Cable clamp connector and knockout size for 6/2 NM and 8/2 NM
First, if it is at all possible to run conduit between panel and on-demand heater location, that's a great way to do it.  That lets you defer the wire size decision until you buy the heater, and simply drop in the individual wires you need.  Conduit allows higher ampacity from the same size wire - #8 is good for 40A in NM, but in conduit, 50A (single circuit) or 44A (2-3 circuits).  If the conduit is metal and non-flexible, the metal conduit provides the ground - no wires needed. A 1&quot; conduit should be plenty.
Another option, since you need a box anyway and seem focused on a 125A heater, fit a 10x14&quot; box that happens to be a subpanel.  Something like a CH8L125SP.  Supply that with #2 Cu or #1/0 Al wire or cable at 125A.  Then you can feed whatever breakers the heater needs at the time you select it.
If you want to do it as planned, you will need a LARGE box.  Each #6 wire needs 5 cubic inches and each #8 needs 3 cubic inches.  That is far too big for a 4x4 box. Consider at least a 6x6 box.
A 1&quot; KO should be alright for a #6.  Use one KO per cable.