I2C Shifter being used to protect against short to much higher supply rail
Using a comparator to protect a circuit is relatively simple.  An op amp output is limited to its supply terminals' voltages, however it's input terminals can usually accept a higher voltage even under such conditions.  Op amps also tend to be sufficiently fast to copy digital data bus signals.  You will have to look at spec sheets and find one that has the voltage limits and response times you need.
Essentially what would happen is that you limit the op amp's output to 0-3V even if the bus is -44-44 V.  If the comparison point is set to 1.5V, it will produce 3V for the range of 1.5-44V and 0V for -44-1.5V.  That would effectively limit what the sensitive device experiences from the high voltage error condition, although you might get bad digital data injected, the amp would be what bears the high voltage and your I2C device would not get fried.
While the action is somewhat similar to a mosfet, you get both high and low side protections over a known wide range, and the comparison point is adjustable.  Adjustability might just let you eek out good signal under bad conditions with a proper circuit.
&quot;if I'm building it I figure may aswell cover all possibilities&quot;
While covering all possibilities may be in the realm of impossibility, you can look to build for potential adjustments in the future.
You can also use comparators to activate other circuits should the voltage on the bus fall out of range, and protect output lines as well (usually as a buffer), although simple high impedance might be better for output scenarios.