{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T23:14:59Z","timestamp":1775862899396,"version":"3.50.1"},"reference-count":37,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"AIR WATER INC.","award":["NOU R7-27"],"award-info":[{"award-number":["NOU R7-27"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background\/Objectives: Mandarin orange peel (MOP) is rich in bioactive polymethoxyflavones, including hesperidin and nobiletin, which have shown neuroprotective effects in rodent models. However, comprehensive safety data in dogs are required to support its development as a therapeutic intervention for canine cognitive dysfunction syndrome. In this study, the safety profile of a standardized MOP formulation was evaluated in four healthy Beagle dogs. Methods: Initially, compositional analysis was performed, and 202 pesticide residues and psoralens were screened to ensure compliance with Japanese pet food safety standards. Subsequently, a dose-escalation study was conducted in which dogs received oral MOP at 2, 6, and 10 g\/head\/day for 3\u20134 weeks at each dose level. Clinical signs, hematology, and serum biochemistry were monitored throughout the study period. Results: The MOP powder composition and residue levels remained within regulatory safety limits. In the dose-escalation study, no significant dose-dependent abnormalities were observed in physical or clinicopathological parameters. One dog exhibited transient loose stools at higher doses and a temporary elevation in alkaline phosphatase levels at 2 g\/head\/day; however, these symptoms resolved spontaneously despite continued administration. Conclusions: MOP was safe and well tolerated in dogs even at 10 g\/head\/day (787\u2013952 mg\/kg\/day), which is approximately five times the anticipated clinical dose. The observed fluctuations in active ingredient concentrations remained within the acceptable range for natural products and did not affect overall safety. Combined with comprehensive screening for residues, these results indicate that MOP is a high-quality and safe dietary intervention for older dogs.<\/jats:p>","DOI":"10.3390\/metabo16030213","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T09:48:42Z","timestamp":1774259322000},"page":"213","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Preliminary Safety Assessment for Mandarin Orange Peel Administration to Dogs Based on Physical Conditions and Blood Examination Parameters"],"prefix":"10.3390","volume":"16","author":[{"given":"Tomohiro","family":"Yonezawa","sequence":"first","affiliation":[{"name":"Laboratory of Veterinary Clinical Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yixue","family":"Lei","sequence":"additional","affiliation":[{"name":"Laboratory of Veterinary Clinical Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5767-2881","authenticated-orcid":false,"given":"Cris Ni\u00f1o Bon B.","family":"Marasigan","sequence":"additional","affiliation":[{"name":"Laboratory of Veterinary Clinical Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mao","family":"Komori","sequence":"additional","affiliation":[{"name":"Laboratory of Veterinary Clinical Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nanasa","family":"Fujiwara","sequence":"additional","affiliation":[{"name":"Laboratory of Veterinary Clinical Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7100-8935","authenticated-orcid":false,"given":"Jun","family":"Nakahigashi","sequence":"additional","affiliation":[{"name":"Wellness Development Research Center, AIR WATER INC., 1-7, Tsukisamu Higashi 2-jo 16-chome, Toyohira-ku, Sapporo 062-0052, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8617-3778","authenticated-orcid":false,"given":"Eiji","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Kobayashi Regenerative Research Institute, LLC, 1 Chayano-cho, Wakayama-shi 640-8263, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Pyrzynska, K. 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