These applications were phased out under the Montreal Protocol in developed countries in 2020 due to the compound's ozone depletion potential (ODP) and high global warming potential (GWP), and in developing countries this process will be completed by 2030.

R-22 is often used as an alternative to the highly ozone-depleting CFC-11 and CFC-12, because of its relatively low ozone depletion potential of 0.055,[4] among the lowest for chlorine-containing haloalkanes.

Hydrofluorocarbons (HFCs) are often substituted for R-22 because of their lower ozone depletion potential, but these refrigerants often have a higher GWP.

Ammonia (R-717), with a GWP of <1, remains a popular substitute on fishing vessels and large industrial applications.

Propane was the de facto refrigerant in systems smaller than industrial scale before the introduction of CFCs.

The reputation of propane refrigerators as a fire hazard kept delivered ice and the ice box the overwhelming consumer choice despite its inconvenience and higher cost until safe CFC systems overcame the negative perceptions of refrigerators.

It is not lawful to use in air conditioners or larger refrigerators because of its flammability and potential for explosion.

[6] R-22 was mostly phased out in new equipment in the United States by regulatory action by the EPA under the Significant New Alternatives Program (SNAP) by rules 20 and 21 of the program,[7] due to its high global warming potential.

The EPA program was consistent with the Montreal Accords, but international agreements must be ratified by the US Senate to have legal effect.

A 2017 decision of the US Court of Appeals for the District of Columbia Circuit[8] held that the US EPA lacked authority to regulate the use of R-22 under SNAP.

In essence the court ruled the EPA's statutory authority[9] was for ozone reduction, not global warming.

R-421A is for use in "air conditioning split systems, heat pumps, supermarket pak systems, dairy chillers, reach-in storage, bakery applications, refrigerated transport, self-contained display cabinets, and walk-in coolers".

R-434A is for use in water cooled and process chillers for air conditioning and medium- and low-temperature applications.