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 Short Chain Alcohol Esters (SCAE C2-C8) category covers esters from a fatty acid (C8-C29) and a C2-C8 alcohol (ethanol, isopropanol, butanol, isobutanol, pentanol, iso-pentanol, hexanol, 2-ethylhexanol or octanol). This category includes both well-defined mono-constituent substances as well as related UVCB substances with varying fatty acid chain lengths.

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, 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.

 

Overview of skin sensitisation

CAS

Skin sensitisation

544-35-4 (b)

ambiguous

10233-13-3 (a)

RA: 110-27-0

110-27-0 (a)

Not sensitising

142-91-6 (a)

RA: 110-27-0

68171-33-5 (a)

RA: 110-27-0

112-11-8 (a)

RA: 110-27-0

91031-58-2 (a)

RA: 110-27-0

63393-93-1 (a)

Not sensitising

85408-76-0 (a)

RA: 163961-32-8

RA: 123-95-5

84988-74-9 (a)

RA: 163961-32-8

RA: 85408-76-0

163961-32-8 (b)

Not sensitising

85865-69-6 (a)

RA: 163961-32-8

RA: 85408-76-0

34316-64-8 (a)

RA: 135800-37-2

20292-08-4 (a)

RA: 135800-37-2

RA: 91031-48-0

29806-73-3 (a)

RA: 135800-37-2

RA: 91031-48-0

22047-49-0 (a)

RA: 135800-37-2

RA: 91031-48-0

91031-48-0 (a)

Not sensitising

85049-37-2 (a)

RA: 91031-48-0

92044-87-6 (a)

RA: 135800-37-2

RA: 34316-64-8

84988-79-4 (a)

RA: 163961-32-8

RA: 85408-76-0

6309-51-9 (a)

 

RA: 110-27-0

RA: 10233-13-3

RA: 34316-64-8

1365095-43-7 (a)

RA: 110-27-0

RA: 10233-13-3

RA: 34316-64-8

2306-88-9 (a)

RA: 135800-37-2

59587-44-9 (a)

RA: 135800-37-2

RA: 91031-48-0

649747-80-8 (a)

RA: 34316-64-8

RA: 110-27-0

RA: 135800-37-2

135800-37-2 (b)

Not sensitising

93572-14-6 (a)

RA: 91031-48-0

RA: 135800-37-2

(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 "--".

Skin sensitisation – Human Data

Several fatty acid C2-8 esters were tested in vivo on human skin. None of the tested fatty acid esters showed any relevant skin sensitisation potential in humans.

Human data on skin sensitisation is available for isopropyl myristate (CAS 110-27-0) (Geier, 2004). Based on the information of the interdisciplinary task force on allergy diagnostics in the metal branch, in 2001, the German Contact Dermatitis Research Group (DKG) compiled two metalworking fluid (MWF) test series with currently and previously used components, respectively (see IUCLID section 7.10.4, Geier, 2004). 251 metalworkers who were patch tested because of suspected MWF dermatitis in 2002 and 2003 were included into a retrospective data analysis. After 2 years of patch testing, the results obtained with these series were presented, based on data of the Information Network of Departments of Dermatology (IVDK). 196 patients were tested for sensitivity to a 10% dilution of the test material in petrolatum in a human patch test according to test guidelines of the International Contact Dermatitis Research Group (ICDRG) and the DKG. None of the 196 patients showed a reaction. Therefore, the test material was found to be not sensitising to human skin.

 

Further data on skin sensitisation in human is available for isopropyl palmitate (CAS 142-91-6). The study was performed according to an internal standard human sensitisation test protocol of the testing facility (Stotts, 1978). Occlusive patches with 0.5 mL of the undiluted test substance (92.1% pure) were applied to the upper arm of 112 volunteers for 24 hours each, 9 times for induction and once for challenge. Scores were determined 48 hours after removal of the patch, shortly before applying the new patch. None of 88 volunteers who concluded the study had any signs of an allergic reaction. Only slight irritating effects were observed. Therefore, based on the results of the study, the test material has no sensitising potential to human skin.

In another study performed according to the same test protocol, patches with test substance were applied to the upper arm of the 98 volunteers (predominantly Caucasian) for 24 hours each, 9 times for induction and once for challenge (Stotts, 1978). Scores were determined 48 hours after removal of the patch, shortly before applying the new patch. Neither irritation no allergic reactions were observed in the 66 volunteers who concluded the study. Thus, the test material is not considered skin sensitising in humans.

 

Additional human data is available for isopropyl lanolate (CAS 63393-93-1). A Maximization Test (Klingmann; Journal of Investigative Dermatology; No.5; 393-409; 1966) in 25 volunteers was performed (CTFA, 1977). Occlusive skin exposure on the volar forearm or the back of all volunteers was conducted for five alternate-day 48-hour periods. The application site was pretreated for 24 h with 2.5 % sodium lauryl sulfate (SLS) under occlusion. After a ten day rest period, a challenge patch of the test material was applied to an untreated site for 48 hours. Prior to challenge SLS was again applied to test site for an hour. Observations were made after removal of the challenge patch and 24 hours thereafter. None of the volunteers showed an allergic reaction; thus, the test material was not sensitising to human skin in this study.

Additionally, a short abstract of a retrospective European survey of allergic contact allergy to cosmetic ingredients is available (Goossens et al., 1991). The observation was made during a 4-months period in 1996 and data were collected in 5 European dermatology centres. Only one case of contact dermatitis was reported. Therefore, the test material is not considered sensitising to human skin.

Further human sensitisation data are available for a structural analogue read across substance: diisopropyl sebacate (CAS 7491-02-3). Similar to the isopropyl ester members of the SCAE (C2-C8) category, this substance will be cleaved upon esterase activity into isopropanol and sebacic acid (decanedioic acid, CAS 111-20-6). The sensitizing potential of diisopropyl sebacate (CAS 7491-02-3) was assessed in a human volunteer study with 13 male and 42 female subjects according to the method of Marzulli and Maibach (Cathalot, 2002). For induction, occlusive exposure to the undiluted test substance for 48 hours, three times a week for three weeks on the back was performed. After a two week recovery period, a challenge exposure was performed under an occlusive dressing for 48 h either on the same site as the induction or another site that had never had contact with the test substance. After each induction exposure, cutaneous reactions were evaluated directly as well as 24 and 48 h after patch removal. No significant reaction attributable to sensitisation was observed in the 51 volunteers finishing the study. Only one subject showed slight irritation at day 9 of induction. Therefore, the test material at 100% when applied to the human skin was found to be not irritating and not sensitising under the test conditions.

Two further publications are available on the allergic potential of the test substance in human. The first is a case report on a 25 year-old woman (De Groot et al., 1991).

 

CAS 2306-88-9

A human patch test is available to evaluate the skin sensitising potential of octyl octanoate (CAS 2306-88-9). 111 volunteers (83 females, 28 males) with 18 to 79 years of age were included in the study (Frank, 2008). Patches soaked with 0.2 mL of 12.5% test material (100% pure) in corn oil were applied under semi-occlusive conditions three times a week on the back for a total of nine applications for induction. Approximately after two weeks of rest period after the final induction patch removal, a challenge patch was applied for 24 hours. The site was scored 24 and 72 hours after application. 105 volunteers concluded the study and none of them showed any reaction.

 

Skin sensitisation – Animal Data

Several fatty acid C2-8 esters were tested in vivo in guinea pigs or in mice (LLNA). One study led to an ambiguous result, but none of the other studies indicated a skin sensitising potential:

Skin sensitisation – Ethyl ester

CAS 544-35-4

A Local Lymph Node Assay was performed with ethyl linoleate (CAS No. 544-35-4) in CBA/J mice according to OECD Guideline 429 (van Otterdijk, 2010). The test substance contained besides 75% ethyl linoleate also 10% ethyl oleate (FA 18:1) as impurity.

Three experimental groups of five female/J mice were treated with test substance concentrations of 25, 50 or 100% w/w on three consecutive days, by open application on the ears. Five vehicle control animals were similarly treated, but with vehicle alone (Acetone/Olive oil (4:1 v/v)).Slight irritation of the ear skin and increased sizes of the auricular lymph nodes were observed by most animals treated at 50 and 100%. However, the ear thickness was not measured. The SI values calculated for the substance concentrations 25, 50 and 100% were 2.3, 6.6 and 8.2, respectively.

However, these test results cannot be interpreted as skin sensitising effects, as previous experiments indicated, that testing of linoleic acid and oleic acid obviously produced false positive results in the LLNA (Kreiling, 2008): The skin sensitization potential of eight unsaturated and one saturated lipid (bio) chemicals was tested in both, the LLNA and the GPMT to address the hypothesis that chemicals with unsaturated carbon–carbon double bonds may result in a higher number of unspecific (false positive) results in the LLNA compared to the GPMT. Seven substances (oleic acid, linoleic acid, linolenic acid, undecylenic acid, maleic acid, squalene and octinol) gave clear positive results in the LLNA (stimulation index (SI) P 3) and thus would require labelling as skin sensitizer. Fumaric acid and succinic acid gave clearly negative results. In the GPMT, besides some sporadic skin reactions, reproducible skin reactions indicating an allergic response were found in a few animals for four test substances. Based on the GPMT results, only undecylenic acid would have to be classified and labelled as a skin sensitizer according to the European Dangerous Substance Directive (67/548/EEC) (results for linoleic acid were inconclusive), while the other seven test substances would not require labelling. Possible mechanisms for unspecific skin cell stimulation and lymph node responses were discussed. In conclusion, the suitability of the LLNA for unsaturated compounds bearing structural similarity to the tested substances should be carefully considered and the GPMT was recommended as an accepted test method for skin sensitization hazard identification.

 

Skin sensitisation - Isopropyl ester

CAS 10233-13-3

A Local Lymph Node Assay was performed with isopropyl laurate (CAS 10233-13-3) according to OECD Guideline 429 (Stitzinger, 2010). Ear skins of 5 female CBA mice were treated with 25μL of the liquid test substance at concentrations of 25, 50 and 100% diluted with acetone/olive oil (4:1 v/v). Alpha-hexylcinnamicaldehyde was used for the six-month reliability check, indicating the sensitivity of the test method in the laboratory. Measurement of radioactivity showed significantly and dose-dependent increases of the disintegrations per minute/animal values: for the experimental groups treated with test substance concentrations 25, 50 and 100% the values were found to be 620, 1324 and 1929 DPM, respectively (corresponding to SI values of 1.7, 3.5, and 5.1). The mean DPM/animal value for the vehicle control group was 375. However, concomitant erythema of the treated skin sites at test substance concentrations of 50 and 100% were observed. Thus, the results cannot be clearly verified as sensitising effects, as skin irritation could also induce a dose-dependent increase of the stimulation index. Therefore, based on the study result, the test substance cannot clearly be classified as skin sensitizer.

 

CAS 110-27-0

A Guinea pig maximisation test was performed with isopropyl myristate (CAS 110-27-0) according to a protocol similar to the OECD Guideline 406 (Potokar, 1984). No range-finding study was performed for dose selection. 15 female Pirbright-Hartley guinea pigs were treated with the test substance at 5% for intra- and epidermal induction on days 1 and 7, respectively. 20 animals served as negative controls (one control animal died during the study). A positive control group was not included in the study and no information is given on periodical testing of strain sensitivity, either. 14 days after the epidermal induction, epidermal challenging was performed with a 25% test material dilution in 2% Carboxymethylcellulose and 0.5% Cremophor. 48 and 72 hours after challenging skin examination revealed no irritation in the test group or in the control group. Thus, the test material was found to be not sensitising to the skin of guinea pigs, when used as 5% solution for induction and 25% solution for challenge.Based on the study results no classification is required according to EU classification criteria for skin sensitisation.

 

CAS 63393-93-1

One animal study is available to assess the skin sensitising potential of isopropyl lanolate (CAS 63393-93-1) (Paul, 1970). In a procedure according to Landsteiner and Jacobs (1935), 10 white guinea pigs were treated with the test material (no data on purity) as follows: A 0.1% solution/suspension of the tests substance was injected intradermally 10 times (three times a week). 24 hours after each injection scorings were recorded. A re-injection (challenge) was done 2 weeks after the tenth injection. A control group was treated with vehicle only. No effects were observed at the evaluation performed 24 h after the challenge. Thus, the test material did not show any sensitising potential in this study.

 

Skin sensitisation - Butyl ester

CAS 163961-32-8

Fatty acids, C16-18 and C18-unsatd., branched and linear, Bu esters (CAS 163961-32-8) was tested in Guinea pig maximisation test according to OECD Guideline 406 (Sanders, 2002). Reliability checks had been performed 2 times a year with 10 test and 5 control animals using alpha-hexylcinnamaldehyde and 2-Mercaptobenzothiazole as positive control substances confirming the sensitivity of the test method. 20 test and 10 control animals (Dunkin-Hartley guinea pigs) were induced intradermally with 1% test substance (no data on purity) in arachis oil BP. The epidermal induction was performed with the undiluted test substance. The animals were challenged with 50% (10 test and 5 control animals) and 75% (10 test and 5 control animals) test substance solutions in arachis oil. 24 and 48 hours after termination of challenge exposure skin readings revealed no indications for a skin sensitising potential of the test substance.

 

CAS 123-95-5

The skin sensitization potential of 0.1% butyl stearate (CAS 123-95-5) in physiological saline was determined in two white male guinea pigs (Busch, 1985).The data is only available from a secondary source. The test material (no data on purity) was injected intradermally every other day or 3 times weekly until a total of 10 injections had been made. The first injection consisted of 0.05 mL of the test material, whereas the subsequent 9 injections consisted of 0.1 mL each. Two weeks following the tenth injection, a challenge injection was made using 0.05 mL of a freshly prepared test solution. Twenty-four hours after each injection, evaluations were made of the diameter, height and colour of skin reactions. No skin sensitisation was observed in either animal.

 

Skin sensitisation - Hexyl ester

CAS 34316-64-8

A guinea pig maximisation test was performed with hexyl laurate (CAS 34316-64-8) according to a protocol similar to OECD Guideline 406 (Gloxhuber, 1978). Only a short summary is available, therefore, detailed information is lacking. 20 female Pirbright-Hartley guinea pigs were induced with the test material (no data on purity). The route of induction procedure and the induction concentration was not specified. Challenge was performed epicutaneously with 1% test material in Vaseline for 24 h. A negative control group of 10 animals was included. No individual data given. However, the experimental and control animals reacted qualitatively identical to the retreatment with perceivable reddening of the parts of the skin treated; this quickly subsided and 24 hours after removal of the patch no further reaction was visible. Thus, based on the results of this study, no sensitisation potential of the test substance was indicated.

Skin sensitisation - Ethylhexyl ester

CAS 29806-73-3

The skin sensitising potential of 2-ethylhexyl palmitate (CAS 29806-73-3) was assessed by a Landsteiner and Jacobs Guinea Pigs sensitization procedure (Bio-Tox Lab, 1972). Groups of male guinea pigs were exposed 10x via intradermal injection (3x a week) to the test substance (no data on purity) at a concentration of 0.1% in physiol. saline. The first injection was done with 0.05 mL, the following injection volume was 0.1 mL each. After two weeks resting time, challenge exposure was also done by intradermal injection of 0.05 mL of 0.1% of the test material. Scoring was done 24 hours following every injection. No reaction was observed in any animal. No control groups were included in the study.Based on the study results no indication for a skin sensitising potential was seen.

 

CAS 91031-48-0

Fatty acids, C16-18, 2-ethylhexyl esters (CAS 91031-48-0) was tested for its skin sensitisation potential in a Guinea pig maximization test according to OECD Guideline 406 (Clouzeau, 1991). 20 test and 10 control animals (Dunkin-Hartley guinea pigs) were induced intradermally with the test substance diluted to 25% in paraffin oil. 7 days later the epidermal induction was performed with the undiluted test substance, as this concentration (100%) was found to be slightly irritating in the range finding test. 12 days after the last induction treatment the animals were challenged with a 50 % test substance solution in paraffin oil. 24 and 48 hours after termination of challenge exposure skin readings revealed no indications for a skin sensitising potential of the test substance.

 

CAS 135800-37-2

A Guinea pig maximisation test was performed with Fatty acids, C8-16, 2-ethylhexyl esters (CAS 135800-37-2) according to OECD Guideline 406 (Steiling, 1991). 19 test and 10 control animals (Dunkin-Hartley guinea pigs) were induced intradermally with 5% test substance (100% pure) diluted in peanut oil on both sides of the spine with and without Freud's complete adjuvant. 7 days later a 40% test substance dilution was used for the epidermal induction for 48 hours. Another 14 days later the animals were challenged by epidermal induction of the sheared flank skin with test substance diluted to 20% with paraffin oil. 24 and 48 hours after termination of challenge exposure skin readings revealed no indications for a skin sensitising potential of the test substance.

 

Skin sensitisation - Additional information

 

The OASIS Database provided from the Danish Environmental Protection Agency and Danish QSAR group, National Food Institute, Technical University of Denmark (DTU) was used to assess the sensitization potential of fatty acid methyl esters by QSAR prediction. The following members were all predicted to have no skin sensitization potential:

 

- Isopropyl laurate (CAS 10233-13-3)

- Isopropyl myristate (CAS 110-27-0)

- Isopropyl palmitate (CAS 142-91-6)

- Isopropyl oleate (CAS 112-11-8)

- Butyl stearate (CAS 123-95-5)

 

Isopropyl laurate (CAS 10233-13-3), isopropyl myristate (CAS 110-27-0), isopropyl palmitate (CAS 142-91-6), and butyl stearate (CAS 123-95-5) are broadly used as leave-on cosmetics. Isopropyl laurate is used in deodorants, sunless tanning, facial moisturizer, whereas isopropyl myristate is used in foundation, moisturizer, eye shadow, concealer, lipstick, facial powder, facial moisturizer, hand cream, hand sanitizer, lip balm. (source: www.cosmeticsdatabase.com).

 

According to the ECETOC Monograph# 32 (ISSN-0773-6347-32, Brussels, 2002) on the Use of Human Data in Hazard Classification for Irritation and Sensitisation, "no classification with R43 is necessary, where a significant number of individuals (e.g. 100,000) have frequent (daily) skin exposure for at least one year and there is a system in place to pick up complaints and adverse reaction reports, and where no or only a few isolated cases of allergic contact dermatitis are observed".

 

Based on the fact, that an eminent number of persons have daily contact with the leave-on cosmetic substances isopropyl laurate, isopropyl myristate and ethyl linoleate and at the same time there were no clinical case reports on the sensitisation potential of these three substances available, a sensitisation potential appears very unlikely.

 

Conclusion for skin sensitisation properties

Taken together, all available data for assessment of the skin sensitising potential indicate that members of the category Fatty acid C2-8 esters have no skin sensitisation potential and classificationaccording to EU classification criteria for skin sensitisation is not required.

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

 


Migrated from Short description of key information:
Based on a weight of evidence approach, SCAE C2-C8 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 group concept is applied to the members of the SCAE C2-C8 category, data will be generated from representative reference substance(s) within the category to avoid unnecessary animal testing. Additionally, once the group concept is applied, substances will be classified and labeled on this basis.

Therefore, based on the group concept, the 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.