Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
12 000
Study duration:
subchronic
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Justification for grouping of substances and read-across

The polyol esters category comprises of 51 aliphatic esters of polyfunctional alcohols containing two to six reactive hydroxyl groups and one to six fatty acid chains. The category contains mono constituent, multi-constituent and UVCB substances with fatty acid carbon chain lengths ranging from C5 - C28, which are mainly saturated but also mono unsaturated C16 and C18, polyunsaturated C18, branched C5 and C9,branched C14 – C22 building mono-, di-, tri-, and tetra esterswith an alcohol (i.e.polyol).

The available data 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.

A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Section 7.1 and 13) and within Chapter 5.1 of the CSR.

Discussion

CAS 71010 -76 -9:

Both a reproductive toxicity screening study and a two-generation reproductive toxicity study on 71010 -76-9 by the dietary route are available to assess the potential of the category members to induce effects on reproduction. Both studies were without adverse effect on fertility and reproductive function parameters, with no effects on estrous cycle, sperm parameters, histological and organ weight changes, and reproductive indices.

Additionally, 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.

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

Conclusion for reproductive toxicity

However, in a reproductive toxicity screening study and a two-generation reproductive toxicity study on 71010 -76 -9, no adverse effects on reproductive endpoints were identified, with the NOAEL for all generations (P, F1 and F2) being the highest dose tested, 12,000ppm in the diet (approx. 1,000mg/kg/d).

Taken together with the results of four 90-day repeated dose studies performed with PE and TMP esters (CAS 403507-18-6, CAS 146289-36-3 and CAS 67762-53-2), where reproductive organs and sperm morphology were examined and no indications for effects on reproductive parameters were found (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 are not considered to have a potential for reproductive toxicity.

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


Short description of key information:
No data available

Effects on developmental toxicity

Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no adverse effect observed
Additional information

Justification for grouping of substances and read-across

The polyol esters category comprises of 51 aliphatic esters of polyfunctional alcohols containing two to six reactive hydroxyl groups and one to six fatty acid chains. The category contains mono constituent, multi-constituent and UVCB substances with fatty acid carbon chain lengths ranging from C5 - C28, which are mainly saturated but also mono unsaturated C16 and C18, polyunsaturated C18, branched C5 and C9,branched C14 – C22 building mono-, di-, tri-, and tetra esters with an alcohol (i.e.polyol).

The available data 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.

A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Section 7.1 and 13) and within Chapter 5.1 of the CSR.

Data matrix for developmental toxicity

CAS

Developmental toxicity

NPG esters

68855-18-5

RA: CAS 11138-60-6

31335-74-7

RA: CAS 11138-60-6

70693-32-2

RA: CAS 11138-60-6

former CAS 85186-86-3

RA: CAS 11138-60-6

85186-86-3

RA: CAS 11138-60-6

85186-95-4

RA: CAS 11138-60-6

85116-81-0

RA: CAS 11138-60-6

91031-27-5

RA: CAS 11138-60-6

42222-50-4

RA: CAS 11138-60-6

85005-25-0

RA: CAS 11138-60-6

TMP esters

78-16-0

RA: CAS 11138-60-6

RA: CAS 67762-53-2

91050-88-3

RA: CAS 11138-60-6

11138-60-6

NOAEL = 2000 mg/kg bw

91050-89-4

RA: CAS 11138-60-6

RA: CAS 67762-53-2

85566-29-6

RA: CAS 11138-60-6

(Formerly 85186-89-6)

RA: CAS 11138-60-6

68002-79-9

RA: CAS 11138-60-6

 (Formerly 85005-23-8)

EC 931-531-4

RA: CAS 11138-60-6

68002-78-8

RA: CAS 11138-60-6

RA: CAS 67762-53-2

 (Formerly 57675-44-2)

EC 931-461-4

RA: CAS 11138-60-6

85186-92-1

RA: CAS 11138-60-6

68541-50-4

RA: CAS 11138-60-6

RA: CAS 67762-53-2

PE esters

15834-04-5

RA: CAS 11138-60-6

RA: CAS 67762-53-2

85116-93-4

RA: CAS 189200-42-8

85711-45-1

RA: CAS 189200-42-8

25151-96-6

RA: CAS 189200-42-8
RA: CAS 11138-60-6

67762-53-2

NOAEL < 800 mg/kg bw

(Formerly 68441-94-1)

RA: CAS 11138-60-6

RA: CAS 189200-42-8

RA: CAS 67762-53-2

(Formerly 68424-30-6)

RA: CAS 11138-60-6

RA: CAS 189200-42-8

RA: CAS 67762-53-2

68424-31-7 (c)

RA: CAS 11138-60-6

RA: CAS 189200-42-8

RA: CAS 67762-53-2

68424-31-7 (d)

RA: CAS 11138-60-6

RA: CAS 189200-42-8

RA: CAS 67762-53-2

68424-31-7 (e)

RA: CAS 11138-60-6

RA: CAS 189200-42-8

RA: CAS 67762-53-2

71010-76-9

RA: CAS 189200-42-8
RA: CAS 67762-53-2

85586-24-9

RA: CAS 11138-60-6

85049-33-8

RA: CAS 11138-60-6

RA: CAS 189200-42-8

RA: CAS 67762-53-2

91050-82-7

RA: CAS 189200-42-8

19321-40-5

RA: CAS 189200-42-8
RA: CAS 11138-60-6

68604-44-4

RA: CAS 189200-42-8

62125-22-8

RA: CAS 189200-42-8

68440-09-5

RA: CAS 189200-42-8
RA: CAS 11138-60-6

189200-42-8

NOAEL = 1000 mg/kg bw

(a) Category members subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in bold font.

(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.

For all category members registered under REACh a full data set for each endpoint is provided. For substances not subject to the current REACh Phase-in registration, lack of data for a given endpoint is indicated by "--".

 (c) CAS 68434-31-7 – Lead registrant

(d) Separate registration of CAS 68434-31-7

(e) Separate registration of CAS 68434-31-7 (2-ethylhexanoic acid)

Discussion

Developmental toxicity

There are three studies available within the polyol esters category to assess the potential to induce developmental effects.

CAS 11138-60-6

Fatty acids, 8-10 (even numbered), di- and triesters with propylidynetrimethanol (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 sex per dose were treated with 200, 600 or 2000 mg/kg bw/day in corn oil on Days 6-15 of gestation. Control animals (25 per sex per dose) received the vehicle. The middle and the high 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 bw/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 67762-53-2

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/day during gestational days 0 to 19. Control animals remained untreated. 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 revealed no differences to controls and thus no indication for teratogenic effects. The only effect found was a dose-dependently increased number of fetuses with levocardia, although no hearth malformations have been detected. Furthermore levocardia was observed in vehicle control foetuses (Smith et al. 1988) and in the control foetuses conducted in the test laboratory. Since levocardia was observed in both treated groups, the NOAEL for embryo-/fetotoxicity and teratogenicity in rats Fatty acids, C5-9, tetraesters with pentaerythritol was found to be < 800 mg/kg bw/day and the LOAEL = 800 mg/kg bw/day.

CAS 189200-42-8

The developmental toxicity of Fatty acids C8-10, mixed esters with dipentaerythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS 189200-42-8) was investigated according to OECD Guideline 414 (prenatal developmental toxicity study) and under GLP conditions (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. Control animals received the vehicle polyethylene glycol (PEG 400). 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. 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 in two high dose females. The NOAEL for embryo-/fetotoxicity and teratogenicity in rats for Fatty acids C8-10, mixed esteres with dipentaerythritol, isooctanoic acid, pentaerythritol and tridipentaerythritol was found to be 1000 mg/kg bw/day.

Conclusion for developmental toxicity

There are three studies available from the Polyol PE and TMP esters which were used to assess the developmental toxicity/teratogenic potential of the polyol esters category members.

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/day since levocardia was found in the pups of both treated groups, although not internal heart malformation was detected. However, prenatal developmental toxicity studies conducted with Fatty acids, 8-10 (even numbered), di- and triesters with propylidynetrimethanol (CAS11138-60-6) and PE ester Fatty acids C8-10, mixed esters with dipentaerythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS 189200-42-8) did not show any developmental toxic effects. The NOAELs are 2000 mg/kg bw/day and 1000 mg/kg bw/day, respectively. Therefore, the members of the polyol esters category were not considered to have a potential for developmental toxicity.

 

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.