Relative developmental toxicities of nine diphenyl ethers related to nitrofen

Abstract

Outbred Swiss mice (Mus musculus) were treated with 2,3‐dichlorophenyl 4′‐nitrophenyl ether (23‐DCN), 2,5‐dichlorophenyl 4′‐nitrophenyl ether (25‐DCN), 2,6‐dichlorophenyl 4′‐nitrophenyl ether (26‐DCN), 3,4‐dichlorophenyl 4′‐nitrophenyl ether (34‐DCN), 3,5‐dichlorophenyl 4′‐nitrophenyl ether (35‐DCN), 2,4,5‐trichlorophenyl 4′‐nitrophenyl ether (245‐TCN), 2,4,6‐trichlorophenyl 4′‐nitrophenyl ether (CNP), 3‐chlorophenyl 4′‐nitrophenyl ether (3‐MCN) or phenyl 4‐bromophenyl ether (4‐BR) at dosages that are highly teratogenic when the known teratogen nitrofen (2,4‐dichlorophenyl 4′‐nitrophenyl ether) is administered. The Chernoff/Kavlock screen was used to assess both prenatal and postnatal toxicity; in addition, effects of each chemical on Harderian glands were evaluated. The monochlorinated analogs and the five dichlorinated nitrofen analogs were inactive at the doses given. 4‐BR was inactive at levels of up to 1,000 mg/kg/d. The trichlorinated analogs caused missing Harderian glands in pups exposed to 10 or 20 mg/kg/d 245‐TCN, 50 or 100 mg/kg/d nitrofen or 250 or 500 mg/kg/d CNP; significant perinatal mortality in litters exposed to 20 mg/kg/d 245‐TCN or 100 mg/kg/d nitrofen; and a high incidence of prenatal mortality in litters exposed to 500 or 750 mg/kg/d CNP. Maternal toxicity other than decreased weight gain was not seen with any compound, even at doses that caused significant prenatal or perinatal mortality. The data demonstrate that the position of chlorine substituents, as well as the number of such substituents, is critical in determining the developmental toxicity of diphenyl ethers.