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Description of key information

Skin irritation / corrosion (modified Draize test, GLP, rabbit): not irritating

Read-across from a key study with analogue source substance Isooctadecanoic acid, ester with oxybis[propanediol] (CAS No. 73296-86-3); further supported by read-across from analogue source substances Hexanedioic acid, mixed esters with decanoic acid, 12-hydroxyoctadecanoic acid, isostearic acid, octanoic acid, 3,3'-oxybis[1,2-propanediol] and stearic acid (CAS No. 130905-60-1) and 1,2,3-Propanetriol, homopolymer, diisooctadecanoate (CAS No. 63705-03-3)

Eye irritation / severe eye damage (modified Draize test, GLP, rabbit): not irritating

Read-across from a key study with analogue source substance Isooctadecanoic acid, ester with oxybis[propanediol] (CAS No. 73296-86-3); further supported by read-across from analogue source substances Hexanedioic acid, mixed esters with decanoic acid, 12-hydroxyoctadecanoic acid, isostearic acid, octanoic acid, 3,3'-oxybis[1,2-propanediol] and stearic acid (CAS No. 130905-60-1) and 1,2,3-Propanetriol, homopolymer, diisooctadecanoate (CAS No. 63705-03-3)

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 from supporting substance (structural analogue or surrogate)
Remarks:
Summary of available data used for the endpoint assessment of the target substance
Adequacy of study:
weight of evidence
Justification for type of information:
Please refer to the Analogue Approach Justification provided in Section 13.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1.3
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: Source, CAS 73296-86-3, Lasem, 2001
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1.3
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: Source, CAS 73296-86-3, Lasem, 2001
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: Source, CAS 73296-86-3, Lasem, 2001
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 48 h
Remarks on result:
other: Source, CAS 73296-86-3, Lasem, 2001
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 48 h
Remarks on result:
other: Source, CAS 73296-86-3, Lasem, 2001
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 72 h
Remarks on result:
other: Source, CAS 73296-86-3, Lasem, 2001

Additional studies and results also considered in the Weight-of-Evidence approach:

CAS 63705-03-3, BASF, 1988b: not irritating (rabbit)

CAS 130905-60-1, Sasol, 1990c: not irritating (rabbit)

Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008.
Conclusions:
Exposure for 24 h of the test substance to the shaved skin of rabbits under occlusive conditions resulted in slight erythema formation. Effects were not fully reversible within the observation period of 72 h. Only slight edema were observed in the study but were fully reversible within the 72 h observation period. However, exposure under semi-occlusive conditions to intact skin in additional studies lead to only slight erythema and no edema formation. In these studies, all effects were fully reversible within the respective observation periods.
Executive summary:

The skin irritation / corrosion potential of the target substance is estimated based on adequate and reliable in vivo studies of structural analogue source substances. Exposure for 24 h of the test substance to the shaved skin of rabbits under occlusive conditions resulted in only slight erythema formation. The observation period in this study was only 72 h and effects were not fully reversible within that time. Only slight edema were observed in the study but were fully reversible within the 72 h observation period. However, exposure under semi-occlusive conditions to intact skin in additional studies lead to only slight erythema and no edema formation. In these studies, all effects were fully reversible within the respective observation periods. Therefore, for the target substance no hazard regarding skin irritation / corrosion is identified based on a Weight-of-Evidence approach. As explained in the analogue justification, the differences in molecular structure between the target and the source substances are unlikely to lead to differences in the skin irritation / corrosion potential.

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 from supporting substance (structural analogue or surrogate)
Remarks:
Summary of available data used for the endpoint assessment of the target substance
Adequacy of study:
key study
Justification for type of information:
Please refer to the Analogue Approach Justification provided in Section 13.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
out of all 6 animals
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: reversibility: not applicable
Remarks on result:
other: Source, CAS 73296-86-3, Lasem, 1990b
Irritation parameter:
iris score
Basis:
mean
Remarks:
out of all 6 animals
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
other: reversibility: not applicable
Remarks on result:
other: Source, CAS 73296-86-3, Lasem, 1990b
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.33
Max. score:
3
Reversibility:
fully reversible within: 48 h
Remarks on result:
other: Source, CAS 73296-86-3, Lasem, 1990b
Irritation parameter:
conjunctivae score
Basis:
animal: #2, #4, #5 and #6
Time point:
24/48/72 h
Score:
0
Max. score:
3
Reversibility:
other: reversibility: not applicable
Remarks on result:
other: Source, CAS 73296-86-3, Lasem, 1990b
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 72 h
Remarks on result:
other: Source, CAS 73296-86-3, Lasem, 1990b
Irritation parameter:
chemosis score
Basis:
animal: #1, #2, #5 and #6
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: reversibility: not applicable
Remarks on result:
other: Source, CAS 73296-86-3, Lasem, 1990b
Irritation parameter:
chemosis score
Basis:
animal: #3 and #4
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 48 h
Remarks on result:
other: Source, CAS 73296-86-3, Lasem, 1990b

Additional studies and results supporting the key study:

CAS 63705-03-3, BASF, 1988c: not irritating (rabbit)

CAS 130905-60-1, Sasol, 1990d: not irritating (rabbit)

Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008.
Conclusions:
Application of the unchanged test substance to the eyes of rabbits resulted in only minor effects regarding corneal opacity and iridial irritation. Effects on conjunctivae (redness and chemosis) were minor to slight. All effects observed were fully reversible within the 72 h observation period of the study.
Executive summary:

The eye irritation potential of the target substance is estimated based on an adequate and reliable in vivo key study of a structural analogue source substance. Application of the unchanged test substance to the eyes of rabbits resulted in only minor effects regarding corneal opacity and iridial irritation. Effects on conjunctivae (redness and chemosis) were minor to slight. All effects observed were fully reversible within the 72 h observation period of the study. The results of the key study are further supported by additional (supporting) studies with analogue source substances. Therefore, for the target substance no potential for eye irritation is identified. As explained in the analogue justification, the differences in molecular structure between the target and the source substances are unlikely to lead to differences in the eye irritation potential.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for read-across

The read-across from structural analogue source substances approach comprises aliphatic esters of the poly-functional alcohols di- and triglycerol. The fatty acid rests of the esters exhibit carbon chain lengths in the range C5 - C20. They are either linear and saturated in nature but also unsaturated C16 and C18 and branched C6 and C18 moieties are present. Since the alcohols employed provide 4 - 5 reactive hydroxyl functions, the esterification degree found in source and target substances ranges from mono- to penta-esters.

The available data allows for an accurate hazard and risk assessment of the target substance and the read-across concept is applied for the assessment of environmental fate and environmental and human health hazards. Thus, where applicable, environmental and human health effects are predicted from adequate and reliable data for source substances by interpolation to the target substance applying the read-across concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No. 1907/2006 (REACH). In particular, for each specific endpoint the source substances structurally closest to the target substance 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 substances are the basis of read-across. A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID section 13).

Skin irritation / corrosion

Since there are no data on the skin irritation or corrosion potential of the target substance, reading-across data from analogue source substances is applied. Although a study performed with the structurally closest analogue substance is available which would qualify to be used as key study, the study cannot be used to conclude on a classification as the observation period was on 72 h instead of 14 days. Hence, the endpoint is assessed using additional studies in a Weight-of-Evidence approach.

The potential to induce skin irritation or corrosion has been investigated using Isooctadecanoic acid, ester with oxybis[propanediol] (CAS No. 73296-86-3) in a modified Draize test under GLP conditions (Lasem, 2001). 0.5 mL of the unchanged test substance was applied to the clipped skin of 2 male and 1 female New Zealand White rabbits for 24 h under occlusive coverage. Residual test substance was removed by gently wiping with water and a paper towel. As opposed to the provisions of the most current OECD TG regarding in vivo skin irritation, the animals were observed for only 72 h after removal of the test substance. Skin reactions were scored using the Draize scheme. Both males exhibited the same irritation response. Moderate erythema (score 2) were observed for both animals at the 24 h reading. The erythema decreased to score 1 at the 48 and 72 h readings. The female showed moderate erythema formation (score 2) at all three readings. The effects were not fully reversible in the observation period of the study. With regard to edema formation, again for both males identical effects were observed. Only slight edema (score 1) were obvioius at the 24 h reading which were completely reversed at the 48 h after application. The female exhibited moderate edema formation (score 2) at the 24 h reading which was reduced to score 1 at the 48 h reading. 72 h after application, no edema was apparent in this animal anymore. No skin reactions other than erythema and edema were observed in any animal at any time. Therefore, the results of this study hint that no classification according to the criteria of the CLP Regulation (EC) No. 1272/2008 is warranted. However, since the observation period in the study was only 72 h instead of 14 days, no definitive classification can be derived based on this study alone.

Supporting evidence for a favourable skin irritation profile diglycerol esters is taken from two studies with adequate source substances. The first supporting skin irritation study was performed with Hexanedioic acid, mixed esters with decanoic acid, 12-hydroxyoctadecanoic acid, isostearic acid, octanoic acid, 3,3'-oxybis[1,2-propanediol] and stearic acid (CAS No. 130905-60-1) according to OECD TG 404 (Sasol, 1990c). The clipped skin of the back of 3 New Zealand White rabbits was exposed to 0.5 mL of the test substance for 4 h under semiocclusive conditions. The rabbits were observed for 3 days. Skin reactions were assessed using the Draize scoring system 30 - 60 min, 24, 48 and 72 h after patch removal. The mean scores for erythema and edema (24/48/72 h) were 0.0, indicating that the test substance is not irritating to the skin.

Another supporting skin irritation study was performed with 1,2,3-Propanetriol, homopolymer, diisooctadecanoate (CAS No. 63705-03-3) equivalent or similar to OECD TG 404 (BASF, 1988b). The shaved skin of the back of 4 male rabbits (Kleinrusse) was exposed to 0.5 mL of the undiluted test substance for 4 h under occlusive conditions. The rabbits were observed for 7 days. Skin reactions were assessed using the Draize scoring system 1, 24, 48 and 72 h and 7 days after patch removal. Very slight to slight erythema formation was observed in 3/4 animals at the 24 and 48 h reading time points. At the 72 h reading time point, slight and moderate erythema formation was observed in 2/4 animals. The mean score for erythema (24/48/72 h) was 1.0, which was fully reversible within 7 days and for edema (24/48/72 h) 0.0. These results indicate that the test substance is not irritating to the skin.

In addition to the animal-derived data obtained with various source substances, there is also a cutaneous patch test for skin irritation in healthy human volunteers with the target substance Isooctadecanoic acid, mixed esters with oxybis[propanediol] available. The study was conducted single-blind. A total of 30 subjects received three 24 h occlusive patch applications. Reading time points were 24 h after removal of the first and second patch and 48 h after removal of the third patch. No adverse events or reactions were reported and the study was completed by all subjects. Mean scores of the test item were 0.12 and 0.07 on Day 3, 0.08 and 0.29 on Day 5 and 0.08 and 0.26 on Day 8 for Grade 2 and Grade 1 of the target substance, respectively. The negative control substance (water) resulted in mean scores of 0.07, 0.03 and 0.05 on Day 3, Day 5 and Day 8, respectively. Sodium lauryl sulfate (SLS), which was used as positive control substance, produced mean scores of 1.67, 1.69 and 1.13 on Day 3, Day 5 and Day 8, respectively. It can be concluded that Grade 2 of the registered substance elicited no more than minimal irritation, whereas Grade 1 induced slight irritation in the human volunteers under the conditions of this patch test.

Eye irritation

Again, no data obtained with the target substance is available regarding eye irritation or severe eye damage. Therefore, the results of a reliable key study performed with the closest structural analogue source substance are used to assess this endpoint. Two additional studies further support the findings of the key study.

The source substance Isooctadecanoic acid, ester with oxybis[propanediol] (CAS No. 73296-86-3) was investigated for its capacity to induce eye irritation or to severly damage eyes (Lasem, 1990b). The study was performed according to a modified Draize test under GLP conditions. The test substance (0.1 mL) was instilled into the conjunctival sack of 3 New Zealand White rabbits of each sex and eye reactions were scored 1, 24, 48 and 72 h after application according to a slightly modified Draize system. The untreated eye of each animal served as concurrent control. Because all eye reactions returned to normal at the 72 h reading, the study was terminated at that time. Positive conjunctival reactions (redness) were observed in all animals at the 1 h observation period (score 1). Effects remained in 2/6 animals at the 24 h reading (scores 1 and 2) and were fully reversed at the 72 h reading in all animals. Chemosis of score 1 was observed in all animals at the 1 h reading time-point and in 2/6 animals 24 h post application. No chemosis was evident at the 48 h reading in all animals. Slight dulling of the cornea was observed in two animals at the 1 and 24 h observation periods, which did not lead to a score (score 0). While the 24/48/72 h-mean scores for corneal and iridial effects were 0 for all 6 animals, the score for redness was 0.33 for 1/6, 1 for 1/6 and 0 for the remaining 4/6 rabbits. With respect to chemosis, the 24/48/72 h-mean scores were 0.33 for 2/6 rabbits and 0 for the remaining 4 animals. All scores returned to normal at the 72 h observation period and the study was terminated. Based on the effects observed and accounting for EU classification criteria, the test substance is not irritating to eyes.

The findings of the key study are supplemented by an eye irritation study performed with Hexanedioic acid, mixed esters with decanoic acid, 12-hydroxyoctadecanoic acid, isostearic acid, octanoic acid, 3,3'-oxybis[1,2-propanediol] and stearic acid (CAS No. 130905-60-1) according to OECD TG 405 (Sasol, 1990d). 3 New Zealand White rabbits were treated with 0.1 mL of the undiluted test substance. The untreated eye served as control and the eyes of the animals were not washed out. The animals were observed for 5 days with reading time points at 30 - 60 min, 24, 48 and 72 h after application. The application of the test substance to one eye of each animal did not result in corneal opacity or iritis at any observation time point. Some definitely hyperhemic blood vessels (grade 1 conjunctival redness) was observed 1 h post-treatment in all 3 animals and in 2/3 animals at 24, 48 and 72 h. In 1/3 animals this reaction was augmented, as diffuse, crimson colour, not easily discernible individual vessels (grade 2 conjunctival redness) were observed at the 24 h reading time point. 48 and 72 h post-treatment only a conjunctival redness, graded 1, remained. Chemosis was observed in 2/3 animals (grade 1 conjunctival chemosis) at 24 h post treatment, which was fully reversible within 48 h after application. All effects turned out to be fully reversible latest within 5 days post-treatment. In conclusion, mean cornea opacity and iris scores of 0.0, a mean conjunctivae score of 1.11 and a mean chemosis score of 0.22 were obtained. Based on these results the test substance is not regarded as eye irritant.

An additional supporting eye irritation study was performed with 1,2,3-Propanetriol, homopolymer, diisooctadecanoate (CAS No. 63705-03-3) equivalent or similar to OECD TG 405 (BASF, 1988c). 4 male rabbits (Kleinrusse) were treated with 0.1 mL of the undiluted test substance. The untreated eye served as control and the eyes of the animals were not washed out. The animals were observed for 3 days with reading time points at 1, 6, 24, 48 and 72 h after application. The application of the test substance to one eye of each animal did not result in corneal opacity, iritis or swelling of the conjunctivae at any observation time point. Very slight redness of the conjunctivae was observed in 1/4 animals at the 24 h reading time point. The effect was reversible within 48 h after the application of the test substance. Thus, mean scores of corneal opacity, iris and chemosis of 0.0 were obtained and a mean conjunctivae score of 0.08. Based on these results the test substance is not regarded as eye irritant.

Conclusion on skin and eye irritation / corrosion

Based on the results of the available key and supporting studies, none of the analogue source substances is considered to cause either skin or eye irritation. Moreover, the cuteneous patch test in human volunteers for skin irritation with the target substance also did not result in significant and relevant irritation responses. Therefore, on the basis of these findings, no skin and eye irritation potential for the target substance Isooctadecanoic acid, mixed esters with oxybis[propanediol] is identified.

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 (REACH) information on intrinsic properties of substances may be generated by means other than tests, e.g. using information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the read-across concept is applied to the target substance Isooctadecanoic acid, mixed esters with oxybis[propanediol], data gaps can be filled by interpolation from representative structural analogue source substances to avoid unnecessary animal testing.

The read-across concept is also used to derive the classification of the target substance taking the properties of the source substances into account. Based on the read-across concept, all available data on skin and eye irritation / corrosion do not meet the classification criteria according to Regulation (EC) No. 1272/2008 (CLP) and are therefore conclusive but not sufficient for classification.