TABLE 5.

Design of Reproductive Toxicity Studies of Gadopiclenol

Study Type	Fertility Including Early Embryonic Development	Embryotoxicity	Embryotoxicity	Prenatal and Postnatal Development	Juvenile Toxicity	Gd Retention Juvenile vs Adults
Species	Rats (SD)	Rats (SD)	Rabbits (NZW)	Rats (SD)	Juvenile rats (SD)	Juvenile or adult rats (SD)
Treatment period	M: 28 d before pairing and continued through euthanasia F: 14 d before pairing and continued through GD 7	GD 6 to 17	GD 6 to 19	GD6 to LD20	Single: PND10 Repeated: every 4 d from PND10 to PND30	Single dose or repeated dose: every 4 d during 8 wk
Dose levels (mmol/kg per day)	0, 2.5, 5, 10	0, 2.5, 5, 10	0, 1, 2.5, 5	0, 2.5, 5, 10	0, 0.6, 1.25, 2.5	0.6
Negative control (control group)	Sterile physiological saline (0.9% NaCl)	Sterile physiological saline (0.9% NaCl)	Sterile physiological saline (0.9% NaCl)	Sterile physiological saline (0.9% NaCl)	Sterile physiological saline (0.9% NaCl)	Reference item for adults (Omniscan, gadodiamide)
Administration route	Intravenous	Intravenous	Intravenous	Intravenous	Intravenous	Intravenous
No. animals	n = 22/sex/group	n = 25 F/group	n = 23 F/group	F0: n = 22 F/group F1: n = 20/sex/group	n = 15/sex/group	n = 6/sex/group
Sacrifice or cesarean (day)	M: day 44 F: GD13	GD20	GD29	F0: after weaning F1 male: after necropsy of the majority of the F1 females F1 female: GD13	2 d or 9 wk after dosing (ie, PND11, PND31, PND71, or PND 91)	1 day or 8 wk after dosing
In-life study parameters	Clinical signs, body weights, food consumption	Clinical signs, body weights, food consumption	Clinical signs, body weights, food consumption	F0/F1: clinical signs, body weights, food consumption F1: postweaning development and behavioral tests	Clinical signs, body weights, food consumption, ophthalmology, tibia length, reflex and physical development, neurobehavioral tests	Clinical signs, body weights, food consumption
Reproductive parameter	M/F: mating, fertility, and fecundity indices F: estrous cyclicity, uterine and ovarian examinations M: sperm analyses	Uterine and ovarian examinations, fetal examinations (external, visceral, and skeletal observations)	Uterine and ovarian examinations, fetal examinations (external, visceral, and skeletal observations)	F0: number of implantations F1: uterine and ovarian examinations, litter parameters (including number of pups born, pup survival, and pup weights)	M/F: sexual maturation F: estrous cyclicity M: sperm analysis	NA
Pathology	Macroscopic examination, reproductive organ weight	Macroscopic examination	Macroscopic examination	Macroscopic examination, organ weight	Macroscopic examination, organ weight, and histopathology	Macroscopic examination, organ weight, and histopathology in selected tissues
Laboratory investigations	NA	NA	NA	Hematology, serum chemistry, and urinalysis (1 F1 pup/sex/litter on PND21 and all surviving adult F1 animals before necropsy), Gd determination in tissues, and in plasma (6 F0 F/group and 1 F1 pup/sex/litter on PND21)	Hematology, serum chemistry and urinalysis, Gd determination in tissues on PND11, PND31, PND71, or PND 91 (6 animals/sex/group)	Gd determination in tissues and in plasma on PND11/D1, PND67/D57, or PND123/D113
No. animals in TK	n = 6/sex/group	n = 9 F/treated group n = 3 F in negative control group	n = 4 F/group	F0: n = 3 F/group F1: n = 1 pup/sex/litter	n = 18/sex/treated group n = 9/sex in negative control group	NA
TK evaluation	Sampling at 0.083, 0.25, 0.5, 1, 3, and 6 hours post the start of injection on day 1, GD 7 (females), and days 44 or 45 (males)	Sampling at 0.167, 0.333, 0.583, 1.083, 3.083, and 6.083 hours after the start of injection on GD 6 and 17	Sampling at 0.167, 0.333, 0.583, 1.083, 3.083, and 6.083 hours after the start of injection on GD 6 and 19	F0: sampling at 0, 17, 0.5, 2, 6, and 24 hours postdose on GD6 and LD20 F1: PND 20	Sampling at 0, 17, 0.5, 2, 6, and 24 hours postdose PND10 or PND30	NA

GD, gestation day; LD, lactation day; PND, postnatal day.