Cefic-lri Programme | European Chemical Industry Council

LRI-C10 – A tiered strategy of modelled doses, analogy concepts, and testing to approach the human hazard of microplastic particles via inhalation pathway (Stage 1)


The range between no effect concentrations and measured data at the workplace or in the environment is essential for the risk assessment of microplastics. Especially when it comes to extrapolation from animal free results from in vitro testing to the situation in vivo, a tiered testing strategy and modelling of the relevant concentrations and doses is not available but required. In a recent perspective paper, properties and descriptors were summarized that serve as basis for a tiered testing strategy (Mitrano et al. 2020). Some stakeholders have explored concepts of analogy to group polymer particles with justification by similarity of selected properties and in vitro testing (e.g. InnoMat.Life stakeholder workshop on June 15th, 2021, adjacent to OECD activities), however, further work is warranted in this area. Combined testing and grouping strategies have proven beneficial for regulatory needs and provide science-based facts to customers and consumers, but they need a calibration by comparison to the testing of representative test materials (RTM) via the applicable OECD TGs. The comparison can be done in a first line by in vitro studies and needs – as a second line – ultimate prove by in vivo testing to inform on human health hazards. In vitro to in vivo dosimetry extrapolation (IVIVE) needs to be applied to ensure realistic test conditions. There is a need in providing basic understanding and application of both IVIVE and calibration methodology towards micro- and nanoplastics to gain a better understanding of the diverse nature of these particles towards potential human health inhalation hazards. This RfP is part of collaborative global efforts in microplastics research where the potential Cefic LRi-funded project targets such calibration for the exposure route of inhalation. The current call focusses on the initial stage of a tiered strategy to approach the human hazard of microplastic particles via inhalation pathway including the selection of representative test materials and targeted testing in vitro. Recommendations for planned work on confirmatory in vivo data are requested.


This project is to establish a tiered strategy of testing the human hazard of microplastic particles via inhalation pathway based on modelling of the relevant doses and correlation with measured no effect levels.

  • Provide a good understanding of the state of the art in understanding properties and descriptors of the hazard potential of particulates in general and with a focus on microplastics. Identify existing schemes for particle dosimetry and assessment, as well as relevant properties (molecular descriptors, particle morphology descriptors, particle interaction descriptors) by search in peer-reviewed literature, other relevant scientific literature, and global regulatory schemes. The literature search and documentation should focus on human health with relevance for the inhalation pathway.
  • Use well-characterised Representative Test Materials (RTM) that cover a large variety of polymeric particulate materials. Align and make use of international repositories of RTM, if already available. Some test materials may be inherited from e.g. InnoMat.Life, JRC (Seghers et al. 2021) or NIST, and should include RTMs of the Poorly Soluble, Low Toxicity (PSLT) polymer category.
  • Perform targeted testing on well-characterised test materials by phys-chem and in-vitro studies to (1) identify the most relevant molecular descriptors, particle morphology descriptors, particle interaction descriptors, (2) transfer concepts of analogy from other solid inhalable particles to microplastics, (3) validate the approach. In vitro methods should respect the doses relevant for the specific tissue as described in the literature for particle deposition and does modelling in vitro (Ma-Hock et al. 2021). Also, in vitro methods should rely on state-of the art methodology and should use cells lines that are relevant and -if possible- standardised and predictive e.g. alveolar macrophages, CALU3, and potentially more complex models. Rank properties by their relevance for human risk assessment, most specifically human hazard by inhalation.
  • Based on the ranking, provide recommendations for subsequent confirmatory in vivo studies. This concerns the evaluation of inhalation studies towards adverse and adaptive effects such as e.g. inflammation, neutrophil invasion, cytokine release, baseline cytotoxicity. Correlations may be included between the dose between in vitro studies and respective in vivo studies as well as considerations on deposition (e.g. by multiple path particle dosimetry modelling as currently validated by US EPA) and measured clearance of the inhalation pathway e.g. by pyrolysis GC-MS and other sensitive analytical techniques. The animal model used are rat as this species is the most studied and regulatorily accepted species for particle assessment in vivo.  Ideally, the suggested in vivo work allows to discard properties out of the initial literature search and Table 1. This may involve the focus on specific size fractions of a polydisperse exposure (e.g. below 2.5µm, below 10µm).
  • Provide the information to and interact with parallel work on deriving a model for human uptake and distribution (Cefic LRI XY), especially concerning the science-based group ranges (in the relevant descriptor) that support adequate binning ranges in the model (by the same descriptors).


Considering that microplastics consist of polymers, the descriptors of molecular structure and physical-chemical interactions as used by the OECD concept of polymers of low concern (Table 1), and general parts of the ECETOC risk assessment framework for polymers are of relevance (ECETOC 2019). Considering the analogy to nanoparticles, the descriptors for REACH registration of nanoforms (ECHA 2017, Commission 2018, Wohlleben et al. 2019) may serve as a baseline to form an initial hypothesis of properties that are likely relevant to assess the toxicity of solid particulate plastics (Table 1, shaded blue).(Andrady 2017, Hüffer et al. 2017, Hartmann et al. 2019). Several studies suggest that inhalation, which is the most critical human exposure route for nanoparticles, is relevant for microplastics as well (Vianello et al. 2019, Wright et al. 2020). There are concepts and initial assessments in place or currently suggested to assess particulate (polymer)particles in a regulatory setting (e.g. Polymers of low concern (PLC), or Table 1). Depending on these properties, many microplastics may belong to a Poorly Soluble, Low Toxicity (PSLT) polymer category (Jarabek et al., 2021), identified by cut-offs of respirable size, extractables, in vitro-reactivity and cytotoxicity, and biodissolution. If a microplastics does not meet all cut-offs, more properties (Table 1) may become relevant for which it needs to be shown that and how they relate to fate and effects, and how they can support other groups. The anticipated work should focus on the effects, shall correlate, and rank relevant properties, discard irrelevant properties, based on comparison to the effects in established available inhalation tests that are deemed as applicable, or shall identify targeted inhalation studies. In vitro assays are indispensable to regulatory acceptance of assessment frameworks and must use IVIVE dosimetry to compare tested doses to the in vivo doses and to measured, reliable aerosol concentrations of human exposure. The current RfP focusses on the initial stage of a tiered strategy to approach the human hazard of microplastic particles via inhalation pathway including the selection of representative test materials and targeted testing in vitro. Recommendations for planned work on confirmatory in vivo data are requested for the second stage. Therefore, the applicant needs to demonstrate experience with in vivo methodology on particle toxicology, too.

All types of solid microplastics are in scope of this anticipated project. The RfP is not restricted to certain type of micro-/nanoplastics e.g. polyolefin origin but shall systematically compare different solid polymer types.

Related links

LRI-C10 - A tiered strategy of modelled doses, analogy concepts, and testing to approach the human hazard of microplastic particles via inhalation pathway (Stage 1)


Andrady, A. L. (2017). "The plastic in microplastics: a review." Marine pollution bulletin 119(1): 12-22.

Commission, E. (2018). Commission Regulation (EU) 2018/1881 of 3 December 2018 amending Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) as regards Annexes I, III,VI, VII, VIII, IX, X, XI, and XII to address nanoforms of substances (Text with EEA relevance.). C/2018/7942. E. Commission.

ECETOC (2019). "The ECETOC Conceptual Framework for Polymer Risk Assessment (CF4Polymers)." ECETOC Technical Report 133-1.

ECHA (2017). "Appendix R.6-1 for nanomaterials applicable to the Guidance on QSARs and Grouping of Chemicals."

ECHA (2017). "How to prepare registration dossiers that cover nanoforms: best practices."

European_Commission (2011). COMMISSION REGULATION (EU) No 10/2011 of 14 January 2011 on plastic materials and articles intended to come into contact with food.

Hoppe, M., P. de Voogt and R. Franz (2016). "Identification and quantification of oligomers as potential migrants in plastics food contact materials with a focus in polycondensates – A review." Trends in Food Science & Technology 50: 118-130.

Hüffer, T., A. Praetorius, S. Wagner, F. Von Der Kammer and T. Hofmann (2017). "Microplastic exposure assessment in aquatic environments: learning from similarities and differences to engineered nanoparticles." Environmental Science & Technology.

Jarabek, A.M., T. Stedeford, G.S. Ladics, O.T. Price, A. Tveit, M.P. Hayes, R.T. Tremblay, S.A. Snyder, K.D. Salazar, S. Osman-Sypher, W. Irwin, M. Odin, J. Melia, H. Carlson-Lynch, M. Sharma, A.O. Stucki, A.J. Clippinger, S. Anderson, and T.R. Henry. (2021) “Poorly Soluble, Low Toxicity (PSLT) Polymer Category: An Integrated Approach to Testing and Assessment (IATA) Including New Approach Methods (NAMs) under the Toxic Substances Control Act (TSCA)”, SOT Poster 2593.

Ma‐Hock, L., Sauer, U.G., Ruggiero, E., Keller, J.G., Wohlleben, W. and Landsiedel, R., 2021. The Use of Nanomaterial In Vivo Organ Burden Data for In Vitro Dose Setting. Small, p.2005725.

Mitrano, D. M. and W. Wohlleben (2020). "Microplastic regulation should be more precise to incentivize both innovation and environmental safety." Nature Communications 11(1): 5324.

Seghers, J., Stefaniak, E.A., La Spina, R. et al. Preparation of a reference material for microplastics in water—evaluation of homogeneity. Anal Bioanal Chem (2021). https://doi.org/10.1007/s00216-021-03198-7

Vianello, A., R. L. Jensen, L. Liu and J. Vollertsen (2019). "Simulating human exposure to indoor airborne microplastics using a Breathing Thermal Manikin." Scientific reports 9(1): 1-11.

Wohlleben, W., B. Hellack, C. Nickel, M. Herrchen, K. Hund-Rinke, K. Kettler, C. Riebeling, A. Haase, B. Funk and D. Kühnel (2019). "The nanoGRAVUR framework to group (nano) materials for their occupational, consumer, environmental risks based on a harmonized set of material properties, applied to 34 case studies." Nanoscale 11(38): 17637-17654.

Wright, S., J. Ulke, A. Font, K. Chan and F. Kelly (2020). "Atmospheric microplastic deposition in an urban environment and an evaluation of transport." Environment international 136: 105411.


Timing: Project to start Q4 2021

LRI funding: 800 000€

Cost: 800 000€

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