Background: Streptokinase and streptodornase (SK-SD) are bacterial enzymes combining fibrinolytic and DNA-hydrolysing activities, long used in suppository form for the local treatment of hemorrhoidal disease and other anorectal conditions; however, comprehensive repeated-dose toxicity data specifically addressing prolonged rectal administration remain limited despite decades of clinical use.

Methods: A 90-day repeated-dose rectal toxicity study was performed in 160 Wistar rats (20 males and 20 females per group) randomized into four groups receiving one suppository daily: blank base (control) or SK-SD at 1fold (1,550 IU SK + 129 IU SD), 5fold (4,650 IU SK + 388 IU SD), and 10fold (15,500 IU SK + 1,292 IU SD) the rat-equivalent human therapeutic dose, derived by body-surface-area scaling. Conducted under GLP principles and guidelines aligned with OECD TG 452, the study monitored clinical signs and local rectal irritation, body weight, and food and water intake, with hematology, serum biochemistry, coagulation parameters (PT, APTT, TT, fibrinogen), inflammatory markers (IL-6, TNF-α, IFN-γ, IL-1β, CRP), anti-streptokinase IgM/IgG, organ coefficients, and histopathology assessed on Days 30, 60, and 90.

Results: No mortality, clinical signs of systemic toxicity, or local rectal irritation were observed at any dose level. No statistically significant differences (p > 0.05) from control were found in body-weight gain, food or water intake, or hematological, biochemical, coagulation, inflammatory, or immunogenicity parameters in either sex. Organ coefficients and the histopathology of systemic organs and the rectal/colonic mucosa were unremarkable, with intact mucosal architecture preserved even in the 10fold group.

Conclusion: Daily rectal administration of SK-SD suppositories for 90 days produced no systemic toxicity, local irritation, or humoral immune sensitization, establishing a no-observed-effect level (NOEL) at the highest tested dose (10fold) and indicating a favourable safety profile for prolonged or repeated clinical use in proctology.