二氧化钛被列为二类致癌物，EMA就片剂包衣、胶囊壳替代材料发声明！

欧洲食品安全局 (EFSA) 于 2021 年 5 月的一项评估揭露二氧化钛（TiO 2；CAS 13463-67-7）的存在遗传毒性的可能，该机构认为有必要禁止二氧化钛在食品中的应用。这让依赖该成分的其他行业感到震惊。欧盟目前已将某些形式的二氧化钛 (TiO 2 )分类为吸入的可疑致癌物（第 2 类），并于2021 年 10 月1日生效。

EMA于随后应欧盟委员会要求就将二氧化钛从批准的食品添加剂清单中删除对药品的影响反馈意见：

概要如下：

Titanium dioxide(TiO2) is extensively used as an opacifier and colourant in medicines due
to its multiple functionalities1.

二氧化钛（TiO2）由于其多种功能，在药物中被广泛用作不透明剂和着色剂。

TiO2 is used very frequently in oral solid dosage forms (e.g. tablets,soft capsules, hard capsules, granules/powders for oral solution and oralsuspensions), in oral semi-solid dosage forms (e.g. oral paste, oral gel). Itis present in many essential medicines for human including antidiabetics,antibiotics and others and several veterinary medicinal products. TiO2 is alsopresent in dosage forms administered via routes other than oral, e.g., productsfor cutaneous, inhalation (capsule shells), or omucosal,sublingual, transdermal and vaginal use.

TiO2常用于口服固体制剂（如片剂、软胶囊、硬胶囊、用于口服溶液和口服悬浮的颗粒/粉末）、口服半固体制剂（如口服软膏、口服凝胶）。它存在于许多人类必需的药物中，包括抗糖尿病药物、抗生素和其他一些兽药。TiO2 也存在于通过口服以外的途径给药的制剂中，例如用于皮肤、吸入（胶囊）、舌下、透皮和阴道使用的产品。

To date, no singlematerial has been identified that provides the same combination of propertiesthat are unique to TiO2 (e.g. opacity,enhancing contrast, inertness, protection from UV light and the finish/smoothnessof the resulting product). Separating out the different functionalities of TiO2 for thosemedicinal products in which it serves more than one function is difficult ormight not be possible at all.

迄今为止，尚未发现任何单一物质可提供 TiO2所独有的属性组合（例如不透明、增强对比度、惰性、防紫外线和由此产生的产品光滑度）。分离出TiO2的不同功能，用于其服务于多个功能的药用产品是困难的，或者根本不可能。

Possiblealternatives identified so far include calcium carbonate, talc and starch. Anumber of disadvantages have been identified with these alternatives (e.g.inability to obtain sufficiently thin films, supply chain issues, minedmaterials with associated elemental impurity risk).

迄今确定的可能替代品包括碳酸钙、滑石和淀粉。这些替代品已发现一些缺点（例如无法获得足够薄的薄膜、供应链问题、具有相关元素杂质风险）。

The feasibility ofreplacing TiO2 cannot be confirmed at this stage. Each affected medicinal product willneed an individual review and assessment, which will require investigation of alternatives,product reformulation, generation of new data related to manufacture, dissolutionand stability etc. and potentially new clinical data (e.g. generation of bioequivalencestudies ), which subsequently will all have to be assessed by the national competentauthorities and EMA.

现阶段无法确认替代 TiO2 的可行性。每个受影响的药用产品都需要一个单独的审查和评估，这将需要调查替代品，产品重新配方，收集与制造、溶解和稳定性等相关的新数据，以及可能的新的临床数据（例如生物等效性研究），这些数据随后都必须由国家主管部门和EMA进行评估。

The direct and indirect impacts on medicines for human and veterinary useare expected to be aggravated in the scenario, where Europe would be the onlyregion globally to ban TiO2 as excipient in medicines, which would requireindustry to develop new formulations for the majority of oral solid doseproducts potentially for the EU only, with titanium dioxide continuing to beused in the majority of medicines globally.

在这种情况下，对人用和兽用药物的直接和间接影响预计将加剧，欧洲将成为全球唯一禁止TiO2作为药用辅料的区域，这将要求工业界为可能只针对欧盟的大多数口服固体制剂产品开发新配方， 二氧化钛继续用于全球大多数药物。

An acceptable transition period for phasing-out TiO2 in all or specificuses in medicines covered by the scope of colouring matters is currentlydifficult to envisage or estimate. The time needed to reformulate eachindividual product could be several years depending on the level of formulationand studies required, to be followed by the necessary regulatory procedures forassessment and approval.

目前很难设想或估计在着色剂所涵盖的药物中逐步淘汰TiO2的所有或特定可接受过渡期。根据所需的配方和研究水平，每个产品所需的时间可能为数年，随后需要制定必要的监管程序进行评估和批准。

Considering the scale of the use of this excipient, the time and costsinvolved in the reformulation and the volume of products impacted, it isconsidered that any requirement to replace TiO2 in medicines will almostcertainly cause significant medicines shortages anddiscontinuations/withdrawals of medicines from the EU/EEA market with major implicationsfor patients and animals. Particular concerns arise in relation to certain vulnerableclasses/types of products such as paediatric medicines, orphan medicines, low salesvolume products, bee products, etc.).

考虑到这一先见之需的使用规模、重新制定所涉及的时间和成本以及受影响的产品数量，我们认为，任何在药品中取代TiO2的要求几乎肯定会造成药品严重短缺，并导致药品从欧盟/欧洲经济区市场停产/退出，对患者和动物产生重大影响。对某些脆弱产品，如儿科药品、孤儿药品、低销售量产品、蜜蜂产品等，尤其令人关注。

EMA表示，许多制造商正在努力开发无TiO2配方，包括：

Tablet coatings

片剂包衣

Coating suppliers have developed titaniumdioxide free coating range. However, these are not currently widely used andthere is therefore limited information available regarding their generalsuitability for use.

包衣供应商已经开发出无二氧化钛包衣系列。然而，这些目前没有广泛使用，因此，关于它们一般适合使用的信息有限。

Capsule shells

胶囊壳

Titanium dioxide free capsule alternativesare available.

现已有无二氧化钛的胶囊替代品可供使用。