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Key value for chemical safety assessment

Additional information

Justification for read-across approach

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 (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 toxicological properties may be predicted from data for reference substance(s) by interpolation to other substances on the basis of structural similarity, the following substances are selected as reference substances for assessment of toxicological endpoints, for which information gaps are identified.

Therefore, the analogue approach endpoint information for

-         acute toxicity via inhalation forFatty acids, C5-10, esters with pentaerythritol (CAS 68424-31-7) and Fatty acids, C5-9, mixed esters with dipentaerythritol and pentaerythritol (CAS 85536-35-2)

-         the subchronic oral repeated dose toxicity forpentanoic acid, mixed esters with pentaerythritol, isopentanoic and isononanoic acid (CAS No. 146289-36-3);

-         the genetic toxicity information for pentaerythritol tetravalerate (CAS 15834-04-5) and Fatty acids, C5-10, esters with pentaerythritol (CAS 68424-31-7)

-         and information for developmental toxicity for Fatty acids C8-10, mixed esteres with diPE, isooctanoic acid, PE and triPe (CAS 189200-42-8) and Trimethylolpropane Caprylate Caprate (CAS 11138-60-6)

are used to predict the same endpoints for dipentaerythritol ester of nC5/iC9 acids (CAS No. 647028-25-9). The analogue substances are considered to be similar on the basis of structural similarity and similar properties and/or activities.

The structural similarities are based on:

(1) common functional groups: The source (reference) and target substances are all characterised by ester bond(s) between a polyol and one or more carboxylic fatty acid chains. The polyol moiety of the source and target substances comprises structurally related molecules: pentaerythritol, di-pentaerythritol, tri-pentaerythritol and trimethylolpropane, all of which share a neopentane backbone as underlying common molecular structure. The fatty acid moieties comprise saturated linear and/or branched chains of 5 to 10 C-atoms length.

(2) common precursors and the likelihood of common breakdown products via biological processes, which result in structurally similar chemicals. The source and target substances are all UVCB substances, except pentaerythritol tetravalerate (CAS 15834-04-5) which is a monoconstituent, produced by esterification of the corresponding polyol and fatty acid mixtures. Ester bond formation is in principle a reversible reaction (hydrolysis). A slow stepwise hydrolysis of the ester bonds by gastrointestinal enzymes is identified as the biological process, by which the breakdown of the source and target substances results in structurally similar chemicals: the respective polyol and fatty acid moieties as stated above.

(3) a constant pattern in the changing of the potency of the properties between source and target substances: For the source and target substances, the constant pattern is characterised by similarities in the potency of properties. The available data on the target and the source substances show similarities in physico-chemical properties, in particular the high molecular weight of the substances. The molecular weight of Dipentaerythritol ester of nC5/iC9 acids ranges from 983 to 1096 g/mol and molecular weights of the target substances ranges from 472.62 to 1039.5 g/mol. In addition, the octanol/water partition coefficient of Dipentaerythritol ester of nC5/iC9 acids is > 6.2 (Lumsden, 2000) and available data on the calculated partition coefficients of the target substances are in the range of 6.74 to 13.59 (as published in respective dossiers on ECHA homepage). Furthermore, the target substance has a low water solubility (see toxicokinetics) and calculated water solubility of the source substances is considered to be low as well (Lumsden, 2000).

The available data on toxicological properties indicate that the source and target substances have a similar toxicokinetic behaviour; especially they are assumed to be slowly hydrolyses (see toxicokinetics). In addition, a low acute oral toxicity was seen for the source substance as well as for Trimethylolpropane Caprylate Caprate and Fatty acids, C5-10, esters with pentaerythritol (as published in respective dossiers on ECHA homepage). A low acute inhalation toxicity for Fatty acids, C5-9, mixed esters with dipentaerythritol and pentaerythritol and Fatty acids, C5-10, esters with pentaerythritol was observed as well (Parr-Dobranski, 1994a,b). Dipentaerythritol ester of nC5/iC9 acids is not skin or eye irritating and have not shown sensitising properties (Allen, 1999a,b,c) and the same is true for the source substances Fatty acids, C5-10, esters with pentaerythritol and Trimethylolpropane Caprylate Caprate (as published in respective dossiers on ECHA homepage). A low toxicity after repeated oral exposure (NOAEL > 1000 mg/kg bw/day) were observed for the source substance and for Fatty acids, C5-10, esters with pentaerythritol (Jones, 2000; Brammer, 1993) and for pentanoic acid, mixed esters with pentaerythritol, isopentanoic and isononanoic acid (NOAEL = 300 mg/kg bw/day; Müller, 1998). In addition, the available data on genotoxicity show that Dipentaerythritol ester of nC5/iC9 acids and the target substance Trimethylolpropane Caprylate Caprate are not genotoxic in the bacterial reverse mutation assay or clastogenic (Thompson, 1992; Wright, 2000; as published in respective dossier on ECHA homepage) and the source substance pentaerythritol tetravalerate did not show genotoxicity in a mammalian cell gene mutation assay (Verspeek-Rip, 2010). The target substance, Fatty acids, C5-10, esters with pentaerythritol did not show clastogenic properties in vivo as well (Griffiths, 1992) and no effect on intrauterine development was seen for Trimethylolpropane Caprylate Caprate and Fatty acids C8-10, mixed esteres with diPE, isooctanoic acid, PE and triPe.

In summary, all available data on the source and target substances show that the constant pattern is characterised by a lack of potency of properties.

In order to avoid the need to test Dipentaerythritol ester of nC5/iC9 acids for every endpoint, the analogue concept (read-across approach) is applied for the assessment of human health hazards. Thus where applicable, human health effects are predicted from adequate and reliable data for the reference substances by interpolation to Dipentaerythritol ester of nC5/iC9 acids 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) as well as in the Chemical Safety Report.

In vitro

A bacterial gene mutation assay (Ames test) was performed with Dipentaerythritol ester of nC5/iC9 acids following OECD guideline 471 and in compliance with GLP. The tested strain were Salmonella typhimurium TA 98, TA 100, TA 1535, TA 1537 and E. coli WP2 uvrA (Thompson, 1992).

The test concentrations for the main study were determined in a preliminary toxicity study with and without metabolic activation at concentrations from 0.15 up to 5000 µg/plate in the strains TA 100 and E. coli WP2 uvrA. The first and second experiment of the main study were performed each in triplicates according to the plate incorporation procedure at concentrations up to 5000 µg/plate (vehicle: acetone) with and without a metabolic activation system (Aroclor 1254-induced rat liver S9-mix). Cytotoxicity was determined by inspection of the bacterial background lawn.

The included positive and negative controls in the experiments showed the expected results and were therefore considered as valid. No increase in the number of revertant colonies was noted in any of the bacterial strains, with and without metabolic activation system. At 5000 µg/plate an oily precipitate was observed in all tested strains. No cytotoxicity was observed up to the highest, precipitating dose.

Under the conditions of this study, the test substance did not induce mutations in the bacterial mutation tests in the absence and presence of a metabolic activation system in any of the strains tested.

An in vitro mammalian chromosome aberration test was conducted with Dipentaerythritol ester of nC5/iC9 acids in accordance with OECD guideline 473 under GLP conditions (Wright, 2000).

The induction of structural chromosome aberrations was evaluated in human lymphocytes in vitro incubated for 4 h with and without metabolic activation system and 20 h without metabolic activation system (S9-mix from rats treated with Aroclor 1245). Concentrations of 39.06-5000 µg/mL (4 h incubation, with and without S9-mix) and 156.25-5000 µg/mL (20 h incubation, without S9-mix) of the test substance were applied. The vehicle used in the testing was acetone. Cytotoxicity was evaluated calculating the mitotic index of 2000 cells and polyploidy was checked.

There was a cloudy appearance of the test material at all concentrations in both treatment groups after 4 h exposure. The negative and positive controls showed the expected results and were within the range of historical control data. No cytotoxicity was observed up to the highest tested concentration. No increase in the incidence of chromosome aberrations was observed under the conditions of the study.

Under the conditions of the study, the test substance did not show clastogenic activity in this chromosomal aberration test performed in human lymphocytes in vitro.

Available data on the vitro mammalian cell gene mutation properties of the structural surrogates Pentaerythritol tetravalerate was considered for read-across and assessment was conducted based on an analogue approach.

An in vitro mammalian cell gene mutation assay was conducted with Pentaerythritol tetravalerate according to OECD guideline 476 under GLP conditions (Verspeek-Rip, 2010).

Gene mutations in the thymidine kinase locus were investigated in L5178Y mouse lymphoma cells in the presence and absence of a metabolic activation system (S9-mix from rats treated with a combination of phenobarbital and β-naphtoflavone) in two independent experiments at concentrations of 0.03, 0.1, 0.3, 1, 3, 10, 33 and 100 µg/mL of the test material (in DMSO). Concentrations of the second experiment without metabolic activation included 200 and 250 µg/mL instead of the concentration 0.03 µg/mL.

The vehicle and positive controls in the study showed the expected results and were within the range of historical control data. No cytotoxicity was observed up to the precipitating concentration of 100 µg/mL and up to 250 µg/mL. There was no significant increase in the number of forward mutations at the thymidine kinase locus of L5178Y mouse lymphoma cells treated with the test material, neither in the presence nor in the absence of a metabolic activation system.

Under the conditions of the study, the test substance Pentaerythritol tetravalerate (CAS No. 15834-04-5) did not show gene mutation activity in this test performed in L5178Y mouse lymphoma cells in vitro.

In summary, the test substance Dipentaerythritol ester of nC5/iC9 acids and the structural surrogate Pentaerythritol tetravalerate showed no genetic toxicity in vitro in different test systems.

In vivo

An in vivo micronucleus assay of the structural analogue the Fatty acids, C5-10, esters with pentaerythritol (CAS No. 68424-31-7) in mice was carried out according to OECD guideline 474 under GLP conditions (Griffiths, 1992).

On the basis of a dose range finding study, the highest concentration for the main study was chosen. A single intraperitoneal injection was given to groups of 5 male and 5 female mice at 5000 mg/kg bw in corn oil. Bone marrow samples were taken 24 and 48 h after dosing. A concurrent negative control with the vehicle alone and a positive control group given cyclophosphamide (65 mg/kg bw) was included in the study.

The negative and positive controls showed the expected results. The test material did not induce a statistically significant increase in the number of micronucleated polychromatic erythrocytes in the bone marrow of the animals.

Comparison of the percentage of polychromatic erythrocytes showed no significant differences between the control and test group females. A small but significant decrease was, however, noted in male mice treated with the test material. This small decrease was considered not to be biologically significant compared to the concurrent control values.

Under the conditions of the study Fatty acids, C5-10, esters with pentaerythritol did not induce chromosomal mutations in the bone marrow of mice.


Justification for selection of genetic toxicity endpoint
No study was selected, since all three in vitro studies and one in vivo study were negative.

Short description of key information:
Negative results in Salmonella typhimurium TA 98, TA 100, TA 1535, TA 1537 and E. coli WP2 uvrA with and without metabolic activation (OECD 471).
Negative results in mammalian chromosomal aberration test in human lymphocytes (OECD 473).
Negative results in mammalian cell gene mutation test with L5178Y mouse lymphoma cells with and without metabolic activation (OECD 476).
Negative results in micronucleus assay in mice (OECD 474)

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

The available data on the genetic toxicity of Dipentaerythritol ester of nC5/iC9 acids does not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and the data are therefore conclusive but not sufficient for classification.

Based on read-across from the structurally similar substances Pentaerythritol tetravalerate and Fatty acids, C5-10, esters with pentaerythritol, the available data on genetic toxicity do not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and the data are therefore conclusive but not sufficient for classification.