Registration Dossier

Administrative data

Description of key information

Repeated dose toxicity: Oral NOAEL (rat, m/f): 1000 mg/kg bw/day (OECD 407) 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

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.

Repeated dose toxicity: oral

Dipentaerythritol ester of nC5/iC9 acids was tested for subacute oral toxicity in a 28-day study according to OECD guideline 407 in compliance with GLP (Jones, 2000).

Groups of 5 Sprague-Dawley rats per sex (main study) were given 150, 500 and 1000 mg/kg bw/day of the test material in arachis oil by gavage. Dose levels were chosen based on the results of a foregoing range-finding study, in which animals were orally exposed to 150, 500 and 1000 mg/kg bw/day by gavage for 14 days (Jones, 2000). A concurrent negative control group receiving the vehicle arachis oil only was included in the main testing.

No clinical signs or mortality occurred in relation to the test substance during the study period in any animal. Isolated and transient observations e.g. noisy respiration in 2 animals and fur loss in one animal were without dose-relationship and therefore considered to be of no toxicological importance.

No adverse effect on clinical chemistry parameters and food and water consumption was observed.

No adverse effect on body weight was noted. A reduction in body weight gain in the high- and mid-dose group in Week 1 was considered to be a result of slightly higher than usual control group body weight gains.

No treatment-related changes in the haematological parameters were measured. However, a reduction in mean corpuscular haemoglobin concentration in the male high-dose group and an increase in platelet count in the male mid-dose group were apparent. In the absence of any other haematological changes, these differences were considered to be accidental.

The functional performance tests showed isolated intergroup differences which were considered to be accidental and of no toxicological significance. No treatment-related effects on organ weights were noted. Males in the mid-dose group showed a reduction in absolute epididymides weight. In the absence of a dose-response relationship, this intergroup difference was considered to be incidental and of no toxicological significance.

Necropsy revealed no substance-related findings. One male and one female animal in the low- dose group and a female in the high-dose group showed dark foci on the lungs. These findings showed no dose-related response and where considered to be of no toxicological importance. Three males of the high-dose group demonstrated globular accumulations of eosinophilic material in the proximal tubular epithelium. The author considered this finding consistent with the appearance of hydrocarbon nephropathy, which results from the excessive accumulation of α2-microglobulin in renal proximal tubular epithelium of adult male rats, which does not represent a hazard to human health. No other histopathological changes were observed including effects on epididymides, testes, uterus and ovaries in any animal.

Based on the lack of adverse effects, a NOAEL of 1000 mg/kg bw/day (m, f), which was the highest dose level tested, was identified in this study.

Available data on the subchronic repeated dose toxicity of the structural analogue Pentanoic acid, mixed esters with pentaerythritol, isopentanoic and isononanoic acid were considered for read-across and health hazard assessment was conducted based on an analogue approach.

Groups of 10 Wistar rats per sex were given 100, 300 and 1000 mg/kg bw/day of the test material in distilled water containing 1% Tween 80 by gavage for a period of 90 days. Furthermore, an additional satellite control and high-dose group were included in the study for investigating the reversibility of possible effects after a post-exposure recovery period of 4 weeks. A concurrent negative control group receiving the vehicle only was included in the testing.

No substance-related mortality was observed during the study period in any animal. Only a few clinical observations were made and considered to be substance independent and were apparent only for a short period of time. None of the animals showed any alterations of their general state of well-being and behaviour at any observation period. No substance-related effects on body weight and food consumption were noted. No alterations in ophthalmoscopic and neurobehavioral parameters were observed in any animal during the study period. No substance dependent changes were observed in the gross pathology in the animals.

Different haematological parameters were influenced in the test animals. In females of the low- and high-dose group, an increased erythrocyte count and decreased packed cell volume was apparent, but considered to be in a normal range of values for the strain used. The fibrinogen concentration was statistically significantly increased in high-dose females being reversible after the recovery period and considered to be substance-related. A reversible dose-dependent increase in the prothrombin time in male animals was considered to be not substance-dependent. A low prothrombin time in male controls was assumed to be the reason of this effect.

The enzyme activity of the alkaline phosphatase was dose-dependently increased in male and female animals of the high-dose group. After the recovery period normal enzyme activity was apparent. A dose-dependently decreased activity of aspartate aminotransferase in male animals of all groups was considered to be incidental. The values in the satellite groups of control and high-dose animals were in the same range as the previous significant values of the male animals of the main testing.

Furthermore, serum urea nitrogen was increased in female animals of the high-dose group and in the mid- and high-dose males. The creatinine content was significantly increased in all male and the high-dose group of female animals. The phosphorus content was significantly increased in all female animals and the sodium content was dose-dependently decreased in male animals. These effects were not observed after the recovery period. The observed effects on the serum urea, creatinine and phosphorus content were considered to be substance-related. Significant differences of the glucose and calcium levels were considered to be incidental due to small, not dose-dependent differences.

Substance-related effects on kidney and liver weights were observed. Kidney weights were increased in all male animals and statistically significant increased in the high-dose group. This effect was still present after the recovery period. Liver weights were increased in both sexes and statistically significant increased in females of the high-dose group being reversible after the recovery period.

The histopathological examination revealed correlating histological effects in the liver. Intracellular lipid droplets in hepatocytes of the female animals in the high- and mid-dose group with cell lesions were dose-dependently observed and considered to be substance-related. In most cases only low grade intracellular lipopexia occurred in male animals. No markedly degenerated hepatocytes or intracellular fat droplets were observed in the satellite groups. Different incidental histological finding were apparent in single animals on stomach, lungs, thymus, skin. These findings were considered to be not substance-related. No histological findings on epididymidis, testes, uterus and ovaries were reported.

Based on the results on liver and kidney, which were considered to be substance-related in the high-dose group, a NOAEL of 300 mg/kg bw/day (m, f) was identified in this study.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The selected study is the most adequate and reliable study conducted with the test material.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Reliable studies via the oral route are available.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Reliable studies via the oral route are available.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Reliable studies via the oral route are available.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
Reliable studies via the oral route are available.

Justification for classification or non-classification

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