The highest CB who is not fatigued will come in to play S. If it is the first substitution of the game and the 3rd CB is not tired and a safety needs to be replaced, it will be the 3rd CB. (Assuming you are playing a formation with 4 DBs)
The only time another CB will come in is if the 3rd CB has already played and he has not recovered from his fatigue yet.
That is not for the Starters at Safety but for replacements on fatigue during the game.
If you fail to fill all your starters, it calculates who it thinks is the best safety from all your non starting DBs ... the equation it uses is unknown, but does not correlate to who I would normally start, so I would not recommend leaving it blank.