REACH revision status report: increased information requirements
The European Commission briefed CARACAL experts at their March meeting on the REACH revision, presenting on the EU executive’s progress to shape the policies that encompass the ambitious revamp of the bloc’s main cross-sectoral chemicals legislation. This article is the second in a series that summarize the status of each of these policies. What follows is a description of new information requirements presented during the meeting that the Commission is now considering incorporating in the REACH annexes to increase the knowledge base on “low-tonnage” chemicals and most harmful substances, including endocrine disruptors.
Regulatory background and context
- Article 5 of the REACH Regulation ( 1907/2006/EC) stipulates that substances – whether on their own, in mixtures, or in articles – must be registered before they can be manufactured or imported in the European Union. Registration entails compiling and documenting a significant amount of substance-related information.
- This “no data, no market” provision under REACH is intended to ensure that sufficient knowledge, including all hazardous properties, uses, and related risks, is obtained and identified to the authorities and the public before the associated substances arrive on the market. In this way, REACH seeks better chemicals management and a high level of protection of human health and the environment while safeguarding a transparent, predictable market for chemicals uniformly throughout Europe. It places the onus of producing the substance-related information squarely on those stakeholders placing the chemicals on the market, i.e., industry.
- The Commission’s Chemicals Strategy for Sustainability (CSS), published on October 14, 2020, envisions an extensive overhaul of the EU chemicals regulatory framework aimed at creating safer products, fostering a circular economy free of toxic materials, and contributing to a safe-and-sustainable-by-design paradigm for chemicals production. Among the changes put forward in the CSS and now being considered by the Commission are increased information requirements for registering certain substances that the EU executive asserts, until now, have not been subject to the collection of sufficient data.
- REACH specifies the information that must be submitted for registration based on the quantity of the substance placed on the market annually pursuant to article 12. Registration is obligatory starting at one metric ton (mt) per year per manufacturer or importer. Until now, smaller amounts manufactured or imported in the EU, e.g., from one to 10 mts, have required less information and fewer testing proposals, while larger quantities, e.g., from 10 mts and up, have demanded increasingly more documentation and more comprehensive testing. The regular obligations for physicochemical, toxicological and ecotoxicological information are laid out in REACH’s annexes VII (1 mt or more), VIII (10 mts or more), IX (100 mts or more), and X (1,000 mts or more).
- The Commission is now prescribing an increase in the information required, including testing data, to register substances in the low- and medium-tonnage bands and those that are most hazardous, including endocrine disruptors. This is because, given the current provisions, the authorities have been unable to obtain sufficient data on them. This dearth of data has hindered adequate chemicals management and resulted in less effectual measures to combat illnesses like cancer and endocrine system-related diseases, according to the CSS. Likewise, without enough knowledge on these chemicals, the authorities are not properly equipped to effectively conduct REACH title VI substance evaluation, the Commission has concluded.
Commission updates CARACAL on information requirements
- The CARACAL experts at their March 28 meeting discussed possible revisions to information requirements under REACH. The Commission’s presentation on its work on the REACH revision included the proposal to increase information for low-tonnage substances and for the most harmful substances, with focus on endocrine disruptors. An overview of some of the ideas was presented for updating the requirements, but the Commission indicated that the details of the amendments were still under discussion.
- A major consideration was the objective to reduce the need for animal testing. To achieve this, the presentation suggested including novel New Approach Methodologies (NAMs), or animal-free methods, wherever possible. For human health and endocrine disruptors, new NAM requirements are under consideration in annex VII of REACH. These include:
- In vitro cytotoxicity (Neutral Red Uptake Assay)
- Toxicokinetics and absorption, distribution, metabolism, and excretion (ADME) testing: in chemico protein binding (e.g., fraction unbound in human plasma); in vitro human hepatic clearance (e.g., isolated human hepatocytes); in vitro intracellular bioaccumulation (e.g., in Caco-2 cells); and in vitro intestinal absorption (e.g., Caco-2 permeability)
- Endocrine disruption-related in vitro mechanistic information relevant to human health and the environment: estrogen receptor transactivation assay (OECD TG 455); androgen receptor transactivation assay (OECD TG 458); H295R steroidogenesis assay (OECD TG 456); and the aromatase assay (OPPTS 890.1200).**
**Please see the Key Documents section below for a complete list of, and links to, the OECD/OPPTS test guidelines explicitly referenced in the Commission’s presentation and cited throughout this article.
- The Commission suggested introducing “triggers” as a way of limiting testing for low-tonnage substances and chemicals of highest concern. For these substances, two possible triggers were presented for discussion: biological half-life predicted from log Kow (> 3) and in vitro toxicokinetics data, which the presentation indicated would be generated after the REACH revision was finalized. Also considered was the possibility of testing for repeated dose toxicity and screening for reproductive/developmental toxicity (OECD TG 422) for low-tonnage substances, as well as using in vivo tests on endocrine disruption. With discussions of these triggers ongoing, this part of the presentation included a direct appeal to the experts for “other ideas.”
- Concerning the environment, the presentation suggested replacing short-term fish toxicity testing with in vitro cytotoxicity (OECD TG 249) or fish embryo toxicity (OECD TG 236) testing. It proposed moving long-term toxicity testing on invertebrates (Daphnia) from REACH’s annex IX to annex VII. Also recommended was replacing bioaccumulation in fish (annex IX) with either (1) in vitro tests according to OECD TG 319A/B (i.e., intrinsic clearance in rainbow trout hepatocytes) and in vitro–in vivo extrapolation (IVIVE) for estimation of kinetic bioconcentration factor (BCF); or bioaccumulation in invertebrates (e.g., Hyalella Azteca bioconcentration test). The Commission posed the question whether registrants should have a choice to use either of the two approaches.
- For endocrine disruptors, the Commission considered basing in vivo follow-up on a weight-of-evidence approach, including for low-tonnage substances. The triggers and waivers that this would involve were still under discussion. Additional requirements for identification of endocrine disruptors for human health and the environment were also proposed. These included uterotrophic bioassay in rodents (OECD TG 440) and Hershberger bioassay in rats (OECD TG 441), as well as amphibian metamorphosis assay (OECD TG 231), fish sexual development test (OECD TG 234), Medaka Ext. One-Generation Reproduction Test (OECD TG 240), and larval amphibian growth and development assay (OECD TG 241).
- To offset the additional requirements for low tonnages and endocrine disruptors – and their associated costs – the Commission proposed deleting several existing requirements from the REACH annexes. These deletions would also align the EU’s testing regime with scientific progress, according to the presentation. These included the following:
- acute oral toxicity in rats (annex VII)
- acute dermal and inhalation toxicity in rats (annex VIII)
- skin corrosion/irritation (annex VIII)
- serious eye damage/eye irritation (annex VIII)
- assessment of toxicokinetic behavior to the extent that can be derived from the relevant available information (annex VIII)
- further studies beyond the 90-day study (annex IX column 2)
- pre-natal developmental toxicity study 2nd species (annex X and trigger in annex IX)
- long-term repeated toxicity study (≥ 12 months) (annex X)
- possibly, carcinogenicity study (annex X).
- The Commission’s presentation indicated that the timeline for publishing the proposed revision of REACH, including the increased information requirements, is scheduled at the “latest” for the last quarter of 2023.
- REACH revision: Overview and specific questions for consultation, AP 4.1 on agenda of CARACAL-48 (28 March 2023)
|OECD TG 231||Amphibian Metamorphosis Assay: an amphibian metamorphosis assay intended to screen substances which may interfere with the normal functioning of the hypothalamo-pituitary-thyroid axis.|
|OECD TG 234||Fish Sexual Development Test: an assay that assesses early life-stage effects and potential adverse consequences of putative endocrine disrupting chemicals (e.g. oestrogens, androgens and steroidogenesis inhibitors) on fish sexual development.|
|OECD TG 236||Fish Embryo Acute Toxicity (FET) Test: a test method intended to determine the acute or lethal toxicity of chemicals on embryonic stages of fish (Danio rerio).|
|OECD TG 240||Medaka Extended One Generation Reproduction Test (MEOGRT): a test method that exposes fish over multiple generations to give data relevant to ecological hazard and risk assessment of chemicals, including suspected endocrine disrupting chemicals (EDCs).|
|OECD TG 241||Larval Amphibian Growth and Development Assay (LAGDA): a toxicity test with an amphibian species (African clawed frog (Xenopus laevis)) that considers growth and development from fertilization through the early juvenile period.|
|OECD TG 249||Fish Cell Line Acute Toxicity – The RTgill-W1 cell line assay: a 24-well plate format fish cell line acute toxicity test using the permanent cell line from rainbow trout (Oncorhynchus mykiss) gill, RTgill-W1.|
|OECD TG 319A||Determination of in vitro intrinsic clearance using cryopreserved rainbow trout hepatocytes (RT-HEP): use of cryopreserved rainbow trout (Oncorhynchus mykiss) hepatocytes (RT-HEP) as a metabolizing system to determine the clearance (CL, IN VITRO, INT) of a test chemical using a substrate depletion approach.|
|OECD TG 319B||Determination of in vitro intrinsic clearance using rainbow trout liver S9 sub-cellular fraction (RT-S9): use of liver S9 sub-cellular fraction (RT-S9) of rainbow trout (Oncorhynchus mykiss) as a metabolizing system to determine the clearance (CL, IN VITRO, INT ) of a test chemical using a substrate depletion approach.|
|OECD TG 422||Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test: effects of a test chemical on male and female reproductive performance; updated with endocrine disruptor endpoints, in particular measure of anogenital distance and male nipple retention in pups and thyroid examination.|
|OECD TG 440||Uterotrophic Bioassay in Rodents: an in vivo short-term screening test based on the increase in uterine weight or uterotrophic response.|
|OECD TG 441||Hershberger Bioassay in Rats: in vivo short–term screening test that evaluates the ability of a chemical to elicit biological activities consistent with androgen agonists, antagonists or 5-alpha reductase inhibitors.|
|OECD TG 455||Performance-Based Test Guideline for Stably Transfected Transactivation In Vitro Assays: in vitro assays which provide the methodology of Stably Transfected Transactivation to detect Estrogen Receptor Agonists and Antagonists (ER TA assays).|
|OECD TG 456||H295R Steroidogenesis Assay: an in vitro screen for chemical effects on steroidogenesis, specifically the production of 17ß-estradiol (E2) and testosterone (T).|
|OECD TG 458||Stably Transfected Human Androgen Receptor Transcriptional Activation Assay for Detection of Androgenic Agonist and Antagonist Activity of Chemicals: in vitro assays which use Androgen Receptor Transactivation (ARTA) to detect Androgen Receptor Agonists and Antagonists.|
|OPPTS 890.1200||Aromatase (Human Recombinant) Assay: a screening assay developed by the U.S. EPA’s Office of Prevention, Pesticides, and Toxic Substances (OPPTS) intended to identify chemicals that may affect the endocrine system (e.g., steroidogenesis) by inhibiting catalytic activity of aromatase, the enzyme responsible for the conversion of androgens to estrogens.|