Registration Dossier

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

Endpoint conclusion:

no adverse effect observed (not irritating)

Endpoint conclusion:

no adverse effect observed (not irritating)

Endpoint conclusion:

no study available

Justification for grouping of substances and read-across

The PFAE Linear (Polyfunctional Aliphatic Ester) category consists of 16 substances, well-defined mono-constituent substances as well as related UVCB substances, respectively with varying fatty alcohol chain lengths and branching. The distinguishing feature of this category of chemicals is that they are diester derivatives of common dicarboxylic acids: namely adipic (C6), azelaic (C9) and sebacic (C10) acids. The alcohol portion of the diesters generally falls in the C3-C20 carbon number range, including linear and branched, even and odd numbered alcohols.

In order to avoid the need to test every substance for every endpoint, 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.

Endpoint specific data matrix:

ID #	CAS	Skin irritation/corrosion	Eye irritation
1	6938-94-9 (a)	Not irritating	Not irritating
2	105-99-7	Not irritating	Not irritating
3	110-33-8	Not irritating	Not irritating
4	1330-86-5	RA: CAS 110-33-8 RA: CAS 105-99-7 RA: CAS 16958-92-2	RA: CAS 110-33-8 RA: CAS 105-99-7 RA: CAS 16958-92-2
5	123-79-5 (b)	--	--
6	103-23-1	--	--
7	68515-75-3	--	--
8	33703-08-1	Not irritating (c)	Not irritating (c)
9	16958-92-2	Not irritating	Not irritating
10	85117-94-8	Not irritating	--
11	103-24-2	RA: CAS 85117-94-8 RA: CAS 69275-01-0	RA: CAS 69275-01-0
12	897626-46-9	RA: CAS 85117-94-8 RA: CAS 69275-01-0	RA: CAS 69275-01-0
13	7491-02-3	Not irritating	Not irritating
14	109-43-3	Not irritating	Not irritating
15	122-62-3	Not irritating	Not irritating
16	69275-01-0	Not irritating	Not irritating

(a) Category members subject 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. Lack of data for a given endpoint is indicated by “--“.

(c) Original data source is not available and thus not used for read-across.

Skin irritation

Diester of Adipic acid

CAS 6938-94-9

The skin irritation potential of Diisopropyl adipate (CAS 6938-94-9) has been investigated in two studies in rabbits.

A study investigating the skin irritation potential of Diisopropyl adipate was performed in New Zealand White rabbits according to OECD guideline 404 (Dufour, 1993). The test substance (0.5 mL) was applied for 4 h to the clipped skin of 3 male animals under semiocclusive conditions. The untreated site of the animals served as control. The scoring of skin reactions (erythema and edema) was performed 24, 48 and 72 h as well as 4, 5, 6 and 7 days after removal of the dressing. Erythema (grade 1) was observed in 2/3 animals at 1 h reading. In one of these animals, very slight erythema and edema were noted at the 24 h reading, which were fully reversible within 5 or 6 days, respectively. One further animal showed erythema (grade 1) at 24 h reading only. Defatting of the skin was evident at the test site in all three animals. The mean erythema and edema scores after 24, 48 and 72 h were 0/0.33/1 and 0/0/1 for the 3 animals, respectively.

In a further study, the skin irritation potential of the test substance was assessed according to the method of Draize as described in the FDA guideline "Appraisal of the safety of chemicals in foods, drugs and cosmetics" by the Staff of the Division of Pharmacology (Levenstein, 1972). The neat test substance (0.5 mL) was applied to the shaved and abraded skin of 3 New Zealand White rabbits for a period of 24 h under occlusive conditions. Skin reactions were scored 24 and 72 h after patch removal. No effects on skin were noted in any of the treated animals at any reading time point, neither under intact or under abraded conditions. For calculation of mean scores, the 48 h values were assumed to be the same as those at 24 h (worst case assumption: persistence of effects seen at 24 h over 48 h). Thus, the mean erythema and edema scores after 24, 48 and 72 h were 0 for all 3 animals.

In summary, Diisopropyl adipate is not irritating to the skin.

CAS 105-99-7

The skin irritation potential of Dibutyl adipate (CAS 105-99-7) has been investigated in several studies in rabbits, mice and humans.

The skin irritation potential of Dibutyl adipate was investigated in a study according to OECD guideline 404 (Mürmann, 1989). The undiluted test substance (0.5 mL) was applied for 4 h to the clipped skin of 3 male Small White Russian, Chbb‐SPF rabbits under semiocclusive conditions. The scoring of skin reactions (erythema and edema) was performed 1, 24, 48 and 72 h as well as 6 and 8 days after removal of the dressing. At the 1 h reading time point, all 3 animals exhibited slight to obvious erythema (grade 2) and very slight edema. At the 24 and 48 h reading, 2/3 animals showed well-defined erythema, which in one animal increased to moderate erythema at the 72 h reading. Only slight erythema was observed after 24, 48 and 72 h reading in the third animal. Erythema was fully reversible after a period of 6 days in each of the animals. The formation of very slight to slight edema was observed in 2/3 animals at 24, 48 and 72 h reading, but was fully reversible within 6 days. In one rabbit, scaling was evident at the treatment side after 6 days, whereas another rabbit exhibited eschar formation at this time point. However, both effects were fully reversible within the 8-day observation period. No signs of systemic toxicity were seen. The mean erythema and edema scores after 24, 48 and 72 h were 2/1/2.33 and 1/0/1.33 for the 3 animals, respectively.

In a further study, the skin compatibility of the test substance was assessed in 5 hairless mice. No infectious symptoms were observed after brushing the substance twice daily onto the skin of the animals for a period of 14 days (Gloxhuber, 1970).

Additional information on skin irritation is provided by a human patch test, in which epicutaneous application of the test substance to the skin of 10 volunteers for 24 h did not result in any skin reactions up to 48 h after patch removal (Gloxhuber, 1970).

In summary, taking into account animal and human data, Dibutyl adipate was not irritating to skin.

CAS 110-33-8

A study similar to OECD guideline 404 was performed to assess the skin irritation potential of Dihexyl adipate in albino rabbits (Birch, 1972). The undiluted test substance (0.5 mL) was applied to the clipped skin of three animals (2 males and 1 female) for 24 h under occlusive conditons. The scoring of skin reactions (erythema and edema) was performed 1, 24, 48, 72, as well as 5 and 7 days after removal of the dressing. At the 1 h reading, no skin reactions were observed in the treated animals. Very slight to slight erythema and very slight edema were observed 24 and 48 h post-application, whereas only very slight erythema and no edema were noted at the 72 h reading time point. Erythema were fully reversible within 5 day) after test substance application and no further reactions were observed at the reading after 7 days. The sample had a slight defatting effect causing the skin to flake off 7 to 10 days after test substance application. However, no injury in depth was observed. The mean erythema and edema scores after 24, 48 and 72 h were 1.67/1/1.33 and 0.67/0.67/0.67 for the 3 animals, respectively

Based on the results of this study, Dihexyl adipate is not irritating to the skin.

CAS 16958-92-2

The skin irritation potential of Bis(tridecyl) adipate (CAS 16958-92-2) has been investigated in three studies in rabbits.

In a GLP-conform study, Bis(tridecyl) adipate was tested for its skin irritation potential in New Zealand White (Hsdlf:NZW) rabbits according to OECD guideline 404 (Sanders, 2012). The test substance was applied to the clipped skin of the back of 1 male and 1 female rabbit using a semi-occlusive dressing. After an exposure period of 4 h, the test substance was removed and scoring of skin reactions (erythema and edema) was performed 1, 24, 48 and 72 h after removal of the dressing. Very slight erythema (grade 1) was noted in 1 animal at the 24 h reading, which was fully reversible 48 h after treatment. No further skin reactions (erythema and edema) were observed in both animals. The mean erythema and edema scores after 24, 48 and 72 h were 0.33 and 0 in one animal. In the other animal, the mean erythema and edema scores after 24, 48 and 72 h were 0, respectively.

Furthermore, the skin irritation potential of the test substance was investigated in a study similar to OECD guideline 404 (Anonymous, 1978). The test substance (0.5 mL) was applied for 4 h to the abraded or non-abraded skin of 6 rabbits under occlusive conditions. The untreated site of the animals served as control. The scoring of skin reactions (erythema and edema) was performed 24 and 72 h after removal of the dressing. The test substance did only induce slight erythema (all animals) and edema (5 out of 6 animals) on intact (non-abraded) skin 24 h after test substance application. Edema was fully reversible within 72 h, whereas erythema was still visible in 2/6 animals at the 72 h reading. For calculation of mean scores, the 48 h values were assumed to be the same as those at 24 h (worst case assumption: persistence of effects seen at 24 h over 48 h). Thus, the mean erythema and edema scores after 24, 48 and 72 h were 0.55 and 0.78 for all 6 animals.

In a further study, the skin irritation potential of the test substance was studied on the abraded and non-abraded skin of 6 New Zealand White rabbits after 4 and 24 h under semiocclusive and after 24 h under open conditions (D'Aleo, 1984). The summary of irritation scores suggests that the study was only slightly irritating to the abraded and non-abraded skin of the rabbits. Since no individual scores were given for erythema and edema at definite reading time points, the data were considered inconclusive for risk assessment.

In summary, Bis(tridecyl) adipate is not irritating to the skin.

CAS 85117-94-8

The skin irritation potential of Bis(2-octyldodecyl) adipate (CAS 85117-94-8) was investigated in New Zealand White rabbits according to OECD guideline 404 (Dufour, 1994).

The test substance was applied to the skin of 3 male animals, whereas the untreated site of the animals served as control. The scoring of skin reactions (erythema and edema) was performed 1, 24, 48, 72 h as well as 5 days after removal of the dressing. Slight erythema (grade 1) was observed in one animal at the 48 and 72 h readings, whereas in a further animal, the same finding was reported 24, 48 and 72 h after test substance application. In both animals, effects on skin were fully reversible within the 5-day observation period. In the third animal, no erythema was observed at any of the observation time points. No edema was observed in all three animals during the whole study period. The mean erythema and edema scores after 24, 48 and 72 h were 0.7/1/0 and 0 for the 3 animals, respectively.

Based on the results of this study, Bis(2-octyldodecyl) adipate is not irritating to the skin.

Diester of Azelaic acid

CAS No. 103-24-2

One study investigating the skin irritation potential of Bis(2-ethylhexyl) azelate (CAS 103-24-2) is available, in which primary skin irritation in rabbits is recorded in a 10-grade ordinal series (Smyth et al., 1962). The evaluation of skin irritation was based on the severest reaction that developed on the clipped skin of each of 5 albino rabbits within 24 h after application of 0.01 mL of undiluted test sample or of solutions up to concentrations 0.01% in water, propylene glycol or acetone under open conditions. According to the scoring system, Grade 1 indicated no irritation and Grade 2 the least visible capillary injection from the undiluted chemical. Grade 6 indicated necrosis when undiluted and Grade 10 indicated necrosis from a 0.01% solution. In the study, skin irritation (grade 3) was observed after treatment with the undiluted test substance. However, these results were inconclusive for risk assessment, since no evaluation of skin irritation according to the Draize scoring system at 24, 48 and 72 h post-application was performed and no observation period was included to evaluate the reversibility of effects.

Diester of Sebacic acid

CAS 7491-02-3

The skin irritation potential of Diisopropyl sebacate (CAS 7491-02-3) has been investigated in two studies in rabbits.

The skin irritation potential of Diisopropyl sebacate was investigated in a study similar to OECD guideline 404 (Wallace, 1976). The undiluted test substance (0.5 mL) was applied to the clipped dorsal skin of 3 male and 3 female rabbits for 24 h under occlusive conditions. The untreated site of the animals served as control. The scoring of skin reactions (erythema and edema) was performed 24 and 72 h after removal of the dressing. No edema and only slight erythema occurred in 2 of 6 animals, which were fully reversible within 72 h after test substance application. For calculation of mean scores, the 48 h values were assumed to be the same as those at 24 h (worst case assumption: persistence of effects seen at 24 h over 48 h). Thus, the mean erythema and edema scores after 24, 48 and 72 h were 0.22 and 0 for all 6 animals.

In a further skin irritation study according to OECD guideline 404, the test substance was applied to the skin of 3 New Zealand White rabbits (Dufour, 1994). The scoring of skin reactions (erythema and edema) was performed 1, 24, 48 and 72 h as well as 7 days after removal of the dressing. Slight erythema and edema were noted in 3/3 and 1/3 animals, respectively, but were fully reversible 7 days after application of the test substance. The mean erythema and edema scores after 24, 48 and 72 h were 1/1.3/1 and 0/1/0 for the 3 animals, respectively.

In summary, Diisopropyl sebacate is not irritating to the skin.

CAS 109-43-3

The skin irritation potential of Dibutyl sebacate (CAS 109-43-3) was investigated in a study similar to OECD guideline 404 (Wallace, 1976).

The undiluted test substance (0.5 mL) was applied for 24 h to the shaved or abraded skin of 3 male and 3 female New Zealand White rabbits under occlusive conditions. The untreated site of the animals served as control. The scoring of skin reactions (erythema and edema) was performed 24 and 72 h after removal of the dressing. No edema was observed after test substance application on intact skin and only slight erythema occurred in 1/6 animals, which was fully reversible within 72 h. Erythema were also observed in 2/6 animals on abraded skin, but also disappeared within 72 h. For calculation of mean scores, the 48 h values were assumed to be the same as those at 24 h (worst case assumption: persistence of effects seen at 24 h over 48 h). Thus, the mean erythema and edema scores after 24, 48 and 72 h were 0.11 and 0 for all 6 animals.

Based on the results of this study, Dibutyl sebacate is not irritating to the skin.

CAS 122-62-3

The skin irritation potential of Bis(2-ethylhexyl) sebacate (CAS 122-62-3) has been investigated in two studies in rabbits.

A skin irritation study with Bis(2-ethylhexyl) sebacate was performed similar to OECD guideline 404 (Wallace, 1976). The shaved or abraded skin of 6 New Zealand White rabbits (3 per sex) was exposed to 0.5 mL of the undiluted test substance for 24 h under occlusive conditions. Skin reactions were assessed 24 and 72 h after removal of the test substance. No reactions were observed on shaved or abraded skin at any reading time point. For calculation of mean scores, the 48 h values were assumed to be the same as those at 24 h (worst case assumption: persistence of effects seen at 24 h over 48 h). Thus, the mean erythema and edema scores after 24, 48 and 72 h were 0 for all 6 animals.

In a further study according to OECD guideline 404, the skin irritation potential of the test substance was investigated in 3 male New Zealand White rabbits (Dufour, 1994). The undiluted test substance was applied to the skin of the animals and skin reactions were scored 1, 24, 48 and 72 h as well as 8 days after removal of the dressing. Slight erythema (grade 1) were observed in all three animals at the 1, 24, 48 and 72 h readings, but were fully reversible 8 days after test substance application. No edema was noted in any of the treated animals. The mean erythema and edema scores after 24, 48 and 72 h were 1/1/1 and 0 for the 3 animals, respectively.

In summary, Bis(2-ethylhexyl) sebacate is not irritating to the skin.

CAS 69275-01-0

The skin irritation potential of Bis(2-octyldodecyl) sebacate (CAS 69275-01-0) was investigated in a GLP-conform study according to OECD guideline 404 (Kästner, 1986).

The undiluted test substance (0.5 mL) was applied to the shaved skin of 5 male Kleinrussen, Chbb: HM rabbits for 4 h under occlusive conditions. The untreated site of the animals served as control. Skin reactions were assessed 1, 24, 48 and 72 h as well as 7 days after removal of the dressing. In 3/5 animals, slight to significant erythema were observed 48 h after test after exposure. In two of these animals, slight erythema persisted at the 72 h reading, but was fully reversible within the 7 day observation period. In the other animal, erythema was reversible 72 h after application. No edema occurred in any of the tested animals at any observation time point. No signs of systemic toxicity were seen. The mean erythema and edema scores after 24, 48 and 72 h were 0.4 and 0 for all 5 animals.

Based on the results of this study, Bis(2-octyldodecyl) sebacate is not irritating to the skin.

Eye irritation

Diester of Adipic acid

CAS 6938-94-9

The eye irritation potential of Diisopropyl adipate (CAS 6938-94-9) was investigated in a study similar to OECD guideline 405 (Levenstein, 1972).

The undiluted test material (0.1 mL) was placed into the conjunctival sac of the right eye of 3 rabbits. The other eye remained untreated and served as control. The eyes were examined and scored 24, 48 and 72 h as well as 4 and 7 days after application. No effects on iris, cornea or conjunctivae were observed in the animals at any reading time point. No further local or systemic toxic effects were observed. The mean cornea, iris, conjunctivae and chemosis scores after 24, 48, and 72 h were 0 for all 3 animals, respectively.

Based on the results of this study, Diisopropyl adipate is not eye irritating.

CAS 105-99-7

The eye irritation potential of Dibutyl adipate (CAS 105-99-7) has been investigated in two studies in rabbits.

An eye irritation study was performed with Dibutyl adipate according to OECD guideline 405 (Mürmann, 1989). The undiluted test substance (0.1 mL) was placed into one eye of 3 Small White Russian, Chbb‐SPF rabbits. The other eye remained untreated and served as control. After 72-h exposure, treated eyes were washed with warm physiological saline. Examination and scoring of effects on the eyes was performed at intervals of 1, 24, 48, 72 h and 6 days after test substance application. At the 1 h reading, obvious conjunctival redness (grade 1) was observed in 2/3 animals which completely disappeared within 24 hours. No irritation reactions on the cornea or iris were noted in the animals at any reading time point. No further local or systemic toxic effects were reported. The mean cornea, iris, conjunctivae and chemosis scores after 24, 48, and 72 h were 0 for all 3 animals, respectively.

In a further study, the mucous membrane compatibility of the test substance was assessed by administration of the test substance into the conjunctivae of rabbits. Treatment with the test substance induced only very slight changes in the conjunctivae, which were fully reversible within a few days (Gloxhuber, 1970).

In summary, Dibutyl adipate is not eye irritating.

CAS 110-33-8

An eye irritation study was performed with Dihexyl adipate (CAS 110-33-8) similar to the criteria defined in OECD guideline 405 (Birch, 1972).

The undiluted test substance (0.1 mL) was placed into the conjunctival sac of the right eye of 3 albino rabbits (2 males and 1 female), whereas the left eye remained untreated and served as control. After 24 h exposure, treated eyes were rinsed with warm isotonic saline solution. Examination and scoring of effects on the eyes was performed at intervals of 1, 24, 48, 72 as well as 5 and 7 daysafter test substance application. Slight to moderate erythema and moderate discharge were observed at the 1 and 24 h readings, but were fully reversible 48 h after test substance application. No conjunctival edema was observed in treated animals at any reading time point. No effects on cornea or iris and no further local or systemic toxic effects were reported. The mean cornea, iris and chemosis scores were 0 for all 3 animals, respectively. The mean conjunctivae scores after 24, 48, and 72 h were 0.67 for all 3 animals.

Based on the results of this study, Dihexyl adipate is not eye irritating.

CAS 16958-92-2

The eye irritation potential of Bis(tridecyl) adipate (CAS 16958-92-2) has been investigated in two studies in rabbits.

The eye irritation potential of Bis(tridecyl) adipate was investigated according to the Federal Hazardous Substances Act Regulations (16 CFR 1500.42) (Moldovan, 1973). The test substance was placed into the conjunctival sac of one eye of 6 rabbits. The other eye remained untreated and served as control. The eyes were examined and scored 24, 48 and 72 h after application. No corneal, iridial or conjunctival effects were noted in the animals at any of the reading time points. No further local or systemic toxic effects were observed. The mean cornea, iris, conjunctivae and chemosis scores after 24, 48, and 72 h were 0 for all 6 animals, respectively.

In a further study similar to OECD guideline 405, the test substance (0.1 mL) was applied to the eyes of 6 rabbits and effects on the eyes were scored 1, 24, 48 and 72 h after treatment (Anonymous, 1978). The other eye remained untreated and served as control. Slight redness and chemosis was observed in all animals at 1 h reading, which was fully reversible within 24 h. One animal still showed slight redness at the 48 h reading, but this effect was no longer evident at 72 h reading. No effects on iris and cornea and no conjunctival discharge were observed during the study. The mean scores for conjunctivae after 24, 48, and 72 h were 0.06 for all 6 animals. The effects on cornea, iris and chemosis after 24, 48, and 72 h were scored 0 for all 6 animals.

In summary, Bis(tridecyl) adipate is not eye irritating.

Diester of Azelaic acid

CAS 103-24-2

One study investigating the eye irritation potential of Bis(2-ethylhexyl) azelate (CAS 103-24-2) is available, in which the eye injury in rabbits was recorded in a 10-grade ordinal series and evaluation of eye injury was based on the degree of corneal necrosis that resulted from instillation of various volumes and concentrations of the test substance (Smyth et al., 1962). At most a very small area of necrosis was observed after installation of 0.5 mL of the undiluted test substance. However, these results were inconclusive for risk assessment, since no evaluation of eye irritation according to the Draize scoring system at 24, 48 and 72 h post-application was performed and no observation period was included to evaluate the reversibility of effects.

Diester of Sebacic acid

CAS 7491-02-3

The eye irritation potential of Diisopropyl sebacate (CAS 7491-02-3) has been investigated in two studies in rabbits.

An eye irritation study was performed with Diisopropyl sebacate according to the Federal Hazardous Substances Labeling Act (FHSLA, 1964) and similar to OECD guideline 405 (Prince, 1971). The undiluted test substance (0.1 mL) was placed into the conjunctival sac of one eye of 6 rabbits. The other eye remained untreated and served as control. The eyes were examined and scored 1, 24, 48 and 72 h as well as 4 and 7 days after application. No corneal, iridial or conjunctival effects were noted in the animals at any of the reading time points. The mean cornea, iris, conjunctivae and chemosis scores after 24, 48, and 72 h were 0 for all 6 animals, respectively.

In a further study similar to OECD guideline 405, the eye irritation potential of the test substance was investigated in 6 albino rabbits (Wallace, 1976). The undiluted test substance (0.1 mL) was placed into the conjunctival sac of one eye of the animals and eyes were examined and scored 24, 48 and 72 h after application. 24 hour after treatment, slight conjunctival irritation was observed in the treated eyes of all animals, which was fully reversible within 48 h in one animal and within 72 h in the remaining animals. No corneal and iridial effects and no chemosis were noted in any animal during the study period. The mean cornea, iris and chemosis scores after 24, 48, and 72 h were 0 for all 6 animals, respectively. The mean score for conjunctivae after 24, 48, and 72 h was 0.5 for all 6 animals.

In summary, Diisopropyl sebacate is not eye irritating.

CAS 109-43-3

The eye irritation potential of Dibutyl sebacate (CAS 109-43-3) has been investigated in two studies in rabbits.

The eye irritation potential of Dibutyl sebacate was investigated according to OECD guideline 405 and in compliance with GLP (Steiling, 1991). The undiluted test substance (0.1 mL) was placed into the conjunctival sac of one eye of 3 male Kleinrussen, Chbb:HM. The other eye remained untreated and served as control. 24 h after test substance application, test substance was removed by rinsing with warm water. The eyes were examined and scored 1, 24, 48 and 72 h after application. Strong exudation was observed in the treated eyes of all three animals at the 1 h reading. The observed conjunctival reactions (erythema and edema) were only mild and disappeared completely within 48 h. No effects on cornea and iris were observed at any reading time point. The mean cornea and iris scores after 24, 48, and 72 h were 0 for all 3 animals. The mean score for conjunctivae and chemosis after 24, 48, and 72 h were 0.33/0/0.33 and 0/0/0.33 for the 3 animals, respectively

In a further study similar to OECD guideline 405, the eye irritation potential of the test substance was investigated in 6 albino rabbits (Wallace, 1976). The undiluted test substance (0.1 mL) was placed into the conjunctival sac of one eye of the animals. The other eye remained untreated and served as control. The eyes were examined and scored 24, 48 and 72 h after application. Four out of six animals showed mild (3/6) to moderate (1/6) conjunctival redness after 24 h exposure. However, this effect was fully reversible within 48 to 72 h. No effects on cornea and iris and no chemosis were noted in any animal during the study period. The mean cornea, iris and chemosis scores after 24, 48, and 72 h were 0 for all 6 animals, respectively. The mean score for conjunctivae after 24, 48, and 72 h was 0.33 for all 6 animals.

In summary, Dibutyl sebacate is not eye irritating.

CAS 122-62-3

The eye irritation potential of Bis(2-ethylhexyl) sebacate (CAS 122-62-3)has been investigated in vivo and in vitro.

An eye irritation study with Bis(2-ethylhexyl) sebacate was conducted according to the Draize test described in the Federal Hazardous Substances Labeling Act (FHSA), which is similar to OECD guideline 405 (Wallace, 1976). The undiluted test material (0.1 mL) was placed into the conjunctival sac of one eye of 6 New Zealand White rabbits. The other eye remained untreated and served as control. The eyes were examined and scored 1, 24, 48 and 72 h after test substance application. No effects on eye were noted in the treated animals at any reading time point. The mean cornea, iris and chemosis scores after 24, 48, and 72 h were 0 for all 6 animals, respectively.

In a further study, the in vitro eye irritation potential was investigated using the Hen's Egg Test on Chorioallantoic Membrane (HET-CAM) test (Boue-Grabot, 2002). In this in vitro assay, the undiluted test substance was applied to the vasculated CAM of each of 4 fertilised white horn chicken eggs for a period of 20 sec and then washed with saline. The CAM of 4 further eggs was treated with physiological saline (negative control) or 3% SDS (positive control), respectively. The blood vessels of the individual eggs were monitored for the onset of haemorrhage, hyperaemia and coagulation 30 sec, 2 min and 5 min after test substance application and scored depending on the time for each reaction to occur. The scores obtained for each parameter were summed to give the irritation index for the individual eggs and the mean score of all eggs per group was calculated to determine the primary irritancy index (IP-CAM). The positive control was valid, since it produced an IP-CAM score of 12.5, which was above the value for classification as severe irritant (IP-CAM ≥ 9). The undiluted test substance did not induce any reactions on the CAM of all 4 eggs, thus the irritation score was 0 for all 4 eggs. Under the experimental conditions of this HET-CAM, the test substance was not considered to be corrosive.

An additional in vitro eye irritation study with the test substance was performed in fibroblasts of the rabbit cornea (SIRC cell line) (Boue-Grabot, 2002). The cells were incubated in triplicate with the undiluted test substance or the negative control (paraffin oil) for periods of 30 min, 1 or 4 h. After exposure, cytotoxicity compared to the negative control was determined using the MTT assay and results were used to calculate the equivalent Ocular Irritation Index (IOeq). Since the IOeq of the test substance was < 15, it was slightly irritating according to the classification criteria given. Thus, a potential to cause an irritation reaction was seen in this in vitro cytotoxicity test, but the results of this study were insufficient and inadequate for classification purposes.

In summary, Bis(2-ethylhexyl) sebacate is not eye irritating.

CAS 69275-01-0

The eye irritation potential of Bis(2-octyldodecyl) sebacate (CAS 69275-01-0) was investigated according to OECD guideline 405 and in compliance with GLP (Kästner, 1986).

The undiluted test material (0.1 mL) was placed into the conjunctival sac of one eye of 4 male Kleinrusse Chbb: HM rabbits, whereas the other eye remained untreated and served as control. The eyes were examined and scored 1, 6, 24 and 48 h after application. From 1 h up to 6 h after application, slight to moderate redness of conjunctivae was observed in all animals. In 2 of the animals, effects on conjunctivae were fully reversible 24 h after application, whereas the other 2 animals were without effects at the 48 h reading. The test substance did not provoke any reactions on cornea and iris and did not induce chemosis of conjunctivae in any of the treated animals. Other effects on treated eyes involved slight to strong exsudation in all animals 1 and 6 h after application, which was fully reversible within 24 h in three of the animals and 48 h in one of the animals, respectively. The mean cornea, iris, and chemosis scores after 24, 48, and 72 h were 0 for all 4 animals, respectively. The mean score for conjunctivae after 24, 48, and 72 h was 0.17 for all 4 animals.

Based on the results of this study, Bis(2-octyldodecyl) sebacate is not eye irritating.

Conclusion for irritation

In conclusion, the skin irritation properties of ten PFAE linear category members have been investigated in vivo indicating no or very low skin irritating properties. Therefore, none of the category members of the PFAE linear group is skin irritating.

In conclusion, the eye irritation properties of nine PFAE linear category members have been investigated in in vivo studies indicating no eye irritation properties. Therefore, none of the category members of the PFAE linear group is eye irritating.

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

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 PFAE linear 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, all available data on skin irritation/corrosion 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.