Overcoming challenges in the processes of characterization, assessment, and registration of your UVCB in Europe

The demand under European regulations for detailed environmental risk assessment of UCVBs is challenging both the industry and regulators alike. Read on to explore the challenges and possible ways of overcoming them.

What is the definition of a UVCB?

A UVCB is a substance with an Unknown or Variable composition and is a Complex mixture derived either from a chemical reaction or from a Biological material. Such substances are found everywhere and contribute greatly to modern society. Examples include industrial coatings, construction materials, paints, inks, essential oils and enzymes. The EU definition of a UVCB is a substance of unknown or variable composition, complex reaction products or biological materials. Characteristically, a UVCB has:

• A relatively large number of constituents and/or
• A composition that is largely unknown and/or
• A variability of composition that is relatively high or poorly predictable

UVCBs are derived from sources and/or produced by methods that make their composition and effects not easily discoverable or definable. For example, if they originate from natural sources, composition may vary with the seasons or geographic location, as with a pine or cedar wood oil. And if the composition is known, the constituents may nevertheless have differing physicochemical and toxicological properties, which complicates assessment of hazards associated with them.

These complexities create significant challenges for the industry in meeting regulatory requirements, such as the European Union Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) regulation. A report by the European Chemicals Agency (ECHA), which implements REACH, said:

“UVCBs … pose the greatest challenge in a number of REACH processes, in particular in the context of dossier and substance evaluation but also in the priority setting activities of the Agency”¹

The ultimate challenge is how do you assess environmental hazards and risks to health – the ultimate purpose of regulations like REACH – if you cannot be sure exactly what a UVCB contains?

What are the regulatory challenges for defining UVCBs?

To register a substance, the first step is to be able to say what it is. In this respect, challenges for registering UVCBs under REACH fall into three categories:

• Identity
• Composition
• Manufacturing process

Identity: what are the constituents of the UVCB?

Before REACH, it was sufficient to define the identity of complex mixtures in very generic ways, for example lubricants by viscosity and molecular weight, petroleum chemicals by boiling point fraction and biological materials by optical activity. REACH brought in requirements to identify substances far more precisely, crucially facilitating better assessment of hazards to human health and the environment but, coincidentally, increasing challenges for registrants. Over time, REACH has evolved, and the amount of information required has risen, increasing the regulatory burden for registrants.

A major challenge has been that the provisions of REACH revolve around the concept of the individual substance and the test results to be obtained for it. So, the multiple constituents of a UVCB must be identified, either as individual constituents or groups of constituents with similar properties. This poses analytical challenges because UVCBs, by their nature, are difficult substances to analyze, for example mixtures of large numbers of isomers or inorganic materials such as slag from smelting processes. Sophisticated analytical and separation techniques are frequently required, such as gas chromatography–mass spectrometry (GC‒MS), 2D gas chromatography (2D GC), liquid chromatography with tandem mass spectrometry (LC-MS/MS) and quantitative nuclear magnetic resonance (NMR).

Composition: what is the ratio of constituents in the UVCB?

ECHA recognizes that it is not always possible to identify all constituents, but it requires identification of all individual constituents or groups of constituents that comprise more than 10% of the substance. Unknown constituents should be identified as far as possible by a generic description of their chemical nature. Furthermore, 100% of the substance must be accounted for in the IUCLID dossier (International Uniform Chemical Information Database dossier), as the concept of impurity is not applicable to UVCBs.²

Manufacturing process: why is this needed for registering UVCBs?

Uniquely for UVCBs, ECHA requires information on the manufacturing process because this helps with understanding what a substance is, i.e. helps identify it. The information is also essential for ECHA to be certain of substance identity when implementing the mandatory data sharing required under REACH.

For registration under REACH, in IUCLID, the information must include:²

• Identity and ratio of starting materials
• Description of reaction steps (in order of occurrence)
• Operating parameters that control the composition (e.g. temperature, pressure, solvent, catalysis type)
• Details of any extraction/isolation, clean-up/purification steps

For registrants, this is potentially a concern because all or part of the manufacturing process is often confidential. However, ECHA ensures this information is used only within ECHA and is never disseminated on the ECHA website, provided the correct fields have been completed in section 1.2 of the IUCLID dossier.

What are the challenges in testing UVCBs?

UVCBs require the same level of regulatory testing as simpler substances, applying Organization for Economic Co-Operation and Development (OECD) tests originally devised for single substances. The first challenge is what to test: whether to test the whole mixture or to test groups of constituents?

The whole-substance approach to UVCB testing

The whole-substance approach might appear more realistic for determining toxicity of a UVCB in the real world but there are many challenges, for example:

• Difficulty maintaining a steady concentration in the testing environment (due to factors such as degradation and volatility)³
• Problems with PBT (persistent, bioaccumalitive and toxic) assessment when constituents have different distributions and/or transformations by biotic/abiotic processes in the environment, i.e. have different environmental fates³
• Problems with water-accommodated fractions (WAFs). Use of the WAF approach to prepare test solutions of complex substances is a standard technique in aquatic toxicity testing. However, constituent depletion and factors such as instability pose problems. WAFs are not always useful for PBT and toxicity/risk assessment because they do not give adequate effect levels, such as no observed effect concentrations (NOECs), for deriving toxicity screening.³
• Constituents make very different contributions to overall solubility, having different individual solubility and mass fraction, which can make the water solubility test, for example, effectively become a leaching test.

Constituent and grouping (‘blocking’) approaches to UVCB testing

To use a constituent approach, the first challenge is that detailed information on constituents may be impossible to obtain, not least because they may not all be identifiable. It is also likely to be impractical to test every constituent. Instead, representative constituents can be selected, though this may be complicated by the variability of a UVCB, for example seasonal variability in its raw materials.

The well-established alternative to testing individual or representative constituents is grouping or ‘blocking’ the constituents on the basis of similarities such as mode of action (for biologicals), functional groups or physicochemical properties. The OECD gives detailed guidance on grouping in report 194 in its series on testing and assessment.⁴

With a grouping approach, it becomes possible to use the powerful tools of read-across and Quantitative Structure–Activity Relationship [(Q)SAR] to exploit information on chemicals in the same category to fill data gaps and reduce in vivo ecotoxicology testing. An example is hydrocarbon block methodology for petroleum UVCBs, which was established as long ago as 1996 and defines blocks according to carbon chain length and chemistry. Its developers, Concawe, now have a library of around 1500 hydrocarbon structures grouped according to characteristics such as boiling point and solubility, incorporated into a risk assessment tool.⁵ It uses (Q)SARs to estimate persistence (P) and bioaccumulation (B); then the blocks that test positive for P and B are evaluated for toxicity (T), identifying PBT blocks that will need further testing.⁶

Currently, for any substance registered, REACH requires a single result to be reported against each test, which is a challenge when different constituents produce different results. We still don’t know how appropriate it is to use and adapt standard tests, designed to generate single-substance fate information, for testing constituent blocks or individual constituents in a UVCB.³ Methods continue to be explored.³

Integrating a whole-substance and constituent-based approach to UVCB testing

To minimize data gaps associated with using only whole-substance or constituent-based information, the two could be integrated in a tiered approach (see Figure 1 for an example).³

Figure 1: A potential tiered approach to testing a UVCB. Adapted from Salvito et al. 2020.³ MoA, mode of action; PBT, persistent, bioaccumulative and toxic; (Q)SAR, quantitative structure–activity relationship

How can you overcome regulatory hurdles when testing your UVCB?

As ever, “know your substance” is the core advice. You will need to take the best practice approaches used for other chemicals but be even more assiduous in their application, because for a UVCB there is more to know.

A WoE approach may involve handling large amounts of data, and the U.S. Environmental Protection Agency (EPA) has produced comprehensive advice on assessing it on a WoE basis.⁷ Its WoE sequence can be summarized as:

• Gather information in-house and from literature searches, publications and secondary data
• Perform screening studies to fill data gaps
• Evaluate evidence, critically examining its relevance, quality and robustness
• Assign weight scores, e.g. the Klimisch score, which is standard use in REACH
• Integrate weighted evidence to support the hypothesis
• Interpret evidence to arrive at an overall conclusion
• Explain ambiguities and discrepancies

How can you ensure the dossier for your UVCB meets ECHA requirements?

The key is to support your UVCB with the most comprehensive identity and test data you can realistically obtain. Ensure you also avoid the following common problems ECHA encounters with ID information in UVCB dossiers:⁸

• Being unclear about the identity of the substance
• Not justifying why the substance is a UVCB
• Omitting the manufacturing process
• Identifying the UVCB as a mono constituent
• Not identifying known constituents
• Not including quantification
• Failing to account for 100% of the composition

What does the future hold for overcoming challenges with UVCBs?

Even after years of discussion, ECHA recognizes the balance between effective regulation and a proportionate approach (accepting some uncertainties in the information) has not been resolved; discussions are ongoing between regulators and industry to overcome challenges.⁹

There are strategies in place to address some of the scientific questions that need answering to develop testing and risk assessment for UVCBs. A major initiative is the CEFIC (European Chemical Industry Council)-funded ECO42 project.

CEFIC ECO42

The aim of the project is to develop new approaches for ecotoxicity testing of UVCBs, where the fate of the constituents is taken into account to ensure that the relevant constituents are tested. An example is where the biodegradation properties of a mixture are investigated and subsequent toxicity testing is conducted on the remaining sample/constituents. The short-term goal is progress on fate-directed toxicity testing for selected UVCBs. The long-term objective is higher quality UVCB testing to underpin future environmental risk assessment.

Other initiatives

Other proposed, completed and ongoing international programs aim to improve approaches to UVCBs, including modeling, new test methods and best practice guidance (Table 1).

Table 1: Examples of proposed, completed and ongoing programs contributing to improve approaches to UVCBs

U.S. EPA, U.S. Environmental Protection Agency; ECCC, Environment and Climate Change Canada; ECHA, European Chemicals Agency; HESI, Health and Environmental Sciences Institute; PetCo, petroleum and coal stream substances.

Conclusions

The regulatory challenges for UVCBs are recognized by industry and regulators alike.⁹ Fortunately, there is a spirit of cooperation in seeking solutions for the common problems of identity, what to test, compositional change during testing, and differing toxicity of constituents in any one UVCB.

Guidance and tools continue to be developed to assist in hazard testing and risk assessment of UVCBs. Increasingly, these rely on computational in silico methods, not just for hazardous property prediction of constituent properties, but also for the prediction of generic structures of very complex mixtures for further assessment and testing.

For your UVCB, successful registration will depend on understanding the substance well, choosing the appropriate testing strategy and keeping abreast of the evolving regulatory environment to ensure you obtain and supply sufficient data.

Want to learn more about how we can support your UVCB characterization, assessment, and registration needs? Contact us here.