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German Chemicals Office Submits Proposal to EU Linking TFA to Reproductive Toxicity

TFA, an atmospheric by-product of HFO-1234yf and other f-gases, is considered by scientists to be a PFAS that persists in the environment.

The German Federal Office for Chemicals (Bundesstelle für Chemikalien or BfC) has submitted to the European Chemical Agency (ECHA), in separate dossiers, its proposal linking reproductive toxicity to trifluoroacetic acid (TFA) and its inorganic salts; TFA is an atmospheric by-product of HFO-1234yf and other f-gases.

BfC is a division of Germany’s Federal Institute for Occupational Safety and Health (Bundesanstalt für Arbeitsschutz und Arbeitsmedizin or BAuA). ECHA is responsible for the safe use of chemicals in the EU.

This is one of the first efforts by a country to associate exposure to small quantities of TFA (concentrations of at least 0.1% to 0.3%) with harmful human health effects. One of the main sources of TFA in the environment is the oxidation of HFO-1234yf and other f-gases in the atmosphere, with TFA absorbed in rainfall. TFA is also formed from the breakdown of pesticides and other anthropogenic sources.

While it is an ultrashort-chain, two-carbon substance, TFA falls under the scientifically accepted “one fully fluorinated carbon” definition of PFAS (per- and polyfluorinated substances) established by the OECD (Organisation for Economic Co-operation and Development). As such, it acts as a “forever chemical” that persists for a very long time in the environment. Longer chain PFAS with a similar chemical architecture (known as perfluoroalkyl carboxylic acids), such as eight-carbon PFOA, have been tied to harmful health impacts, including reproductive toxicity, ulcerative colitis and cancer.

BfC’s proposal was submitted to ECHA’s “registry of classification and labelling (CLH) intentions until outcome,” which lists the intentions and proposals for a new or revised harmonized classification and labelling of a substance. The proposals are submitted by EU Member State competent authorities, manufacturers, importers or downstream users.

The German agency’s two classification and labelling proposal dossiers linking reproductive toxicity to TFA, sodium trifluoroacetate and TFA’s other inorganic salts can be found here and here. The dossiers were submitted for an “accordance check” on June 11, under which ECHA will check whether the dossiers fulfil its internal requirements and, if necessary, recommend a revision.

BfC informed ECHA of its intention to submit these dossiers last November.

In particular, BfC’s “proposed harmonised classification” connects TFA and its salts to Repr. (reproductive toxicity) 1B, H360Df (suspected of damaging fertility). It would also change TFA’s current classification of Acute Toxicity 4 H332 (harmful if inhaled) to Acute Toxicity 3 H331 (toxic if inhaled), adding proposed specific concentration limits of 3mg/L (vapor) for inhalation ATE (acute toxicity estimate).

In addition, the proposal categorizes TFA and its inorganic salts under hazard classes PMT (persistent, mobile and toxic) and vPvM (very persistent, very mobile). TFA and its salts are tied to PMT EUH450 (can cause long-lasting and diffuse contamination of water resources) and vPvM EUH451 (can cause very long-lasting and diffuse contamination of water resources).

Under the new proposal, TFA continues to be classified as Aquatic Chronic 3, H412 (harmful to aquatic life with long-lasting effects) and Skin Corrosion 1A, H314 (causes severe skin burns and eye damage).

“Based on new study results, we consider the classification of TFA and its inorganic salts as Repr. 1B to be necessary,” said Dr. Jan Averbeck, representing the BfC, in March. The proposal to make this binding throughout the EU, takes into account “all available data.”

The BfC proposal submission marks the start of a legal period of 18 months within which ECHA’s Committee for Risk Assessment (RAC) receives input. (If there are revisions to the proposal, the process would start on the submission of the revised proposal.)  At the beginning of this phase, ECHA publishes the two dossiers and opens a form for commenting. Averbeck encouraged stakeholders to “contribute to the dossiers with their arguments and data.”  BfC, as the author of the dossiers, will provide a response to the comments.

RAC discusses the submitted information and adopts an opinion on the classification proposal that is submitted to the EU Commission. The Commission reaches a decision over a one-year period and publishes an update of classifications in an “Adaptation to Technical Progress,” following which the new classification becomes effective after a specified transitional period (usually 18 months).

A representative of the European Fluorocarbons Technical Committee (EFCTC), which represents chemical manufacturers, said the organization is “aware” of the BfC’s TFA classification proposal but did not comment further.

Averbeck noted that BfC’s proposal is “not directly related” to the ongoing restriction proposal for PFAS being evaluated by ECHA. That proposal would restrict the manufacture, use or sale of TFA as well as certain f-gas refrigerants, among many other PFAS, under REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals), the EU’s chemicals regulation.

Definition of reproductive toxicity

According to the UN’s Globally Harmonized System (GHS) of Classification and Labelling of Chemicals, reproductive toxicity refers to “adverse effects of a chemical substance/mixture on sexual function and fertility in adult males and females, as well as developmental toxicity in the offspring.” Developmental toxicity pertains to adverse toxic effects in developing embryos or fetuses. Under GHS, Category 1B refers to presumed human reproductive toxicants, largely based on animal studies. (Category 1A refers to known human reproductive toxicants based on evidence from humans.)

The GHS also lists the minimum concentration for a hazardous substance to trigger the classification of a mixture containing it. For the reproductive toxicity classification 1B, the minimum concentration is 0.1% in the U.S. and Canada and 0.3% in the EU, Japan, Australia and other countries.

The GHS says that if a reproductive toxicant is present in a mixture as an ingredient at a concentration between 0.1 and 0.3%, every regulatory authority would require information on the safety data sheet (SDS) for that ingredient; a label would be optional. However, if the concentration is equal to or greater than 0.3%, both SDS information and a label would generally be expected.

The German Environment Agency (Umweltbundesamt or UBA) has set a human health-based guideline value of 60μg/L for TFA in drinking water and a “precautionary measure” of 10μg/L. This guideline value is based “a dose-dependent activation of the enzyme ALT [alanin-amino-transferase], which is an indicator of possible liver toxicity,” said Dr. Alexander Eckhardt, Researcher for UBA’s Department of Toxicology of Drinking Water and Swimming Pool Water. In 2020, UBA published a study showing the link between TFA and ALT in rats. In a study of Indiana households published last year, the median concentration of TFA found in drinking water was 79ng/L, and the median concentration of TFA in blood serum was 6ng/mL.

A classification of TFA in reproductive toxicity class 1B “does not necessarily prompt a change in the guideline value,” noted Eckhardt. The guideline value, he added, is based on the most sensitive toxicologic endpoint, which for TFA is the dose-dependent activation of ALT. “Only if reproductive toxicity induced by TFA proves to be a more sensitive endpoint than its liver toxicity will a new guideline value be established,” he said, adding that, to date, UBA lacks the study data to make that determination.

However, Germany’s CLH proposal on reproductive toxicity is “intended to communicate the hazardous intrinsic properties of TFA and make them binding,” said Averbeck. In addition, the classification would triggers some “protective measures,” he noted. For example, substances or mixtures classified as Repr. 1A or 1B may not be supplied to the general public.

Related studies

For this proposal, BfC used study summaries from ECHA’s non-confidential registration dossiers. For example, ECHA posted a 2022 internal study on rats that concluded that 3000/1500 ppm (approximating 242–265 mg NaTFA/kg/day) was the No Observed Adverse Effect Level (NOAEL) for both reproductive performance/offspring development and for general systemic toxicity.

In another study from 2021 provided by ECHA, eye malformations occurred in all three dose groups of rabbits administered TFA. The study concluded that the No-Observed-Adverse-Effect-Level (NOAEL) of sodium trifluoroacetate for maternal toxicity in rabbits was considered to be 180 mg/kg/day, and the NOAEL of sodium trifluoroacetate for embryo-fetal developmental toxicity in rabbits was considered to be less than 180 mg/kg/day. The source of the study is not provided.

Though BfC’s TFA proposal is not related to ECHA’s PFAS restriction proposal, the reproductive toxicity effects of TFA and sodium TFA are described in the PFAS restriction proposal’s Annex B “Information on hazard and risk,” chapter 5. In particular chapter 5.2.2 “Toxicity to Reproduction” presents some qualitative data on TFA’s effects on rabbits:

  • developmental effect: litter loss, malformation in offspring.
  • reduced weight of reproductive organs.
  • pup weight gain during lactation.

The TFA data in Annex B stems from two Covance Lab studies in 2020:

  • Covance Laboratories (2020): Sodium Trifluoroacetate: Preliminary Study for Effects on Embryo-Fetal Development in the New Zealand White Rabbit by Oral Gavage Administration. YQ44HR Covance Laboratories Limited, Eye Suffolk, IP23 7PX UK; and
  • Covance Laboratories (2020): Sodium Trifluoroacetate: Study for Effects on Embryo-Fetal Development in the New Zealand White Rabbit by Oral Gavage Administration. 8437242. Covance Laboratories Limited, Eye Suffolk, IP23 7PX UK.

Last year, in a report on PFAS, the U.K.’s Health and Safety Executive (HSE) identified TFA as being “a concern for developmental toxicity” and needing “further evaluation and investigation.” The report cited the study in the EU REACH registration dossier indicating that TFA and other short-chain PFAS “might cause rare abnormalities in rabbit offspring.”

HSE said it has started the Mandatory Classification and Labelling (MCL) process for TFA. “Since initiating this process, industry stakeholders have generated additional data of potential relevance to the proposal,” it added. HSE anticipates holding a public consultation on the MCL proposal for TFA during the financial year 2024/25. Within one year of the start of the public consultation HSE will produce a technical report, followed by an agency opinion, which forms the basis of recommendations on a new or revised MCL.

“Anyone who has relevant information on TFA can submit this to HSE, now or during the public consultation,” said HSE News Desk. More is available on HSE’s website.

A new study published in May by the European Pesticide Action Network (PAN Europe) found TFA in samples from 23 rivers and six aquifers across Europe at levels that in four of the rivers surpass the 2.2mcg/L TFA drinking water limit established in the Netherlands. PAN Europe urged a “swift ban on PFAS pesticides and f-gases” – the two largest contributors to TFA in the environment, citing a 2023 study by the UBA.

At the ATMOsphere America conference in Washington, D.C., last month, three scientists considered the potential health and environmental risks of HFOs and TFA, following a keynote from famed PFAS attorney Robert Bilott.

The chemical industry addressed the environmental deposition of TFA in an October 2021 study funded by the Global Forum for Advanced Climate Technologies (globalFACT), which represents f-gas producers Chemours, Honeywell, Arkema and Koura (and equipment manufacturer Daikin). The study concluded that “with the current knowledge of the effects of TFA on humans and ecosystems, the projected emissions through 2040 would not be detrimental.” But the study also acknowledged that “the major uncertainty in the knowledge of the TFA concentrations and their spatial distributions is due to uncertainties in the future projected emissions.”

This article was updated on July 2 with new information from BfC on ECHA’s accordance check and on the process for commenting on BfC’s dossiers, and on July 9 with a comment from the European Fluorocarbons Technical Committee (EFCTC).

“Based on new study results, we consider the classification of TFA and its inorganic salts as Repr. 1B to be necessary.”

Dr. Jan Averbeck, BfC

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