An exploratory study on fluorine-containing compounds and
their environmental risk
Literature Thesis
Msc Chemistry: Science for Energy and Sustainability
by
Rhea Lambregts
UvA: 10734996 VU: 2563935Examiner: Prof. Dr. Jacob de Boer Second Examiner: Dr. Sicco Brandsma
Abstract
In the past, several fluorine-containing compounds have caused significant environmental issues. For example, chlorofluorocarbons contributed to the depletion of the ozone layer and per-and polyfluorinated substances (PFAS), especially perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), have recently been shown to be highly persistent, bioaccumulative and toxic (PBT). In this review, fluorine-containing substances that are not categorized as PFAS or (chloro)fluorocarbons are considered. Their environmental risk is established based on the level of exposure, toxicity, persistence and the potential to bioaccumulate. Fluorinated polycyclic aromatic hydrocarbons, dyes and pigments, polymers and liquid crystals were found to have PBT properties, but their environmental concentration is unknown. Due to stricter regulations on agrochemicals and pharmaceuticals, their production or sales are known. Often, they were found to possess an environmental risk. However, after these findings, no measures were taken by authorities. In the case of firefighting foams, PFOS was replaced by substances that posed a similar risk to the environment and were insufficiently regulated. Therefore, an environmental risk assessment of all fluorine-containing substances before they are put on the market is recommended. Also, regulations can be applied to reduce the exposure of substances with a possible environmental risk.
2 Table of Contents
1. Introduction ... 3
2. Environmental Risk Assessment... 5
3. Per- and Polyfluorinated Substances ... 6
4. Aromatics ... 7
4.1 Polycyclic aromatic hydrocarbons ... 7
4.2 Dyes and Pigments ... 8
5. Pharmaceuticals ... 11 5.1 Anaesthetics ... 11 5.2 Other pharmaceuticals ... 12 6. Agrochemicals ... 14 7. Materials ... 15 7.1 Polymers ... 15 7.2 Liquid crystals ... 17 8. Other Applications ... 18 8.1 Firefighting foams ... 18 8.2 Nuclear applications ... 19
9. Conclusions and Outlook ... 19
Appendix A: Fluorinated pharmaceuticals including their risk ... 21
Appendix B: Fluorinated agrochemicals including their risk ... 22
Appendix C: Commercially available fluorinated polymers classified as PFAS ... 23
Appendix D: Commercially available non-PFAS fluorinated polymers ... 24
3
1. Introduction
The field of fluorine chemistry started with the isolation of elemental fluorine in 1886 by Moissan.1 Fluorine is the most electronegative atom in the periodic table, creating strong bonds with other atoms.2 This gives rise to unique properties, such as high thermal and oxidative stability. Increasing the amount of fluorine atoms to a carbon atom increases the stability and decreases the reactivity of the compound.3 Since fluorine is such a small atom, it can easily be incorporated into the compound without completely changing the atomic structure.4 Consequently, fluorine became essential in modern life and fluorine-containing compounds are widely used in different industries, ranging from electronics to pharmaceuticals.5 However, due to the stability of the fluorine-containing compounds, they tend to be more persistent in the environment and bioaccumulate in the food chain.3
In the past, several fluorine-containing substances have been known to be harmful to the environment. For example, chlorofluorocarbons (CFCs), methane or ethane-based hydrocarbons in which all hydrogen atoms are replaced by chloride or fluorine atoms. Examples are given in Figure 1.6 These substances were discovered around 1930 and have excellent energy efficiencies, are very stable, non-toxic and non-flammable.2 This made them suitable for a wide range
of refrigerant applications, such as aerosols and blowing agents.7 Nevertheless, in the early 1970s, the CFCs were studied for their possible contribution to the ozone depletion.8 Due to the stability of the compounds, CFCs end up in the stratosphere where they are degraded by UV-radiation. Chloride radicals are formed that react with ozone, causing the ozone depletion. In 1987, the Montreal Protocol came into effect to phase out CFCs.7,9 During the phase-out, alternatives to CFCs were introduced, such as hydrofluorocarbons (HFCs). These compounds contain no chloride but only hydrogen and fluoride. Unfortunately, HFCs have a large global warming potential, for example HFC-23 has a global warming potential of 12,000 CO2 equivalents.10 Therefore, the phase-out of these substances has started.6
Figure 1: Chemical Representation of some well-known CFCs
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Another example of fluorine-containing compounds that pose a risk for the environment are per-and-poly fluorinated substances (PFAS). These are carbon chains which are fully fluorinated (per) or partially fluorinated (poly), but contain at least one perfluoroalkyl moiety (-CnF2n-).11 They have been used in industry for their water and grease repulsion, chemical stability and heat resistance.12 Besides these properties, they are also known for their persistency and potential to bioaccumulate in the environment and human body.13 They have been found in different environmental matrices, including water, air, sediment and organisms. Researchers have found a variety of health issues arising upon exposure to PFAS and even low doses of PFAS can cause long-term health issues.12 PFAS are produced since the 1940s and had an exponential growth in the 1950s and 1960s.12 The main industrial fabricated PFAS were perfluorooctane sulfonate
(PFOS) and perfluorooctanoic acid (PFOA), see Figure 2. In 2009, PFOS was added to the list of Persistent Organic Pollutants in the Stockholm Convention, due to the persistent, bioaccumulative and toxic (PBT) properties of the chemical, restricting the use and manufacturing of PFOS.14 The use of PFOA, on the other hand, was restricted in the European Union only in 2017.3,15 However,
due to the lack of regulations, many other PFAS or related compounds are still produced to substitute PFOS and PFOA.12 The substitutes are often compounds with a shorter chain length or with an oxygen atom in the carbon chain, which have a lower potential to bioaccumulate.16 However, they often possess the same persistency as the longer regulated PFAS.16
Since PFAS and CFCs have had a big impact on the environment and humans, it raises the question whether there are more fluorine-containing substances that might be harmful that cannot be categorized into PFAS or CFCs. In earlier research, industries in which fluorine plays a significant part have been identified.1,2,17 Additionally, some sectors have a clear overview of their fluorine-containing substances. However, these overviews often lack an environmental risk assessment of these substances.
In this study, first the parameters for a risk assessment are explained, such as toxicity, persistency and bioacummulation. Subsequently, different categories of fluorine-containing substances will be
Figure 2: Chemical structure of PFOS (top) and PFOA (bottom)
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evaluated. The categories considered in this overview are aromatic compounds, such as fluorinated polycyclic aromatic hydrocarbons (PAHs) and pigments, anaesthetics, pharmaceuticals, agrochemicals, polymers, liquid crystals and some smaller categories such as firefighting foams and compounds in the nuclear fuel cycle. For every category, the substances with the highest production volumes are evaluated for their potential risk.
2. Environmental Risk Assessment
To determine the risk of a chemical, the exposure and hazard of the chemical should be considered. The hazard of a chemical is described based on its toxicity. The exposure of chemicals is determined by its fate. The fate tells where the compound, after emission, migrates and ends up in the environment. It is based on the physical-chemical properties of the compound.18 The fate can be determined by the estimated net rate of degradation, transport and transfer processes.
In general, three factors are used to prioritize the contaminants in the environment: persistence (P), bioaccumulation (B) and toxicity (T).19 The REACH agreement has established the requirements for a substance to be classified P, B or T, which are applicable for the European Union.20 It should be noted that these requirements differ from those established by the United States.
Persistence, the time required to half the concentration in a certain medium, is often measured in half-life. A chemical is persistent if i) the half-life in water is greater than 60 days ii) the half-life in soil is greater than 180 days iii) the half-life of the chemical in sediment is greater than 180 days or iv) if other evidence is available that indicates the persistency of the chemical.18 Bioaccumulation is the potential of a chemical to accumulate in the food chain. A chemical is bioaccumulative if i) the bio-concentration factor in aquatic species is greater than 5,000 ii) the octanol-water partitioning coefficient Kow is larger than 5 iii) there is evidence that it presents other reasons for concern or iv) there is evidence in biota indicating the potential for bioaccumulation. A substance is toxic if i) the no observed effect concentration (NOEC) for marine and freshwater organisms is smaller than 0.01 mg/L ii) the substance is classified as carcinogenic (cat. 1 or 2), mutagenic (cat. 1 or 2) or toxic for reproduction (cat. 1, 2 or 3) or iii) there is other evidence of chronic toxicity.
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3. Per- and Polyfluorinated Substances
Per-and polyfluoroalkyl substances (PFAS) are defined as aliphatic substances for which at least one carbon atom all its hydrogen atoms are replaced by fluoride atoms. In other words, they contain at least one perfluoroalkyl moiety (-CnF2n-).21 They can be distinguished into three categories11:
1. Perfluoroalkyl, per-and polyfluoroalkyl acids (PFAAs)
This category contains perfluoroalkyl carboxcylic acids, perfluoroalkane sulfonic acids, perfluoroalkyl phosphonic acids, perfluoroalkyl phosphinic acids, per-and polyfluoroether carboxylic acids and per-and polyfluoroether sulfonic acids. The chemical formula of this group can be described as CnF(2n+1) or CnF(2n+1)OCmF2mA, with A as an acid group.
2.
PFAA precursorsThis category is based on the next two substances and their derivatives:
a. Perfluoroalkane sulfonyl fluorides CnF(2n+1)SO2F and its derivatives CnF(2n+1)SO2R with R ranging from non-polymers, as NH, NHCH2OH to fluorinated polymers as urethane.
b. Perfluoroalkyliodides CnF(2n+1)I, fluorotelomer iodides CnF(2n+1)CH2CH2I and its derivatives CnF(2n+1)CH2CH2R, with R ranging from non-polymers, as NH, NHCH2OH to fluorinated polymers as urethane.
3.
Other PFASThis category exists of fluoropolymers, such as polytetrafluoroethylene (PTFE), polyvinyl fluoride (PVF) and perfluoropolyethers, which can be described with the formula: HOCH2O2(CmF2mO)nCH2OH.
Besides these clearly defined categories there are other substances that are highly fluorinated and match the definition of PFAS, but are not regarded as PFAS.11 Examples of these substances are perfluorinated alkanes, perfluorinated alkenes, perfluroalkyl alchohols, perfluroalkyl ketones, semi-fluorinated ketones, side-chain fluorinated aromatics and hydrofluorocarbons. A full range of these, including their chemical formula can be be found in the report by Organisation for Economic Co-operation and Development.11
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4. Aromatics
4.1 Polycyclic aromatic hydrocarbons
Polycyclic aromatic hydrocarbons (PAHs) consist of two or more benzene rings fused together.22 They are naturally produced by plants, however, their anthropogenic sources are larger.23 PAHs are released by the production of petroleum products and from combustion processes, such as wood and textile combustion.24 PAHs are currently under investigation for their industrial use as an organic semiconductors.25,26
PAHs are hydrophobic and therefore, tend to sorb to soil and sediment particles, leading to smaller biodegradation rates.27 This is mainly the case for the larger PAHs that consist of four or more benzene rings. These larger PAHs are often linked to carcinogenicity and mutagenicity, while on the other hand the small PAHs are more linked to toxicity and low carcinogenicity.28 All in all, both the small and large PAHs possess a big risk for the environment.
Since 1980, halogenated PAHs (HPAHs) have been found in different environmental matrices, such as urban air, soil, snow and tap water.29 The found substances contained either chloride, bromide or chloride and bromide atoms.30 The HPAHs are often of concern due to their increased toxicity compared to their corresponding parent PAHs.31 Humans can be exposed to them through food, primarily vegetables. The European Food Safety Authority has even suggested to monitor PAHs in vegetables, due to their potential toxicity.31 However, the environmental behaviour of HPAHs is still not clear and more research is necessary.30
Until now, it is unknown whether there are fluorine PAHs (F-PAHs) occurring in the environment. In 2000, Luthe and Brinkman suggested that they are not present in the environment, since they are not produced naturally and their production amounts are insignificant.32 It is a possibility that the production amounts have changed since 2000, due to the developing fluorine industry, however, this is unclear. Nevertheless, the toxicity and carcinogenic potential of several F-PAHs have been examined. Fu et al. have investigated the possible carcinogenicity of eleven anthracene-based F-PAHs that were published in 1984.29 They
Figure 3: Chemical structure of two anthracene-based F-PAHs that are highly carcinogenic
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concluded that four of them are moderately carcinogenic, while 2 were found highly carcinogenic. These latter two are represented in Figure 3.
Although no study has indicated the persistency of F-PAHs, it can be assumed that they are persistent in the environment since most halogenated PAHs are persistent, similarly to their corresponding parent compounds. Furthermore, most of the halogenated PAHs are also bioaccumulative and toxic, which would also apply for F-PAHs. However, more research should determine the occurrence, the stability, health risk and environmental behaviour of F-PAHs.
4.2 Dyes and Pigments
Another class of aromatic compounds is dyes and pigments. These colour possessing chemicals have i) an absorption in the visible light region, ii) contain at least one chromophore, for example anthraquinone, azo or phathalocyanine, iii) have a conjugated system and iv) exhibit resonance of electrons.33 If one of these four is lacking, there is no colour present and the chemical is not considered a dye or pigment. In order to have useful dyes, they must be chemically and photolytically stable.34 Furthermore, most dyes are considered to be non-biodegradable, and therefore, persistent when released to the environment.35
Dyes and pigments can be categorized depending on either their chemical structure or their application, of which the
former will be used here. Matsui showed that fluorine-containing substances are present in some categories.36 In Figure 4, the key structures are given of the dye categories that can include fluorinated dyes. However, their commercial availability is unknown, and no public database exists, making a comprehensive analysis impossible. Here, the environmental impact of the categories, which have been suggested to contain fluorinated compounds are investigated.36 Afterwards, some examples of commercially available fluorinated dyes are listed.
The biggest category is azo dyes, making up 70% of all organic dyes produced and can be used for several applications, such as ink and cosmetics.34 Azo dyes consist of one, two, three or more
Figure 3: Dye categories based on chemical structure that can contain fluorine dyes
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-N=N- groups, which in general couples two aromatic compounds.37 Azo dyes are known to cause severe contamination in river and ground water close to dyeing factories.38 Most of the azo dyes
are not toxic, but their degradation products pose a risk.34 The degradation products often contain aromatic amines, such as benzidine, which are known to be toxic and carcinogenic.37 Aromatic amines are often persistent and have the potential to bioaccumulate.38 A list of 22 aromatic amines has been incorporated by the REACH agreement, banning dyes that can degrade into these aromatic amines.39
Anthraquinone dyes are the second most important class of dyes, with 15% of the dyes produced.40 These are based on 9,10-anthraquinone and by adding electron donating groups on position 1, 4, 5 or 8 a colour is introduced.41 Due to their fused aromatic structure, they are highly resistant to biodegradation and are thus very persistent in the environment.42 Some of the dyes are known to be toxic for aquatic organisms.42 Not much more information is available on the toxicity of anthraquinone dyes.43 However, they have a low potential for bioaccumulation,.44
Di-and triarylmethanes dyes belong to the class of polymethine dyes.41 They consist of a methane in which two or three hydrogen atoms have been replaced by an aryl ring. Gessener et al. gave an overview of important dyes and their toxicity.45 They concluded that most of the di-and triarylmethane dyes have a mutagenic and toxic potential. However, none of these suggested dyes contained a fluorine atom, and thus more dyes should be investigated to check if F-containing species exist. Furthermore, these dyes are expected to be persistent in the environment, but do not have the potential to bioaccumulate.35
Coumarin dyes is a category that contains dyes with a fused pyrone and benzene ring.46 The substance coumarin is naturally produced and can be categorized as a secondary metabolite.47 It has been suggested to be nontoxic for humans, and only carcinogenic above a certain threshold.48 The coumarin dyes, on the other hand, are not studied thoroughly and the toxicity, bioaccumulation and occurrence is unknown. However, it is known that they have a low solubility and are photochemically instable in water, suggesting a low persistency.49
Also, the environmental risk of fluorinated cyanine dyes is unknown due to the lack of research into the topic. Cyanine dyes contain two nitrogen atoms bound together by a polymethide chain.50 Their commercial use is limited, and they are shown to be nontoxic.51,52 Some cyanine dyes even
10
have the possibility to be anti-tumour agents, since they have the potential to accumulate in tumour cells. Some fluorine-containing dyes that are commercially available are listed in Table 1, including their substance category. The risk of these dyes is unknown.
Table 1: Commercially available dyes and their structure category
Trade name Structure category Pigment 154 Azo
Pigment orange 60 Azo Acid red 266 Azo Reactive red 147 Azo
Vat blue 21 Anthraquinone Vat blue 30 Anthraquinone Coumarin 152 Coumarin Coumarin 153 Coumarin
Another way to incorporate fluorine into dyes, is through a reactive fragment. It can be used to covalently bind a chromophore to the fibre and has the advantage that this binding can happen at lower temperatures.41 Also, the reactive fragment can be changed to increase or decrease the reactivity with the fibre, without altering the dye itself. To change the reactivity often a halogen is added. Three reactive fragments that contain fluorine atoms are commercially used, they are listed in Table 2, including their risk. These fragments are not persistent and bioaccumulative, however, they can have the potential to be toxic for organisms.
Table 2: Commercially available fluorine containing reactive fragments that are used in reactive dyes.
Ciba-geigy is known as Novartis, Bayer as Dystar and Sandoz as Clariant.5354
Reactive fragment Trade name55,56 Company Environmental Risk
2,4,6-trifluoro-5-chloropyrimidine Dimarene K/F Levafix E-A Verofix Sandoz Bayer Bayer Potentially carcinogenic
Not persistent or bioaccumulative 2,4-difluoro-5-chloro-
6-methylpyrimidine
Levafix PN Bayer Not persistent or bioaccumulative 2,4,6-trifluoro-s- Triazine Cibacron F Levafix EN Ciba-geigy Bayer Toxic
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In summary, it can be concluded that there is no adequate overview of fluorinated dyes, making an environmental risk assessment difficult. However, a brief environmental risk assessment is carried out for the categories that are said to contain fluorinated dyes. It showed that azo dyes pose the largest environmental risk, followed by anthraquinone and di-and triarylmethyl dyes. Coumarin and cyanine dyes have little potential to pose an environmental risk. Nevertheless, it should be borne in mind that the dyes within the categories vary widely and that the number of fluorine containing dyes is unknown within these categories. Therefore, an overview of all the commercially available fluorinated dyes should be made first, after which a more comprehensive environmental risk assessment can be carried out.
5. Pharmaceuticals
5.1 Anaesthetics
Fluorinated anaesthetics are non-flammable gasses and are therefore often more safe then nonfluorinated anaesthetics.57 Furthermore, they have low blood-gas partition coefficients and they have a relatively low metabolizing rate due to the strong C-F bond.2,57 The first fluorinated anaesthetic was synthesized in 1953 and called fluoroxene.2 It was banned from the market after 1974, because one of the metabolites was found to be toxic.58 Afterwards, several other
fluorinated anaesthetics were introduced. In 2015, the major fluorinated anaesthetics were: desflurane, enflurane, halothane, isoflurane and sevoflurane.57 They are shown in Figure 5. Desflurane and sevoflurane are fluorinated hydrocarbons, while enflurane, halothane and isoflurane are chlorofluorocarbons.59 These latter three are not included in the Montreal Protocol, since it is assumed that they only have a small contribution to ozone depletion compared to other anaesthetics, such as N2O.60 Furthermore, it is known that the degradation products of the anaesthetics are often toxic for the liver. This is the biggest problem for halothane, causing a restriction of the use in certain countries.58 However, the complete toxicity effects of the
Figure 5: The major fluorinated anaesthetics used in 2015
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degradation products on patients is not clearly studied, despite their worldwide use.57 Besides the toxicity concerns, the fluorinated anaesthetics are greenhouse gasses.57 In 2014, they have caused a release of 3 million tonnes CO2 equivalents, of which roughly 80% is caused by desflurane.60 All in all, it can be concluded that the fluorinated anaesthetics have a high potential to form a risk for the environment.
5.2 Other pharmaceuticals
After the replacement of a hydrogen atom with fluorine in hydrocortisone, around 1950, the more potent fludrocortisone was synthesized.4 This has led to an increase in the interest in using fluorine in the pharmaceutical industry. From 1980s, many fluorinated pharmaceuticals were introduced into the market, probably due to the development in synthetic routes.4 Nowadays, it has been estimated that roughly 15% of the pharmaceuticals introduced in the market contain at least one fluorine atom.4 Also, the replacement of a hydrogen atom by fluorine is a common strategy in drug development.61
Incorporating fluorine atoms into natural products can completely change the biological properties of the product, while it only causes modest changes in molecular size and shape.4,62 An important feature of fluorine is the increased lipid solubility, which increases absorption and transport through the body.63 Furthermore, reactivity and stability can be increased due to the electronegativity and the strong bond. However, incorporating fluorine into drugs can also increase the toxicity of the substance and its metabolites.4
Potential side effects of pharmaceuticals are relatively well tested on human health, while the impact on the environment and non-target organisms is not tested regularly.64 In order to establish the risk of the fluorinated pharmaceuticals, a list of 200 pharmaceuticals, containing 28 fluorinated ones, with the highest retail sales in the USA in 2019 was evaluated.65 Since the sales are considered, it tells us that it is probable that the production volumes are relatively high, and therefore their usage, increasing their potential risk for the environment.
The list of 2019 contains older and new pharmaceuticals. In general, pharmaceuticals approved after 2006 undergo an environmental risk assessment (ERA), but exceptions are made.64 One reason is that the predicted environmental concentration is low and, therefore, not posing a risk. If an ERA was performed and the substance was found to pose a risk to the environment, the
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authorities have never banned it from being put in the market.64 Furthermore, since the pharmaceuticals are relatively new, they are not well investigated by other studies. Substances that have been approved for a longer time than the implementation of ERA procedures, have often not been intensively studied by authorities for a potential environmental risk.66
In Table 3, the fluorinated pharmaceuticals of the top 200 highest sales in the USA in 2019 are listed that have the potential to possess an ecological risk. Other fluorinated pharmaceuticals (atorvastatin, ciprofloxacin, fluconazol and fluoxetine) are added to the list since they used to have high production amounts and are often detected in waste streams.66 A list of all the fluorinated pharmaceuticals including their risk is presented in Appendix A.
Overall, it can be concluded that often the persistence and toxicity of the pharmaceuticals are not evaluated, due an estimated low risk. Also, often there is no qualitative data provided to prove the statements made by the ESA. However, it can be concluded that several fluorinated pharmaceuticals pose a risk to the environment. Sorafenib poses the biggest risk, since it is persistent, bioaccumulative and toxic. Regulations should be fortified to decrease the exposure levels in the environment and the replacement of sorafenib should be investigated.
Table 3: Evaluated pharmaceuticals that pose an environmental risk Pharmaceutical Persistence* Bioaccumulation*
(Log Kow)
Toxicity* PBT
Atorvastatin*** Not evaluated
Potentially persistent67
6.6** Not evaluated PB
Ciprofloxacin*** Persistent, but more research necessary68
0.28** Toxic68 PT
Fluconazol*** Potentially persistent69 0.5** Potentially
toxic69
PT Fluoxetine Relatively persistent70 4.05** Potentially
toxic70
PT
Fulvestrant 23 to 29 days 7.67 Toxic BT
Riociguat Longer than 100 days 2.3-2.4 Toxic PT
Sorafenib 187 days 3.7
BCF of 7250
Toxic PBT
* If no source is given, data is based on risk assessment reports of ESA ** Data obtained from drugs bank and NCBI
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6. Agrochemicals
Since incorporating a fluorine atom into a molecule can enhance the biological activity of it, this has also been of interest for the agro industry. The use of fluorinated agrochemicals has led to improved efficiency, with less material and often less impact on the environment.71 This caused an enormous increase in the number of fluorinated agrochemicals in the last decades. Several authors have reviewed the fluorine-containing agrochemicals, for example Dolbier et al.2 However, their environmental risk is often not evaluated.
Every year, the Netherlands Bureau of Statistics (CBS) publishes the volumes of production and usage of agrochemicals in the Netherlands. The fluorinated agrochemicals have been evaluated from the list of 2018, with a production more than 5,000 kg/year. The substances that have two of the three criteria to be persistent, bioaccumulative and toxic (PBT) are listed in Table 4, the full list can be seen in Appendix B. The analysis is based on the data from the European Food and Security Agency (EFSA), including qualitative measures for the persistency and bioaccumulation. The toxicity of the compounds stated by the EFSA is often not comparable with the regulations of the PBT characteristics enclosed in the REACH agreement. Furthermore, it should be considered that, due to the smaller size of the country, the agrochemical sector of the Netherlands is relatively small compared to the other countries in the European Union.72
Table 4: Fluorinated agrochemicals, with a production larger than 5,000 kg/year, that pose an
environmental risk, based on production and usage in the Netherlands in 2018. Information based on pesticide risk assessments form the European Food and Security Agency (EFSA)
Agrochemical Persistence (DT50 in
soil)
Bioaccumulation (Log Kow)
Toxicity PBT
Benfluralin 31.7 to 198 days 5.19 at pH 8 Toxic to aquatic organisms PBT Epoxiconazole 98 to 694 days 3.3 at 25°C Toxic, reproduction cat 3. PT Fluopicolide 196 to 413 days 2.9 at pH 7 and
20°C
Very toxic to aquatic organisms
PT Fluxapyroxad 89.3 to 696 days 3.08 at 20°C Very toxic to aquatic
organisms
PT Pyridalyl 53 to 272 days 8.1 at 20°C High risk to aquatic
organisms
PBT
It can be concluded that there is a lot of information on the usage of agrochemicals and their environmental risk in the Netherlands. However, agrochemicals that possess an environmental risk, such as benfluralin and pyridalyl, are still being used. Therefore, more strict regulations on these substances must be enacted.
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7. Materials
7.1 Polymers
If a polymer contains a perfluoroalkyl moiety (-CnF2n-) it can be classified into PFAS according to the definitions given by OECD (see Chapter 3).73 However, they are often overlooked, since they were only globally recognized as PFAS in 2018.21 Fluorinated polymers have unique properties compared to their non-fluorinated analogues. They are more resistant to high temperatures and have improved mechanical, optical and physical properties.74 Also, they are non-flammable, making them useful for many applications.75 In Appendix C the commercially available fluorinated polymers that are classified PFAS are listed, including their monomers and their sales numbers.76 These substances are found to be persistent, but not toxic or bioaccumulative, giving rise to the suggestion by Henry et al. that they should not be considered PFAS due to their low environmental risk.20
Originally, fluorinated polymers were produced with the use of ammonium salts of PFOA and PFOS.76 This created a waste stream containing PFOA and PFOS. This process was re-evaluated after the phase-out of these two chemicals. Several manufacturers have found replacement substances to produce the fluorinated polymers, examples are ADONA and APFDO, which can be seen in Figure 6. These substances are also considered to be PFAS. ADONA was found to be less toxic and persistent compared to PFOA.77 However, it has already been detected in a variety of environmental samples and in the plasma of blood donors.78 Therefore,
replacement substances, which are not considered PFAS, should still be investigated. Also, the research into the PBT properties of these molecules should be expanded, since the findings were preliminary, without any quantitative values given.
Besides the polymers listed in Appendix C other fluoropolymers exists that are not considered PFAS, for example because they consist of aromatic monomers. One example is the polymer Flare, which was commercially available from AlliedSignal Inc. (now Honeywell) and which was based on decafluorbiphenyl.79 After improvements of the polymer, the fluorine atoms were discarded, leading to a fluorine-free polymer.80
Figure 6: Chemical structure of ADONA and APFDO, which are replacements for PFOS and PFOA
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An available polymer database is used to establish whether there are other commercially available fluorinated polymers besides Flare.81 A list of these is shown in Appendix D. Unfortunately, their production volumes are unknown and no environmental risk assessment has been carried out for these polymers. By considering the individual fluorinated monomers, an estimated risk could be given to the polymers. However, also no environmental risk assessment has been done for the monomers. The only available information is on the toxicity of these monomers, which are shown in Table 5 including the production volumes in the EU.
Table 5: Monomers of commercially available fluorinated polymers, including their toxicity and
production volumes. Data from ECHA substance information if not otherwise indicated.
Monomer Toxicity Production and import
volumes in the EU (tonnes per year)
6FDA (hexafluoroispropylidene diphthalic anhydride)*
Harmful to humans Unknown mPDA (m-Phenylenediamine) Toxic for humans, very
toxic to aquatic organisms
10,000 to 100,000 pPDA (p-Phenylenediamine) Toxic for humans, very
toxic to aquatic organisms
10,000 to 100,000 Durene
(1,2,4,5-Tetramethylbenzene)
Harmful to aquatic life Unknown ODA (4,4-Oxydianiline) Very toxic to aquatic life 10 to 100 4BDAF
(2,2Bis[4-(4-aminophenoxy)phenyl] hexafluoropropane)
Harmful to humans82 Unknown
BTDA (3,3’,4,4’-benzophenone Tetracarboxylic dianhydride)
Harmful to aquatic life 100 to 1,000 PMDA (pyromellitic dianhydride) Toxic for aquatic life, might
be harmful to humans
100 to 1,000 Bisphenol AF Very toxic to aquatic life,
might be harmful to humans
100 to 1,000
4-Fluorostyrene No hazards classified Unknown
Vinyl fluoride No hazards classified 10,000 to 100,000 TFPMS (tetrafluoro propyl
methylsiloxane)
No data Unknown
* The 6FDA monomers are known to have high production costs. It is unclear whether these are still commercially available.83
In addition to the toxicity, the bioaccumulation and persistency of the compounds must be considered. In general, polymers are very persistent in the environment.84 Also, accumulation of smaller polymer chains in animals occurs. However, the level of bioaccumulation and persistency depends on the length and weight of the polymer. It can be concluded that fluorinated polymers
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are persistent, most of them are harmful or toxic for living beings, and that the smaller chains have the potential to bioaccumulate. The largest environmental risk is for the fluorinated polymers that contain the monomers mPDa, pPDA, ODA, PMDA or Bipshenol AF, due to their toxicity. However, more research is necessary to support this. Also, the translation from the monomers to the polymers should be investigated.
7.2 Liquid crystals
Liquid crystal displays (LCD) are the predominant display technology.85 Fluorine is an essential component in most liquid crystalline materials that are used in LCD devices.85 A liquid crystal can be defined as a state in which it is fluid, but still containing a crystalline ordering.86 Many liquid crystalline substances have a strong dipole moment, easy polarizable groups and they often contain conjugated segments.87 By incorporating a fluorine atom, the reliability of LCD devices is enhanced.85 The fluorine atom can be incorporated into the liquid crystal in different ways: thermal position, fluorinated chain as terminal chain, as linking group or as lateral position.86
A study from 2019 by Su et al. considered the persistence, bioaccumulative and toxic properties of liquid crystals commonly used in LCD devices.88 From the 362 materials, 87 were identified as persistent and bioaccumulative, while 10 were identified as very persistent and very bioaccumulative. A full list of substances can be found in the paper by Su et al.88 They identified 33 substances in mobile phone displays, which all have the potential to bioaccumulate in the environment after release. From these 33 substances, 26 contained a fluorine atom, which emphasizes the environmental risk a fluorine atom can bring to a substance. Lastly, they considered the possible toxicity of the liquid crystals. They found that the toxicity possessed was often the same as to dioxin-like compounds and flame retardants. From this it can clearly be stated that fluorine containing liquid crystals are often persistent and bioaccumulative and have the potential to be toxic. Therefore, more research into fluorine containing liquid crystals is necessary. This should include the making an overview of all substances, determining the PBT characteristics and the environmental occurrence of them. If it is found that these substances have a high environmental risk, replacement substances should be investigated, and the use and fabrication of fluorinated liquid crystals must be restricted rather sooner than later.
18
8. Other Applications
8.1 Firefighting foams
Aqueous film forming foams (AFFF) are effective to extinguish liquid fuel fires.89 A key ingredient of AFFF is perfluorooctane sulfonate (PFOS), shown in Figure 2. PFOS is a perfluoronated eight-carbon substance and a well-known PFAS. It is toxic to organisms and can accumulate in blood of animals and humans.89 Due to this, the manufacturing and use of PFOS has been banned in many countries.
PFOS can be replaced by either non-fluorine containing surfactants or novel fluorosurfactants. Several non-fluorine containing foams have been introduced to the market. However, they often do not have such an excellent performance as PFOS.90 Additionally, the active substance is often not disclosed, so it cannot be excluded that fluorine is still present and environmental properties are of concern.89,91 Furthermore, the impact of these substances and their degradation products on the environment is not well studied, and asks for a better environmental risk assessment.
The novel fluoro-surfactants often consist of a mixture of different PFAS. Six-carbon substances are mostly used, but smaller chain lengths have also been observed.92 The environmental impact of these is often unknown, but is suggested to be less than the longer chain length PFOS materials.89,91 However, this is doubtful, as, for example, fluorotelomercaptoalkylamido sulfonate (FTSAS) and 6:2 fluorotelomer sulfonamide alkylbetaine (FTAB) are known to be precursors of persistent end products, just like the longer-chain PFOS molecules.66,93 Also, the shorter chain compounds have a better water solubility. The bioaccumulation of these compounds is less but the concentrations in surface water are then more serious. This can create a drinking water contamination problem, as removal of PFAS from water is difficult.
Another substance that has been used to replace PFOS is sodium p-perfluorous noneoxybenzene sulfonate, shown in Figure 6.94 It has been estimated to be produced with 3500t per year in China and can be categorized into PFAS with an aromatic moiety. OBS is likely to be toxic and persistent in the environment. However, this substance lacks further research. From this, it can be concluded that the novel fluoro-surfactants are often also PFAS.
Figure 4: Chemical structure of sodium p-perfluorous noneoxcybenzene sulfonate
19
They are also persistent, and toxic just as PFOS, which was originally used. Bioaccumulation maybe less but the water solubility and mobility are often higher. However, also for this category, more research is necessary.
8.2 Nuclear applications
Uranium hexafluoride UF6 is a key element in the nuclear industry.95,96 Uranium ores are mined and milled to form U3O8, also known as yellow cake. This contains roughly 0.71% of 235U and 99.28% of 238U. 235U is the isotope that releases energy during fission and for nuclear power reactors a 235U percentage of 3 to 5 is required. Therefore, uranium enrichment is necessary. To do so, U3O8 must first be converted into UO2(NO3)2 with HNO3. Then UO3 is synthesized and reduced into UO2. This can then be converted into UF4 (s) with the use of hydrofluoric acid (HF). Lastly, UF4 is fluorinated with fluorine gas to UF6 (g). Afterwards the uranium enrichment can take place using either gas diffusion or gas centrifugation, both based on the physical property differences between 235UF6 and 238UF6. After enrichment of UF6 it can be stored as UF6, U3O8 or converted into pallets of UO2. These pallets can then be used for fission of the 235U atoms, generating heat and eventually electricity.
One of the waste streams is the depleted UF6. In 2010, it was estimated to be roughly 700,000 tonnes for only the United States.97 In general, during processing and storage no acute risk is considered with UF6.98 However, when it is released into the air, it rapidly reacts to form UO2F2 and HF. HF is a corrosive gas that in even small amounts could lead to irreversible damage and even death.99
Also, UF4 could potentially leak into the environment. When this compound is inhaled or ingested, it enters the bloodstream.98 Which, due to its potential radioactivity, could lead to an increased risk to cancer. From this it can be concluded that the fluorine containing substances that are released into the air are potentially toxic. However, the probability of these compounds to be released into the environment is relatively small.
9. Conclusions and Outlook
To conclude, fluorinated polycyclic aromatic hydrocarbons are PBT substances, but their environmental concentration is seemingly low and therefore their environmental risk is low.
20
Furthermore, there is no comprehensive overview of fluorine-containing dyes and their production volumes, but it can be concluded that if fluorine-containing azo dyes, which make up the largest category of dyes, occur in the environment that they would pose an environmental risk. This is due to the degradation into aromatic amines that are persistent, bioaccumulative and toxic. The production volumes of fluorine-containing agrochemicals and pharmaceuticals are known since they are regulated. Also, they often undergo an environmental risk assessment. Some fluorinated pharmaceuticals and agrochemicals clearly pose a risk to the environment, such as sorafenib and benfluralin. Authorities have often been late in taking measures against those substances. Polymers and liquid crystals on the other hand are not strictly regulated and no environmental risks assessment has been carried out. Studies on polymers suggested that the PFAS polymers are persistent, but are not toxic or bioaccumulative. Non-PFAS fluorinated polymers are not well studied, and no clear risk could be established beside the toxicity of the monomers. Fluorinated liquid crystals have recently been studied, and some were found to be persistent, bioaccumulative and potentially toxic.
For further research, it is important to fill the gaps in the environmental risk assessment of the fluorine chemistries evaluated here. This includes the identification of exact substances, their environmental concentrations and PBT properties. When a substance is found to be persistent, bioaccumulative and toxic it should either not be put on or banned from on the market or banned, or it should only be allowed in small amounts for essential use when no good substitute is available. If an environmental risk assessment is not carried out for a substance, the production volumes should stay low, until an assessment has been carried out, and the risk is clear. This will decrease the environmental risk of these substances. For the categories evaluated here, this would mean that it is necessary to ban or lower the production of at least the pharmaceutical sorafenib, the agrochemicals benfluralin and pyridalyl, the polymers based on bipshenol AF, mPDA, mPDA, ODA and PMDA. For liquid crystals this would mean that fluorinated substances should not be used in any LCD devices. Furthermore, other categories, with high production volumes can be investigated, such as fluorinating agents.
21
Appendix A: Fluorinated pharmaceuticals including their risk
Pharmaceutical Persistence (DT50 in
soil) *
Bioaccumulation* (Log Kow)
Toxicity* PBT
Afoxolaner No data No data Insignificant exposure
Atorvastatin*** Not evaluated
Potentially persistent67
6.36** Not evaluated PB
Bictegravir 96.5 to 911 days 2.2 Not toxic P
Canagliflozin Not persistent 3.44** Not toxic
Ciprofloxacin*** Persistent, but more research necessary68
0.28** Toxic68 PT
Dabrafenib 162 to 307 days in water 3.3 Not toxic P
Dolutegravir Not biodegradable -2.45 Not toxic P
Elvitegravir Longer than 100 days 3.4-4.3 Not overtly toxic P
Emtricitabine 81 to 209 days -0.7 Not toxic P
Fluconazol*** Potentially persistent69 0.5** Potentially toxic69 PT
Fluticasone furoate 3% biodegradation in 64 days
2.61 Not toxic, but no data provided
P Fluticasone
propionate
Not evaluated 2.78** Not evaluated
Fluoxetine Relatively persistent70 4.05** Potentially toxic70 PT
Fulvestrant 23 to 29 days 7.67 Toxic BT
Glecaprevir Study not finished 3.95-3.26** Study not finished
Lansoprazole*** Likely to be persistent100 2.8-3.0** Insufficient data100 P
Nilotinib Not evaluated 4.5-5.4** Not evaluated
Olaparib Not evaluated 2.0-2.7** Not evaluated
Paliperidone palmitate
Not evaluated 1.8** Not evaluated
Pibrentasvir Study not finished > 3 6.0-7.6**
Study not finished
Raltegravir 180 days 0.45 Not toxic P
Riociguat Longer than 100 days 2.3-2.4 Toxic PT
Rosuvastatin Not persistent 0.13** No data
Sitagliptin 15 to 56 days -0.03 Not toxic
Sofusbuvir 51 to 56 days in water -1.3 to -0.42 Not toxic, but study not yet completed
Sorafenib 187 days 3.7
BCF of 7250
Toxic PBT
Sunitinib malate Not evaluated 5.2** Not evaluated
Teriflunomide Not evaluated 0.925 Not evaluated
Tezacaftor 27 days in water 3.58 Not evaluated
Ticagrelor 49 to 66 days > 4.0 Potentially toxic T
Trametinib Not evaluated 4.04 Not evaluated
* If no source is given, data is based on risk assessment reports of ESA ** Data obtained from drugs bank and NCBI
22
Appendix B: Fluorinated agrochemicals including their risk
Agrochemical Persistence (DT50 in
soil) *
Bioaccumulation (Log Kow) *
Toxicity * PBT
Amisulbrom 48.4 to 360 days 4.4 at pH 6,4 and 40°C
Not toxic for fish P Benfluralin 31.7 to 198 days 5.19 at pH 8 Toxic to aquatic
organisms
PBT Benthiavali
carbisopropyl
10.6 to 19.1 days 2.6 at 20°C Not toxic
Epoxiconazole 98 to 694 days 3.3 at 25°C Toxic, reproduction cat. 3
PT Flonicamid 0.7 to 1.8 days -0.24 at 20°C Low toxicity
Fludioxonil 119 to 599 days in dark, 0.86 to 2 days in light
4.12 at 25°C Not toxic P
Flufenacet Low 3.2 Toxic T
Fluopicolide 196 to 413 days 2.9 at pH 7 and 20°C Very toxic to aquatic organisms
PT
Fluopyram 162 to 464 days 3.3 at 20°C Not toxic P
Fluroxypyr 2.7 to 39.6 days 2 at pH 5 0.04 at pH7
Toxic to aquatic organisms
T Fluoxastrobin 16 to 119 days 2.86 at 20°C Not toxic
Flutolanil 119 to 412 days 3.17 at 21°C Not toxic P
Fluxapyroxad 89.3 to 696 days 3.08 at 20°C Very toxic to aquatic organisms
PT
Pyridalyl 53 to 272 days 8.1 at 20°C Toxic for fish PBT
Sulfury fluoride Low in soil, but highly persistent in air
0.14 at 20°C Very toxic to aquatic organisms
T Tembotrione 3.8 to 49.2 days -1.09 at pH 7 Low risk to all
organisms
Trifloxystrobin 0.13 to 4.3 days 4.5 Assumed not toxic
23
Appendix C: Commercially available fluorinated polymers classified as PFAS
Polymer Monomers Sales
(Tonnes/yr)76
Polytetrafluoroethylene (PTFE)
Tetrafluoroethylene (TFE) 126,000
PFA TFE + perfluoropropyl vinyl ether 3,000
MFA TFE + perfluorinated methyl vinyl ether 3,000
Polychlorotrifluoro- ethylene (PCTFE) Chlorotrifluoroethylene (CTFE) 6,000 Polyvinylidene fluoride (PVDF) Vinyldifluoride (VDF) 36,000 Fluorinated ethylene propylene (FEP) TFE + hexafluoropropene 19,000
ETFE TFE + ethylene (E) 7,000
THV TFE + HFP + VDF 1,000
ECTFE CTFE + E 2,000
Teflon AF Perfluorodimethyldioxole (PDD) + TFE <1,000 Hyflon AD 2,2,4-trifluoro-5-trifluoromethoxy-1,3-dioxole
(TDD) + TFE
24
Appendix D: Commercially available non-PFAS fluorinated polymers
Polymer Class Tradename Supplier
6FDA-3,3’-6FDA Polyimide Sixef 33 Ethyl corporation
6FDA-4,4’-6FDA Polyimide Sixef44 Ethyl corporation
6FDA-mPDA/pPDA Polyimide Ayimid N
NR-150-B2
Du Pont
6FDA-durene Polyimide Sixef Durene Ethyl corporation
6FDA-ODA Polyimide NR-150-A2
Pyralin PI-2466
Du Pont
6FDA-TPE Polyimide Thermid EL 5512
Thermid FA 700
Notional Starch & Chemicals
6FDA-4BDAF Polyimide Eymeyd HP40 Ethyl corporation
BTDA-4BDAF Polyimide Eymeyd L20-L20N Ethyl corporation PMDA-4BDAF Polyimide Eymeyd L30-L30N Ethyl corporation Bipshenol AF polycarbonate Polycarbonates
Poly(4-fluorostyrene) Styrenes
Poly(vinyl fluoride) Fluorocarbons Dalvor
Tedlar PVF films
Diamond Shamrock Du Pont
Poly (trifluoro
propylmethylsilocane)
25
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