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UFC president Dana White confirmed MacDonald's withdrawal during a press conference on Saturday. It remains unknown whether Penn will remain on the UFC 152 card in Toronto.
"Rory is out," White said. "He got cut open today -- wide open. No contact for a month."
White added the cut required, "38 to 48 stitches," and is above the left eyebrow.
MacDonald (13-1) has been one of the fastest rising stars of the UFC since his debut in January 2010. The 23-year-old Canadian already holds wins over Nate Diaz and Mike Pyle.
He was literally seconds away from a victory over current No. 1 contender Carlos Condit at UFC 115 before suffering a TKO loss in the final round.
After considering retirement since his last fight in October 2011, Penn (16-8-2) ultimately opted to extend his career against MacDonald. The former two-division UFC champion is 1-3-1 in his last five fights.