The protracted conflict not only "severely affects" the lives of millions of people in Syria but also threatens the stability of the entire region, Stephen O'Brien said at a press conference in Damascus.
The stark warning comes amid a surge in violence as Syrian government troops, Islamic militants and rebels carried out attacks that killed and wounded dozens Monday, including in President Bashar Assad's coastal stronghold of Latakia.
Government air raids on Sunday killed at least 96 people in the eastern Damascus suburb of Douma, making it one of the deadliest single incidents since the crisis began in March 2011. The airstrikes hit a vegetable market in the suburb, which is a stronghold of the Islam Army rebel group.
Syria's conflict has killed more than 250,000 people, according to United Nations.
"I am particularly appalled by reports of airstrikes yesterday, causing scores of civilian deaths and hundreds injured, right in the center of Douma," O'Brien said. "I am horrified by the total disrespect for civilian life in this conflict."
O'Brien also lambasted armed groups for cutting off water in Damascus, saying it was unacceptable to "use access to water and other services as a weapon of war."
Water cuts have been used before in the Syrian civil war, with Damascus and the northern city of Aleppo, Syria's largest city and former commercial center, most affected.
In Washington, State Department spokesman John Kirby said the United States "condemns in the strongest possible terms the Assad regime's deadly airstrikes" on the Douma market.
U.N. Special envoy Staffan de Mistura also condemned the Douma airstrikes.
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