The toxicity of a novel series of ten pyranothiazolopyrimidine derivatives (1–9a,b) against the insect Aphis gossypii (Glover, 1887) has been determined. In addition, the safety profile of two selected compounds 2,8 against earthworms was determined. Acetamiprid insecticide was utilized as a reference insecticide. Spectroscopic data and elemental analyses were used for verifying the structures of the synthesized compounds. Studying the toxicity of synthesized derivatives against the Aphis gossypii (Glover, 1887) revealed that compounds 2,8 were more active than the reference insecticide acetamiprid against Aphis gossypii (Glover, 1887), while the remaining compounds exhibited moderate to low activities. But, in detecting the safety profile against earthworms (Aporrectodea caliginosa) for compounds 2,8, it was found that; compound 2 (LC50 = 32.7753–22.4079) and compound 8 (LC50 = 131.6081–101.0537) are less toxic and safer on earthworms than acetamiprid (LC50 = 0.1992–0.0086) after 5 and 10 days of test. Also, the chemical characteristics of the investigated soil holding the used earthworms diversified significantly before and after treatment with agrochemicals.