It's not a value set in /etc/exim.conf.localopts?When the value is changed in the WHM interface we update /etc/exim.pl.local with the following value:
our $O_DIRECTORY = 65536;
You really need to be able to make every configuration change through a command-line process. Because logging into 50 different WHMs to make a change isn't feasible. But you can use something like Cluster SSH to log into 50 servers all at once and mirror the same command to all 50 servers.