I talked too soon. This won't work, and I have no idea why: 

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\setuplabeltext [en] [and-1={{, }}, and-2={{ and }}]    % Should be:  1, 2 and 3
\setuplabeltext [es] [and-1={{, }}, and-2={{ y }}]    % Should be: 1, 2 y 3
\setuplabeltext [de] [and-1={{, }}, and-2={{ und }}]  % Should be: 1, 2 und 3

\starttext
\commalistsentence[one,two,three,four] % works as expected

\language[es]
\commalistsentence[uno,dos,tres,cuatro] % takes [en] settings

\language[de]
\commalistsentence[1,2,3,4] % takes [en] settings. 
\stoptext
%%%%%%%%%%%%%%%%%%%%%%%%%%

If I change \mainlanguage, the main language is used in all three cases. 

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Los fines no justifican los medios, porque la medida verdadera de nuestro carácter está dada por los medios que estamos dispuestos a utilizar, no por los fines que proclamamos.
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“You develop an instant global consciousness, a people orientation, an intense dissatisfaction with the state of the world, and a compulsion to do something about it. From out there on the moon, international politics look so petty. You want to grab a politician by the scruff of the neck and drag him a quarter of a million miles out and say, ‘Look at that, you son of a bitch.’” — Apollo 14 astronaut Edgar Mitchell