I have about 50 active mods running right now, is it safe to clean them all at once using TEStool, or shall I do them one at a time?

I'm not aware of any tool that cleans everything at once.
You always do one esp at a time... (unless I've forgotten something obvious)

Regardless, cleaning one at a time ensures that if any problems arise you can pinpoint them much easier.

I would use TES3cmd to clean mods rather than TESTool. TESTool is pretty old and the only thing I use it for is merged objects, since there is no other tool for that. I have cleaned them all at once using Yacoby's Wrye Mash, which has integrated TES3cmd cleaning, and an option to clean everything at once. The actual cleaning through happens one at a time, but the command allows you to just do it with one click adn then sit back and wait an hour for it to clean everything. I have never had any problems doing it that way, but it takes a while. Pluto is right though, it is probably safer to clean one at a time.

TEStool can clean all ESP's at once if you highlight them all before executing the program. I tried it and it worked, but you're right about pinpointing problems easier.

Turija, do you have a download link for Yacoby's Wrye Mash?

You can get Yacoby's standalone Wrye Mash with integrated TES3cmd and mlox from the latest github link in this http://www.gamesas.com/topic/1180562-yacobys-wrye-mash-fork/.

There's problems using the latest versions of mlox with Yacoby's Wrye Mash Standalone. Those problems have to be fixed on the Mash side. I've added some info into the latest downloads of mlox on how to get the two working together.

If Yacoby bundles mlox and/or tes3cmd with WMSA then grab the https://code.google.com/p/mlox/ as it's years since Yacoby made his fork.

If you do use TESTool for cleaning then, to minimise potential problems, I'd recommend enabling both "Restricted Dialog Cleaning" and "Restricted Cell Cleaning". And look, I http://wiki.theassimilationlab.com/mmw/TESTool