4.4.1 means your server could not complete a connection to the receiving host. It is a transport problem rather than a policy one. Retry, but investigate if it is concentrated on one route or one destination.
What it looks like in the log
421 4.4.1 Connection timed out
451 4.4.1 Connection refused
Why it happens
The receiving host is down or overloaded.
A firewall between you and them is dropping the connection, sometimes silently.
Your IP is being tarpitted, which is a reputation signal wearing a network costume.
MX resolves to a host with no working A record.
What to do
Retry on normal backoff. Most occurrences are genuinely transient.
If it is one destination only, test from a different egress IP. If that works, it is reputation, not networking.
If it is every destination, the problem is on your side: routing, firewall or DNS.