Johnny Sexton is out of Ireland's tour to South Africa because of a shoulder injury while brothers Rob and Dave Kearney will also miss the Test series.
Leinster fly-half Sexton was injured in Saturday's Pro12 final defeat by Connacht and requires surgery.
Full-back Rob Kearney has a hamstring injury with his brother Dave, a winger, ruled out by a torn calf muscle.
Ian Madigan, Craig Gilroy and uncapped Connacht duo Tiernan O'Halloran and Matt Healy have all been called up.
Payne a full-back option for Ireland
With Munster's Simon Zebo already missing the tour, Ulster's Jared Payne looks in line to be switched from his regular centre role to full-back.
Payne has played at full-back for most of his career but was moved to centre by Ireland coach Joe Schmidt to help fill the midfield void left following Brian O'Driscoll's retirement.
Connacht's O'Halloran will be the other full-back option in Schmidt's squad.
Bordeaux-bound Madigan was a notable omission from Schmidt's initial squad but Sexton's absence means a reprieve for the former Leinster fly-half.
"We initially hoped it [Sexton's injury] could be managed but it will require surgery," said Schmidt, who added the fly-half will be ruled out for three months.
While Sexton's injury has meant a call up for Madigan, Ulster's Paddy Jackson now looks in position to start in the First Test in Cape Town on Saturday week.
Wing Luke Fitzgerald, Sexton's club-mate, was ruled out of the tour earlier this week after also being injured in the Pro12 decider.
Schmidt says Ireland can challenge Springboks
Schmidt already has a long list of absentees, which includes backs Zebo and Tommy Bowe, and forwards Cian Healy, Denis Buckley, Nathan White, Sean O'Brien, Peter O'Mahony and Josh van der Flier.
Despite the injuries, Schmidt believes his side can still strongly challenge the Springboks.
"My expectation is that the players will work hard, they'll unite really effectively under [captain] Rory Best's leadership and that we will be competitive," said the Ireland coach.
"Whether that's enough, we'll find out on the 11th, 18th and 25th of June (the dates for the three Tests)."
Ireland, who have never won in South Africa, face the Springboks in the first Test in Cape Town on 11 June, with the sides meeting again over the following two weekends in Johannesburg and Port Elizabeth.
The three June Tests will influence rankings for the 2019 World Cup.
Forwards: Finlay Bealham (Connacht), Rory Best (Ulster), Sean Cronin (Leinster), Ultan Dillane (Connacht), Tadgh Furlong (Leinster), Jamie Heaslip (Leinster), Iain Henderson (Ulster), David Kilcoyne (Munster), Jack McGrath (Leinster), Jordi Murphy (Leinster), Sean Reidy (Ulster), Mike Ross (Leinster), Quinn Roux (Connacht), Rhys Ruddock (Leinster), Donnacha Ryan (Munster), CJ Stander (Munster), Richardt Strauss (Leinster), Devin Toner (Leinster).
Backs: Keith Earls (Munster), Robbie Henshaw (Connacht), Paddy Jackson (Ulster), Matt Healy (Connacht), Tiernan O'Halloran (Connacht), Ian Madigan (Bordeaux), Craig Gilroy (Ulster), Kieran Marmion (Connacht), Luke Marshall (Ulster), Conor Murray (Munster), Stuart Olding (Ulster), Jared Payne (Ulster), Eoin Reddan (Leinster), Andrew Trimble (Ulster).