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BMC Pharmacology and Toxicology

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

BMC Pharmacology and Toxicology201516:17

https://doi.org/10.1186/s40360-015-0018-9

Received: 3 December 2014

Accepted: 26 May 2015

Published: 13 June 2015

Abstract

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.

Keywords

Environmental exposurePhthalic acidsDibutyl Phthalate (DBP)Diethyl Phthalate (DEP)Polyvinylacetate Phthalate (PVAP)ExcipientsPhthalate

Background

Phthalates are synthetic chemical esters of phthalic acid, that are broadly divided into low molecular weight (LMW) phthalates, which include the likes of dibutyl phthalate (DBP), diethyl phthalate (DEP) and dimethyl phthalate (DMP); high molecular weight (HMW) phthalates, which encompass butylbenzyl phthalate (BBzP), di-2-ethylhexyl phthalate (DEHP), di-isodecyl phthalate (DiDP), di-isononyl phthalate (DiNP) and di-n-octyl phthalate (DnOP); and phthalate polymers, such as cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP) and polyvinyl acetate phthalate (PVAP). They confer numerous properties, including those as a lubricant, a solvent, a softener and a plasticizer, which increases flexibility and durability. Consequently they were once widely found in a variety of consumer products, thus leading to ubiquitous daily exposure [1].

However, concerns have been raised regarding the effects of certain phthalates on reproduction and development. These worries predominantly stem from their endocrine-disrupting properties, and associated anti-androgen implications. They have been well documented pre-clinically, particularly in the rat, where prenatal exposure to particular phthalates has affected male and female offspring, with respect to numerous parameters including anogenital distance (AGD), gender ratio, nipple retention, ear and eye unfolding, vaginal opening and foetal weight and viability [24]. In addition, it has been demonstrated that their effects are additive when combined with each other, as well as, different classes of anti-androgen chemicals [5]. In fact the endocrine-disrupting effects of phthalates in the rat are so robust that within endocrinology laboratories, phthalates are often used as tools to induce testicular dysgenesis syndrome (TDS). By contrast to the preclinical arena, where there are vast studies evaluating the health implications of phthalates, too many to discuss within the scope of this article, clinical data are few and far between. Those that exist come from human association studies and suggest that prenatal exposure to certain phthalates reduces the AGD amongst male offspring, possibly indicative that it compromises virilisation [6, 7]. There is also evidence to suggest that prenatal exposure reduces masculine-play behaviour amongst pre-school males [8]. Furthermore, evaluation of phthalate exposure during adulthood demonstrates that it may contribute to both a reduction in the levels of circulating steroid hormones and sperm quality in males, as well as reduced fertility, in both males and females [912].

Whilst it is acknowledged that clinical data are limited and, in some cases inconsistent, regulatory bodies affiliated with consumer goods that contain phthalates deemed it necessary to take precautionary measures. Consequently, guidelines have been developed aimed at reducing exposure to certain phthalates in cosmetics [13], childcare articles [14], plastics in contact with food [15] and medical devices [1618]. Certain medicines represent a source of phthalate exposure, where they exist as excipients, that is, inactive components. Since phthalates are insoluble in acidic environments and soluble in neutral and alkaline conditions, they are commonly used as plasticizing agents in gastro-resistant film coatings for tablets, capsules, beads and granules, thus enabling targeted delivery of active ingredient(s) to the more alkaline environment of the intestine. This is likely the reason that drugs for gastrointestinal indications have been identified as particularly high sources of phthalate exposure [19, 20]. Furthermore, animal and human pharmacokinetic studies have shown that LMW phthalates, such as DBP and DEP, have near complete intestinal absorption, with 78–90 % of the administered dose excreted in the urine within 24 h [2123]. However, for the HMW phthalates CAP, PVAP and HPMCP, there is currently no pharmacokinetic data available.

Accordingly in 2012, the Food and Drug Administration (FDA) also developed guidelines aimed at minimising phthalate exposure in products regulated by the Centre for Drug Evaluation and Research (CDER) [24]. Specifically, the Agency determined that there is evidence that exposure to DBP and DEHP from pharmaceuticals presents a potential risk of developmental and reproductive toxicity. While the Agency recognised that drug products may carry inherent risks, it stated that DBP and DEHP are used as excipients, and safer alternatives are available. Therefore, the Agency recommends that DBP and DEHP be avoided as excipients in CDER-regulated drug and biologic products [24]. In line with the FDA, the EMA’s Committee for Medicinal Products for Human Use (CHMP) is currently drafting its own recommendations on the use of phthalates as excipients in human medicinal products [1]. Whilst these guidelines have yet to be finalised, they are expected to propose permitted daily exposures (PDE) of ≤ 0.01, 4 and 2 mg/kg for DBP, DEP and PVAP, respectively and are predicted to be enforced in 2015. For existing authorised medicinal products, the EMA is proposing to set a time limit of three years (after coming into force of the final guideline) for the implementation of formulation changes and consequential regulatory applications, as necessary. Ahead of their implementation, the authors of this study aimed to identify which United Kingdom (UK)- licensed drugs are likely to be affected by the proposed EMA guidelines, in order to help prepare for potential consequences.

Methods

The first step in this process was to identify which UK licensed medicines contain at least one of the three precautionary phthalates, DBP, DEP and PVAP, named in the draft EMA guidelines. The electronic Medicines Compendium (eMC) [25] was deemed an effective way to find these medicines, as it contains up to date information about most medicines licensed in the UK and is checked and approved by either the Medicines and Healthcare products Regulatory Agency (MHRA) or the EMA. The eMC was utilised via the algorithm depicted in Fig. 1.
Fig. 1

Algorithm for using the eMC to identify which UK licensed medicines contain at least one of the three precautionary phthalates, DBP, DEP and PVAP, named in the draft EMA guidelines on the use of phthalates as excipients in human medicinal products

The eMC provided the medical information email address associated with each medicine found to contain the precautionary phthalates. The next stage was to contact the companies affiliated with each of the medicines identified as containing the precautionary phthalates. In many cases, a single medical information address was affiliated with numerous products, thus it was only necessary to issue emails to 28 different medical information companies, requesting information about the maximum daily exposure of the relevant phthalate(s) in their product(s). Twenty-seven companies were contacted using the medical information email address provided by the eMC and one was contacted by an online enquiry form. The companies were made aware of the proposed EMA guidelines and their phthalate containing product(s) was identified together with a request for information on the maximum daily exposure of the affiliated phthalate(s).

Results

The eMC search to identify UK medicines containing at least one of the three precautionary phthalates, DBP, DEP and PVAP, named in the draft EMA guidelines, produced 50 hits (information correct as of 9th June 2014), one of which was deemed a false positive because the drug was listed as discontinued (Maxolon SR 15 mg Capsules). The remaining 49 hits, consisted of 54 branded medicines, five of which contained DBP alone, 17 contained DEP alone, 27 contained PVAP alone, four contained DEP in combination with PVAP and one contained DBP in combination with DEP (Table 1). It should be noted that this list will only contain those drugs registered on the eMC.
Table 1

UK licensed medicines that contain DBP, DEP and/or PVAP and respective maximum daily exposures relative to proposed EMA guidelines

Trade Name (generic name)

License holder

Phthalate

Phthalate content (mg) per tablet/capsule

Maximum licensed daily dose of drug

Phthalate (mg) at maximum daily dose

Chronic/Acute

Use in pregnancy

Phthalate in tablet/capsule/liquid formulation

       

Asacol 800 mg MR Tablets (mesalazine)

Warner Chilcott UK Ltd

DBP

8.00c

4.8 mg

48.00

Chronic

Benefit>Risk

Coracten XL 30 mg (Nifedipine)

UCB Pharma Ltd

DBP

0.14

90 mg

0.42

Chronic

No

Coracten XL 60 mg (Nifedipine)

UCB Pharma Ltd

DBP

0.28

90 mg

0.28

Chronic

No

Occlusal (Salicylic acid)

Alliance Pharmaceuticals

DBP

N/A

RTD

RTD

Acute

Benefit>Risk

Timodine Cream (Nystatin, Dimeticone, Hydrocortisone & Benzalkonium Chloride)

Alliance Pharmaceuticals

DBP

N/A

RTD

RTD

Acute

No

Vivotif (Salmonella enterica serovar Typhi)

Crucell Italy S.r.l

DBP / DEP

8.00 / 8.00

1 tablet

8.00 / 8.00

Acute

Benefit>Risk

Kenzem 120 mg SR Capsules (Diltiazem hydrochloride)

Kent Pharmaceuticals

DEP

NR

480 mg

NR

Chronic

No

Kenzem 90 mg SR Capsules (Diltiazem hydrochloride)

Kent Pharmaceuticals

DEP

NR

480 mg

NR

Chronic

No

Kenzem 60 mg SR Capsules (Diltiazem hydrochloride)

Kent Pharmaceuticals

DEP

NR

480 mg

NR

Chronic

No

Omeprazole 40 mg Gastro-resistant Capsules, Hard (Omeprazole)

Accord Healthcare Ltd

DEP

0.15

120 mg

0.45

Chronicd

Yes

Omeprazole 20 mg Gastro-resistant Capsules, Hard (Omeprazole)

Accord Healthcare Ltd

DEP

0.15

120 mg

0.90

Chronicd

Yes

Reminyl XL 24 mg Prolonged Release Capsules (Galantamine)

Shire Pharmaceuticals Ltd

DEP

NR

24 mg

NR

Chronic

Benefit>Risk

Reminyl XL 16 mg Prolonged Release Capsules (Galantamine)

Shire Pharmaceuticals Ltd

DEP

NR

24 mg

NR

Chronic

Benefit>Risk

Reminyl XL 8 mg Prolonged Release Capsules (Galantamine)

Shire Pharmaceuticals Ltd

DEP

NR

24 mg

NR

Chronic

Benefit>Risk

Rheumatac Retard 75 mg Tablets (Diclofenac sodium)

Adipharm Mercury Company Ltd

DEP

0.95

150 mg

1.90

Acute

No

Surgical Spirit BP (Virgin castor oil & Methyl salicylate

Thornton & Ross Ltd

DEP

N/A

N/A

UTQ

Acute

Benefit>Risk

Videx EC 400 mg Gastro-resistant Capsules (Didanosine)

Bristol-Myers Squibb Pharmaceuticals Ltd

DEP

RTD

400 mg

RTD

Chronic

Benefit>Risk

Videx EC 250 mg Gastro-resistant Capsules (Didanosine)

Bristol-Myers Squibb Pharmaceuticals Ltd

DEP

RTD

400 mg

RTD

Chronic

Benefit>Risk

Videx EC 200 mg Gastro-resistant Capsules (Didanosine)

Bristol-Myers Squibb Pharmaceuticals Ltd

DEP

RTD

400 mg

RTD

Chronic

Benefit>Risk

Videx EC 125 mg Gastro-resistant Capsules (Didanosine)

Bristol-Myers Squibb Pharmaceuticals Ltd

DEP

RTD

400 mg

RTD

Chronic

Benefit>Risk

Volsaid Retard 100 mg Tablets (Diclofenac Sodium)

Chiesi Ltd

DEP

1.27

100 mg

1.27

Acute

No

Volsaid Retard 75 mg Tablets (Diclofenac Sodium)

Chiesi Ltd

DEP

0.95

150 mg

1.90

Acute

No

Boots Constipation Relief Tablets 40s (Bisacodyl)

Dr. Reddy’s Laboratories (UK) Ltd

DEP

NR

2 tablets

NR

Acute

No

Epilim 500 Gastro-resistant Tablets (Sodium valproate)

Sanofi

DEP / PVAP

2.31 / 23.31

2500 mg

11.55 / 116.55

Chronic

No

Epilim 200 Gastro-resistant Tablets (Sodium valproate)

Sanofi

DEP / PVAP

1.23 / 12.43

2500 mg

14.76 / 149.16

Chronic

No

Zentiva 500 mg Gastro-resistant Tablets (Sodium valproate)

Winthrop Pharmaceuticals UK Ltd

DEP / PVAP

2.31 / 23.31

2500 mg

11.55 / 116.55

Chronic

No

Zentiva 200 mg Gastro-resistant Tablets (Sodium valproate)

Winthrop Pharmaceuticals UK Ltd

DEP / PVAP

1.23 / 12.43

2500 mg

14.76 / 149.16

Chronic

No

Boots Alternatives Laxative Tablets (Senna, Aloin, Cascara bark extract)

G.R. Lane Health Products Ltd

PVAP

2.10

2 tablets

4.20

Acute

No

Boots Period Pain Relief 250 mg Gastro-resistant Tablets (Naproxen)

Teva UK Ltd

PVAP

NR

500 mg

NR

Acute

No

Deltacortril 2.5 mg Gastro-resistant Tablets (Prednisolone)

Alliance Pharmaceuticals

PVAP

RTD

60 mg

RTD

Chronicd

Benefit>Risk

Deltacortril 5 mg Gastro-resistant Tablets (Prednisolone)

Alliance Pharmaceuticals

PVAP

RTD

60 mg

RTD

Chronicd

Benefit>Risk

Disipal 50 mg Tablets (Orphenadrine hydrochloride)

Astellas Pharma Ltd

PVAP

17.30

400 mg

138.40

Chronic

Benefit>Risk

Feminax Ultra 250 mg Gastro-resistant Tablets (Naproxen)

Teva UK Ltd

PVAP

NR

750 mg

NR

Acute

No

Ferrous Gluconate 300 mg Tablets (Ferrous gluconate)

Kent Pharmaceuticals

PVAP

NR

1800 mg

NR

Chronicd

Yes

Nardil 15 mg Tablets (Phenelzine)

Archimedes Pharma UK Ltd

PVAP

1.42

90 mg

8.52

Chronic

No

Prednisolone 5 mg Gastro-resistant Tablets (Prednisolone)

Actavis UK Ltd

PVAP

12.00

60 mg

144.00

Chronicd

Benefit>Risk

Prednisolone 2.5 mg Gastro-resistant Tablets (Prednisolone)

Actavis UK Ltd

PVAP

12.00

60 mg

288.00

Chronicd

Benefit>Risk

Pancrex Granules (Pancreatin)

Essential Pharmaceuticals Ltd

PVAP

RTD

variablea

RTD

Chronic

Benefit>Risk

Pancrex V Tablets (Pancreatin)

Essential Pharmaceuticals Ltd

PVAP

RTD

variablea

RTD

Chronic

Benefit>Risk

Pancrex V Forte Tablets (Pancreatin)

Essential Pharmaceuticals Ltd

PVAP

RTD

variablea

RTD

Chronic

Benefit>Risk

Phthalate in tablet/capsule logo ink

       

Aloxi 500 μg Soft Capsules (Palonosetron)

Sinclair IS Pharma

PVAP

UTQ

500 μg

UTQ

Acute

No

Amitiza 24 μg Soft Capsules (Lubiprostone)

Sucampo Pharma Europe Ltd

PVAP

0.21

48 μg

0.42

Acute

No

Anadin Ultra Double Strength/LiquiFast 400 mg Capsules (Aspirin)

Pfizer Consumer Healthcare

PVAP

<0.01

1200 mg

0.03

Acute

No

Anadin Ultra/LiquiFast 200 mg Capsules (Aspirin)

Pfizer Consumer Healthcare

PVAP

<0.01

1200 mg

0.05

Acute

No

Aptivus 250 mg soft Capsules (Tipranavir)

Boehringer Ingelheim Ltd

PVAP

UTQ

1000 mg

UTQ

Chronic

Benefit>Risk

Benadryl Allergy Liquid Release 10 mg Capsules (Certirizine dihydrochloride)

McNeil Products Ltd

PVAP

1.00

10 mg

1

Chronicd

Benefit>Risk

Nurofen Express 200 mg Liquid Capsules (Ibuprofen)

Reckitt Benckiser Healthcare (UK) Ltd

PVAP

NR

1200 mg

NR

Acute

No

Nurofen Express 400 mg Liquid Capsules (Ibuprofen)

Reckitt Benckiser Healthcare (UK) Ltd

PVAP

NR

1200 mg

NR

Acute

No

Targretin 75 mg Capsules (Bexarotene)

Eisai Ltd

PVAP

UTQ

21 capsulesb

UTQ

Acute

No

Xtandi 40 mg Soft Capsules (Enzalutamide)

Astellas Pharma Ltd

PVAP

UTQ

160 mg

UTQ

Acute

No

Zemplar Soft Capsules 2 μg (Paricalcitol)

AbbVie Ltd

PVAP

0.86

32 μg

13.76

Chronic

Benefit>Risk

Zemplar Soft Capsules 1 μg (Paricalcitol)

AbbVie Ltd

PVAP

0.86

32 μg

27.52

Chronic

Benefit>Risk

All calculations are based on the maximum licensed dose. If a drug has multiple indications, the indication with the highest dose was used for the calculation. For drugs that cannot be given at the maximum dose due to their dose increment, (i.e. sodium valproate 200 mg – max dose 2500 mg), the maximum achievable dose within the product license was used

UTQ denotes unable to quantify, RTD denotes licence holder refused to declare, NR denotes no response

a Dosing regime of Pancrex is dependent on frequency of meals/snacks

b Based on a dose of 650 mg/m2/day for a person with a body surface area of 2.38–2.62 m2

c Information in the public domain [26, 27], license holder refused to confirm

d These medications are also used in acute settings

Whilst some companies provided maximum daily exposure as requested, thus enabling direct comparison with those set out in the draft guidelines, others did not specify exposure levels but instead commented on how exposure compared with the guidelines. In some instances, companies stipulated the amount of phthalate present in a single unit of the medicine, thus requiring the authors to calculate the maximum daily exposure based on maximum indicated dose as per the ‘summary of product characteristics’ (SPC). There were five cases where companies stated that they were unable to quantify (UTQ) exposure and for 11 products, companies refused to declare (RTD). Remaining companies provided no response (NR) at all which amounted to 12 products. Responses are summarised in Table 1, however, we were unable to include the phthalate content for 23 products because either the licence holder refused to declare or provided no response.

The proposed permitted daily exposures (PDE) in the EMA guidance equates to < 0.7 mg for DBP, 280 mg for DEP and 140 mg for PVAP, for an individual with 70 kg body weight.

Phthalate in tablet/capsule logo ink

For some preparations, the phthalate was contained in the tablet/capsule logo ink on the surface of the dosage formulation. In all of these preparations, the phthalate was PVAP. For those companies who responded, the level of PVAP in the ink in each preparation was below proposed EMA PDE in all products. In some cases, the manufacturer declared that the phthalate content was so low per dosage form that it was negligible or too low to measure accurately.

Phthalate in tablet/capsule/liquid formulation

Where the phthalate was contained as an excipient within the dosage form, the level of phthalate varied considerably. The EMA proposes that the presence in medicinal products of DBP, DEP or PVAP at levels giving rise to daily exposures above the PDEs may be accepted as exceptions, on a case-by-case basis taking into consideration the intended patient population, the disease seriousness and the presence (or not) of alternative treatment options. Furthermore, the EMA also proposes that in severe or terminal disease conditions, the strict application of the PDE may not be considered necessary for DBP, DEP or PVAP-containing medicinal products, where the risk of reproductive and developmental toxicity is outweighed by the benefits of treatment for patients.

Consequently, the drugs were assessed in terms of whether or not they are used acutely or chronically. Where a drug may be used in either an acute or a chronic condition, it was categorised as “chronicd”, due to the possibility that the drug may be prescribed on a long-term basis. Drugs were also categorised according to whether or not they are licensed for use in pregnancy. The SPC for some drugs advises caution in pregnancy or the drug may be used where the benefit outweighs the risk. For both of these categories, drugs were described as “benefit > risk” (Table 1).

Where the licence holder supplied information regarding DBP content, the level was above the proposed EMA PDE of 0.7 mg for 70 kg body weight in Asacol 800 mg MR (Warner Chilcott UK Ltd) and Vivotif (Crucell Italy S.r.l), the levels being 48 mg and 8 mg, respectively, at the maximum daily dose.

For DEP, the proposed EMA PDE is 280 mg per 70 kg body weight. Where the licence holder supplied information, this level was not exceeded at maximum daily dose in the DEP-containing products.

The proposed EMA PDE for PVAP is 140 mg per 70 kg body weight. There were two PVAP-containing products where the level exceeded this. These were Prednisolone 2.5 mg Gastro-resistant Tablets and Prednisolone 5 mg Gastro-resistant Tablets (Actavis UK Ltd), where the levels at the maximum licensed daily dose were 288 and 144 mg, respectively.

Four preparations contained a combination of DEP and PVAP. Of these, Epilim 200 Gastro-resistant Tablets (Sanofi) and Zentiva 200 mg Gastro-resistant Tablets (Winthrop Pharmaceuticals UK Limited) contained a level of PVAP that was above the EMA PDE. The PVAP level was 149.16 mg in both sodium valproate 200 mg formulations.

Discussion

Summary

The aim of this study was to identify which UK licensed medicines are likely to be affected by proposed EMA guidelines on the use of phthalates as excipients in human medicinal products. Although we attempted to identify as many phthalate-containing preparations as possible by reviewing SPCs, this list cannot be considered exhaustive. For 23 products, the licence holder refused to declare the phthalate content or gave no response. At face value, it appeared that many medicines would be impacted by the recommendations as 54 medicines were identified as containing the precautionary phthalates DBP, DEP and PVAP, named in the guidelines. However, for those medicines where companies responded, once maximum daily phthalate exposures were established, only six branded medicines, namely Asacol 800 mg MR (Warner Chilcott UK Ltd), Epilim 200 Gastro-resistant Tablets (Sanofi), Prednisolone 2.5 and 5 mg Gastro-resistant Tablets (Actavis UK Ltd), Vivotif (Crucell Italy S.r.l), and Zentiva 200 mg Gastro-resistant Tablets (Winthrop Pharmaceuticals UK Limited), were identified as exceeding the EMA’s proposed recommendations. Thus, this study will help to appease those concerned about the implications of enforcement of these guidelines.

Strengths and limitations

To the authors’ knowledge, this study has provided the first review of the presence of phthalates in UK licenced medications. Furthermore, it has identified, where possible, which phthalate-containing medications will be affected by EMA guidance once it comes into practice. By virtue of the limited information in the public domain and the proprietary nature of drug formulations, information on the concentration of phthalates was limited to only 57 % of the drugs identified. This highlights the potential difficulty in clinical practice when undertaking a risk/benefit approach in the preceding 3 years before the enforcement of this guidance. In addition, not all SPC’s are available on the eMC, further hindering the ability of making an informed decision in certain patient populations.

Conclusion

For those medicines identified as exceeding the EMA’s recommendations, this study has highlighted the need to instigate a risk-benefit review, particularly in patients of childbearing age and/or with chronic conditions. To facilitate this process, the EMA, suggests taking into account factors such as the presence of non-phthalate containing alternatives, the intended patient population and the severity of the disease being treated.

Abbreviations

AGD: 

Anogenital distance

BBzP: 

Butylbenzyl phthalate

CAP: 

Cellulose acetate phthalate

CDER: 

Centre for Drug Evaluation and Research

DBP: 

Dibutyl phthalate

DEHP: 

Di-2-ethylhexyl phthalate

DEP: 

Diethyl phthalate

DiDP: 

Di-isodecyl phthalate

DMP: 

Dimethyl phthalate

DnOP: 

Di-n-octyl phthalate

EMA: 

European Medicines Agency

eMC: 

Electronic medicines compendium

FDA: 

Food and Drug Administration

HMW: 

High molecular weight

HPMCP: 

Hydroxypropyl methylcellulose phthalate

LMW: 

Low molecular weight

MHRA: 

Medicines and Healthcare products Regulatory Agency

NR: 

No response

PDE: 

Permitted daily exposure

PVAP: 

Polyvinylacetate phthalate

RTD: 

Refused to declare

SPC: 

Summary of product characteristics

TDS: 

Testicular dysgenesis syndrome

UTQ: 

Unable to quantify

Declarations

Funding

The study was funded by Tillotts Pharma UK Ltd.

Authors’ Affiliations

(1)
Enucleo Limited
(2)
Tillotts Pharma UK Ltd.

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© Jamieson and McCully. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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