Registration Dossier

Administrative data

Key value for chemical safety assessment

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 genetic toxicity

CAS

Bacterial gene mutation

cytogenicity in mammalian cells in vitro

Mammalian gene mutation

Genotoxicity in vivo

NPG esters

 

68855-18-5 (a)

RA: CAS 31335-74-7

negative

negative

--

G31335-74-7

negative

RA: CAS 68855-18-5

RA: CAS 68855-18-5

RA: CAS 42222-50-4

--

70693-32-2

RA: CAS 97281-24-8

RA: CAS 85186-86-3

RA: CAS 403507-18-6

RA: CAS 68855-18-5

RA: CAS 42222-50-4

--

former CAS 85186-86-3

RA: CAS 85186-86-3

RA: CAS 85186-86-3

RA: CAS 68855-18-5

RA: CAS 42222-50-4

--

85186-86-3

negative

negative

RA: CAS 68855-18-5

RA: CAS 42222-50-4

--

85186-95-4

RA: CAS 85186-86-3

RA: CAS 85186-86-3

RA: CAS 68855-18-5

RA: CAS 42222-50-4

--

85116-81-0

RA: CAS 85186-86-3

RA: CAS 68855-18-5

RA: CAS 85186-86-3

RA: CAS 68855-18-5

RA: CAS 42222-50-4

--

91031-27-5

RA: CAS 85186-86-3

RA: CAS 68855-18-5

RA: CAS 85186-86-3

RA: CAS 68855-18-5

RA: CAS 42222-50-4

--

42222-50-4

RA: CAS 403507-18-6

RA: CAS 85186-86-3

RA: CAS 403507-18-6

RA: CAS 85186-86-3

negative

--

85005-25-0

RA: CAS 85186-86-3

RA: CAS 85186-86-3

RA: CAS 68855-18-5

RA: CAS 42222-50-4

--

TMP esters

 

78-16-0 (a)

negative

RA: CAS 189120-64-7

RA: CAS 11138-60-6

RA: CAS 85186-89-6

--

91050-88-3

RA: CAS 85186-89-6

RA: CAS 403507-18-6

RA: CAS 11138-60-6

RA: CAS 85186-89-6

RA: CAS 68424-31-7

97281-24-8(b)

negative

--

--

--

189120-64-7

--

negative

--

--

11138-60-6

negative

negative

RA: CAS 85186-89-6

RA: CAS 68424-31-7

91050-89-4

negative

RA: CAS 11138-60-6

RA: CAS 85186-89-6

--

85566-29-6

RA: CAS 11138-60-6

RA: CAS 403507-18-6

RA: CAS 11138-60-6

RA: CAS 85186-89-6

RA: CAS 68424-31-7

85186-89-6

negative

RA: CAS 403507-18-6

RA: CAS 11138-60-6

negative

RA: CAS 68424-31-7

403507-18-6

negative

negative

--

--

68002-79-9

RA: CAS 11138-60-6

RA: CAS 85005-23-8

RA: CAS 403507-18-6

RA: CAS 85186-89-6

RA: CAS 68424-31-7

 (Formerly 85005-23-8)

EC 931-531-4

negative

RA: CAS 403507-18-6

RA: CAS 11138-60-6

RA: CAS 85186-89-6

RA: CAS 68424-31-7

68002-78-8

RA: CAS 403507-18-6

RA: CAS 85186-89-6

RA: CAS 403507-18-6

RA: CAS 85186-89-6

--

 (Formerly 57675-44-2)

EC 931-461-4

RA: CAS 85005-23-8

RA: CAS 403507-18-6

RA: CAS 85186-89-6

RA: CAS 68424-31-7

85186-92-1

RA: CAS 85005-23-8

RA: CAS 403507-18-6

RA: CAS 11138-60-6

RA: CAS 85186-89-6

RA: CAS 42222-50-4

RA: CAS 68424-31-7

68541-50-4

RA: CAS 403507-18-6

RA: CAS 85186-89-6

RA: CAS 403507-18-6

RA: CAS 85186-89-6

--

PE esters

 

15834-04-5 (b)

RA: CAS 11138-60-6

RA: 67762-53-2

RA: CAS 189200-42-8

negative

RA: CAS 68424-31-7

85116-93-4

negative

RA: CAS 403507-18-6

RA: CAS 85186-89-6

RA: CAS 68424-31-7

85711-45-1 (a)

RA: CAS 85116-93-4
RA: CAS 85186-89-6

RA: CAS 403507-18-6

RA: CAS 85186-89-6

--

25151-96-6

RA: CAS 85116-93-4

RA: CAS 403507-18-6

RA: CAS 85186-89-6

--

67762-53-2


negative

 

RA: CAS 189200-42-8

RA: CAS 15834-04-5

--

(Formerly 68441-94-1)

RA: CAS 68441-68-9

RA: CAS 189200-42-8

RA: CAS 11138-60-6

 

 

RA: CAS 189200-42-8

RA: CAS 15834-04-5

RA: CAS 68424-31-7

(Formerly 68424-30-6)

RA: CAS 68441-68-9

RA: CAS 189200-42-8

RA: CAS 189200-42-8

RA: CAS 15834-04-5

RA: CAS 68424-31-7

68424-31-7 (c)

RA: CAS 11138-60-6

RA: 67762-53-2

RA: CAS 189200-42-8

RA: CAS 15834-04-5

RA: CAS 68424-31-7

68424-31-7 (d)

RA: CAS 11138-60-6

RA: 67762-53-2

RA: CAS 189200-42-8

RA: CAS 15834-04-5

RA: CAS 68424-31-7

68424-31-7 (e)

RA: CAS 11138-60-6

RA: 67762-53-2

RA: CAS 189200-42-8

RA: CAS 15834-04-5

RA: CAS 68424-31-7

71010-76-9

RA: CAS 68441-68-9
RA: CAS 189200-42-8

RA: CAS 189200-42-8

RA: CAS 15834-04-5

--

68441-68-9

negative

RA: CAS 189200-42-8

RA: CAS 15834-04-5

--

85586-24-9

negative

RA: CAS 189200-42-8

RA: CAS 15834-04-5

--

85049-33-8

RA: CAS 189200-42-8

RA: CAS 67762-53-2

RA: CAS 189200-42-8

RA: CAS 403507-18-6

RA: CAS 85186-89-6

RA: CAS 68424-31-7

91050-82-7

RA: CAS 85116-93-4

RA: CAS 403507-18-6

RA: CAS 85186-89-6

--

19321-40-5

RA: CAS 85116-93-4

RA: CAS 403507-18-6

RA: CAS 85186-89-6

--

68604-44-4

RA: CAS 85116-93-4
RA: CAS 85186-89-6

RA: CAS 403507-18-6

RA: CAS 85186-89-6

--

62125-22-8

RA: CAS 85116-93-4

RA: CAS 403507-18-6

RA: CAS 85186-89-6

--

68440-09-5

RA: CAS 85116-93-4
RA: CAS 85186-89-6

RA: CAS 403507-18-6
RA: CAS 189200-42-8

RA: CAS 85186-89-6
RA: CAS 15834-04-5

--

189200-42-8

negative

negative

---

--

 

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

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

In vitro gene mutation in bacteria

CAS 31335-74-7

The mutagenic potential of 2,2-dimethyl-1,3-propanediyl dioctanoate (CAS 31335-74-7) was tested in two reverse mutation assays performed comparable to OECD Guideline 471 and under GLP conditions (Callender, 1995 & 1996). Salmonella typhimurium strains TA1535, TA1537, TA98, TA100 and E. coli WP2P and WP2 uvrA were used. Within the first experiment, tester strains were incubated with test material concentrations of 100, 200, 500, 1000, 2500 and 5000 µg/plate dissolved in DMSO with and without the addition of a metabolic activation system (phenobarbitale and beta-naphthoflavone induced rat liver S9 mix) in a plate incorporation test. The repeat experiment within both studies was done with an additional 1 hour pre-incubation period. Vehicle and appropriate positive controls were included into the study design. Positive control materials induced statistically significant increases in the frequency of revertant colonies indicating the satisfactory performance of the test and the activity of the metabolizing system. No increase in the frequency of revertant colonies compared to concurrent vehicle controls was observed in all strains treated with the test substance in both experiments, neither in the presence nor in the absence of metabolic activation. No cytotoxicity was observed. Thus, 2,2-dimethyl-1,3-propanediyl dioctanoate did not induce point mutations by base-pair changes or frame-shifts in the genome of the strains tested under the conditions of these tests.

CAS 85186-86-3

The mutagenic potential of Fatty acids, C8-18 and C18-unsatd., esters with neopentylglycol (CAS 85186-86-3) was tested in a reverse mutation assay performed comparable to OECD Guideline 471 and under GLP conditions (Bowles, 2012). Salmonella typhimurium strains TA1535, TA1537, TA98, TA100 and E. coli WP2 uvrA were used. Tester strains were incubated with test material concentrations of 50, 150, 500, 1500, and 5000 µg/plate dissolved in acetone with and without the addition of a metabolic activation system (phenobarbitale and beta-naphthoflavone induced rat liver S9 mix). The first experiment was a plate incorporation assay and the repeat experiment was carried out using an additional 20 min pre-incubation. Vehicle, negative and appropriate positive controls were included into the study design. Positive control materials induced statistically significant increases in the frequency of revertant colonies indicating the satisfactory performance of the test and the activity of the metabolizing system. No increase in the frequency of revertant colonies compared to concurrent controls was observed in all strains treated with the test substance, neither in the presence nor in the absence of metabolic activation. No cytotoxicity was observed in the plate incorporation assay. However, cytotoxicity was seen at 5000 µg/plate without S9 mix in the TA100, TA1535 and TA1537 strains in the pre-incubation assay. Thus, Fatty acids, C8-18 and C18-unsatd., esters with neopentylglycol did not induce point mutations by base-pair changes or frame-shifts in the genome of the strains tested under the conditions of this test.

CAS 78-16-0

There are 4 studies available investigating the mutagenic potential of 2-ethyl-2-[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate (CAS 78-16-0) in bacteria.

In the first study, the mutagenic potential of the test substance was investigated in a reverse mutation assay performed comparable to OECD Guideline 471 and under GLP conditions (Wagner, 1997). Salmonella typhimurium strains TA1535, TA1537, TA98, TA100, TA1538 and E. coli WP2 uvrA were used. Tester strains were incubated with the test material dissolved in ethanol at concentrations of 10, 33, 100, 333 and 1000 µg/plate without metabolic activation and at 33, 100, 333, 1000 and 5000 µg/plate with metabolic activation (Arochlor 1254 induced rat liver S9 mix). Vehicle and appropriate positive controls were included into the study design. Positive control materials induced statistically significant increases in the frequency of revertant colonies indicating the satisfactory performance of the test and the activity of the metabolizing system. No increase in the frequency of revertant colonies compared to concurrent vehicle controls was observed in all strains treated with the test substance, neither in the presence nor in the absence of metabolic activation. No cytotoxicity was observed, but the test substance was tested up to precipitating concentrations. Thus, 2-ethyl-2-[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate did not induce point mutations by base-pair changes or frame-shifts in the genome of the strains tested under the conditions of this test.

There is a second Ames test available for which only a summary of the results was given (Callander, 1991). Salmonella typhimurium strains TA1535, TA1537, TA98, TA100 and E. coli WP2P and WP2P uvrA were tested. No test concentrations were given, but all strains were tested in a plate incorporation assay with and without metabolic activation. TA98 and TA100 were additionally tested in a preincubation assay. No increases in the frequency of revertant colonies in the strains treated with the test substance were found.

There are two additional studies available. Another Ames test was conducted which only contained 1 plate per incubation and no repeat experiment. Additionally, gene mutation in Saccharomyces cerevisiae D4 was examined. However, again only one plate per concentration was used and the validity of the positive control was doubtful. Due to these methodological deficiencies, both studies were not considered for assessment of mutagenic potential.

In summary, 2-ethyl-2-[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate is not considered to have mutagenic potential in bacteria.

CAS 97281-24-8

The mutagenic potential of Fatty acids, C8-10, mixed esters with neopentyl glycol and trimethylolpropane (CAS 97281-24-8) was tested in a reverse mutation assay comparable to OECD Guideline 471 and under GLP conditions (Banduhn, 1988). Salmonella typhimurium strains TA1535, TA1537, TA98, TA100 and TA1538 were used. Tester strains were incubated with test material dissolved in Tween 80/water at concentrations of 8, 40, 200, 1000 and 5000 µg/plate with and without the addition of a metabolic activation system (Aroclor 1254 induced rat liver S9 mix). Vehicle and appropriate positive controls were included into the study design. Positive control materials induced statistically significant increases in the frequency of revertant colonies indicating the satisfactory performance of the test and the activity of the metabolizing system. No increase in the frequency of revertant colonies compared to concurrent vehicle controls was observed in all strains treated with the test substance, neither in the presence nor in the absence of metabolic activation. No cytotoxicity was observed. Thus, Fatty acids, C8-10, mixed esters with neopentyl glycol and trimethylolpropane did not induce point mutations by base-pair changes or frame-shifts in the genome of the strains tested.

CAS 91050-89-4

The mutagenic potential of Fatty acids, C8-10, triesters with trimethylolpropane (CAS 91050-89-4) was tested in a reverse mutation assay comparable to OECD Guideline 471 and under GLP conditions (Banduhn, 1993). Salmonella typhimurium strains TA1535, TA1537, TA98, TA100 and TA1538 were used. Tester strains were incubated with test material dissolved in Tween 80 and water at concentrations of 8, 40, 200, 1000 and 5000 µg/plate with and without the addition of a metabolic activation system (Arochlor 1254 induced rat liver S9 mix). Vehicle, negative and appropriate positive controls were included into the study design. Positive control materials induced statistically significant increases in the frequency of revertant colonies indicating the satisfactory performance of the test and the activity of the metabolizing system. No increase in the frequency of revertant colonies compared to concurrent controls was observed in all strains treated with the test substance, neither in the presence nor in the absence of metabolic activation. No cytotoxicity was observed, but the test substance was tested up to precipitating concentrations. Thus, Fatty acids, C8-10, triesters with trimethylolpropane did not induce point mutations by base-pair changes or frame-shifts in the genome of the strains tested.

CAS 11138-60-6

In an Ames test conducted with the Fatty acids, 8-10 (even numbered), di- and triesters with propylidynetrimethanol (CAS 11138-60-6), Salmonella typhimurium strains TA 1535, TA 1537, TA 1538, TA 98, TA 100 and E.coli WP2 uvr A were treated according to OECD Guideline 471 (Bailey, 1996). The test substance was diluted in ethanol and test substance concentrations of 0, 10, 33, 100, 333 and 1000 µg/plate were tested in triplicate, both with and without the addition of a rat liver homogenate metabolising system (S9). Precipitation of the test substance was observed at and above 100 µg/plate. The test material caused no cytotoxicity up to the highest, precipitating dose. No significant increases in the frequency of revertant colonies were recorded for any of the bacterial strains, with any dose of the test material, either with or without metabolic activation.

 

Formerly 85186-89-6

The mutagenic potential of Fatty acids, C8-18 and C18-unsatd., esters with trimethylolpropane (Formerly CAS 85186-89-6) was examined in a reverse mutation assay comparable to OECD Guideline 471 and under GLP conditions (Wiebel, 1999). Salmonella typhimurium strains TA1535, TA1537, TA98, TA100 and TA1538 were used. Tester strains were incubated with test material dissolved in acetone at concentrations of 8, 40, 200, 1000 and 5000 µg/plate (no toxicity but tested up to precipitating concentrations) with and without the addition of a metabolic activation system (phenobarbitale and beta-naphthoflavone induced rat liver S9 mix). Vehicle, negative and appropriate positive controls were included into the study design. Positive control materials induced statistically significant increases in the frequency of revertant colonies indicating the satisfactory performance of the test and the activity of the metabolizing system. No increase in the frequency of revertant colonies compared to concurrent controls was observed in all strains treated with the test substance, neither in the presence nor in the absence of metabolic activation. No cytotoxicity was observed but the test substance was tested up to limit concentrations. Thus, Fatty acids, C8-18 and C18-unsatd., esters with trimethylolpropane did not induce point mutations by base-pair changes or frame-shifts in the genome of the strains tested.

CAS 403507-18-6

The mutagenic potential of Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane (CAS 403507-18-6) was tested in a reverse mutation assay comparable to OECD Guideline 471 and under GLP conditions (Bowles, 2002). Salmonella typhimurium strains TA1535, TA1537, TA98, TA100 and TA102 were used. Tester strains were incubated with test material dissolved in acetone at concentrations of 50, 150, 500, 1500 and 5000 µg/plate with and without the addition of a metabolic activation system (phenobarbitale and beta-naphthoflavone induced rat liver S9 mix). Vehicle and appropriate positive controls were included into the study design. Positive control materials induced statistically significant increases in the frequency of revertant colonies indicating the satisfactory performance of the test and the activity of the metabolizing system. No increase in the frequency of revertant colonies compared to concurrent vehicle controls was observed in all strains treated with the test substance, neither in the presence nor in the absence of metabolic activation. No cytotoxicity was observed, but the test substance was tested up to precipitating concentrations. Thus, Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane did not induce point mutations by base-pair changes or frame-shifts in the genome of the strains tested.

CAS 85005-23-8

In an Ames test, Salmonella typhimurium strains TA 1535, TA 1537, TA 98 and TA 100 as well as E. coli WP2 uvr A were treated with the test substance diluted in Tween 80 according to OECD Guideline 471 (Verspeek-Rip, 1997). Test substance concentrations of 3, 10, 33, 100, 333, 1000, 3330 or 5000 µg/plate were tested in triplicate, both with and without the addition of a rat liver homogenate metabolising system (S9-mix). Precipitation of the test substance was observed at and above 3330 µg/plate. The test material caused no cytotoxicity up to the highest, precipitating dose. No significant increases in the frequency of revertant colonies were recorded for any of the bacterial strains, with any dose of the test material, either with or without metabolic activation. The value of the controls for TA1537, in the presence of S9-mix, was just outside the historical control range but not considered to affect the validity of the study.

CAS 85116-93-4

The mutagenic potential of Fatty acids, C16-18 (even numbered), esters with pentaerythritol (CAS 85116-93-4) was tested in a reverse mutation assay comparable to OECD Guideline 471 and under GLP conditions (Banduhn, 1991). Salmonella typhimurium strains TA1535, TA1537, TA98, TA100 and TA1538 were used. Tester strains were incubated with test material dissolved in Tween 80 at concentrations of 8, 40, 200, 1000 and 5000 µg/plate (no toxicity but tested up to precipitating concentrations) with and without the addition of a metabolic activation system (Aroclor 1254 induced rat liver S9 mix). Vehicle, negative and appropriate positive controls were included into the study design. Positive control materials induced statistically significant increases in the frequency of revertant colonies indicating the satisfactory performance of the test and the activity of the metabolizing system. No increase in the frequency of revertant colonies compared to concurrent controls was observed in all strains treated with the test substance, neither in the presence nor in the absence of metabolic activation. Thus, Fatty acids, C16-18, esters with pentaerythritol did not induce point mutations by base-pair changes or frame-shifts in the genome of the strains tested.

CAS 67762-53-2

The mutagenic potential of Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2) was tested in a reverse mutation assay according to OECD Guideline 471 and under GLP conditions (Mecchi, 1999). Salmonella typhimurium strains TA1535, TA1537, TA98, TA100 and E. coli WP2 uvrA were used. Tester strains were incubated with test material dissolved in ethanol at concentrations of 33.3, 100, 333, 1000, 3330 and 5000 µg/plate with and without the addition of a metabolic activation system (Aroclor 1254 induced rat liver S9 mix). Vehicle and appropriate positive controls were included into the study design. Positive control materials induced statistically significant increases in the frequency of revertant colonies indicating the satisfactory performance of the test and the activity of the metabolizing system. No increase in the frequency of revertant colonies compared to concurrent negative controls was observed in all strains treated with the test material, neither in the presence nor in the absence of metabolic activation. Thus, Fatty acids, C5-9, tetraesters with pentaerythritol did not induce point mutations by base-pair changes or frame-shifts in the genome of the strains tested.

Formerly 68441-94-1

The mutagenic potential of Reaction mass of Heptanoic acid 3-pentanoyloxy-2,2-bis-pentanoyloxymethyl-propyl ester, Heptanoic acid 2-heptanoyloxymethyl-3-pentanoyloxy-2-pentanoyloxymethyl-propyl ester and Heptanoic acid 3-heptanoyloxy-2-heptanoyloxymethyl-2-pentanoyloxymethyl-propyl ester (CAS 68441-68-9) was tested in a reverse mutation assay according to OECD Guideline 471 and under GLP (Banduhn, 1991). Salmonella typhimurium strains TA1535, TA1537, TA98, TA100 and TA1538 were used. Tester strains were incubated with test material dissolved in Tween 80 at concentrations of 8, 40, 200, 1000 and 5000 µg/plate (no toxicity but tested up to precipitating concentrations) with and without the addition of a metabolic activation system (Arochlor 1254 induced rat liver S9 mix). Vehicle, negative and appropriate positive controls were included into the study design. Positive control materials induced statistically significant increases in the frequency of revertant colonies indicating the satisfactory performance of the test and the activity of the metabolizing system. No increase in the frequency of revertant colonies compared to concurrent negative controls was observed in all strains treated with the test material, neither in the presence nor in the absence of metabolic activation. No cytotoxicity was observed but the test substance was tested up to limit concentrations. Thus, Decanoic acid, mixed esters with octanoic acid and pentaerythritol did not induce point mutations by base-pair changes or frame-shifts in the genome of the strains tested.

CAS 85586-24-9

The mutagenic potential of Fatty acids, C8-10, tetraesters with pentaerythritol (CAS 85586-24-9) was tested in a reverse mutation assay comparable to OECD Guideline 471 and under GLP conditions (Banduhn, 1991). Salmonella typhimurium strains TA1535, TA1537, TA98, TA100 and TA1538 were used. Tester strains were incubated with the test material dissolved in Tween 80 at concentrations of 8, 40, 200, 1000 and 5000 µg/plate (no toxicity but tested up to the limit concentration) with and without the addition of a metabolic activation system (Aroclor 1254 induced rat liver S9 mix). Vehicle, negative and appropriate positive controls were included into the study design. Positive control materials induced statistically significant increases in the frequency of revertant colonies indicating the satisfactory performance of the test and the activity of the metabolizing system. No increase in the frequency of revertant colonies compared to concurrent negative controls was observed in all strains treated with the test material, neither in the presence nor in the absence of metabolic activation. Thus, Fatty acids, C8-10, tetraesters with pentaerythritol did not induce point mutations by base-pair changes or frame-shifts in the genome of the strains tested.

CAS 189200-42-8

The mutagenic potential of Fatty acids C8-10, mixed esters with dipentaerythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS 189200-42-8) was tested in a reverse mutation assay comparable to OECD Guideline 471 and under GLP conditions (Przygoda, 1995). The following Salmonella typhimurium strains TA1535, TA1537, TA98, TA100 and TA1538 were used. Tester strains were incubated with the test material dissolved in acetone at concentrations of 0.5, 5, 50, 500, 5000 µg/plate in the first experiment and 50, 100, 500, 1000 and 5000 µg/plate in the repeat experiment with and without the addition of a metabolic activation system (Arochlor 1254 induced rat liver S9 mix). Vehicle, negative and appropriate positive controls were included into the study design. Positive control materials induced statistically significant increases in the frequency of revertant colonies indicating the satisfactory performance of the test and the activity of the metabolizing system. No increase in the frequency of revertant colonies compared to concurrent negative controls was observed in all strains treated with the test material, neither in the presence nor in the absence of metabolic activation. No cytotoxicity was observed but beading of the test substance occured in the initial assay and repeat assay at 500 µg/plate and above with and without metabolic activation in all strains. Thus, Fatty acids C8-10, mixed esters with dipentaerythritol, isooctanoic acid, pentaerythritoland tripentaerythritoldid not induce point mutations by base-pair changes or frame-shifts in the genome of the strains tested.

In vitro cytogenicity in mammalian cells

CAS 68855-18-5

A chromosome aberration test was conducted with the test substance according to OECD TG 473 and under GLP conditions in human lymphocytes.

Duplicate cultures of human lymphocytes, treated with the test item, were evaluated for chromosome aberrations at three dose levels, together with vehicle and positive controls.

Four treatments conditions were used for the study. In Experiment 1, 4 hours in the presence of an induced rat liver homogenate metabolising system (S9), at a 2% final concentration with cell harvest after a 20-hour expression period and a 4 hours exposure in the absence of metabolic activation (S9) with a 20-hour expression period. In Experiment 2, the 4 hours exposure with addition of S9 was repeated (using a 1% final S9 concentration), whilst in the absence of metabolic activation the exposure time was increased to 24 hours.

The dose levels used in the main experiments, selected using data from the preliminary toxicity test, were 12.5, 25, 50, 100, 200, 400 µg/mL for all the four treatment conditions.

All vehicle (solvent) controls had frequencies of cells with aberrations within the range expected for normal human lymphocytes.

All the positive control items induced statistically significant increases in the frequency of cells with aberrations indicating the satisfactory performance of the test and the activity of the metabolising system.

The test item did not induce any statistically significant increases in the frequency of cells with aberrations, in either the absence or presence of S9, in two separate experiments.

In conclusions the test item was considered to be non-clastogenic to human lymphocytes in vitro.

CAS 85186-86-3

An in vitro mammalian chromosome aberration test was performed with Fatty acids, C8-18 and C18-unsatd., esters with neopentylglycol (CAS 85186-86-3) in cultured peripheral human lymphocytes comparable to OECD Guideline 473 and under GLP conditions (Morris, 2012). Duplicate cultures of human lymphocytes were evaluated for chromosome aberrations in the presence and absence of metabolic activation (rat liver S9-mix). In the first experiment cells were exposed for 4 hours to the test substance dissolved in acetone at concentrations of 40, 80, 160, 320, 480, 640, 960, 1280 µg/mL with and without metabolic activation. In the second experiment cells were exposed for 24 hours without metabolic activation and for 4 hours with metabolic activation. The test substance did not induce cytotoxicity. A cloudy/oily precipitate was visible at 80 µg/mL and above with metabolic activation and at 160 µg/mL without metabolic activation. Vehicle (solvent) controls induced aberration frequencies within the range expected for normal human lymphocytes. Mitomycin C and Cyclophosphamide were used as positive control substances inducing statistically significant increases in aberration frequencies indicating the satisfactory performance of the test and of the activity of the metabolizing system. Evaluation of 100 well-spread metaphase cells from each culture for structural chromosomal aberrations revealed no increase in the frequency of chromosome aberrations and polyploid cells at any dose level tested in comparison to the negative controls. The test material was therefore considered to be non-clastogenic to human lymphocytes in vitro.

CAS 189120-64-7

An in vitro mammalian chromosome aberration test was performed with Fatty acids, C7-8, triesters with trimethylolpropane (CAS 189120-64-7) in Chinese Hamster Ovary cells (CHO) according to OECD Guideline 473 and under GLP conditions (Chirdon, 2000). Duplicate cultures of CHO cells were evaluated for chromosome aberrations in the presence and absence of metabolic activation (Arochlor 1254 induced rat liver S9-mix). A range-finder toxicity test was conducted and the test item was tested at the following doses 20, 39, 78, 156, 313, 625, 1250 and 2500 µg/mL (3 h treatment), with and without S9. In the main experiments, cells were exposed for 3 hours with and without metabolic activation. The test substance was dissolved in acetone and used at concentrations of 75, 250, 2500 µg/mL without metabolic activation and 25, 250, 2500 µg/mL in acetone with metabolic activation. Cytotoxicity was observed at the highest dose tested regardless of metabolic activation. Vehicle (solvent) controls induced aberration frequencies within the range expected. 9,10-Dimethylbenzanthracene and 1-Methyl-3-Nitro-1-Nitrosoguanidine were used as positive control materials inducing statistically significant increases in aberration frequencies indicating the satisfactory performance of the test and of the activity of the metabolizing system. Evaluation of 100 well-spread metaphase cells from each culture for structural chromosomal aberrations revealed no increase in the frequency of chromosome aberrations at any dose level tested in comparison to the negative controls. The test material was therefore considered to be non-clastogenic to CHO cells in vitro.

CAS 11138-60-6

An in vitro mammalian chromosome aberration test was performed with Fatty acids, 8-10 (even numbered), di- and triesters with propylidynetrimethanol (CAS 11138-60-6) in Chinese Hamster Ovary cells (CHO) according to OECD Guideline 473 and under GLP conditions (Gudi, 1996). Duplicate cultures of CHO cells were evaluated for chromosome aberrations in the presence and absence of metabolic activation (Arochlor 1254 induced rat liver S9-mix). Cells were exposed for 4 and 20 hours without and for 4 hours with metabolic activation. The test substance was dissolved in ethanol and used at concentrations of 625, 1250, 2500, 5000 µg/mL. Cytotoxicity was observed at the highest dose tested regardless of metabolic activation. Mitomycin C and cyclophosphamide was used as positive control without and with metabolic activation respectively. Vehicle (solvent) controls induced aberration frequencies within the range expected. Positive control material induced statistically significant increases in aberration frequencies indicating the satisfactory performance of the test and of the activity of the metabolizing system. Evaluation of 200 well-spread metaphase cells from each culture for structural chromosomal aberrations revealed no increase in the frequency of chromosome aberrations at any dose level tested in comparison to the negative controls. The test material was therefore considered to be non-clastogenic to CHO cells in vitro.

CAS 403507-18-6

An in vitro mammalian chromosome aberration test was performed with Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane (CAS 403507-18-6) in cultured peripheral human lymphocytes comparable to OECD Guideline 473 and under GLP conditions (Durward, 2004). Duplicate cultures of human lymphocytes were evaluated for chromosome aberrations in the presence and absence of metabolic activation (rat liver S9-mix). In the first experiment cells were exposed for 4 hours to the test substance dissolved in acetone at concentrations of 240, 320, 400 µg/mL with and without metabolic activation. In the second experiment cells were exposed for 4 hours to 240, 320, 400 µg/mL with metabolic activation and for 24 hours to 240, 320, 400 µg/mL followed by 24 hours expression time without metabolic activation. The test substance did not induce cytotoxicity but a cloudy precipitate was already visible at 40 µg/mL. Vehicle (solvent) controls induced aberration frequencies within the range expected for normal human lymphocytes. Mitomycin C and Cyclophosphamide were used as positive control materials inducing statistically significant increases in aberration frequencies indicating the satisfactory performance of the test and of the activity of the metabolizing system. Evaluation of 200 well-spread metaphase cells from each culture for structural chromosomal aberrations revealed no increase in the frequency of chromosome aberrations and polyploid cells at any dose level tested in comparison to the negative controls. The test material was therefore considered to be non-clastogenic to human lymphocytes in vitro.

CAS 189200-42-8

An in vitro mammalian chromosome aberration test was performed with Fatty acids C8-10, mixed esters with dipentaerythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS 189200-42-8) in Chinese hamster ovary cells (CHO cells) comparable to OECD Guideline 473 and under GLP conditions (Przygody, 1995). Duplicate cultures of CHO cells were evaluated for chromosome aberrations in the presence and absence of metabolic activation (rat liver S9-mix). In the first experiment, cells were exposed to the test substance for 3 hours and for 16 hours followed by 16 hours expression time with and without metabolic activation, respectively. The test substance was dissolved in acetone and used at concentrations of 40, 80 and 160 µg/mL. In the second experiment cells were again exposed for 3 hours and for 16 hours followed by 16 hours expression time with and without metabolic activation, respectively. Additionally, cells were exposed for 3 and 16 hours followed by 40 hours expression time with and without metabolic activation, respectively. The same substance concentrations as in first experiment were used. The test substance did not induce cytotoxicity but a precipitate was visible in the second experiment at 160 µg/mL after 16 hours incubation without metabolic activation. Vehicle (solvent) controls induced aberration frequencies within the range expected for normal human lymphocytes. N-Methyl-N-Nitro-N-Nitrosoguanidine and 7,12-Dimethylbenz[a]anthracene were used as positive control materials inducing statistically significant increases in aberration frequencies indicating the satisfactory performance of the test and of the activity of the metabolizing system. Evaluation of 100 well-spread metaphase cells from each culture for structural chromosomal aberrations revealed no increase in the frequency of chromosome aberrations and polyploid cells at any dose level tested in comparison to the negative controls. The test material was therefore considered to be non-clastogenic to CHO cells in vitro.

In vitro gene mutation in mammalian cells

CAS 68855-18-5

A L5178Y mouse lymphoma assay was conducted according to OECDTG 476 and under GLP conditions.

Two independent experiments were performed. In Experiment 1, L51787Y TK +/- 3.7.3 c mouse lymphoma cells (heterozygous at the thymidine kinase locus) were treated with the test item at eight dose levels, in duplicate, together with vehicle (solvent) and positive controls using 4 h exposure groups both in absence and presence of metabolic activation(2% S9). In Experiment 2, the cells were treated with the test item at eight dose levels using a 4- h exposure group in the presence of metabolic activation (1% S9) and a 24 h exposure group in the absence of metabolic activation.

The dose range of the test substance was selected following the results of a preliminary toxicity test and was determined to be 1.6 to 102.5 µg/mL in both the absence and presence of metabolic activation in Experiment 1. In Experiment 2 the dose range was 1.6 to 102.5 µg/mL in the absence of metabolic activation, and 3.2 to 205 µg/mL in the presence of metabolic activation.

The maximum dose levels used in the test were limited by precipitate and test substance induced toxicity. A precipitate of the substance was observed at and above 102.5 µg/mL in the mutagenicity test. The vehicle (solvent) controls had acceptable mutant frequency values that were within the normal range for L5178Y cell line at the TK +/- locus. The positive control items induced marked increases in the mutant frequency indicating the satisfactory performance of the test and of the activity of the metabolising system.

The test item did not induce any toxicologically significant dose-related increases in the mutant frequency at any dose level, either with or without metabolic activation, in either the first or the second experiment.

CAS 42222-50-4

An in vitro Mammalian Cell Gene Mutation Assay according to OECD Guideline 476 and GLP was performed with 2,2-dimethyl-1,3-propanediyldioleate (CAS 42222-50-4) in mouse lymphoma L5178Y cells (Flügge, 2012). The cells were treated for 3 hours with and without S9-mix in the first experiment, for 24 hours without S9 mix in the second experiment and again for 3 hours with S9 mix in the third experiment. The test substance was tested at 312.5, 625, 1250, 2500 and 5000 μg/mL. 3-Methylcholanthrene and Methylmethanesulfonate were used as positive controls with and without S9 mix, respectively. No toxicity was observed and all dose levels were evaluated in the absence and presence of S9-mix. Positive and negative controls were valid and in range of historical control data. No significant increase in the mutation frequency at the TK locus was observed after treatment with the test substance either in the absence or in the presence of S9-mix. Thus, it was concluded that 2,2-dimethyl-1,3-propanediyldioleate is not mutagenic in the mouse lymphoma L5178Y test system under the experimental conditions described.

Formerly 85186-89-6

An in vitro Mammalian Cell Gene Mutation Assay according to OECD Guideline 476 and GLP was performed with Fatty acids, C8-10(even), C14-18(even) and C16-18(even)-unsatd., triesters with trimethylolpropane (CAS 85186-89-6) in mouse lymphoma L5178Y cells (Verspeek-Rip, 2010). The cells were treated for 3 and 24 hours with 8% (v/v) and without S9-mix in the first experiment, respectively, and with 12% (v/v) with and without S9-mix in the second experiment, respectively. In the first experiment the test substance was tested at 0.3, 1, 3, 10, 33, 100, 333 and 750 μg/mL up to precipitation with 8% (v/v) and without S9-mix for 3 h. In the second experiment the test substance was tested at 0.3, 1, 3, 10, 33, 100, 333 and 750 μg/mL up to precipitation with 12% (v/v) for 3 hours and without S9-mix for 24 hours Cyclophosphamide and Methylmethanesulfonate were used as positive controls with and without S9 mix, respectively. No toxicity was observed and all dose levels were evaluated in the absence and presence of S9-mix. Positive and negative controls were valid and in range of historical control data. No significant increase in the mutation frequency at the TK locus was observed after treatment with the test substance either in the absence or in the presence of S9-mix. It was concluded that Fatty acids, C8-18 and C18-unsatd., esters with trimethylolpropane is not mutagenic in the mouse lymphoma L5178Y test system under the experimental conditions described.

CAS 15834-04-5

An in vitro Mammalian Cell Gene Mutation Assay according to OECD Guideline 476 and GLP was performed with 2,2-bis[[(1-oxopentyl)oxy]methyl]propane-1,3-diyl divalerate (CAS 15834-04-5) in mouse lymphoma L5178Y cells (Verspeek-Rip, 2010). In the first experiment, the cells were treated for 3 hours with 0.03, 0.1, 0.3, 1, 3, 10, 33, 100 µg/mL in the presence or absence of S9-mix (8% (v/v)). In the second experiment, test concentrations of 0.03, 0.1, 0.3, 1, 3, 10, 33, 100 µg/mL were applied with metabolic activation (12%, v/v) for 3 h and 0.1, 1, 3, 10, 33, 100, 200, 250 µg/mL without metabolic activation for 24 hours. The test substance was tested up to precipitating concentrations (100 µg/mL and above). Cyclophosphamide and methylmethanesulfonate were used as positive controls with and without S9 mix, respectively. No toxicity was observed and all dose levels were evaluated in the absence and presence of S9-mix. Positive and negative controls were valid and in range of historical control data. No significant increase in the mutation frequency at the TK locus was observed after treatment with the test substance either in the absence or in the presence of S9-mix. It was concluded that 2,2-bis[[(1-oxopentyl)oxy]methyl]propane-1,3-diyl divalerate is not mutagenic in the mouse lymphoma L5178Y test system under the experimental conditions described.

 

Genotoxicity in vivo

Fatty acids, C5-10, esters with pentraerythritol (CAS No. 68424-31-7) were found to be not genotoxic in the micronucleus assay in vivo after intraperitoneal application. A single intraperitoneal injection was given to groups of 5 male and 5 female mice at a dose level of 5000 mg/kg bw. Bone marrow samples were taken 24 and 48 hours after dosing.

No statistically or biologically significant increases in the incidence of micronucleated polychromatic erythrocytes over the vehicle control values were seen in either sex at either of the sampling times.

Comparison of the percentage of polychromatic erythrocytes showed no significant differences between the female animals treated with the vehicle control or with the test material. A small, but significant decrease was, however, noted in male mice treated with the test material at 5000 mg/kg bw. This small decrease is, however, considered not to be biologically significant compared to the concurrent control values.

The positive control induced statistically significant and biologically meaningful increases in micronucleated polychromatic erythrocytes, compared to the vehicle control values, thus demonstrating the sensitivity of the test system to a known clastogen (Griffiths, 1992).

Conclusion for genetic toxicity

In summary, several studies are available to assess the mutagenic potential in bacteria within the polyol esters category all providing negative results. Furthermore, no cytogenicity in mammalian cells in-vitro and no mutagenicity in mammalian cells in-vitro were observed with members of the polyol esters category.

In conclusion, all available and reliable in vitro and in vivo studies conducted with polyol esters category members revealed no effects on genetic toxicity. 

 


Short description of key information:
In none of these studies mutagenicity in bacteria could be observed.
In none of these studies clastogenic effects in mammalian cells could be observed.
In none of these studies mutagenicity in mammalian cells could be observed.

Endpoint Conclusion: No adverse effect observed (negative)

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 genetic 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.