Registration Dossier

Administrative data

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 the Polyol DiPE substance Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol (CAS# 68604-38-6) to assess the potential of 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. 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 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

The 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) exposed to the substance (purity not specified) at 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. Reproductive organs (ovaries, epididymides, prostate and seminal vesicles, testes, uterus and vagina) as all other organs were found without any sign of systemic toxicity. Additionally, cauda epididymel 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 on 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 for 6 hours/day, 5 days/week at concentrations of 0.05, 0.15 and 0.5 mg/L air. The respective controls inhaled clean air under the same conditions. Reproductive parameters examined included reproductive organs and testicular spermatid count and 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 air.

 

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 esteres with diPE, isooctanoic acid, PE and triPE (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 the test substance 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 the Polyol DiPE substance Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol 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

As no indications for effects on reproductive parameters (reproductive organs and sperm parameters) were found in the three 90-day repeated dose studies (NOAEL > 1000 mg/kg bw/day, NOAEL > 2000 mg/kg bw/day and NOAEC > 0.5 mg/L air), the Polyol DiPE substance fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol was not considered to have a potential for reproductive toxicity.

Effects on developmental toxicity

Description of key information
Oral (OECD 414), rat: NOAEL >= 1000 mg/kg bw/day;
Dermal (OECD 414), rat: NOAEL < 800 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 due to read-across) from a reference substance with similar structure and intrinsic properties. Read-across is justified based on similar functional groups and similar precursors/breakdown products (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 due to read-across) from a reference substance with similar structure and intrinsic properties. Read-across is justified based on similar functional groups and similar precursors/breakdown products (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 the developmental 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 IX, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, a 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 developmental toxicity

CAS

Toxicity

CAS 68604-38-6 (a)

Target substance

RA: CAS 67762-53-2

RA: CAS 11138-60-6

RA: CAS 189200-42-8

CAS 67762-53-2 (b)

NOAEL < 800 mg/kg bw (rat, dermal)

CAS 11138-60-6

NOAEL = 2000 mg/kg bw (rat, dermal)

CAS 189200-42-8

NOAEL > 1000 mg/kg bw (rat, oral)

(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

Developmental toxicity

CAS 68604-38-6

There is no developmental toxicity study available for the Polyol DiPE substance Fatty acids, C16-18 and C18-unsatd., hexaesters with dipentaerythritol (CAS# 68604-38-6). Therefore, an analogue based read-across,in accordance to Regulation (EC) No. 1907/2006 Annex XI, 1.5,was applied based on molecular structure similarities and similarities in physicochemical properties using read-across from Fatty acids, C5-9, tetraesters with pentaerythritol (CAS# 67762-53-2), Decanoic acid, ester with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol octanoate (CAS# 11138-60-6) and Fatty acids C8-10, mixed esters with diPE, isooctanoic acid, PE and triPE (CAS# 189200-42-8).

The developmental toxicity of Fatty acids, C5-9, tetraesters with pentaerythritol (CAS# 67762-53-2) was investigated comparable to OECD Guideline 414 (prenatal developmental toxicity study) (Feusten, 1988). Groups of 15 presumed pregnant female Sprague-Dawley rats received daily dermal doses of the test substance at concentrations of 800 and 2000 mg/kg bw/d during gestational days 0 to 19. On day 20 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 2000 mg/kg bw/day. 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 no differences to control and no indication for teratogenic effects. The only effect found was an increased number of fetuses with levocardia. It is known that levocardia was also found in control animals in other studies. However, since levocardia was only found in treated groups the NOAEL for embryo-/fetotoxicity and teratogenicity in rats for 2-ethylhexyl stearate was found to be < 800 mg/kg bw/day and the LOAEL = 800 mg/kg bw/day.

The developmental toxicity of Fatty acids C8-10, mixed esteres 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 esteres with diPE, isooctanoic acid, PE and triPE was found to be 1000 mg/kg bw/day.

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.

Conclusion for developmental toxicity

There is no study available for the Polyol DiPE substance to be registered. The prenatal developmental toxicity study with Fatty acids, C5-9, tetraesters with pentaerythritol (CAS# 67762-53-2) using Sprague-Dawley rats resulted in a NOAEL lower than 800 mg/kg bw since levocardia was found in the pups of treated groups. Levocardia is an effect which is sometimes observed in all animals including control. To ensure that this effect was not due to developmental toxicity two additional prenatal developmental toxicity studies are assessed with source substances Decanoic acid, ester with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol octanoate (CAS# 11138-60-6) and Fatty acids C8-10, mixed esters with diPE, isooctanoic acid, PE and triPE (CAS# 189200-42-8). Both studies were also conducted with Sprague-Dawley rats and did not show any developmental toxic effects. The NOAELs are 2000 mg/kg bw and 1000 mg/kg bw, respectively. Therefore, the Polyol DiPE substance was not considered to have a potential for develomental toxicity.


Justification for selection of Effect on developmental toxicity: via oral 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 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 the structurally similar substances, the 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.