Trifluoroacetic Acid: A Narrative Review on Physico-Chemical Properties, Exposure Pathways, and Toxicological Concerns
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsReview of the paper 'Physico-chemical characterization, sources and routes of exposure,
biokinetics, and human health risks of trifluoroacetic acid: a narrative review' by
Andrea Moscato, Maria Valentina Longo, Margherita Ferrante and Maria Fiore.
In a recent review of a paper reporting TFA measurements in river water in Switzerland, Tim Wallington noted (EGUsphere - Trifluoroacetate (TFA) in Precipitation and Surface Waters in Switzerland: Trends, Source Attribution, and Budget) and the authors should consider these comments in their review.
Extract from Wallington's review
The United Nations Environmental Effects Assessment Panel of which some of us are members has assessed that the risks to human and ecosystem health from trifluoroacetate formed as a degradation product of ODS replacements are currently de minimis (Neale et al., 2025). For balance in the introduction where the toxicological effects are discussed the authors may wish to mention the assessment of the UNEP panel and note the need for further work to reconcile the divergent assessments in the literature.
Second, there are new measurements published by the German UBA (Umweltbundesamt) of trifluoroacetate in samples from the Atlantic Ocean collected from surface waters (n = 33) and from seven distinct depth profiles (n = 41) in 2022–23. Using these data, Neale et al. estimated that the mass of TFA measured in the oceans in the late 1990s and early 2000s, assuming even distribution of 200 ng L−1, was about 500–1000 times higher than the estimated total anthropogenic TFA input to the environment (including Montreal Protocol gases, pesticides, pharmaceuticals, and industrial uses) over the period 1930–1999. The evidence for the contribution of one or more natural source(s) of TFA to the marine environment is relevant and should be mentioned.
As discussed in Neale et al. (2025), TFA in the environment is present as salts that are highly water soluble and easily excreted. TFA-salts do not biomagnify in food webs and there are no known biochemicals or receptors that interact with TFA, although it is a moderately strong acid (pKa = 0.23), it is unreactive. There are wide margins of safety between current and predicted future concentrations in surface- and ground-waters levels of concern for human and environmental health. While continuous monitoring would be useful in quantifying future rates of change in concentrations, this should be focused on key matrices and should include measurements of systemic doses in the general population, such as those conducted in the NHANES program [1].
T. J. Wallington, S. Madronich, O. J. Nielsen, K. R. Solomon, M. P. Sulbaek Andersen
References
Neale et al. Environmental consequences of interacting effects of changes in stratospheric ozone, ultraviolet radiation and climate: UNEP Environmental Effects Assessment Panel, Update 2024, Photochem. Photobiol. Sci., 24, 357 (2025). https://doi.org/10.1007/s43630-025-00687-x
UBA. (2024). Untersuchung von aktuellen Meerwasserproben auf Trifluoressigsäure. TZW: DVGW-Technologiezentrum Wasser, Karlsruhe, Umweltbundesamt, Dessau-Roßlau, Germany. https://www.umweltbundesamt.de/publikationen/untersuchung-von-aktuellen-meerwasserproben-auf
Some comment about natural sources of TFA are needed.
In section 3.2 it is stated that HFC-134a has a yield of TFA of 20%, first, I cannot find any reference to TFA in reference 15, I think that you are referring to ref 17 and references therein?
It reacts with oxygen radicals and has a TFA yield close to 100%, leading to significantly higher environmental dispersion [18].
The point about the HFOs is that they have much higher yields of TFA than HFCs in general but the much higher predicted TFA is in the main because it is oxidised very close to the source due to its short lifetime and this leads to much higher surface levels (see ref 17 for example).
HFO-1234yf and TFA exhibit a seasonal pattern: the former shows higher mean
concentrations in winter (6.06 pptv) and lower in summer (2.70 pptv), while the latter
follows the opposite trend [19]. These patterns are primarily influenced by meteorological
conditions [2].
The anti-correlation simply reflects that the main oxidant of the HFO is OH radicals and these are highest in summer leading to higher conversions of HFO to TFA, reducing the HFO in summer and raising the TFA level.
Minor comments
Abstract
compounds such as hydrofluorocarbons, hydrofluoroolefins ... should also include hydrochlorofluorocarbons (HCFCs) and even some planned HCFOs , hydrochlorofluoroolefins as some of these can also generate TFA.
Introduction
air conditioning systems and climate change ... suggest changing and to due to
Author Response
Comment 1: Review of the paper 'Physico-chemical characterization, sources and routes of exposure,
biokinetics, and human health risks of trifluoroacetic acid: a narrative review' by
Andrea Moscato, Maria Valentina Longo, Margherita Ferrante and Maria Fiore.
In a recent review of a paper reporting TFA measurements in river water in Switzerland, Tim Wallington noted (EGUsphere - Trifluoroacetate (TFA) in Precipitation and Surface Waters in Switzerland: Trends, Source Attribution, and Budget) and the authors should consider these comments in their review. Extract from Wallington's review. The United Nations Environmental Effects Assessment Panel of which some of us are members has assessed that the risks to human and ecosystem health from trifluoroacetate formed as a degradation product of ODS replacements are currently de minimis (Neale et al., 2025). For balance in the introduction where the toxicological effects are discussed the authors may wish to mention the assessment of the UNEP panel and note the need for further work to reconcile the divergent assessments in the literature.
Response 1: The reviewer makes a valid point. So, we have revised the introduction to include the recent risk assessment by the United Nations Environmental Effects Assessment Panel.
Comment 2: Second, there are new measurements published by the German UBA (Umweltbundesamt) of trifluoroacetate in samples from the Atlantic Ocean collected from surface waters (n = 33) and from seven distinct depth profiles (n = 41) in 2022–23. Using these data, Neale et al. estimated that the mass of TFA measured in the oceans in the late 1990s and early 2000s, assuming even distribution of 200 ng L−1, was about 500–1000 times higher than the estimated total anthropogenic TFA input to the environment (including Montreal Protocol gases, pesticides, pharmaceuticals, and industrial uses) over the period 1930–1999. The evidence for the contribution of one or more natural source(s) of TFA to the marine environment is relevant and should be mentioned.
Response 2: Many thanks for this comment. In Section 3.2.4, we have now included the recent data reported by the German Environment Agency (UBA, 2024).
Comment 3: As discussed in Neale et al. (2025), TFA in the environment is present as salts that are highly water soluble and easily excreted. TFA-salts do not biomagnify in food webs and there are no known biochemicals or receptors that interact with TFA, although it is a moderately strong acid (pKa = 0.23), it is unreactive. There are wide margins of safety between current and predicted future concentrations in surface- and ground-waters levels of concern for human and environmental health. While continuous monitoring would be useful in quantifying future rates of change in concentrations, this should be focused on key matrices and should include measurements of systemic doses in the general population, such as those conducted in the NHANES program [1].
Response 3: Thank you for this observation. We have now included, at the end of Section 3.1, a summary of the environmental behavior of TFA, emphasizing its high water solubility, lack of bioaccumulation, current environmental risk assessment and need of continuous monitoring.
Comment 4: Some comment about natural sources of TFA are needed.
Response 4: Done as suggested.
Comment 5: In section 3.2 it is stated that HFC-134a has a yield of TFA of 20%, first, I cannot find any reference to TFA in reference 15, I think that you are referring to ref 17 and references therein?
It reacts with oxygen radicals and has a TFA yield close to 100%, leading to significantly higher environmental dispersion [18].
Response 5: The reviewer makes a valid point. Therefore, we removed the reference 15 and instead refer to reference 17, as suggested.
Comment 6: The point about the HFOs is that they have much higher yields of TFA than HFCs in general but the much higher predicted TFA is in the main because it is oxidised very close to the source due to its short lifetime and this leads to much higher surface levels (see ref 17 for example).
Response 6: The reviewer makes a valid point. Therefore, in the section 3.2.1 of the manuscript, we have included the explanation that HFOs generally yield much higher amounts of TFA compared to HFCs, primarily due to their short atmospheric lifetimes and near-source oxidation, which results in higher surface-level TFA concentrations.
Comnet 7: HFO-1234yf and TFA exhibit a seasonal pattern: the former shows higher mean
concentrations in winter (6.06 pptv) and lower in summer (2.70 pptv), while the latter
follows the opposite trend [19]. These patterns are primarily influenced by meteorological
conditions [2].
The anti-correlation simply reflects that the main oxidant of the HFO is OH radicals and these are highest in summer leading to higher conversions of HFO to TFA, reducing the HFO in summer and raising the TFA level.
Response 7: The reviewer makes a valid point. We have added the explanation regarding the anti-correlation between HFO and TFA levels, driven by the seasonal variation in OH radical concentrations, to Section 3.2.1 of the manuscript.
Minor comments
Abstract
Comment 8: compounds such as hydrofluorocarbons, hydrofluoroolefins ... should also include hydrochlorofluorocarbons (HCFCs) and even some planned HCFOs , hydrochlorofluoroolefins as some of these can also generate TFA.
Response 8: As suggested by the reviewr we have included hydrochlorofluorocarbons (HCFCs) and planned hydrochlorofluoroolefins (HCFOs).
Introduction
Comment 9: air conditioning systems and climate change ... suggest changing and to due to
Response 9: Thank you for the suggestion. We included the phrase “Therefore, in Europe, due to climate change, leading to higher ambient temperatures, and the resulting increased use of air conditioning systems, an upward trend in environmental release and accumulation of TFA is expected in the coming decades.
Author Response File: 
Author Response.docx
Reviewer 2 Report
Comments and Suggestions for AuthorsThank you for the opportunity to review the paper. I hope that my comments are helpful to the authors in order to improve the quality of their manuscript for acceptance. Below find my comments; I try to be brief as much as possible.
GENERAL COMMENTS
The study is well-structured and offers a comprehensive review of various aspects of this emerging contaminant. The English is fluent and well-articulated, making the text accessible and easy to follow. Overall, offers a comprehensive overview of the environmental behavior and toxicity of TFA, and it serves as a valuable foundation for future scientific research and for informing environmental and public health policies in Europe and beyond.
However, in my humble opinion, it would be strengthened by incorporating a dedicated section on the occurrence of TFA in food, particularly in plant-derived products. Adding discussion of this pathway for human exposure—supported by current literature—would significantly enhance the manuscript’s relevance for food safety and public health policy in Europe and globally.”
In addition, the manuscript would benefit from a dedicated paragraph discussing the analytical challenges associated with the detection of trifluoroacetic acid (TFA). Including this aspect, along with appropriate literature references, would provide a more complete overview of the practical limitations and considerations in TFA monitoring.
Therefore, in my opinion, the manuscript is susceptible to being accepted for publication after MAJOR revision.
Individual comments are listed below.
Title: The current title appears somewhat lengthy and could benefit from being more concise. A shorter, more focused title would improve clarity and impact.
Abstract: correct the sentence : “To summarize current knowledge on the environmental fate, human exposure, toxicokinetics, ecotoxicology, and regulation of TFA, a literature search was conducted using PubMed and Scopus (Dec 2024–Jan 2025), including peer-reviewed articles, technical reports, and regulatory documents.
Introduction:
- remove the space: “These properties make it highly persistent…”
- — including surface and groundwater, atmospheric precipitation [3], soil, and biota — Align the position of the citations by moving this reference to the end of the sentence
Results and Discussion:
- 4 Toxicokinetic Evaluation (ADME) define the acronym at the begin of the paragraph
- Clearly Define CYP2E1 as Cytochrome P450 2E1
- “While TFA is not considered bioaccumulative according to aquatic organism criteria [29],…” As noted above, align the position of the citations by moving this reference to the end of the sentence
- “EU CLP Regulation” define the acronym in the text
- “ErC10” define the acronym in the text
- “EC50” define the acronym in the text
- “NGO” define the acronym in the text
- 3 Exposure Routes paragraph - It would be recommended to include a dedicated paragraph on the occurrence of TFA in food, particularly in plant-derived products. Emerging evidence indicates that TFA can accumulate in crops via root uptake from contaminated soils and irrigation water (e.g. wheat, maize, leafy vegetables showing levels up to hundreds of µg/kg) Furthermore, recent EU-wide monitoring efforts have detected substantial TFA concentrations in foodstuffs such as wine (median ~110–122 µg/L; peaks >300 µg/L) and cereal products including bread, pasta, and breakfast cereals, especially from conventionally farmed sources.Adding discussion of this pathway for human exposure—supported by current literature—would significantly enhance the manuscript’s relevance for food safety and public health policy in Europe and globally.
Scheurer M, Nödler K. Ultrashort-chain perfluoroalkyl substance trifluoroacetate (TFA) in beer and tea - An unintended aqueous extraction. Food Chem. 2021 Jul 30;351:129304.
Arp, et al.. The Global Threat from the Irreversible Accumulation of Trifluoroacetic Acid (TFA). Environ Sci Technol. 2024;58(45):19925-19935 (already mentioned by the authors)
- It would be recommended to include a dedicated paragraph discussing the analytical challenges associated with the detection of trifluoroacetic acid (TFA). Given its high polarity, low molecular weight, TFA requires advanced techniques such as LC-MS/MS using specific chromatographic column. Additionally, the widespread environmental presence of TFA increases the risk of laboratory contamination, making blank controls and rigorous quality assurance protocols essential. Including this aspect, along with appropriate literature references (e.g., Scheurer & Nödler, 2021; Arp et al., 2024), would provide a more complete overview of the practical limitations and considerations in TFA monitoring.
Author Response
Reviewer 2
Thank you for the opportunity to review the paper. I hope that my comments are helpful to the authors in order to improve the quality of their manuscript for acceptance. Below find my comments; I try to be brief as much as possible.
GENERAL COMMENTS
The study is well-structured and offers a comprehensive review of various aspects of this emerging contaminant. The English is fluent and well-articulated, making the text accessible and easy to follow. Overall, offers a comprehensive overview of the environmental behavior and toxicity of TFA, and it serves as a valuable foundation for future scientific research and for informing environmental and public health policies in Europe and beyond.
Comment 1: However, in my humble opinion, it would be strengthened by incorporating a dedicated section on the occurrence of TFA in food, particularly in plant-derived products. Adding discussion of this pathway for human exposure, supported by current literature, would significantly enhance the manuscript’s relevance for food safety and public health policy in Europe and globally.
Response 1: The reviewer makes a valid point. We have added a paragraph in the section “Exposure Routes” addressing the occurrence of TFA in food products, particularly plant-derived foods and beverages.
Comment 2: In addition, the manuscript would benefit from a dedicated paragraph discussing the analytical challenges associated with the detection of trifluoroacetic acid (TFA). Including this aspect, along with appropriate literature references, would provide a more complete overview of the practical limitations and considerations in TFA monitoring.
Response 2: The reviewer makes a valid point. We have added the paragraph 3.7 “Analytical challenges in TFA detection”
Therefore, in my opinion, the manuscript is susceptible to being accepted for publication after MAJOR revision.
Individual comments are listed below.
Comment 3: Title: The current title appears somewhat lengthy and could benefit from being more concise. A shorter, more focused title would improve clarity and impact.
Response 3: The reviewer makes a valid point. We have replaced the original title with the following “Trifluoroacetic Acid: a narrative review on physico-chemical properties, exposure pathways, and toxicological concerns”.
Comment 4: Abstract: correct the sentence: “To summarize current knowledge on the environmental fate, human exposure, toxicokinetics, ecotoxicology, and regulation of TFA, a literature search was conducted using PubMed and Scopus (Dec 2024–Jan 2025), including peer-reviewed articles, technical reports, and regulatory documents.
Response 4: The reviewer makes a valid point. We have revised and corrected the sentence. The updated version now reads: "To provide an overview of current knowledge on TFA, we conducted a literature search (PubMed and Scopus, Dec 2024–Jan 2025) focusing on its environmental fate, human exposure, toxicokinetics, ecotoxicology, and regulation."
Introduction:
Comment 5: remove the space: “These properties make it highly persistent…”
Response 5: Done as suggested.
Comment 6: — including surface and groundwater, atmospheric precipitation [3], soil, and biota — Align the position of the citations by moving this reference to the end of the sentence
Response 6: Done as suggested.
Results and Discussion:
Comment 7: Toxicokinetic Evaluation (ADME) define the acronym at the begin of the paragraph
Response7: Done as suggested.
Comment 8: Clearly Define CYP2E1 as Cytochrome P450 2E1
Response 8: Done as suggested.
Comment 9: “While TFA is not considered bioaccumulative according to aquatic organism criteria [29],…” As noted above, align the position of the citations by moving this reference to the end of the sentence
Response 9: Done as suggested.
Comment 10: “EU CLP Regulation” define the acronym in the text
Response 10: Done as suggested.
Comment 11: “ErC10” define the acronym in the text
Response 11: Done as suggested.
Comment 12: “EC50” define the acronym in the text
Response 12: Done as suggested.
Comment 13: “NGO” define the acronym in the text
Response 13: Done as suggested.
Comment 14: Exposure Routes paragraph - It would be recommended to include a dedicated paragraph on the occurrence of TFA in food, particularly in plant-derived products. Emerging evidence indicates that TFA can accumulate in crops via root uptake from contaminated soils and irrigation water (e.g. wheat, maize, leafy vegetables showing levels up to hundreds of µg/kg) Furthermore, recent EU-wide monitoring efforts have detected substantial TFA concentrations in foodstuffs such as wine (median ~110–122 µg/L; peaks >300 µg/L) and cereal products including bread, pasta, and breakfast cereals, especially from conventionally farmed sources.Adding discussion of this pathway for human exposure—supported by current literature—would significantly enhance the manuscript’s relevance for food safety and public health policy in Europe and globally.
Scheurer M, Nödler K. Ultrashort-chain perfluoroalkyl substance trifluoroacetate (TFA) in beer and tea - An unintended aqueous extraction. Food Chem. 2021 Jul 30;351:129304.
Arp, et al.. The Global Threat from the Irreversible Accumulation of Trifluoroacetic Acid (TFA). Environ Sci Technol. 2024;58(45):19925-19935 (already mentioned by the authors)
Response14: The reviewer makes a valid point. We have added a new paragraph in the section “Exposure Routes” addressing the occurrence of TFA in food products, particularly plant-derived foods and beverages.
Comment 15: It would be recommended to include a dedicated paragraph discussing the analytical challenges associated with the detection of trifluoroacetic acid (TFA). Given its high polarity, low molecular weight, TFA requires advanced techniques such as LC-MS/MS using specific chromatographic column. Additionally, the widespread environmental presence of TFA increases the risk of laboratory contamination, making blank controls and rigorous quality assurance protocols essential. Including this aspect, along with appropriate literature references (e.g., Scheurer & Nödler, 2021; Arp et al., 2024), would provide a more complete overview of the practical limitations and considerations in TFA monitoring.
Response 15: The reviewer makes a valid point. We have added the paragraph 3.7 “Analytical challenges in TFA detection”
Author Response File: Author Response.docx
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsI thank the authors for addressing my comments. The article can now be accepted for publication in its current form.
