Caelan Doris and Quinn Roux will miss Ireland's opening Guinness Six Nations clash with Wales through injury, while Munster backrow Gavin Coombes and Leinster lock Ryan Baird have been called up to the squad.
Doris has flagged some symptoms that the IRFU claim "could be associated with concussion".
He has returned to Leinster to allow his symptoms to be appropriately assessed and investigated.
Roux has a neck complaint that has not settled and will go back to Connacht.
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"I don't know how long they will be out for," said forwards coach Paul O'Connell.
"Caelan has obviously flagged concussion symptoms, so he has gone back to Leinster. He will go through the procedures and protocols there to get checked.
"Quinn has a neck injury, so he will have to go back and get checked.
"They are two injuries you don't ever want to be missing around with. You have to be careful.
"I'm not sure, we have no length of time on either of them. It's frustrating for them and for us.
"Caelan is obviously a fantastic player. I would have worked with him with the U-20s and he was incredible. He has that x-factor and you need those players in world rugby now.
"Quinn, I played against Quinn towards the end of my time and he was excellent.
"My last game against Connacht, I think, we lost to them at the Sportsground and he was brilliant that day.
"He's a big man, great ideas at the lineout, you know, so well coached by Jimmy Duffy up in Connacht so it’s been disappointing not have him in now going forward but we have no timeframe on when they’ll be back."
O'Connell targets immediate improvement
All other squad members are expected to train this week ahead of the opening Guinness Six Nations clash with Wales on Sunday.
The IRFU confirmed to RTÉ Sport that Coombes and Baird have come straight into the camp having gone through the necessary Covid-19 safety protocols but neither player is expected to feature in the game in Cardiff.
Meanwhile, the French rugby union (FFR) has been given the go-ahead for Les Bleus to partake in the tournament by the French government.
Following a briefing from the FFR and Six Nations, the French authorities are satisfied that improved Covid-19 protection measures are in place.
Fabien Galthie's side face Italy in Rome on Saturday.
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