2,2-bis[[(2-hexyl-1-oxodecyl)oxy]methyl]-1,3-propanediyl bis(2-hexyldecanoate)

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

The registered substance is substantially similar to the PE esters of the polyol ester category. The category NOAEL values for maternal toxicity and embryotoxicity/fetoxocity and teratogenity in rats was very high.

Therefore, based on the group concept, all available data on toxicity to reproduction 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. The category justification is found in IUCLID section 13.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because (i) the substance is of low toxicological activity (no evidence of toxicity seen in any of the tests available), (ii) it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure (e.g. plasma/blood concentrations below detection limit using a sensitive method and absence of the substance and of metabolites of the substance in urine, bile or exhaled air) and (iii) there is no or no significant human exposure

other:

Reproductive effects observed:

not specified

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

The available data for the polyol ester category allows for an accurate hazard and risk assessment of the category and the category concept is applied for the assessment of environmental fate and environmental and human health hazards. Thus, where applicable, environmental and human health effects are predicted from adequate and reliable data for source substance(s) within the group by interpolation to the target substances in the group (read-across approach) applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. In particular, for each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across.

There are no studies available within the polyol esters category to assess the potential of the category members to induce effects on reproduction. In accordance with Regulation (EC) No 1907/2006, Annex IX, 8.7.3, further reproductive studies do 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 with Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane (CAS 403507-18-6) and Pentaerythritol ester of pentanoic acids and isononanoic acid (CAS 146289-36-3) reproductive organs were examined. Likewise, reproductive organs and sperm morphology/count were assessed in the 90-day dermal and inhalation toxicity studies with Fatty acids, C5-9 tetraesters with pentaerythritol (CAS 67762-53-2).

- CAS 403507-18-6

The 90day oral toxicity study with Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane (CAS 403507-18-6) was performed comparable to OECD Guideline 408 under GLP conditions (McRae, 2004). Groups of 10 male and female Sprague-Dawley rats each were once daily (7 days/week) exposed to the substance by gavage at concentrations of 5, 50 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 reproductive tissues (ovaries, epididymides, prostate, testes and uterus), the examination of organ weights as well as gross and histo-pathology revealed no 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 for Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane in Sprague-Dawley rats.

- 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 for Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane in Sprague-Dawley rats.

- CAS 67762-53-2

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 each were once daily (5 days/week) exposed to the substance (purity not specified) at concentrations of 800 and 2000 mg/kg bw for 90 days (65 applications in total). Application to the skin was done open without coverage. Reproductive endpoints examined were sperm morphology and weights of reproductive organs. Overall, there were no adverse effects found after dermal application of the test substance for 90 days. Examination of reproductive organs (ovaries, epididymides, prostate and seminal vesicles, testes, uterus and vagina) revealed no substance-related findings. Additionally, cauda epididymal sperm of the control and high dose groups, examined at the end of the treatment period, did not show changes in morphology. Based on the absence of effects concerning weight of reproductive organs and sperm morphology up to the highest dose tested, the 90-day dermal reproductive NOAEL was found to exceed 2000 mg/kg bw/day for Fatty acids, C5-9, tetraesters with pentaerythritol in Sprague-Dawley rats.

A 90-day subchronic inhalation toxicity study was performed with Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2) comparable to OECD guideline 413 in Sprague-Dawley rats (Dulbey, 1992). 15 males and 15 females per group were whole body exposed to the test substance for 6 hours/day, 5 days/week at concentrations of 0.05, 0.15 and 0.5 mg/L. The respective controls inhaled clean air under the same conditions. Reproductive parameters examined included reproductive organs and testicular spermatid count as well as epididymal sperm count and morphology. No changes in reproductive organs or effects on sperm count and morphology could be detected in the high dose group compared to the control animals. The NOAEC for reproductive effects was therefore found to exceed 0.5 mg/L.

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, C5-9 tetraesters with pentaerythritol (CAS 67762-53 -2) and Fatty acids, C8-10 mixed esters with dipenaterythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS 189200-42-8) 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 members of the polyol esters category exhibit no or only low toxicological potency. As determined in the toxicokinetic assessment, only a moderate to low potential for absorption is considered for the polyol esters category members.

In addition polyol esters have a common metabolic fate that involves stepwise hydrolysis to fatty acids and the respective polyols. This process is catalysed by esterases. Whereas the carboxylic acids are naturally occurring substances with an effective metabolic turnover, the polar polyols (Kow>-2) are rapidly excreted in the urine, either un-metabolised or with hydroxylation. Therefore, no long term exposure with the test material is expected, even if applied in repeated doses.

In conclusion, regarding the available studies on members of the polyol esters category or read-across substances, polyol esters are 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.

The registered substance is substantially similar to to the polyol ester category for which there are no specific reproductive toxicity studies available for the polyol esters category members. However, in four 90 -day repeated dose studies performed with PE and TMP esters, the reproductive organs and sperm morphology were examined. As no indications for effects on reproductive parameters were found in all four 90-day studies (NOAEL > 1000 mg/kg bw/day, NOAEL > 2000 mg/kg bw/day and NOAEC > 0.5 mg/L), the members of the polyol esters category were not considered to have a potential for reproductive toxicity.

A detailed reference list is provided in the technical dossier (see IUCLID, section 13).

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

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

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint".

Since the category concept is applied to the polyol esters, data gaps will be filled by interpolation, as part of a read across approach from a representative category member(s) to avoid unnecessary animal testing. Additionally, once the category concept is applied, substances will be classified and labelled on this basis.

Therefore, based on the group concept, all available data on toxicity to reproduction 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.