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 PFAE fumarates (Polyfunctional Aliphatic Ester) category consists of seven members, which are either well-defined mono-constituent substances or related UVCB substances, with varying fatty alcohol chain lengths. The distinguishing feature of this category of chemicals is that its members are diester derivatives of fumaric acid (CAS 110-17-8). The alcohol moiety of the dicarboxylic esters generally falls in the C12-C22 carbon number range, including linear, 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, environmental toxicity 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 inter- or extrapolation 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. Structural similarities and similarities in properties and/or activities of the source and target substances in the category are the basis of read-across.

The available studies providing information on the human health hazard assessment within the PFAE fumarates category were conducted with the category member Didodecyl fumarate (CAS 2402-58-6). This substance represents the category member with the shortest fatty alcohol side chain, and consequently with the lowest molecular weight, which is regarded as worst-case approach in terms of hazard assessment of the PFAE fumarates for the local as well as for systemic effects. Additionally, experimental data is available from the category member Di-C12-15 Alkyl Fumarate.

Furthermore, the category is supported by another polyfunctional aliphatic ester, namely Bis(2-ethylhexyl) adipate (CAS 103-23-1). This supporting chemical is used to cover toxicological endpoints, exclusively. The read across of Bis(2-ethylhexyl) adipate (CAS 103-23-1) to the PFAE fumarate category is justified due to the similar structural and physico-chemical properties, as well as their toxicological, and ecotoxicological profiles.

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

1

2402-58-6

Experimental result: Not sensitising

2

10341-03-4

RA: CAS 2402-58-6

3

no CAS / List No. 938-575-3

RA: CAS 2402-58-6

RA: Di-C12-15 Alkyl Fumarate

4

no CAS / Di-C12-15 Alkyl Fumarate

Experimental result: Not sensitising

5

no CAS / List No. 938-576-9

RA: CAS 2402-58-6

RA: Di-C12-15 Alkyl Fumarate

6

1187576-41-5

RA: CAS 2402-58-6

RA: Di-C12-15 Alkyl Fumarate

7

68921-53-9

RA: CAS 2402-58-6

 

Discussion

CAS 2402-58-6

There is a reliable GLP guideline study according to OECD 442B (Höger, 2013) in order to assess the skin sensitising potential of Didodecyl fumarate (CAS 2402-58-6). In this local lymph node assay five female CBA mice per group were tested with the test item at concentrations of 10, 25 and 50% (w/w) in the vehicle methyl ethyl ketone (MEK). The animals did not show any signs of systemic toxicity or local findings during the course of the study and no cases of mortality were observed. In the positive control (alpha-hexylcinnamaldehyde) scaling and incrustations were observed. A statistically significant or biologically relevant increase in ear weights was not observed in any treated group in comparison to the vehicle control group. Furthermore, the cut-off-value for a positive response regarding the ear weight index of 1.25 was not exceeded in any dose group. A test item is regarded as a sensitizer in the LLNA if exposure to one or more test item concentration results in a 1.6-fold or greater increase in incorporation of BrdU compared with concurrent controls, as indicated by the Stimulation Index (S.I.). The estimated test item concentration required to produce a S.I. of 1.6 is referred to as the EC1.6 value. In this study Stimulation Indices (S.I.) of 1.2, 0.9 and 0.9 were determined with the test item at concentrations of 10, 25 and 50 % (w/w) in MEK. An unusual dose response was observed. An EC1.6 value could not be determined as all S.I. obtained were below the threshold of 1.6. A statistically significant or biologically relevant increase in BrdU incorporation and also in lymph node weight, cell count and ear weight measurement was not observed in any of the test item dose groups in comparison to the vehicle control group. Furthermore, the cut off-value for a positive response regarding the lymph node cell count index of 1.55 reported for BALB/c mice was not exceeded in any of the tested dose groups (Ehling et al., 2005). As expected, a statistical and biological relevant increase in BrdU labelling, lymph node weight, lymph node cell count and ear weight measurement was determined in the positive control. The test item was thus not a skin sensitiser under the test conditions of this study.

Di-C12-15 Alkyl Fumarate

In order to assess the cutaneous allergic potential of Di-C12-15 Alkyl Fumarate, a guinea pig maximization test (GPMT) was performed in 15 (10 test and 5 control) male albino guinea pigs according to OECD test guideline 406. The intradermal induction of sensitisation in the test group was performed in the nuchal region with a 50% dilution of the test item in corn oil and in an emulsion of Freund´s Complete Adjuvant (FCA) / physiological saline. The epidermal induction was conducted for 48 h under occlusion with the test item at 75% in corn oil one week after the intradermal induction and following pretreatment with 10% Sodium-Lauryl-Sulfate approx. 24 h prior to application of the test item. The animals of the control group were intradermally induced with corn oil and FCA / physiological saline and epidermally induced with corn oil under occlusion following pretreatment with 10% SLS. Two weeks after epidermal induction the control and the test animals were challenged by epidermal application of the test item at 75% and 15% in corn oil and corn oil alone under occlusive dressing. Cutaneous reactions were evaluated at 24 and 48 h after removal of the dressing. Not oxic symptoms were evident in the animals of the control or the test group. No deaths occurred. None of the control and test animals showed skin reactions after the challenge treatment with the test material. Based on the findings, the test material is not considered to cause skin sensitisation under the experimental conditions chosen.

 

Conclusions for skin sensitisation

In vivo skin sensitisation studies were performed using Didodecyl fumarate (CAS 2402-58-6) and Di-C12-15 Alkyl Fumarate, showing no potential for skin sensitisation. As dermal absorption is expected to decrease with increasing fatty alcohol chain length, Didodecyl fumarate (CAS 2402-58-6) the category member with the shortest fatty alcohol side chain and thus lowest log Pow, represents a worst-case within the category.

In conclusion, the available data indicate that no hazard for skin sensitisation for any category member has to be expected.


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

Justification for selection of skin sensitisation endpoint:
Hazard assessment is conducted by means of read-across. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties and overall quality assessment (refer to the endpoint discussion for further details).

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on read-across from category members, the available data on skin 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.

There are no data available on respiratory sensitisation.