Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Justification for grouping of substances and read-across

The Polyfunctional acid ester (PFAE) aromatic category covers fatty alcohol esters of Benzene-1,2,4-tricarboxylic acid. The category contains both mono constituent and UVCB substances with fatty alcohol carbon chain lengths from C8-C13 (linear and iso-alcohols) building tri-esters with Benzene-1,2,4-tricarboxylic acid in variable proportions. A further surrogate substance of similar structure is included, namely a triester of Benzene-1,2,4-tricarboxylic acid with a C8 alcohol, but the alcohol moiety is branched (2-ethylhexyl).

The available data allows for an accurate hazard and risk assessment of the category and the category concept is applied for the assessment of environmental fate, environmental and human health hazards. Thus, where applicable, environmental and human health effects are predicted from adequate and reliable data for source substance(s) within the group by interpolation to the target substances in the group (read-across approach) applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. In particular, for each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across.

A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Sections 7.1 and 13) and within Chapter 5.1 of the CSR.

 

Endpoint specific data matrix:

Table: Skin sensitisation

ID No.

CAS

Skin Sensitisation

#1

3319-31-1 (c)

Not sensitising

#2

90218-76-1 (b) (former CAS: 67989-23-5)

Not sensitising

#3

36631-30-8

Not sensitising (human)

#4

94279-36-4 (a)

RA: 90218-76-1

RA: 3319-31-1

#5

72361-35-4

RA: 90218-76-1

RA: 3319-31-1

(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 either chemicals forming part of a related category of structurally similar fatty acid esters or precursors/breakdown products of category members (i.e. alcohol and fatty acid moieties). Available data on these substances are used for assessment of toxicological properties by read-across on the same basis of structural similarity and/or mechanistic reasoning as described below for the present category.

 

Skin sensitisation

CAS 90218-76-1

The skin sensitising potential of 1,2,4-Benzenetricarboxylic acid, mixed decyl and octyl triesters was investigated in a study performed according to OECD guideline 406 (no GLP) in a guinea pig maximisation test (GPMT). The concentrations selected for both induction and challenge phase were based on a pilot study where no irritation was observed at a concentration of 100% of the test material. For the intradermal induction, the scapular region of the animals was clipped and three pairs of intradermal injections (0.1 mL/site) were made in this area as follows: A 1:1 mixture of Freunds' Complete Adjuvant with water; the test substance at a 10% concentration in vehicle; the test substance at a 10% concentration in a 1:1 mixture of the vehicle and Freunds' Complete Adjuvant. A control group, consisting of 10 animals, was injected in the same way, but in all injections the test substance was missing. Local reactions after intradermal application were observed in test and control animals. The effects observed after intradermal induction in the test group as well as in the control animals included severe erythema, edema, and necrosis on the FCA-treated injection sites and well defined erythema and edema on the non-FCA treated injection sites. One week after the intradermal induction, the epicutaneous induction treatment with the undiluted test substance or the vehicle alone was conducted in the treated or control animals on the regions of the intradermal injections for a exposure duration of 48 h under occlusive conditions. In order to induce slight to moderate signs of irritation, the skin was pre-treated with sodium dodecyl sulphate (10% in Vaseline) 24 h before the dermal induction treatment started. Local reactions after epicutaneous induction included erythema and edema as well as inflamed or bloody lesions, restlessness of the animals and scratching in the application area. The challenge reaction was performed two weeks after the epicutaneous induction. The left flank of the animals (in the test group and in the controls) was clipped, and 2-3 hours later the undiluted test material was applied on the skin for 24 hours under occlusive conditions. Any signs indicating an irritation response were scored 24 and 48 h later. No signs of dermal irritation were found in any of the test animals or the control animals 24 and 48 h after the challenge treatment. No clinical signs were noted. The body weight gain was comparable in control and test animals. No positive control data were integrated in the study report for confirmation of the validity of the test system used. Nevertheless, since challenge was conducted with 100% test substance under occlusive conditions and the study was performed according to OECD 406, the results obtained are considered to be acceptable for assessment.

CAS 3319-31-1

The skin sensitising potential of Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate (CAS 3319-31-1) has been investigated in two studies.

A study was performed according to a protocol equivalent to OECD 406 (no data on GLP). Guinea pigs were treated with Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate (no data on purity) in a guinea pig maximisation test (GPMT) (Southwood, 1987). No data on a range-finding study were given. In the first induction phase, intradermal injections of the test substance in corn oil at a concentration of 30% and/or FCA were applied into the shorn scapular region of 20 animals. 9 control animals were treated with FCA/vehicle only. One week later, the animals were induced epidermally with the test substance at 100% and the control animals with vehicle only for 48 h under occlusive conditions. No data on irritation effects after the induction exposures was provided in the study report. 2 weeks later, challenge was performed with the test substance at 10% and 30% in the test group and in the control group. Challenge duration was 24 h under occlusive conditions. Evaluation was performed 24 and 48 h after patch removal.

No erythema were observed in any of the animals, test or control following challenge with a 10% solution. Scattered mild redness was observed in one of the 20 animals and in one of the 9 controls following challenge with a 30%. No positive control group was included and it is not stated if the sensitivity of method and strain was proven in a separate study. Furthermore, there was no range-finding study and possible effects after the induction procedure are not reported. As only one animal of the test group showed a positive result after challenge und there was a positive result in one of the negative control animals, too, the test substance was considered non-sensitising in this study.

Further evidence for the non-sensitising effects of the test substance is provided from another study in guinea pigs (Gilmann, 1981). The test was performed according to the modified Buehler method as described in Buehler E.v. (Arch Dermat 91:171-175, 1965) (Delayed contact hypersensitivity in the guinea pig) under GLP conditions. 10 male Albino guinea pigs were epidermally treated for 24-hours with 0.5 mL of Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate (98.95% pure) under occlusive conditions at an unspecified site at the trunk The treatment was repeated at the same application site on 10 consecutive days. After a resting period of 2 weeks, a challenge application with 0.5 mL of the neat test substance was performed for 24 h at a different application site under occlusive conditions. Scoring of skin reactions according to Draize was performed 24 h after induction application as well as 24 h and 48 h after challenge. No range-finding study was conducted and no controls (neither positive nor negative controls) were included. None of the animals showed a positive reaction after the challenge exposure. Thus, the test substance was non-sensitising in this study. Due to deficiencies in method and reporting, this study is not considered reliable and suitable for assessment, but it provides supporting information.

Overall, Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate showed no skin sensitising potential.

Human data

CAS 36631-30-8

There is one study investigating the skin sensitising potential of Triisodecyl benzene-1,2,4-tricarboxylate (CAS 36631-30-8) in a repeated insult patch test in humans according to the method of Marzulli and Maibach (Cathalot, 2002). The study was conducted under Good Clinical Practice (GCP) conditions. The undiluted test substance (no data on purity) was applied to the skin of 55 volunteers (51 thereof terminated the study). None of the subjects (13 males, 42 females) had a history of acute or chronic dermatologic medical or physical conditions that could interfere with dermal scoring. Induction procedure consisted of occlusive exposure to the test substance for 48 h. This treatment was repeated 3 times a week for 3 weeks always on the same site at the upper back of the subjects. No data on the applied amount was given. Cutaneous reactions were evaluated directly as well as 24 and 48 h after patch removal after each exposure. After 2 weeks without treatment, a challenge exposure was performed under occlusive conditions for 48 h either on the same site as induction or another site. Evaluation was performed 72 and 96 hours after treatment. No significant reaction attributable to sensitisation was observed in any subject. Only one subject showed slight irritation on day 9 of induction. Thus, the test substance did not show a skin sensitising potential in a study with human volunteers.

Conclusion for sensitisation

Within the PFAE aromatic category two guinea pig maximisation tests (CAS 90218-76-1, CAS 3319-31-1), and a modified Buehler test (CAS 3319-31-1) gave no indication for sensitising potential for the category members. In a human patch test (CAS 3319-31-1) no skin sensitising potential could be detected, either. In addition, to elicit these sensitising properties a substance needs to penetrate the skin, dermal penetration rates are predicted to be very low (< 1E-10 mg/cm²/event) for members of the PFAE aromatic category (QSAR, Danish EPA, 2010). Thus, the members of the PFAE aromatic category are not considered skin sensitising.


Migrated from Short description of key information:
The overall assessment of the available information gave no indication for sensitising properties of the category members.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the group concept is applied to the members of the PFAE aromatic 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 labelled on this basis.

Based on the group concept, all available data on sensitisation do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.