Task III: Risk assessment of pre- & pro-haptens
1. Why do we address pre- and pro-haptens under the same task?
The issues around pre- and pro-haptens have been highlighted and it is important to find a common agreement on how to assess the risk related to these materials.
By definition both pre- and pro-haptens are not allergenic themselves but can give rise to allergenic species. According to the general understanding:
It is important to understand that the discrimination between pre- and pro-haptens cannot always be made and it is quite common that a chemical substance be converted into a hapten both via biotic and abiotic pathways (e.g. hydrolysis and oxidation can happen both biotically or abiotically). Given that the resulting hapten is often the same regardless of the conversion pathway, we recommend to use the term “abiotic/biotic transformations” rather than pre- and pro-haptens.
2. What should be discussed with regard to abiotic transformation?
Air oxidation can transform benign fragrance ingredients into allergenic species. A substantial body of research (mainly publications by A.T. Karlberg), partly funded by the fragrance industry, to identify the allergenic species resulting from oxidation has been carried out. Industry has collected information on the presence of oxidized materials in fragrance raw materials, compounds and finished products, both unopened and after being opened and used for up to five years. Such analytical information of ‘real life exposure’ in combination with clinical data helps to understand the importance of this mechanism. However, many knowledge gaps remain. Therefore, we recommend that a dialogue be established to discuss the need for additional research on the abiotic transformation. The questions to be addressed can be divided into two categories:
→ Technical questions related to the manufacturing process:
→ Toxicological questions:
Given the complexity of this debate, we suggest that a workshop be organized with experts to clearly define what the issues are and how to progress and manage them.
3. What should be discussed in relation to the hydrolysis issue?
Some fragrance ingredient categories (esters, acetals, Schiff bases) can undergo a biotic or abiotic transformation of hydrolysis to produce a skin sensitizer. Depending on the degradation pathway (biotic or abiotic), the suggested actions differ:
3.1. Abiotic transformation
In the case of hydrolysis we know what would be the potential allergen formed and its potency. Formation of this allergen during production and shelf life can be monitored, and it would therefore be possible, based on historical or analytical data, to determine the risk of hapten formation by hydrolysis, taking into consideration the complexity resulting from various product categories. It is important to notice that each ester (or acetal or Schiff base) has its own chemical reactivity, and kinetic studies may lead to an enhanced understanding of the hydrolysis issue. The outcome of such studies would be the estimated probability to observe hydrolysis products for a given material in a given matrix.
As mentioned under item 2, an in-depth dialogue between experts, starting with a workshop and followed by research options, may be necessary to define these issues and how to manage them.
3.2 Biotic transformation
Less information is available on whether hydrolysis in the skin is an important mechanism, especially on the kinetics of this process. Limited studies with isolated rat skin cytosol and rat skin microsomes on Isoeugenyl- and Eugenyl-acetate indicate that these esters do not fully hydrolyse in a time-dependent manner. This preliminary study did not give clear-cut answers and confirmatory results are needed.
Kinetic and skin penetration studies should be a key to understand what happens on the skin. Isoeugenyl esters may be a possible starting point as they are the sole materials for which significant rates of positive patch tests have been reported. The data resulting from these studies should be of help to answer the following questions: