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Developmental Toxicity Studies in Rats and Rabbits and Two-Generation Reproduction Study in Rats on 4-(2,4-DichIorophenoxy)butyric Acid

Charles & Conn, LLC, Durham, North Carolina, USA

Susan M. Henwood

Covance Laboratories Inc., Madison, Wisconsin, USA

Nicholas M. Leeming

Covance Laboratories Limited, Harrogate, England

4-(2,4-Dichlorophenoxy)butyric acid (2,4-DB) is principally used in the USA on peanuts, soybeans, and alfalfa. The developmental toxicity in rats (25/group) was studied at dose levels of 0, 31.25, 62.5, and 125 mg/kg/day. The maximum tolerated dose (MTD) was clearly exceeded at 125 mg/kg/day, as evidenced by a net weight loss in the dams during the dosing period, resulting in four dams totally resorbing their fetuses. The no-observed-effect level (NOEL) for maternal toxicity was 31.25 mg/kg/day based on a slight, but consistent, body weight effect at 62.5 mg/kg/day. The NOEL for embryo/fetal toxicity was 31.25 mg/kg/day based on increases in fetal skeletal variations at 62.5 mg/kg/day. The developmental toxicity in rabbits (16/group) was evaluated at dose levels of 0, 15, 30, or 60 mg/kg/day. The MTD was clearly exceeded at 60 mg/kg/day as evidenced by severe weight-gain depression during the dosing period in the does, resulting in two does aborting and two does being sacrificed in a moribund condition. The NOEL for maternal toxicity was 30 mg/kg/day based on the above noted effects at 60 mg/kg/day. The NOEL for embryo/fetal toxicity was 60 mg/kg/day due to the lack of any effects noted. The reproductive toxicity of 2,4-DB was investigated in a two-generation study with two litters bred per generation. Rats (28/sex/group for the F0 generation and 24/sex/group for the F1 generation) were fed dietary concentrations of 0, 60,300, and 1500 ppm during the first generation, but because it proved impossible to rear a filial generation at 1500 ppm, the second generation was continued at doses of 0, 60, and 300 ppm. Mating performance, fertility, and pregnancy rate were unimpaired. A NOEL for reproductive toxicity was 1500 ppm (111.8 mg/kg/day for males and 110.6 mg/kg/day for females); however, severe postnatal toxicity was produced at this level. The NOEL for postnatal toxicity was 300 ppm (22.5-32.6 mg/kg/day for males and 26.4-36.7 mg/kg/day for females depending on the generation). The NOELs for developmental and reproductive toxicity are in general agreement with those reported for 2,4-dichlorophenoxyacetic acid (2,4-D), the major metabolite of 2,4-DB.

International Journal of Toxicology, Vol. 18, No. 3, 177-189 (1999)
DOI: 10.1080/109158199225477


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