Document XR2agMy9Gdydr0N4RqNOQVXxR
Report summary medicinal products
(active pharmaceutical ingredients, diagnostics, anesthetics and intermediates)
1
Contents
Preface .....................................................................................................................................................3 1. Uses / Applications...............................................................................................................................4 2. APIs with PFAS like moieties ................................................................................................................4 3. Tonnage band ......................................................................................................................................6 4. Manufacturing & Market data ............................................................................................................. 8 5. Emissions............................................................................................................................................11 6. Exposure.............................................................................................................................................11 7. General discussion on emission and exposure ..................................................................................12 8. Alternatives........................................................................................................................................12 9. Economic impacts in case of a full PFAS ban .....................................................................................12 10 Methods used & uncertainties .........................................................................................................12 References .............................................................................................................................................13 Annex .....................................................................................................................................................14
2
Preface
The scope of this report summary is to present the results of a quick scan on PFAS use in the medical sector, more specific in medicinal products. This report does not contain the PFAS production stage (like for the manufacturing of PTFE, PFOA etc.) nor the end of life/waste stage. As a consequence, the manufacturing of the active pharmaceutical ingredients (API) and medical products, hence reagents or solvents is not addressed here. Medical devices is described in a separate summary. It should be noted that the tonnages APIs are currently based on the molecular weight of the API and not on the fluorinated part only. Anesthetics and contrast media in this report are reported individually, so not directly into medicinal products. They are both named in the medicinal products summary and medical applications summary. The lists presented in this document reflect non exhaustive lists.
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1. Uses / Applications
The following main uses can be distinguished. Medicinal Products (APIs, diagnostics, anesthetics) Medicinal Products and Medical Technology production ingredients (e.g., intermediates,)
2. APIs with PFAS like moieties
Starting point of the selection of fluoro-containing medicinal products was a recent paper (Inoue, Sumii et al. 2020), who listed 340 of such compounds that are present in the database of the WHO Collaborating Centre for Drug Statistics Methodology hosted by the Norwegian Institute of Public Health1, not necessarily all in use in EU.
68 APIs with one or more CF2 or CF3 group were found with a market registration for human use in the EU or in one or more of its member states. The substances cover a broad and diverse application range with a large variety mode of actions. They are distributed over 56 chemical-therapeuticalpharmacological groups according the WHO-ATC system and are presented in table 1.
Table 1 Overview of registered PFAS-APIs with 1 or 2 CF2 groups are indicated by asterix, the other APIs contain
at least one CF3-group.
API
CASNR
ATC
alpelisib
1217486-61-7
L01XX
apalutamide
956104-40-8
L02BB
aprepitant
170729-80-3
A04AD
bendroflumethiazide
78-48-3
C03AA C03AB C03EA
benfluorex bicalutamide
cangrelor
23602-78-0 90357-06-5 163706-06-7
A10BX L02BB B01AC
celecoxib
169590-42-5
C08CA L01XX M01AH
cinacalcet delamanid desflurane dexfenfluramine doravirine
dutasteride
efavirenz eflornithine* elexacaftor enzalutamide fenfluramine
flecainide fluoxetine
flunixin fluphenazine
226256-56-0 681492-22-8 57041-67-5
3239-44-9 1338225-97-0
164656-23-9
154598-52-4 70052-12-9 2216712-66-0 915087-33-1
458-24-2 54143-55-4 54910-89-3 38677-85-9
69-23-8
H05BX J04AK N01AB A08AA J05AG G04CA G04CB J05AG D11AX R07AXa L02BB A08AA C01BC N06AB QM01AG N05AB
1 https://www.whocc.no/atc_ddd_index/
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API fluvoxamine fosaprepitant fosnetupitant fulvestrant gemcitabine* glecaprevir* isoflurane ivosidenib*
CASNR 54739-18-3 172673-20-0 1703748-89-3 129453-61-8 95058-81-4 1365970-03-1 26675-46-7 1448347-49-6
ATC N06AB A04ADb A04ADb L02BA L01BC J05AP N01AB L01XX
lansoprazole
103577-45-3
A02BC A02BD
ledipasvir* leflunomide letermovir lomitapide lumacaftor* maraviroc*
1256388-51-8 75706-12-6 917389-32-3 182431-12-5 936727-05-8 376348-65-1
J05AP L04AA J05AX C10AX R07AX J05AX
mefloquine
53230-10-7
P01BC P01BF
netupitant
290297-26-6
A04ADb
nilotinib nilutamide nitisinone
641571-10-0 63612-50-0 104206-65-7
L01XE L02BB A16AX
pantoprazole* penfluridol
102625-70-7 26864-56-2
A02BC A02BD
N05AG
perflutren
76-19-7
V08DA
ponatinib
943319-70-8
L01XE
pretomanid
187235-37-6
unknown
regorafenib
755037-03-7
L01XE
riluzole
1744-22-5
N07XX
roflumilast*
162401-32-3
R03DX
rolapitant
552292-08-7
A04AD
sevoflurane
28523-86-6
N01AB
silodosin
160970-54-7
G04CA
siponimod
1230487-00-9
L04AA
sitagliptin
486460-32-6
A10BH
sonidegib
956697-53-3
L01XX
sorafenib
284461-73-0
L01XE
tafluprost*
209860-87-7
S01EE
telotristat
1033805-22-9
A16AX
teriflunomide
163451-81-8
L04AA
tezacaftor*
1152311-62-0
R07AX
tipranavir
174484-41-4
J05AE
travoprost
157283-68-6
S01EE
trifluoperazine
117-89-5
N05AB
upadacitinib
1310726-60-3
L04AA
vinflunine*
162652-95-1
L01CA
voxilaprevir*
1535212-07-7
J05AP
a no ATC code available, based on similarity with tezacaftor and ivacaftor we tentatively assigned the code R07AX
b no ATC code available, based on similarity with aprepitant and rolapitant we tentatively assigns the code A04AD
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3. Tonnage band
Pharmaceutical prescriptions
Data on pharmaceutical prescriptions were collected from the Dutch GIP Databank.2 This databank amongst others shows a ranking of the top 500 pharmaceuticals in the Netherlands based on total number of DDD (daily defined dosage) delivered to patients in the years 2015-2019. This enables calculation of a mass (tonnage) of PFAS pharmaceuticals, using the following formula:
= 27 10-9
()
where:
DDD = daily defined dosage (#) dosage = typical mass of a DDD (mg) Population = total population in EU (#) 10-9 = conversion factor for mg to ton
Amounts of medicinal products used in the Netherlands (population 17,407,575 at 1-1-2020) have been extrapolated to the EU27 by correction for the population (447,706,200 at 1-1-2020)3. The typical dosage of one DDD was retrieved from the WHO ATC/DDD website4. Prescription of pharmaceuticals is registered by insurance companies in the Netherlands. Since health insurance is obligatory in the Netherlands, the data present a accurate view of prescribed medicinal products. Although, OTC5 medicinal products are not included, this will probably not largely influence the total tonnage since not many PFAS containing APIs are present in over the counter drugs.
The use of prescribed APIs with at least one CF2 or CF3 group in the EU in 2019 is, based on the above, estimated to be 400-500 tonnes per year and the use seems to increase with 3.4% per year. Therefore, we further report a use of >500 tonnes medical products per year. See figure 1. Please note that tonnages for medicinal products and intermediates are given based on the total molecular weight of the molecule, rather than on the fluorinated part of the molecule only.
2 Top 500 van geneesmiddelen o.b.v. het aantal DDD's in 2019 | GIPdatabank.nl 3 https://ec.europa.eu/eurostat/documents/2995521/11081093/3-10072020-AP-EN.pdf/d2f799bf-4412-05cc-a357-7b49b93615f1 4 WHOCC - ATC/DDD Index
5 OTC medicinal products: over the counter medicinal products
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Figure 1 Overview of estimated usage of PFAS used in medicinal products and the manufacturing thereof and their potential environmental dispersal. Midpoint of the uncertainty range in ton/y. See orange for medicinal products. Note: Medical devices are also mentioned a.o. for comparing with medicinal products (and intermediates).
PFAS non-polymers
Next to the above consultation & calculation a list of 80 PFAS non-polymers and their medical use is obtained from two sources:
1) The ECHA database 2) Response to the Call for evidence (summer 2020)
An overview of tonnages and number of non-polymers (excluding APIs) has been constructed (table 2). It shows that the ECHA database gives approximately 4 times higher tonnages than the Response to the Call for Evidence (CfE) in 2020. A possible explanation is that only a selection of companies has responded to the CfE and that companies have not recognized their use as a medical use. Also no response has been received with respect to pharmaceutical production, whereas in the ECHA data Pharmaceutical production there is a separate category with substantial amount of data.6
Table 2 Tonnage range (ton/year) of non-polymer PFAS based on two data-sources.
Data source #
All substances
Response CfE 36
(2020)
ECHA
11
Intermediates only
Response CfE 8
(2020)
ECHA
6
C1-C6 PFAS
range
midpoint
1,100 - 2,200
1,600
26,000 - 47,000 36,000
26 - 210
120
2,100 - 6,000
3,000
C7-C26 PFAS
# range
midpoint
17 610 -790
400
33 225 - 11,000
5,400
1 50
50
19 170 - 8,200
4,200
Total
# range 53 5,400 - 17,000 44 26,000 - 57,000 9 78 - 270 25 2,200 - 14,000
midpoint 11,000 42,000 170 8,200
Many non-polymer PFAS and their medical use are used for multiple purposes. One category is relatively unique and these are the intermediates, mostly for pharmaceutical products. The volumes of intermediates are reported separately.
6 The database was searched for PFAS substances via P29 (an ECHA code for Pharmaceutical industry) and any record from other production categories that contained "medical", "drug", "pharmaceutical" or "API".
7
Approximately 8,200 ton/y PFAS pharmaceutical intermediates have been calculated based on the ECHA data. This is much larger than the calculated volume of 400-500 ton human medicinal products per year that has been estimated earlier in this report.
Metered Dose Inhalers (MDI)
Metered-Dose Inhalers (MDIs), typically used for the treatment of asthma and other respiratory conditions, use hydrofluorocarbons as propellants. The volume of F-gases for metered dose inhalers has been estimated in four different ways:
1) Production based on stakeholder information; Based on communication with the trade organisation an amount of 5,000-6,000 ton propellants /year propellants is produced in the EU. This includes production for export.
2) Production based on ECHA database; Total F-gases in relation to metered dose inhalers is 15,000 to >30,000 ton/y
3) Use based on MDI sales; Based on average F-gas content and sold cannisters extrapolated to the EU, a volume of approximately 160 up to 1.8 million ton F-gases used on the EU market is estimated. The amount reflects the use by patients in the EU.
4) Use derivation from the report of Health Care Without Harm (HCWH 2019); As with anesthesia, global data on emissions from MDIs is not available, however, UNFCCC Annex 1 nations report data on emissions from this source. For UNFCCC Annex 1 nations, emissions from MDI use totaled 6.9Mt CO2 equivalents. The full global emissions from MDIs can be expected to be substantially greater than this figure (HCWH 2019). For the EU this equals approximately 400 ton F-gas propellants. The amount reflects the use by patients in the EU.
The emission factor of propellants by MDI use is set at 100% whereas the emission factor of propellants during production is much lower, probably < 10% (see ECHA's environmental release categories in Appendix 1, Table 5). The approaches for volume estimation are summarized in Table 3.
Table 3 Annual production, use and emissions of F-gases from metered dose inhalers in the European Union to the atmosphere. Worst case emission factors were used for a preliminary assessment of atmospheric release.
Volume
Emission factor
Atmospheric emissions
(ton/y)
Use
160-400
100%
160-400
4. Manufacturing & Market data
The use of prescribed PFAS-pharmaceuticals in the EU in 2019 is estimated to be > 500 tonnes per year and the use seems to increase with 3.4% per year (see figure 2). In table 3 the market data/tonnages of the main PFAS moieties containing APIs in the period 2015-2019 are displayed.
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Use of PFAS pharmaceuticals in EU
500
450
Pantoprazole (acid reflux)
400 Flecainid (elevated heart rate)
350
300
Celecoxib (pain, rheumatic arthritis)
Tonnes
250
Sitagliptine: diabetis type 2
200
Fluvoxamine (obsessive compulsive disorders) 150
100
Fluoxetine (major depressive disorders)
50
0 2015
2016
2017 year
2018
Efavirenz (HIV/aids) 2019 Other PFAS pharmaceuticals
Figure 2: Estimated trend in the use of PFAS-pharmaceuticals and their major field of application in the European Union. Note: Pantoprazole has a CF2-unit but formally is outside the chemical scope of the restriction preparation.
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Table 3: Total mass of main PFAS containing API 2015-2019.
ATC-code
2.015
2.016
A02BC02 C01BC04 M01AH01 A10BD07+A10BH01 N06AB08 N06AB03 J05AR06
S01EE04 L02BB03 S01EE05 A02BC03 H05BX01 L04AA13 G04CA04 N05AG03 L02BA03 L04AA31 N05AF01 G04CB02
Pantoprazol Flecainide Celecoxib Sitagliptine (sum) Fluvoxamine Fluoxetine Efavirenz (+emtricitabine+tenofovi sum others:
190,4 45,0 38,7 18,8 16,6 9,7 16,61 21,2
others:
Travoprost
7,0
Bicalutamide
5,1
Tafluprost
3,2
Lansoprazol
3,1
Cinacalcet
1,4
Leflunomide
0,7
Silodosine
0,3
Penfluridol
0,1
Fulvestrant
0,1
Teriflunomide
0,1
Flupentixol
0,1
Dutasteride
0,1
Total mass
378,1
218,0 44,7 38,5 18,4 16,1 9,9 13,97 21,0
6,9 4,8 3,2 3,0 1,5 0,8 0,3 0,1 0,1 0,1 0,1 0,1
401,4
Tonnage (EU)
2.017
2.018
235,9 44,2 38,3 18,4 15,6 9,9 11,34 20,6
255,6 43,2 39,0 19,3 15,3 10,4 9,94 20,2
2.019
278,6 42,7 39,2 22,0 14,9 10,7 8,49 19,8
Change (ton per year)
2.015
2.016
Percentage
2.017
2.018
2.019
Change % per year
21,4
68% 78% 85%
92% 100% 8%
-0,6
105% 105% 104%
101% 100% -1%
0,2
99% 98% 98%
100% 100% 0%
0,7
86% 83% 84%
88% 100% 3%
-0,4
111% 108% 104%
102% 100% -3%
0,3
91% 92% 93%
97% 100% 2%
-2,0
196% 165% 134%
117% 100% -24%
-0,4
107% 106% 104%
102% 100% -2%
6,6
6,2
5,9
-0,3
4,6
4,5
4,3
-0,2
3,1
3,1
3,1
0,0
2,8
2,7
2,6
-0,1
1,6
1,6
1,7
0,1
0,8
0,9
0,9
0,0
0,4
0,4
0,5
0,0
0,2
0,2
0,2
0,0
0,2
0,2
0,2
0,0
0,1
0,1
0,2
0,0
0,1
0,1
0,1
0,0
0,1
0,1
0,1
0,0
415,0
433,2
436,4
14,8
119% 119% 101% 118% 84% 79% 59% 41% 36% 32% 94% 117%
87%
117% 112% 103% 114% 92% 86% 71% 43% 45% 57% 96% 117%
92%
112% 109% 99% 109% 96% 90% 83% 65% 65% 74% 99% 106%
95%
106% 100% -5% 105% 100% -4% 99% 100% -1% 104% 100% -5% 98% 100% 4% 94% 100% 5% 91% 100% 10% 92% 100% 17% 85% 100% 17% 87% 100% 16% 98% 100% 1% 102% 100% -5%
99% 100% 3%
No. of production sites: 79 companies indicated in the Call for Evidence (2020) that they produce, import or distribute PFAS substances for medicines. Most likely the actual number may be much higher.
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5. Emissions
Emission factors used were, in general, 90% for pharmaceuticals, propellants, anesthetics and contrast media used by patients (consumers) or physicians. A factor of 10% for non-polymer PFAS in industrial processes (heat transfer agents, specialty cleaners, formulation and processing aids, intermediates and end-products) was applied. This range finding approach could be refined for individual substances or substances group using EUSES environmental release categories7 and OECD emissions scenarios.
Table 4: Overview of PFAS volumes in the medical sector (both medicinal products and medical devices) and provisional estimation of their potential dispersal. H(igh)= dispersal to water, air or soil through PFAS excretion by humans or animals; M(edium) = PFAS may be disposed of as waste, recovered after the production processes or treated in industrial waste treatment plants; L(ow)= PFAS in products that are collected as waste.
non-polymers
Use
ton/year 27,000-58,000
source approx. 160
volume distribution over molecular size (based on midpoint of uncertainty range)
C1-C6 C7-C25 >C25 total
dispersal potential
Medicinal products (use)
human
>500
68
veterinary
unknown
3
anesthetics (use)
2-1000*
5
contrast media (use)
2-100
1
propellants (use)
160-400**
3
>500 M
500 50 280
High (90-100%) >1,300 ton/y
intermediates
2,200-14,000
27
Industrial processes
24,000-43,000
54
including
F-gases production
polymers
3,700-14,000
4,000 32,000
4,200 1,200
8,900
Medium (10%)
4,200 ton/y
Low (1%) 90 t/y
Total
31,000-71,000
37,000 >5,900 8,900
71%
12%
17%
*: Might be an overestimation as HCWH 2019 is looking broader than needed here
**: Might be an underestimation as Dutch (extrapolated) data will lead to roughly doubling of the range.
52,000
5,600
6. Exposure
Although the medicines may be beneficial for patients with certain diseases, the exposure of nontarget individuals and ecosystems may lead to negative side-effects. Medicines are excreted unchanged or as metabolites in hours to days after they have entered the body. The fluorinated parts of the molecules are likely conserved in the excreta. Depending on the chemical properties of the medicines they end up in air or in sewage system.
No further information was available.
7 What is Environmental Release Category (ERC) and How It is Used for Environmental Risk Assessment (chemsafetypro.com)
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7. General discussion on emission and exposure
Reported volumes are compared with estimations that we have based on statistics from other sources and databases (for instance EMA, WHO, Eurostat and ECHA). In the ECHA database there is information about non-polymers only, so for polymer volumes we used information from the Call for Evidence (CfE). Depending on the chemical properties of the medicinal products they end up in air or in sewage systems. Persistent medicinal products will ultimately reach the surface water system, which has already been demonstrated for several medicinal products. Veterinary medicinal products will also reach the soil, through spreading of manure.
8. Alternatives
For medicinal products non-PFAS alternatives are available. It is outside the scope of this document to go into detail about actual alternatives.
9. Economic impacts in case of a full PFAS ban
No information has been provided.
10 Methods used & uncertainties
Data research was mainly based on Call for Evidence information (2020)., literature and (extrapolated) insurance data from the Netherlands. Uncertainties of the volume estimates are considerable, therefore midpoint estimations have been given.
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References
HCWH (2019). Health care's climate footprint. How the health sector contributes to the global climate crisis and opporrtunities for action: 48
Inoue, M., Y. Sumii and N. Shibata (2020). "Contribution of organofluorine compunds to pharmaceuticals." ACS Omega 5: 10633-10640.
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Annex
For the medicines (human), medicines (veterinary) and pharmaceutical intermediates, tonnages, market trend and emissions are presented below.
Sub-use
Medicines (human medicinal products)
Tonnage PFAS/y in EEA
> 500**
Expected tonnage trend (--/-/0/+/++)*
+
Emission/y EEA (tonnes PFAS)
>500**
Medicines
No data
No data
(veterinary medicinal
products)
Pharmaceutical**
8,200 (ECHA)
No data
intermediates
*--=strong decrease, -=decrease, +-=increase, ++=strong increase, 0=neutral
**: Molecular weight of API is used in this calculation, not the fluorinated part only
No data No data
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