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)

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 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 for the repeated dose toxicity of 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate (CAS# 93803-89-5). In order to fulfil 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, 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, oral

CAS

oral

NOAEL (rat) mg/kg bw/day

93803-89-5 (a)

RA: CAS 68424-31-7

RA: CAS 647028-25-9

RA: CAS 146289-36-3

68424-31-7(b)

1450 (m)

1613 (f)

146289-36-3

1000(m,f)

647028-25-9

1000 (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 either already registered under REACh or not subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in normal font.

The above mentioned substances are considered to be similar on the basis of the structural and similar properties and/or activities. The available endpoint information is used to predict the same endpoints for 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate (CAS# 93803-89-5).

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

Since no studies investigating the repeated dose toxicity of 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate(CAS# 93803-89-5) 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 nC5/iC9 acids (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 sings 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 146289-36-3

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.

 

CAS 647028-25-9

A 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.

 

 

Conclusion for Repeated Dose Toxicity – Oral

In summary, two 28-day study conducted with Fatty acids, C5-10, esters with pentaerythritol (CAS# 68424-31-7) 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.

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

 


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.