Review: UK medicines likely to be affected by the proposed European Medicines Agency’s guidelines on phthalates

BMC Clinical Pharmacology

William McCully¹  Lisa Jamieson² 

[1] Tillotts Pharma UK Ltd., Larbourne Suite, 8 The Stables, Wellingore Hall, Wellingore, Lincoln LN5 0HX, UK;Enucleo Limited, Farnham, Surrey, UK

关键词: Phthalate;    Excipients;    Polyvinylacetate Phthalate (PVAP);    Diethyl Phthalate (DEP);    Dibutyl Phthalate (DBP);    Phthalic acids;    Environmental exposure;   

Others  :  1218912
DOI  :  10.1186/s40360-015-0018-9

 received in 2014-12-03, accepted in 2015-05-26,  发布年份 2015

【 摘 要 】

Background

Phthalates are excipients in drug formulations. However, concerns have been raised about the effects of particular phthalates on reproduction and development. As a result the EMA has introduced guidelines for permitted daily exposure (PDE) limits for certain phthalates. Therefore, the objective of this study was to identify UK licensed medicines that contain the relevant phthalates and determine if they fall within the recommended PDE.

Methods

The eMC was used to identify which UK licensed medicines contain the phthalates in question. Companies were then contacted for information on the phthalate levels in their products, which was compared with the PDE recommended by the EMA.

Results

The eMC search revealed that 54 medicines contained at least one of the phthalates in question. However, only six medicines, namely Asacol 800 mg MR (Warner Chilcott UK), Epilim 200 Gastro-resistant tablets (Sanofi), Prednisolone 2.5 mg and 5 mg Gastro-resistant tablets (Actavis UK), Vivotif (Crucell Italy S.r.l), and Zentiva 200 mg Gastro-resistant tablets (Winthrop Pharmaceuticals UK), were identified as containing levels that exceeded the recommended PDE.

Conclusions

These findings indicate that very few UK licensed medicines will be affected by the proposed EMA guidelines. For those medicines identified as exceeding recommendations, these findings highlight the need to instigate a risk-benefit review.

【 授权许可】

   
2015 Jamieson and McCully.

【 图 表 】

Fig. 1.

【 参考文献 】

• [1]European Medicines Agency. Guideline on the use of phthalates as excipients in human medicinal products: EMA/CHMP/SWP/362974/2012. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/05/WC500143140.pdf. Accessed 10 July 2014.
• [2]Lee KY, Shibutani M, Takagi H, Kato N, Takigami S, Uneyama C et al.. Diverse developmental toxicity of di-n-butyl phthalate in both sexes of rat offspring after maternal exposure during the period from late gestation through lactation. Toxicology. 2004; 203:221-38.
• [3]Fujii S, Yabe K, Furukawa M, Hirata M, Kiguchi M, Ikka T. A two-generation reproductive toxicity study of diethyl phthalate (DEP) in rats. J Toxicol Sci. 2005; 30:97-116.
• [4]Schoneker DR, DeMerlis CC, Borzelleca JF. Evaluation of the toxicity of polyvinylacetate phthalate in experimental animals. Food Chem Toxicol. 2003; 41:405-13.
• [5]Rider CV, Furr J, Wilson VS. A mixture of seven antiandrogens induces reproductive malformations in rats. Int J Androl. 2008; 31:249-62.
• [6]Swan SH, Main KM, Liu F, Stewart SL, Kruse RL, Calafat AM et al.. Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environ Health Perspect. 2005; 113:1056-61.
• [7]Suzuki Y, Yoshinaga J, Mizumoto Y, Serizawa S, Shiraishi H. Foetal exposure to phthalate esters and anogenital distance in male newborns. Int J Androl. 2012; 35:236-44.
• [8]Swan SH, Liu F, Hines M, Kruse RL, Wang C, Redmon JB et al.. Prenatal phthalate exposure and reduced masculine play in boys. Int J Androl. 2010; 33:259-69.
• [9]Meeker JD, Calafat AM, Hauser R. Urinary metabolites of di(2-ethylhexyl) phthalate are associated with decreased steroid hormone levels in adult men. J Androl. 2009; 30:287-97.
• [10]Pan G, Hanaoka T, Yoshimura M, Zhang S, Wang P, Tsukino H et al.. Decreased serum free testosterone in workers exposed to high levels of di-n-butyl phthalate (DBP) and di-2-ethylhexyl phthalate (DEHP): a cross-sectional study in China. Environ Health Perspect. 2006; 114:1643-8.
• [11]Hauser R, Meeker JD, Duty S, Silva MJ, Calafat AM. Altered semen quality in relation to urinary concentrations of phthalate monoester and oxidative metabolites. Epidemiology. 2006; 17:682-691.
• [12]Tranfo G, Caporossi L, Paci E, Aragone C, Romazi D, De Carolis C et al.. Urinary phthalate monoesters concentration in couples with infertility problems. Toxicol Lett. 2012; 213:15-20.
• [13]Council Directive 76/768/EEC of 27 July 1976 on the approximation of the laws of the Member States relating to cosmetic products. OJ L. 1976; 262:169-200.
• [14]Directive 2005/84/EC of the European parliament and of the council of 14 December 2005 amending for the 22nd time Council Directive 76/769/EEC on the approximation of the laws, regulations and administrative provisions of the Member States relating to restrictions on the marketing and use of certain dangerous substances and preparations (phthalates in toys and childcare articles). OJ L. 2005; 344:40-43.
• [15]Commission directive 2007/19/EC of 30 March 2007 amending directive 2002/72/EC relating to plastic materials and articles intended to come into contact with food and Council Directive 85/572/EEC laying down the list of simulants to be used for testing migration of constituents of plastic materials and articles intended to come into contact with foodstuffs. OJ L. 2007; 91:17-36.
• [16]Directive 2007/47/EC of the European parliament and of the council of 5 September 2007 amending Council Directive 90/385/EEC on the approximation of the laws of the Member States relating to active implantable medical devices, Council Directive 93/42/EEC concerning medical devices and Directive 98/8/EC concerning the placing of biocidal products on the market. OJ L. 2007; 247:21-55.
• [17]Huang PC, Kuo PL, Chou YY, Lin SJ, Lee CC. Association between prenatal exposure to phthalates and the health of newborns. Environ Int. 2009; 35:14-20.
• [18]Jönsson BA, Richthoff J, Rylander L, Giwercman A, Hagmar L. Urinary phthalate metabolites and biomarkers of reproductive function in young men. Epidemiology. 2005; 16:487-93.
• [19]Hernández-Díaz S, Su YC, Mitchell AA, Kelley KE, Calafat AM, Hauser R. Medications as a potential source of exposure to phthalates among women of childbearing age. Reprod Toxicol. 2013; 37:1-5.
• [20]Hauser R, Duty S, Godfrey-Bailey L, Calafat AM. Medications as a source of human exposure to phthalates. Environ Health Perspect. 2004; 112:751-3.
• [21]Api AM. Toxicological profile of diethyl phthalate: a vehicle for fragrance and cosmetic ingredients. Food Chem Toxicol. 2001; 39(2):97-108.
• [22]Koch HM, Christensen KL, Harth V, Lorber M, Brüning T. Di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) metabolism in a human volunteer after single oral doses. Arch Toxicol. 2012; 86(12):1829-39.
• [23]Seckin E, Fromme H, Völkel W. Determination of total and free mono-n-butyl phthalate in human urine samples after medication of a di-n-butyl phthalate containing capsule. Toxicol Lett. 2009; 188(1):33-7.
• [24]U.S Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). Guidance for Industry Limiting the Use of Certain Phthalates as Excipients in CDER-Regulated Products. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm330792.htm. Accessed 10 July 2014.
• [25]Electronic medicines compendium (eMC). www.medicines.org.uk/emc. Accessed 10 July 2014.
• [26]Warner Chilcott. Asacol HD highlights of prescribing information. http://pi.actavis.com/data_stream.asp?product_group=1875&p=pi&language=E. Accessed 10 July 2014.
• [27]U.S Food and Drug Administration. Asacol (mesalamine) delayed release tablets. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm215476.htm. Accessed 10 July 2014.