Calcium nitrate tetrahydrate, used in fertilizers, wastewater treatment, and concrete admixtures, has limited toxicity data despite extensive industrial use. This study evaluated its repeated-dose and reproductive/developmental toxicity in Sprague Dawley rats following OECD TG 422, which combines TG 407 and 421 to extend dosing than TG 407 and reduce animal use compared with separate studies. Rats were administered 0, 100, 300, or 1000 mg/kg/day. Males were treated for 49 days and females from 2 weeks pre-mating to postpartum day 13; the recovery group was observed for an additional 2 weeks. Endpoints included clinical signs, body weight, food consumption, hematology, serum biochemistry, organ weights, histopathology, reproductive performance, and F1 development. No systemic toxicity was observed in F0 males. Minimal prostate atrophy occurred in high-dose males but was considered non-adverse due to limited severity. One high-dose female died on PPD 1, and high-dose F1 litters showed decreased litter size, increased post-implantation loss, and a reduced live-born index. Based on these results, NOAELs were cautiously assigned 1000 mg/kg/day for repeated-dose and male reproductive toxicity and 300 mg/kg/day for female reproductive and developmental toxicity. TG 422 efficiently characterized hazards while reducing animal use, though its limited duration and scope indicate the need for complementary studies.