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:

Three assays were conducted on this mix of isobutyl esters.

In a non-standard guideline study in guinea pigs, animals were induced using 4 weekly intradermal injections of 1% of the test material in dimethylphthalate followed by a challenge 15 days later of a 100% solution and a 10% solution in Dimethylphthalate. This study was negative with some minor signs of irritation that were observed in both test and control animals.

A second Guinea pig study, a full guideline GPMT assay, was also negative. The intradermal induction was done with a 5% solution and 100% solutions were used for the topical induction and Challenge. No animals were sensitised in this assay.

Finally, in a standard guideline LLNA study this substance was tested at concentrations up to 100%. At the highest dose the Stimulation index reached >3 compared to control and as such a very weak positive response was reported. The EC3 value was calculated to be approximately 90%.

In the many years that this substance has been used as a solvent and in cosmetics there has been no evidence that it possesses any sesntising potential in humans. The result of this LLNA assay is therefore inconsistent with the existing guinea pig studies and human data. It is also inconsistent with what is known about the methyl esters of the same mix of dibasic acids and the acids themselves, namely, these methyl esters and the adipic acid are not sensitising. Due to the weak response in the LLNA it was considered that this may be a false positive result and may not be entirely predictive of the actual skin sensitising potential of the isobutyl esters. Additional support for the hypothesis that the LLNA is a false positive result comes from the following facts.

1) dermal penetration of this material is expected to be limited by the high log Kow which indicates a potential to sit within the epidermis rather than penetrate through the skin.

2) The Methyl esters of the same acids were not sensitisers in the LLNA and the GPMT

3) Following repeated application, this substance will be irritating due to solvent activity, this may have produced a non-specific response lymphnode proliferation in the mice rather than a specific sensitising response.

Based on the above information it is concluded that this substance is not a sensitiser to humans.

Migrated from Short description of key information:

2 maximisation tests conducted using Guinea pigs

A local lymph node assay conducted using mice

read across to the structurally similar substances (methyl esters of the same acids) (LLNA and GPMT)

Respiratory sensitisation

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

There is no direct link between the ability of something to induce an immune response via the skin in an animal study such as the LLNA or GPMT and the ability to sensitise via inhalation. Therefore it is not possible to conclusively state that this substance is or is not a respiratory sensitiser. Considering that the overall weight of evidence suggest this substance is not a human sensitiser it is unlikely it would be a respiratory sensitiser.

Migrated from Short description of key information:

No data available

Justification for classification or non-classification

No classification required.

In the recent publication by Basketter et al. (2009) it is argued that decisions on whether to classify should be based on the weight of evidence rather than the results of a single assay. The potential for a compound to produce a positive response in an assay should also be assessed in light of its chemical properties including it's reactivity.

The structurally related methyl esters of the three acids (adipic, succinic and glutaric) are not sensitisers in animal studies and are not reactive in genotoxicity assays. This indicates that they are also unlikely to be protein reactive and capable of forming a hapten. The acids are not considered to be sensitisers based on data generated using adipic acid (cited in the US HPV dossier). Overall this data indicate it is unlikely that the isobutyl esters of the acids would be sensitising. These esters are larger and so should penetrate the skin less, and the isobutanol, if released following hydrolysis is also not known to be a sensitiser (although it would be an irritant).

The isobutyl esters are used as a solvent and in cosmetics and to date there is no evidence that workers or consumers have become sensitised to them whilst handling. The GPMT studies were very clearly negative, and the LLNA was only positive at the highest dose (100%). Taken together it is argued that this susbtance does not present a risk of skin sensitising potential to humans and as such should not be classfied.

Reference:

Basketter et al., (2009); Application of a weight of evidence approach in assessing discordant datasets: Implications for REACH. Regulatory Toxicology and Pharmacology 55 (2009) 90–96