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EC number: 615-229-7 | CAS number: 70969-57-2
Skin sensitisation (OECD 406, GPMT and Buehler; human repeated insult patch test): not skin sensitising
Read-across from structural analogue source substances Dipentaerythritol hexaesters with fatty acids, C5 and C9iso (CAS No. 647028-25-9), Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids (CAS No. 68424-31-7), Fatty acids, C5-9 tetraesters with pentaerythritol (CAS No. 67762-53-2), and Fatty acids, C8-10 mixed esters with dipenaterythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS No. 189200-42-8)
In the test group and the irritation control animals, the 3 intradermal injections of the intradermal induction produced slight to moderate redness around the injection sites at either 1 and 24 h after injection. The topical application of 100% of the test substance for 24 h under occlusive conditions leads to very slight to well-defined erythema in 18/20 animals and severe erythema to slight eschar formation in one animal at the 1 and 24 h observations. Moderate to severe erythema formation was observed in one animal after 24 h. At the 1 h reading, very slight to slight edema were noted in 12/20 animals. At the 24 h reading, very slight to moderate edema were observed in 19/20 animals.
The topical application of peanut oil produced results similar to the treated animals. In all 10 irritation control animals, very slight to severe erythema and very slight to slight edema were noted at the 1 and 24 h observation time points.
The topical challenge dose of 50% test substance in peanut oil leads to very slight erythema in 11/20 animals and to well-defined erythema in 7/20 animals at the 24 h evaluations in test group animals. At the 48 h reading, 6/20 animals had very slight erythema, one animal had well-defined erythema and 13/20 animals were free of erythema. Very slight edema were observed in 4/20 treated animals at the 24 h observation and in one animal at the 48 h observation. In the irritation control group, the topical application of 50% test substance in peanut oil produced very slight erythema in 4/10 animals and well-defined erythema in 5/10 animals at the 24 h reading. At the 48 h observation, 6/10 animals had very slight erythema and one animal had well-defined erythema. Edema was not observed in any irritation control animal at the 24 or 48 h reading.
Since the severity of the erythema was similar between the treated group and the irritation control group and the incidence of erythema was higher in the irritation control group, the response was considered an irritation response and not a sensitization response. An examination of the individual animals' responses showed that the majority of the irritation scores decreased from the 24 h evaluation to the 48 h evaluation, which also is indicative of an irritation and not a sensitization response. However, since there was some irritation from the challenge application, it was decided to rechallenge at a lower concentration to confirm that the test material possessed no sensitization potential.
The rechallenge was performed with 10% test substance in peanut oil and produced very slight erythema in 4/20 animals at the 24 h observation. All animals were free of erythema at the 48 h evaluation. Edema was not observed in any treated animals at the 24 or 48 h observations.
In the irritation control group, topical application of 10% test substance in peanut oil leads to very slight erythema in 4/10 animals and well-defined erythema in one animal at the 24 h observation. All animals were free of erythema at the 48 h evaluation. Edema were not observed in any irritation
control animal at the 24 or 48 h observations.
No information on positive control group included in study report.
Justification for grouping of substances and read-across
The read-across from analogue source substances approach comprises aliphatic esters of poly-functional alcohols containing two to six reactive hydroxyl groups and one to six fatty acid chains. The analogue approach contains mono constituent, multi-constituent and UVCB substances with fatty acid carbon chain lengths ranging from C5 - C22, which are mainly saturated but also mono unsaturated C16 and C18, polyunsaturated C18, branched C5 and C9, branched C14 - C22 building mono-, di-, tri-, tetra- and hexa esters with an alcohol (i.e. the polyol).
The available data allows for an accurate hazard and risk assessment of the target substance and the read-across 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 substances within the group by interpolation to the target substance applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No. 1907/2006. In particular, for each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across.
A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Section 7.1 and 13).
Skin sensitisation potential
There are several reliable animal studies and one repeated insult patch test with humans available for structural analogue source substances investigating the skin sensitisation potential. All studies are accounted for in a Weight-of-Evidence approach.
The skin sensitisation potential of Dipentaerythritol hexaesters with fatty acids, C5 and C9iso (CAS No. 647028-25-9) was tested in a guinea pig maximisation test (GPMT) equivalent to OECD Guideline 406 and under GLP conditions (WoE, RA-A, 647028-25-9, 1999b). Suitable doses were investigated by means of a range finding study prior to the main test. 10 male Dunkin-Hartley guinea pigs were treated with the test substance at 25% (diluted in arachis oil BP) for intra- and 100% for epidermal induction on days 1 and 7, respectively. 5 animals served as negative controls. There was no positive control group included in the study but information was given that the incidence of sensitisation in the historical positive controls using 2-Mercaptobenzothiazole was 70-100 %. Epicutaneous challenge was performed on Day 20 with undiluted (right flank) and 75% (diluted in arachis oil BP, left flank) test material under occlusive conditions for 24 h and skin reactions were evaluated 24 h and 48 h after removal of the patches. No animal in either the test or control groups exhibited skin reactions at any reading time point. Therefore, the test substance was considered not to be skin sensitising.
The skin sensitisation potential of Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids (CAS No. 68424-31-7) was evaluated in guinea pigs with a Buehler test for (WoE, RA-A, 68424-31-7, 1991). 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 h and 48 h after challenge. No signs for irritation or sensitisation were observed during induction and challenge of the animals.
A guinea pig maximisation test (GPMT) was performed with Fatty acids, C5-9, tetraesters with pentaerythritol (CAS No. 67762-53-2) comparable to the OECD Guideline 406 (Exxon, 1999d). 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% for 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 h 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.
A guinea pig maximisation test was performed with Fatty acids, C8-10 mixed esters with dipenaterythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS No. 189200-42-8) according to a protocol comparable to the OECD Guideline 406 (Exxon, 1995c). 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 solution 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.
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 bis(isooctadecanoate) (CAS No. 62125-22-8) in 55 human volunteers from the general population (Key, RA-A, 62125-22-8, 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.
Conclusion on skin sensitisation
Several reliable studies performed with analogue source substances are available investigating the skin sensitisation potential both in animals as well as in humans. All data indicate no potential for skin sensitisation in adequate GPMT, Buehler and human repeated insult patch tests. Thus, no hazard for skin sensitisation is identified for the target substance Octadecanoic acid, 1,1'-[2-[[3-[(1-oxooctadecyl)oxy]-2,2-bis[[(1-oxooctadecyl)oxy]methyl]propoxy]methyl]-2-[[(1-oxooctadecyl)oxy]methyl]-1,3-propanediyl] ester (CAS No. 70967-57-2) either.
According to Article 13 of Regulation (EC) No. 1907/2006 information on intrinsic properties of substances may be generated by means other than tests, e.g. using information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI 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 read-across concept is applied to the target Octadecanoic acid, 1,1'-[2-[[3-[(1-oxooctadecyl)oxy]-2,2-bis[[(1-oxooctadecyl)oxy]methyl]propoxy]methyl]-2-[[(1-oxooctadecyl)oxy]methyl]-1,3-propanediyl] ester (CAS No. 70967-57-2), data gaps can be filled by interpolation from representative structural analogue source substances to avoid unnecessary animal testing.
The read-across concept is also used to derive the classification of the target substance taking the properties of the source substances into account. Based on the read-across concept, all available data on skin sensitisation in animals and humans do not meet the classification criteria according to Regulation (EC) No. 1272/2008 (CLP) and are therefore conclusive but not sufficient for classification.
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