation assay was conducted with 2-ethylhexan-1-ol (CAS No. 104-76-7) according to the procedures described by Ames et al. (1975) using strains TA 98, 100, 1535, 1537 and 1538 (Kirby, 1983). Test substance concentrations of 0, 0.01, 0.05, 0.25, 0.5 and 1.0 µL/plate diluted in DMSO were tested in duplicates in the presence and absence of metabolic activation. Preliminary toxicity studies using Salmonella typhimurium tester strain TA-100 indicated that 2-ethylhexanol was cytotoxic at concentrations ≥ 1 µL/plate. Under the given test conditions no increase in the number of revertant colonies at any dose level was observed in the tested Salmonella strains.

Genetic toxicity (cytogenicity) in mammalian cells in vitro

CAS 61788-89-4

A chromosomal aberration assay in human blood lymphocytes from male donors was performed with the read across substance fatty acids, C18 unsatd., dimers (CAS No. 61788-89-4) according to OECD guideline 473 (Akhurst, 1993). The cells were treated without S-9 mix with 37.5, 75, 150 and 300 µg/mL, with S-9 mix with 75, 150 and 300 µg/mL and harvested after 18h. Additionally the cells were treated without S-9 mix with 9.4, 18.8, 37.5, 75, 150 and 300 µg/mL, with S-9 mix with 18.8, 37.5, 75, 150 and 300 µg/mL and harvested after 32h. Cytotoxicity was observed without metabolic activation at 300 µg/ml (18 h) and 150 µg/ml (32 h). The number of revertant cells was not increased by the treatment and therefore fatty acids, C18 unsatd., dimers were determined to be non-clastogenic.

Genetic toxicity (mutagenicity) in mammalian cells in vitro

CAS 61788-89-4

A mammalian cell gene mutation assay with mouse lymphoma L5178Y cells was performed with the read across substance fatty acids, C18 unsatd., dimers (CAS No. 61788-89-4) according to OECD guideline 476 (Adams, 1993). The cells were treated with 25, 50, 100, 150, 225, 250, 275 and 300 µg/mL with and without metabolic activation for 3h. After an expression time of 48h and a selection time of 12 days, survival and mutant frequency were determined. The test substance was cytotoxic with (≥ 150µg/mL) and without metabolic activation (≥300µg/mL) but showed no influence on the mutation rate of mouse lymphoma L5178Y cells.

CAS 104-76-7

An in vitro L5178Y TK+/- mouse lymphoma mutagenicity assay was performed with 2-ethylhexan-1-ol (CAS No. 104-76-7) according to the procedures described by Clive and Spector (Kirby, 1983). Test substance concentrations in the range of 0.013 µL/mL to 1.0 µL/mL were tested in the presence and absence of metabolic activation in mouse lymphoma L5178Y cells. Preliminary toxicity tests with ethylhexanol demonstrated complete toxicity at concentrations ≥ 1.0 µl/mL. None of the cultures treated with ethylhexanol at any dose level, exhibited mutation frequencies that were significantly greater (twofold greater than background) than that of the corresponding ethanol solvent control. The positive control chemicals, on the other hand, demonstrated significant increases in mutation frequencies for both S9 activated and non-activated cultures. These results indicate that under the experimental conditions, ethylhexanol was not mutagenic in the L5178Y TK+/- mammalian mutagenicity assay.

Genetic toxicity in vivo

CAS 104-76-7

An in vivo cytogenetic assay was performed with 2-ethylhexan-1-ol (CAS No. 104-76-7) in rats similar to OECD Guideline 475 (Putman, 1983). Groups of 5 male Fischer 344 rats received daily oral gavage doses of 0, 0.21, 0.07 and 0.02 mL/kg bw/day on 5 consecutive days diluted in corn oil. A triethylenemelamine (TEM)-positive control group received a single intraperitoneal injection of 0.5 mg/kg TEM one day prior to sacrifice.

There were no overt toxicological signs in any test or control animal during the five-day treatment period. The number of cells with chromosomal aberrations for 2-ethylhexanol treatment groups was not increased relative to the corn oil control group. In addition, there were no apparent changes in the percentage of aneuploid cells or mitotic index. The number of chromatid gaps was increased; however, since the genetic significance of chromatid gaps is not clearly understood, they were not included in determination of number of metaphases with aberrations or total number of cells with one or more aberrations. The positive controls demonstrated severe damage, with approximately 26% of all cells analysed containing one or more aberrations. Based on the results of this study, it is concluded that under the conditions of the test, 2-ethylhexanol did not induce detectable chromosomal damage after oral administration.

Overall conclusion for genetic toxicity

No genetic toxicity studies are available with Fatty acids, C18-unsatd., dimers, 2-ethylhexyl esters itself, but several studies are available, which were performed with appropriate analogue substances. Neither results from in vitro gene mutation tests in bacteriae and mammalian cells nor results from cytogenicity tests in mammalian cells and in vivo revealed any mutagenic or clastogenic effects. Based on the available data Fatty acids, C18-unsatd., dimers, 2-ethylhexyl esters is considered to be not mutagenic in vitro and not clastogenic in vitro and in vivo.


Justification for selection of genetic toxicity endpoint
Hazard assessment is conducted by means of read-across from structural analogues/surrogates. No study was selected, since all available in vitro genetic toxicity studies were negative. All available studies are adequate and reliable based on the identified similarities in structure and intrinsic properties between source and target substances and overall quality assessment (refer to the endpoint discussion for further details).

Short description of key information:
Read across from fatty acids, C18 unsatd., dimers hydrogenated (CAS No. 61788-89-4):
Ames Test: negative; in vitro chromosome aberration assay: negative; in vitro mouse lymphoma assay: negative
Read across from 2-ethylhexan-1-ol (CAS No. 104-76-7):
Ames Test: negative; in vitro mouse lymphoma assay: negative; in vivo chromosome aberration test in rats: negative;

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Upon systemic uptake Fatty acids, C18-unsatd., dimers, 2-ethylhexyl esters will be cleaved to dimeric fatty acids on the one and 2 -ethylhexanol on the other hand. None of the genotoxicity studies available for both metabolites gave indications for a genotoxic potential. Therefore, the available data on skin sensitisation do not meet the classification criteria according to DSD (67/548/EEC) or CLP (1272/2008/EC), and are therefore conclusive but not sufficient for classification.