Registration Dossier

Administrative data

Description of key information

All available studies on skin and eye irritation showed no irritating potential of the category members.

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for grouping of substances and read-across

The long-chain aliphatic ester (LCAE) category covers mono-esters of a fatty acid and a fatty alcohol. The category contains both mono-constituent and UVCB substances. The fatty acid carbon chain lengths range is C8 - C22 (even and uneven numbered, including saturated, unsaturated, branched and linear chains) esterified with fatty alcohols with chain lengths from C8 - C22 (even and uneven numbered, including saturated, unsaturated, branched and linear) in varying proportions to mono-esters.

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 for 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 irritation / corrosion

CAS

Skin Irritation

Eye Irritation

20292-08-4 (b)

Experimental result:

not irritating

Experimental result:

not irritating

91031-48-0

--

Experimental result:

not irritating

26399-02-0

Experimental result:

not irritating

--

3687-46-5

Experimental result:

not irritating

--

59231-34-4 (a)

RA: CAS 3234-85-3, 3687-46-5,

 93803-87-3

RA: CAS 72576-80-8,

93803-87-3, 20292-08-4

36078-10-1

RA: CAS 3234-85-3,

3687-46-5, 93803-87-3

RA: CAS 72576-80-8,

93803-87-3, 20292-08-4

95912-86-0

Experimental result:

not irritating

RA: CAS 72576-80-8,

93803-87-3, 20292-08-4:

95912-87-1

RA: CAS 3234-85-3, 3687-46-5,

 93803-87-3

RA: CAS 72576-80-8,

93803-87-3, 20292-08-4

91031-91-3

RA: CAS 3234-85-3,

3687-46-5, 93803-87-3

RA: CAS 72576-80-8,

93803-87-3, 20292-08-4

85116-88-7

RA: CAS 3234-85-3,

3687-46-5, 93803-87-3

RA: CAS 72576-80-8,

93803-87-3, 20292-08-4

95912-88-2

Experimental result:

not irritating

Experimental result:

not irritating

3234-85-3

Experimental result:

not irritating

Experimental result and RA:

CAS 20292-08-4:

not irritating

22393-85-7

RA: CAS 3234-85-3, 3687-46-5,

 93803-87-3

RA: CAS 72576-80-8,

93803-87-3, 20292-08-4

101227-09-2

RA: CAS 3234-85-3, 3687-46-5,

 93803-87-3

RA: CAS 72576-80-8,

93803-87-3, 20292-08-4

72576-80-8

Experimental result:

not irritating

Experimental result:

not irritating

3687-45-4

RA: CAS 3234-85-3, 3687-46-5,

 93803-87-3

RA: CAS 72576-80-8,

93803-87-3, 20292-08-4

17673-56-2

RA: CAS 3234-85-3, 3687-46-5,

 93803-87-3

RA: CAS 72576-80-8,

93803-87-3, 20292-08-4

96690-38-9

RA: CAS 3234-85-3, 3687-46-5,

 93803-87-3

RA: CAS 72576-80-8,

93803-87-3, 20292-08-4

93803-87-3

Experimental result:

not irritating

Experimental result:

not irritating

17671-27-1

Experimental result: not irritating

RA: CAS 3234-85-3, 3687-46-5,

 93803-87-3

CAS 72576-80-8,

93803-87-3, 20292-08-4

111937-03-2 (c)

Experimental result:

not irritating

Experimental result:

not irritating

(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. Lack of data for a given endpoint is indicated by “--“.

(c) Surrogate substances are chemicals of structurally similar fatty acid esters. Available data on these substances are used for assessment of (eco-)toxicological properties by read-across on the same basis of structural similarity and/or mechanistic reasoning as described below for the present category.

Discussion

Skin irritation

CAS 3687-46-5

Decyl oleate (CAS 3687-46-5) was tested for its skin irritation potential in a study similar to OECD 404 (Dufour, 1994). The shaved skin of 3 male rabbits was exposed to an undisclosed amount of undiluted test material for 4 hours under semi-occlusive conditions. 3/3 animals had very slight erythema (score 1) 1 hour after exposure ended. At the 24-hour reading time point 2/3 animals still had very slight erythema and 1/3 had well-defined erythema. The mean erythema scores (over 24, 48 and 72 h) were 1, 0.33 and 1.33. Very slight edema (score 1) was observed in 1/3 rabbits from the 1-hour- up to and including the 72-hour reading time point. All irritation reactions were completely reversible within 5 days.

In a non-guideline study an unknown amount of the substance was applied to the shaved skin of 2 rabbits and covered with a patch for 6 hours (Potokar, 1970). Slight redness was noted at the application site; the effect was fully reversible within 48 hours. The study was insufficient for assessment as only a short abstract on method and results was available.

Several non-guideline tests were performed by Potokar (1970), in which rabbits or rodents were exposed to the test substance repeatedly during the course of 30 minutes (rabbit) or daily for 14 days (rats, and mice). Two studies performed in humans evaluated the effect of repeated exposure during 30 minutes or a single-patch exposure for 2 hours. Although none of the results indicated skin irritation, the studies were alone insufficient for assessment as they do not meet important criteria of today's standard methods. However, they support the overall weight of evidence that the substance is not irritating to the skin.

 

CAS 59231-34-4

The review publication on isodecyl oleate (CAS No. 59231-34-4) by the Cosmetic Ingredient Review, included two animal studies and two human volunteer studies that were briefly summarised (CIR Expert Panel, 1982). Very low primary irritation scores and/or slight skin irritation effects were reported.

In a publication by Guillot (1977), the results of a study performed according to a French national guideline (1971) similar to OECD 404 were presented. Undiluted or a 15% solution of isodecyl oleate was applied to the skin of rabbits under occlusive conditions in two tests. As no individual scores were given and only a primary irritation index of 0 and 0.13 reported, the study results were disregarded. Guillot (1977) also presented the results of a repeated exposure study in rabbits, using a 15% solution of undiluted test substance. The study was disregarded as it does not meet important criteria of today’s standard methods.

 

CAS 95912-86-0

A skin irritation study was performed with Fatty acids, C8-10, C12-18 alkyl esters (CAS 95912-86-0), according to a protocol similar to OECD 404 (Dufour, 1991). 0.5 mL of the test substance was applied to the shaved skin of 3 male rabbits and held in place by an occlusive dressing for 4 hours. 1 hour after exposure, all the animals had slight to well-defined erythema, while 2/3 had very slight to slight edema. These effects gradually reduced in severity. 24 hours after exposure ended, 1/3 animals had very slight erythema and slight edema. The edema persisted until the 48-hour reading time point. All skin irritation effects had cleared completely within 72 hours after the exposure ended.

The skin irritation potential of the test substance from two sources was assessed in a non-guideline study, described in a short abstract (Potokar, 1981). 0.5 mL of the test substance was applied to the skin of 5 rabbits for 4 hours under occlusive conditions. The scoring of irritation reactions was done according to a scale of 0-100% (not irritating to severely irritating), leading to a maximum score of 7.5%. Since the study does not meet important criteria of today’s standard methods, the results were considered insufficient for assessment. In a series of non-guideline studies performed by Potokar (1970, 1981), the effect of repeated applications of the test substance to the skin of rabbits or hairless mice was assessed. The results of the studies were disregarded as they do not meet important criteria of today's standard methods.

A human patch test was performed with 50 volunteers, which were exposed to an unknown amount of the test substance for an unknown length of time (Herzberg, 1968). No skin irritation was observed 24 and 48 hours after patch removal.

 

CAS 95912-87-1

In a non-guideline study, hairless mice were repeatedly exposed to a 0.0012% solution of Fatty acids, C16-18, C12-18 alkyl esters (CAS 95912-87-1) (Kästner, 1977). The results were considered insufficient for assessment, as the study does not meet important criteria of today's standard methods.

In a human skin irritation test (Burckhardt test), a 0.01% solution of the test substance was applied 60 times within 30 minutes to the skin of 5 volunteers (Kästner, 1977). In 1/5 volunteers, blotchy redness was observed until 1 hour after exposure ended. The results were considered insufficient for assessment, as the study does not meet important criteria of today's standard methods.

 

CAS 95912-88-2

Fatty acids, C16-18, isotridecyl esters (CAS 95912-88-2) was tested for its skin irritation potential in a study similar to OECD 404 (Kästner, 1987). 0.5 mL of the undiluted test substance was applied to the shaved skin of 5 male rabbits for 4 hours under occlusive conditions. At the 24-hour reading time point, 3/5 animals had very slight erythema and edema. By the 48-hour reading time point, the severity had increased to well-defined erythema in 2/5 animals, while 2/5 had very slight erythema. Very slight to well-defined erythema persisted in 3/5 rabbits until 72 hours after exposure. The individual mean erythema scores were 1, 0.33, 1.33, 1.67 and 0, respectively. 2/5 animals had very slight edema until the 72-hour reading time point. All the irritation effects had cleared completely within 7 days. The substance was not skin irritating under the conditions of the study.

 

CAS 3234-85-3

A skin irritation study was performed according to a protocol similar to OECD 404 with tetradecanoic acid, tetradecyl ester (CAS 3234-85-3) (Planchette, 1985). The test substance was applied to the shaved or shaved and abraded skin of 6 male rabbits and held under occlusive conditions for 24 hours. The reading time points were 24- and 72 hours after patch removal. 1/6 animals had slight erythema (score 1 of 4) on the intact skin at the 24-hour reading time point, which had cleared completely by the 72-hour reading time point. No other skin irritation effects were observed in any animals (6/6). 1/6 animals had slight erythema (score 1 of 4) at the 24-hour reading time point on the abraded skin site. The skin irritation had cleared within 48 hours. The limited irritation effects on the abraded skin indicate that the substance is not a skin irritant and the results are therefore considered to be valid for the skin irritation potential assessment.

In a non-guideline skin irritation study performed by Cade (1976), 0.5 mL of a 50% solution of the test substance in corn oil was applied to the shaved and intact or abraded skin of 6 rabbits under occlusive conditions for 24 hours. The skin irritation effects were scored 24 and 72 hours after patch removal. 1/6 animals had very slight erythema at the 72-hour reading time point on both the intact and abraded skin site. No other skin irritation effects were observed.

In a non-guideline study, 10% (w/v) of an oily preparation was applied twice daily for 14 days to the same skin area on the backs of 10 female mice (Potokar, 1983). The study was considered insufficient for assessment, as it does not meet important criteria of today's standard methods.

The review publication on tetradecanoic acid, tetradecyl ester by the Cosmetic Ingredient Review, included five animal studies and a human volunteer study that were briefly summarised (CIR Expert Panel, 1982). All the summaries indicated the substance is not irritating.

 

CAS 101227-09-2

The results of a non-guideline study with Fatty acids, C16-18, 2-hexyldecyl esters (CAS 101227-09-2) were presented in a summary report with limited information (Kästner, 1984). 0.5 mL undiluted test substance was applied to the skin of rabbits under occlusive conditions for 2 hours. 1/5 rabbits had slight erythema at the 2- and 48-hour reading time points. As no individual scores were reported and observations were reported only until 48 hours after patch removal, the study results were considered insufficient for assessment.

 

CAS 72576-80-8

A study was performed according to EU Method B.4 (similar to OECD 404) to assess the skin irritation potential of hexadecanoic acid isooctadecyl ester (CAS 72576-80-8) (Bouffechoux, 1999). 0.5 g test substance was applied to the shaved skin of rabbits under semi-occlusive conditions for 4 hours. The skin irritation was scored 1, 24, 48 and 72 hours after exposure ended. No erythema or edema was observed in any animal at any time point.

 

CAS 93803-87-3

A study was performed according to OECD 404 to assess the skin irritation potential of 2-octyldodecyl isooctadecanoate (CAS 93803-87-3) (Busschers, 1998). 0.5 g test substance was applied to the shaved skin of rabbits under semi-occlusive conditions for 4 hours. 3/3 animals had well-defined erythema (score 2) at the 1-hr reading time point. The erythema had reduced in severity by 24 hours after exposure in 3/3 rabbits (score 1, 1, 1), and had cleared completely within 72 hours for 3/3 rabbits. The mean score for the 24, 48 and 72 evaluation times was 0.67, 0.33 and 0.33. No edema was observed in any animal at any time point.

 

CAS 17671-27-1

In a single exposure patch test, the undiluted test substance was applied to the back skin of 11 volunteers for 24 hours under occlusive conditions. The skin irritation effects (erythema and edema) were assessed 30 minutes and 24 hours after patch removal. Slight to moderate erythema was observed at the test site in 3/10 subjects at the 30-minute reading time point and in 1/10 24 hours after patch removal. The positive control (1% sodium sulphate) was shown to be valid. 1/11 subjects were excluded as moderate erythema was noted at the negative control site (water).

 

Eye irritation

CAS 20292-08-4

An acute eye irritation test performed according to OECD Guideline 405 was performed to evaluate the eye irritation potential of 2-ethylhexyl laurate (CAS 20292-08-4) (Bouffechoux, 1996). The test substance was instilled into one eye of 3 rabbits. The animals were observed for 7 days. Slight conjunctival effects (mean score = 0.33 in all animals) were observed up to 24 h. These effects were fully reversible within 48 h. No information is given if these effects were reddening or swelling of the conjunctivae as only a summary of the results is available. However, based on the results of the study the test substance is not considered to be eye irritating.

 

CAS 3687-46-5

In a non-guideline study, 3 drops of a 50% solution of decyl oleate in olive oil was instilled into one eye of rabbits (Potokar, 1970). No irritation effects were observed at the reading time points 2, 6, 24 and 48 hours after instillation. The study was considered insufficient for assessment, as very limited data on the method and results were available.

 

CAS 59231-34-4

The review publication on tetradecanoic acid, tetradecyl ester (CAS 59231-34-4) by the Cosmetic Ingredient Review, included two studies that were briefly summarised (CIR Expert Panel, 1982). 0.1 mL undiluted isodecyl oleate or a 15% solution in corn oil was instilled in to one eye of rabbits and the irritation effects scored. No eye irritation was observed. The studies were considered insufficient for assessment, as only limited documentation was available. 

In a publication by Guillot (1977), the results of a study performed according to a French national guideline (1971) similar to OECD 405 were presented. Undiluted or a 15% solution (in 3% polyoxyethylene sorbitan stearate, 80% water, 2% unknown preservative) of the test substance was instilled into the eye of rabbits and the irritation reactions scored up to 7 days after exposure. Only the ocular index was reported, which was 4.0 1 hour after instillation and 0 at later reading time points. The result was considered insufficient for assessment due the limited documentation of the study.

 

CAS 95912-86-0

The eye irritation potential of Fatty acids, C8-10, C12-18 alkyl esters (CAS 95912-86-0) from 2 sources was assessed in a non-guideline study, and described in a very summary report (Potokar, 1981). 0.1 mL was instilled into the eye of 5 rabbits/source and the reaction was scored 2, 6 and 24 hours after exposure. The irritation reactions observed were < 4% and < 10% of the maximum possible severity in the 2 substance sources, respectively, 2 hours after exposure ended. The effects had reversed completely within 24 hours. As the scoring system was unclear, the results cannot be used for classification purposes.

In a non-guideline study performed by Potokar (1970), a 10% solution of the test substance was instilled into one eye of rabbits. The result of the study was considered insufficient for assessment, as it does not meet important criteria of today's standard methods.

 

CAS 95912-87-1

In a non-guideline study performed by Kästner (1977), a 0.004% solution of Fatty acids, C16-18, C12-18 alkyl esters (CAS 95912-87-1) was instilled into one eye of rabbits. The result of the study was considered insufficient for assessment, as it does not meet important criteria of today's standard methods.

 

CAS 95912-88-2

A study was performed by Kästner (1987) according to a protocol similar to OECD 405, using Fatty acids, C16-18, isotridecyl esters (CAS 95912-88-2). 0.1 mL of the undiluted test substance was instilled into one eye of 4 rabbits. The eyes were not washed after the treatment. 1 hour after exposure, 4/4 rabbits had discharge from the treated eye, while 3/4 rabbits showed slight redness of the eye. These effects cleared completely within 24 hours. No erythema and edema was observed at any of the other reading time points (24, 48 and 72 hours).

 

CAS 3234-85-3

A study was performed by Cade (1976) using tetradecanoic acid, tetradecyl ester (CAS 3234-85-3) according to a protocol similar to OECD 405, and summarised in a short report. 0.1 mL of a 50% solution of the test substance in corn oil was instilled into the eye of 6 rabbits. The eyes were not washed after the treatment. Slight redness was observed in 4/6 animals at the 24-hour reading time point, which had cleared completely within 72 hours (individual mean scores: 0.66, 0.33, 0, 0.33, 0.33, 0). No other eye irritation effects were observed in any of the animals. As a dilution was used, the results cannot be used for classification purposes.

The review publication on tetradecanoic acid, tetradecyl ester by the Cosmetic Ingredient Review, included three studies that were briefly summarised (CIR Expert Panel, 1982). The mean ocular irritation index was 0-2.67, indicating low eye irritation potential under the conditions of the studies. In a non-guideline study, 0.1 mL heated 1% oily dilution of the test substance was instilled into one eye of 6 rabbits (Potokar, 1983). The study was considered insufficient for assessment, as it does not meet important criteria of today's standard methods.

 

CAS 101227-09-2

The results of a non-guideline study with Fatty acids, C16-18, 2-hexyldecyl esters (CAS 101227-09-2) were presented in a summary report with limited information (Kästner, 1984). 0.1 mL of the test substance was instilled into one eye of 3 rabbits and rinsed out with water after 10 seconds. The eye irritation effects were scored 1, 6, 24 and 48 hours after exposure. Moderate conjunctival effects were observed in the treated eye of 3/3 rabbits at the 1-hour reading time point, which had cleared within 48 hours. The average severity was given as 36.5% of 100% 1 hour after exposure; which decreased gradually to 0% after 48 hours. As no objective scoring system was used, the study was considered insufficient for assessment.

 

CAS 72576-80-8

In a study performed according to OECD 405 by Bouffechoux (1999), the eye irritation potential of hexadecanoic acid isooctadecyl ester (CAS 72576-80-8) was evaluated. 0.1 mL test substance was instilled into one eye of 3 rabbits. At the 1-hour reading time point, 3/3 rabbits had slight-moderate conjunctivae (scores 1, 1, 2) and 2/3 had slight chemosis (scores 0, 1, 1). The chemosis had cleared by the 24-hour reading time point, while 3/3 animals still had slight conjunctivae (scores 1, 1, 1). All eye irritation effects were fully reversible within 48 hours.

 

CAS 93803-87-3

The eye irritation potential of 2-octyldodecyl isooctadecanoate (CAS 93803-87-3) was evaluated in a study performed according to OECD 405 (Busschers, 1998). 0.1 mL was instilled into one eye of 3 rabbits and left without washing. Remains of the test substance were noted in the treated eye of 3/3 animals on Day 1, while remains were present on the outside of the eyelids on Day 2 in 1/3 animals. At the 1-hour reading time point 3/3 rabbits had slight conjunctivae (score 1, 1, 1), which was still present in 1/3 rabbits at the 24-hour reading time point. The effect had cleared completely within 48 hours. No other eye irritation effects were observed in any rabbit at any time point.

 

CAS 17671-27-1

Two non-guideline in vitro studies were performed to assess the eye corrosion effects of docosyl docosanoate (CAS 17671-27-1). The first test was a cytotoxicity assay in which fibroblasts from rabbit cornea (SIRC cell line) were exposed to docosyl docosanoate (Boue-Grabot and Guibaud, 2005). The fibroblasts were incubated in plates with a 15% dilution of the test substance in paraffin oil for 30 min, 1h and 4 hrs (at 37 °C), before the cells were dyed with MTT dye. Using the MTT test, the cytotoxicity was determined by measuring the absorption at 570 nm. The ocular irritation was 0.1 of a maximum score of 50 (Ocular Irritation index), indicating a slight irritation potential.

In the second test, the Hen's Egg Test-Chorioallantoic Membrane (HET-CAM) assay was applied according to a protocol endorsed by ICCVAM (Boue-Grabot and Guibaud, 2005). The potential of the test substance to cause (severe) ocular irritancy was measured by its ability to induce toxicity in the chorioallantoic membrane of a chicken egg. A 15% dilution of docosyl docosanoate in paraffin oil was applied to the chorioallantoic membrane of 4 eggs for 20 seconds before rinsing the membrane with 5 mL saline (at 37 °C). The effects were measured by scoring the occurrence and intensity of haemorrhage, coagulation and vessel lysis (hyperaemia). The score is used to classify the irritancy level of the test substance, with a maximum score of 21 indicating a corrosive effect. Hyperaemia score 1 (of 5) was noted in 4/4 eggs, adding up to a combined score of 1.0. This indicates slight irritation according to the scoring system, but no corrosive effects.

 

Overall conclusion for skin and eye irritation

The results of all the skin irritation studies (representative studies include: Bouffechoux, 1999; Busschers, 1998; Dufour, 1994) indicate that the category members will not cause skin irritation. The results of all the eye irritation studies (representative studies include: Bouffechoux, 1996; Bouffechoux, 1999; Busschers, 1998) indicate that the members of the category will not cause eye irritation.

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

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 LCAE category, data will be generated from data for reference source substance(s) to avoid unnecessary animal testing. Additionally, once the group concept is applied, substances will be classified and labelled on this basis.

Therefore, based on the group concept, the available data on skin and eye irritation 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.