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

TFA is at atmospheric by-product of HFO-1234yf and other f-gases.

The German Federal Office for Chemicals (Bundesstelle für Chemikalien or BfC) has informed the European Chemical Agency (ECHA) of its intention to propose linking reproductive toxicity to trifluoroacetic acid (TFA), an atmospheric by-product of HFO-1234yf and other f-gases.

The 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 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.

While an ultrashort-chain carbon-fluorine molecule, TFA falls under the widely accepted 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 PFOA, have been tied to harmful health impacts, including reproductive toxicity.

The BfC also intends to propose linking reproductive toxicity to sodium trifluoroacetate and other inorganic salts of TFA and linking toxicity if inhaled to TFA. The agency’s intention to submit these classification and labelling (CLH) proposals can be found here and here. The expected date of submission is the end of May 2024.

In particular, the proposal would connect TFA and it salts to Repr. (reproductive toxicity) 1B and TFA to Acute Toxicity 3 H331 (toxic if inhaled) under the ECHA classification and labelling system. TFA is already classified as Aquatic Chronic 3, H412 (harmful to aquatic life with long-lasting effects), Acute Toxicity 4 H332 (harmful if inhaled) 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. “To ensure that this is binding throughout the EU, we will submit a corresponding proposal to the ECHA in the coming weeks, taking into account all available data.”

“Once ECHA has accepted the proposal,” he added, “it will be published as soon as possible so that everyone has the opportunity to contribute to the dossier with their arguments and data in a consultation process.”

The submission will mark the start of a legal period of 18 months within which ECHA’s Committee for Risk Assessment (RAC) receives input and submits an opinion to the European 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).

Averbeck noted that the BfC’s proposals are “not directly related” to the ongoing restriction proposal for PFAS (per- and polyfluoroalkyl substances) being evaluated by ECHA. This 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.

The American Chemistry Council, which represents global manufacturers of fluorinated chemicals, declined to comment for this article.

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 the developing embryo or fetus. 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 (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 the 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, from which is derived its guideline and precautionary values. 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 proposals on reproductive toxicity are “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 in which it is 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.

Though the BfC’s TFA proposals are 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:

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

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

  • Covance Laboratories (2020a): 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 (2020b): 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 a study (not named) indicating that TFA and other short-chain PFCAs “might cause rare abnormalities in rabbit offspring.” According to the HSE News Desk, information on the study was “provided by the registrants of trifluoroacetic acid in their EU REACH registration dossier.”

This information, said the HSE, was made public in the substance’s brief profile published on ECHA’s website in a note on developmental toxicity. The note refers to the “lowest-observed-adverse-effect-level” of 180mg/kg of body weight/day for no less than 24 hours and no greater than 10% of the total lifespan of the test rabbit.

In response to a recent query about the status of its investigation of TFA, the HSE said it has started the Mandatory Classification and Labelling (MCL) process. “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 the HSE News Desk. More is available on the HSE website.

In February, the French NGO Générations Futures unveiled analysis showing significant contamination by TFA and triflic acidin surface water and drinking water around a Solvay plant in Salindres, France, that manufactures the chemicalsThe group measured TFA concentrations of 7.6mg/l in the discharge, up to 7.5mg/l and 3.9mg/l in nearby waterways. TFA levels of 16µg/l were found in the Gard river approximately 20km (12.4mi) from Salindres.

Générations Futures called for the “expansion of monitoring of aquatic environments (surface and groundwater)around Salindres and throughout France, including regular monitoring of TFA, triflic acid, and the 24 PFAS deemed priorities by Europe.” The NGO also said it “is considering” a referral to the French Agency for Food, Environmental and Occupational Health & Safety (ANSES) to assess the impact of TFA and triflic acid on health and the environment, and to obtain a position on the reproductive toxicity of TFA as well as a health value for drinking water.

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 to include additional information from the UBA on Germany’s health-based guideline value for TFA in drinking water.

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

Dr. Jan Averbeck, representing the he German Federal Office for Chemicals (BfC)

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