Dipentaerythritol hexaesters of 3,5,5-trimethylhexanoic, n-decanoic, n-heptanoic, and n-octanoic acids

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Combined Repeated-Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening test, rat, GLP, according to OECD 422 (substance-specific data)

NOAEL for parents (general systemic toxicity): 1000 mg/kg bw/day (female) and 500 mg/kg bw/day (males)

NOAEL for parents (reproductive toxicity): 1000 mg/kg bw/day (males and females)

NOAEL for offspring (developmental toxicity): 1000 mg/kg bw/day (males and females)

The hazard assessment is based on the data currently available. New studies with the registered substance and/or other member substances of the polyol esters family will be conducted in the future. The finalised studies will be included in the technical dossier as soon as they become available and the hazard assessment will be re-evaluated accordingly.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The toxicity of the test substance to reproduction was assessed in a combined 28-day repeated dose toxicity study with the reproductive/developmental toxicity screening study according to OECD TG 422, under GLP conditions (RL1). The study is considered of reliable quality and validity, and is suitable for assessment of the present endpoint.

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 hazard assessment is based on the data currently available. New studies with the registered substance and/or other member substances of the polyol esters family will be conducted in the future. The finalised studies will be included in the technical dossier as soon as they become available and the hazard assessment will be re-evaluated accordingly.

 

Reproductive toxicity study via the oral route

One recent study is available for EC 453-490-7 (former CAS 70983-72-1), which was a combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening study in the rat (Nyco, 2022). The study was conducted under GLP conditions and according to OECD 422. The study is considered reliable and valid. This study was designed to investigate the potential adverse effects of the test substance on reproductive / developmental capabilities during a subacute exposure period in Wistar rats. Females were dosed (50 to 60 days) throughout the study. This included two weeks prior to mating, the variable time to conception, the duration of pregnancy and thirteen days after delivery, up to and including the day before scheduled sacrifice. Males were dosed from the premating period throughout mating and until after mating until a total dosing period of 28 days was reached. Parental animals received the test substance in corn oil orally via gavage once daily at doses of 250, 500 and 1000 mg/kg bw/day. A similarly constituted control group received the vehicle (corn oil) only. After parturition, each litter was examined for number and sex of pups, still births, live births, runts and the presence of gross abnormalities. The anogenital distance in the pups was also measured, and the numbers of nipples /areaolae was recorded. All animals sacrificed terminally (males on day 29 and females at lactation day 14) were subjected to a detailed necropsy with special emphasis on the reproductive organs. The results of the study suggest that there were no abortion/premature deliveries observed in any of the dose levels during the study period. No other pregnancy and litter parameters were adversely affected. The reproductive organ weight data, gross and histopathological examination of reproductive organs did not reveal any test item related changes. The only effect noted in the study was a slight decrease in body weight and body weight gain in parental males during pre-mating and mating. Hence, the systemic toxicity NOAEL for males was set at 500 mg/kg bw/day, while the corresponding systemic toxicity NOAEL for females was established at 1000 mg/kg bw/day. Importantly, due to the absence of any adverse effects on reproductive and developmental parameters in parents and offspring, the NOAEL for reproduction/development was set at 1000 mg/kg bw/day, the highest dose tested.

In accordance with Regulation (EC) No 1907/2006, Annex IX, 8.7.3, column 1, an Extended One-Generation Reproductive Toxicity Study is required if “the available repeated dose toxicity studies (e.g. 28-day or 90-day studies, OECD 421 or 422 screening studies) indicate adverse effects on reproductive organs or tissues”.

For Dipentaerythritol hexaesters of 3,5,5-trimethylhexanoic, n-decanoic, n-heptanoic, and n-octanoic acids (EC 453-490-7), a reliable combined 28-Day Repeated dose Toxicity study in rats with the reproduction/developmental toxicity screening study is available, which was conducted according to OECD 422 and compliant with GLP. In this study there were no adverse effects on reproduction, neither in the parents nor in the offspring. Therefore, the maternal and offspring NOAEL for reproductive toxicity was 1000 mg/kg bw/day, which was the highest dose tested.

Furthermore, data on repeated-dose toxicity studies are available for similar substances, including the Pentaerythritol ester of pentanoic acids and isononanoic acid (CAS# 146289-36-3). Pentaerythritol ester of pentanoic acids and isononanoic acid category member (CAS# 146289-36-3) did not show adverse effects on reproductive organs and tissues including testes, epididymides, prostate, seminal vesicles, ovaries, and uterus after oral exposure over 90-days. 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, 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, Dipentaerythritol hexaesters of 3,5,5-trimethylhexanoic, n-decanoic, n-heptanoic, and n-octanoic acids (EC 453-490-7) is considered to exhibit low toxicological activity and systemic absorption. Especially, no toxic effects to reproduction were observed in the combined 28-Day Repeated dose Toxicity study with the reproduction/developmental toxicity screening study and the other available studies with analogue source substances. 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

 

The available data from a combined repeated-dose toxicity study with the reproductive/developmental screening test (according to OECD 422) performed in Wistar rats revealed no signs of reproductive toxicity up to the highest dose of 1000 mg/kg bw/day stested.

Additionally, 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. As no indications for effects on reproductive organs were found (NOAEL > 1000 mg/kg bw/day) Fatty acids C5-10 esters with dipentaerythritol (CAS# 70893-72-1) were not considered to have toxic effects on reproductive organs.

Effects on developmental toxicity

Description of key information

Oral (OECD 422), rat: NOAEL >= 1000 mg/kg bw/day (substance-specific data)
Oral (OECD 414), rat: NOAEL >= 1000 mg/kg bw/day (substance-specific data);
Oral  (OECD 414), rat: NOAEL = 1000 mg/kg bw/day (analogue approach);
Dermal (OECD 414), rat: NOAEL= 2000 mg/kg bw/day (analogue approach)

The hazard assessment is based on the data currently available. New studies with the registered substance and/or other member substances of the polyol esters family will be conducted in the future. The finalised studies will be included in the technical dossier as soon as they become available and the hazard assessment will be re-evaluated accordingly.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises adequate, reliable study (Klimisch score 2) from reference substances with similar structure and intrinsic properties, as well as substance-specific data. 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

The hazard assessment is based on the data currently available. New studies with the registered substance and/or other member substances of the polyol esters family will be conducted in the future. The finalised studies will be included in the technical dossier as soon as they become available and the hazard assessment will be re-evaluated accordingly.

Justification for grouping of substances and read-across

Apart from one combined 28-day repeated dose toxicity study with the reproduction/developmental screening test, there are no data available for developmental toxicity of the substance Fatty acids C5-10 esters with dipentaerythritol (CAS# 70983-72-1). 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
70983-72-1 (a) Target substance	RA: CAS 11138-60-6 RA: CAS 189200-42-8 RA: CAS 111937-03-2 NOAEL ≥ 1000 mg/kg bw/day
11138--60-6 (b)	NOAEL = 2000 mg/kg bw/day
189200-42-8	NOAEL ≥ 1000 mg/kg bw/day
111937-03-2	NOAEL ≥ 1000 mg/kg bw/day

(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.

 

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 Fatty acids C5-10 esters with dipentaerythritol (CAS# 70983-72-1).

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

 

Discussion

Developmental toxcitiy

 

EC 453-490-7 (former CAS 70983-72-1)

One recent study is available for EC 453-490-7, which was a combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening study in the rat (Nyco, 2022). The study was conducted under GLP conditions and according to OECD 422. The study is considered reliable and valid. This study was designed to investigate the potential adverse effects of the test substance upon repeated, subacute exposure period in Wistar rats, including potential adverse effects on reproductive/developmental endpoints. Females were dosed (50 to 60 days) throughout the study. This included two weeks prior to mating, the variable time to conception, the duration of pregnancy and thirteen days after delivery, up to and including the day before scheduled sacrifice. Males were dosed from the premating period throughout mating and until after mating until a total dosing period of 28 days was reached. Parental animals received the test substance in corn oil orally via gavage once daily at doses of 250, 500 and 1000 mg/kg bw/day. A similarly constituted control group received the vehicle (corn oil) only. After parturition, each litter was examined for number and sex of pups, still births, live births, runts and the presence of gross abnormalities. The anogenital distance in the pups was also measured, and the numbers of nipples /areaolae was recorded. All animals sacrificed terminally (males on day 29 and females at lactation day 14) were subjected to a detailed necropsy with special emphasis on the reproductive organs. The results of the study suggest that there were abortion/premature deliveries observed in any of the dose levels during the study period. No other pregnancy and litter parameters were adversely affected. The reproductive organ weight data, gross and histopathological examination of reproductive organs did not reveal any test item related changes. The only effect noted in the study was a slight decrease in body weight and body weight gain in parental males during the premating and mating periods. Hence, the systemic toxicity NOAEL for males was set at 500 mg/kg bw/day, while the corresponding systemic toxicity NOAEL for females was established at 1000 mg/kg bw/day. Importantly, due to the absence of any adverse effects on reproductive and developmental parameters in parents and offspring, the NOAEL for reproduction/development was set at 1000 mg/kg bw/day, the highest dose tested.

 

Addtionally, in accordance to Regulation (EC) No. 1907/2006 Annex XI, 1.5 a read-across from thesource 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 (Exxon Mobil, 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 (BASF, 1997). 23-24 pregnant female Sprague-Dawley rats/dose level were administered 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, there was an adverse effect on body weight and body weight gain in male rats (NOAEL: 500 mg/kg bw/day). In contrast, the available 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

 

The available data from a combined repeated-dose toxicity study with the reproductive/developmental screening test (according to OECD 422) performed in Wistar rats revealed no signs of developmental toxicity up to the highest dose of 1000 mg/kg bw/day tested. No prenatal developmental toxicity studies are available for Fatty acids C5-10 esters with dipentaerythritol (CAS# 70893-72-1) 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, Fatty acids C5-10 esters with dipentaerythritol (CAS# 70893-72-1) was not considered to have a potential for developmental toxicity.

Justification for classification or non-classification

Based on substance-specific data and 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.