Registration Dossier

Administrative data

Description of key information

All available subacute and subchronic repeated dose oral toxicity studies resulted in NOAELs of 1000 mg/kg bw/day or greater.
The available subchronic repeated dose inhalation toxicity study results in NOAEC 0.5mg/L.
The available subchronic repeated dose dermal toxicity study results in NOAEL of 2000 mg/kg bw/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
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 Sections 7.1 and 13) and within Chapter 5.1 of the CSR.

 

Data matrix for repeated dose toxicity

CAS

oral

NOAEL, rat (sex) mg/kg bw/day

Inhalation

NOAEC, rat (sex) mg/L air

Dermal

NOAEL, rat (sex) mg/kg bw/day

NPG esters

68855-18-5(a)

RA: CAS 189120-64-7

RA: CAS 68424-31-7

RA: CAS 146289-36-3

RA: CAS 403507-18-6

RA: CAS 67762-53-2

RA: CAS 67762-53-2

31335-74-7

RA: CAS 189120-64-7

RA: CAS 68424-31-7

RA: CAS 146289-36-3

RA: CAS 403507-18-6

RA: CAS 67762-53-2

RA: CAS 67762-53-2

70693-32-2

RA: CAS 189120-64-7

RA: CAS 68424-31-7

RA: CAS 146289-36-3

RA: CAS 403507-18-6

RA: CAS 67762-53-2

RA: CAS 67762-53-2

former CAS 85186-86-3

RA: CAS 189120-64-7

RA: CAS 68424-31-7

RA: CAS 146289-36-3

RA: CAS 403507-18-6

RA: CAS 67762-53-2

RA: CAS 67762-53-2

85186-86-3

RA: CAS 189120-64-7

RA: CAS 68424-31-7

RA: CAS 146289-36-3

RA: CAS 403507-18-6

RA: CAS 67762-53-2

RA: CAS 67762-53-2

85186-95-4

RA: CAS 189120-64-7

RA: CAS 68424-31-7

RA: CAS 146289-36-3

RA: CAS 403507-18-6

RA: CAS 67762-53-2

RA: CAS 67762-53-2

85116-81-0

RA: CAS 189120-64-7

RA: CAS 68424-31-7

RA: CAS 146289-36-3

RA: CAS 403507-18-6

RA: CAS 67762-53-2

RA: CAS 67762-53-2

91031-27-5

RA: CAS 189120-64-7

RA: CAS 68424-31-7

RA: CAS 146289-36-3

RA: CAS 403507-18-6

RA: CAS 67762-53-2

RA: CAS 67762-53-2

42222-50-4

RA: CAS 189120-64-7

RA: CAS 68424-31-7

RA: CAS 146289-36-3

RA: CAS 403507-18-6

RA: CAS 67762-53-2

RA: CAS 67762-53-2

85005-25-0

RA: CAS 189120-64-7

RA: CAS 68424-31-7

RA: CAS 146289-36-3

RA: CAS 403507-18-6

RA: CAS 67762-53-2

RA: CAS 67762-53-2

TMP esters

78-16-0 (a)

RA: CAS 189120-64-7

RA: CAS 68424-31-7

RA: CAS 146289-36-3

RA: CAS 403507-18-6

RA: CAS 67762-53-2

RA: CAS 67762-53-2

91050-88-3

RA: CAS 189120-64-7

RA: CAS 68424-31-7

RA: CAS 146289-36-3

RA: CAS 403507-18-6

RA: CAS 67762-53-2

RA: CAS 67762-53-2

189120-64-7(b)

1000 (28-day, m, f)

--

--

11138-60-6 (d)

RA: CAS 189120-64-7

RA: CAS 68424-31-7

RA: CAS 146289-36-3

RA: CAS 403507-18-6

RA: CAS 67762-53-2

RA: CAS 67762-53-2

91050-89-4

RA: CAS 189120-64-7

RA: CAS 68424-31-7

RA: CAS 146289-36-3

RA: CAS 403507-18-6

RA: CAS 67762-53-2

RA: CAS 67762-53-2

85566-29-6

RA: CAS 189120-64-7

RA: CAS 68424-31-7

RA: CAS 146289-36-3

RA: CAS 403507-18-6

RA: CAS 67762-53-2

RA: CAS 67762-53-2

(Formerly 85186-89-6)

RA: CAS 189120-64-7

RA: CAS 68424-31-7

RA: CAS 146289-36-3

RA: CAS 403507-18-6

RA: CAS 67762-53-2

RA: CAS 67762-53-2

403507-18-6

1000 (90-day, m, f)

--

--

68002-79-9

RA: CAS 189120-64-7

RA: CAS 68424-31-7

RA: CAS 146289-36-3

RA: CAS 403507-18-6

RA: CAS 67762-53-2

RA: CAS 67762-53-2

(Formerly 85005-23-8)

RA: CAS 189120-64-7

RA: CAS 68424-31-7

RA: CAS 146289-36-3

RA: CAS 403507-18-6

RA: CAS 67762-53-2

RA: CAS 67762-53-2

68002-78-8

RA: CAS 189120-64-7

RA: CAS 68424-31-7

RA: CAS 146289-36-3

RA: CAS 403507-18-6

RA: CAS 67762-53-2

RA: CAS 67762-53-2

 (Formerly 57675-44-2)

RA: CAS 189120-64-7

RA: CAS 68424-31-7

RA: CAS 146289-36-3

RA: CAS 403507-18-6

RA: CAS 67762-53-2

RA: CAS 67762-53-2

85186-92-1

RA: CAS 189120-64-7

RA: CAS 68424-31-7

RA: CAS 146289-36-3

RA: CAS 403507-18-6

RA: CAS 67762-53-2

RA: CAS 67762-53-2

68541-50-4

RA: CAS 189120-64-7

RA: CAS 68424-31-7

RA: CAS 146289-36-3

RA: CAS 403507-18-6

RA: CAS 67762-53-2

RA: CAS 67762-53-2

PE esters

15834-04-5

RA: CAS 68424-31-7

RA: CAS 146289-36-3

RA: CAS 67762-53-2

RA: CAS 67762-53-2

85116-93-4

RA: CAS 68424-31-7

RA: CAS 146289-36-3

RA: CAS 67762-53-2

RA: CAS 67762-53-2

85711-45-1 (a)

RA: CAS 146289-36-3

RA: CAS 67762-53-2

RA: CAS 67762-53-2

25151-96-6

RA: CAS 146289-36-3

RA: CAS 67762-53-2

RA: CAS 67762-53-2

67762-53-2

RA: CAS 146289-36-3

0.50 (90-day, m, f)

> 2000 (90-day, m, f)

(Formerly 68441-94-1)

RA: CAS 68424-31-7

RA: CAS 146289-36-3

RA: CAS 67762-53-2

RA: CAS 67762-53-2

(Formerly 68424-30-6)

RA: CAS 68424-31-7

RA: CAS 146289-36-3

RA: CAS 67762-53-2

RA: CAS 67762-53-2

146289-36-3 (b)

1000 (90-day, m, f)

--

--

68424-31-7 (c)

1613 (28-day, f)

RA: CAS 146289-36-3

RA: CAS 67762-53-2

RA: CAS 67762-53-2

68424-31-7 (d)

1613 (28-day, f)

RA: CAS 146289-36-3

RA: CAS 67762-53-2

RA: CAS 67762-53-2

68424-31-7 (e)

1613 (28-day, f)

RA: CAS 146289-36-3

RA: CAS 67762-53-2

RA: CAS 67762-53-2

71010-76-9

RA: CAS 146289-36-3

RA: CAS 67762-53-2

RA: CAS 67762-53-2

85586-24-9

RA: CAS 146289-36-3

RA: CAS 67762-53-2

RA: CAS 67762-53-2

85049-33-8

RA: CAS 68424-31-7

RA: CAS 146289-36-3

RA: CAS 67762-53-2

RA: CAS 67762-53-2

91050-82-7

RA: CAS 146289-36-3

RA: CAS 67762-53-2

RA: CAS 67762-53-2

19321-40-5

RA: CAS 146289-36-3

RA: CAS 67762-53-2

RA: CAS 67762-53-2

68604-44-4

RA: CAS 146289-36-3

RA: CAS 67762-53-2

RA: CAS 67762-53-2

62125-22-8

RA: CAS 146289-36-3

RA: CAS 67762-53-2

RA: CAS 67762-53-2

68440-09-5

RA: CAS 146289-36-3

RA: CAS 67762-53-2

RA: CAS 67762-53-2

 

(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

Repeated Dose Toxicity - Oral

There are no studies available assessing the oral repeated dose toxicity of the substances to be registered. To assess the potential for toxicity following repeated oral uptake, data from two category members belonging to the polyol PE and TMP esters were considered applying a category based read-across, in accordance to Regulation (EC) No. 1907/2006 Annex XI, Item 1.5. Fatty acids, C7-8, triesters with trimethylolpropane (CAS# 189120-64-7), Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane (CAS# 403507-18-6), Pentaerythritol ester of pentanoic acids and isononanoic acid (CAS# 146289-36-3) and Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids, and were used as read-across substances.

Subacute Oral Repeated Rose Toxicity

A 28-day oral feeding toxicity study with Fatty acids, C7-8, triesters with trimethylolpropane (CAS# 189120-64-7) was performed according to OECD Guideline 407 and under GLP conditions (Trimmer, 2000). Groups of 5 male and 5 female Cr:CD BR rats were exposed to the substance at 100, 300 and 1000 mg/kg bw/day by gavage, 7 days/week for 28 days. Control animals (5 per sex and dose) received the concurrent vehicle, peanut oil. Observations and examinations of the animals included clinical signs, body weight, food consumption, haematology, clinical chemistry, organ weights, neurobehaviour, gross necropsy and histopathology. Female animals tolerated the daily oral administration of the test substance without any adverse effects (included mortality) up to the high dose of 1000 mg/kg bw/day. In male animals no adverse effects were observed for all investigated parameters except for histopathology. An increased amount of hyaline droplets (the main constituent of which is alpha-2µ-globulin) in the proximal cortical tubular epithelium was confirmed microscopically in the cytoplasm of the renal cortical tubular epithelial cells in male rats treated with 300 and 1000 mg/kg bw/day, respectively. As this phenomenon is widely accepted to be specific to the male rat and as such is considered to have no relevance to man, the 28-day oral NOAEL, for Fatty acids, C7-8, triesters with trimethylolpropane was found 1000 mg/kg bw/day for male and female rats.

Furthermore, a 28 day study with Fatty acids, C5-10, esters with pentraerythritol (CAS# 68424-31-7) was conducted according to OECD Guideline 407 and under GLP conditions (Brammer, 1993). The test substance was administered in concentrations of 1000 ppm, 5000 ppm and 12500 ppm (corresponding to 112, 562 and 1450 mg/kg bw/day for male and 119, 586 and 1613 mg/kg bw/day for female rats) to 5 Alpk:APfSD rats per sex and dose for 28 consecutive days. Control animals (5 per sex and dose) received the plain diet. There were no toxicologically significant effects on body weight, food consumption and clinical condition and mortality up to and including the highest dose level. Changes in clinical chemistry and red cell-related parameters were observed in male rats at 12500 ppm, but these were minor and considered not to be of toxicological significance. A minimal hepatocyte hypertrophy present in males of the 12500 ppm group was observed and considered to be evidence of an adaptive response. Microscopic examination of the kidneys from male animals from all dose groups revealed an increase in hyaline droplet formation (the main constituent of which is alpha-2µ-globulin) and tubular basophilia. This phenomenon is widely accepted to be specific to the male rat and as such is considered to have no relevance to man. A NOAEL of 1450 and 1613 mg/kg/d could be identified for male and female rats, respectively.

Subchronic Oral Repeated Dose Toxicity

A 90-day oral feeding 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 and under GLP conditions (McRae, 2004). Groups of 10 male and 10 female Sprague-Dawley rats were exposed to the substance at 5, 50 and 1000 mg/kg bw/day by gavage, 7 days/week for 90 days. Control animals (10 per sex and dose) received the concurrent vehicle, arachis oil. Observations and examinations of the animals included clinical sings, body weight, food consumption, haematology, clinical chemistry, organ weights, neurobehaviour, gross necropsy and histopathology. The daily oral administration of the test substance was tolerated without any adverse effects up to the high dose of 1000 mg/kg bw/day. There were no toxicologically significant effects on body weight, food consumption and clinical condition and mortality up to and including the highest dose level. Some incidental and spontaneous effects during histophathology examinations were observed but those were not due to the test substance administration. Therefore, a 90-day oral NOAEL of 1000 mg/kg bw/day was found for Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane in male and female rats.

Another 90-day oral feeding toxicity study with Pentaerythritol ester of pentanoic acids and isononanoic acid (CAS# 146289-36-3) was performed according to OECD Guideline 408 and under GLP conditions (Müller, 1998). Groups of 10 male and 10 female Wistar rats were exposed to the substance at 100, 300 and 1000 mg/kg bw/day by gavage daily, 7 days/week for 90 days. Satellite control and high dose groups containing 10 male and female animals each were observed for additional 28 days. Control animals (10 per sex and dose) received the concurrent vehicle, distilled water containing 1% Tween 80. Observations and examinations of the animals included clinical signs, body weight, food consumption, haematology, clinical chemistry, organ weights, neurobehaviour, gross necropsy and histopathology. The daily oral administration of the test substance was tolerated without any adverse effects up to 1000 mg/kg bw/day. No mortality was observed except for two animals that died shortly after administration due to incorrect gavage. Absolute and relative kidney weights were increased in all male animals in the high dose group which was still present after the recovery period. However, histopathology revealed no adverse effects in the kidney. Absolute and relative liver weights were increased in both sexes but this was no longer apparent after the recovery period in females. Other significant differences seem to be incidental. The activity of alkaline phosphatase of the serum significantly increased in the high dose group, males and females. This indicates damage to liver cells and/or an increased function rate. This finding was no longer apparent at the end of the treatment-free period. Except for the increased kidney weights and liver weight in the males, all changes (e.g. clinical chemical changes) were no longer apparent at the end of the treatment-free period. The increase in kidney weights in all male animals could be correlated to the formation of hyaline droplets a phenomenon widely accepted to be specific to the male rat and as such considered to have no relevance to man, a 90-day oral NOAEL of 1000 mg/kg bw/day was found for Pentaerythritol ester of pentanoic acids and isononanoic acid in male and female rats.

Conclusion for Repeated Dose Toxicity - Oral

In summary, two 28-day studies conducted with Fatty acids, C7-8, triesters with trimethylolpropane (CAS# 189120-64-7) and Fatty acids, C5-10, esters with pentraerythritol (CAS# 68424-31-7) showed no signs of overt toxicity. However, in both studies formation of an increased amount of hyaline droplets in the proximal cortical tubular epithelium of the kidney was observed. The 90-day study with Pentaerythritol ester of pentanoic acids and isononanoic acid (CAS# 146289-36-3) did not show any sign of overt toxicity. However, increased kidney and liver weights in the male animals was observed.

A further 90-day oral feeding toxicity study with Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane (CAS# 403507-18-6) show no toxicologically significant effects on body weight, food consumption and clinical condition and mortality up to and including the highest dose level.

In conclusion, since the effects observed are not considered to be systemic and relevant for humans, the NOAEL was found to exceed 1000 mg/kg bw for all substances based on the result from the 28 and 90-day studies.

Repeated Dose Toxicity - Inhalation

With regard to the endpoint repeated dose toxicity inhalation, one study is available within the polyol esters category.

Subchronic Inhalation Repeated Dose Toxicity

A 90-day subchronic inhalation toxicity study was performed with 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 aerosol for 6 hours/day, 5 days/week at concentrations of 0.05, 0.15 and 0.5 mg/L. The respective controls (15 animals per sex and dose) inhaled clean air under the same conditions. Animals were observed for clinical sings, body weight, haematology, clinical chemistry, organ weights, gross necropsy and histopathological examinations. 10 additional male animals were included in every group for examination of pulmonary function tests and pulmonary hydroxyproline following exposure. No substance-related adverse effects were observed for body weight, body weight gain, mortality, clinical biochemistry and haematological parameters. The lungs of the high dose animals had a minimal increase in weight which correlated with slightly increased numbers of macrophages in the pulmonary alveoli. Thus, the NOAEC were found to be 0.5 mg/L.

Conclusion for Repeated Dose Toxicity - inhalation

For repeated dose inhalation toxicity, one study is available within the polyol esters category which was considered for assessment of all category members by category based read-across. The 90-day sub-chronic inhalation toxicity study showed a minimal effect on lungs including increased weight and slightly increased numbers of macrophages in pulmonary alveoli. Therefore, the NOAEC for repeated inhalation toxicity was found to be 0.5 mg/L for the polyol esters category.

Repeated Dose Toxicity – dermal

With regard to the toxicity after repeated dermal application, one study is available within the polyol esters category. Therefore, category based read-across, in accordance to Regulation (EC) No. 1907/2006 Annex XI, Item 1.5, from a polyol PE ester was applied. 

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 were once daily (5 days/week, 24 hours/day) exposed to the substance at 800 and 2000 mg/kg bw for 90 days (65 applications in total). Application to the skin was done open without coverage. Animals were observed for clinical signs, body weight, dermal irritation, haematology, clinical chemistry, urinalysis, organ weights, gross necropsy and histopathological examinations.

Overall there were no adverse effects found after dermal application of the test substance for 90 days on the parameters investigated. Treated males gained less body weight than control animals. Since the effect was low and no dose-relation was observed, it was not considered to be due to systemic toxicity. Some serum parameters of the high dose group animals were significant different to the control, but since the differences were small and they did not present any pattern suggestive of effects on a specific organ, they were considered not to be of toxicological relevance. Both treated groups exhibited minimal erythema and flaking of the skin during the dosing phase. At microscopic examination it was identified as very minor epidermal hyperplasia and chronic inflammation of the superficial dermis. Since no effects of systemic toxicity were identified up to the highest dose tested, the 90 day dermal NOAEL was found to be 2000 mg/kg bw/day for Fatty acids, C5-9, tetraesters with pentaerythritol in Sprague-Dawley rats.

Conclusion for Repeated Dose Toxicity - dermal

For repeated dermal toxicity, one study is available within the polyol esters category and was considered for assessment of all

 

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 repeated dose 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.