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QSARs and Read-Across for Thiochemicals: A Case Study of Using Alternative Information for REACH Registrations

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Ecotoxicological QSARs

Part of the book series: Methods in Pharmacology and Toxicology ((MIPT))

Abstract

A case study on acute aquatic toxicity of thiochemicals shows the possibilities and limitations of filling data gaps with alternative information in accordance with the requirements of REACH. It is the objective of this study to extract as much information as possible from available experimental studies with fish, daphnia, and algae to estimate required data by QSARs and read-across.

Thiochemicals are considered to be toxic with an unspecific reactive mode of action (MoA) causing so-called excess toxicity, i.e., the effects are much higher than estimated from log KOW-dependent baseline QSARs. Differences in toxicity between groups of thiochemicals, for example, thioglycolates or mercaptopropionates, are thought to be due to differences in reactivity of the respective sulfur moiety, i.e., toxicodynamic differences. Thiochemicals within each group are different with regard to partitioning between biophases related to, e.g., increasing aliphatic chain length, i.e., toxicokinetic differences.

Due to the toxicodynamic and toxicokinetic differences, QSARs and read-across are limited to thiochemicals within the same group. Since the database per group of thiochemicals is too small to derive scientifically valid QSARs, most of the 36 data gaps for 16 thiochemicals to be registered by 2018 were closed by read-across. Testing strategies to fill remaining data gaps include tests with algae (six substances) and daphnia (six substances). Only for two substances, experimental (limit) fish studies are recommended. Overall, a substantial (>60%) reduction of tests by predictive in silico methods is possible.

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Notes

  1. 1.

    REACH: EU regulation on registration, evaluation, authorization, and restriction of chemicals [1]

  2. 2.

    The concept of functional similarity can support the MoA classification of chemicals by combining toxicological knowledge (which toxicity pathways can happen in which species under which exposure conditions) with chemical expertise (which parts of the chemical structures and physicochemical properties are involved in which interactions) [16,17,18,19].

  3. 3.

    OECD criteria for the scientific validity of QSAR models [30]: (1) a defined endpoint; (2) an unambiguous algorithm; (3) a defined domain of applicability; (4) appropriate measures of goodness of fit, robustness, and predictivity; and (5) a mechanistic interpretation, if possible

  4. 4.

    Note that QSARs are always performed on a molar basis.

  5. 5.

    https://aopwiki.org/

  6. 6.

    TMPMP: Trimethylolpropane trimercaptopropionate, CAS 33007-83-9

  7. 7.

    TEMPIC: Tris[2-(3-mercaptopropionyloxy)ethyl]isocyanurate, CAS 36196-44-8

  8. 8.

    PETMA: Pentaerythritol tetrakis(mercaptoacetate), CAS 10193-99-4

  9. 9.

    GDMP: Glycol di(3-mercaptopropionate), CAS 22504-50-3

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Author information

Authors and Affiliations

  1. Analytical Laboratory, Luhnstedt, Germany

    Monika Nendza

  2. Consultant, Berlin, Germany

    Jan Ahlers

  3. Bruno Bock Thiochemicals, Marschacht, Germany

    Dirk Schwartz

Authors
  1. Monika Nendza
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  2. Jan Ahlers
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  3. Dirk Schwartz
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Corresponding author

Correspondence to Monika Nendza .

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Editors and Affiliations

  1. Drug Theoretics and Cheminformatics Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India

    Kunal Roy

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Nendza, M., Ahlers, J., Schwartz, D. (2020). QSARs and Read-Across for Thiochemicals: A Case Study of Using Alternative Information for REACH Registrations. In: Roy, K. (eds) Ecotoxicological QSARs. Methods in Pharmacology and Toxicology. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-0150-1_22

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  • DOI: https://doi.org/10.1007/978-1-0716-0150-1_22

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-0149-5

  • Online ISBN: 978-1-0716-0150-1

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