REACH

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

Vertebrate animal studies have long served as the backbone in human health toxicological assessments. They are also central to some endpoints in eco-toxicological registrations. As a pillar of REACH legislation is to avoid unnecessary animal studies, registrants must consider appropriate New Approach Methodologies (NAMs) to fulfil information requirements in order to avoid unnecessary animal studies in testing each substance. Read-across (RA) is a commonly used alternative approach for data gap filling. RA involves the use of relevant information from analogous “source” substances to predict properties of the “target” substances under consideration. Relevant information requires primarily structural or compositional characterisation, as well as physical chemical properties and biological activity profiles. In addition to reducing animal use, the proper application of RA can improve the quality of the hazard assessment by bringing into consideration the weight of evidence of closely related substances and reduce the time required to provide compliant information for a substance.

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 and carbon number range of a given substance and High-Performance Liquid Chromatography (HPLC) to quantify the different aromatic classes present. These techniques 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 RA. 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 complex 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.

Human Health

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 structural read-across (RA, discussed above) to relevant data on related substances. A thorough data gap analysis then identified the need for the generation of new data on toxicity endpoints (incl. genotoxicity, repeated dose toxicity and/or reproductive toxicity) for several Concawe petroleum product categories where no historical data was available and read-across not applicable.

For instance, reproductive toxicity data is a standard requirement in REACH, comprising of two endpoints: i) Pre-Natal Developmental Toxicity (PNDT) and ii) fertility (more recently by an Extended One-Generation Reproductive Toxicity Study (EOGRTS)). As permission from ECHA is required before conducting a higher-tier toxicity test in vertebrate animals to satisfy these endpoints, in 2010 Concawe submitted testing proposals to conduct two PNDT and six EOGRT studies covering the identified data gaps in six substance categories firstly assessed including Gas Oil categories. A more recent re-evaluation of the Concawe dossiers indicated that further testing will be needed to address endpoints in additional petroleum substance categories. The current paradigm expects all testing proposals for non-CMR substances to submitted by 2030. This is part of the overall Concawe REACH strategy for Human Health, which consists of reducing and refining animal testing and the development (and application) of (in-vitro) alternative approaches e.g., to assess biological coherence and to strengthen RA justifications.

As such, a multi-year research project was initiated to bolster the read-across argument with detailed structural and biological data. A first step has been to better understand the variable composition within each substance and category to be able to identify representative samples for testing. The central tenet to the toxicology hypothesis is that reproductive toxicity is correlated to, and a product of, the quantity of 3-7 ring polycyclic aromatic hydrocarbons (PAHs) in petroleum substances. However, in order to not underestimate the hazards, the tested samples should also be representative of the whole hydrocarbon space of the considered substances and categories. Thus, samples will be chosen based on their weight-percent PAH and their hydrocarbon space mapping.

A second step is to support biological similarity. This is done with standard shorter-term animal testing, or bridging studies. Results from these oral and dermal 28-day screening studies (following the OECD 422 protocol) are compared such that they may allow Concawe 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) across the category. As OECD 422 studies do not require a decision from ECHA, nor Member State input, these tests can be performed prior to PNDT and EOGRT Testing Proposal submissions, or during their consideration period, with the potential to better inform (and potentially adapt) them.

The inherent complexity and variability of UVCBs present considerable challenges for establishing sufficient substance similarity based on chemical characteristics or other data. Thus, in addition to bridging studies, we hypothesized that animal testing alternatives (new approach methodologies (NAMs)), can be used to demonstrate similarity of UVCBs.

This was the main aim of the Cat-App project led by Concawe where 141 petroleum substances were tested as representative UVCBs in a compendium of 15 human cell types (including transformed cell lines, induced pluripotent stem cell (iPSC)-derived and primary cells) representing a variety of tissues and developmental contexts. Review of the vast amount of data, demonstrated that bioactivity data-based groupings of petroleum substances were generally consistent with the current substance process category-based grouping. We also showed that these bioactivity data can be used to rank substances in a manner highly concordant with their expected in vivo hazard potential based on their chemical composition. Overall, this study demonstrates that NAMs can be used to inform groupings of UVCBs and to identify representative substances of each category.

The future hope is to apply these in-vitro biological techniques and omics technologies (that aim at the collective characterization and quantification of pools of biological molecules in a given organism) through the lens of the more classical OECD 422 results with hydrocarbon composition data to minimize the need of future animal testing.

Environment     

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.