Table 2: Isolated embryo-fetal eﬀects noted during necropsy observations/examinations in the developmental toxicity study in rats. Journal of Toxicology Eﬀect Fusion of placentae Rudimentary tail Visceral anomaly: ventricular septal defect Visceral variants: thymic neck remnant, supernumerary coronary ostium, left umbilical artery, and renal pelvis dilation Skeletal anomalies/malformations: wavy and nodulated ribs Skeletal variants: foramen hypoglossi double, closure of transverse foramen of one or more cervical vertebral arches, transverse foramen opening in 7th cervical arch, splitting of ossiﬁcation centers in thoracic vertebral bodies, hemicentric thoracic centrum, dumbbell ossiﬁcation of thoracic centrum, lumbarization, cervical ribs, short supernumerary 14th rib, reduced 13th ribs, splitting of sternebrae oﬀspring born alive. SE5-OH administration to male rats did not aﬀect any of the sperm parameters evaluated, which included sperm motility, percentage and type of abnormal sperm, tailless sperm, sperm count, or the number of homogenization-resistant sperm (see Table 9). 3.2.2. Oﬀspring Development. Reproductive performance for the F0 generation was initiated with 26 mating pairs. While not statistically signiﬁcant, 2, 2, and 1 pairs in the 200, 1000, and 2000 mg/kg/day dose groups, respectively, did not copulate. In the copulating pairs, nonpregnant females were observed in 1, 2, and 3 cases of the control, 1000, and 2000 mg/kg/day groups, respectively; again, this did not result in a signiﬁcant diﬀerence in the fertility index. The F0 breeding resulted in 25, 24, 22, and 22 dams in the control, 200, 1000, and 2000 mg/kg/day dose groups, respectively. The number of litters delivered resulted in 24, 23, 22, and 22 litters/dose in the control, 200, 1000, and 2000 mg/kg/day dose groups, respectively (see Table 10). One complete litter in the 1000 mg/kg/day dose group was lost on PND 2. For F1 rat pups, one male and one female were randomly selected from each litter on PND 21 and were used as breeding animals in the F1 generation (siblings not paired). One male pup in the control group died on PND 21, and one female 1000 mg/kg/day pup died on PND 22. In addition, two F1 females in the control group and one F1 male in the 1000 mg/kg group that had no mating partner were not subjected to mating. This resulted in 22, 23, 20, and 22 breeding F1 pairs in the control, 200, 1000, and 2000 mg/kg/day dose groups, respectively. All mating pairs copulated except for one pair in each of the control and 200 mg/kg/day groups. Three, 3, 1, and 1, nonpregnant females occurred in control, 200, 1000, and 2000 mg/kg/day dose groups, respectively. One female died with vaginal hemorrhage on GD 23 in the 200 mg/kg/day dose group, 5 Occurrence Occurred in one dam in the 200 mg/kg dose group. No other placental abnormalities identiﬁed in any group. Occurred in one fetus of the 1000 mg/kg dose group. No other external fetal abnormalities identiﬁed in any group. Occurred in one control group fetus and one 2000 mg/kg group fetus. No other anomalies identiﬁed in any group. Occurred with equal incidence in the control and 2000 mg/kg groups. Occurred in one 2000 mg/kg group fetus. No other anomalies identiﬁed in any group. Incidence of dumbbell ossiﬁcation of thoracic centrum was signiﬁcantly low in the 2000 mg/kg dosing group but was judged incidental with no toxicological signiﬁcance. which was not considered to be test article-related. One male of the control group could not fertilize the mating female, and one male of the 2000 mg/kg/day dose group exhibited unilateral small and soft testis and small epididymis, and the mated female of this male had only one implantation with no delivery. These eﬀects were not signiﬁcant and not considered to be related to test article administration, as they were not dose-related responses. Of the dose groups, 18, 18, 19, and 21 F1 dams gave birth to live F2 oﬀspring (see Table 11). There were no changes attributable to the test article in parturition or nursing. Total litter loss was observed for one dam each in the 200 and 2000 mg/kg/day dose groups on PND 4 and PND 1, respectively; however, this was judged to be incidental as this was not a dose-dependent eﬀect. In the F2 generation, the number of female oﬀspring was reduced at the 2000 mg/kg/day dose on PND 4 (P < .05), but neither the number of live oﬀspring on PND 21 nor the viability index was aﬀected. This reduction was not caused by prenatal death or a diﬀerence in the birth index, but was only a reﬂection of a nonsigniﬁcant reduction in the number of implantations. The total litter loss on PND 1 was judged to be incidental, as there was no dose dependency in the incidence and no abnormalities in the maternal behavior in the dams. There were no adverse eﬀects observed in any treatment group of F1 and F2 oﬀspring: clinical signs, body weight, external anomalies, sex ratios, viability index, physical development, reﬂex function, organ weight, necropsy ﬁndings, and sexual maturation (data not shown), or viability index (see Table 11). 4. Discussion Soy is the most widely used food plant in the world and has been cultivated for over 4500 years, resulting in human soy isoﬂavone consumption for several millennia [29]. Recently