“Could Genesis 6:12 be referring to a dramatic physical/biological change, violating God's 4 categories? Perhaps mixing or altering the physical traits of creation?”
You ask an intriguing question. One that is difficult to verify scripturally. The reason it is difficult is because of the traditional interpretation of this period of time.
Genesis 6:4 talks about the sons of god interacting with the daughters of men. And depending on your understanding of this, namely, were? the sons of god ‘angels’? - this will shape the answer to your Q. With all of thisthis in mind ..
The genetic makeup of ‘a human’ would be compromised in a union between ‘angel’ and ‘man’. God created man, but the result of this union would not be what God created. And, over 100s of years, it’s clear that the whole earth was compromised - genetically.
GEN 6:9 [snip] Noah was a righteous man, blameless among the people of his time
‘Blameless’ - tāmîm - complete, whole, entire, wholesome.
Noah was ‘without blemish’ - how do I get that? Because tāmîm is the exact same word used to describe the ‘condition’ the lambs used for sacrifice had to meet - without blemish. Noah was a ‘complete’, genetically ‘pure’. One required condition for him being saved!
Now when we consider some extra biblical sources, we also learn that prior to the flood, there was ‘genetic’ manipulation of animals - that is, ‘kinds’ were being ‘mixed’. And the result of this animal interbreeding were the unclean animals. God did not create anything unclean! So here we have another part of the answer to your Q - that is, yes, there was genetic mixing, that is, biological changes to flesh.
However, many will not accept this answer as it challenges the traditional view which is well established, and this view I outline also uses extra non-canonical sources,so you will need to decide for yourself whether you may accept all/part/none of what I outlined.