What is REACH?
REACH is the European Regulation (EC) No 1907/2006, on the Registration, Evaluation, Authorisation and Restriction of Chemicals adopted to improve the protection of human health and the environment from the risks that can be posed by chemicals. It aims to enhance the competitiveness of the European Union (EU) chemicals industry and promote alternative methods for the hazard assessment of substances in order to reduce the number of tests on animals.
REACH entered into force in 2007, and shifted the responsibility from public authorities to industry with regards to assessing and managing the risks posed by chemicals and providing appropriate safety information for users.
The REACH Regulatory Process
Registrations for substances, manufactured or imported in the EU were made to meet three volume-based deadlines in 2010, 2013 and 2018, starting with the highest tonnages. Registered substances are currently subject to ongoing Evaluation, with prioritization of substances considered to pose greatest risk to human health and the environment.
The European Chemicals Agency (ECHA) carries out Dossier Evaluations to evaluate any testing proposals and can impose compliance checks.
Testing proposals included in the registration dossiers are Evaluated to confirm the proposed studies will effectively generate sufficient data for the assessment of the substance, but also to check that the studies will not result in unnecessary testing, especially on animals.
Compliance checks are to ensure that the information required is sufficient for the regulators to properly evaluate the substance and its uses. Should the regulators identify that there are gaps in the information, registrants are given notice and a deadline to generate the missing information and update their dossiers.
Once ECHA have completed compliance checks, local competent authorities (Member State) may select substances for substance evaluation.
One of the objectives of Evaluation is to identify Substances of Very High Concern (SVHC). To expedite this objective, the European Commission developed the SVHC Roadmap” to identify all known SVHCs and add these to the Candidate List for authorisation”.
Properties of SVHCs
The possible outcomes of the substance Evaluation process
Petroleum Substances and REACH
In 2022, 889 million tons of petroleum substances were registered for REACH (manufactured or imported into the EU). 96% of this tonnage is currently used as either fuel or as an intermediate.
During the Registration phase, Concawe had a formal role as the Substance Information Exchange Forum (SIEF) Formation Facilitator for all registered petroleum substances and is now managing the Evaluation phase on behalf of the SIEFs participants. The SIEFs allow for data generated for REACH (by Concawe or one or more of the registrants) to be shared amongst all registrants of the same substance, thus avoiding duplication of effort. The Commission implementing regulation on data sharing ((EU) 2016/9) allows a fair share of the cost incurred in generating data for REACH to be shared amongst co-registrants (post-SIEF). Currently, there are around 4,100 active registrations of Concawe petroleum substances.
Concawe aims to prioritise petroleum substances for which further work is really needed to inform proper regulatory assessment of all Concawe petroleum substances. The current Evaluation strategy aims to maximise assessment efficiency in terms of time, animal welfare, and cost, while not underestimating potential risks to human health and the environment.
Substance Identity and Composition
Petroleum substances in Concawe’s portfolio are of Unknown or Variable composition, Complex reaction products or Biological materials (UVCB). The precise identity and composition of every constituent is most of the time unknown and the composition may vary across samples of the same substance.
The biggest challenge in applying REACH to petroleum substances is to account for their UVCB nature. The complexity of UVCB substances means it is impossible to determine the precise chemical composition to the level of each constituent for the majority of petroleum substances. The variability in detailed composition and the large number of constituents which could reach over a million molecules makes it difficult to represent the composition of petroleum substances at such a detailed level. For many applications of petroleum products, a detailed chemical composition is not necessary, because industry practice is to manufacture and market petroleum substances according to physico-chemical parameters specified in European Standards. Different samples from the same process in a refinery will show some variability in detailed composition, whilst still remaining within the specifications that identify the substance.
Read-across and substance similarity
As vertebrate animal studies form the basis to assess human health toxicity and some endpoints in eco-toxicological hazard assessment, registrants must consider appropriate alternative approaches to fulfil information requirements in order to avoid unnecessary animal studies in testing each substance. Read-across is a commonly used alternative approach for data gap filling, which involves the use of relevant information from analogous substances, the ‘source’ information, to predict properties of the ‘target’ substances under consideration. Relevant information requires primarily structural or compositional characterisation, but physical chemical properties and biological activity profiles are also required. The application of read across can not only reduce the time required to provide compliant information per substance, but also improve the quality of the assessment of hazard by bringing into consideration the weight of evidence of closely related substances.
Compositional information for petroleum substances is typically obtained using industry standard methodologies such as Simulated Distillation Gas Chromatography (SIMDIS-GC) to determine the boiling point/carbon number range and High-Performance Liquid Chromatography (HPLC) to quantify the different aromatic classes present. These methodologies are the same as those used by registrants when generating Substance Identity Profiles (SIPs) to identify the appropriate substance registration for data sharing in REACH Annex VI. However, they are insufficient to meet the data requirements to justify compositional similarity for read across.To demonstrate an understanding of the identity, concentration and variability of substance constituents to meet the information requirements for read across, additional non-standard analytical techniques such as Comprehensive Two-Dimensional Gas Chromatography (GCxGC) are required to characterise petroleum substances. This technique provides detailed quantitative information on the carbon number range of the constituents and on the types of hydrocarbon classes present for each carbon number that can be used to map the hydrocarbon space of a group of substances and identify combinations of test samples that best represent the type and concentration of constituents of the group.
For the 2010 REACH registration deadline, the Concawe dossiers were completed with all available toxicological information on petroleum substances. Specific endpoint requirements were either fulfilled with actual data on the substance itself, or by application of read-across to relevant data on related substances. A thorough data gap analysis then identified the need for the generation of new data on the reproductive toxicity endpoint for six Concawe petroleum product categories, where no historical data was available and read-across not applicable.
Reproductive toxicity data is a standard requirement in REACH, comprising of two endpoints namely i) Pre-Natal Development Toxicity (PNDT) and, ii) fertility (Extended One-Generation Reproductive Toxicity Study (EOGRTS)). Permission from ECHA is required before a higher-tier1 guideline toxicity test in vertebrate animals can be conducted. In 2010 registrations, Concawe submitted testing proposals to conduct two PNDT and six EOGRTS studies covering the identified data gaps in these six categories.
A multi-year research project was initiated to further underpin the read-across argumentation. A first step is to have a better understanding of the composition and its variability within each substance and category to be able to identify representative samples for testing. The toxicology hypothesis is that reproductive toxicity is related to the level of 3-7 ring polycyclic aromatic hydrocarbon (PAH) in petroleum substances. However, in order not to underestimate the hazards, the tested samples should also be representative of the whole hydrocarbon space of the considered substances and categories.
A second step is to support biological similarity. This is done with standard short-term animal testing, using bridging studies, with the meaning that results from studies sharing the same protocol, in this case a screening study over 28 days using the oral route (OECD 422), can be compared side by side. Similar results between studies allows to ‘bridge’ the substances and read results across from the source substance that will be subject to higher tier testing, to the target substance(s).
The OECD 422 standard does not require a decision from ECHA and member states according to REACH. Over 28-days it provides the widest possible toxicological screening for a substance.
The inherent complexity and variability of UVCBs present considerable challenges for establishing sufficient substance similarity based on chemical characteristics or other data, in addition to bridging studies, we hypothesized that animal alternatives new approach methodologies (NAMs), including in vitro test-derived biological activity signatures to characterize substance similarity, can be used to demonstrate similarity of UVCBs.
This was the main aim of the Cat App project led by Concawe over the last years where 141 petroleum substances were tested as representative UVCBs in a compendium of 15 human cell types representing a variety of tissues. Petroleum substances were assayed in dilution series to identify the concentration at which an effect could be identified for each cell type. As such assays generate a high amount of data, extensive quality control measures were taken to ensure that only high-confidence in vitro data are used to determine whether current groupings of these petroleum substances in categories are justifiable. Overall, it was found that bioactivity data-based groupings of petroleum substances were generally consistent with the current categories grouping. We also showed that these data, especially bioactivity from human induced pluripotent stem cell (iPSC)-derived and primary cells, can be used to rank substances in a manner highly concordant with their expected in vivo hazard potential based on their chemical compositional profile. Overall, this study demonstrates that NAMs can be used to inform groupings of UVCBs and to identify representative substances of each category, for further read-across to fill data gaps and inform further testing, where needed.
The intention therefore is to apply these in-vitro biological techniques also to the substances subject to testing proposal to be able to specifically compare all results available for these sample on hydrocarbon composition together with in vivo and in vitro data.
Apart from the current focus on the reproductive toxicity endpoints, more recent re-evaluation of the Concawe dossiers indicated that some further testing will need to be done to address endpoints in categories where the currently available data or read-across argumentation is not sufficiently robust. This is part of the overall REACH strategy for human health, which consists of limited lower- and higher tier animal testing (an informed strategy to testing is applied to prevent unnecessary animal use) as well as the development and application of in-vitro alternative approaches.
For successful substance registration under REACH and appropriate classification under CLP, several types of environmental assessments are needed:
- An environmental risk assessment to determine whether the specific uses of a substance can be considered safe for the environment
- Data on ecotoxicity and fate to ensure accurate classification
- An assessment of persistence, bioaccumulation, and toxicity to determine whether the substance fulfils the criteria of PBT or vPvB
Due to the complex nature of petroleum substances, the hydrocarbon block method (HCBM) was developed by Concawe to evaluate the behaviour of these substances when released into the environment. The HCBM divides a petroleum substance into blocks of related constituents on the basis of chemical classes (e.g. n-paraffins, isoparaffins, naphthenics, and aromatics) and carbon number distribution. The separation of petroleum substance constituents to permit the HCBM is typically done using 2-dimensional gas chromatography coupled with flame ionization detector.
The fate and effects of these blocks can then be modelled to assess the environmental risks posed by a substance and its uses. This environmental risk assessment is performed using a tool known as Petrorisk.
In addition to the risk assessment which is conducted using Petrorisk, Concawe has filled the information requirements in the registration dossiers for REACH and for classification and labelling by compiling experimental ecotoxicity data for petroleum substances and using models, like the EpiSuite models and PetroTox. Concawe developed Petrotox, which simulates aquatic toxicity testing of petroleum substances based on compositional information using similar principles to Petrorisk.
The PBT/vPvB assessment must consider all relevant constituents and impurities of a substance composition. This poses a significant challenge for UVCBs, which contain a large number of constituents. Concawe’s PBT/vPvB assessment is based on hydrocarbon blocks and utilises a combination of experimental data for individual hydrocarbons and model data for a library of 16,000 representative constituents. This assessment is documented in the Concawe PBT report.
Concawe undertakes multiple research projects to generate further experimental data to support the assessment of petroleum substances. These include novel approaches to assess the biodegradation of hydrocarbons, bioaccumulation in terrestrial organisms, methods to evaluate endocrine disruption, and approaches to evaluate complex UVBC substances.
Concawe also actively engages with regulatory initiatives, like the PetCo Working Group and PBT Expert Group to work collaboratively with ECHA and MSCAs to address concerns about the PBT/vPvB assessment of petroleum substances.
The information that Concawe provides on its Website represents opinions and is intended for guidance only. Whilst the information is provided in utmost good faith and has been based on the best information currently available, it is to be relied upon at the user’s own risk. No representations or warranties are made with regards to its completeness or accuracy and no liability will be accepted for damages of any nature whatsoever resulting from the use of, or reliance on, the information.
Documents published by Concawe are based on interpretations of Regulation (EC) 1907/2006 (REACH Regulation) and Regulation (EC) 1272/2008 (CLP Regulation) as well as guidance provided by and information obtained from the European Chemicals Agency (ECHA).