Registration Dossier

Administrative data

Description of key information

Repeated dose toxicity: Oral NOAEL (rat, m/f): 1000 mg/kg bw/day (OECD 408, GLP analogue approach)
Repeated dose toxicity: Inhalation NOAEC (rat, m/f): 5.5 mg/L (OECD 413, analogue approach)
Repeated dose toxicity: Dermal NOAEL (rat, m/f): 2000 mg/kg bw/day (OECD 411, analogue approach)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 2) studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on common origin, common precursors and breakdown products of hydrolysis and consistent trends in toxicological profile (refer to endpoint discussion for further details). The selected studies are thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate, reliable (Klimisch score 2) study from reference substances with similar structure and intrinsic properties. Read-across is justified based on common origin, common precursors and breakdown products of hydrolysis and consistent trends in toxicological profile (refer to endpoint discussion for further details). The selected studies are thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, in accordance with AnnexXI, 1.5, of Regulation (EC) No 1907/2006

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate, reliable (Klimisch score 2) study from reference substances with similar structure and intrinsic properties. Read-across is justified based on common origin, common precursors and breakdown products of hydrolysis and consistent trends in toxicological profile (refer to endpoint discussion for further details). The selected studies are thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, in accordance with AnnexXI, 1.5, of Regulation (EC) No 1907/2006

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for grouping of substances and read-across

There are no data available for the repeated dose toxicity of Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol (CAS# 68604-38-6). In order to fulfil the standard information requirements set out in Annex VIII and IX, 8.6, 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 (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.

Overview for repeated dose toxicity

CAS

oral

NOAEL (rat) mg/kg bw/day

Inhalation

NOAEC (rat) mg/L air

Dermal

NOAEL (rat) mg/kg bw/day

CAS 68604-38-6 (a)

RA: CAS 189200-42-8

RA: CAS 146289-36-3

RA: CAS 647028 -25 -9

RA: CAS 67762-53-2

RA: CAS 67762-53-2

CAS 67762-53-2 (b)

--

0.50 (m, f)

2000 (m, f)

CAS 146289-36-3

1000 (90-day, m, f)

--

--

CAS 189200-42-8

1000 (28-day, m, f)

--

--

CAS 647028-25-9

1000 (28-day, m, f)

--

--

 (a) Substances subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in bold font. Only for this substance a full set of experimental results and/or read-across is given.

 (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. 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 resulting in similar properties and/or activities. The available endpoint information is used to predict the same endpoints for Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol (CAS# 68604-38-6).

A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Discussion

Repeated Dose Toxicity

There are no studies available assessing the oral, inhalation and dermal repeated dose toxicity of Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol (CAS# 68604-38-6). To evaluate potential for toxicity following repeated oral, inhalation and dermal uptake data from Fatty acids C8-10, mixed esters with diPE, isooctanoic acid, PE and triPE (CAS# 189200-42-8), Dipentaerythritol ester of nC5/iC9 acids (CAS # 647028-25-9), Pentaerythritol ester of pentanoic acids and isononanoic acid (CAS# 146289-36-3), and Fatty acids, C5-9, tetraesters with pentaerythritol (CAS# 67762-53-2) were used applying an analogue based read-across approach, in accordance to Regulation (EC) No. 1907/2006 Annex XI, 1.5.

Subacute Oral Repeated Dose Toxicity

CAS 189200 -42 -8

A subacute 28 day oral feeding toxicity study with Fatty acids C8-10, mixed esters with diPE, isooctanoic acid, PE and triPE (CAS# 189200-42-8) was performed comparable to OECD Guideline 407 and under GLP (Trimmer, 1995). Groups of 5 male and 5 female Cr:CD BR rats were exposed to the substance at 100, 500 and 1000 mg/kg bw/day by oral gavage daily, 7 days/week for 28 days. Control animals received the concurrent vehicle, polyethylene glycol (PEG400). Animals were observed for clinical signs, body weight, food consumption, haematology, clinical chemistry, organ weights, gross necropsy and histopathological examinations.

The daily oral administration of the test substance was tolerated without any marked effects even at the high dose of 1000 mg/kg bw/day. All animals survived the study period (except for one animals of the 500 mg/kg bw group that died after the first application due a gavage error and that was promptly replaced) to the scheduled termination.

No clinical signs occurred that were judged to be related to the treatment with the test substance.

No effects on body weight and food consumption were observed after treatment with the test substance.

There were no significant differences in the haematology parameters between the negative control and the animals receiving the test substance.

There were no significant differences in mean absolute organ weight between the treated and negative control animals. In the mid dose group, there was a statistically significant increase in the mean relative testes weight. Due to the absence of a dose-response pattern, this effect was judged to be incidental.

The necropsy revealed no treatment-related finding except for some incidental findings not treatment related (e.g. dilated renal pelvis , scabs, thickened/roughened stomach) and distended uterus.

No treatment-related histopathologic changes were observed in any of the organs or tissues examined. However some common spontaneously occurring incidental findings were observed as focal mononuclear or mixed inflammatory cell infiltrations in the liver and the heart. Furthermore, focal tubular degeneration in the kidneys of male rats of all groups was observed. This effect was not observed in any dose group in the kidneys of the female rats.

The changes observed were considered to have been spontaneous in origin and were typical of incidental findings commonly encountered in laboratory rats of this age and strain. Because these changes occurred at similar incidence and intensity among all groups, they were not considered to be related to treatment.

Thus, the 28 day oral NOAEL, for Fatty acids C8-10, mixed esteres with diPE, isoocatnoic acid, PE and triPE was found to be 1000 mg/kg bw/day for male and female rats.

 

CAS # 647028-25-9

Another subacute 28 day oral study with Dipentaerythritol ester of nC5/iC9 acids (CAS # 647028-25-9) was conducted according to OECD guideline 407 under GLP conditions (Jones, 2000).

Groups of 5 male and female 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. A concurrent negative control group receiving the vehicle arachis oil only was included in the main test.

No clinical signs or mortality occurred in relation to the treatment during the study period in any animal. Isolated and transient observations such as noisy respiration in 2 animals and fur loss in one animal were observed 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 relevance. 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 treatment-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 results of the study, a NOAEL of 1000 mg/kg bw/day for male and female rats was identified in this study.

Subchronic Oral Repeated Dose Toxicity

A 90-day oral feeding toxicity study with the source substance Pentaerythritol ester of pentanoic acids and isononanoic acid (CAS# 146289-36-3) was performed according to OECD Guideline 408 and under GLP conditions (Müller, 1998). Groups of 10 male and 10 female Wistar rats were exposed to the substance at 100, 300 and 1000 mg/kg bw/day by gavage daily, 7 days/week for 90 days. Satellite control and high dose groups containing 10 male and female animals each were observed for additional 28 days. Control animals (10 per sex and dose) received the concurrent vehicle, distilled water containing 1% Tween 80. Observations and examinations of the animals included clinical signs, body weight, food consumption, haematology, clinical chemistry, organ weights, neurobehaviour, gross necropsy and histopathology. The daily oral administration of the test substance was tolerated without any adverse effects up to 1000 mg/kg bw/day. No mortality was observed except for two animals that died shortly after administration due to incorrect gavage. Absolute and relative kidney weights were increased in all male animals in the high dose group which was still present after the recovery period. However, histopathology revealed no adverse effects in the kidney. Absolute and relative liver weights were increased in both sexes but this was no longer apparent after the recovery period in females. Other significant differences seem to be incidental. The activity of alkaline phosphatase of the serum significantly increased in the high dose group, males and females. This indicates damage to liver cells and/or an increased function rate. This finding was no longer apparent at the end of the treatment-free period. Except for the increased kidney weights and liver weight in the males, all changes (e.g. clinical chemical changes) were no longer apparent at the end of the treatment-free period. The increase in kidney weights in all male animals could be correlated to the formation of hyaline droplets a phenomenon widely accepted to be specific to the male rat and as such considered to have no relevance to man, a 90-day oral NOAEL of 1000 mg/kg bw/day was found for Pentaerythritol ester of pentanoic acids and isononanoic acid in male and female rats.

Conclusion for Repeated Dose Toxicity - Oral

In summary, two 28-day study conducted with Fatty acids C8-10, mixed esteres with diPE, isoocatnoic acid, PE and triPE (CAS# 189200-42-8) and dipentaerythritol ester of nC5/iC9 acids (CAS # 647028-25-9)showed no signs of overt toxicity..The 90-day study Pentaerythritol ester of pentanoic acids and isononanoic acid (CAS# 146289-36-3) did not show any sign of overt toxicity. However, increased kidney and liver weights in the male animals was observed.

In conclusion, since the effects observed are not considered to be systemic and relevant for humans, the NOAEL was found to exceed 1000 mg/kg bw for all substances based on the result from the 28 and 90-day studies.

Repeated Dose Toxicity - Inhalation

Subchronic Inhalation Repeated Dose Toxicity

A 90-day subchronic inhalation toxicity study was performed with source substance Sprague-Dawley rats with Fatty acids, C5-9, tetraesters with pentaerythritol (CAS# 67762-53-2) comparable to OECD guideline 413 (Dulbey, 1992). 15 males and 15 females per group were whole body exposed to the test substance aerosol for 6 hours/day, 5 days/week at concentrations of 0.05, 0.15 and 0.5 mg/L air. The respective controls (15 animals per sex and dose) inhaled clean air under the same conditions. Animals were observed for clinical sings, body weight, haematology, clinical chemistry, organ weights, gross necropsy and histopathological examinations. 10 additional male animals were included in every group for examination of pulmonary function tests and pulmonary hydroxyproline following exposure. No substance-related adverse effects were observed for body weight, body weight gain, mortality, clinical biochemistry and haematological parameters. The lungs of the high dose animals had a minimal increase in weight which correlated with slightly increased numbers of macrophages in the pulmonary alveoli. Thus, the NOAEC were found to be 0.5 mg/L air.

Conclusion for Repeated Dose Toxicity - inhalation

The available 90-day sub-chronic inhalation toxicity study showed a minimal effect on lungs including increased weight and slightly increased numbers of macrophages in pulmonary alveoli. Therefore, the NOAEC for repeated inhalation toxicity was found to be 0.5 mg/L air Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol

Repeated Dose Toxicity – dermal

A 90-day dermal toxicity study with Fatty acids, C5-9, tetraesters with pentaerythritol (CAS# 67762-53-2) was performed comparable to OECD Guideline 411 (Cruzan, 1988). Groups of 10 male and female Sprague-Dawley rats were once daily (5 days/week, 24 hours/day) exposed to the substance at 800 and 2000 mg/kg bw for 90 days (65 applications in total). Application to the skin was done open without coverage. Animals were observed for clinical sings, body weight, dermal irritation, haematology, clinical chemistry, urinalysis, organ weights, gross necropsy and histopathological examinations.

Overall there were no adverse effects found after dermal application of the test substance for 90 days on the parameters investigated. Treated males gained less body weight than control animals. Since the effect was low and no dose-relation was observed, it was not considered to be due to systemic toxicity. Some serum parameters of the high dose group animals were significant different to the control, but since the differences were small and they did not present any pattern suggestive of effects on a specific organ, they were considered not to be of toxicological relevance. Both treated groups exhibited minimal erythema and flaking of the skin during the dosing phase. At microscopic examination it was identified as very minor epidermal hyperplasia and chronic inflammation of the superficial dermis. Since no effects of systemic toxicity were identified up to the highest dose tested, the 90 day dermal NOAEL was found to be 2000 mg/kg bw/day for Fatty acids, C5-9, tetraesters with pentaerythritol in Sprague-Dawley rats.

Conclusion for Repeated Dose Toxicity - dermal

For repeated dermal toxicity, the available study from the source substance Fatty acids, C5-9, tetraesters with pentaerythritol (CAS# 67762-53-2) was considered for the assessment of Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol. The 90-day dermal toxicity study did not show any effects of systemic toxicity. Therefore, the NOAEL for repeated dermal toxicity was found to be 2000 mg/kg bw/day for Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol .


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Hazard assessment is conducted by means of read-across from structural analogues. 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).

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
There is only one study available.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
There is only one study available.

Justification for classification or non-classification

Based on read-across from structurally similar substances, the available data on repeated dose toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.