Nara Research & Development Center, Santen Pharmaceutical Co., Ltd., Japan.
J Toxicol Sci. 2013;38(4):531-7. doi: 10.2131/jts.38.531.
We performed repeated toxicity studies of benzalkonium chloride (BAK)-containing vehicles of ophthalmic solutions in monkeys and rabbits to assess the local toxicity of BAK after repeated applications on the ocular surface. Local toxicity of BAK was evaluated by toxicity studies in which a 0.01% BAK-containing vehicle was applied twice/day for 52 weeks, 4 times/day for 39 weeks, or 6 times/day for 13 weeks, or in which a 0.005% BAK-containing vehicle was applied 6 times/day for 52 weeks or twice/day for 4 weeks in monkeys. Local toxicity of BAK was also evaluated where a 0.01% BAK-containing vehicle was applied 6 times/day for 6 weeks, or a 0.005% BAK-containing vehicle was applied twice/day for 39 weeks or 8 times/day for 4 weeks in rabbits. These doses were chosen because BAK is generally used at concentrations up to 0.01% in ophthalmic solutions. The BAK-containing vehicle did not cause ophthalmological changes suggestive of irritation, allergy, or corneal damage. We also did not observe any histopathological changes in the eyeball, eyelid, lacrimal gland, and nasal cavity, with repeated applications of BAK for up to 52 weeks, up to 8 times/day, or at concentrations up to 0.01%, in monkeys and rabbits. Our results suggest that BAK in concentrations up to 0.01% in ophthalmic solution is non-toxic to the eyeball, its accessory organs, and the nasal cavity after long repeated applications.
我们对含有苯扎氯铵（BAK）的眼用溶液载体在猴子和兔子中进行了重复毒性研究，以评估眼表面重复应用 BAK 后的局部毒性。通过毒性研究评估 BAK 的局部毒性，其中 0.01%含 BAK 的载体每天应用 2 次，持续 52 周；每天应用 4 次，持续 39 周；或每天应用 6 次，持续 13 周；或 0.005%含 BAK 的载体每天应用 6 次，持续 52 周或每天应用 2 次，持续 4 周。在猴子中，还评估了 0.01%含 BAK 的载体每天应用 6 次，持续 6 周；或 0.005%含 BAK 的载体每天应用 2 次，持续 39 周或每天应用 8 次，持续 4 周的局部毒性。选择这些剂量是因为 BAK 通常在眼用溶液中的浓度高达 0.01%。含 BAK 的载体未引起提示刺激、过敏或角膜损伤的眼部变化。我们还没有观察到任何眼球、眼睑、泪腺和鼻腔的组织病理学变化，在猴子和兔子中，重复应用 BAK 长达 52 周，每天应用 8 次，或浓度高达 0.01%。我们的结果表明，眼用溶液中浓度高达 0.01%的 BAK 在长时间重复应用后对眼球、其附属器官和鼻腔无毒。
