Practical Guide 5: How to report (Q)SARs - ECHA - Europa

Practical guide 5:
How to report (Q)SARs

LEGAL NOTICE
This document contains guidance on REACH explaining the REACH obligations and how to fulfil
them. However, users are reminded that the text of the REACH regulation is the only authentic
legal reference and that the information in this document does not constitute legal advice. The
European Chemicals Agency does not accept any liability with regard to the contents of this
document.
Practical guide 5: How to report (Q)SARs
Reference: ECHA-10-B-10-EN
ISBN-13: 978-92-9217-004-2
ISSN: 1831-6727
Date: 24/03/2010
Language: EN
© European Chemicals Agency, 2009.
Cover page © European Chemicals Agency
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TABLE OF CONTENTS
1. INTRODUCTION .................................................................................................................. 1
2. HOW TO GET STARTED WITH (Q)SARS .......................................................................... 2
2.1. Substance characterisation ..................................................................................................... 2
2.2. (Q)SAR models .......................................................................................................................... 2
2.3. Overall Assessment of adequacy and reporting .................................................................... 2
3. QUESTIONS ON HOW TO APPLY AND REPORT (Q)SAR UNDER REACH ................... 4
3.1. Which Guidance documents should I read? .......................................................................... 4
3.2. Is the (Q)SAR model valid? ...................................................................................................... 4
3.3. Does the substance fall within the applicability domain of the (Q)SAR model? ................ 5
3.4. Is the model prediction adequate for the purpose of classification and labelling
and/or risk assessment? .......................................................................................................... 5
3.5. How do I report a (Q)SAR prediction in IUCLID 5? ................................................................ 6

1. INTRODUCTION
Regulation (EC) No 1907/2006 concerning the Registration, Evaluation, Authorisation
and Restriction of Chemicals (hereafter, REACH) foresees the use of non test methods
such as (Quantitative) Structure-Activity Relationships [(Q)SARs], grouping of
substances and read-across for adaptation of the standard testing regimes. More
specifically, Recital 47 of REACH determines the objectives of the Regulation with
respect to avoidance of unnecessary testing on vertebrate animals:
“[…] it is necessary to replace, reduce or refine testing on vertebrate animals.
Implementation of this Regulation should be based on the use of alternative test
methods, suitable for the assessment of health and environmental hazards of
chemicals, wherever possible. The use of animals should be avoided by recourse to
alternative methods validated by the Commission or international bodies, or
recognised by the Commission or the Agency as appropriate to meet the information
requirements under this Regulation.”
These methods and other data sources have to be explored before considering
vertebrate animal testing. This practical guide provides an overview of important aspects
when predicting properties of substances using (Q)SAR models as defined in the
REACH Regulation. More detailed information is available in the Guidance documents
(see 3.1.).
The information given in this practical guide does not describe the requirements to pass
the technical completeness check which are illustrated in the Dossier Submission
Manual (No. 05 - How to complete a technical dossier for registrations and PPORD
notifications).
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2. HOW TO GET STARTED WITH (Q)SARS
The use of (Q)SAR models with software is rather straightforward. However, experience
and a thorough understanding of (Q)SARs will be needed when it comes to the
assessment of whether predictions are reliable and adequate for the purpose of
classification and labelling and/or risk assessment and can thus be used instead of
testing.
2.1. Substance characterisation
The chemical structure needs to be well defined, following the Guidance on identification
and naming of substances under REACH. All individual constituents of multi-constituent
substances should be addressed. The composition of the well defined substances has to
include also known impurities (and additives, if any). For UVCBs, expert judgement is
needed to decide whether structures can be identified which are representative for the
substance. In case of a stable transformation product, it should be identified. A suitable
structural representation for the chemical (SMILES, mol file etc.) is usually required.
Stereochemistry should be taken into account if necessary.
2.2. (Q)SAR models
SAR and QSAR models, collectively referred to as (Q)SARs, are theoretical models that
can be used to predict in a quantitative or qualitative manner the physico-chemical,
biological (e.g. a (eco)toxicological) and environmental fate properties of compounds
from the knowledge of their chemical structure. A SAR is a qualitative relationship that
relates a (sub)structure to the presence or absence of a property or activity of interest. A
QSAR is a mathematical model relating one or more quantitative parameters, which are
derived from the chemical structure, to a quantitative measure of a property or activity. In
order to predict a property of a chemical, the validity of the selected (Q)SAR model
should be assessed, and it should be verified that the chemical falls within the
applicability domain to give a reliable prediction.
2.3. Overall Assessment of adequacy and reporting
In order to generate a reliable and adequate prediction of the presence or absence of a
chemical’s property to fulfil the information requirements under REACH, (i) a (Q)SAR
model should be used whose scientific validity has been established and (ii) the
substance should fall within the applicability domain of the (Q)SAR model, (iii) the
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prediction should be fit for the regulatory purpose, and (iv) the information should be well
documented. An assessment of the first three points above is expected to be included in
the registration dossier if substance properties are predicted using (Q)SAR models. In
case there is not sufficient information to address all of them, a prediction could be used
as part of a weight-of-evidence approach or as supporting information. The closer the
outcome is to a regulatory decision point (e.g. classification of a substance as hazardous
versus non classification), the more accurate predictions or a more detailed justification
is needed. The consequences of a wrong decision based on predicted properties will
indicate how much uncertainty for the prediction can be accepted.
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3. QUESTIONS ON HOW TO APPLY AND REPORT
(Q)SAR UNDER REACH
3.1. Which Guidance documents should I read?
A four pages summary on how to use non-testing data obtained by applying (Q)SARs is
available in the Guidance on information requirements and chemical safety assessment
in:
Chapter R.4: Evaluation of available Information:
R.4.3.2.1 (Q)SAR data
A dedicated part on computational methodologies is available in the Guidance on
information requirements and chemical safety assessment in
Chapter R.6: (Q)SARs and grouping of chemicals:
R.6.1 Guidance on (Q)SARs
Relevant tools and approaches for the endpoint(s) of interest are offered by each
endpoint specific guidance document included in the Guidance on information
requirements and chemical safety assessment in:
Chapter R.7: Endpoint specific Guidance.
Information on the use of non-testing degradation and bioaccumulation data for
persistent, bioaccumulative and toxic (PBT) chemicals is accessible from the Guidance
on information requirements and chemical safety assessment in:
3.2. Is the (Q)SAR model valid?
Chapter R.11: PBT Assessment.
The validity of (Q)SAR models for regulatory purposes is characterised and documented
according to the five agreed OECD principles, as described in the REACH guidance
R.6.1 Guidance on (Q)SARs:
1. The (Q)SAR model should be associated with a defined endpoint.
2. The (Q)SAR model should be expressed in form of an unambiguous algorithm.
3. The (Q)SAR model should be associated with a defined domain of applicability.
4. The (Q)SAR model should be associated with appropriate performance of the
model (the statistical “goodness” of the model, robustness and predictivity).
5. The (Q)SAR model should be associated with a mechanistic interpretation for
human health and ecotoxicological endpoints, if possible.
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A reference to a well-documented model or a (Q)SAR Model Reporting Form (QMRF),
attached to a dossier, will be beneficial for the dossier submitter and is highly
recommended. See the Guidance on information requirements and chemical safety
assessment, Chapter R.6: (Q)SARs and grouping of chemicals (R.6.1.9.1) for more
details on how to generate in the QMRF. Please note that the JRC (Q)SAR Model
Database (QMDB) is intended to provide information on (Q)SAR models submitted to
JRC for peer review (http://qsardb.jrc.it/qmrf/search_catalogs.jsp).
There is no formal adoption process foreseen for (Q)SAR models; the validity,
applicability and adequacy of (Q)SAR models for regulatory purposes will be assessed
on a case-by-case basis.
NOTE: A valid (Q)SAR model does not necessarily produce a valid prediction. It is
necessary to assess whether the substance falls within the applicability domain of the
(Q)SAR model, that the results are adequate for the purpose of classification and
labelling and/or risk assessment, and that adequate and reliable documentation of the
applied method is provided.
3.3. Does the substance fall within the applicability domain of
the (Q)SAR model?
In order to get a reliable prediction, it is important to verify that the chemical of interest
falls within the applicability domain of the model. The concept of applicability domain
was introduced to assess the probability of a chemical being covered by the (Q)SAR
training set and it is connected to the reliability of the prediction. The applicability of a
model could, for example, be based on the (sub)structures present in the molecules
and/or a range of molecular descriptor or prediction values. The applicability domain can
also be defined by chemicals (or their metabolites/degradation products) having the
same reaction mechanisms: e.g. types of reactivity or interaction with biomolecules.
Sometimes it is not the chemical itself which reacts with biomolecules but its
metabolites/degradation products. Therefore, it is also important to investigate
metabolic/degradation pathways and the reactivity of the metabolites/degradation
products. See the Guidance on information requirements and chemical safety
assessment, Chapter R.6: (Q)SARs and grouping of chemicals (R.6.1.5.3) for more
details.
3.4. Is the model prediction adequate for the purpose of
classification and labelling and/or risk assessment?
For a (Q)SAR prediction to be adequate, it should be not only reliable, but also relevant
for regulatory decision. The adequacy of the model prediction for the purpose of
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classification and labelling and/or risk assessment will be very much endpointdependent.
Additional information might be needed to assess the generated prediction
for adequacy in the context of a regulatory decision. Therefore, the validity (are the five
OECD principles on scientific validity of a model fulfilled?), applicability (can reliable
predictions be expected if the model is applied to the substance of interest?) and
relevance (is the information generated which is needed for the risk assessment and/or
classification and labelling?) needs to be assessed for each individual prediction.
Scientifically valid
(Q)SAR model
Reliable (Q)SAR
result
Adequate
(Q)SAR result
(Q)SAR model
relevant for the
regulatory
purpose
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(Q)SAR model
applicable to
query chemical
3.5. How do I report a (Q)SAR prediction in IUCLID 5?
To report a (Q)SAR prediction in IUCLID 5, the following information has to be provided:
1. Information on the validity of the (Q)SAR model.
2. Verification that the substance falls within the applicability domain of the (Q)SAR
model.
3. Assess the adequacy of the results for the purpose of classification and labelling
and/or risk assessment.
The information on these three points should be compiled according to the (Q)SAR
Prediction Reporting Format (QPRF). See the Guidance on information requirements
and chemical safety assessment, Chapter R.6: (Q)SARs and grouping of chemicals
(R.6.1.10.1) for more details on QPRF.
Note: the substance for which the registration is being made may contain more than one
constituent and/or impurities. In such cases it may be useful to prepare an individual
endpoint study record for each constituent in order to be able to address each chemical
separately (recommended if constituents have different properties and thus different
models, assessments, etc. have to be applied).
The information shall be reported in the IUCLID 5 endpoint study records as follows:

Select “all fields” in the “Detail level” dropdown menu.
Block “Administrative data”
− the field “Purpose flag” to state whether the estimate is used as a key study, a
weight-of-evidence approach, or as supporting information
− the field “Study result type” to state “(Q)SAR”
Select a suitable reliability score but bear in mind that for (Q)SAR predictions it should
normally be maximum 2.
Block “Data source”
− the field “Reference type” to state whether the reference is a publication, from a
software, company in-house model etc.
− the fields “Author” and “Year” is used to include data on who developed the
model and the year when it was developed/published. Additionally, “Title” field to
state the name of the software and its version and/or publication, and
“Bibliographic source” to provide information where the model can be retrieved.
− the field “Data access” to provide information on accessibility of the prediction.
Block “Materials and methods”
− make sure that the field “Test guideline” is filled, e.g. “other guideline” plus text in
the adjacent field. The REACH Guidance document on the validation of the
(Q)SAR models or the test guidelines used to generate the data for the training
set could be cited.
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− the field “Principles of method other than guideline” is used to include the name
of the model.
Block “Test materials”
− select “yes” in the drop down menu "Test material same as for substance defined
in section 1 (if not read across)”, if the (Q)SAR model is applied to the substance
as reported in section 1.1 of the IUCLID 5 dossier. If the (Q)SAR prediction refers
to one constituent of the substance, select “no” and indicate the identity of the
constituent in the “Test material identity”
− the field “Test material identity” is used to include information on the substance
for which the prediction was made. Please note, that the substance for which the
registration is being made may contain more than one constituent. Each
individual constituent for which the prediction is made should be listed in this
field. Please note that it may be useful to prepare in such cases an individual
endpoint study record for each constituent in order to be able to address each
chemical separately (recommended if constituents have different properties and
different models, assessments, etc have to be applied).
− the field “Details on test material” is used to include the structural representation
(e.g. SMILES notation, mol file as attachment etc.) and possible descriptor values
if used and as used to derive the prediction. If the substance contains impurities
for which a prediction is made, the chemical identification should be reported in
the “Details on the test material”, including the structural representation or
possible descriptor values used. As for constituents, the generation of an
individual endpoint study record for an impurity can be useful, particularly when
different models, assessments, etc have to be applied because of different
chemical properties.
− Confidential information can be placed in “Confidential details on test material”.
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Block “Results and discussion”
• In a standard case you are requested to provide results in the foreseen result
fields (repeatable block). It will allow you to transfer information automatically in
these result fields to the CSR when the IUCLID 5 CSR plug-in is used. The list of
fields to be filled in the “Results and discussion” block will vary depending on the
endpoint. Therefore we recommend consulting the Data Submission Manual 5
“How to complete a technical dossier for registrations and PPORD notifications”
available in the ECHA website at http://echa.europa.eu/help/help_docs_en.asp,
for instructions on how to fill in the results.
• The field “Details on results” or the field “Any other information on results incl.
tables” is used to include the description of the applicability domain, reference to
the type of model used, description and results of any possible structural
analogues of the substance to assess the reliability of the prediction, uncertainty
of the prediction and the mechanistic domain (for toxicity and ecotoxicity
endpoints, if possible). It is advisable to create additionally, an endpoint study
summary when more than one endpoint study record is available and provide the
justification on read-across/ category in the “Discussion” field of the endpoint
study summary together with the overall assessment on the particular endpoint.
This will enable the automatic transfer of this information in the CSR when the
IUCLID 5 CSR plug-in is used. In case there is only one endpoint study record
provided on read-across, you may still copy-paste the justification from the
endpoint study record to the “Discussion” field in the endpoint study summary for
the above stated reasons.
Block “Overall remarks, attachments” and/or “Applicant’s summary and
conclusions”
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− the result of the adequacy assessment for a regulatory purpose (risk
assessment, classification & labelling, PBT analysis) should be reported in
“Overall remarks”, “Conclusion” and/or “Executive summary”.
Additionally, the (Q)SAR Prediction Reporting Format (QPRF) and (Q)SAR Model
Reporting Format (QMRF) can be attached as a stand alone document. Please note that
the endpoint summary record shall contain sufficient information on the prediction and
the (Q)SAR model applied in order to allow an independent assessment of the adequacy
of the predicted property. Summary information in the endpoint study record can be
complemented with more detailed information in attached files (QMRF and QPRF).
NOTE: In order to evaluate the validity of a specific model, a filled QMRF might be
needed. The completed QMRF can be attached to the endpoint study record in the
IUCLID dossier.
If necessary, use the Endpoint summary to conclude on the prediction for the substance
which you want to register (the substance as reported in Section 1.1 of IUCLUD 5).
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FURTHER INFORMATION
• Guidance on information requirements and chemical safety assessment
http://guidance.echa.europa.eu/docs/guidance_document/information_requireme
nts_r6_en.pdf?vers=20_08_08
• (Q)SAR Application Toolbox
www.oecd.org/env/existingchemicals/qsar
• OECD categories by OECD
http://cs3-hq.oecd.org/scripts/hpv/;
• OECD Global Portal (eChemPortal)
http://webnet3.oecd.org/eChemPortal/Home.aspx
• DSM 4 ‘How to complete the Dossier header’ available at ECHA website
http://echa.europa.eu/reachit/supp_docs_en.asp
• DSM 5 ‘How to complete a technical dossier for registrations and PPORD
notifications’
http://echa.europa.eu/help/help_docs_en.asp
• IUM 7 ‘Joint submission’
http://echa.europa.eu/reachit/joint_submission_en.asp
• IUC 5 ‘End-user manual’
http://iuclid.echa.europa.eu/index.php?fuseaction=home.documentation&type=pu
blic
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