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Once a structural assessment has been completed, each impurity should be categorized according to its mutagenic hazard. The five‐class classification scheme, defined by Müller et al. [12], was ultimately adopted for this purpose, and this is shown in Table 3.2.

Table 3.2 The Mueller five‐class classification scheme.

Class	Definition	Proposed action for control (details in section 3.2.6.7)
1	Known mutagenic carcinogens	Control at or below compound‐specific acceptable limit
2	Known mutagens with unknown carcinogenic potential (bacterial mutagenicity positive, no rodent carcinogenicity data)	Control at or below acceptable limits (generic or adjusted TTC)
3	Alerting structure, unrelated to the structure of the drug substance; no mutagenicity data	Control at or below acceptable limits (generic or adjusted TTC) or do bacterial mutagenicity assay; If non‐mutagenic = Class 5 If mutagenic = Class 2
4	Alerting structure, same alert in drug substance which has been tested and is non‐mutagenic	Treat as non‐mutagenic impurity
5	No structural alerts, or alerting structure with sufficient data to demonstrate lack of mutagenicity	Treat as non‐mutagenic impurity

It is important to be aware that the SAR evaluation procedures can only be as good as the databases and rule sets that underpin the SAR systems. It is known that there are complexities in the models for some compound classes, for example those relating to anilines and heteroaromatic amines. It may be advisable to treat these cases where expert elicitation becomes essential with the option to consider safety testing (Ames test).

Although in silico systems are comprehensive in terms of the compound classes covered, there are nevertheless examples of classes that are not covered and for which there is no closely related data in the underlying database. This point was made by Dobo et al. [3] in respect of heteroaromatic nitro compounds. Hence, it is important for the recipients of the SAR output to scrutinize the findings. If an impurity has no flags for mutagenicity, but is used in the process as an electrophile, then it would be prudent to seek expert judgment with respect to the strength of the underlying data set. In such cases and particularly if the synthetic route is likely to remain the same up to and beyond marketing authorization, further assessment, i.e. an Ames test, may be prudent as this is likely to be ultimately required as part of worker safety expectations.

Evaluation of mutagenic risk can also be augmented by data derived from within the public domain. Indeed, such data forms the basis of the ICH M7 addendum table [8], and the review of common chemicals conducted by Bercu et al. [13]. This topic is explored in detail in Chapter 7.

Data sources include:

 Hazardous Substances Databank (HSDB),

 Chemical Carcinogenesis Research Information System (CCRIS), and

 Integrated Risk Information System (IRS).

These provide an excellent source of safety data for many common chemicals. Another related system is the Berkeley database. Indeed, as described in Chapter 7, it is often possible with common reagents to locate sufficient safety data to allow mutagenic risk to be assessed on a compound‐specific basis rather than simply applying the TTC. Until recently these, and a number of other references, were accessible via TOXNET, a searchable database provided by the US Library of Medicine. TOXNET provided access to a series of databases through a common portal. While TOXNET is no longer available, alternative search engines such as TOXPLANET are available. Additionally, Lhasa has now reproduced the Berkeley database, which is accessible via their website. As well as the original Berkeley database, which is no longer maintained, the Lhasa database includes more recent data available since the freezing of the Berkeley database. See Chapter 7 for a detailed overview.