2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate

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

Additional information

There are no specific reproductive toxicity studies available for 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate (CAS# 93803-89-5) to assess the potential to induce effects on reproduction.In accordance with Regulation (EC) No 1907/2006, Annex IX, 8.7.3, column 1, a two-Generation Reproduction Toxicity Study does not need to be conducted as the results of a 28-day or 90-day repeated dose toxicity study do not demonstrate any adverse effects on reproductive organs or tissues.

In the 13-week oral repeated-dose toxicity study in rats, pentaerythritol ester of pentanoic acids and isononanoic acid (CAS# 146289-36-3) reproductive organs were examined.

 

CAS 146289-36-3

 

In a 13-week oral repeated-dose toxicity study performed comparable to OECD Guideline 408 with Pentaerythritol ester of pentanoic acids and isononanoic acid in rats (CAS# 146289-36-3) reproductive organs were examined as well (Müller, 1998). Groups of 10 male and female Wistar rats each were once daily (7 days/week) exposed to the substance) by gavage at 100, 300 and 1000 mg/kg bw for 90 days. Overall, there were no adverse effects found after oral application of the test substance for 90 days. With special regard to the reproductive organs (ovaries, epididymides, prostate, testes and uterus), the examination of organ weights as well as gross and histo-pathology revealed to substance-related findings.Based on the absence of effects up to the highest dose tested, the 90-day oral reproductive NOAEL was found to exceed 1000 mg/kg bw/day.

In addition, developmental toxicity studies with structural similar substances including Decanoic acid, ester with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol octanoate (CAS# 11138-60-6), Fatty acids C8-10, mixed esters with diPE, isooctanoic acid, PE and triPE (CAS# 189200-42-8) and Isononanoic acid, C16-18-alkyl esters (CAS# 111937-03-2) did not show an influence on the observed fertility parameters.

Moreover, according to Regulation (EC) No 1907/2006, Annex IX, 8.7.3, column 2, ”reproductive toxicity studies do not need to be conducted if the substance is of low toxicological activity and it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure”. In accordance with the general rules set out in Regulation (EC) No 1907/2006, Annex XI, section 1.2, a weight of evidence approach considering “several independent sources of information”, available toxicity data demonstrate that the test substance exhibit no or only low toxicological potency. As determined in the toxicokinetic assessment, only a low potential for absorption is considered for the test substance.

In conclusion, regarding the available studies on source substance, 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate (CAS# 93803-89-5) is considered to exhibit low toxicological activity and systemic absorption.Therefore, according to Regulation (EC) No 1907/2006 and with respect to animal welfare, further reproductive toxicity studies would be scientifically unjustified.

 

 

Conclusion for reproductive toxicity

No reproductive toxicity studies are available for 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate (CAS# 93803-89-5). However in one 90-day study with structural related analogue substance pentaerythritol ester of pentanoic acids and isononanoic acid (CAS# 146289-36-3)showed no indications for effects on reproductive organs were examined. As no indications for effects on reproductive organs were found (NOAEL > 1000 mg/kg bw/day 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate (CAS# 93803-89-5).were not considered to have toxic effects on reproductive organs.

 

Effects on developmental toxicity

Description of key information

Oral (OECD 414), rat: NOAEL >= 1000 mg/kg bw/day;
Oral  (OECD 414), rat: NOAEL = 1000 mg/kg bw/day;
Dermal (OECD 414), rat: NOAEL= 2000 mg/kg bw/day

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises an adequate, reliable study (Klimisch score 2) from a reference substance 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 study is thus sufficient to fulfil the standard information requirements set out in Annex IX, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

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

Quality of whole database:

The available information comprises an adequate, reliable study (Klimisch score 2) from a reference substance 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 study is thus sufficient to fulfil the standard information requirements set out in Annex IX, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Additional information

Justification for grouping of substances and read-across

There are no data available for developmental toxicity of the substance 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 IX, 8.7, 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 toxicological properties may be predicted from data for the reference substance(s) on the basis of structural similarity, the substances listed below are selected as reference substances for assessment of toxicological endpoints, for which information gaps are identified.

 

Overview for developmental toxicity

CAS	Toxicity
93803-89-5 (a) Target substance	RA: CAS 11138-60-6 RA: CAS 189200-42-8 RA: CAS 111937-03-2
11138-60-6 (b)	NOAEL = 2000 mg/kg bw
189200-42-8	NOAEL ≥ 1000 mg/kg bw
111937-03-2	NOAEL ≥ 1000 mg/kg bw

  (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 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).

 

Discussion

Developmental toxcity

Since no studies investigating the developmental 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 source substances Fatty acids, C8-10, mixed esters with dipenaterythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS# 189200-42-8), Decanoic acid, ester with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol octanoate (CAS# 11138-60-6), and Isononanoic acid, C16-18-alkyl esters (CAS# 111937-03-2) was conducted.

CAS 189200-42-8

The developmental toxicity of Fatty acids C8-10, mixed esters with diPE, isooctanoic acid, PE and triPE (CAS# 189200-42-8) was investigated according to OECD Guideline 414 (prenatal developmental toxicity study) and under GLP (Trimmer, 1995). 50 male Sprague-Dawley rats were mated with females to achieve groups of 25 pregnant Sprague-Dawley rats which then received daily oral gavage doses of the test substance at concentrations of 100, 500 and 1000 mg/kg bw/day during gestational Days 6 to 15. On Day 21 of gestation the animals were euthanized and examined for maternal and fetal parameters. There were no adverse effects found for all parameters examined in maternal animals. Based on the number of implantations, number of total litter losses by resorption, mortality, clinical signs, body weight, gross pathology and organ weights of maternal animals the NOAEL for maternal toxicity was found to be 1000 mg/kg bw/day, the highest dose tested. Examination of fetus litter size and weights, offspring viability (number alive and number dead), sex ratio, grossly visible abnormalities, external, head, soft tissue and skeletal abnormalities showed only incidental malformations. The NOAEL for embryo-/fetotoxicity and teratogenicity in rats for Fatty acids C8-10, mixed esters with diPE, isooctanoic acid, PE and triPE was found to be 1000 mg/kg bw/day.

 

CAS 11138-60-6

Decanoic acid, ester with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol octanoate (CAS# 11138-60-6) was tested in a prenatal developmental toxicity study comparable to OECD Guideline 414 (Azuka and Daston, 2004). 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 or 2000 mg/kg/day in corn oil on days 6-15 after gestation.

The two highest dose levels caused some local irritation at the site of application, but no decreases in maternal weight gain or food consumption. There were no differences from control in any of the developmental parameters measured, including embryo/fetal viability, fetal weight, malformations, or variations. Therefore, a NOAEL of 2000 mg/kg/day was derived for prenatal development and for systemic maternal toxicity. Due to the irritation effects on skin, the local maternal NOAEL was found to be 200 mg/kg bw/day.

 

CAS 111937-03-2

The potential of Isononanoic acid, C16-18 alkyl esters (CAS# 111937-03-2) to cause developmental toxicity was assessed in a study performed using a study protocol similar to OECD Guideline 414 (Pitterman, 1997). 23-24 pregnant female Sprague-Dawley rats/dose level were administered 0, 100, 300 and 1000 mg/kg bw/day of the test substance by gavage on gestation Day 6 to 15.

No signs of systemic toxicity were observed in the P-females and no treatment-related effects were observed. One female in the high-dose group had blood in the uterine horn, but this is not considered to be treatment-related as no related effects were observed. One female in each of the control group and the low-dose group did not become pregnant, while all the pregnant females had viable fetuses. No treatment-related effects on the reproductive parameters (number of corpora lutea, implantation sites, pre-implantation loss, post-implantation loss, embryonic deaths, embryonic resorptions, fetal resorptions, live fetuses, dead fetuses) were observed.

The external examination of the F1-foetuses did not reveal any treatment-related macroscopic findings. The skeletal examination showed a statistically significant increase in the number of foetuses with 6 ossified sternebrae in the high-dose group. As there were no increases in ossification anywhere else and no overall increase in abnormal findings for this group, the result is considered to be incidental. The results for the remaining offspring parameters (body weight, placental weight, sex ratio) were comparable between the control and treatment groups.   

The NOAEL developmental is considered to be ≥ 1000 mg/kg bw/day.

In summary, based on a weight of evidence approach, all reliable studies consistently showed no treatment-related effects on maternal and developmental toxicity and the overall NOAEL was found to exceed 1000 mg/kg bw/day for maternal systemic and developmental toxicity.

 

Conclusion for developmental toxicity

No prenatal developmental toxicity studies are available for 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate (CAS# 93803-89-5) but a read-across from Decanoic acid, ester with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol octanoate (CAS# 11138-60-6), Fatty acids C8-10, mixed esters with diPE, isooctanoic acid, PE and triPE (CAS# 189200-42-8) and Isononanoic acid, C16-18-alkyl esters (CAS# 111937-03-2) was applied to assess developmental toxicity. All studies were conducted with Sprague-Dawley rats and did not show any developmental toxic effects. The NOAELs are 2000 and 1000 mg/kg bw/day, respectively.Therefore 2,2-bis[[(1-oxoisononyl)oxy]methyl]-1,3-propanediyl diisononanoate (CAS# 93803-89-5) was not considered to have a potential for developmental toxicity.

 

Justification for selection of Effect on developmental toxicity: via oral route:
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 Effect on developmental toxicity: via dermal route:
Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance 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 developmental 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.