Constituent lists cannot be filtered based on the presence of an active email address. Thus, a list with over 50,000 constituents cannot be used for an email distribution even though fewer than 50,000 have an active email address. The end result is that the constituent list needs to be based on a static query created in the database view, and then that list needs to be refreshed each time an email is sent.
Also, when using a workflow to add an action after an email is sent, it adds the action to all of the records who do not have an email address.