Open Access

Proposal for a harmonised PBT identification across different regulatory frameworks

  • Caren Rauert1Email author,
  • Anton Friesen2,
  • Georgia Hermann3,
  • Ulrich Jöhncke4,
  • Anja Kehrer2,
  • Michael Neumann4,
  • Ines Prutz5,
  • Jens Schönfeld5,
  • Astrid Wiemann5,
  • Karen Willhaus2,
  • Janina Wöltjen3 and
  • Sabine Duquesne3
Environmental Sciences EuropeBridging Science and Regulation at the Regional and European Level201426:9

https://doi.org/10.1186/2190-4715-26-9

Received: 21 November 2013

Accepted: 22 April 2014

Published: 12 May 2014

Abstract

European regulatory frameworks for chemicals (i.e. registered under REACH, plant protection products (PPPs), biocides, human and veterinary medicinal products) require that substances undergo an assessment to identify whether they are persistent (P), bioaccumulative (B) and toxic (T), or very persistent (vP) and very bioaccumulative (vB), i.e. to identify them as PBT substances or vPvB substances according to their properties. We screened current practices, evaluated possibilities and made a proposal for a harmonised assessment. Our proposal assumes that it should be possible to identify PBT and vPvB substances on the basis of the data available according to the requirements of the respective legal frameworks. For substances registered as PPPs and mostly also biocides and medicinal products, a ‘definitive assessment’ is often possible. Within REACH, the registrant has to provide all information necessary for PBT assessment regardless of the yearly tonnage of chemicals. But in cases of limited data availability, we suggest using a weight of evidence approach to account for such differences in data availability and type of data across different frameworks and to make use of valuable additional information. We propose to base the evaluation of persistence on degradation half-lives and to normalise a number of parameters (e.g. type of kinetics used, temperature). But further work is needed, e.g. for deriving DegT50 for water and sediment compartments. For the B-criterion, information other than BCF in fish could be considered and more information related to bioaccumulation processes should be gathered (e.g. in species other than fish, different uptake routes). Testing for T identification is focused on standard aquatic species but could also be complemented by e.g. information from other species. Information such as those read-across from structurally related substances and QSAR are often of importance for screening assessments. The aim of PBT and vPvB identification is to reliably target the problematic substances, with as few false negatives or positives as possible, regardless of the regulatory framework. Each aspect was thus considered in the context of the others for a final balanced decision. As the need for conservatism is interpreted differently under the various frameworks, harmonizing this identification is a challenging task.

Keywords

PBT identificationPersistenceBioaccumulationToxicityREACHPlant protection productsBiocidesHuman medicinal productsVeterinary medicinal productsHarmonisationRegulatory framework

Background

The different European substance regulations (e.g. REACH [1], plant protection products regulation [2], biocidal products regulation [3], human and veterinary medicinal products regulations [4, 5]) have all recognised that substances that are either persistent (P), bioaccumulative (B) and toxic (T) (PBT substances) or very persistent (vP) and very bioaccumulative (vB) (vPvB substances) must be considered as hazardous for the environment due to their potential for eliciting long-term adverse effects. The goal of preventing exposure of humans and the environment to PBT and vPvB substances is thus shared among all EU-based regulatory frameworks. In a comparison between different European and International regulations, Moermond et al. [6] reported that there are differences in how this goal is achieved, not only regarding technical criteria but also conceptual criteria (e.g. regulatory consequences for PBT and vPvB substances).

In terms of numerical criteria, the identification of PBT and vPvB substances is based on substance properties which are addressed by the same trigger values in all European substance regulations (see Table 1).
Table 1

PBT and vPvB criteria across the various European substance regulations

Criterion

PBT identification

vPvB identification

Persistence

• Half-life (degradation) > 60 days in marine water, or

• Half-life (degradation) > 60 days in marine, fresh or estuarine water, or

• Half-life (degradation) > 40 days in fresh or estuarine water, or

• Half-life (degradation) > 180 days in marine sediment, or

• Half-life (degradation) > 180 days in marine, fresh or estuarine sediment, or

• Half-life (degradation) > 120 days in fresh or estuarine sediment, or

• Half-life (degradation) > 120 days in soil

• Half-life (degradation) > 180 days in soil

Bioaccumulation

• BCF > 2,000 L/kg

• BCF > 5,000 L/kg

Toxicity

• NOEC (long-term) < 0.01 mg/L for marine or freshwater organisms, or

• Not applicable

• Classification as carcinogenic (category 1 or 2), mutagenic (category 1 or 2), or toxic for reproduction (category 1 or 2), or

• Other evidence of chronic toxicity, as identified by the classifications STOT RE 1 or STOT RE 2 pursuant to Regulation (EC) No 1272/2008

Therefore, it could be assumed that the identification of a PBT or vPvB substance should be independent of both the use of the substance and the regulatory framework under which it is assessed. However, the decision on whether a substance fulfils the PBT or vPvB criteria not only depends on substance properties, but also on the framework under which the substance is evaluated. For substances whose properties are near the trigger values, this decision may differ due to differences between the different legal frameworks in
  1. (i)

    The assessment procedures,

     
  2. (ii)

    The interpretation of PBT/vPvB criteria,

     
  3. (iii)

    Available data within the assessment process (see next subsection), and

     
  4. (iv)

    The regulatory consequences

     
Although based on the same principle (i.e. avoiding emissions of potentially harmful substances to the environment), the mandatory measures imposed by regulation for a substance identified as a PBT or vPvB vary between the different regulatory frameworks:
  • For substances registered under REACH, the revised Annex XIII [7] not only gives the criteria but also the information relevant for the screening and assessment of P, vP, B, vB and T properties. Also, ECHA provides extensive guidance on PBT/vPvB assessment [8, 9]. Substances of very high concern (SVHC) (e.g. PBT/vPvB) are included in the ‘candidate list’ for authorisation, based on the outcome of the scientific assessment of intrinsic properties. Substances on the ‘candidate list’ can then be prioritised for authorisation and finally listed in Annex XIV of the REACH regulation. Some substances may be listed with specific exemptions that do not require authorisation. For each substance included in Annex XIV, a deadline will be set after which use of that substance in the EU must stop (known as the ‘sunset date’), unless authorized by the European Commission.

  • The EU Biocidal Products Regulation [3] refers to Annex XIII of REACH [7] and to the ECHA guidance for PBT/vPvB assessment [8, 9]. However, for biocides, generally no authorisation will be granted for products containing substances identified as PBT or vPvB. Additionally, biocides that fulfil two of the three criteria are flagged as candidates for substitution and are subjected to a comparative assessment.

  • For the assessment of veterinary medicinal products, guidance has been developed by the European Medicines Agency [10], which also refers to ECHA guidance [8, 9]. A benefit-risk analysis is conducted in support of the decision on whether to authorise the substance or not [5]. In this context, an identification as a PBT substance is generally regarded as a serious concern.

  • For medicinal products for human use (which are usually emitted via sewage treatment plants), no restrictions are envisaged as human health is prioritised over environmental issues [4]. ECHA guidance [8, 9] is used for the assessment.

  • By contrast, the PPP Regulation [2] simply stipulates the PBT/vPvB criteria, oblivious to any other guidance. As for biocides, no authorisation will be granted for those substances identified as PBT or vPvB. Additionally, PPPs that fulfil two of the three criteria are flagged as candidates for substitution and are subjected to a comparative assessment, as is the case for biocides. The draft guidance developed by DG Sanco [11] focuses primarily on the identification of candidates for substitution.

Although the substances differ in their properties, uses, exposure pathways and regulatory consequences, the outcome of a PBT/vPvB assessment should not depend on the framework under which they are evaluated, since the protection goals do not differ. This will avoid situations where a substance with different uses is identified as a PBT substance under one regulation, and not under another. This is relevant because, for example, many biocides are also used as PPPs or veterinary medicinal products. Since regulatory authorities should aim at making predictable and consistent decisions, a strategy for harmonised PBT identification across the different frameworks is needed. The focus of this paper is on the assessment procedure; it proposes a reasonable interpretation of the available data while considering not only substance properties but also keeping in mind the regulatory consequences.

Dealing with differences in data requirements and data availability between regulatory frameworks

For substances registered as plant protection products (PPPs), as well as most biocides and medicinal products, requirements for environmental risk assessment usually include sufficient information for PBT/vPvB identification. Therefore, a ‘definitive assessment’ based on a direct comparison to the trigger values (see Table 1) of the three criteria should be possible in most cases.

For chemicals registered under REACH, data requirements depend on the quantities which are manufactured or imported per year; for high production volume (HPV) chemicals, more data has to be provided, and for substances below 10 t/a, only a basic data set is mandatory. Table 2 provides an overview of test requirements for persistence. The registrant also has to provide all information needed for PBT/vPvB assessment regardless of the tonnage manufactured or imported annually. However, the necessary information is not always included in the dossiers so a direct comparison of measured data with the criteria is not always possible. Unfortunately, in many cases, registrants submitted dossiers which show deficiencies and do not comply with the requirements of REACH or the Technical Guidance Document, e.g. necessary tests are missing [12, 13]. In such cases, only a ‘screening assessment’ can be performed. In such an assessment screening information such as that listed in Annex XIII of REACH [7] should be considered; this should be supplemented by data from non-standardised tests and from the literature, by information on relevant endpoints based on quantitative structure-activity relationships (QSARs) if adequately documented as well as by read-across from structurally related substances or grouping approaches. Only if the available information is considered unreliable or insufficient and/or does not permit a conclusion on each criterion to be drawn with sufficient confidence, additional testing will be necessary.
Table 2

Persistence testing requirements under the various European substance regulations

 

Test on ready biodegradability (OECD 301)

Laboratory degradation simulation test in soil (OECD 307)

Laboratory degradation simulation test in a water-sediment system (OECD 308)

Laboratory degradation simulation test in water (OECD 309)

Field degradation test

PPPs

Required

Required in four soils if not readily biodegradable

Required in two test systems if not readily biodegradable

Required if not readily biodegradable

Required if DegT50lab >60 days (20°C, pF2)

Human medicinal products

Required

Required in four soils if not readily biodegradable and Koc > 10,000 L/kg

Required in two test systems if not readily biodegradable

Not required

Not required

Veterinary medicinal products

Not required

Required in four soils

Required in two test systems for aquaculture or if risk is identified for aquatic organism

Not required

Not required

Biocides

Required

Required in four soils if not readily biodegradable and/or depending on emission pathway

Required in two test systems if not readily biodegradable depending on substance properties and emission pathway

Required if not readily biodegradable depending on substance properties and emission pathway

Required if PEC/PNECsoils >1 and DegT50lab >60 days (20°C, pF2) or DegT90lab >200 days (20°C, pF2)

Chemicals (REACH)

Required for all substances > 10 t/a

One simulation study in the ‘compartment of concern’ required for all substances >100 t/a if not readily biodegradable

Not required

Because of the large differences in data requirements across the different frameworks and type of data (e.g. QSARs, non-standardised tests), we recommend considering all available information in a weight of evidence (WoE) approach - as suggested in REACH (Annex XI 1.2 of [1]). The WoE approach means that all available information is assessed through expert judgement for its suitability and reliability, and relative weights are assigned (e.g. quality of the data, consistency of results and/or data, nature and severity of effects, relevance of the information for the given regulatory endpoint). The use of this WoE approach depends on the amount of information needed, the importance of the decision to be taken, and the likelihood and consequences of taking a wrong decision [14]. The WoE approach also has the advantage, such that it uses valuable additional information whose submission is not mandatory (e.g. field data, alternative testing strategies). This approach is proposed in REACH, and we suggest that it should also be used to improve PBT assessment under the other frameworks in cases where it could deliver valuable additional information.

Discussion

Persistence, bioaccumulation and toxicity criteria

In this chapter, we introduce the three criteria, i.e. persistence (P), bioaccumulation (B) and toxicity (T). The general scheme is to test sequentially for P, then B and lastly for T, as only substances with high persistence must be considered further for PBT identification. This sequence is further justified by the need to limit testing for animal welfare reasons.

A substance is considered a PBT or vPvB substance if it fulfills the P, B and T or the vP and vB criteria. In the following sections, for each PBT criterion, the criteria for the ‘definitive assessment’ are presented first. This is followed by the criteria for the ‘screening assessment’, which is carried out in cases of limited data availability.

Persistence

The persistence of a substance in soil, water or sediment is controlled by its intrinsic properties and also influenced by environmental conditions (e.g. temperature, presence of degraders, pH, moisture content in case of soil, bioavailability of the substance). The assessment of persistence is influenced by the type and quality of available studies and also by the interpretation of the available data.

Persistence is not characterised consistently in the different frameworks, but, as suggested by Boethling et al. [15] and in [9], it is the degradation half-life (DegT50) which should be compared to the trigger values in the various compartments, as a mere transfer (dissipation) from one compartment to the other does not affect the persistence of a substance. DegT50 values are commonly estimated from the parent substance in extractable residues in degradation simulation studies performed according to e.g. OECD test guidelines 307, 308 or 309 [1618].

In the context of PBT identification, DT50 should not refer to dissipation half-lives (DissT50) as these refer to cases where the substance may not be degraded but only redistributed (e.g. from the water phase to sediment or the atmosphere, or leaching, run-off, volatilisation or uptake into plants). This is explicitly mentioned in the revised Annex XIII of the REACH regulation [7], while the PPP Regulation [2] only refers to half-lives in general.

Definitive assessment

If degradation simulation tests have been conducted to meet legal requirements, a sufficient amount of reliable data is usually available to complete a definitive assessment by comparing the DegT50 values directly to the criteria as reported in Table 1. However, a number of issues related to these values should be addressed.

Type of kinetics for deriving DegT50

We suggest using single first-order (SFO) kinetics to derive DegT50 values for the purpose of comparing them to the trigger values. Best fit kinetics such as first-order multi-compartment (FOMC) can be used if they are recalculated by dividing the DegT90 values by a factor of 3.32 or by using the degradation rate constant of the slower phase in case of double first-order in parallel model (DFOP) or Hockey stick (HS) kinetics. This proposal is based on the Guidance Document on Estimating Persistence and Degradation Kinetics from Environmental Fate Studies on Pesticides in EU Registration [19]. This document gives detailed guidance on the derivation of DegT50 values, which is used for risk assessment of biocides, medicinal products and PPPs and could be applied to other substance groups as well.

Normalisation of the DegT50 to specific conditions

Variable conditions such as temperature, humidity, microbial populations and others have a large influence on the rate of degradation of a chemical substance. Simulation studies in the laboratory are conducted at various temperatures: OECD test guidelines 307 and 308 on transformation in soil and in water-sediment systems [16, 17] recommend testing at 20°C and 10°C (if the substance is used in colder climates), the US EPA recommends 22°C for soil testing [20] and for many pesticides, tests have been performed both at 20°C and 10°C. For the purpose of comparing different data, half-lives should thus be normalised to a defined temperature since it is a criterion which strongly influences the outcome of a degradation test and, furthermore, is quantifiable unlike other related criteria such as differences in microorganism populations. For PBT identification, normalisation of DegT50 values to a temperature of 12°C has been applied to many biocides and other chemicals, as prescribed in the TGD [21], and is included as an option in the REACH guidance on information requirements and chemical safety assessment (Chapter R.7b [8]). This temperature of 12°C is also included in the draft ‘Guidance on the assessment of persistent, bioaccumulative and toxic (PBT) or very persistent and very bioaccumulative (vPvB) substances in veterinary medicine’ [22]. By contrast, DegT50 values for PPPs are normalised to 20°C, both for laboratory and field data for risk assessment; this temperature has also been proposed for PBT identification [11]. For a consistent approach between frameworks, we propose normalising the DegT50 values to 12°C because this temperature is established or suggested under the majority of frameworks (i.e. Biocides Regulation, REACH and medicinal products Directives).

Degradation in soil: inclusion of field studies

Laboratory simulation studies can provide information on both route and rate of degradation. This permits the estimation of primary degradation rates (DegT50), as well as the measurement of carbon dioxide evolution and of formation of metabolites and bound residues. But the small size of the test systems is a limiting factor for both the test duration and the diversity of the microbial population (which may limit the probability of having competent degraders and which usually also decreases over time).

For PPPs, terrestrial field (dissipation) studies under realistic outdoor conditions are required when the DegT50 exceeds 60 days at 20°C in laboratory studies [2]. Such field studies allow DT50 values to be derived under conditions going beyond the limitations of laboratory tests. A number of conditions may be more realistic compared to laboratory studies (e.g., prolonged duration, fluctuating temperature and humidity, higher biological activity, larger test system), but may not be as easy to compare or reproduce. A limiting aspect in such testing is that a dissipation half-life, and not a degradation half-life, will be derived. The measured residues result from biotic degradation but also from photolytic transformation and field dissipation processes like volatilisation, leaching and run-off. However, a novel approach to estimate a DegT50 in field studies has recently been proposed by EFSA [23] in which dissipation processes on the soil surface are estimated separately from biodegradation in the soil compartment. This DegT50 has to be normalised for temperature and humidity for comparability reasons. Although this guidance was developed for the evaluation of persistence of PPPs in field studies, in principle, its rationale and approach should also be applicable to other types of substances. Thus, we suggest including field studies in persistence assessment as additional data, provided that it is possible to derive DegT50 values. This is in line with the WoE approach, which considers all available information in the decision process.

Evaluation of DegT50 values for the water and sediment compartments

There is no standardised test that measures true degradation only in the sediment compartment. The test on ‘aerobic and anaerobic transformation in aquatic sediment systems’ (OECD test guideline 308 [17]) is generally used to assess the fate of compounds in water and sediment systems, but reliable separate DegT50 values for water and for sediment cannot usually be derived from the study results. Therefore, separate DegT50 values are generally not available for comparison with the trigger values.

Available DT50 values for the water phase in many cases only refer to dissipation, as many substances, especially those with high log KOC and low water solubility, are quickly transferred to the sediment. The Aerobic Mineralisation in Surface Water – Simulation Biodegradation Test (OECD 309 [18]) is available to measure degradation in the water phase, but to date it has rarely been used for the assessment of environmental fate.

We suggest comparing the DegT50 of the total system to the two trigger values for water and sediment. More specifically, in the case of a substance that is rapidly transferred into the sediment, the DegT50 of the total system should be compared with the trigger value for sediment (120 and 180 days for persistence assessment). For substances that mostly remain in the water phase, the DegT50 values should be compared with the trigger values for water (40 and 60 days for persistence assessment). There will be many cases where a substance can be found in both the water and sediment phases, which means that clear criteria are necessary to judge which of the trigger values is appropriate.

Selection of an adequate DegT50 from multiple studies

As explained above, testing requirements for persistence differ greatly between regulatory frameworks. The information is summarized in Table 2.

If several valid degradation studies for one compartment are available, their quality and reliability are an important consideration. We propose the following approach to processing the information gathered:
  • When a small number of studies is available (i.e. up to 4 DegT50 values), we suggest selecting the worst-case DegT50 rather than performing a weak statistical evaluation.

  • When more studies are available (i.e. 5 and more DegT50 values), various approaches are possible:

The most conservative approach would be to use the worst-case DegT50;

A less conservative approach is the geometric mean, which gives a medium degradation rate, but does not provide information on the range of variability of the values and may produce some false negatives, i.e. fail to recognise some persistent substances;

An intermediate approach is the 90th percentile which may produce some false positives.
  • In cases where the studies are not equally reliable, the range and distribution of all available DegT50 values should be examined in the WoE approach. This is done by assigning different weights to them according to the quality of the studies, in order to select an acceptable value (or range of values) to represent the persistence of the substance.

If five or more DegT50 values are available, we suggest selecting the geometric mean. This is to be considered together with the decision to normalise the DegT50 values to a temperature of 12°C, in order to achieve an overall reasonable conservatism (i.e. target the problematic substances).

This choice is illustrated by the evaluation of a number of substances (64) with 5 and more soil laboratory DegT50 values available, whose the degradation data have been recently assessed as part of the regular national PPP registration process in Germany. This exercise indicates how many substances would be identified as P, on the basis of the above evaluation parameters.
  • For degradation in soil, only data from laboratory studies was used. Field studies were excluded since no evaluations according to the new EFSA scientific opinion [23] were available yet.

  • For water-sediment studies, the total system DegT50 was used and compared to the sediment value of 120 days.

  • Temperature was normalised both to 12°C and 20°C;

  • The maximum DegT50 value (worst-case scenario) and the geometric mean of all DegT50 were used.

The results indicate that the percentage of substances fulfilling the P criterion varies from about 39% for the least conservative approach (20°C and geometric mean) to 73% for the most conservative approach (12°C and maximum DegT50) and is intermediate (i.e. about 53%) when the geometric mean and a temperature of 12°C are used (Table 3).
Table 3

Estimation of percentages of substances fulfilling P criterion

Parameter

Persistent in both soil and w/s system

Persistent in soil only

Persistent in w/s system only

Total

Maximum

12°C

45%

17%

11%

73%

(29 of 64)

(11 of 64)

(7 of 64)

(47 of 64)

20°C

34%

8%

13%

55%

(22 of 64)

(5 of 64)

(8 of 64)

(35 of 64)

Geo mean

12°C

30%

3%

20%

53%

(19 of 64)

(2 of 64)

(13 of 64)

(34 of 64)

20°C

14%

3%

22%

39%

(9 of 64)

(2 of 64)

(14 of 64)

(25 of 64)

This evaluation was performed with a dataset of 64 PPP.

Screening assessment

For many chemicals, especially those registered under REACH, only a limited data set is available, as explained in Chapter 2. In this case, the assessment of persistence has to be based on screening data. If no further data are presented, the result of the screening assessment (i.e. screening P) should be used for further regulatory action unless refuted by more definitive data such as valid simulation test data.

In the screening approach, the evaluation of persistence is mainly based on tests on ready biodegradability (OECD 301 A-F [24] and OECD 310 [25]).

Substances which are readily degradable are considered not to be persistent (not P) [26], as the test is fairly stringent. Due to the high rate of mineralisation, an accumulation or formation of relevant metabolites is improbable. On the other hand, substances that are not readily biodegradable are considered to be potentially persistent (potentially P, sometimes also called ‘screening P’), until further data are presented. Due to the stringency of the test, this results in a high number of false positives; thus, ‘enhanced ready biodegradability’ tests (based on ready biodegradability tests but with prolonged test duration, higher concentration of microbial biomass, increased test volumes, but no pre-adaptation) may be used for chemicals registered under REACH to prove their degradability without having to conduct more expensive and time-consuming simulation studies.

Other available data on persistence also have to be examined. This may include data on abiotic degradation, monitoring data, QSAR estimations and read across from structurally related substances.

Main outcomes and open points

Our proposal is to base P identification on degradation, and not on dissipation, as recommended previously [6, 17]. Thus, trigger values should be compared to DegT50 values. The final identification of substances as persistent should be based on a reasonable conservatism for the various regulatory frameworks and not on a combination of various worst-case choices. Our proposal is summarised in Table 4.
Table 4

Main elements of our proposal for a harmonized assessment of persistence across regulatory frameworks

 

Persistence

Definitive assessment

Screening assessment

Criteria

Half-life

Ready biodegradability

 Water:

Enhanced ready biodegradability

  > 60 days in marine (>60 days)

  > 40 days in fresh- or estuarine (>60 days)

 Sediment:

  > 180 days in marine (>180 days)

  > 120 days in fresh- or estuarine (>180 days)

 Soil:

  > 120 days (>180 days)

Proposal

Considering DegT50 and not DissT50

Other information to consider

 Normalising DegT50 to 12°C

 Abiotic degradation

 Inclusion of field studies if DegT50 can be derived

 Monitoring data

 Selecting DegT50 from multiple studies:

 QSAR

  For ≤4 values: worst case

 Read-across from structurally related substances

  For ≥5 values: geometric mean, or WoE

  Water and sediment systems: comparing DegT50 to trigger

  Values of water and sediment; need clear criteria

Other information to consider

 Formation of NER or mineralisation rate

The P and vP criteria are included for definitive and screening assessments.

It should be noted that in the P assessment, other information generated in degradation simulation studies such as the formation of non-extractable residues (NER) or the mineralisation rate are not formally considered. Such information can only be taken into account in a WoE approach but should not be ignored. Where NER are the result of degradation and incorporation into the microbial biomass, their formation can be considered as a detoxification step. On the other hand, where the original substance may be remobilised, NER formation should be interpreted as a specific form of compound persistency. The issue of NER is currently being examined in various contexts [2729].

Bioaccumulation

Substances with a high potential for bioaccumulation are of special concern even if introduced into the environment in low concentrations. They are taken up by biota and their concentrations in the tissues result from the combination of uptake and depuration. Uptake occurs either via the surrounding medium - water or soil - (bioconcentration), food (dietary bioaccumulation) or the food chain (biomagnification). These processes are driven by the properties of the substance (mostly hydrophobicity as determined by octanol/water or octanol/air partition coefficient, i.e. KOW or Koa, as well as other characteristics, e.g. protein-binding properties) but they also depend on the environmental matrices (i.e. aquatic, terrestrial) and on the biological, ecological and trophic characteristics of the organisms.

The bioconcentration factor (BCF) is the usual basis for defining the B criterion in PBT assessment although it is not always the most relevant indicator of the environmental bioaccumulation potential of a substance, as stated in [30]. Indeed other available data (e.g. monitoring data, biomagnification, bioaccumulation in other species, literature data) should also be taken into account [3032]. We propose therefore that all available relevant information on bioaccumulation should be considered in a WoE approach.

Definitive assessment

The definitive assessment of the bioaccumulation potential is based on the bioconcentration factor (BCF) in an aquatic species. The trigger value for the BCF is set at >2,000 L/kg for B assessment and at >5,000 L/kg for vB assessment.

Bioconcentration

The bioconcentration factor (BCF) is defined as the ratio of concentration in fish to the concentration in the surrounding medium. It is generally derived experimentally according to OECD Test Guideline 305 I (bioconcentration flow-through fish test [33]). This test is appropriate for substances with moderate hydrophobicity, so it is necessary to determine the concentration of the test substance in the exposure medium and in fish. The test is mandatory for risk assessment for PPPs, biocides and human medicinal products if log KOW exceeds 3, and for veterinary pharmaceuticals if log KOW exceeds 4. It is also required for REACH substances with a production volume above 100 t/a and a log KOW >3.

The BCF should be normalised to a lipid content of 5% of total body weight (average lipid content of fish commonly used in [33, 34]). Potential growth dilution should also be taken into account [26, 33], as well as indications of slow or poor depuration.

Bioaccumulation and biomagnification

Bioaccumulation and biomagnification should also be taken into account for species such as fish since the relevant route of exposure may be the food, especially for substances with high log KOW and for substances poorly soluble or non-soluble in water. Indeed for such substances, it may be technically difficult or not feasible (i) to conduct a bioconcentration fish test since aqueous exposure via gill uptake is reduced and no longer accounts for the dominant exposure pathway, and/or (ii) to analyse the concentration in water. Instead, a dietary fish test has been developed to determine uptake by ingestion, yielding a biomagnification factor (BMF) [33].

A BMF >1 is a supportive indication of high bioaccumulation and the B criterion is thus considered as fulfilled. Nevertheless, a definitive trigger value for BMF has not yet been established. Hence, a bioaccumulation potential cannot be excluded in cases of BMF < 1. Recalculation of the dietary study data into aquatic BCF values has been suggested [26] but these methods have to be checked carefully for their domain of applicability [35].

Supplementary information
Other reliable data should also be considered, when available:
  • High bioaccumulation in organisms other than fish, as mentioned in the Stockholm Convention [36] and the revised Annex XIII criteria in REACH [7]; e.g. bioaccumulation in mussels [37] or oligochaetes [38]. In some cases, lipid normalisation concentrations should be revised since a normalisation to a lipid content of 5% of the body weight - as proposed for fish (see above) - may not be suitable for species with low lipid content (e.g. mussels);

  • Indicators other than BCF calculated from environmental data (i.e. measured in mesocosms or in the field), assessing the accumulation of substances from water and diet such as the bioaccumulation factor (BAF), their specific accumulation in food webs expressed as biomagnification factor (BMF) or trophic magnification factor (TMF);

  • Bioaccumulation via different uptake routes, e.g. terrestric or benthic oligochaetes [38, 39]. As bioaccumulation may differ between water- and air-breathing organisms, aquatic bioaccumulation data should not be transfered to air-breathing organisms [31];

  • Accumulation in specific tissues, e.g. substances such as PCBs accumulate extensively in fatty tissues and organs from wildlife samples [40]. In some cases, inefficient or nonexistent detoxification processes may be responsible for high BCF values (e.g. TBT in molluscs) [41, 42].

  • Non-lipid-based accumulation for substances such as perfluorinated acids, which bioaccumulate in blood plasma proteins [43, 44]. Perfluorooctane sulfonate (PFOS) can be considered as bioaccumulative even though the BCF is below the trigger value (<2,000) but it has a long half-life, high toxicity and high biomagnification.

  • Toxicokinetic and chronic studies with mammals as well as in vitro data on aquatic bioaccumulation as required for human toxicological assessment are also available.

Screening assessment

The screening criterion for assessing bioaccumulative properties is derived from the hydrophobicity of the compound. A substance is considered to potentially fulfil the B criterion when log KOW exceeds a value of 4.5 [21].

Suitable quantitative structure-activity relationship (QSAR) models for estimating the BCF could be used if log KOW is between 4.5 and 6, as the available BCF QSAR models are linear between log KOW 2 to 6 [21, 45]. For highly hydrophobic substances (log KOW > 6), the potential for bioaccumulation must be assessed through expert judgement and on a case-by-case basis, taking into account the specific physico-chemical properties of the substance (e.g. molecular size and weight, log KOW) and the available BCF QSAR models (e.g. parabolic equation in [21, 46]).

Since hydrophobicity does not drive all bioaccumulation processes, other information has to be considered, e.g. surface activity, structural alerts, high log KOA (octanol/air partition coefficient) as an indicator of a possible bioaccumulation in air-breathing organisms or read-across approaches from structurally related substances.

Main outcomes and open points
Our proposal (see Table 5) is to consider all available endpoints in addition to the BCF for aquatic organisms in the WoE approach, as there are other standardised tests resulting in the derivation of other BAFs (e.g. benthic oligochaetes [38]; terrestric oligochaetes [39]) and BMFs (fish dietary test guideline [33]). Currently, a comparison between the results of these tests (e.g. BMF, BAF) and a BCF is difficult to make for several reasons such as different uptake mechanisms of different taxa. Also, in vitro tests for bioaccumulation (e.g. [47]) are being developed and using information from field studies and TMF (e.g. [42, 48]) is being considered. Taking into account these various aspects will improve the assessment of bioaccumulation.
Table 5

Main elements of our proposal for a harmonized assessment of bioaccumulation across the regulatory frameworks

 

Bioaccumulation

Definitive assessment

Screening assessment

Criteria

BCF > 2,000 L/kg (>5,000 L/kg)

Log KOW > 4.5

Proposal

BCF (normalised to 5% lipid content)

QSAR if log KOW is between 4.5 and 6, log KOW > 6: expert judgement, case- by-case

For high log KOW and poorly soluble or non-soluble: consider BAF, BMF (BMF > 1 indicative)

Other information to consider

Other information to consider

 Surface-activity

 High bioaccumulation in species other than fish

 Structural alerts

 Different uptake routes

 High log KOA for air-breathing organisms

 Accumulation in specific tissues

 Read-across from structurally related substances.

 Non-lipid based accumulation

 Toxicokinetic and chronic studies with mammals

In vitro data on aquatic bioaccumulation

The B and vB criteria are included for definitive and screening assessments.

Toxicity

For substances with high persistence and bioaccumulation potential, i.e. fulfilling the P and the B criteria, long-term exposure of organisms can be expected, which may cover the whole life-span of the exposed organisms and even several generations. Therefore, long-term and/or chronic ecotoxicity data, ideally covering the reproductive stages, should be used for assessing the T criterion in the context of a PBT assessment.

Definitive assessment
The substance fulfils the T criterion in any of the following situations:
  1. 1.

    Long-term or chronic NOEC or EC10 values from ecotoxicological tests with aquatic organisms are below the trigger of 0.01 mg/L, or

     
  2. 2.

    It is classified as carcinogenic, categories 1 and 2 [49] or 1A and 1B [50], mutagenic, categories 1 and 2 [49] or 1A and 1B [50] or toxic for reproduction, categories 1, 2 and 3 [49] or 1A, 1B and 2 [50], so-called CMR substances, or

     
  3. 3.

    There is other evidence of chronic toxicity, as identified by the classification of the substance as T, R45, R46, R48, R60 and R61 or Xn, R48, R62, R63, R64 [49], or specific target organ toxicity and repeated exposure (STOT RE category 1 or 2) [50].

     

If any classification criteria under 2 or 3 are met, there is no need to perform any further aquatic studies for evaluation of toxicity.

Supplementary information

When substances such as PPPs and biocides (i.e. produced to control pests) are tested for toxic effects, it is likely that these will occur both in the target species and in non-target species belonging to the same taxonomic group. Testing for the T criterion refers only to aquatic organisms. However, effects on non-aquatic species could be relevant as well, bearing in mind, however, that the use of vertebrates for testing should generally be minimised.

In this context, we recommend that other reliable data should also be considered where available:
  • For PPPs and biocides, results of subchronic, chronic or reproduction studies with birds and mammals may be available. In this context, a NOEC of ≤30 mg/kg food in a long-term bird study should be considered as an indication that the T criterion is met [21, 26].

  • It could be relevant to use toxicity data from long-term ecotoxicological tests on terrestrial organisms, e.g. OECD TG 222 [51]. However, in such a case, it has to be clarified whether such an assessment should (i) be based on trigger values comparable to those used in the assessment of toxicity for aquatic organisms (e.g. <0.01 mg/kg dry soil), and (ii) take into account differences in the exposure of the respective organisms.

  • For substances with high log K ow, tests performed with sediment-dwelling species may provide better information than tests with pelagic species. Indeed, the results may be more reliable if the substance partitions out of solution. Also, the information gathered may be more useful if it is focused on the compartment in which the substance will likely be found. A way to determine whether a substance has equivalent toxicity in sediment as in the water column should be proposed.

Furthermore, information on aquatic toxicity other than that gathered from standard studies and provided for in relevant test guidelines, i.e. information from non-standard studies and non-standard endpoints, could be used as supporting data. Also, the endocrine disrupting potential of chemical substances is an issue. It is planned to develop a general concept for EDCs which should be consistent and should ensure that endocrine disruptors are dealt with in a consistent and coordinated manner across the different regulatory frameworks [52]. This issue has been discussed by a panel of experts of the German Federal Environment Agency (UBA) [53]. This could be considered for inclusion of EDC potential in the harmonised assessment of the T criterion.

Screening assessment
The screening criteria for assessing toxicity are based on short-term (acute) toxicity of the compound on aquatic organisms. They are as follows:
  • A substance with at least one acute LC50/EC50 value below 0.1 mg/L is considered to be potentially toxic (potentially T, sometimes called ‘screening T’ under REACH). This classification can only be revoked by adequate chronic data, i.e. for determination of definitive criteria for T [26];

  • A substance with acute LC50/EC50 values below 0.01 mg/L is considered to be toxic (T), as NOEC or EC10 values from prolonged or chronic toxicity studies will always be below acute LC50 or EC50 values for the same taxon [26].

Other possibilities include the use of QSAR and read-across from structurally related substances, if testing of the substance is technically impossible because of its physico-chemical properties or in cases of data poor situations.

Main outcomes
The criteria for the definitive and the screening assessment of the T criterion are to a large extent consistent between the different regulatory frameworks. However, in situations where data availability or adequacy is too poor to support a definitive or a screening assessment, we propose that other indications of toxicity potential should be taken into account (Table 6). These include, for example, endpoints from toxicity tests with terrestrial organisms, endocrine-disrupting properties, QSAR calculations or harmonised toxicological classifications. Since trigger values have not yet been set for these endpoints, a WoE approach is needed to decide on a case-by-case basis whether a substance fulfils the T criterion as part of PBT assessment.
Table 6

Main elements of our proposal for a harmonized assessment of toxicity across regulatory frameworks

 

Toxicity

Definitive assessment

Screening assessment

Criteria

NOEC (long-term) < 0.01 mg/L, marine or freshwater species

≥1 value for acute LC50/EC50 < 0.1 mg/L: potentially toxic

CMR substances

Acute LC50/EC50 values < 0.01 mg/L: toxic

Other evidence of chronic toxicity

Proposal

Other information to consider

Other information to consider

 NOEC ≤ 30 mg/kg food, birds and mammals

 QSAR

 Long-term tests on terrestrial organisms

 Read-across from structurally related substances.

 High log KOW: sediment-dwelling species tests

 Information from non-standard aquatic studies and endpoints

 Endocrine-disrupting potential

The T criteria for definitive and screening assessments is included.

Considering metabolites and transformation products

Transformation products can be as or even more persistent than their parent compounds and thus must be included in chemical assessment. However, the regulatory frameworks for substances differ with respect to the inclusion of metabolites or transformation products in PBT identification. For PPPs, the consideration of metabolites in the context of PBT identification has been controversially discussed, as PPPs Regulation 1107/2009 [2] does not address this issue precisely and only refers to the relevance of metabolites in a general sense (Art. 3(32) Annex II point 3.3). However, a current proposal envisages excluding metabolites in the process of PBT identification and in the identification of candidates for substitution (i.e. substances that meet two of the three criteria) [11]. REACH requires that registration documents for chemicals produced or imported in excess of 100 t/a include information about metabolites and transformation products [54]. They are to be considered in PBT identification if they exceed 0.1% of the substance weight [9, 26]. For both human and veterinary medicinal products, transformation products >10% are considered to be ‘relevant’ and thus included in risk assessment as well as in PBT assessment. In the assessment of biocides, major metabolites (≥10% or ≥5% at two consecutive sampling points or maximum not reached but ≥5% of the active substance at the final time point) are considered in PBT identification and minor metabolites only if data are available or there is any reason for concern. It is questionable whether relevance can be defined in terms of any percentage. Since humans and the environment should be protected from exposure to PBT and vPvB substances, the same criteria should apply to metabolites or transformation products as to the parent compounds. We suggest that in all regulatory frameworks, metabolites and transformation products should be included in the assessment.

Conclusions

The various European regulatory frameworks on chemical substances agree that exposure of humans and the environment to substances identified as PBT or vPvB must be avoided. But the decision-making process is not straightforward and harmonisation between the frameworks is a real challenge. Indeed, despite the same trigger values, the identification of a PBT or vPvB substance will depend on how the criteria are used in the various frameworks to determine.
  1. (i)

    For persistence, the half-lives in terms of e.g. temperature normalisation, how field studies are considered, appropriate statistics, and others,

     
  2. (ii)

    For bioaccumulation, e.g. the endpoints - in addition to the BCF for aquatic organisms - considered in a WoE approach, and

     
  3. (iii)

    For toxicity, e.g. indications of toxicity potential considered when availability or adequacy of data is too poor to support a definitive or a screening assessment.

     

Differences in testing requirements, data availability, data evaluation and interpretation were screened and discussed to identify the best methods. The current proposal is thus characterised by its robustness against those differences and by its reasonable conservatism.

For example, the proposal for the Persistence criterion is based on the outcome of an evaluation performed on a set of selected active substances of PPPs. We recommend (i) normalising the DegT50 values to a temperature of 12°C as this is established in biocides legislation and suggested in other regulations (REACH and medicinal products directives), and (ii) selecting the geometric mean if five or more DegT50 values are available, or a suitable value or range of DegT50 values in a WoE approach if the studies are not equally reliable.

Finally, the differing mandatory measures imposed by the various regulations should be considered together with the present proposal on harmonised PBT/vPvB identification in order to ensure that the truly problematic substances are identified.

Abbreviations

B: 

Bioaccumulation

BAF: 

bioaccumulation factor

BCF: 

bioconcentration factor

BMF: 

biomagnification factor

CMR: 

carcinogenic, mutagenic and toxic for reproduction

DegT50: 

degradation half-life

DissT50: 

dissipation half-life

EC10: 

effect concentration, 10%

EC50: 

effect concentration, 50%

EDCs: 

endocrine-disrupting chemicals

EFSA: 

European Food Safety Agency

EU: 

European Union

FOMC: 

first-order multi-compartment

KOW: 

octanol/water partition coefficient

Koa: 

octanol/air partition coefficient

LC50: 

lethal concentration, 50%

NER: 

non-extractable residues

NOEC: 

no observed effect concentration

OECD: 

Organisation for Economic Cooperation and Development

P: 

persistence

PBT: 

persistent, bioaccumulative and toxic

PCBs: 

polychlorinated biphenyls

PFOS: 

perfluorooctane sulfonate

PPPs: 

plant protection products

QSAR: 

quantitative structure-activity relationships

REACH: 

Registration, Evaluation, Authorisation and Restriction of Chemicals

SETAC: 

Society for Environmental Toxicology and Chemistry

SFO: 

single first order

STOT RE: 

specific target organ toxicity - repeated exposure

SVHC: 

substances of very high concern

T: 

toxicity

t/a: 

tons per year

TBT: 

tributyltin hydride

TG: 

test guideline

TGD: 

Technical Guidance Document

TMF: 

trophic magnification factor

UBA: 

Umweltbundesamt (German Federal Environment Agency)

US EPA: 

United States Environmental Protection Agency

vPvB: 

very persistent and very bioaccumulative

WoE: 

weight of evidence.

Declarations

Acknowledgements

We thank our colleagues from the Federal Environment Agency (Umweltbundesamt, UBA, Germany) and other authorities as well as colleagues from academia and industries for fruitful discussions.

Authors’ Affiliations

(1)
Section International Chemicals Management, Federal Environment Agency (UBA)
(2)
Section Biocides, Federal Environment Agency (UBA)
(3)
Section Plant Protection Products, Federal Environment Agency (UBA)
(4)
Section Chemicals, Federal Environment Agency (UBA)
(5)
Section Pharmaceuticals, Washing and Cleaning Agents, Federal Environment Agency (UBA)

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