Acetic acid, oxo-, sodium salt, reaction products with ethylenediamine and phenol, iron sodium salts

Endpoint summary

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

There are two studies at hand that evaluated the skin sensitizing potential of the UVCB FeNaEDDHA:

The skin sensitisation potential of the UVCB FeNaEDDHA was examined in the Maximisation Test of Magnusson and Kligman (GPMT) in guinea pigs according to OECD Guideline 406. Under the experimental conditions employed, 20 and 55% of the animals of the test group showed skin reactions 24 and 48 hours after removing the dressings, respectively. However, the positive reactions observed for erythema and oedema were ''very slight/barely perceptible". With only slight/barely perceptible reactions needing 48 h to develop for a major part of the animals, and based on a challenge concentration that was only half of what was needed to induce irritation in the animals (pre-test), the skin sensitizing potential, if any, is only very minimal at most. 

In a Local Lymph Node Assay (LLNA) according to OECD Guideline 429 the skin sensitization potential of the UVCB FeNaEDDHA was determined. In this study, Stimulation Indices of 1.59, 2.89, and 2.99 were established at concentrations of 5, 10 and 25% in dimethylformamide, respectively.  Statistically significant increases in DPM/animal and in lymph node weights were observed in all treated groups in comparison to the vehicle control group (p=0.008) and an EC3 value of 25% (w/w) was derived. However, the results for the UVCB FeNaEDDHA, with SI values below 3, were considered ambiguous for skin sensitisation under the test conditions of this study (see further).

Overall, the results of the two available studies with FeNaEDDHA show a weak or ambiguous result of the UVCB with respect to skin sensitizing potential. The methylated structural analogue UVCB FeNaEDDHMA (CAS: 84539-53-7) is very similar in its physical/chemical properties (high water solubility, low Kow, no hydrolysis in water, no reactivity to protein). This analogue can therefore be expected to behave very similar with respect to dermal penetration and subsequent availability in viable dermis and protein reactivity needed for sensitisation. However, various studies have not indicated a skin sensitizing potential for this analogue (see also the read across document in section 13).

It is noted that FeNaEDDHA does not interact with protein, which is considered a requirement for sensitization (needed for haptenisation). In addition, because a comparable analogue, the UVCB FeNaEDDHMA, has no skin sensitization potential and the skin penetration of chelating agents is very low (e.g. EDTA: <0.001%), and decades of use of this substance did not result in any reports of people becoming sensitized, FeNaEDDHA is considered  not a skin sensitising substance. It is most likely that the ambiguous results in the available animal studies were induced by an intrinsic impurity of the UVCB, viz. ethylenediamine (EDA), that has skin sensitising potential. The concentration of EDA in the UVCB was 0.2% in the LLNA study inducing a borderline positive result (SI of 2.99). Therefore, FeNaEDDHA itself is concluded to be a non-sensitiser, but in case of the presence of the skin sensitising impurity ethylenediamine at >=0.2%, the classification of the UVCB FeNaEDDHA containing >=0.2% ethylenediamine as skin sensitizer cat. 1B is warranted.

Short description of key information:
A sensitisation test in albino guinea pigs was performed to determine the contact allergenic potency of the UVCB in albino guinea pigs. This test was based on the OECD Guideline No. 406 (Skin Sensitisation). Under the experimental conditions employed, 20% and 55% of the animals of the test group showed skin reactions 24 and 48 hours after removing the dressings, respectively. However, with only slight/barely perceptible reactions needing 48 h to develop for a major part of the animals, and based on a challenge concentration that is only half of what is needed to induce irritation in the animals in this study, the skin sensitizing potential of the UVCB, if any, could only be considered very minimal at most. In addition, to study skin sensitization potential of the UVCB FeNaEDDHA, a Local Lymph Node Assay (LLNA) was performed according to OECD Guideline 429. Three groups each of five female mice were treated daily with the UVCB FeNaEDDHA at concentrations of 5, 10 and 25% (w/w) in dimethylformamide by topical application to the dorsum of each ear (left and right) once daily for three consecutive days. Under the conditions of this study, it resulted in an SI value of 2.99 at the highest tested concentration of 25%. The results can be considered ambiguous as both the conclusion non-sensiting and sensiting - with an EC3 value of 25% (w/w) - are equally justified. Also in this study, with results showing a maximum SI of about 2.99 and a comparable SI value of 2.89 at 10% concentration (factor 2.5 difference in concentration), it could be argued that these results were mediated by an accidentally low response in the control group.

Justification for classification or non-classification

The available experimental test data are conclusive for classification purposes under Regulation (EC) No 1272/2008. Two available studies indicate either a possible weak or an ambiguous result for sensitisation of the UVCB. A structural analogue (FeNaEDDHMA) and other comparable chelates are not sensitizing which is supported by the fact that these substances do not interact with protein and decades of use of this substance did not result in any reports of skin sensitization. It is therefore considered highly likely that the weak/ambiguous results in the two available animal studies were induced by an intrinsic impurity of the UVCB, viz. ethylenediamine (EDA), that has skin sensitising potential and is officially classified accordingly.

In conclusion, the UVCB substance FeNaEDDHA should not be classified for skin sensitisation under Regulation (EC) No 1272/2008. However, in case of preparations of FeNaEDDHA containing the skin sensitising impurity ethylene diamine at levels >=0.2%, such FeNaEDDHA UVCBs should be classified as skin sensitiser Cat. 1B according to Regulation (EC) No 1272/2008.