3-[3-(pentanoyloxy)-2,2-bis[(pantanoyloxy)methyl]propoxyl]-2,2-bis[(pentanoyloxy)methyl]propyl pentanoate 3-{3-[(3,5,5-trimethylhexanoyl)oxy]-2,2-bis({[(3,5,5-trimethylhexanoyl)oxy]methyl}propoxy)-2,2-bis({[(3,5,5-trimethylhexanoyl)oxy]methyl}propyl 3,5,5-trimethylhexanoate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Description of key information

Developmental toxicity: Oral NOAEL (rat): 1000 mg/kg bw/day (OECD 414) 
Developmental toxicity: Dermal NOAEL (rat): 2000 mg/kg bw/day (OECD 414) 

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Quality of whole database:

The key study is GLP compliant and is of high quality (Klimisch score = 2).

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

2 000 mg/kg bw/day

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.

Available data on the developmental toxicity of the structural surrogate mixed ester of pentaerythritol technical grade with isooctanoic and C8C10 fatty acids (CAS No. 189200-42-8) and decanoic acid, ester with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol octanoate (CAS No. 11138-60-6) were considered for read-across and assessment was conducted based on an analogue and weight of evidence approach.

Mixed ester of pentaerythritol technical grade with isooctanoic and C8C10 fatty was tested in a prenatal developmental toxicity study equivalent to OECD guideline 414 in compliance with GLP (Trimmer, 1995). The test material was orally applied to Crl:CD BR VAF/Plus rats by gavage from gestation days (GD) 6-15. The dose levels during the study period were 100, 500 and 1000 mg/kg bw/day of the test substance in the vehicle polyethylene glycol (PEG 400). A concurrent vehicle control group was included in the study.

No treatment-related mortality or clinical signs of toxicity were observed in the maternal animals during the study period. The most frequent observation was soft stool in the treatment and control animals and was therefore considered to be a response to the vehicle rather than to the test substance.

There were no statistically significant differences in mean body weight, body weight change, uterine weight, corrected body weight or food consumption between treated and control animals.

Additionally, there were no adverse postmortem signs which were considered treatment-related.

In the foetuses, there was no evidence of growth retardation or increased foetal death in the treated groups compared with controls.

There were no significant differences from control in any of the developmental parameters measured. No significant differences were observed in the number of corpora lutea, implantation sites, pre- and post implantation loss, resorptions and sex ratio among the groups.

Additionally, there were no biologically significant differences in total or individual variations or malformations (external, visceral or skeletal) in the treated groups when compared with controls on either a per foetus or per litter basis. All malformations were considered incidental and not to be treatment-related.

Statistically significant differences in incidences of variations were limited to a decrease in hypoplastic skull bones of the mid-dose group and a decrease in unossified stemebrae of the high-dose group compared with controls. All variations were considered to be of no biological importance.

Therefore, the test substance was not considered embryotoxic. Accordingly, the maternal and developmental NOAELs were established at 1000 mg/kg bw/day. The results indicate that test substance was not a selective developmental toxicant and was not embryotoxic or teratogenic under the conditions of this study.

Furthermore, available data on the teratogenic potential and influence on prenatal development of the structural surrogate decanoic acid, ester with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol octanoate (CAS No. 11138-60-6) was considered for read-across and assessment was conducted based on an analogue and weight of evidence approach (Azuka and Daston, 2004).

Decanoic acid, ester with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol octanoate was tested in a prenatal developmental toxicity study equivalent to OECD guideline 414.

The test substance was percutaneously applied to Sprague-Dawley rats for 6 h/day under occlusive conditions. 25 animals per dose were treated with 200, 600 and 2000 mg/kg bw/day in corn oil on Days 6-15. A concurrent vehicle control group was included in the testing.

No effects on maternal body weight gain or food consumption were observed. In the mid- and high-dose group, local irritation at the site of application was apparent. Necropsy findings were limited to skin flaking and scabbing first identified in life and observations related to wearing the Elizabethan collar.

One dam of the mid-dose group (1/25) had a litter consisting of seven early resorptions. This result was pointed out as single non-dosage dependent event and to be within the historical ranges.

There were no significant differences from control in any of the developmental parameters measured. No differences were observed in the number of corpora lutea, implantation sites, pre- and post implantation loss, live and dead foetuses, resorptions and sex ratio among the groups, foetal weight, malformations, or variations. The observed effects in foetuses were dose-independent and regarded to be incidental and of no toxicological relevance.

Therefore, a NOAEL of 2000 mg/kg bw/day was derived for maternal toxicity and development toxicity. Furthermore, a local NOAEL of 200 mg/kg bw/day was derived, due to local irritation at the application site.

Justification for selection of Effect on developmental toxicity: via oral route:
Only one study available.

Justification for selection of Effect on developmental toxicity: via inhalation route:
Reliable studies via the oral and dermal route are available.

Justification for selection of Effect on developmental toxicity: via dermal route:
Only one study available.

Justification for classification or non-classification

Based on read-across from the surrogate substances Fatty acids, C8-10 mixed esters with dipenaterythritol, isooctanoic acid, pentaerythritol and tripentaerythritol and Trimethylolpropane Caprylate Caprate following an analogue and weight of evidence approach, the test substance 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.

No information is available on effects via lactation.