Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
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 skin sensitisation

CAS

Skin Sensitization

NPG esters

68855-18-5 (a)

Not sensitising

31335-74-7

RA: CAS 68855-18-5

QSAR: no protein binding

70693-32-2

RA: CAS 68855-18-5

RA: CAS 91031-85-5

former CAS 85186-86-3

RA: CAS 68855-18-5

RA: CAS 85186-86-3

RA: CAS 91031-85-5

85186-86-3

Not sensitising

85186-95-4

RA: CAS 68855-18-5

RA: CAS 85186-86-3

RA: CAS 91031-85-5

91031-85-5 (b)

Not sensitising

85116-81-0

RA: CAS 85816-86-3

91031-27-5

RA: CAS 68855-18-5

RA: CAS 85186-86-3

RA: CAS 91031-85-5

42222-50-4

RA: CAS 85186-86-3

RA: CAS 91031-85-5

85005-25-0

RA: CAS 68855-18-5

RA: CAS 85186-86-3

RA: CAS 91031-85-5

TMP esters

78-16-0 (a)

RA: CAS 11138-60-6

RA: CAS 68855-18-5

91050-88-3

RA: CAS 91050-90-7

RA: CAS 11138-60-6

11138-60-6

Not sensitising

91050-89-4

RA: CAS 11138-60-6

68002-79-9

Not sensitising

(Formerly 85005-23-8)

EC 931-531-4

RA: CAS 11138-60-6

RA: CAS 68002-79-9

68002-78-8

RA: CAS 68002-79-9

(Formerly 57675-44-2)

EC 931-461-4

RA: CAS 68002-79-9

85186-89-6

RA: CAS 11138-60-6

RA: CAS 68002-79-9

85186-92-1

RA: CAS 11138-60-6

RA: CAS 68002-79-9

68541-50-4

RA: CAS 68002-79-9

PE esters

15834-04-5

RA: CAS 68424-31-7

85116-93-4

RA: CAS 68424-31-7

85711-45-1 (a)

RA: CAS 68424-31-7

QSAR: no protein binding

25151-96-6

RA: CAS 68424-31-7

67762-53-2

Not sensitising

(Formerly 68441-94-1)

RA: CAS 189200-42-8

RA: CAS 68424-31-7

RA: CAS 67762-53-2

(Formerly 68424-30-6)

RA: CAS 189200-42-8

RA: CAS 68424-31-7

RA: CAS 67762-53-2

68424-31-7 (c)

RA: CAS 68424-31-7

68424-31-7 (d)

RA: CAS 68424-31-7

68424-31-7 (e)

RA: CAS 68424-31-7

71010-76-9

RA: CAS 189200-42-8
RA: CAS 68424-31-7
RA: CAS 67762-53-2

85586-24-9

RA: CAS 68424-31-7

85049-33-8

RA: CAS 68424-31-7

91050-82-7

RA: CAS 68424-31-7

19321-40-5

RA: CAS 68424-31-7

68604-44-4

RA: CAS 68424-31-7

QSAR: no protein binding

62125-22-8

Not sensitising (human data)
RA: CAS 68424-31-7

68440-09-5

RA: CAS 68424-31-7

189200-42-8

Not sensitising

 

(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.

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

There are several studies available within the polyol esters category investigating the skin sensitising potential of polyol esters category members. They were used for assessment of NPG, TMP and PE esters within the polyol esters category. Read-across was conducted based on a category and/or weight of evidence approach.

CAS 68855-18-5

The skin sensitisation potential of Heptanoic acid, ester with 2,2-dimethyl-1,3-propanediol (CAS 68855-18-5) was evaluated in guinea pigs with a Buehler test for skin sensitisation performed according to OECD 406 under GLP conditions (Doyle, 1996). 20 male Dunkin-Hartley guinea pigs were treated with the test substance and compared to 10 male control animals. Three epidermal inductions were performed with 100% test substance in weekly intervals for 6 hours under occlusive conditions. 14 days after the last induction treatment, all animals were challenged for 6 hours epicutaneously with 100% (left top flank) and 30% (right top flank) test substance (diluted in corn oil) under occlusive conditions. Animals were evaluated for skin reactions 24 and 48 h after challenge. 1/20 animals (5%) of the test group responded to the challenge with 100% test substance formulation with scattered mild redness 24 h after challenge, which was reversible until the second reading after 48 h. No further signs for irritation or sensitisation were observed during induction and challenge of the animals. The test item is considered not to be sensitising to the skin of guinea pigs under the conditions of the test.

CAS 31335-74-7

A Local Lymph node assay assessing the skin sensitising potential of 2,2-dimethyl-1,3-propanediyl dioctanoate is available (CAS 31335-74-7). This was reported only as a short summary (Bugg, 1992). No details on the study protocol or the data interpretation were given. The test item was applied in concentrations of 0.3, 1, 3, and 10% w/v. No significant increase in isotope incorporation was detected after repeated application. The CPM (Counts per minute) was 0.0123 and 0.0139 for the vehicle controls and 0.0125, 0.0104, 0.0102, 0.0108 for the 0.3, 1, 3 and 10% groups, respectively. The stimulation index was 1.02 for the 0.3% application, 0.85 for 1%, 0.83 for the 3% and 0.78 for 10% application. These results indicate that the test substance could not elicit an SI of 3. Thus, the item is considered not to be sensitising under the test conditions.

In addition, the protein binding properties of 2,2-dimethyl-1,3-propanediyl dioctanoate were assessed to predict skin sensitisation potential using the OECD QSAR Toolbox, v2.3 (Sica, 2012). The substance was predicted negative for protein binding potential. This is in line with the prediction of the OASIS Database provided from the Danish Environmental Protection Agency and Danish QSAR group, National Food Institute, Technical University of Denmark (Danish EPA, QSAR prediction skin sensitisation, 2013), which revealed no skin sensitising potential for the test substance.

CAS 85186-86-3

The skin sensitisation potential of Fatty acids, C8-18 and C18-unsatd., esters with neopentylglycol (CAS 85186-86-3) was evaluated in mice in a Local Lymph Node Assay performed according to OECD 429 under GLP conditions (Pooles, 2012). The test substance was applied in concentrations of 25, 50, and 100% on three consecutive days to the dorsal surface of each ear of 4 female CBA/Ca (CBA/CaOlaHsd) mice each. Hexyl cinnamic aldehyde , 25% (v/v) in aceton/olive oil 4:1 served as positive control. On Day 6 the animals received 250 µL of phosphate buffered saline (PBS) containing ³H-methyl thymidine and were sacrificed 5 h later for measurement of radioactivity. Disintegrations per minute were slightly increased by the test item. However, no dose-dependent increase was seen. The stimulation indices calculated for 25, 50 and 100 % test item were 2.45, 1.49 and 1.68, respectively. These results indicate that the test substance could not elicit an SI of 3. Therefore, the test item is considered to be not sensitising to the skin under the conditions of the test.

CAS 91031-85-5

The skin sensitisation potential of Fatty acids, coco, 2,2-dimethyl-1,3-propanediyl esters (CAS 91031-85-5) was evaluated in mice using the Local Lymph Node Assay which was conducted according to OECD 429 and under GLP conditions (Huygevoort, A. H. B. M., 2006). The test substance was applied in concentrations of 25, 50, and 100% on three consecutive days to the dorsum of both ears of 5 female CBA inbred mice each. On Day 6 the animals received approx. 20 µCi of 3H-methly thymidine and were sacrificed 5 h later for measurement of radioactivity. Slight irritation was noted among the animals of the control group and in all animals treated at 25%. Slight or well-defined irritation was noted among the animals of the higher dose groups. No significant increase in isotope incorporation was detected after repeated application. The stimulation index, calculated by comparison of the CPM of the control and the treated animals, was 1.1 for the 25% application, 0.9 for 50% and 2.3 for the 100% application. The SI value calculated for the control group (vehicle) was 1.0. These results indicate that the test substance could not elicit an SI of 3. Therefore, the test item is considered to be not sensitising to the skin under the conditions of the test.

CAS 78-16-0

There are two studies available assessing the skin sensitization potential of 2-ethyl-2-[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate (CAS 78-16-0). In the first study, a Buehler Test was conducted, but the concentrations for induction and challenge were not tested in a preliminary skin irritation test (Robinson, 1991). In the second study a mixture was tested comprising only 24.4% of the test substance (Sheldon, 1993). Due to the methodologic deficiencies, both studies were not used for assessing the skin sensitization potential of 2-ethyl-2-[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate.

CAS 11138-60-6

A Guinea Pig Maximisation Test was performed with Fatty acids, 8-10 (even numbered), di- and triesters with propylidynetrimethanol (CAS 11138-60-6) according to OECD Guideline 406 under GLP conditions (Blanset, 1997). 20 male and female Dunkin-Harley guinea pigs were treated with the test substance and compared with 10 negative control animals (5 per sex). A 5% dilution of the test substance in propylene glycol was used for intradermal induction in the shoulder region on Day 1. 100% of the test item was used for topical induction in the shoulder region on Day 8. 14 days after the last induction treatment, all animals were challenged epicutaneously with the undiluted test substance. 24 hours after challenge, one out of twenty animals (5%) showed a skin reaction compared to 3 out of ten (30%) for the positive control. 48 hours after challenge none of the test animals showed any skin reactions. The sensitivity of the animal strain was tested confirmed using Hexylcinnamic aldehyde (HCA) as a positive control substance. Thus, the test substance is not considered to have skin sensitizing potential.

In summary, Fatty acids, 8-10 (even numbered), di- and triesters with propylidynetrimethanol is not considered to have skin sensitising potential.

CAS 68002-79-9

A Buehler test was performed with Fatty acids, C16-18 (even numbered) and C16-18 unsatd. (even numbered), triesters with trimethylolpropane (CAS 68002-79-9) according to OECD Guideline 406 (Pittermann, 1994) and under GLP conditions. 20 female Pirbright white guinea pigs were treated with the test substance and compared with 10 negative female control animals. Data for a positive control substance are not reported. A range finding test was conducted for dose selection. Three epidermal inductions were performed with 100% test substance in weekly intervals for 6 hours under occlusive conditions. 14 days after the last induction treatment, all animals were challenged for 6 hours epicutaneously with 100% test under occlusive conditions. Animals were evaluated for skin reactions 24, 48 and 72 h after challenge. In the test group, no reactions were seen at the first reading time point, while at the second and third reading time point 5 and 1 animal showed a slight skin erythema on the right flank, respectively. Slight dermal effects on the right flank were seen in one animal of the control group at the first and second reading-. Thus, the test substance was found not to be skin sensitizing.

CAS 91050-90-7

Fatty acids, C16-18, triesters with trimethylolpropane (CAS No. 91050-90-7) were tested for their skin irritation potential according to OECD Guideline 404 (Steiling, 1989).Three Kleinrussen, Chbb:HM rabbits were exposed to 0.5 g test material for 4 hours under semi-occlusive conditions. The rabbits were observed for 72 hours. Skin reactions were assessed using the Draize scheme 24, 48 and 72 hours after removal of the test substance. All three animals had very slight erythema 1 day after removal of the test substance. Effects were completely reversible within 48 h (2 animals) and 72 h (1 animal).No other effects were observed.

 

In summary, Fatty acids, C16-18 (even numbered) and C16-18 unsatd. (even numbered), triesters with trimethylolpropane is not considered to have skin sensitising properties.

CAS 85711-45-1

The protein binding properties of Fatty acids, C16-18 and C18-unsatd., esters with pentaerythritol (CAS 85711-45-1) was assessed to predict the skin sensitisation potential using the OECD QSAR Toolbox, v2.3 (Sica, 2012).

The OECD Toolbox only supports analysis of monoconstituents, i.e. single substances. The test substance Fatty acids, C16 -C18 -unsatd., esters with pentaerythritol (CAS 85711-45-1) is a UVCB. Therefore, the two main components (C16 FA monoester component, C18:1 FA tetraester componenent) were assessed for their protein binding potential individually.

Both monoconstituents were predicted negative for protein binding properties.

CAS 67762-53-2

A Guinea pig maximisation test was performed with Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2) comparable to the OECD Guideline 406 (Zolyniene, 1999). A range-finding study was performed for dose selection. 10 albino guinea pigs were treated with the test substance at 5% for intra- and 100% epidermal induction on Days 1 and 7, respectively. 5 animals served as negative controls. A positive control group was not included in the study but information is given on periodical testing of strain sensitivity using hexylcinnamic aldehyde (HCA). 14 days after the epidermal induction, epidermal challenging was performed with 50 and 100% test material dilution in propylene glycol. 24 and 48 hours after challenging skin examination revealed no irritation in the test group and control group. Thus, the test material was found to be not sensitising to the skin of guinea pigs, under the conditions of this test.

CAS 68424-31-7

Four studies were conducted with Fatty acids, C5-10, esters with pentraerythritol (CAS 68424-31-7) according to OECD Guideline 406 (Buehler Test) and OECD Guideline 429 (Local Lymph Node Assay). In the first test, the skin sensitisation potential of the test substance was evaluated in guinea pigs with a Buehler test for (Lees, 1991a). 20 male albino guinea pigs were treated with the test substance and compared with 10 control animals. Three epidermal inductions were performed with 100 % test substance in weekly intervals for 6 hours under occlusive conditions. 14 days after the last induction treatment, all animals were challenged for 6 hours epicutaneously with 100% (left shorn flank) and 30% (right shorn flank) test substance (diluted in corn oil) under occlusive conditions. Animals were evaluated for skin reactions 24 and 48 h after challenge. No signs for irritation or sensitisation were observed during induction and challenge of the animals.

This result is supported by the findings of a Local Lymph Node Assay (Bugg, 1992). Only a short summary with no details on the study protocol or data interpretation was given. Nevertheless, test substance concentrations of 1%, 3%, and 10% indicated that the test substance was not a sensitizer under the conditions chosen.

Furthermore, another Local Lymph Node Assay was conducted (Robinson, 1991b). The test substance was applied in concentrations of 3%, 10% and 30% on three consecutive days to the dorsum of both ears of 4 female CBA/Ca mice each. Five days later the animals received approx. 20 µCi of 3H-methly thymidine and were sacrificed 5 h later for measurement of radioactivity. No significant increase in isotope incorporation was detected after repeated application. The stimulation index, calculated by comparison of the CPM of the control and the treated animals, was 0.45 for the 3% application, 2.05 for 10% and 1.21 for the 30% application. According to the provider, the test substance contained up to 2% of an additional package which was not further defined. This might contribute to the result of this test. Therefore the result cannot be clearly assigned to the test substance and this study is not considered for classification.

In a fourth study, a Local Lymph Node Assay, was conducted analogously to the first one reported for the test substance, but with significant methodical deficiencies (Robinson, 1991c). The test substance was investigated at low concentrations of 3 and 10%. In addition, the test substance comprised additives which were not further specified. Therefore the results obtained do not allow the derivation of a dose dependency and are insufficient for assessment.

68604-44-4

The skin sensitising potential of Fatty acids, C16-18 and C18-unsatd., tetraesters with pentaerythritol (CAS 68604-44-4) was assessed using the OECD QSAR Toolbox, v2.3 (Sica, 2012).

The databases Protein binding by OASIS, Protein binding by OECD and Protein Binding Potency contain structural alerts (e.g. a functional group) that indicate a protein binding potential. A structural alert is an indication that a substance may have the potential to cause skin sensitisation. By comparing a substance (the molecular structure) with the list of alerts, a potential skin sensitiser may be identified.

The OECD Toolbox only supports analysis of monoconstituents, i.e. single substances. The test substance Fatty acids, C16 -C18 -unsatd., tetraesters with pentaerythritol (CAS 68604-44-4) is a UVCB. Therefore, the three main monomers (C16 FA component, C18 FA component and C18:1 FA componenent) were assessed for their protein binding potential individually.

The three main monomers (C16 FA component, C18 FA component and C18:1 FA componenent) were assessed for their protein binding potential (predictor of skin sensitisation) individually.

All monoconstituents were predicted negative for protein binding properties.

CAS 62125-22-8

A repeated insult human patch test (RIPT) was conducted to assess the sensitizing potential of 2,2-bis[[(1-oxoisooctadecyl)oxy]methyl]-1,3-propanediyl (CAS 62125-22-8) in 55 human volunteers from the general population (Frank, 1985). Induction was carried out by 10 repeated semiocclusive applications of the unchanged test substance. Patches were placed on the back of volunteers for 24 hours, followed by a 24 hour rest period (48 hours on weekends). The 10 induction patches were applied to the same site. The induction phase was followed by a resting period of 14 days. Challenge patches were applied to the same site on the back and to a naïve site. Skin reactions were assessed 24 and 48 hours after patch removal. None of the human volunteers showed any skin reactions at the end of the study period. Thus, the test material is not considered sensitising to humans.

CAS 189200-42-8

A guinea pig maximisation test was performed with Fatty acids C8-10, mixed esters with dipentaerythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS 189200-42-8) according to a protocol comparable to the OECD Guideline 406 (Trimmer, 1995). A range-finding study was performed for dose selection. 20 female Hartley albino guinea pigs were treated with the test substance at 5% for intra- and 100% for epidermal induction on days 1 and 7, respectively. 10 animals served as negative controls. A positive control group treated with 2-Mercaptobenzothiazole (MBT) (intradermal induction: 3%, epicutaneous induction: 25%, challenge: 0.5%; no rechallenge) was included in the study which showed 100% sensitising reactions. 14 days after the epidermal induction, epidermal challenging was performed with a 50% test material dilution in peanut oil. At the first reading, 24 hours after challenge, skin examination revealed irritation reactions in the test group for 18 of 20 animals and in the control group for 9 of 10 animals. 48 hours after challenge, 7 animals in test and control group each showed skin irritation reactions. Since the 50% challenge concentration resulted in skin irritation, a rechallenge was done using 10% test substance. 5 of 10 control animals (50%) and 4 of 20 (20%) test group animals showed skin irritation 24 hours after rechallenge. All skin reactions were completely reversed 48 hours after rechallenge in both groups. Thus, the test material was found to be not sensitising to the skin of guinea pigs, when used as 5% solution for induction and 10% solution for challenge. Based on the study results no classification is required according to EU classification criteria for skin sensitisation.

Conclusion for skin sensitization

Taken together, all available and reliable data on members of the polyol esters category reveal no skin sensitising potential

 


Migrated from Short description of key information:
Based on the data available, the polyol esters have no sensitsing potential.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

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 skin sensitisation 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.