A safe boot does not clear all caches. One that is not cleared and could
be involved in your problem is the DNS cache. Offhand I don't know of a utility that flushes the DNS cache but the command line used to be
sudo killall -HUP mDNSResponder
The correct command is apparently
sudo dscacheutil -flushcache; sudo killall -HUP mDNSResponder
all on one line, but it didn't help.
It seems to me that I had the same problem after either a MFIF or FTM update years ago, and clearing the DNS cache turned the trick that time.
Working backwards from my safe boot, during which my problem didn't manifest itself, my only startup item that affects Safari is SessionRestore, and I've tried every which way to work around it if it's indeed the culprit, but with no joy.