Isononanoic acid, mixed esters with dipentaerythritol, heptanoic acid and pentaerythritol

Endpoint summary

Description of key information

Repeated dose toxicity: Oral NOAEL (rat, m/f): >= 1000 mg/kg bw/day (OECD 407, GLP, 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, partially due to read across) 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 environmental fate, ecotoxicological and 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 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 grouping of substances and read-across

There are no data available for the repeated dose toxicity of 3,5,5-trimethylhexanoic acid, mixed esters with dipentaerythritol (UVCB, CAS 84418-63-3). 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, the substances Fatty acids, C5-10, esters with pentaerythritol (CAS 68424-31-7), and Dipentaerythritol ester of fatty acids C5 and C9iso (CAS 647028-25-9) are selected as source for risk assessment. 

Repeated dose toxicity: oral

Since no studies investigating the repeated dose toxicity of 3,5,5-trimethylhexanoic acid, mixed esters with dipentaerythritol (UVCB, CAS 84418-63-3) are available, in accordance to Regulation (EC) No. 1907/2006 Annex XI, 1.5 a read-across from the structurally related analogue substances Fatty acids, C5-10, esters with pentaerythritol (CAS 68424-31-7), Pentaerythritol ester of pentanoic acids and isononanoic acid (CAS 146289-36-3) and Dipentaerythritol ester of fatty acids C5 and C9iso (CAS 647028-25-9) was conducted.

CAS 68424-31-7

A 28 day study was conducted according to OECD Guideline 407 with Fatty acids, C5-10, esters with pentaerythritol (CAS 68424-31-7) (Brammer, 1993). The test substance was administered in concentrations of 1000 ppm, 5000 ppm, 12500 ppm resembling 112, 562 and 1450 mg/kg bw/day for male and 119, 586 and 1613 mg/kg bw/day for female rats, respectively to 5 animals per sex and dose for 28 consecutive days.

There were no toxicologically significant effects on body weight, food consumption and clinical condition up to and including the highest dose level. Changes in some clinical chemistry and red cell-related parameters were observed in male rats at 12500 ppm but these were minor and considered not to be of toxicological significance. There were no clinical signs indicative of neurological changes in the brains of the 12500 ppm group. A minimal hepatocyte hypertrophy, present in males in the 12500 ppm group, is considered to be evidence of an adaptive response. Microscopic examination of the kidneys from male animals from all dose groups revealed an increase in hyaline droplet formation (the main constituent of which is alpha-2µ-globulin) and tubular basophilia; this phenomenon is widely accepted to be specific to the male rat and as such is considered to have no relevance to man. A NOAEL of 1450 and 1613 mg/kg/day could be identified for male and female rats, respectively.

CAS 647028-25-9

A subacute 28 day oral study with Dipentaerythritol ester of fatty acids C5 and C9iso (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.

Conclusion for Repeated Dose Toxicity – Oral

Since there are no studies available investigating the repeated oral toxicity of 3,5,5-trimethylhexanoic acid, mixed esters with dipentaerythritol (UVCB, CAS 84418-63-3) read-across from structurally related analogue substances was applied in order to fulfill the standard information requirements set out in Annex VII and IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006. The 28 day oral toxicity studies with Fatty acids, C5-10, esters with pentaerythritol (CAS 68424-31-7), and with Dipentaerythritol ester of fatty acids C5 and C9iso (CAS 647028-25-9) showed no overt signs of toxicity up to the high dose group of 1000 mg/kg bw.

There is no data available on the repeated dose toxicity after dermal application and inhalation.

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 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.