Fatty acids, C14-18 and C18-unsatd., branched and linear, 2-ethylhexyl esters

Endpoint summary

Description of key information

Using a Read Across Category approach with Long Chain Acid Esters substancves (C8 to C18) according to the Annex XI Item 1.5, of Regulation (EC) No 1907/2006, all available skin and eye irritation studies within this category resulted in not irritation to skin or eye after the treatment of the animals. Hence, according to the CLP criteria, the test item Isostearate 2-Ethyl Hexyl was not classified for eye and skin irritation.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Read Across Category Target Substance Endpoint Record

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Remarks on result:

no indication of irritation

Table 1: Results from key studies on source chemicals of the category for skin irritation and corrosion tests

ID#	CAS	Skin irritation or skin corrosion
Fatty acids, C8-16, 2- ethylhexyl esters	135800-37-2	Experimental result: Not irritating
Fatty acids, coco, 2-ethylhexyl esters	92044-87-6	Experimental result: Not irritating
2-Ethylhexyl palmitate	29806-73-3	Experimental result: Not irritating
Fatty acids, C16-18 and C18-unsatd., 2- ethylhexyl esters	85049-37-2	No data
Fatty acids, C16-18, 2-ethylhexyl esters	91031-48-0	No data
2-Ethylhexyloleate	26399-02-0	Experimental result: Not irritating
2-Ethylhexylstearate	22047-49-0	Experimental result: Not irritating

 

According to the current literature, esterase enzymes were present into the skin of different mammalian species (as human, rodents or minpigs). These enzymes, as carboxylesterase, hydrolyzed different substrates as xenobiotic or different ester as fatty acids esters (C. Jewell, 2007; J.J. Prusakiewicz, 2006). Based on this principle, when applied on skin, the source and the target substances are expected to be substrates of these carboxylesterase. They are hydrolyzed into fatty acids and alcohols. In the case that the products of hydrolysis could across the dermal barrier to reach systemic system, they have the same behavior as oral ingestion. The potential toxicity should be bring by these hydrolyzed products.

According to their very low solubility in water and their log Kow values, these substances are not expected to be strong acid or basic substances. However, based on the probable pH values of these substances, acid reserve value is necessary to assess potential irritation/corrosion effect (Young J.R and M.J. How, 1994). Despite no acid reserve value, and regarding the potential nonacid or basic pH of these substances, no local adverse effect, as irritation or corrosion, is expected in skin for the target substance..

 

Based on the available key studies, the members of the category were considered as not irritating when applied on skin. Hence, the target substance was not classified for skin irritation according to CLP criteria and the category approach.

 

Interpretation of results:

GHS criteria not met

Conclusions:

According to the results from experimental study performed on the substances of the LCAE Category, the category substances did not led to irritation when applied on rabbit skin. Hence, according to the CLP criteria and the category approach, the registered substance was not classified for Skin Irritation.

Executive summary:

According to the Regulation (EC) NO. 1907/2006, Annex XI, 1.5, A Read-Across Category for Long Chain Fatty Acid was performed in order to provide informations on the Isostearate Ethyl Hexyl.

This category was based on common and shared physico-chemical and structural properties as:

-       common functional group,

-       common precursors and the likehood of common impurities as well as common breakdown products via biological processes, which are chemically structurally similar, and

-       constant pattern in the changing of the potency of the properties across the category.

The fatty acids linked with 2-ethylhexyl esters have a common metabolic fate in organisms as glycolytic and fatty acid pathways after first hydrolysis step which led in breakdown products. The common toxicokinetic properties and behavior are expected due to the constant pattern (ethylhexyl esters and the fatty acid chain). The toxicological profiles between the members of the category are expected to be the same.

Several studies were performed to assess skin irritation for members of the category. They are considered as reliable (GLP compliant, method equivalent or similar to OECD 404 guideline method). Rabbits were used for these experimental studies. Shaved or clipped skin were treated under semi occlusive condition for 72 hours and observations were performed at differents timepoints (24, 48 and 72 hours) according to Draize scheme. No reaction or slight reaction was observed (recovery within 24 hours).

According to the results from experimental study performed on the substances of the LCAE Category, the category substances did not led to irritation when applied on rabbit skin. Hence, according to the CLP criteria and the category approach, the registered substance was not classified for Skin Irritation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Read Across Category Target Substance Endpoint Record

Remarks on result:

no indication of irritation

Table 1: Results from key studies on source chemicals of the category for eye irritation and corrosion tests

ID#	CAS	Eye irritation
Fatty acids, C8-16, 2- ethylhexyl esters	135800-37-2	No data
Fatty acids, coco, 2-ethylhexyl esters	92044-87-6	Experimental result: Noti rritating
2-Ethylhexyl palmitate	29806-73-3	Experimental result: Not irritating
Fatty acids, C16-18 and C18-unsatd., 2- ethylhexylesters	85049-37-2	No data
Fatty acids, C16-18, 2-ethylhexyl esters	91031-48-0	Experimental result: Not Irritating
2-Ethylhexyl oleate	26399-02-0	No data
2-Ethylhexyl stearate	22047-49-0	No data

 

Similar toxicokinetic behavior and toxicity profile

In eye, some esterase enzyme could have the same ability to hydrolyze the category substances (V.H.L. Lee, 1982) into alcohol and fatty acids. They could vehicle potential irritation or corrosion effect. But, none of the source substances, which were assessed for eye irritation, showed any adverse effect on rabbit eyes as expected.

 

Based on the available key studies, the members of the category were considered as not irritating when applied on eye. Hence, the target substance was not classified for eye irritation according to CLP criteria and the category approach.

 

 

Interpretation of results:

GHS criteria not met

Conclusions:

According to the results from experimental study performed on the substances of the LCAE Category, the category substances did not led to irritation when applied on rabbit eye. Hence, according to the CLP criteria and the category approach, the registered substance was not classified for eye Irritation.

Executive summary:

According to the Regulation (EC) NO. 1907/2006, Annex XI, 1.5, A Read-Across Category for Long Chain Fatty Acid was performed in order to provide informations on the Isostearate Ethyl Hexyl.

This category was based on common and shared physico-chemical and structural properties as:

-       common functional group,

-       common precursors and the likehood of common impurities as well as common breakdown products via biological processes, which are chemically structurally similar, and

-       constant pattern in the changing of the potency of the properties across the category.

The fatty acids linked with 2-ethylhexyl esters have a common metabolic fate in skin as hydrolysis step by esterase enzymes which led in breakdown products. The common toxicokinetic properties and behavior are expected due to the constant pattern (ethylhexyl esters and the fatty acid chain). The toxicological profiles between the members of the category are expected to be the same.

Experimental studies were available. These studies were performed for two category members. They are considered as reliable (GLP compliant, OECD 405 method). Rabbits were treated with the substance on the eye and observations were performed 24, 48 and 72 hours after the treatment for the first study; except in one study, observations were performed at 2, 6 and 24 hours. No ocular lesions or only slight swelling of blood vessels were observed after 1 hour post treatment which was reversible within 24 hours.

According to the results from experimental key studies performed on the substances of the LCAE Category, the source substances did not led to irritation when applied on rabbit eye as expected. Hence, according to the CLP criteria and the category approach, the registered and target substance Isostearate Ethyl hexyl was not classified for Eye Irritation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Additional information

Justification and rationale of the category approach for the Isostearate 2-ethyl hexyl :

This category group covers 2-ethyl hexyl esters linked with fatty acid chains (C8 to C18) unsatured and satured. This category includes monoconstituent substances and UVCB substances varying fatty acid chain length. This category was made in order to provide sufficient information for physicochemical, ecotoxicological and toxicological caracterisation of the Fatty acids, C14-18 and C18-unsatd., branched and linear, 2-ethylhexyl esters (CAS No 85186-76-1)

The category group includes:

- 2-Ethyl hexyl stearate (CAS No 22047-49-0)

- Fatty acids, C8-16, 2-ethylhexyl esters (CAS No 135800-37-2)

- Fatty acids, C16-18 and C18-unsatd., 2-ethylhexyl esters (CAS No 85049-37-2)

- Fatty acids, coco, 2-ethylhexyl esters (CAS No 92044-87-6)

- Fatty acids, C16-18, 2-ethylhexyl esters (CAS No 91031-48-0)

- Fatty acids, C8-16, 2-ethylhexyl esters (CAS No 135800-37-2)

- 2-Ethylhexyl oleate (CAS No 26399-02-0)

Target substance for Category Approach : Fatty acids, C14-18 and C18-unsatd., branched and linear, 2-ethylhexyl esters (CAS No 85186-76-1)

In accordance with article 13 (1) of Regulation (EC) No. 1907.2006, “information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met. In particular for human toxicity, environmental fate and ecotoxicity, information shall be generated whenever possible by means other than vertebrate animal tests which includes the use of information from structurally related substances (grouping or read across)”. Therefore, the available experimental data were collected and evaluated according to Annex XI requirements.

Summary of the available studies for skin irritation

Fatty acids, C8-C16, 2-ethylhexyl esters CAS 135800-37-2

One key study is available (Steiling 1990). The substance was assessed in a in vivo irritation study performed according to OECD guideline 404. 4 rabbits were exposed during 4 hours with 0.5 mL of substance under occlusive conditions. Observations of skin integrity was performed on 1; 24, 48, 72 hours and daily during 7 days. The test substance, when administered to rabbit skin for 24h, caused only slight irritations that were fully reversible within 7 days. It was considered as not irritating.

2-Ethylhexyl palmitate CAS 29806-73-3

Three studies performed with 2-Ethylhexyl Palmitate (CAS 29806-73-3) to assess the skin irritating potential are available.

An acute dermal irritation test was performed according to OECD Guideline 404 under GLP conditions (Key sudy, Guest, 1990). In this key study, the shaved skin of three New Zealand White rabbits was exposed to 0.5 mL of the unchanged test substance (no data on purity) for 4 hours under semi-occlusive conditions. The treated skin sites were examined according to the Draize scoring system 24, 48 and 72 hours after application. Only very slight erythema (mean scores = 0.67, 0.33, and 0.67) occurred, which were fully reversible within 48 to 72 hours.

In a second acute dermal irritation study (considered as supporting study) performed according to a protocol similar to OECD Guideline 404, three albino rabbits were treated with 0.5 mL of the unchanged test material (no data on purity) for 24 hours under occlusive conditions at shaved intact and abraded skin sites (Green, 1972). Scoring according to Draize was performed 24 and 72 h after application. No irritation reaction was observed even when the test substance was applied on abraded skin sites (worst case exposure scenario).

An additional supporting study was performed according to a protocol similar to OECD Guideline 404 (Planchette, 1985). Six New Zealand White rabbits were treated with 0.5 mL of the unchanged test substance (no data on purity) for 24 h under occlusive conditions. The animals were observed for 72 hours and scoring according to Draize was performed 24 and 72 h after application. No skin reaction was observed in any animal at any time point of the study.

Fatty acids, coco, 2-ethylhexyl esters CAS 92044-87-6

The skin irritation/corrosion potential of Fatty acids, coco, 2-Ethylhexyl Esters (CAS 92044-87-6) was tested in a primary dermal irritation study according to OECD Guideline 404 under GLP conditions (considered as the key study, Weterings 1987). The clipped skin of three New Zealand White rabbits was exposed to 0.5 mL unchanged test material (approx. 100% pure) for 4 hours under semi-occlusive conditions. The rabbits were observed for 7 days. Skin reactions were assessed using the Draize scheme 45 min, 24, 48, 72 hours, and 7 days after patch removal. Slight erythema (mean scores = 1.0, 1.0, and 0.67) and slight oedema (mean scores = 1.0, 0.67, and 0.67) were observed in all animals. All effects were fully reversible within 72 h to 7 days. Thus, the test substance was is not irritating in this study.

In the supporting study performed according to a protocol similar to OECD Guideline 404 six New Zealand rabbits were treated with 0.5 mL of the test substance (no data on purity) for 24 h under occlusive conditions on intact and incised skin (Masson, 1985). The animals were observed for 72 h and scoring according to Draize was performed 24 and 72 h after patch removal. No reactions were observed in any animals and thus, the test substance is not considered irritating.

2-ethylhexyl oleate CAS NO 26399-02-0

One key study is available (Dufour, 1991). The substance was assessed in a in vivo skin irritation study performed according to OECD guideline 404. 3 rabbits were exposed during 4 hours with 0.5 mL of substance under occlusive conditions. Observations of skin integrity was performed on 1; 24, 48, 72 hour. When administered to rabbits, the test substance caused only slight irritations in one animal after 24h that were fully reversible within 48h.  

2-ethylhexyl stearate CAS 22047-49-0

One study is available (Weight of Evidence Masson, 1985). The substance was assessed in a in vivo skin irritation study performed similarly to OECD guideline 404. 6 males rabbits were exposed during 4 hours with 0.5 mL of substance under occlusive conditions on intact skin and abraded skin. Observations of skin integrity were performed on 1, 24 and 72 hour. When administered to rabbits, the test substance caused only slight irritations. All signs of irritation were completely reversible at 72 hours time point. This study has deviations : lack of details on test substance, lack of 48 hour reading time point, occlusive 24h application and limited documentation.

In summary, based on the study results the target substance is not considered as skin irritating

Summary of available studies for eye irritation of the category members

2-Ethylhexyl Palmitate CAS 29806-73-3

Four studies are available to evaluate the eye irritation potential of 2-Ethylhexyl Palmitate (CAS 29806-73-3):

The key study is an acute eye irritation study which was performed according to OECD Guideline 405 under GLP conditions (Guest, 1990). 0.1 mL of the unchanged test substance (no data on purity) was instilled to the right eye of three New Zealand White rabbits. The untreated left eye served as control. Examination of the treated eyes 24, 48 and 72 hours after instillation revealed no ocular changes.

In a second study (considered as supporting study) performed according to a protocol similar to OECD Guideline 405, 0.1 mL of the test substance was instilled in one eye of six New Zealand White rabbits (Sugar, 1980). The animals were observed for 72 hours and scoring according to Draize was performed 24, 48, and 72 hours after instillation. Slight effects were observed on conjunctivae (redness and swelling) and in one animal on iris (grade 1 at 24 h). All effects were fully reversible within 72 h except in one animal (conjunctivae redness grade 1 at 72 h). However, full reversibility in case of a prolonged and thus adequate observation period is assumed. Therefore, the test substance is not considered eye irritating in this study.

Another eye irritation supporting study was performed according to a protocol similar to OECD Guideline 405 (Sugar, 1981). 0.1 mL of the undiluted test substance (no data on purity) was instilled in the eyes of 6 New Zealand White rabbits. The animals were observed for 72 hours and scoring was performed 24, 48 and 72 hours after application according to the Draize scoring system. Slight effects on conjunctivae redness and swelling were observed that were fully reversible within 72 and 48 hours, respectively. Hence, in this study the test substance caused no irritation in the rabbit eye.

A further supporting study on the eye irritation potential of the test substance is available (Green, 1972). It was performed according to a protocol similar to OECD Guideline 405. 0.1 mL of the unchanged test substance was instilled in one eye of three albino rabbits. The animals were observed for ocular effects for 7 days. Scoring according to the Draize scheme was performed 1 hour after application and daily afterwards. Slight iris and conjunctivae effects were observed in all 3 animals one hour after instillation. These effects were fully reversible within 24 hours.

Based on the results of all four studies, the2 -ethylhexyl palmitate is not considered eye irritating.

Fatty acids, coco, 2-Ethylhexyl Esters CAS 92044-87-6

One study with Fatty acids, coco, 2-Ethylhexyl Esters (CAS 92044-87-6) for the assessment of the acute eye irritation/corrosion potential is available (Weterings, 1987). The key study was performed according to OECD Guideline 405 under GLP conditions. 0.1 mL of the test substance (approx. 100% pure) was instilled into the eyes of three female New Zealand White rabbits. The animals were observed for 72 hours and scoring according to Draize was performed 1, 24, 48, and 72 hours after application. 2/3 animals showed only slight swelling of the blood-vessels in the conjunctivae 1 hour after instillation. The effects were fully reversible within 24 hours. The fluorescein analysis 24 hours after instillation did not reveal any epithelial damage. Based on the results of the study, the Fatty acids, coco, 2-Ethylhexyl Esters

is not considered irritating to the eyes.

Fatty acids, C16-18, 2-Ethylhexyl Esters  CAS 91031-48-0

Fatty acids, C16-18, 2-Ethylhexyl Esters (CAS 91031-48-0) was examined for its eye irritation potential in a study performed equivalent to OECD Guideline 405 (Potokar, 1978). 0.05 mL undiluted test substance (no data on purity) was instilled into the right eye of 2 rabbits. 2, 6 and 24 hours after instillation examination of the treated eyes revealed no ocular lesions. Thus, based on the study results, the test substance showed no eye irritating potential.

In summary, based on the study results on the source substances which are include in the category, the target substance is not considered as eye irritating

Justification for classification or non-classification

Using a Read Across Category approach with Long Chain Acid Esters substances (C8 to C18) according to the Annex XI Item 1.5, of Regulation (EC) No 1907/2006, all available skin and eye irritation studies within this category resulted in not irritation to skin or eye after the treatment of the animals. Hence, according to the CLP criteria, the test item Isostearate Ethyl Hexyl was not classified for eye and skin irritation.