The Threshold of Toxicological Concern (TTC) in risk assessment

The Threshold of Toxicological Concern (TTC) is a level of human intake or exposure that is considered to be of negligible risk, despite the absence of chemical-specific toxicity data. The TTC approach is a form of risk characterisation in which uncertainties arising from the use of data on other compounds are balanced against the low level of exposure. The approach was initially developed by the FDA for packaging migrants, and used a single threshold value of 1.5mug/day (called the threshold of regulation). Subsequent analyses of chronic toxicity data resulted in the development of TTC values for three structural classes with different potentials for toxicity (1,800, 540 and 90mug/day). These TTC values have been incorporated into the procedure that is used internationally for the evaluation of flavouring substances. Further developments included additional TTC values for certain structural alerts for genotoxicity (0.15mug/day), and for the presence of an organophosphate group (18mug/day). All of these TTC values were incorporated into an extended decision tree for chemicals, such as contaminants, which might be present in human foods. The TTC approach has been shown to have potential applications to risk assessments of cosmetic ingredients, household products and impurities in therapeutic drugs.     

奥美沙坦酯中4-氯甲基-5-甲基-1,3-二氧杂环戊烯-2-酮和4,5-二氯甲基-1,3-二氧杂环戊烯-2-酮的HPLC法测定

目的：建立高效液相色谱法（HPLC）测定奥美沙坦酯中氯代烷基结构类潜在基因毒性杂质（4-氯甲基-5-甲基-1,3-二氧杂环戊烯-2-酮（杂质1）和4,5二氯甲基-1,3-二氧杂环戊烯-2-酮（杂质2））。方法：采用色谱柱为Kromasil Eternity 5-PhenylHexyl 柱 250×4.6 mm;检测波长：215 nm,流动相A：乙腈：2.04 g?L-1磷酸二氢钾溶液（用1.73 g/L磷酸溶液调节pH值至3.4）（20：80）;流动相B：2.04 g?L-1磷酸二氢钾溶液（用1.73 g?L-1磷酸溶液调节pH值至3.4）：乙腈（20：80）,进行梯度洗脱,流速为1.0 mL·min-1,柱温40 ℃,进样量10 μL。结果：杂质1和杂质2与主峰分离良好,在浓度为0.1066~0.7104 μg·mL-1和0.1235~0.6174 μg·mL-1范围内杂质1和杂质2的线性关系良好（相关系数分别为1.0000和0.9971）;杂质1和杂质2的平均回收率分别为98.09%和114.85%,RSD（n=9）分别为7%和7%。结论：经方法学验证,本法准确性好、灵敏度高,适用于奥美沙坦酯中的杂质1和杂质2的定量控制。     

药物中杂质及有害物质控制限度的研究进展

随着药物研发技术和检测方法的快速发展,各国均制定了杂质或有害物质残留控制的指导原则。遵循＂建立研究目标→确立杂质检测方法→样品检测→综合评价→建立限度并进行控制＂的研究思路,根据杂质的不同来源、杂质的危害性、过程中去除的难易等因素来确定其在终产品中是否定入质量标准。从以上几方面综述了近年来药物中杂质及有害物质控制限度的研究进展。     

Contact allergy to allergy to allyl glycidyl ether present as an impurity in 3-glycidyloxypropyltrimethoxysilane, a fixing additive in silicone and polyurethane resins

We present a 43-year-old man who worked in the plastics industry and who suffered from an occupational dermatitis on the hands and forearms. He was found to be allergic to an epoxy silane compound that was contaminated with allyl glycidyl ether, a reactive epoxy diluent. HPLC analysis and patch testing indicated that this impurity was probablyt the only sensitizer. Moreover, the gloves used provided absolutely no protection, as the inner side also generated strong positive reactions.     

A case of contact dermatitis due to impurities of cetyl alcohol

A 29-year-old man being treated for itchy lesions on the amputation stump of the thigh became allergic to betamethasone valerate and gentamicin sulfate cream (Rinderon VG®. Closed patch tests with all the ingredients of the cream revealed positive reactions to cetyl alcohol 30% to 5% pet. Gas chromatographic analysis of the cetyl alcohol in the cream base detected stearyl alcohol (C₁₈), myristyl alcohol (C₁₄) and lauryl alcohol (C₁₂) in addition to the main component of cetyl alcohol (C₁₆). Patch testing with 99% pure analytical reagent grade saturated alcohols. (C₁₀, C₁₁, C₁₂, C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, C₁₈, C₁₉, C₂₀) showed negative reactions. Thus, it is concluded that some minor impurities in cetyl alcohol not detected by gas chromatography might be the cause of this dermatitis.     

HPLC法测定注射用盐酸头孢吡肟中2-巯基苯并噻唑

摘要：目的 建立HPLC法测定注射用盐酸头孢吡肟中2-巯基苯并噻唑基因毒性杂质含量的方法。方法 HPLC法,采用 Inertsil ODS-3柱(250 mm×4.6 mm,5 μm),以50 mmol/L磷酸氢二钠溶液(用磷酸调pH值至6.25)-甲醇-80%乙腈(60:10:30, V/V/V) 为流动相,等度洗脱,流速为1 mL/min,柱温为35℃,检测波长为320 nm,进样体积为10 μL。结果 2-巯基苯并噻唑在浓度 0.01~102.9 μg/mL范围内,呈良好的线性关系,回归方程y= 70652x+2167.2,相关系数r=0.9999;定量限为0.3 ng,检测限为 0.1 ng, 回收率均值(n=9)为91.7%。结论 本方法专属性强、准确、快捷、灵敏且耐用性良好,为测定注射用盐 酸头孢吡肟中2-巯基苯 并噻唑含量的有效补充检测与定量方法,并为该产品临床应用安全性提供保障。     

3-Dimethylaminopropylamine: a key substance in contact allergy to cocamidopropylbetaine?

In the past year, 1200 consecutive eczematous patients were tested with cocamidopropylbetaine 1% aq. Contact allergy was evinced in 46 subjects (3.8%), while irritant reactions (slight erythema only) were observed in 15 cases (1.25%). 30 out of 46 patients with allergic reactions were subsequently tested with the substances used in the synthesis of cocamidopropylbetaine, together with a sample of cocamidopropylbetaine declared by the supplier to possess a greater purity. In all 30 subjects, positive reactions were obtained to 3-dimethylaminopropylamine (DMPA) 1% aq., while the cocamidopropylbetaine denned of purer grade, at 0.5% and 1% aq., gave positive reactions in 10% and 53% of cases, respectively. These results suggest that the DMPA present at various levels as an impurity in the commercial product is responsible for cocamidopropylbetaine allergy. Owing to the inconsistency of positive reactions to cocamidopropylbetaine of variable purity, and to the consistency of positive reactions to DMPA, it seems likely that these reactions may also be connected with the presence in the product, defined of purer grade, of unknown amounts of DMPA as impurity. Structural similarities between the 2 molecules cannot be considered in this case, because the DMPA structure is radically changed in its transformation to the betaine structure, Further experiments with other molecules related to the above structures are in hand.     

Copper – a rare sensitizer

To determine the incidence of patch test reactions to copper, 2% copper sulphate was included in our routine patch test series. The allergic potential of copper sulphate was evaluated by the guinea pig maximization test method (GPMT). 13 of the 1190 eczema patients showed reactions (1.1%), but they were considered non-relevant. 3 series of GPMT demonstrated that copper sulphate was a grade I allergen. A critical review of the literature disclosed that several reports on cases of allergic contact dermatitis to copper must be regarded as uncertain or non-relevant. 4 cases were considered relevant and another 20 cases probably relevant. It is suggested that a test reaction to copper sulphate should be verified by a serial dilution test (SDT). Furthermore, the sensitivity of patients to other metals should be stated, so that one can be aware that false positive reactions from metal impurities, especially nickel, in the copper salt used for testing may occur.     

药物中痕量磺酸酯类物质的检测技术研究进展

烷基磺酸酯和芳基磺酸酯类化合物作为潜在性基因毒性杂质,严重威胁人类健康,因此需要控制食品及药品中磺酸酯的限度。主要介绍了磺酸酯类物质的痕量分析检测技术手段,如GC-MS、HPLC-MS、NMR等,同时阐述了各种检测技术的优缺点。另外,还论述了这些杂质产生的条件,从而提出了避免生成该类杂质的具体措施。因此,主要从避免杂质的产生和痕量检测两方面进行了综述,讨论了有效控制药品中基因毒杂质限度的方法,以保证用药安全。