Legal notice
The views or positions expressed in this General Report do not necessarily represent in legal terms
the official position of the European Chemicals Agency. The European Chemicals Agency assumes no
responsibility or liability for any errors or inaccuracies that may appear.
The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
Reference: ECHA-11-R-004-EN
ISBN-13: 978-92-95035-96-6
Publ.date: 30/06/2011
Language: EN
© European Chemicals Agency, 2011
Reproduction is authorised provided the source is fully acknowledged in the form “Source:
European Chemicals Agency, http://echa.europa.eu/”, and written notification is given via the
Contact ECHA page at: http://echa.europa.eu/about/contact_en.asp
If you have questions or comments in relation to this document please send them (quote the
reference and issue date) using the information request form. The information request form
can be accessed via the Contact ECHA page at: http://echa.europa.eu/about/contact_en.asp
European Chemicals Agency
Mailing address: P.O. Box 400, FI-00121 Helsinki, Finland
Visiting address: Annankatu 18, Helsinki, Finland
Table of Contents
FOREWORD BY THE EXECUTIVE DIRECTOR.....................................................................1
EXECUTIVE SUMMARY .........................................................................................................2
PREFACE ................................................................................................................................5
LIST OF ABBREVIATIONS.....................................................................................................6
LIST OF THE TERMS (GLOSSARY) ......................................................................................7
LIST OF LEGISLATION ..........................................................................................................8
1 General............................................................................................................................................ 9
1.1 Background.............................................................................................................................................. 9
1.2 Standard information requirements in the REACH Regulation and the safe use of chemical substances9
1.3 The sharing and joint submission of information.................................................................................... 10
1.4 Principal possibilities for registrants to avoid unnecessary animal tests ................................................ 10
1.5 Implementation and use of non-animal testing methods: responsibilities and roles............................... 11
1.6 Progress in the development of alternatives to animal testing ............................................................... 14
2 Data Analysis................................................................................................................................ 18
2.1 Analysis of endpoint data in the registration dossiers ............................................................................ 18
2.2 Endpoint Study Record (ESR) approach................................................................................................ 22
2.3 Substance approach .............................................................................................................................. 22
2.4 Studies conducted or proposed for the purpose of REACH................................................................... 22
3 Results .......................................................................................................................................... 24
3.1 The sharing and joint submission of information.................................................................................... 24
3.2 Endpoint analysis................................................................................................................................... 24
3.3 Substance approach .............................................................................................................................. 46
3.4 Studies conducted or proposed for the purpose of REACH................................................................... 49
4 ECHA evaluation of the use of adaptations to standard information requirement by
registrants........................................................................................................................................ 54
5 Conclusions.................................................................................................................................. 55
LITERATURE.........................................................................................................................56
APPENDIX I...........................................................................................................................60
Table of Figures
Figure 1: Schematic of data analysis for individual endpoints .............................................................. 21
Figure 2: Acute Toxicity......................................................................................................................... 26
Figure 3: Skin irritation in vitro............................................................................................................... 27
Figure 4: Skin irritation in vivo. .............................................................................................................. 28
Figure 5: Eye irritation in vitro................................................................................................................ 29
Figure 6: Eye irritation in vivo. ............................................................................................................... 30
Figure 7: Skin sensitisation in vivo. ....................................................................................................... 31
Figure 8: Repeated dose toxicity – all routes, all study durations......................................................... 33
Figure 9: Genetic toxicity in vitro. .......................................................................................................... 35
Figure 10: Genetic toxicity in vivo.......................................................................................................... 36
Figure 11: Toxicity to reproduction........................................................................................................ 38
Figure 12: Developmental toxicity. ........................................................................................................ 39
Figure 13: Carcinogenicity..................................................................................................................... 40
Figure 14: Bioaccumulation in fish ........................................................................................................ 42
Figure 15: Short-term toxicity (fish) ....................................................................................................... 43
Figure 16: Long-term toxicity (fish)........................................................................................................ 44
Figure 17: Long-term toxicity (birds)...................................................................................................... 45
Figure 18: Relative proportions of the principal options to fulfil information requirements for human
health endpoints for the substances . ................................................................................. 46
Figure 19: Relative proportions of the principal options to fulfil information requirements on
environmental endpoints for the substances....................................................................... 48
Index of Tables
Table 1: Registration dossiers within the scope of in-depth analysis of this report……………………..20
Table 2: Studies with the reference date of 2009 or later………………………………………………….50
Table 3: Testing proposals submitted to ECHA……………………………………………………………..53
Table 4: HH Endpoint Study Records (1 of 2)……………………………………………………………….61
Table 5: HH Endpoint Study Records (2 of 2)……………………………………………………………….62
Table 6: ENV Endpoint Study Records………………………………………………………………………63
Foreword by the Executive Director
One of the fundamental aims of the REACH Regulation – the most ambitious chemicals
legislation in the world – was to understand better and more thoroughly, the impact of
chemicals on human health and the environment. That in turn means that industry can make
decisions in order to manage the risks posed more effectively and that we all, as workers and
consumers, can make more informed decisions about the chemicals that we use daily.
To understand the impact of chemicals better, we need reliable hazard and exposure
information which demonstrates that they can be used safely. The hazard data has been
traditionally generated through experimental animal testing but there are a number of other
ways – by comparing substances with similar ones; by grouping them together into logical
categories; by doing specialised computer modelling; by using weight of evidence; by using a
validated alternative test; and, therefore, testing them on live animals should be seen as a
last resort.
The REACH Regulation is clear that every effort must be made so that testing chemicals on
animals is truly a last resort – when there is no other scientifically reliable way of showing the
impact on humans or the environment. REACH also demands that companies in possession
of data on a chemical must share it (and share the cost) with any other companies making
the same substance, thereby removing the potential for duplicate testing.
This report is a legal requirement of REACH – ECHA needs to report to the European
Commission every three years on how companies are using alternatives to testing on
animals to provide the information demanded by the Regulation on the chemical substances
that they produce or import. I am conscious that, although this report is formally addressed to
the European Commission, it is of interest and will be read by many others. In order to make
what is essentially a very technical subject accessible to a wider audience, we have also
produced a short summary which is available in 22 EU languages.
This is the first such report and demonstrates the Agency’s experience based largely on
registration dossiers that were submitted for the first deadline in 2010. In many ways it is too
early to give an accurate picture because, as yet, relatively few dossiers have been
evaluated by our in-house scientists. Nevertheless, this report clearly shows that companies
have shared data or made extensive use of the alternative methods available so as to avoid
the need to test chemicals on animals, which is positive. The report provides detailed
information on the methods they have chosen to generate the data for the so-called
“endpoints” – the intrinsic properties of chemicals for which traditionally tests on animals
were used such as: effects on the developing foetus; acute toxicity (the impact of a single
high dose); chronic toxicity (the impact of a low level but longer term exposure); and the
bioaccumulation of substances in aquatic animals like fish.
The use of alternative methods is a work in progress. I take this opportunity to thank
companies for taking this aspect of REACH so seriously – and urge them to reflect on the
justifications that they have provided for using alternative methods and to improve them
where they can. Companies - the registration dossiers you submitted are yours and you can
and indeed must update them at any time if you have new information to give.
I welcome the continued work of the European Commission and others to introduce a
pragmatic approach to reducing experimentation on live animals and on the introduction of
validated alternatives. Although REACH is European legislation, the work to have safer
chemicals and find alternatives to testing on animals is truly international and we in ECHA
are proud to play our part in that.
Thank you and I hope that you will find the report of interest.
Geert Dancet, Executive Director
1
Executive Summary
One of the objectives of the REACH Regulation is to promote non-animal test methods. This
is the first report written by the European Chemicals Agency (ECHA) to the European
Commission since REACH came into effect which provides the latest information on the
status of non-animal test methods and alternative testing strategies used to generate
information for registration purposes. The aim of this report is to describe to the extent to
which registrants used non-animal test methods within their registration dossiers to fulfil the
information requirements stated in Annexes VII to VIII of the legislation and to what extent
they have proposed to use such approaches for the higher-tier studies of Annexes IX and X.
The Agency will prepare such a report every three years.
The 24 560 registration dossiers successfully submitted by registrants from 1 June 2008 until
28 February 2011 have been used as the source of data for this report. The relevant
information in the registration dossiers has been identified, extracted and analysed using
specifically-developed data extraction tools which have been applied to data stored in
ECHA’s IUCLID database. The data-sharing mechanism has been analysed using both
information from the inquiry process and by analysing the data in the dossiers of Lead
Registrants versus that in dossiers submitted jointly (i.e. where there is more than one
registrant per substance). Data extraction tools were also used to analyse how registrants
applied adaptations of the standard information requirements that are used to account for the
use of non-standard information on the properties of their substances. The focus is on those
dossiers with the greatest amount of data, i.e. substances imported or manufactured in
volumes at or above 100 tonnes per year. In line with the purpose of the report, only hazard
endpoints that may require testing on vertebrate animals were investigated. The number and
content of testing proposals in registration dossiers have also been analysed for all tonnage
levels.
Data sharing is a core principle of REACH and one of its aims is to require that testing in
vertebrate animals is not repeated. Registrants use the data sharing mechanism to avoid
unnecessary animal testing. The legislation provides several mechanisms to ensure the
sharing of data: companies may need to inquire if data has already been submitted on their
substance; share information from animal studies and, with some exceptions, submit joint
registration dossiers with other registrants for the same substance.
Potential registrants of so called non-phase-in substances or of phase-in substances not preregistered
must inquire of ECHA whether a registration has been made for the same
substance, with a view to sharing data. The inquiry process ensures the sharing of existing
data between registrants of the same substance. For non-phase-in substances and for
phase-in substances not pre-registered, the inquiry process ensures the sharing of existing
data between registrants of the same substance. The Agency has successfully processed
almost 1 500 inquiries made by potential registrants, and of these, about 50 % have led to
registration afterwards.
For phase-in substances, each legal entity that has pre-registered on time and wishes to
then register the substance does so by submitting a dossier to ECHA. If there is more than
one registrant for the same substance, the registrants must form a substance information
exchange forum (SIEF), to collect and share data. The Lead Registrant submits a dossier
with the joint information, describing properties and hazards of the substance, and other
SIEF participants submit member dossiers with their company-specific information.
The joint submission of information worked well in general as shown by the proportion of total
registrations submitted jointly: nearly 90% of the total number, the remaining part also
covering individual submissions of non-phase-in substances. From nearly 3000 joint
submissions containing almost 20 000 member dossiers, there were only 135 member
dossiers with opt-outs for one or more end-points as described in Articles 11(3) and 19(2) of
2
REACH. An overview of the main reasons for opt-outs is provided in the report ‘The
Operation of REACH and CLP 2011’ provided in accordance with Article 117 (2) of REACH.
However, a more detailed analysis reveals that in some cases the registrants, instead of
opting out, within the joint submission, instead submitted separate registration dossiers. For
about 250 substances, ECHA received either multiple joint submissions or, in addition to the
joint submissions, one or more individual submissions on the same substance. ECHA is
currently examining the explanations for these situations.
The sharing and joint submission of information generally worked and the registrants used it
to fulfil the information requirements and to avoid unnecessary animal testing. However, the
number of separate registration dossiers for the same substances indicate that the sharing
and joint submission of information still needs further improvement.
Registrants also made full use of the adaptation possibilities provided by the legislation. The
standard information required for registration comprises a number of hazard endpoints (such
as repeat-dose toxicity and irritation effects) which are usually based on information from
standard experimental studies with vertebrate animals. The standard data requirements are
linked to the tonnage of the substance and are listed in Annexes VII to X of the legislation.
Core data are those specified in Annexes VII and VIII and higher-tier data, as specified in
Annexes IX and X. If data gaps have been identified and cannot be filled otherwise, studies
may need to be conducted. In the case of missing higher-tier data, a testing proposal has to
be submitted by the Lead Registrant. This report focuses on 15 endpoints that may require
studies on vertebrate animals.
Information on each endpoint for a substance is included in an endpoint study record (ESR)
within the registration dossier. Data from ESRs available in ECHA´s database have been
analysed in two ways for this report. The first is to sum the total number of endpoint study
records in Lead Registrant and stand-alone dossiers (i.e. summing up all available
information over all dossiers and substances within the scope of this report). A second type
of analysis gives an insight to the relative proportions of either experimental studies, testing
proposals or alternative methods used by the registrants when fulfilling the information
requirements for substances at or above 1 000 tonnes per year. When considering these
two ways of presenting the findings, it is important to understand that the ESRs are provided
by registrants and the quality of the contents of these ESRs were not scrutinised by the
Agency.
Any deficiencies identified during the compliance checks that are part of dossier evaluation
and could result in the Agency requesting further studies on vertebrate animals are not
included in this report.
For substances at or above 100 tonnes per annum, the ESR data show that registrants used
data from studies conducted prior to the entry into force of REACH as the main source of
information to meet both the core and higher tier information requirements. Especially for
longer-term animal studies, the second most common means of fulfilling the information
requirements was predicting substance properties by read-across. Other adaptations of the
standard testing requirements were also used to justify omitting studies. The use of these
options varied between endpoints. When assessing the available information for all relevant
substances it became clear that a higher proportion of substances had experimental studies
for acute toxicity than were available for higher-tier toxicological endpoints (e.g. reproduction
toxicity and repeat-dose toxicity). For a number of toxicological endpoints required by
REACH there are accepted in vitro tests that can be used instead of the corresponding
animal study. Hence, for these endpoints the in vitro studies are presented separately to the
data on animal studies.
Annexes IX and X include those information requirements that involve testing on a large
number of vertebrate animals and that are also the most expensive. Before embarking on
such testing, registrants have to submit a testing proposal to ECHA. When a testing proposal
concerns a study involving vertebrate animals, ECHA publishes the name of the substance
3
and the hazard endpoint for which testing is proposed on its website and invites third parties
to submit existing scientifically valid information, with a view to avoid the need for conducting
a new study. The Agency has to examine and decide on all testing proposals before
registrants can initiate such studies on vertebrate animals.
Fewer testing proposals for the higher-tier endpoints have been submitted than had been
anticipated based on previous estimates from the European Commission or from interested
scientists. This lower number of testing proposals is due, at least in part, to registrants using
the read across or category approach to fill data gaps for these higher-tier studies, i.e. a
study on one substance to cover information requirements for another, or multiple
substances. Between 2008 and February 2011, the Agency received registration for 3 308
phase-in and 1 347 non-phase-in substances (at all tonnages). Testing proposals were made
in 574 dossiers covering a total of 1 175 tests, of which 711 were vertebrate animal studies.
The totals include 78 substances that were submitted as category dossiers, covering 17
chemical categories and testing proposals for 104 animal studies.
It seems reasonable to conclude that in general registrants have first considered other
options to meet the higher-tier data requirements, before resorting to a testing proposal.
Based on the data with a reference year of 2009 or later, the dossiers analysed demonstrate
that companies carried out relatively few new studies for their registration dossiers. In total,
3 340 such studies have been conducted, of which 1 849 involved tests on vertebrate
animals. In total 107 higher tier studies appeared to be conducted in the absence of testing
proposals. This information will be further analysed in future compliance checks.
Results from dossier evaluation conducted as part of compliance checks show that the use
of read-across and category prediction methods are often not well-justified. In addition, the
experimental data provided in the dossiers are in some cases also not sufficient to meet
information requirements under REACH. Further analysis of the submitted data and the
outcomes of compliance checks in the future will enable ECHA and stakeholders to develop
a better understanding of the reliability of animal and non-animal test methods used by
registrants so far. Currently it is expected that more animal testing will need to be requested
by ECHA to ensure the safe use of chemical substances.
The Agency has disseminated the endpoint information from the registrations and will
continue to do so whenever registrants submit new data either spontaneously or after the
evaluation decisions. This will assist future registrants as they may be able to predict the
properties of their substance by read-across to existing data on analogus substances. The
amount and quality of disseminated information will increase as more substances are
registered and registrants undertake the higher-tier studies after testing proposals are
approved and occasional extra studies on registered substances are conducted as an
outcome of compliance checks or other REACH processes such as substance evaluation.
This report provides, for the first time, an overall insight into the options the registrants
followed to meet the information requirements under REACH. Based on these findings,
ECHA will continue with efforts to facilitate the use of non-animal test methods by actively
informing registrants about alternatives for animal testing and their use via guidance
documents, awareness raising campaigns, events, the Helpdesk, special services for Lead
Registrants, and through the dissemination website.
4
Preface
This report is intended to meet ECHA’s legal obligation under Article 117(3) of the REACH
Regulation which states that: “Pursuant to Article 117(3) of the REACH Regulation, every
three years the Agency, in accordance with the objective of promoting non-animal test
methods, shall submit to the Commission a report on the status of implementation and use of
non-animal test methods and testing strategies used to generate information on intrinsic
properties and for risk assessment to meet the requirements of this Regulation.“ The primary
source of information for this report is that available to ECHA in the registration dossiers
submitted by manufacturers and importers. The results of ECHA’s dossier evaluations
(compliance checks and examinations of testing proposals) is another source of information
but relates only to a fraction of the dossiers submitted.
This report analyses the data submitted by registrants with a view to describing the extent to
which alternative test methods and test strategies have been used. This analysis is
complemented by the observations obtained from dossier evaluation. Such findings are also
reported by ECHA in its annual evaluation progress report. Pursuant to Article 54 of the
REACH Regulation, an evaluation progress report is published in February each year.
This report was submitted to the Commission in parallel with the first report by ECHA on the
operation of the REACH Regulation in accordance with Article 117(2) thereof.
These reports contribute to the monitoring of the implementation of the REACH Regulation
and are intended to provide useful information for the Commission when reviewing the
legislation.
5
List of abbreviations
CASPER IT Characterisation Application for Selection, Prioritisation, Evaluation
CLP Classification, Labelling and Packaging
CMR Carcinogenic, Mutagenic, Reprotoxic
Commission European Commission
DG JRC Directorate General Joint Research Centre
DSD Dangerous Substances Directive
ECHA European Chemicals Agency
ECVAM European Centre for the Validation of Alternative Methods
EFSA European Food Safety Authority
EINECS European Inventory of Existing Commercial Chemical Substances
EMA European Medicines Agency
ESR Endpoint Study Record
EU European Union
GLP Good Laboratory Practice
ICAPO International Council on Animal Protection
IUCLID International Uniform Chemical Information Database
MS Member State
MSC Member State Committee
MSCA Member State Competent Authority
NONS Notified Substances (substances already notified in accordance with
Directive 67/548/EEC that are considered as registered according to
Art. 24 of REACH)
OECD Organisation for Economic Cooperation and Development
PARERE Preliminary Analysis of Regulatory Relevance
PPORD Product and Process Oriented Research and Development
QSAR Quantitative Structure-Activity Relationships
REACH Registration, Evaluation, Authorisation and Restriction of Chemicals
REACH-IT REACH-IT is the central IT system providing support for REACH
SIEF Substance Information Exchange Forum
TCC Technical Completeness Check
TG Test guideline
TMR Test Methods Regulation
TSAR Tracking System for Alternative test methods Review, Validation and
Approval in the Context of EU Regulations on Chemicals
6
List of the terms (glossary)
Alternative test: alternative techniques that can provide the same level of information as
current animal tests, but which use fewer animals, cause less suffering or avoid the use of
animals completely. Such methods, as they become available, must be considered wherever
possible for hazard characterisation and consequent classification and labelling for intrinsic
hazards and chemical safety assessment.
Endpoint study record: IUCLID format of the technical dossier used to report study
summaries and robust study summaries of the information derived for the specific endpoint
according to Annexes VII to XI of the REACH Regulation.
Endpoint: an observable or measurable inherent property/data point of a chemical
substance. It can for example refer to a physical-chemical property like vapour pressure or to
degradability or to a biological effect that a given substance has on human health or the
environment, e.g. carcinogenicity, irritation, aquatic toxicity.
Hazard: a property or set of properties of the chemical substance that may cause an adverse
health or ecological effect provided if there is an exposure at a sufficient level.
In vitro test: literally stands for “in glass” or “in tube”, refers to the test taking place outside
of the body of an organism, usually involving isolated organs, tissues, cells, or biochemical
systems.
In vivo test: a test conducted within a living organism.
IUCLID flag: an option used in the IUCLID software to indicate submitted data type (e.g.
experimental data) or their use for regulatory purposes (e.g. confidentiality).
Prediction model: a theoretical formula, algorithm or program used to convert the
experimental results obtained by using a test method into a prediction of the toxic
property/effect of the chemical substance.
QSARs and SARs (Q(SAR)): theoretical models that can be used to predict in a quantitative
or qualitative manner the physicochemical, biological (e.g. (eco)toxicological) and
environmental fate properties of compounds from 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.
Test (or assay): an experimental system set up to obtain information on the intrinsic
properties or adverse effects of a chemical substance.
Validated test: a test for which its performance characteristics, advantages, and limitations
have been adequately determined for a specific purpose.
Validation: the process by which the reliability and relevance of a test method are evaluated
for the purpose of supporting a specific use.
Vertebrate animal: animals that belong to the subphylum Vertebrata, chordates with
backbones and spinal columns.
7
List of legislation
CLP Regulation Regulation (EC) No 1272/2008 on classification,
labelling and packaging of substances and mixtures
DSD Dangerous Substances Directive; Council Directive
67/548/EEC of 27 June 1967 on the approximation of
laws, regulations and administrative provisions relating
to the classification, packaging and labelling of
dangerous substances
Existing Substances Regulation Council Regulation (EEC) No 793/93 of 23 March 1993
on the evaluation and control of the risks of existing
substances
Good Laboratory Practice Directive 2004/10/EC of the European Parliament and
of the Council of 11 February 2004on the harmonisation
of laws, regulations and administrative provisions
relating to the application of the principles of good
laboratory practice and the verification of their
applications for tests on chemical substances (codified
version)
Protection of animals Directive 2010/63/EU of the European Parliament and
of The Council of 22 September 2010 on the protection
of animals used for scientific purposes
Council Directive of 24 November 1986 on the
approximation of laws, regulations and administrative
provisions of the Member States regarding the
protection of animals used for experimental and other
scientific purposes (86/609/EEC)
REACH Regulation Regulation (EC) No 1907/2006 of the European
Parliament and of the Council of 18 December 2006
concerning the Registration, Evaluation, Authorisation
and Restriction of Chemicals (REACH), establishing a
European Chemicals Agency, amending Directive
1999/45/EC and repealing Council Regulation (EEC) No
793/93 and Commission Regulation (EC) No 1488/94
as well as Council Directive 76/769/EEC and
Commission Directives 91/155/EEC, 93/67/EEC,
93/105/EC and 2000/21/EC
Test Methods Regulation Commission Regulation (EC) No 440/2008 of 30 May
2008 laying down test methods pursuant to Regulation
(EC) No 1907/2006 of the European Parliament and of
the Council on the Registration, Evaluation,
Authorisation and Restriction of Chemicals (REACH)
8
The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
1 General
1.1 Background
One of the main reasons for developing and adopting the REACH Regulation was that a
large number of substances have been manufactured and placed on the market in Europe
for many years, sometimes in very high amounts, and yet there has been limited information
on the hazards that they might pose to human health and the environment. It was considered
that there is a need to fill these information gaps which would help to ensure that industry is
able to assess hazards and risks, and to identify and implement the necessary risk
management measures in order to protect human health and the environment.
It has been known and accepted since the drafting of the REACH Regulation that the need to
fill the data gaps would result in an increased use of laboratory animals for the next ten years
until that goal has been reached. Nevertheless, in order to avoid unnecessary animal tests,
the REACH Regulation provides mechanisms to share data and to adapt the standard
information requirements and use existing data and alternative data generation approaches
instead.
In particular tests on vertebrate animals may only be carried out as last resort and studies
involving vertebrate animals shall not be repeated. The current scientific status still is that for
some hazard endpoints, such as repeated dose toxicity or reproductive toxicity, results from
animal tests will be needed although there is still the possibility to use ‘read-across’ study
results from a tested source substance to structurally-related analogue target substance(s).
This is counterbalanced by the obligation on the participants in the Substance Information
Exchange Fora (SIEFs) to share available information from vertebrate tests on phase-in
substances and for corresponding data sharing obligations for non-phase-in substances. The
REACH Regulation also provides specific rules in Annexes VII to X (column 2) to omit animal
studies in certain circumstances and general rules in Annex XI on how to adapt the standard
information requirements to enable alternative methods to be used for the endpoint. In any
case, it is up to the registrant to justify that alternative data are sufficient for the purpose of
classification and labelling and/or risk assessment.
1.2 Standard information requirements in the REACH Regulation
and the safe use of chemical substances
The principal objective of assessing the risks from the use of chemical substances is to
provide a reliable basis for deciding on adequate safety measures (risk management). Any
risk assessment on chemical substances comprises two distinct elements: an evaluation of
the properties which are intrinsic to the substance, called hazard assessment, and an
estimation of the exposure which depends on the use of the substance.
The hazard assessment identifies the hazardous intrinsic properties (e.g. sensitising,
carcinogenic, toxic for the aquatic environment) and determines the potency of the chemical
substance with respect to these hazardous properties. The exposure assessment identifies
the sources of the substance which leads to exposure and calculates the amount taken up by
an exposed organism or estimates the release of the substance into a particular
compartment of the environment.
Since one of the most important measures for ensuring safe use of substances is that
sufficient information on the hazardous properties is available to the manufacturers,
9
The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
importers and users, REACH specifies the standard information that is required. The
standard data requirements, which are linked to the tonnage of the substance, are listed in
Annexes VII to X of the REACH Regulation, with core data (as required in Annexes VII and
VIII) to be included in the registration at submission. If data gaps have been identified and
cannot be filled otherwise, registrants will have to conduct higher-tier studies to fulfil the
requirements of Annexes IX and X and only after the approval of their testing proposals by
ECHA. The information requirements increase with increasing volume of the substance
manufactured or imported. A higher volume of a substance is regarded as an indicator of a
higher potential to cause damage to human health and/or the environment and therefore
needs to be investigated more thoroughly than lower volumes. Therefore, the standard
information requirements are highest for substances at or above 1 000 tonnes per annum
(tpa).
1.3 The sharing and joint submission of information
The principle of ‘one substance one registration’ set by REACH requires that cooperation
between potential registrants must be established and data must be shared and submitted
jointly. This is a core principle within REACH intended to prevent duplicated testing in
vertebrate animals.
According to Article 11 and Article 19 of the REACH Regulation, when a substance is
intended to be registered by more than one legal entity, the information for the classification
and labelling of the substance, study summaries, robust study summaries and testing
proposals shall be submitted by one registrant (the Lead Registrant) acting with the
agreement of the other assenting registrants. That is to say, a joint submission shall be
created.
REACH distinguishes between so called non-phase-in substances and phase-in substances.
In the case of non-phase-in substances, potential registrants are obliged to ascertain the
availability of information they may require from any registrants of the same substance using
an inquiry process operated by ECHA. For phase-in substances, the Substance Information
Exchange Fora (SIEFs) should have been set up, where potential registrants of the same
substance collaborate on obtaining and sharing the necessary information.
In either case outlined above, potential registrants have an obligation to request that studies
involving vertebrate animals are shared. This principle applies to both phase-in and nonphase-in
substances. Studies, involving testing on vertebrate animals, can only be conducted
if the necessary data cannot be obtained from a registrant or potential registrant of the same
substance. The test may sometimes actually be conducted at a later date, if REACH
stipulates that a testing proposal shall first be submitted to ECHA.
ECHA is only obliged to step in, if an owner of a study is not willing to share the study, if the
SIEF members cannot agree on sharing the costs, or if the SIEF members cannot agree on
who should carry out a new study for filling data gaps.
1.4 Principal possibilities for registrants to avoid unnecessary
animal tests
The REACH Regulation also provides registrants with the possibility to adapt the standard
information requirements based on the specific conditions listed in column 2 of Annexes VII
to X and more general conditions given in Annex XI of the Regulation. Appropriate use of
these options allows registrants to avoid unnecessary testing, including vertebrate animal
testing. Column 2 of the Annexes VII-X of the REACH Regulation provides endpoint specific
conditions under which a test does not need to be conducted. In addition, Annex XI specifies
several other options for possibilities to omit animal testing. These are when testing does not
10
The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
appear to be scientifically necessary, it is technically not possible or when substance-tailored
exposure-driven testing may be applied. In addition, before any new tests are carried out, all
available in vitro data, in vivo data, historical human data, data from valid quantitative
structure-activity relationships ((Q)SAR)s and predictions from structurally related
substances (read-across of intrinsic hazard properties within groups or categories of
substances) shall be assessed first by the registrant. Such alternative methods can be
applied if they are scientifically valid and provide results that are adequate for classification
and labelling and/or risk assessment.
However, every adaptation to the standard information requirements in column 1 of Annexes
VII to X needs a valid justification based on the provisions in column 2 of the Annexes or on
the provisions in Annex XI. Detailed explanations for registrants on possibilities to adapt
information requirements are provided in ECHA’s Practical Guide 10 How to avoid
unnecessary testing on animals, available on ECHA’s website.
Before embarking on testing for fulfilling the data requirements specified in Annexes IX and X
(which include those tests requiring the largest number of vertebrate animals and which are
the most expensive), the registrants have to submit a testing proposal to ECHA (see 3.7.2).
1.5 Implementation and use of non-animal testing methods:
responsibilities and roles
This section describes the roles and responsibilities of different involved parties in the
context of the REACH Regulation. It does not cover all other activities of national or
international bodies concerned with the development, validation and assessment of
alternative methods.
1.5.1 Registrants
One of the main obligations of registrants is to share data on animal tests. This has been
earlier described in section 1.3. A further obligation for the registrants is to obtain data on
their substances as specified in Annexes VI to X of REACH. Annex VI of REACH provides a
basic four-steps procedure for fulfilling the information requirements. The procedure
comprises the following steps: (i) Gather and share existing information; (ii) Consider
information needs; (iii) Identify information gaps; and (iv) Generate new data/Propose testing
strategy. Furthermore, testing on vertebrate animals should only be undertaken as a last
resort. The principal possibilities for registrants to avoid unnecessary testing on animals have
been described in section 1.4. Before embarking on testing for fulfilling the data requirements
in Annexes IX and X, registrants have to submit testing proposals to ECHA. This process is
further described in section 3.4.2.
It should be noted that registrants are fully responsible for the content and data quality of
their registration dossiers, including the choices they make for fulfilling the standard
information requirements.
Detailed explanations on duties and responsibilities of registrants are provided in Guidance
on Registration and in Practical Guide 10 How to avoid unnecessary testing on animals,
available on ECHA’s website. This Guide brings together in one place information from a
number of ECHA guidance documents.
1.5.2 ECHA
The principle of animal testing as the last resort is implemented in the REACH Annexes as
described above. ECHA’s role is to help registrants to implement these provisions and to
promote alternative methods to animals testing. ECHA has a role to play in facilitating the
11
The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
duties of the various actors in meeting the legislative requirements which balance the need to
assess the risks of substances to human health and the environment and to avoid
unnecessary animal testing. ECHA fulfils this role by a number of means:
• ECHA has developed a series of Guidance documents, among them, e.g. Guidance on
Registration, Guidance on Information Requirements and Chemical Safety Assessment,
Guidance on Data Sharing and a range of Practical Guides supporting the registrants in
all their tasks.
• From June 2007 to December 2010 the ECHA Helpdesk dealt with more than 570
enquiries on information requirements, (Q)SARs, read-across, adaptation rules and
testing proposals. In 2010 the ECHA Helpdesk also advised on data sharing issues in
more than 150 cases. During the six months prior to the first registration deadline, the
ECHA Helpdesk dealt with in excess of 5500 enquiries from companies and proactively
contacted almost 500 companies.
• ECHA facilitates and promotes the formation of SIEFs to allow better data sharing for
phase-in substances and runs the inquiry process for non-phase-in substances.
• ECHA organises targeted awareness raising and stakeholder support activities, including
workshops, Stakeholder Days, webinars and other web-based information and tools.
• ECHA publishes the Annual Progress Reports on Evaluation, describing the progress the
Agency has made in evaluating registration dossiers and provides recommendations for
the registrants to improve the quality of future registrations. The first report has been
published in 2009. In these reports the results of the examination of testing proposals are
described in detail. ECHA has an obligation to examine all testing proposals, including
the running of third party consultations for tests involving vertebrate animals. More
information is provided in the section 3.4.2. Furthermore, in compliance checks, ECHA
verifies whether the registration dossier is compliant with the information requirements of
the REACH Regulation. This includes the evaluation of whether alternative methods or
approaches used are adequate for the purpose of classification and labelling and/or risk
assessment. When information is missing or not adequate, ECHA may require the
registrant to submit any information needed to bring the registration into compliance with
the relevant information requirements. See the section below on the role of the Member
States.
• At the end of 2009, ECHA has started to publish on its website hazard and safe-use
information on chemical substances that have been registered. This disseminated
information allows other registrants and stakeholders the access to information formerly
not available to the public. It may help future registrants to fill data gaps in their
registration dossiers and may facilitate further developments of prediction methods. The
number of substances for which information is available in the database will increase
considerably over time as more registrations are received by ECHA. Currently the
database contains more than 4000 disseminated data sets.
• Since June 2007, ECHA has published eleven News Alerts and nine Press Releases
addressing questions on animal testing issues, on its website. Of particular relevance to
avoid unnecessary animal testing, in 2009 ECHA has informed registrants of the
possibilities to omit short-term repeated dose toxicity or screening for repeated
dose/reproductive toxicity studies if they provide either the results or testing proposals for
long term tests (ECHA/PR/09/13) to achieve a technically complete registration dossier.
• Internationally-agreed test methods are especially important for avoiding unnecessary
animal testing, since they standardise the study protocols. These standardised protocols
can be used in regulatory contexts worldwide and the results are generally accepted by
different regulatory agencies. Further development of test methods, in terms of refining,
reducing or replacing animal tests (so called 3Rs principle), has to be assessed in the
context of the REACH requirements. Therefore ECHA contributes to such developments
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
by participating in EU and OECD working groups, and maintaining links with other
important actors, such as the Member States as well as with the Directorate Generals
(e.g. DG JRC) and agencies (e.g. EFSA, EMA) of the European Commission.
1.5.3 Member States
As explained above, ECHA checks whether the information requirements of the REACH
Annexes are met (in compliance checks) and examines testing proposals. In both cases, the
result may be a draft decision requesting further information including results from tests on
animals. The Member States Competent Authorities review draft decisions and may propose
amendments, and if so, the case is referred to the Member State Committee. The
representatives of the Member States seek agreement on the draft evaluation decisions in
that committee. These decisions have to be unanimously agreed ensuring a broad
consensus on the need for further animal testing. If no agreement can be reached, the
European Commission will decide.
In the European Union, enforcement is a task of the Member States.
1.5.4 Third parties
“Third parties”, such as Non-governmental organisations (NGOs) or research institutes, may
play a role in ensuring that best use is made of existing information, and thereby, contribute
to ensuring that testing in vertebrate animals is performed as a last resort. On its website,
ECHA publishes all testing proposals involving vertebrate animals, for endpoints specified in
Annexes IX and X under REACH. These are the costly tests for complex endpoints which
require most animals. Third parties then have 45 days to submit scientifically valid
information and studies that address the relevant substance and hazard end-point, relating to
the testing proposal. All scientific information thus collected is taken into account by ECHA
during preparation of the final decision on the testing proposal, which, as stated above, also
includes representatives of the Member States.
1.5.5 European Commission
The protection and welfare of animals is an area covered by a wide range of EU legislation.
The conduct of studies on animals, whether it is for the development or production of new
medicines, for studying physiological or environmental effects, or for the testing of chemical
substances or new food additives, have to be carried out in compliance with EU legislation.
On 22 September 2010 the EU adopted Directive 2010/63/EC to update the 1986 Directive
86/609/EEC on the protection of animals used for scientific purposes. The aim of the new
Directive is to strengthen the legislation, and improve the welfare of those animals use of
which in experimental procedures is still necessary and to firmly anchor the principle of the
3Rs in EU legislation.
Duplication of testing may be avoided if tests are conducted according to GLP. The purpose
of the principles of good laboratory practice is to promote the development of good quality
test data such that individual countries can confidently rely on test data developed in other
countries. The REACH Regulation requires new (eco)toxicological tests and analyses shall
be carried out in compliance with the principles of GLP provided for in Directive 2004/10/EC
or other international standards recognised as being equivalent by the Commission or the
Agency. Annex XI of REACH provides for some exemptions for existing data in case that
testing does not appear scientifically necessary.
The Test Methods Regulation (Commission Regulation (EC) No 440/2008) governs the
conduct of testing for the REACH Regulation. Prior to changes in the Test Method
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
Regulation, the regulatory acceptance of a method in the EU has to be ensured. The
Commission has a responsibility, having consulted stakeholders, to propose changes to the
Test Methods Regulation. It was recognised that there was a need to streamline the
procedures relating to the regulatory acceptance of validated alternatives to animal testing.
The Commission committed itself to improve the acceptance process by introducing a
mechanism of “preliminary analysis of regulatory relevance” (PARERE) to be established.
The consultation networks involve EU Member State contact points and relevant agencies
and committees including ECHA.
The Commission also collects and publishes statistics on the use of animals used for
experimental procedures. The latest report (2010) provides statistics from 2008 (available at
http://ec.europa.eu/environment/chemicals/lab_animals/statistics_en.htm).
Newly-developed alternative methods have to be validated in order to assess their relevance
and reliability. In 1991, the Commission set up the European Centre for the Validation of
Alternative Methods, ECVAM, to promote the validation of alternative methods. ECVAM is
part of the Institute for Health and Consumer Protection (IHCP) of Directorate General Joint
Research Centre (DG JRC) of the European Commission. One of the main tasks of ECVAM
is to validate alternative methods that replace, reduce and refine the use of animals in
scientific procedures. The work carried out by ECVAM is essential to reduce animal
experiments in the EU.
The new Directive 2010/63/EU has further developed the role of ECVAM (referred to therein
as the Union Reference Laboratory), and its duties and tasks are defined as follows:
o Coordinating and promoting the development and use of alternatives to
procedures including in the areas of basic and applied research and regulatory
testing;
o Coordinating the validation of alternative approaches at Union level;
o Acting as a focal point for the exchange of information on the development of
alternative approaches;
o Setting up, maintaining and managing public databases and information systems
on alternative approaches and their state of development;
o Promoting dialogue between legislators, regulators, and all relevant stakeholders,
in particular, industry, biomedical scientists, consumer organisations and animalwelfare
groups, with a view to the development, validation, regulatory acceptance,
international recognition, and application of alternative approaches;
o It is intended that ECVAM will coordinate requests and input from the PARERE
networks.
ECVAM thus seeks to promote the scientific and regulatory acceptance of alternative
methods through research, new test development and validation, and the establishment of
specialised databases, with the aim of contributing to the replacement, reduction and
refinement of laboratory animal procedures (in accordance with the 3Rs concept).
1.6 Progress in the development of alternatives to animal testing
This section provides an overview on the development of alternative methods to animal
testing. It is not meant to give a comprehensive review of all activities of this area, but only
addresses REACH relevant approaches.
1.6.1 Development of alternative methods
There are many research projects ongoing within and beyond the EU that focus on
replacement, reduction or refinement of animal testing. Important examples within the EU are
research initiatives that have been launched in recent last years. These include the
development and optimisation of reproductive toxicology (Re-Pro-Tect; 2004-2009), acute
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
toxicity (A-Cute-Tox; 2004-2009), skin and respiratory sensitisation (sens-it-iv; 2005-2010),
carcinogenicity (Carcinogenomics; 2006-2011), chronic toxicity (Predict-iv; 2008-2013) and
repeated dose toxicity (COLIPA-DG RTD Joint Research Initiative; 2009). In the future, these
research projects may deliver in the future new approaches to combine different tests in the
most optimal way (testing strategies) for these endpoints. For more details, please visit the
ECVAM website.
It has to be noted that the results of research projects and new or refined methods based on
those results can be used for regulatory purposes once they are validated and adopted. In
the area of alternative methods to animal testing, such validations are conducted according
to internationally agreed principles. In Europe, ECVAM is the responsible body for the
validation of these methods, and more internationally, the OECD plays a role. This process is
rather time consuming and may take years for a specific method to be internationally
validated and accepted for regulatory purposes.
1.6.2 Progress in validation and adoption of in vitro test methods
This section refers to the test methods performed in vitro. These tests are performed in a
controlled environment, such as a test tube or Petri dish, and usually involve the use of
isolated organs, tissues, cells, or biochemical systems.
The ECVAM technical report (Zuang et al., 2010) and the recent overview paper of Adler et
al (2011) both describe the current status of in vitro methods.
Currently, there are in vitro test methods under validation for assessing potential skin
sensitisation, severe ocular irritants and non-irritants. The methods listed here have the
potential to be used under the REACH Regulation (Annex XI 1.4.). A test battery consisting
of three tests (Direct peptide reactivity assay, the Myeloid U397 Skin Sensitisation Test
(MUSST), and the human cell line activation test (h-CLAT)) for detecting potential skin
sensitisers has entered the ECVAM pre-validation process in 2009. In the area of ocular
irritation, tests assessing irritant potential of substances such as the SkinEthicTM
HCE test
and the EpiOcular assay, are also under validation.
In the past three years a number of in vitro test methods that are suitable for REACH
purposes have been adopted and incorporated into the Test Methods Regulation. These
methods are:
in vitro skin irritation test, B.46 (2009)/OECD TG 439 (2010); bovine corneal opacity and
permeability test method for identifying ocular corrosives and severe irritants (BCOP) B.47
(2010)/OECD TG 438 (2009); isolated chicken eye test method for identifying ocular
corrosives and severe irritants (ICE) B.48 (2010)/OECD TG 438 (2009); and skin absorption
in vitro B.45 (2008)/OECD TG 428, 2008).
More information on other test methods that have been validated by ECVAM and adopted by
OECD can be found on the respective websites as well as on the TSAR database provided
by the Institute for Health and Consumer Protection, a scientific institute of the Joint
Research Centre (JRC).
1.6.3 Progress in concepts for read across, categories, (Q)SARs and new
approaches
Substances with physicochemical, toxicological and ecotoxicological properties that are likely
to be similar or follow a regular pattern as a result of structural similarity, may be considered
as a “group”, or ‘category’ of substances. Applying the group concept means that the
physicochemical properties, human health effects and environmental effects or
environmental fate may be predicted from data available for reference substance(s) within
the group by interpolation to other substances in the group (read-across approach). This
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
avoids the need to test every substance in the group for every hazard endpoint. Preferably, a
category should include all similar substances. REACH Annex XI, section 1.5 sets out the
requirements for the application of this strategy.
The original concept for the read-across approach and category building was implemented at
OECD level. The REACH Regulation and the ECHA Guidance on Information Requirements
and Chemical Safety Assessment developed such concepts further. Therefore, ECHA has
an in-house team of experts on non-test method approaches and the supporting specialist
software. This team exploits the information available since the first registration deadline to
facilitate future assessments of chemical properties.
Animal tests can be avoided if the hazardous properties of a substance can be predicted
using computer models, sometimes referred to as “in-silico” methods. The (Q)SAR
[(quantitative) structure-activity relationship] approach seeks to predict the intrinsic properties
of chemicals by using various databases and theoretical models, instead of conducting tests.
Based on knowledge of chemical structure, QSAR quantitatively relates characteristics of the
chemical to a measure of a particular activity. QSAR should be distinguished from SAR,
which makes qualitative conclusions about the presence or absence of a property of a
substance, based on a structural feature of the substance.
The OECD QSAR Toolbox is an important tool for supporting and enabling category building.
ECHA actively contributes to the further development of this Toolbox. This freely available
software is useful to group chemicals and apply read-across techniques for assessing the
(eco)toxicity hazards of chemical substances under REACH.
ECHA is collaborating with the JRC Computational Toxicology Group in its mission to
promote the availability for regulatory use of valid computer-based methods, for example,
QSARs, used for assessing the intrinsic properties of chemical substances. More
information, including structured and peer-reviewed documentation of (Q)SAR models and
free access to JRC QSAR Model Database is available from the JRC website.
In September 2010, ECHA held a first workshop on dealing with uncertainty related to the
application of non-test methods under REACH. This workshop concentrated on how to deal
with scientific uncertainties when non-test methods are used for predicting intrinsic properties
within the context of the regulatory decision making process.
1.6.4 OECD
The Organisation for Economic Cooperation and Development (OECD) is the main
organisation for developing and validating both conventional and alternative test methods.
The adoption of valid test guidelines by OECD gives them international recognition and a
possibility for regulatory use. More information on the recent activities is available from the
OECD website. The regulatory use of OECD test methods in the EU may require changes to
the legislation which applies to a number of different industry sectors.
1.6.5 Promotion platforms and other organisations
There are a number of promotion platforms and organisations which actively contribute to the
promotion and/or development of alternative methods, e.g. the European Partnership for
Alternative Approaches to Animal Testing (EPAA), European Consensus-Platform for
Alternatives (ECOPA), and many others.
The International Council on Animal Protection in OECD Programmes, ICAPO is an
international organisation that develops guidelines and programmes for the testing of
chemicals. ICAPO is currently working with the Working Group of National Co-ordinators of
the Test Guideline Program, Task Forces on Endocrine Disruptor Testing and Assessment
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
and Existing Chemicals, including (Q)SAR, and in the Validation Management Groups for
Non-Animal testing and for Mammalian testing.
For the up-to-date progress in the development of alternatives to animal testing the reader is
referred to the above listed organisations and their websites, which provide useful
information.
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
2 Data Analysis
The main data set used for analysis in this report is based on the available endpoint study
records in the registration dossiers submitted for phase-in substances at or above 1 000 tpa.
In addition, also the available dossiers for phase-in substances at or above 100 tpa have
been analysed and dossiers for non-phase-in substances at or above 100 tpa were also
analysed. Dossiers may be updated by registrants after submission and so for this analysis,
the data that were available up to a cut-off date of 28 February 2011 were used.
Endpoint study records are specific entries filled by registrants for the hazard endpoints in
the IUCLID dossiers. It is important to note that there may be more than one or even many
endpoint study records submitted per endpoint.
In section 2.1, the scope of this analysis, in terms of dossier types, is further described in
details.
In sections 2.2 to 2.4, the statistical analysis of endpoint information from three perspectives
is described:
(1) from the endpoint study record perspective (further called in this report “ESR approach”),
which analyses the overall quantitative picture of options used by registrants for dossiers
within the scope of this analysis (see section 2.1, Table 1)
(2) from the substance perspective (registered phase-in substances at or above 1 000 tpa,
excluding category dossiers and dossiers for only intermediates), further called “substance
approach”. This analyses the strategic choices the registrants have made to fulfil the
information requirements, and
(3) from the perspective of new vertebrate animal testing for REACH purposes to evaluate
how many studies have been performed for REACH or are planned to be performed for
REACH (across all dossiers and all substances, excluding category dossiers and dossiers for
only intermediates).
2.1 Analysis of endpoint data in the registration dossiers
By the first registration deadline for phase-in substances of 30 November 2010, ECHA
received registration dossiers for phase-in substances manufactured or imported in
quantities of 1 000 tonnes or more per year, phase-in substances classified as R50/53 in
accordance with Directive 67/548/EEC and manufactured or imported in quantities of 100
tonnes or more per year and phase-in substances classified as CMR, category 1 or 2, in
accordance with Directive 67/548/EEC and manufactured or imported in quantities of 1 or
more tonne per year. In addition, other registrations were made for non-phase-in substances
and early registrations of phase-in substances with later deadlines. The total number of
registration dossiers received by the said deadline was 24 560.
The in-depth analysis of registration data for this report is on registrations received by at the
30 November 2010 deadline for substances at or above 100 tonnes per annum, both phasein
and non-phase-in substances. These dossiers should contain the core data of Annex VII
and VIII in order to be accepted for registration (and pass the Technical Completeness
Check). If data gaps have been identified by the registrants, that could not be filled
otherwise, where appropriate they should contain testing proposals for the necessary highertier
studies of Annex IX (for substances at or above 100 tpa) and Annex X (for substances
above 1 000 tpa). Hence, these dossiers allow an assessment of the use of non-animal data
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
used to meet the core data registration needs and also to investigate how registrants plan to
use non-test data for higher-tier endpoints, i.e. analysis of these dossiers provides a good
source of data to examine the use of alternative methods and options chosen by the
registrants to fulfil information requirements under REACH.
Certain submissions were excluded from the scope of this analysis: substances
manufactured or imported only for use as intermediates under strictly controlled conditions,
substances notified for use in process-orientated research and development (so-called
‘PPORD’s’) and notified substances under the former regulatory scheme (so-called ‘NONS’
substances) for which no update in respect of a tonnage band increase had been received.
On-site isolated (Article 17) and transported (Article 18) intermediates can benefit from
reduced information requirements provided they are used under strictly controlled conditions.
Studies on properties are not needed for these registrations, except for transported isolated
intermediates at or above 1 000 tpa for which only Annex VII data are needed. For all other
intermediates, registrants submit only the existing information on properties. Therefore,
intermediates are not considered in this analysis. From 1 June 2008 to 28 February 2011
ECHA received 5 079 dossiers on intermediates covering 2 231 unique substances.
According to Article 3 (22) of the REACH Regulation product and process oriented research
and development (PPORD) is defined as “any scientific development related to product
development or the further development of a substance, on its own, in mixtures or in articles
in the course of which pilot plant or production trials are used to develop the production
process and/or to test the fields of application of the substance”. In order to promote
innovation, Article 9 of the REACH Regulation specifies that substances manufactured or
imported on their own or in mixtures, as well as substances incorporated in articles or
imported in articles for the purpose of PPORD can be exempted from the duty to register for
a period of five years. Studies on the properties of PPORD substances are not mandatory for
a PPORD notification, therefore, PPORDs are not considered in this analysis. From 1 June
2008 to 28 February 2011 ECHA has received 679 PPORD notifications.
So called ‘NONS’ substances’ are those which were placed on the European Community
market after September 1981 i.e. substances that were not included in the inventory of
substances on the Community market (EINECS-list). Such substances had to be notified
according to Council Directive 67/548/EEC to the Member States Competent Authorities. As
with the REACH Regulation, the information requirements were also tonnage dependant for
such notified substances, however, the information requirements were not the same as for
the REACH Regulation. Such notified substances are regarded as registered substances
according to Article 24 of the REACH Regulation. The IUCLID database contains migrated
files from the old data base, but this migration does not produce fully completed records and
so these were not suitable for analysis using the tools developed for the purposes of this
report.
From the original number of 24 560 registration dossiers, 17 062 dossiers were identified to
be registration dossiers with a tonnage band at or above 100 tpa. It was necessary to
exclude dossiers for ‘chemical categories’ (i.e. IUCLID category dossiers) from the in-depth
analysis due to the complex endpoint interrelationship between dossiers that currently did not
allow a reliable data analysis to be performed. At or above 100 tpa, there were 568 IUCLID
category dossiers (i.e. 2.3% of the total number of dossiers) covering 85 substances, so the
overall findings of this report are not unduly affected, because 16 494 dossiers remained in
the data set for analysis.
From the remaining 16 494 dossiers, only the lead registrant’s dossiers, dossiers submitted
under the opt-out provisions from joint submissions and dossiers for individual registrations
contained endpoint information for the registered substances. Thus, the total number of
dossiers to be considered for the in-depth analyses was reduced to 1 862.
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
These dossiers were analysed within three groups: dossiers for phase-in substance at or
above 1 000 tpa, phase-in substance dossiers at between 100 and 1 000 tpa and non-phasein
dossiers with a tonnage band of 100 tpa or more (see Table 1)
Table 1: Registration dossiers within the scope of in-depth analysis of this report
Tonnage band Phase-in Non phase-in Total
All
22 995
(3 308 substances)
1 565
(1 347 substances)
24 560
(4 599* substances)
Registration dossiers with tonnage band > 100 tpa
> 1 000 tpa 15 421
100 - <1 000 tpa 1 469
172
17 062
(2 219 substances)
Registration dossiers excluding category dossiers
> 1 000 tpa 14 875
100 - <1 000 tpa 1 448
171
16 494
(2 134 substances)
Lead and individual dossiers
> 1 000 tpa 1 504
100 - <1 000 tpa 218
140
1 862
(1 789 substances)
*56 substances were classified as phase-in by some registrants and non-phase-in by other registrants, so they
count as both. Therefore, whilst the sum of 3 308 and 1 347 is 4 655, this is actually 4 599 unique substances.
In order to analyse data submitted by registrants in the registration procedure to ECHA, the
Agency has developed an IT application allowing identification of substances fulfilling predefined
criteria. These selection criteria were designed to find and extract information on the
number and type of different options used by the registrant in order to meet the information
requirements under REACH.
Further information on the selection criteria applied in data analysis for the individual
endpoints is presented in Figure 1.
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
Figure 1: Schematic of data analysis for individual endpoints
*IUCLID flags to omit the study are set by the registrant to omit the submission of the required data filling the
“data waiving” pick-list. These are used when testing does not appear to be: scientifically necessary; technically
not possible; or not necessary based on low exposure considerations
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
2.2 Endpoint Study Record (ESR) approach
The ESR approach consists of the analysis of all endpoint study records submitted for the
1 862 dossiers for a given endpoint. For each endpoint, more than one or even many
endpoint study records are possible and were summarised for these dossiers (see below).
The ESR approach provides the overall quantitative picture of options used by registrants for
dossiers within the scope of this analysis (see section 3.2). .
The results of this approach show what information has been submitted for a given endpoint
cumulatively in all dossiers. This analysis provides an overall data availability for endpoints.
However, it does not cover which of these data have been used as key data to fulfil the
information requirements and it does not allow assessing the degree to which data
redundancy is involved per substance.
2.3 Substance approach
Whereas the ESR approach is based on dossiers collectively, it is of further interest to
analyse at substance level, how the registrants used alternative approaches. Such an
analysis provides the relative proportions of the principal options used by registrants to fill the
information requirements per endpoint. These options have been categorised as testing
proposals, experimental studies and alternative methods.
If there was a testing proposal included this was taken as evidence that the endpoint
was supposed to be filled by future testing;
If there was one ESR entry referring to an experimental study, this was taken as
evidence that the endpoint on the substance level was filled with experimental data
(including a weight of evidence approach also using experimental data); and
If there was no ESR entry referring to an experimental study but listing either a
possibility to omit the information or to fill the information requirements using
alternative approaches, it was counted as evidence that the endpoint on the
substance level was filled with alternative method.
Each of these options has been only counted once per endpoint at substance level.
Therefore this way of analysing the data does not provide a frequency distribution on how
many experimental or alternative studies have been entered per endpoint at substance level.
Such a frequency distribution will be different between individual substances, depending on
their extent and history of use.
2.4 Studies conducted or proposed for the purpose of REACH
Beside the cumulative analysis of endpoint data from the selected registration dossiers (see
section 2.1 for dossier inclusion criteria) , the ESR approach has also been used to perform a
complete statistical analysis of these registration dossiers to assess what new studies had
been conducted in order to complete the core data requirements and what testing proposals
had been made, which may ultimately require the conduct of new studies using vertebrate
animals to fulfil the higher-tier information requirements.
In this analysis all vertebrate animal testing proposals and experimental studies performed in
2009 or later have been counted for all tonnage bands for both phase-in and non-phase-in
dossiers. For this analysis an assumption was made that studies described in the IUCLID
dossier with a reference date of 2009 or later had been conducted for REACH. It should be
noted that this assumption will overestimate the number of new animal studies for two
reasons. Firstly some studies may have been conducted for purposes other than REACH,
e.g. for other non-EU chemical control schemes. Secondly the study may have commenced
earlier but the date of the study report was 2009 or later.
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
In this analysis all reproduction toxicity screening studies (performed according to OECD test
guideline 422 or 421 or the equivalent US EPA guidelines) have been counted and
presented separately as they can be used to fulfil information requirements for Annex VII
core data for one or more different endpoints (i.e. repeated dose toxicity and reproductive
toxicity). Hence, counting them at the endpoint level could lead to double-counting (e.g. a
single test could be counted once for repeated dose toxicity and counted again for
reproductive toxicity), therefore potentially overestimating the overall number of tests
conducted. Furthermore, some registrants have argued in their dossiers that this screening
reproduction toxicity study can be used to meet the higher-tier Annex IX and X data
requirements of developmental toxicity and fertility studies instead of making testing
proposals. This practice results in an incorrect impression that higher-tier two-generation
fertility studies or prenatal developmental toxicity studies have been conducted without the
submission of a testing proposal. In order to analyse the use of these reproduction toxicity
screening studies, all the respective dossiers had to be checked manually.
It is important to add some explanations on the numbers of testing proposals provided in
different results sections of this report. The reference numbers of testing proposals for all
dossiers are provided in section 3.4. The different scope of the dossiers within the analyses
explains differences in the numbers of testing proposals in other sections.
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
3 Results
3.1 The sharing and joint submission of information
The joint submission of information worked well in general as shown by the proportion of total
registrations submitted jointly: nearly 90% of the total number, the remaining part also
covering individual submissions of non-phase-in substances. From nearly 3000 joint
submissions containing almost 20 000 member dossiers, there were only 135 member
dossiers with opt-outs for one or more end-points as described in Articles 11(3) and 19(2) of
REACH. An overview of the main reasons for opt-outs is provided in the report ‘The
Operation of REACH and CLP 2011’ produced in accordance with Article 117 (2) of REACH.
However, a more detailed analysis reveals that in some cases the registrants, instead of
opting out, within the joint submission, instead submitted separate registration dossiers. For
about 250 substances, ECHA received either multiple joint submissions or, in addition to the
joint submissions, one or more individual submissions on the same substance. ECHA is
currently examining the explanations for these situations. The joint submission of information
generally worked well in general as shown by the proportion of total registrations submitted
jointly: 90% of the total number of dossiers, the remaining part also covering individual
submissions of non-phase-in substances. From nearly 3 000 joint submissions covering
almost 20 000registrations, there were only 135 member dossiers with opt-outs for one or
more end-points in accordance with Articles 11(3) and 19(2) of REACH. An overview of the
opt-out reasons given per end-point type is provided in the Article 117 (2) report.
More specifically, for the registration dossiers in the focus of this report (phase-in substances
with a tonnage band of at or above 1 000 tpa (excluding categories)), 82 dossiers covering
60 substances have been flagged by the registrants for opting out from a joint submission. Of
these, 19 “opt-outs” concerned endpoints which required testing on animals
For non-phase-in substances and for phase-in substances not pre-registered, the inquiry
process ensures the sharing of existing data between registrants of the same substance. The
Agency has successfully processed almost 1 500 inquiries made by potential registrants, and
of these, about 50 % have led to registration afterwards.
In conclusion, these numbers demonstrate that generally the sharing and joint submission of
information worked and that the registrants used them to fulfil the information requirements.
However, the number of separate registration dossiers for the same substances indicate that
the sharing and joint submission of information still needs further improvement.
3.2 Endpoint analysis
The results of the ESR approach are presented for each endpoint of concern in the endpoint
sections below. In addition, Tables 4 to 6 in Appendix I provide detailed data from the ESR
perspective. During the creation of the study records in IUCLID5, the registrant can select
from a number of pre-defined options depending on the purpose of that study record. For the
purpose of this analysis, the following groups of options have been used:
• “Experimental studies: classified by the registrant as “experimental result” from the
pick-list of options in the field “Study result type” (abbreviation: ES; in vitro and in vivo
studies are treated separately if applicable)
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
• “Testing proposal”: classified by the registrant as “experimental study planned” from
the pick-list of options in the field called “Study result type” (abbreviation TP).
• “Read-across”: classified by the registrant as read-across from the pick-list of options
in the field called “Study result type” (abbreviation RA).
• “IUCLID flags to omit the study”: selected by the registrant to omit the submission of
the required data by choosing the appropriate option from those available in the picklist
in the field called “data waiving”. These options are to be used to indicate when
testing does not appear to be: scientifically necessary; technically not possible; or not
necessary based on low exposure considerations (abbreviation FO).
• “Weight of Evidence1
”: classified by the registrant as weight of evidence in the
“purpose flag” pick-list (abbreviation WE).
• “(Q)SAR studies”: classified by the registrant as “(Q)SAR studies” in the pick-list
called “Study result type” (abbreviation QS).
• “Miscellaneous”: classified by the registrant as “other” in the pick-list called “Study
result type”; their content cannot be further verified without detailed examination
(abbreviation MS).
In the endpoint charts, the above described options have been used to graphically represent
the findings for registration dossiers for phase-in substances at or above 1 000 tpa.
The results from the substance perspective have been presented in the form of bar charts for
all relevant endpoints and described in the section 3.3.
The results of a separate cumulative analysis of the studies conducted or proposed for the
purpose of REACH are presented in the section 3.4.
It is important when considering these findings to understand that the ESRs are provided by
the registrants and the contents of the ESRs were not scrutinised by ECHA, and there will
certainly be some errors in the dossiers. Nevertheless it is possible to get a general picture of
the animal studies submitted in registrations and how non-animal data were used instead.
It is possible to get insight into the quality of the information in registration dossiers from the
compliance checks which are conducted on some registrations in accordance with the
REACH Regulation. The results of the compliance checks performed up to December 2010
are contained in the Article 54 reports on Evaluation published in February each year by
ECHA. When interpreting the findings of the ESR analysis, it should be noted that in principle
there may be deficiencies discovered in the compliance check dossier evaluation work that
results in further animal studies being requested if the quality of the non-standard data in the
dossier is discovered to be inadequate (see section 4).
1
Weight of evidence option covers various combinations of old experimental data, literature information and readacross
possibilities and it is assumed that it does not contain new animal tests performed for the registered
substance. In order to avoid double counting whenever the study was classified by the registrant as weight of
evidence, it was counted and excluded from the further analysis of the other options.
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
3.2.1 Acute toxicity
The information requirement for an acute toxicity study conducted using the oral route
applies at or above 1 tpa (Annex VII) and is therefore part of the core data for all the
registrations. The requirement for such a study can be adapted, for example if the substance
is corrosive. Acute toxicity by either dermal or inhalation exposure, or in some cases both
routes, is needed for all substances (except gases) at or above 10 tpa (Annex VIII),
depending on the likely human exposure, and is therefore also part of the core data for the
registrations in this study. The purpose is to have information on the toxicity of a chemical
substance. The standard laboratory animal species used for this purpose is the rat, but the
mouse is also used. The effects of the administered dose(s) are monitored and reported
according to EU TMR/OECD TG standard protocols ensuring that the results can be used
worldwide. In vitro approaches for this endpoint have not been validated yet. Available
alternative approaches are therefore mainly prediction methods (read-across and grouping)
or Weight of Evidence using experimental methods in combination with prediction methods.
In analysing this endpoint, records were observed addressing the oral, dermal, or inhalation
route only, or all possible combinations.
Acute toxicity - all (HH)
No. ESR % ESR
ES 7 328 56.9
TP 0 0.0
RA 2 756 21.4
FO 1 184 9.2
WE 1 116 8.7
QS 11 0.1
MS 479 3.7
Total 12 874 100
Figure 2: Acute Toxicity (all routes, 1 504 dossiers covering phase–in substances > 1 000 tpa, one or
more ESR may be present per dossier) - Legend: ES - Experimental studies; TP - Testing proposal;
RA - Read-across; FO - IUCLID flags to omit the study; WE - Weight of Evidence; QS - (Q)SAR
studies; MS - Miscellaneous.
In the dossiers for phase-in substances at or above 1 000 tpa, 12 874 entries (100 %) have
been counted in total. A Weight of Evidence approach was flagged by the registrant in 1 116
(8.7 %) of these entries, thereby indicating that in these cases several independent sources
of information, including animal studies had been used to cover this endpoint. Experimental
studies have been used for 7 328 (56.9%) of the ESRs.
The IUCLID flags to omit the information have been used in 1 184 (9.2 %) of all ESRs and
read-across approaches have been flagged in 2 756 (21.4 %) of ESRs. In 479 (3.7 %) of
ESR, the registrant flagged other information sources for covering this endpoint. In 11 cases
(0.1 %) QSAR was used as the ESR. The percentages of different ESR types for phase-in
substances in the 100 to 1 000 tpa range did not vary significantly from those of phase-in
substances at or above 1 000 tpa. For non-phase-in substances at or above 100 tpa the total
percentage of entries for experimental studies was 38.9 % of the total. Analyses which
separated the acute toxicity endpoint by route of administration did not provide significantly
different results (see rows 1.0, 1.1, 1.2 and 1.3 in Table 4).
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
3.2.2 Skin irritation/corrosion
The studies used to investigate this endpoint predict the local effects of the test substance on
humans at the site of first contact (skin, eye, mucous membrane of respiratory or
gastrointestinal tract) after a single exposure. Observed local effects can be further
differentiated as either irritant or corrosive effects, depending on their severity, reversibility or
irreversibility. For in vivo studies, the substance to be tested is applied in a single dose to the
skin of an experimental animal, the preferred species being the albino rabbit, for four hours;
untreated skin areas of the test animal serve as the control.
The standard information requirements for this endpoint are provided in Annexes VII to X of
the REACH Regulation and differ depending on the tonnage band. Annex VII (1 to 10 tpa)
requires only in vitro studies, while Annex VIII (10 – 100 tpa) requires a confirmatory
additional in vivo test, unless the substance is classified as an irritant or corrosive, and hence
should be included in all the registrations for this study. Alternative options to fulfill standard
information requirements for this endpoint under REACH include prediction methods, weight
of evidence approach and possibilities to adapt information requirements according to
column 2 of Annexes VII to X. The potential to cause irritation or corrosion can be also
predicted based on physicochemical properties of the chemical (e.g. the substance is a
strong acid/base or is spontaneously flammable). According to Annex XI 1.4, the registrant
can also adapt the standard information requirements based on the results of in vitro studies.
There are validated in vitro methods available for this endpoint that can be used by the
registrants in a tiered testing strategy within a weight of evidence approach to fully replace
testing on animals. For studying skin corrosion/severe irritation, these methods include, for
example, EU TMR/OECD TG standard protocols such as the transcutaneous electrical
resistance (TER) test, human skin model test and 3T3 NRU phototoxicity test. For skin
irritation, a reconstructed human epidermis test method is available.
In Table 4 the endpoint study records for in vitro and in vivo studies on skin
irritation/corrosion for non-phase-in and phase-in substances manufactured or imported at or
above 100 tpa are summarized in rows 2.1 and 2.2.
Skin irritation – in vitro (HH)
No. ESR % ESR
ES 252 76.6
TP 0 0.0
RA 39 11.9
FO 2 0.6
WE 35 10.6
QS 0 0.0
MS 1 0.3
Total 329 100
Figure 3: Skin irritation in vitro (1 504 dossiers covering phase–in substances > 1 000 tpa, one or
more ESR may be present per dossier) - Legend: ES - Experimental studies; TP - Testing proposal;
RA - Read-across; FO - IUCLID flags to omit the study; WE - Weight of Evidence; QS - (Q)SAR
studies; MS - Miscellaneous.
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
As presented in Figure 3, for dossiers of phase-in substances at or above 1 000 tpa, there
were 329 (100 %) ESRs in total. Experimental studies have been used for 252 (76.6 %) of all
ESRs submitted for this endpoint. In 35 (10.6 %) of the entries Weight of Evidence approach
was flagged by the registrant. Two registrants have used IUCLID flags to omit the information
and read-across approaches have been flagged in 39 (11.9 %) of ESRs.
For the dossiers of phase-in substances manufactured or imported at 100 – 1 000 tpa only
24 ESRs for skin irritation in vitro have been found, while for the non-phase-in substances
produced at or above 100 tpa only one old study has been submitted.
Skin irritation – in vivo (HH)
No. ESR % ESR
ES 3 343 64.1
TP 0 0.0
RA 1 113 21.3
FO 216 4.1
WE 402 7.7
QS 5 0.1
MS 137 2.6
Total 5 216 100
Figure 4: Skin irritation in vivo (1 504 dossiers covering phase–in substances > 1 000 tpa, one or
more ESRs may be present per dossier) - Legend: ES - Experimental studies; TP - Testing proposal;
RA - Read-across; FO - IUCLID flags to omit the study; WE - Weight of Evidence; QS - (Q)SAR
studies; MS - Miscellaneous.
The registrants submitted in total 5 216 ESRs of skin irritation in vivo to fulfil the information
requirements for the phase-in substances at or above 1 000 tpa. In comparison with the skin
irritation in vitro endpoint, significant differences in the strategy used by registrants to fulfil the
information requirements were noted. Experimental studies have been used for 3 343 (64.1
%) of all ESRs. In 402 (7.7 %) of these entries, a Weight of Evidence approach was flagged
by the registrant.
The IUCLID flags to omit the information have been used in 216 (4.1 %) of all ESR and readacross
approaches have been flagged in 1 113 (21.3 %) cases. Registrants have used five
(Q)SAR predictions for this endpoint, and other information has been flagged in 137 (2.6 %)
of ESR.
For the dossiers of phase-in substances produced at 100 to 1 000 tpa the total number of
ESRs was almost nine times less (600 ESR entries) when compared with the substances
produced at or above 1 000 tpa, but no significant differences in the proportional distribution
of various options of ESR were observed.
For non-phase-in substances at or above 100 tpa, 157 ESRs have been submitted for this
endpoint. In 45.9 % of cases, the registrants have provided experimental data, other
information has been chosen in 26 % of ESRs, read-across approach has been selected in
14.6 % of cases and 8.9 % of ESRs have been flagged in IUCLID to omit the study.
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
3.2.3 Eye irritation
As with the skin irritation/corrosion endpoint, studies on eye irritation are used to predict the
local effects of the test substance on human eyes following a single exposure. For in vivo
studies conducted according to EU TMR/OECD TG standard protocols, the substance to be
tested is applied in a single dose to the eye of an experimental animal, usually the albino
rabbit, for 24 hours; the untreated eye of the test animal serves as the control. The effects of
the substance on the exposed animals are usually monitored for 72 hours and reported in a
standardised format.
The potential of a substance to cause eye irritation can be assessed using an in vitro test for
registration(s) at less than 10 tpa (Annex VII) and with an in vivo study at or above 10 tpa
(Annex VIII) unless the substance is already classified as an eye irritant or corrosive, is a
strong acid or base, or is flammable in air at room temperature. The standard information
requirements, and the possibilities to adapt them according to column 2 of Annexes VII to X
for eye irritation under REACH, are similar to those for skin irritation/corrosion.
There are in vitro methods that have undergone a validation process that could be used by
the registrants to fulfill information requirements for this endpoint. A positive outcome from invitro
assays such as the bovine corneal opacity and permeability (BCOP) or isolated chicken
eye (ICE) tests is sufficient to classify severe eye irritants under Annex VII and Annex VIII
using adaptations of the standard testing regime specified in Annex XI.
In Table 4, the endpoint study records for in vitro and in vivo studies on eye
irritation/corrosion for non-phase-in and phase-in substances manufactured or imported at or
above 100 tpa are summarised in rows 3.1 and 3.2.
Eye irritation – in vitro (HH)
No. ESR % ESR
ES 149 86.6
TP 0 0.0
RA 12 7.0
FO 1 0.6
WE 5 2.9
QS 0 0.0
MS 5 2.9
Total 172 100
Figure 5: Eye irritation in vitro (1 504 dossiers covering phase–in substances > 1 000 tpa, one or more
ESRs may be present per dossier) - Legend: ES - Experimental studies; TP - Testing proposal; RA Read-across;
FO - IUCLID flags to omit the study; WE - Weight of Evidence; QS - (Q)SAR studies; MS
- Miscellaneous.
For the dossiers for phase-in substances at or above 1 000 tpa, a total of 172 ESRs have
been counted. Experimental studies have been used for 149 (86.6 %) of all ESRs for this
endpoint. In five (2.9 %) of the entries, a Weight of Evidence approach was flagged by the
registrant and the same number of ESRs have been flagged as other information. In 12
cases (7.0%) registrants have used read-across approaches.
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
Eye irritation – in vivo (HH))
No. ESR % ESR
ES 2 714 64.3
TP 0 0.0
RA 884 20.9
FO 219 5.2
WE 279 6.6
QS 0 0.0
MS 125 3.0
Total 4 221 100
Figure 6: Eye irritation in vivo (1 504 dossiers covering phase–in substances > 1 000 tpa, one or more
ESRs may be present per dossier) - Legend: ES - Experimental studies; TP - Testing proposal; RA Read-across;
FO - IUCLID flags to omit the study; WE - Weight of Evidence; QS - (Q)SAR studies; MS
- Miscellaneous.
For the dossiers of phase-in substances manufactured or imported at 100 – 1 000 tpa only
27 ESRs for eye irritation in vivo have been found; from those, 19 ESRs (70.4 %) have been
filled with experimental data. For the non-phase-in substances produced at or above 100 tpa
only one old study has been submitted.
The registrants submitted in total 4 221 ESRs of eye irritation in vivo to fulfil the information
requirements for the phase-in substances at or above 1 000 tpa. Experimental studies have
been used for 2 714 (64.3 %) of the ESRs. In 884 (20.9 %) of theses entries, a read-across
approach was flagged by the registrant.
The IUCLID flags to omit the information have been used in 219 (5.2 %) of all ESRs and
Weight of Evidence approaches have been flagged in 279 (6.6 %) cases. Registrants have
flagged “other information” in IUCLID in 125 (3.0 %) of the cases.
For the dossiers of phase-in substances produced at 100 – 1 000 tpa total number of ESRs
was 8 times less (524 ESR entries) when compared to the those available for substances
produced at or above 1 000 tpa, but no significant differences in the proportional distribution
of various options of ESR were observed (ref. Table 4 row 3.1).
For non-phase-in substances at or above 100 tpa 140 ESR have been submitted for this
endpoint. In 45 % of cases registrants have provided experimental data, other information
has been chosen in 27.9 % of ESRs, a read-across approach has been selected in 11.4 % of
cases and 10.7 % of ESRs have been flagged in IUCLID to omit the study.
3.2.4 Skin sensitisation
Skin sensitisation is the toxicological endpoint associated with chemical substances that
have the intrinsic property to cause skin sensitisation and allergic contact dermatitis in
humans following repeated exposures to a substance.
The standard skin sensitisation test methods, for which EU TMR/OECD TG are available,
include the guinea pig maximisation test (GPMT), the occluded patch test of Buehler and the
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
murine local lymph node assay (LLNA). In the GPMT, guinea pigs are exposed to the test
substance by intradermal injection and topical application by occlusion. Following a rest
period of ten to fourteen days, the challenge dose is introduced dermally. The extent and
degree of skin reactions to this challenge exposure are then compared with control animals.
In the Buehler test, guinea pigs are repeatedly exposed to the test substance by topical
application under occlusion. Following a rest period of twelve days, a dermal challenge
treatment is performed under occlusive conditions. In the LLNA, the test substance is applied
to the ears of mice for three days and later tritiated radioactive thymidine is introduced to
measure cell proliferation in auricular lymph nodes. An increase in lymph node cell
proliferation compared to control animals indicates sensitisation. There are currently no
validated non-animal alternative methods to identify skin sensitisation hazard potential.
The information requirements for skin sensitisation are described in REACH Annex VII. Data
on skin sensitisation are required for substances produced or imported at or above 1 tpa, and
hence should be in all the registrations for this study. In vivo studies do not need to be
conducted, if there is enough evidence that the substance should be classified or based on
physicochemical properties of the test substance (strong acid or base or flammable in air at
room temperature). The murine local lymph node assay (LLNA) is the first choice method for
in vivo testing and another test should only be chosen in exceptional circumstances that
have to be correctly justified. The LLNA is regarded as being more capable of predicting the
relative potency of skin sensitising chemicals, i.e. the chemical’s relative power/strength to
induce skin sensitisation.
In Table 4, the endpoint study records for in vitro and in vivo studies on skin sensitisation for
non-phase-in and phase-in substances manufactured or imported at or above 100 tpa are
summarised in rows 4.1 and 4.2.
For dossiers for phase-in substances at or above 1 000 tpa, there were 21 entries for in vitro
skin sensitisation studies. Further analysis revealed that in most cases, these entries were
(in vivo) LLNA tests that were misclassified by registrants as in vitro tests.
Skin sensitisation – in vivo
(HH)
No. ESR % ESR
ES 2 080 55.4
TP 0 0.0
RA 782 20.8
FO 264 7.0
WE 513 13.7
QS 18 0.5
MS 97 2.6
Total 3 754 100
Figure 7: Skin sensitisation in vivo (1 504 dossiers covering phase–in substances > 1 000 tpa, one or
more ESRs may be present per dossier) - Legend: ES - Experimental studies; TP - Testing proposal;
RA - Read-across; FO - IUCLID flags to omit the study; WE - Weight of Evidence; QS - (Q)SAR
studies; MS - Miscellaneous.
For the skin sensitisation in vivo endpoint many more ESR entries have been filled.
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
For phase-in substances at or above 1 000 tpa 3 754 ESRs have been counted. In 2 080
(55.4 %) of theses entries registrants have used experimental data. The IUCLID flags to omit
the information has been used in 264 (7.0 %) of all ESR and read-across approaches have
been flagged in 782 (20.8 %) of ESRs. Weight of Evidence has been used in 513 (13.7 %)
ESRs and other information has been flagged in 97 (2.6 %) cases. Comparison of the phasein
dossiers at 100 – 1 000 tpa with the results described above (see Table 4 row 4.2) did not
result in the observation of significant differences.
For the non-phase-in substances only 176 ESRs have been created by the registrants. The
percentage of experimental studies in total reached 41.5 %, other information has been
chosen in 21.0 % of cases and the read-across approaches have been flagged in 15.3 % of
the ESRs. The number of selected IUCLID flags to omit the study was 19.9%.
3.2.5 Repeated dose toxicity
Information on repeated dose toxicity is used to predict the effects of longer term exposure of
chemical substances to humans. During the study, purpose-bred animals such as the rat or
mouse receive repeated doses of a substance via oral, dermal or inhalation routes of
exposure. In Annex VIII, a study with a duration of 28 days (sub-acute) is the standard
information requirement, but note as described below that there was the possibility to omit
this study from the core data set at the time of registration to achieve a technically complete
dossier by making a testing proposal for a 90-day study if adequate risk management
measures are in place. At Annex IX additionally a study with 90-days duration (sub-chronic)
is the standard information requirement. The oral route in many cases is the default, but
depending on the relevant exposure route for humans also dermal application or inhalation
may be needed. At Annex X long term studies with duration up to two years (chronic) can be
proposed by the registrant or can be used to fill the endpoint.
In vitro methods have not been validated for repeated dose toxicity and cannot be predicted
by QSAR. Alternative methods are therefore mainly other prediction methods (read-across
and grouping), Weight of Evidence approaches and the possibilities to omit the studies in
accordance with the requirements in column 2 of Annexes VII to X and in Annex XI.
In IUCLID the repeated dose endpoint is one of the most complicated ones. It can have
entries for studies with different durations and for different routes and for all combinations of
these. In addition, a so-called combined screening study, combining studies of repeated
dose toxicity with reproductive toxicity, may have been used by the registrant to meet the
core data requirements (Annex VIII) for this endpoint. For all types of studies, the effects of
the substance on the test animals are monitored and reported according to EU TMR/OECD
TG standard protocols thereby ensuring that the results can be used worldwide. In vitro
methods have not been validated for this endpoint. The alternative methods used are
therefore mainly prediction methods (read-across and grouping), Weight of Evidence
approaches and the possibilities to omit the studies provided by column 2 of Annexes VII to
X and in Annex XI.
In Table 5 summarising ESRs for repeated dose toxicity the total number of entries for this
endpoint separated by route and duration is collected.
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
Figure 8: Repeated dose toxicity – all routes, all study durations (1 504 dossiers covering phase–in
substances > 1 000 tpa, one or more ESRs may be present per dossier) - Legend: ES - Experimental
studies; TP - Testing proposal; RA - Read-across; FO - IUCLID flags to omit the study; WE - Weight of
Evidence; QS - (Q)SAR studies; MS - Miscellaneous.
In Figure 8 for the dossiers for phase-in substances at or above 1 000 tpa, 10 790 entries
(100 %) have been counted in total as ESRs. In 4 546 cases (42.1 %) registrants used
experimental data for these endpoints. In 104 (1 %) ESRs, testing proposals have been
submitted for these phase-in substances at or above 1 000 tpa. Read-across approaches
have been used in 3 032 (28.1 %) of the ESRs. Weight of evidence was flagged by the
registrants in 709 entries (6.6 %). Flags to omit the information have been set by the
registrants in 2 032 cases (18.8 %). QSAR predictions are not very relevant to these
endpoints and correspondingly have been used only in 9 cases (0.1 %). Other information
has been flagged in 357 cases (3.3 %). It should be noted that this analysis covers all routes
and all study durations. More detailed information is provided in Table 5.
With the aim of helping the companies to meet the first registration deadline and to avoid
unnecessary vertebrate animal testing, in 2009 ECHA issued a dedicated press release and
a related fact sheet elaborating on the information requirements for substances
manufactured or imported at or above 100 tpa. ECHA stated that registration dossiers for
substances at or above 100 tpa will be considered as technically complete even if they do
not contain the results of a 28-day repeated dose toxicity study, if instead a testing proposal
for a 90-day repeat-dose toxicity study is submitted in the registration and appropriate risk
management measures are in place. Among Annex IX dossiers, submitted to ECHA by the
first deadline, 55 dossiers did not contain a sub-acute (28-day) repeated dose toxicity study,
but did contain a testing proposal for sub-chronic, 90-day study. This analysis was performed
assuming that the missing 28-day study and TP for a 90-day study was for the same route.
RDT – all routes, all study
durations (HH)
No. ESR % ESR
ES 4 546 42.1
TP 104 1.0
RA 3 032 28.1
FO 2 033 18.8
WE 709 6.6
QS 9 0.1
MS 357 3.3
Total 10 790 100
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
3.2.6 Genetic toxicity
The aims of testing for genetic toxicity (genotoxicity) are to assess the mutagenic potential of
substances, i.e. their ability to induce genotoxic effects which may lead to cancer or cause
heritable damage in humans. Information is required on the capability of substances
capability to induce gene mutations, structural chromosome aberrations (clastogenicity) and
numerical chromosome aberrations (aneugenicity). To obtain such information, many in vitro
and in vivo test methods officially adopted by the EU or the OECD are available. Non-testing
options, for example (Q)SAR and the use of read-across approaches, may also provide
information on the mutagenic potential of chemical substances.
Standard information requirements on mutagenicity under REACH are described in the
Annexes VI to XI and the specific rules to omit, replace, and adapt the required standard
data or to use alternative options are listed in column 2 of the Annexes VII-X.
For substances manufactured or imported at the lower tonnage (1-10 tpa), only an in vitro
gene mutation study in bacteria is required (Annex VII). No further studies at this tonnage
level are required if the result is negative (i.e. no signs of adverse effects).
For substances falling under the Annex VIII information requirements of REACH, additional
in vitro tests are required. An in vitro cytogenicity study or an in vitro micronucleus study in
mammalian cells needs to be conducted but may be omitted if reliable data from an in vivo
mammalian cell gene mutation test are available or if the substance is already classified as a
carcinogen or mutagen. If both the in vitro gene mutation study in bacteria and the
cytogenicity study in mammalian cells are negative, another in vitro study – gene mutation in
mammalian cells – is required, unless reliable in vivo mammalian gene mutation data are
available. At this tonnage level, in vivo mutagenicity studies shall only be considered in cases
of a positive (i.e. signs of an adverse effect) result in any of the required in vitro tests.
For substances manufactured or imported between at 100-1 000 tpa, if there is a positive
result in any of the in vitro genotoxicity studies and no reliable in vivo data available,
registrants have to submit testing proposal for an in vivo somatic cell genotoxicity study. For
substances falling under the Annex X requirements of REACH, a positive result in any in vitro
studies may additionally trigger a need for a second in vivo somatic cell test. For all
substances manufactured at 100 tpa or more, a positive outcome from in vivo somatic cells
test should lead to considerations on the potential for germ cell mutagenicity.
In summary, generally only in vitro mutagenicity tests are needed for the core data, and
some in vivo confirmatory mutagenicity studies may be necessary as higher-tier studies to be
conducted after the testing proposals have been approved.
In Table 4 on the ESRs for genetic toxicity the total number of entries for this endpoint
separated by in vitro and in vivo test is summarised in the rows 5.1 and 5.2
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
Figure 9: Genetic toxicity in vitro (1 504 dossiers covering phase–in substances > 1 000 tpa, one or
more ESRs may be present per dossier) - Legend: ES - Experimental studies; TP - Testing proposal;
RA - Read-across; FO - IUCLID flags to omit the study; WE - Weight of Evidence; QS - (Q)SAR
studies; MS - Miscellaneous.
As presented in Figure 9, for the dossiers for phase-in substances at or above 1 000 tpa,
10 322 entries (100 %) have been counted in total as ESRs. Experimental studies have been
used for 5 908 (57.2 %) of all ESRs for this endpoint. In 1 245 (12.1 %) of theses entries
Weight of Evidence approach was flagged by the registrant.
The IUCLID flags to omit the information have been used in 394 (3.8 %) of all ESRs and
read-across approaches have been flagged in 2 272 (22.0 %) of ESRs. QSAR was used in 5
ESRs, and other information has been flagged in 498 (4.8 %) ESRs.
For the dossiers of phase-in substances produced at 100 – 1 000 tpa, a total number of
ESRs was almost six times less (1 745 ESR entries) than at the higher tonnage described
above. Comparison of the distribution of options to fulfil information requirements among
ESRs with the results for dossiers at or above 1 000 tpa described above (see Table 4 row
5.1) did not result in the observation of significant differences.
For the non-phase-in substances produced at or above 100 tpa, the results were slightly
different. The percentage of experimental studies in total reached only 51.3 % and the readacross
approaches have been flagged in only 10.3 % of the ESRs. Weight of Evidence has
been only flagged in 2.8 % of all ESRs, while the flags to omit the study have been chosen in
9.1 % of the cases. For non-phase-in substances the registrants have used many more other
options to fulfil information requirements (26 % of the ESRs).
Genetic toxicity - in vitro (HH)
No. ESR % ESR
ES 5 908 57.2
TP 0 0.0
RA 2 272 22.0
FO 394 3.8
WE 1 245 12.1
QS 5 0.0
MS 498 4.8
Total 10 322 100
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Genetic toxicity – in vivo
(HH)
No. ESR % ESR
ES 1 852 52.4
TP 18 0.5
RA 875 24.8
FO 221 6.3
WE 389 11.0
QS 0 0.0
MS 177 5.0
Total 3 533 100
Figure 10: Genetic toxicity in vivo (1 504 dossiers covering phase–in substances > 1 000 tpa, one or
more ESRs may be present per dossier) - Legend: ES - Experimental studies; TP - Testing proposal;
RA - Read-across; FO - IUCLID flags to omit the study; WE - Weight of Evidence; QS - (Q)SAR
studies; MS - Miscellaneous.
The registrants submitted in total 3 533 ESRs (100 %) of genetic toxicity in vivo studies to
fulfil the information requirements for the phase-in substances manufactured or imported at
or above 1 000 tpa. The distribution among the different options to fulfil the information
requirements under REACH seemed to be similar to the genetic toxicity in vitro endpoint.
Experimental studies have been used for 1 852 (52.4 %) of all ESRs for this endpoint. In 389
(11.0 %) of these entries a Weight of Evidence approach was flagged by the registrant.
The IUCLID flags to omit the information have been used in 221 (6.3 %) of all ESRs and
read-across approaches have been flagged in 875 (24.8 %) cases. Registrants have not
used QSAR predictions for this endpoint, and other information has been flagged in 177 (5.0
%) ESRs.
For the dossiers of phase-in substances produced at 100 – 1 000 tpa, the total number of
ESRs was again almost six times smaller (596 ESR entries) when compared with the
substances produced at or above 1 000 tpa, but no significant differences in the proportional
distribution of various options of ESRs were observed (ref. Table 4 row 5.2).
For the non-phase-in substances at or above 100 tpa, almost 50 % of ESRs have been filled
with experimental studies data, and the other options have been chosen in 36.2 % of the
cases. Read-across approaches have been flagged in only 5.3 % of the ESRs and only one
ESR has been flagged as Weight of Evidence.
3.2.7 Toxicity to reproduction
The aims of testing for reproductive toxicity are focused on two related endpoints which are
usually tested separately: a prenatal developmental toxicity study analysing possible
damaging effects on the developing organism and a reproduction toxicity study covering one
or more generations and analysing possible damaging effects on the ability to breed or on
the development of the offspring. Both study types are essential for discovering hazards to
reproduction and therefore evaluate potentially very serious consequences for human
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
reproduction as well as foetal and child development. The standard laboratory animals used
for these study types are rat, rabbit or mouse for the developmental tests or rat and mouse
for the reproduction studies. Alternative in vitro tests or stand alone computational prediction
methods are currently not able to predict the impact that disturbing single or multiples of
these mechanisms could have on the entire reproductive process including the normal
postnatal development. Therefore, read-across and grouping or weight of evidence can be
used if scientifically justified as possibilities to omit the testing for these endpoints
Standard information requirements on toxicity to reproduction under REACH apply for the
substances manufactured on imported at or above 10 tpa (Annex VIII-X substances).
Possibilities for the registrants to adapt these requirements are addressed in column 2 of
relevant Annexes as well as in Annex XI.
For the substances of 10-100 tpa, a reproduction/developmental toxicity screening test (ref.
OECD TG 421 or 422) is usually required to meet the core data requirements. There was the
possibility to omit this study from the core data set at the time of registration to achieve a
technically complete dossier by making testing proposals for higher-tier studies and providing
that there were adequate risk management measures. This screening test cannot be used as
an alternative or replacement for the higher-tier studies on reproductive toxicity. However,
should the screening study show clear adverse effects on reproduction functions or
reproductive organs and provided that these screening results are sufficient for classification
and risk assessment, there may be no need for further testing.
For substances manufactured or imported between 100-1 000 tpa, in addition to the
screening study, a prenatal developmental toxicity study (ref. OECD 414, EU B.31) is usually
required. Annex IX provides that this study has to be performed in one species. It is
noteworthy that, since the information for developmental toxicity in one species is required by
both Annexes IX and X and the requirements are additive, the information requirements from
these two Annexes comprise pre-natal developmental toxicity tests in two species. However,
according to column 2 of Annex IX, 8.7.2, the decision on the need for performing the test in
a second species should be based on the outcome of the study on the first species and all
other relevant data.
For substances falling under Annex X requirements of REACH, in addition to the lower tier
tests, a two-generation reproduction toxicity study (ref. OECD TG 416, EU B.35) is required.
In Table 4 on endpoint study records (ESR) for reproductive toxicity the total number of
entries for this endpoint (toxicity to reproduction, developmental toxicity, and toxicity to
reproduction – other studies) is summarised in the rows 6.0, 7.0 and 8.0.
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Toxicity to reproduction
(HH)
No. ESR % ESR
ES 1 121 31.7
TP 150 4.2
RA 840 23.8
FO 904 25.6
WE 428 12.1
QS 4 0.1
MS 88 2.5
Total 3 535 100
Figure 11: Toxicity to reproduction (1 504 dossiers covering phase–in substances > 1 000 tpa, one or
more ESRs may be present per dossier) - Legend: ES - Experimental studies; TP - Testing proposal;
RA - Read-across; FO - IUCLID flags to omit the study; WE - Weight of Evidence; QS - (Q)SAR
studies; MS - Miscellaneous.
For the dossiers for phase-in substances at or above 1 000 tpa, registrants submitted 3 535
entries as ESRs. Experimental data have been used for 1 121 (31.7 %) of the ESRs. The
IUCLID flags to omit the information have been used in 904 (25.6 %) of these entries, and a
read-across approach was selected in 840 ESRs (23.8 %). Registrants also submitted 150
testing proposals to fulfil information requirements for this endpoint – the second highest
number of testing proposals among all analysed endpoints and ESRs (Table 4 row 6.0).
QSAR predictions were used in 4 ESRs, and miscellaneous studies were submitted in 88
(2.5 %) of the cases.
For the dossiers of phase-in substances produced at 100 – 1 000 tpa, the total number of
ESRs was more than seven times less (487 ESR entries) than at the higher tonnage. No
significant percentage differences among selected options to fulfil information requirements
with the results for dossiers at or above 1 000 tpa described above (see Table 4 row 6.0)
were noted. However, only nine testing proposals have been submitted (1.8% of all cases).
For the non-phase-in substances produced at or above 100 tpa, the registrants submitted
only 156 ESRs and the chosen options varied from the ones used for phase-in substances.
The percentage of experimental studies in total reached only 26.3 % and the read-across
approaches have been flagged in only 7.1 % of the ESRs. In contrast to phase-in
substances, the flags to omit the study have been chosen in 41 % of the cases. The
registrants have also used many more other options to fulfil information requirements (17.3
% of the ESRs).
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Development toxicity (HH)
No. ESR % ESR
ES 1 783 42.3
TP 151 3.6
RA 1 254 29.7
FO 460 10.9
WE 451 10.7
QS 7 0.2
MS 111 2.6
Total 4 217 100
Figure 12: Developmental toxicity (1 504 dossiers covering phase–in substances > 1 000 tpa, one or
more ESRs may be present per dossier) - Legend: ES - Experimental studies; TP - Testing proposal;
RA - Read-across; FO - IUCLID flags to omit the study; WE - Weight of Evidence; QS - (Q)SAR
studies; MS - Miscellaneous.
For the prenatal developmental toxicity, registrants have submitted 4 217 entries for phase-in
substances at or above 1 000 tpa. 1 783 ESRs were filled by experimental data (42.3 % of
the entries). Registrants submitted the highest number - 151 testing proposals for prenatal
developmental toxicity, corresponding to 3.6 % of the ESRs. In 1 254 (29.7 %) of these
entries registrants flagged read-across approach. IUCLID flags to omit the study and to use
Weight of Evidence have been selected in 10.9 % and 10.7 % of ESRs, respectively.
Only seven entries were filled by the QSAR predictions, while 111 ESRs referred to
miscellaneous information (2.6 %).
For the dossiers of phase-in substances produced at 100 – 1 000 tpa, 589 ESR entries were
extracted from the IUCLID database. In 260 (44.1 %) of the cases, registrants referred to the
experimental studies and submitted 34 testing proposals. A read-across approach has been
flagged in 29.5 % of ESRs.
The percentage of experimental studies for the non-phase-in substances at or above 100 tpa
reached only 29.8 % and the read-across approaches have been flagged in 9.9 % of the
ESRs. IUCLID flags to omit the study have been chosen in 33.1 % of the cases.
In the above mentioned press release, ECHA has also highlighted that registration dossiers
submitted for substances at or above 100 tpa will be considered as technically complete
even if they do not contain the results of a screening study for reproductive/developmental
study if instead a testing proposal for the higher-tier developmental toxicity study and twogeneration
study (if applicable for the tonnage) are submitted in the registration and
appropriate risk management measures are in place. Among Annex IX dossiers, submitted to
ECHA by the first deadline, 175 dossiers did not contain screening for
reproductive/developmental toxicity study, but testing proposal for pre-natal developmental
toxicity. When screening the Annex X dossiers, ECHA has obtained 61 cases where the
approach of registrant was consistent with the conditions above (dossiers did not contain
screening study but testing proposals for both prenatal developmental and two-generation
reproductive toxicity).
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3.2.8 Carcinogenicity
The objective of carcinogenicity studies on chemical substances is to identify potential
human carcinogens, their mode(s) of action and their potency. Human data are available for
only a few substances; therefore animal tests are generally used for detecting such a
property.
Once a substance has been identified as a carcinogen, the next step is to assess whether a
known carcinogen is directly genotoxic or not. Exposure conditions are utmost important as
the hazard and a mode of action of a carcinogen may be highly dependent on, for example,
the route of exposure.
Based on the complexity and length of the process of carcinogenesis, complex biological
interactions and many different modes of action involved, even for the same substance, it is
not possible to date to get a full understanding and complete mimicking by the use of
alternative, non-animal tests. The 2-year cancer assay in rodents, usually the rat or mouse,
is typically conducted to evaluate the cancer hazard and potency of a substance. Standard
information requirements for carcinogenicity endpoint under REACH are laid down in Annex
X, thus they are applicable for the highest tonnage substances (at 1 000 tpa or above).
However, the information needs will vary from substance to substance, based on its
toxicological properties, use and potential exposure(s). The specific rules and conditions to
omit, replace or adapt standard information requirements are provided in column 2 of Annex
X, 8.9.1.
Carcinogenicity (HH)
No. ESR % ESR
ES 1 377 38.7
TP 2 0.1
RA 992 27.9
FO 530 14.9
WE 434 12.2
QS 7 0.2
MS 217 6.1
Total 3 559 100
Figure 13: Carcinogenicity (1 504 dossiers covering phase–in substances > 1 000 tpa, one or more
ESRs may be present per dossier) - Legend: ES - Experimental studies; TP - Testing proposal; RA Read-across;
FO - IUCLID flags to omit the study; WE - Weight of Evidence; QS - (Q)SAR studies; MS
- Miscellaneous.
For the Annex X phase-in substances, 3 559 ESRs have been submitted on carcinogenicity.
38.7 % of them were experimental studies, in 27.9 % registrants chose read-across
approach, 14.9 % of ESRs were flagged as studies to be omitted and in 12.2 % of the
entries, a Weight of Evidence approach was flagged by the registrant. Two testing proposals
on carcinogenicity have been submitted. QSAR predictions have been proposed seven
times.
For the dossiers of phase-in substances produced at 100 – 1 000 tpa, in total 451 ESR
entries were extracted from the IUCLID database. For this tonnage level, more experimental
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
data were used to cover the endpoint (56.3 % of ESRs). A read-across approach was
selected in 22.2 % of the cases and IUCLID flags to omit the studies have been selected in
13.1 % of the entries. Only 29 ESRs for non-phase-in substances at or above 100 tpa have
been found.
3.2.9 Bioaccumulation in fish
Information on accumulation in aquatic organisms is a vital part to understand the
environmental fate and behaviour of a substance. This information is used for hazard
classification and PBT assessment as well as wildlife and human food chain exposure
modelling for the chemical safety assessment. It is also a factor in deciding whether longterm
ecotoxicity testing might be necessary. This is because the accumulation of a chemical
substance following long-term exposures, even when external concentrations are very low,
may result in internal concentrations of a substance which causes toxicity to the organism.
Highly bioaccumulative chemical substances may also be transferred through the food web,
which in some cases may lead to biomagnification.
Under REACH, standard information requirements on bioaccumulation in aquatic organisms,
preferably fish, are included in Annex IX, thus are applicable to substances manufactured or
imported at or above 100 tpa. Reliable measured data are preferred if available, but the
study needs not to be conducted if the substance has low potential for bioaccumulation or
direct and indirect exposure of the aquatic compartment is unlikely. REACH Annex XI also
applies, encouraging the use of alternative information at all supply levels before a new test
on fish is conducted. Prediction techniques are well developed for many classes of organic
substances, and surrogate information (e.g. the octanol-water partition coefficient or Kow) as
well as invertebrate tests may sometimes suffice on its own or as part of a weight of
evidence approach. For this analysis, as it was focussed only on the use of vertebrates, only
those records in which registrants declared the use of fish as the test species were counted
i.e.ESRs where either the test species was declared as a species other than fish or was not
specified were not counted. Therefore, ESR in which the species related to invertebrates
were not analysed for the purposes of this report. The number of testing proposals was
confirmed manually.
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Bioaccumulation – fish
(ENV)
No. ESR % ESR
ES 336 42.1
TP 12 1.5
RA 197 24.7
FO 0 0.0
WE 204 25.6
QS 25 3.1
MS 24 3.0
Total 786 100
Figure 14: Bioaccumulation in fish (1 504 dossiers covering phase–in substances > 1 000 tpa, one or
more ESRs may be present per dossier) - Legend: ES - Experimental studies; TP - Testing proposal;
RA - Read-across; FO - IUCLID flags to omit the study; WE - Weight of Evidence; QS - (Q)SAR
studies; MS - Miscellaneous.
For the phase-in substances at or above 1 000 tpa, registrants have submitted 798 ESRs
related to the fish bioaccumulation study in the IUCLID database. Of these ESRs, 336 (42.1
%) were filled by experimental data. In 197 (24.7 %) of “fish” ESR entries for this endpoint
registrants flagged read-across approach. Weight of Evidence option had been selected in
25.6 % of ESRs, and 25 ESRs were filled by QSAR predictions where the fish species was
declared. Twelve testing proposals were submitted for the highest tonnage band.
For the selected dossiers of phase-in substances produced at 100 – 1 000 tpa, 278 ESR
entries were identified in the IUCLID database. In 59 (21.2 %) of the cases, registrants
referred to the experimental studies and submitted 103 (37.1%) ESRs on read-across
results. Weight of evidence was flagged in 38.5 % of ESRs. 5 testing proposals have been
submitted for this tonnage band.
Twenty ESRs were found for non-phase-in substances at or above 100 tpa and mainly
referred to experimental data (70 %), read across (15 %) and other studies (10 %).
3.2.10 Toxicity to fish
Information on aquatic toxicity is used to assess the hazards and risks of a test substance to
freshwater and marine organisms living in the water column. In addition, the data obtained
from testing on aquatic species may also serve as a basis for extrapolation of the effects to
other compartments such as sediment and soil. Data on fish toxicity are generated for
environmental hazard assessment of substances (i.e. classification and derivation of PNEC)
and the estimation of toxicity in the PBT assessment.
Short-term toxicity testing on fish is required for substances covered by Annex VIII of REACH
(produced or imported in a quantity of at least 10 tpa). However this test does not need to be
conducted if there are mitigating factors indicating that aquatic toxicity is unlikely to occur
(e.g. the substance is highly insoluble in water or the substance is unlikely to cross biological
membranes). However, if the chemical safety assessment according to Annex I indicates the
need to investigate further effects on aquatic organisms, long-term testing as described in
Annex IX shall be considered. Long-term testing should also be considered if the substance
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
is poorly water soluble. Hence, in general acute fish toxicity is part of the core data for all the
registered substances in this study whereas long-term fish toxicity is a higher-tier study to be
covered in a testing proposal.
Regarding acceptance of the use of alternative methods covering this endpoint, at present,
there are no EU or OECD guidelines for in vitro tests of relevance to aquatic toxicity.
Regarding the (Q)SAR predictions for aquatic toxicity, the validity of applied models should
be assessed according to the OECD validation principles for QSARs (and the criteria
mentioned in Annex XI) and the results of the analysis should be reported in detail in a
transparent way in the form of a template so called: QSAR model reporting formats (QMRFs)
and QSAR prediction reporting formats (QPRFs). In addition there is the possibility to assess
toxicity to fish using read-across approaches if scientifically justified.
Short-term toxicity to fish
(ENV)
No. ESR % ESR
ES 3 653 52.6
TP 0 0.0
RA 1 400 20.2
FO 124 1.8
WE 983 14.2
QS 147 2.1
MS 635 9.1
Total 6 942 100
Figure 15: Short-term toxicity (fish) (1 504 dossiers covering phase–in substances at or above 1 000
tpa, one or more ESRs may be present per dossier) - Legend: (ES) - Experimental studies; (TP) Testing
proposal; (RA) - Read-across; (FO) - IUCLID flags to omit the study ; (WE) - Weight of
Evidence; (QS) - (Q)SAR studies; (MS) - Miscellaneous.
For the short-term toxicity to fish, registrants have submitted 6 942 ESR entries for phase-in
substances at or above 1 000 tpa (Annex X). Experimental data were indicated in 3 653
ESRs (52.6 % of the entries). Registrants flagged 1 400 entries as a read-across approach,
covering 20.2 % of all ESRs submitted for this endpoint. In 983 (14.2 %) of these entries
registrants chose to use Weight of Evidence approach. In 635 cases (9.1% of the ESRs)
registrants filled the endpoint by submitting other information. For this endpoint and this
tonnage, however, the highest number of QSAR predictions has been found – 147 ESRs,
even though, this corresponds to only 2.1% of all extracted entries.
For Annex IX dossiers, 1 405 ESR entries were filled by the registrants. The distribution of
the options chosen by the registrants to fulfil information requirements for this tonnage did
not differ from the Annex X dossiers (ref. Table 6 row 12.0). However, slightly more readacross
approaches (27.3 %) and substantially less QSAR studies (18 ESRs) were submitted.
For non-phase-in substances at or above 100 tpa, in total 143 ESRs have been identified in
the IUCLID database (see table 6 row 12.0). The difference between the selected strategies
to fulfil information requirements for phase-in and non-phase-in substances was mainly
noticeable in the number of miscellaneous studies that reached 28.0 % of the submitted
ESRs for analysed dossiers of non-phase–in substances.
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Long-term toxicity to fish
(ENV)
No. ESR % ESR
ES 899 27.4
TP 27 0.8
RA 697 21.2
FO 1 113 33.9
WE 296 9.0
QS 141 4.3
MS 108 3.3
Total 3 281 100
Figure 16: Long-term toxicity (fish) (1 504 dossiers covering phase–in substances > 1 000 tpa, one or
more ESRs may be present per dossier) - Legend: ES - Experimental studies; TP - Testing proposal;
RA - Read-across; FO - IUCLID flags to omit the study; WE - Weight of Evidence; QS - (Q)SAR
studies; MS - Miscellaneous.
Registrants have submitted 3 281 ESR entries for long-term toxicity to fish for phase-in
substances at or above 1 000 tpa. A total of 899 ESRs were filled by experimental data (27.4
% of the entries) and 27 ESRs – by testing proposals (0.8 % of all entries). IUCLID flags to
omit the study and the use of read-across approaches have been selected in 33.9 % and
21.2 % of ESRs, respectively. In 296 (9.0 %) of the ESRs registrants flagged Weight of
Evidence. QSAR predictions were reported in 141 ESRs which is a similar amount to those
QSAR predicitions found in the short-term toxicity to fish entries.
For the Annex IX dossiers, 812 ESR entries were identified. In 288 (35.5 %) of cases,
registrants used experimental data and submitted ten testing proposals. A read-across
approach was flagged in 34.7 % of ESRs. Registrants chose to omit studies in 17.1% of
submitted entries and in 67 cases a Weight of Evidence approach was taken. Ten ESRs
contained QSAR predictions.
In contrast with phase-in, the percentage of experimental studies for the non-phase-in
substances at or above 100 tpa reached was 13.9 % while the most frequent option chosen
by registrants was to select IUCLID flags to omit the study (65.3 % of the cases).
3.2.11 Long-term or reproductive toxicity to birds
Information on long-term or reproductive avian toxicity needs to be considered only for
substances manufactured or imported in quantities of at least 1 000 tpa (i.e. an Annex X
requirement).
The data may be needed to assess the secondary poisoning risks to predators following
chronic exposure to a substance via the fish and earthworm food chains. Given that
mammalian toxicity is considered in detail for human health protection, the need for
additional data for birds must be considered very carefully – new tests are a last resort in the
data collection process. However, birds are fundamentally different from mammals in certain
aspects of their physiology (e.g. the control of sexual differentiation, egg laying, etc.), and so
mammalian toxicity data are of limited predictive value for birds.
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The need to conduct a secondary poisoning assessment is triggered by a number of factors.
If these criteria are not met, then further investigation of chronic avian toxicity is
unnecessary. However, if the substance has a bioaccumulation potential and a low
degradability (e.g. not readily biodegradable or not hydrolysable) and has also a potential to
cause toxic effects if accumulated in higher organisms, a detailed assessment of secondary
poisoning should be conducted.
Avian toxicity tests are often carried out for substances with intentional biological activity as a
result of other regulatory approval requirements (especially active substances used in plant
protection products, veterinary medicines and in biocides). They are rarely performed for
most other substances. When available from other regulatory approval requirements such
data are relevant for REACH purposes as a source of analogue data or when the substance
also has other uses which need to be registered under REACH. In addition avian toxicity
data may be considered on a case-by-case basis in the assessment of toxicity for PBT
assessment but avian toxicity data will not only be necessary for this purpose alone.
No specific avian in vitro methods are currently available or under development.
Long-term toxicity to birds
(ENV)
No. ESR % ESR
ES 216 10.8
TP 4 0.2
RA 128 6.4
FO 1 460 72.7
WE 198 9.9
QS 1 0.0
MS 0 0.0
Total 2 007 100
Figure 17: Long-term toxicity (birds) (1 504 dossiers covering phase–in substances > 1 000 tpa, one or
more ESRs may be present per dossier) - Legend: ES - Experimental studies; TP - Testing proposal;
RA - Read-across; FO - IUCLID flags to omit the study; WE - Weight of Evidence; QS - (Q)SAR
studies; MS - Miscellaneous.
For phase-in substances at or above 1 000 tpa for this endpoint ECHA has found 2 007 ESR
entries. Only 216 of ESRs contained experimental studies (10.8 % of all ESR entries for this
endpoint) and four testing proposals were submitted. In most of the cases (72.7 %),
registrants chose to select IUCLID flags to omit the study and to use a weight of evidence
approach (9.9 % of ESRs). 128 entries contained data on read-across.
For the Annex IX dossiers, 350 ESR entries were identified. Slightly fewer registrants used
experimental data (16.3 % of the cases), yet 41.4 % of the ESRs there was a flag to omit the
study. Weight of Evidence approach was chosen in 28.9 % of the entries.
For the non-phase-in substances at or above 100 tpa, only 36 ESRs have been submitted
and almost all of them contained IUCLID flags to omit the study (91.7 %).
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3.3 Substance approach
This analysis provides the relative proportions of the principal options used by registrants to
fill the information requirements by endpoint. These options have been categorised as testing
proposals, experimental studies and alternative methods (see section 2.3. for more details).
For some endpoints, the need to address an information requirement is conditioned on
findings from other endpoints. For example, if the results of the required in vitro tests for
mutagenicity are negative, in vivo testing may not be required. In such cases there is no
obligation for the registrant to enter information. Such situations are characterised by “no
data” (ND).
0% 25% 50% 75% 100%
RDT (all routes, all durations)
Developmental toxicity
Toxicity to reproduction
Genetic toxicity in vivo
Genetic toxicity in vitro
Skin sensitisation
Eye irritation
Skin irritation
Acute toxicity (all routes)
ES TP AM ND
Figure 18: Relative proportions of the principal options to fulfil information requirements for human
health endpoints for the substances (phase-in, at or above 1 000 tpa, 1 453 substances) - Legend; ES
- Experimental studies; TP- Testing proposal; AM - Alternative methods; ND - No data .
This analysis provides an overall relation between experimental studies and alternative
options for the REACH relevant endpoints. The experimental studies have been counted per
substance without checking the study type or the quality of the information for the endpoints.
Therefore, it is important to note that an entry as experimental study under an endpoint does
not mean that the information requirement is filled according to the requirements in the
REACH Annexes. This is specifically relevant for repeated dose toxicity, toxicity to
reproduction and developmental toxicity. The percentages shown in the bar chart represent
an upper boundary for experimental data availability for the endpoints. Further analysis,
focusing on study types on the basis of the test guideline number only, provides much lower
numbers for experimental data availability for these endpoints.
For instance, further analysis at the substance level for repeated dose toxicity, extracting
only study types clearly related to 90-day study (Annex IX requirement) or chronic studies,
revealed that 465 substances had studies covering such tests, representing about 32 % of
1 453 substances. The gap between the upper and lower boundaries on experimental data
availability for this endpoint is mainly due to the presence of 28-day and screening studies.
Further analysis at the substance level for toxicity to reproduction, extracting only study types
clearly related to one or more generation studies, revealed that 182 substances had studies
covering such tests, representing about 12 % of 1 453 substances. Further analysis for the
prenatal developmental toxicity endpoint, extracting only study types clearly related to
prenatal developmental toxicity studies, revealed that 425 substances had studies covering
such tests, representing about 30 % of 1 453 substances. The gap between the upper and
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
lower boundaries on experimental data availability is mainly due to the screening studies. For
example, registrants may report these data in repeated dose toxicity and reproductive toxicity
endpoints. They may also refer to screening studies as “other studies” in developmental
toxicity endpoint. One reason is that there is no option to report screening studies in the
developmental toxicity endpoint in IUCLID separately.
Acute toxicity
For acute toxicity, in 85 % of cases the endpoint was filled with experimental data, the rest
was filled with information using only alternative options. Testing proposals are not used for
this endpoint since it is not an Annex IX or X requirement.
Skin irritation
In Figure 18, the combined results used to fill the endpoint of skin irritation per analysed
substance are shown. In 78 % of the cases the endpoint was filled with experimental data,
while in 22 % of the cases registrants chose only alternative options. As for acute toxicity,
testing proposals are not used for this endpoint since it is an Annex VII standard information
requirement.
Eye irritation
Similarly, as with skin irritation, the eye irritation endpoint was covered by experimental data
in 75 % of the cases. No testing proposals are submitted as information requirements for eye
irritation also fall under Annex VII of the REACH Regulation.
Skin sensitisation
For this Annex VII endpoint 63 % of data submitted referred to the experimental studies and
37 % of cases were covered by alternative options.
Repeated dose toxicity
Around 67 % of the submitted data were experimental studies. In 7 % of the cases,
registrants submitted testing proposals for this endpoint and the remaining 26 % of the
entries chosen were covered by alternative options.
Genetic toxicity
The genetic toxicity in vitro endpoint was covered by experimental data in more than 77 % of
the cases while for the remaining cases alternative options were used. In contrast to the in
vitro studies, experimental data were only available to cover 41 % of the cases of genetic
toxicity in vivo. In 32 % of the cases, alternative options to fulfil standard information
requirements were chosen, while there were no completed endpoint study records for 26 %
of the cases. This is due to the fact that in vivo tests may not need to be conducted for this
endpoint, depending on the results of the in vitro studies.
Toxicity to reproduction and pre-natal developmental toxicity
Specifically for these endpoints, as already explained above, experimental data availability
does not mean that the information requirements are filled according to the requirements in
the REACH Annexes.
As presented in Figure 18, almost 42 % of the analysed phase-in substances at or above
1 000 tpa already had experimental data on toxicity to reproduction, while in 48 % of the
cases registrants used alternative options to cover the endpoint. In 10 % of the cases,
registrants have submitted testing proposals.
Experimental pre-natal developmental toxicity studies were available for 47 % of substances,
while in 43 % of the cases registrants used alternative options to make their dossiers
complete. As for toxicity to reproduction, in 10 % of cases testing proposals were submitted.
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0% 25% 50% 75% 100%
Toxicity to other terrestrial organisms
Long-term toxicity to mammals
Long-term toxicity to birds
Long-term toxicity to fish
Short-term toxicity to fish
Bioaccumulation (fish)
ES TP AM ND
Figure 19: Relative proportions of the principal options to fulfil information requirements on
environmental endpoints for the substances (phase-in, at or above 1 000 tpa, 1 453 substances) Legend:
ES - Experimental studies; TP- Testing proposal: AM - Alternative methods; ND - No data
Bioaccumulation (fish)
Experimental data on bioaccumulation in fish were available for only 14.8 % of the analysed
substances. For 0.8% of the substances, testing proposals were submitted and for 84.4 % of
the substances registrants used alternative options (in most cases, read-across approaches
or weight of evidence) to cover this endpoint. Please note that experimental data on
invertebrates have been counted as alternative methods for the purpose of this report.
Toxicity to fish
With regard to this endpoint, experimental studies were available for almost 75 % of the
cases. Registrants used various alternative options to cover the remaining 25 % of the
entries.
For the long-term toxicity to fish, registrants submitted experimental data for only less then
16 % of the covered substances while in 82 % of the cases they used alternative options
(justifications to omit the study).
Long-term toxicity to birds
For this endpoint information might be required under Annex X. Experimental data covered
only 7 % of the selected substances while in 92 % of the cases registrants chose alternative
options (in most cases, justifications to omit the study) to cover this endpoint.
Long-term toxicity to mammals
The availability of experimental data was indicated for 1.8 % of the analysed substances
while for 91 % of the substances, registrants reported that no data were available. The
remaining 7 % were filled by alternative options.
Toxicity to other terrestrial organisms
The results on data availability for this endpoint were similar those presented for long-term
toxicity to mammals. Registrants provided experimental studies for 4 % of the selected
substances, while in 92 % of the cases, no data were available.
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3.4 Studies conducted or proposed for the purpose of REACH
3.4.1 Studies conducted for the purpose of REACH
For this analysis an assumption was made that studies described in the IUCLID dossier as of
2009 or later had been conducted for the purpose of fulfilling the REACH requirements. It
should be noted that this assumption will overestimate the number of new animal studies for
two reasons. Firstly some studies may have been conducted for other reasons, e.g. for other
non-EU chemical substance control schemes. Secondly the study may have begun earlier
but the date of the study report was 2009 or later.
The basis for the year identification is an entry in the IUCLID reference fields. Whenever
different dates were indicated for the same study, the oldest date was taken for further
analysis assuming that all later dates refer to the literature publications or quotations of the
older study. In such a way, double counting of the studies was avoided.
As shown in Table 2, most of the new studies have been conducted on genetic toxicity in
vitro, thus without involving of vertebrate animals. A substantial number of new studies were
also submitted to fill the data gaps for the Annex VII and VIII endpoints (acute toxicity, eye
and skin irritation, skin sensitisation, sub-acute repeated dose toxicity, repeated
dose/reproductive toxicity screening study, short-term toxicity on fish) that do not require
testing proposals a priori.
Regarding the performance of new studies on vertebrate animals required for Annexes IX
and X after REACH entered into force, new tests were carried out for bioaccumulation in fish,
repeated dose toxicity (sub-chronic and chronic duration, all routes), pre-natal developmental
toxicity, and reproductive toxicity (one- and two-generation studies). However, in the context
of the overall number of all ESRs extracted from registration dossiers of all tonnage bands,
and both phase-in and non-phase-in substances, new studies represented less than 1% of
the total ESRs extracted for these endpoints (total ESRs are presented in Tables 4 to 6 of
Appendix I). Therefore, it can be concluded that registrants mainly used old experimental
data as well as the options for the adaptation of the standard information requirements and
other alternatives before electing to conduct new studies to meet their obligations and make
their registration dossiers compliant under REACH.
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Table 2: Studies with the reference date of 2009 or later (all tonnages, phase-in and non-phase-in
substances, excluding IUCLID category dossiers and dossiers covering only intermediates). Annex IX
and X endpoints counts were manually verified.
Endpoint name Species usually tested
New experimental
study
Skin irritation In Vitro 301
Eye irritation In Vitro 206
Genetic toxicity In Vitro 984
Total number of “new” experimental studies in vitro 1 491
Acute toxicity (oral) Rat or mouse 211
Acute toxicity (inhalation) Rat or mouse 114
Acute toxicity (dermal) Rat or mouse 161
Skin irritation Rabbit 135
Eye irritation Rabbit 188
Skin sensitisation Guinea pig or mouse 336
Repeated dose toxicity (oral) Rat or mouse, subacute 79
Rat or mouse, subchronic 16
Rat or mouse, chronic 1
Repeated dose toxicity (dermal) Rat or mouse, subacute 7
Rat or mouse, subchronic 1
Rat or mouse, chronic 0
Repeated dose toxicity (inhalation) Rat or mouse, subacute 23
Rat or mouse, subchronic 2
Rat or mouse, chronic 0
Genetic toxicity Rat or mouse 33
Carcinogenicity Rat or mouse 0
Screening studies (OECD TG 422 Or 421 Or EPA
Guidelines)
Rat 234
Toxicity to reproduction (One (1) And Two (9)
Generation Studies) Rat or mouse
10
Prenatal developmental toxicity Rat or rabbit 24
Bioaccumulation: aquatic / sediment Fish 7
Short-term toxicity to fish Fish 254
Long-term toxicity to fish Fish 13
Long-term toxicity to birds Bird 0
Toxicity to other above-ground organisms 0
Additional ecotoxicological information 0
Total number of “new” experimental studies in vivo 1 849
Total number of “new” experimental studies 3 340
For the purposes of generating data for this table, a number of ESRs had a test type assigned by the
registrant as “other”, which when manually checked were found to be incorrect and reassigned as
either in vitro or in vivo, as appropriate.
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Acute toxicity
Registrants conducted 211 oral, 114 inhalation and 161 dermal acute toxicity studies with the
date of 2009 or later.
Skin irritation
For skin irritation, 301 in vitro studies and 135 in vivo studies dated at 2009 or later were
identified. These numbers demonstrate an increasing use of in vitro studies for this endpoint.
Eye irritation
Regarding the new studies conducted for this endpoint (see Table 2), registrants performed
almost the same number of in vitro and in vivo tests dated at 2009 or later (206 and 188
studies, respectively).
Skin sensitisation
For this Annex VII endpoint, as provided in Table 2, 336 in vivo studies were dated at 2009
or later.
Repeated dose toxicity
Registrants have conducted 109 28-day repeated dose toxicity studies (all routes), 19 new
studies on 90-day repeated dose toxicity (all routes) and one chronic study (oral route) dated
2009 or later.
Genetic toxicity
The registrants conducted 984 in vitro studies on genetic toxicity. Regarding in vivo tests, 33
studies were dated 2009 or later.
Toxicity to reproduction/prenatal developmental toxicity
In this analysis all reproduction toxicity screening studies dated 2009 or later (performed
according to OECD test guideline number 422 or 421, as well as according to the various
equivalent US EPA guidelines) have been counted and presented separately as they can be
used to fulfil information requirements for Annex VII core data under different endpoints (i.e.
repeated dose toxicity and reproductive toxicity). Hence counting them at the endpoint level
could lead to double counting, therefore potentially overestimatng the number of tests
conducted. Furthermore, some registrants have stated in their dossiers that this screening
reproduction toxicity study can be used to meet the higher-tier Annex IX and X data
requirements of developmental toxicity and fertility studies instead of making testing
proposals. This inappropriate practice results in an incorrect impression that higher-tier twogeneration
fertility studies or prenatal developmental toxicity studies have been conducted
without the submission of a testing proposal. In order to interpret the dossiers with these
reproduction toxicity screening studies, all the dossiers had to be checked manually.
After subtracting the screening studies from the total number of studies entered for
reproductive toxicity, registrants conducted 10 new one or two-generation reproductive
toxicity studies.
After subtracting the screening studies from the total number of studies entered for pre-natal
developmental toxicity, 24 studies dated from 2009 or later were detected in the data base.
Bioaccumulation (fish)
Registrants conducted seven studies in 2009 or later. However, as already explained above,
the purpose to perform new studies on vertebrate animals without submitting a testing
proposal to ECHA cannot be clarified unless a compliance check is opened.
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Toxicity to fish
254 new studies were conducted to investigate short-term toxicity to fish. 13 new
experimental studies on long-term toxicity to fish were dated from 2009 or later.
The new studies were largely for the core Annex VII and VIII data obligatory for registration,
as would be expected, because higher-tier Annex IX and X studies require approval of
testing proposals before being conducted. The dossiers analysed demonstrate that
companies carried out relatively few new studies for their registration dossiers. In total, 3 340
such studies have been conducted, of which 1 849 involved tests on vertebrate animals. In
total 107 Annex IX and X studies appeared to be conducted in the absence of testing
proposals. If tests have been conducted without submitting a testing proposal for higher tier
tests, the registrant has to justify them. Examples for justifications determined by ECHA so
far include testing triggered by non-EU legislation or testing required by a MSCA decision for
notified or existing substances (Dangerous Substances Directive 67/548 EEC, and Existing
Substances Regulation 793/93 EEC). If ECHA observes that a test was performed for an
endpoint, for which a testing proposal is required under REACH, the Member States are
informed by ECHA and are responsible for taking, if relevant, enforcement actions.
3.4.2 Studies proposed for the purpose of the REACH Regulation
Registrants have to fulfil the higher-tier data requirements as specified in Annexes IX and X
either by providing available data or by submitting a testing proposal intended to obtain the
information. They should not undertake new Annex IX or Annex X studies until the decision
taking process has been completed and ECHA issues a decision requiring the registrant to
carry out a proposed test. When a testing proposal concerns a study involving vertebrate
animals, ECHA publishes the name of the substance and the hazard endpoints for which
testing is proposed. Third parties are invited to submit scientifically valid information and
reports of studies that address the hazard endpoint. This consultation is in essence a call for
data to identify specific studies on the substance that might already have been conducted but
not available to the registrant, or relevant information on close chemical analogues that can
be used for read-across.
Following the end of the consultation period, ECHA will draft one of the following decisions: a
decision accepting the testing proposal, a decision accepting the testing proposal with
modified conditions, a decision rejecting the testing proposal, or a decision accepting or
rejecting the testing proposal but requiring one or more additional tests to be carried out.
These draft decisions can also be made if several registrants or downstream users have
submitted proposals for the same test. In preparing the draft decision ECHA will take into
account all information contained in the registration dossier as well any scientifically-valid
information obtained from the public call for data. It may be that ECHA has to add extra
vertebrate animal studies to the testing proposal if the registrant has omitted Annex IX or X
endpoints without fulfilling the specific rules for adaptation including an adequate scientific
justification.
The decision of ECHA involves the consultation of the registrant who submitted the testing
proposal, the Member State competent authorities and, if necessary, ECHA’s Member State
Committee (MSC). Although yet to happen, if the MSC were not able to reach a unanimous
agreement, ECHA would refer the draft decision to the European Commission which would
take the final decision after further consultation with the Member States. This procedure was
established to ensure that the best possible use is made of existing information, and that
animal testing is required only when the necessary information is unavailable.
As of February 2011 ECHA now publishes brief conclusions of third parties’ comments and
information provided during consultations.
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Table 3: Testing proposals submitted to ECHA (all tonnages, phase-in and non-phase-in substances,
including IUCLID category dossiers)
Endpoint Name Number
Repeated dose toxicity (oral) 121
Repeated dose toxicity (dermal) 6
Repeated dose toxicity (inhalation) 27
Genetic toxicity (in vivo) 25
Carcinogenicity 3
Toxicity to reproduction 231
Developmental toxicity 239
Bioaccumulation: aquatic / sediment 17
Long-term toxicity to fish 38
Long-term toxicity to birds 4
Total 711*
*In addition, two testing proposals have been received for a dermal absorption endpoint. However, this endpoint is not a standard
information requirement under Annex IX or X of the REACH Regulation
Between 2008 and February 2011, the Agency received registration for 3 308 phase-in and
1 347 non-phase-in substances (at all tonnages). Testing proposals were made in 574
dossiers covering a total of 1 175 tests, of which 711 were vertebrate animal studies. The
totals include 78 substances that were submitted as category dossiers, covering 17 chemical
substance categories and testing proposals for 104 animal studies.
The total number of testing proposals submitted to ECHA appears to be at the low end of the
range that might have been expected. This is confirmed by the results of compliance checks
(see section 4). These results seem to indicate that adaptations to the standard information
requirements for higher tier testing are often insufficiently justified and testing proposals
should have been submitted for some cases instead. In addition, experimental data provided
for the higher tier endpoints, often do not meet the information requirements under the
REACH Regulation and testing proposals should also have been submitted in those cases.
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4 ECHA evaluation of the use of adaptations to standard
information requirement by registrants
It is possible to get an insight into the quality of the information in registration dossiers from
the compliance checks which are conducted on some registrations in accordance with the
REACH Regulation. The results of such compliance checks performed up to December 2010
are contained in the Article 54 reports on Evaluation published in February each year by
ECHA. The latest report covered findings of 2010 and reported results from only a limited
number of final decisions. The following conclusions therefore also take into account findings
from dossiers still in the decision making process and therefore lacking confirmation by the
Member States Competent Authorities.
When interpreting the findings of the ESR analysis, it should be noted that in principle there
may be deficiencies discovered in the compliance check dossier evaluation work that result
in further animal studies being requested if the quality of either the experimental data or the
justifications for the adaptations in the dossiers is discovered to be inadequate. This was
found for read-across approaches as well as for the options to omit the study. These two
approaches are identified in the current report as the main options used by the registrants for
higher tier tests if they did not use experimental data or submitted a testing proposal. It was
also noted that for some higher tier test requirements, screening studies had been submitted
in place of the actual test(s) specified in REACH. If such results are found under compliance
checks, ECHA may be obliged to ask the registrant for the missing information. This may
result in additional, new animal testing compared with the results provided in this report.
Another option is that registrants may voluntarily update their dossiers either providing better
justifications for adapting standard information requirements or submitting new testing
proposals, if the latter is not possible.
ECHA will continue using all available tools to promote a better quality of the dossiers. This
will include further efforts to educate registrants in a compliant use of adaptation possibilities,
communication efforts to increase voluntary actions and compliance checks to ask for
missing information.
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5 Conclusions
The principle in REACH of ‘one substance one registration’ requires that cooperation
between potential registrants must be established and that data must be shared and
submitted jointly. In general, the sharing and joint submission of information worked and the
registrants used it to fulfil the information requirements and to avoid unnecessary animal
testing. However, the number of separate registration dossiers for the same substances
indicate that the sharing and joint submission of information still needs further improvement.
The REACH Annexes VII-X and XI provide a number of adaptation possibilities allowing
registrants to avoid unnecessary animal testing. Registrants made full use of these
adaptation options. The data in this report showed that registrants mainly used the results of
animal studies conducted prior to the entry into force of REACH. Predicting substance
properties by ‘read-across’ was the second most common means of fulfilling the information
requirements, followed by other alternative options.
Registrants submitted testing proposals for the higher-tier studies specified in Annexes IX
and X testing before conducting such tests. Fewer testing proposals have been submitted
than had been anticipated based on previous estimations made taking into account the
estimates of experimental data availability for the higher-tier endpoints. One reason for this
appears to be that registrants used other adaptation possibilities before resorting to making a
testing proposal. Another reason is that, at least in part, registrants used the ‘category’ or
‘read-across’ approach to fill data gaps for these higher-tier studies, i.e. proposing to conduct
one study to cover more than one substance.
The report also provides the number of studies that appear to have been conducted for the
purpose of the REACH Regulation. Such new studies were largely for the core Annex VII and
VIII data obligatory for registration, as would be expected, because higher-tier Annex IX and
X studies require the approval of testing proposals before being conducted. In total 107
Annex IX and X studies appeared to be conducted in the absence of testing proposals. This
will be further analysed in future compliance checks.
The number of studies using animals conducted or proposed for the purpose of REACH are
lower than expected in previous publications predicting animal tests to be performed for
REACH Regulation. The reasons are that the number of high tonnage level (Annex X)
substances is considered somewhat lower than expected, data sharing was working well
between the registrants, and the adaptation possibilities have been fully used by the
registrants.
It is possible to get insight into the quality of the information in registration dossiers from the
compliance checks which are conducted on some registrations in accordance with the
REACH Regulation. When interpreting the findings in this report, it should be noted that in
principle there may be deficiencies discovered in the compliance check dossier evaluation
work that result in further animal studies being requested if the quality of either the
experimental data or alternative approaches in the dossier are discovered to be inadequate.
In the future, ECHA will use all available tools to promote a better quality of the dossiers.
This will include further efforts to educate registrants in a compliant use of adaptation
possibilities, communication efforts to increase voluntary actions and compliance checks to
ask for missing information.
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Literature
Information about ECHA:
European Chemicals Agency:
http://echa.europa.eu
ECHA and events:
http://echa.europa.eu/news/events_en.asp
ECHA News:
http://echa.europa.eu/news_en.asp
ECHA Webinars:
http://echa.europa.eu/news/webinars_en.asp
Examination of testing proposals:
http://echa.europa.eu/consultations/test_proposals_en.asp
ECHA Evaluation website:
http://echa.europa.eu/reach/evaluation_en.asp
ECHA Dissemination website:
http://apps.echa.europa.eu/registered/registered-sub.aspx
Evaluation progress reports:
http://echa.europa.eu/publications_en.asp
The legislation:
Regulation (EC) No 1907/2006 (REACH Regulation)
http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONSLEG:2006R1907:20090627:EN:PDF
Regulation (EC) 1272/2008 on Classification, Labelling and packaging (CLP Regulation)
http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2008:353:0001:1355:EN:PDF
Dangerous Substance Directive 67/548/EEC and Existing Substances Regulation (EEC) No.
793/93
http://europa.eu/legislation_summaries/consumers/product_labelling_and_packaging/l21276_en.htm#
amendingact
Regulation (EC) No 440/2008 on test methods
http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONSLEG:2008R0440:20090827:EN:PDF
Directive 2010/63/EU of the European on the protection of animals used for scientific
purposes:
http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2010:276:0033:0079:EN:PDF
56
The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
Test methods:
ECVAM pre-validated test methods
http://ecvam.jrc.it/
http://tsar.jrc.ec.europa.eu/
Practical Guides
Practical guide 1: How to report in vitro data
http://echa.europa.eu/doc/publications/practical_guides/pg_report_in_vitro_data.pdf
Practical guide 2: How to report weight of evidence
http://echa.europa.eu/doc/publications/practical_guides/pg_report_weight_of_evidence.pdf
Practical guide 3: How to report robust study summaries
http://echa.europa.eu/doc/publications/practical_guides/pg_report_robust_study_summaries.pdf
Practical guide 4: How to report data waiving
http://echa.europa.eu/doc/publications/practical_guides/pg_report_data_waiving.pdf
Practical guide 5: How to report (Q)SARs
http://echa.europa.eu/doc/publications/practical_guides/pg_report_qsars.pdf
Practical guide 6: How to report read-across and categories
http://echa.europa.eu/doc/publications/practical_guides/pg_report_qsars.pdf
Practical guide 10: How to avoid unnecessary testing on animals
http://echa.europa.eu/doc/publications/practical_guides/pg_10_avoid_animal_testing_en.pdf
Practical guide 12: How to communicate with ECHA in dossier evaluation
http://echa.europa.eu/doc/publications/practical_guides/pg_12_how_to_comm_with_echa_in_dossier_
evaluation.pdf
Guidance:
Guidance on Registration
http://guidance.echa.europa.eu/docs/guidance_document/registration_en.pdf?vers=31_01_11
Guidance on data sharing
http://guidance.echa.europa.eu/docs/guidance_document/data_sharing_en.pdf
OECD guidance for the testing of chemicals
http://www.oecd.org/
Other information:
ECHA information toolkit website:
http://echa.europa.eu/reach/information_toolkit_en.asp
JRC computational toxicology website
http://ecb.jrc.ec.europa.eu/qsar/
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
Priority existing substances before the REACH Regulation entered into force
http://ecb.jrc.ec.europa.eu/esis/index.php?PGM=ora
Sixth Report on the Statistics on the Number of Animals used for Experimental and other
Scientific Purposes in the Member States of the European Union COM(2010) 511:
http://ec.europa.eu/environment/chemicals/lab_animals/pdf/sec_2010_1107.pdf
The European Partnership for Alternative Approaches to Animal Testing (EPAA):
http://ec.europa.eu/enterprise/epaa/index_en.htm
European Consensus-Platform for Alternatives (ECOPA):
http://www.ecopa.eu/
International Council on Animal Protection in OECD Programmes (ICAPO):
http://www.icapo.org/
OECD (Q)SARs project:
http://www.oecd.org/document/23/0,3343,en_2649_34379_33957015_1_1_1_1,00.html
OECD guidelines on the 3R-principles:
http://www.oecd.org/document/48/0,3343,en_2649_34377_40695856_1_1_1_1,00.html
US Environmental Protection Agency:
http://www.epa.gov/
Other:
Adler S., D. Basketter, S.Creton, O. Pelkonen, J. van Benthem, V. Zuang, K. Ejner
Andersen, A. Angers-Loustau, A. Aptula, A. Bal-Price, E. Benfenati, U. Bernauer, J.
Bessems, F. Y. Bois, A. Boobis, E. Brandon, S. Bremer, T. Broschard, S. Casati, S. Coecke,
R. Corvi, M. Cronin, G. Daston, W. Dekant, S. Felter, E. Grignard, U. Gundert-Remy, T.
Heinonen, I. Kimber, J. Kleinjans, H. Komulainen, R. Kreiling, J. Kreysa, S. Batista Leite, G.
Loizou, G. Maxwell, P. Mazzatorta, S. Munn, S. Pfuhler, P. Phrakonkham, A. Piersma, A.
Poth, P. Prieto, G. Repetto, V. Rogiers, G. Schoeters, M. Schwarz, R. Serafimova, H. Tahti,
E. Testai, J. van Delft, H. van Loveren, M. Vinken, A. Worth, & J. M. Zaldivar (2011).
Alternative (non-animal) methods for cosmetics testing: current status and future prospects—
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Allanou R., B.G. Hansen & Y. van der Bilt (1999). Public availability of data on EU High
Production Volume Chemicals. EC DG JRC Report EUR 18996.
European Commission (2010). Report on the Development, Validation and Legal Acceptance
of Alternative Methods to Animal Tests in the Field of Cosmetics (2008). COM (2010) 480
final.
European Commission (2001). White Paper: Strategy for a future Chemicals Policy.
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Pedersen F., J. de Bruijn, S. Munn, & K. van Leeuwen (2003). Assessment of additional
testing needs under REACH – effects of (Q)SARs, risk based testing and voluntary industry
initiatives. EC DG JRC Report EUR 20863.
Van der Jagt K., S. Munn, J. Tørsløv & J. de Bruijn (2004). Alternative approaches can
reduce the use of test animals under REACH. Addendum to the report: Assessment of
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
additional testing needs under REACH. Effects of (Q)SARs, risk based testing and voluntary
industry initiatives. EC, DG JRC.
Van Leeuwen C. J., F. Bro-Rasmussen, T. C .J. Feijtel, R. Amdt, B. M. Bussian, D. Calamari,
P. Glynn, N. J. Grandy, B. G. Hansen, J. J. Van Hemmen, P. Hurst, N. King, R. Koch, M.
Miiller, J. F. Solb, G. A. B. Speijers, & T. Vermeire (1996). Risk assessment and
management of new and existing chemicals. Environmental Toxicology and Pharmacology 2,
243-299.
Zuang V., J. Barroso, S. Bremer, S. Casati, M. Ceridono, S. Coecke, R. Corvi, C. Eskes, A.
Kinsner, C. Pellizzer, P. Prieto, A. Worth & J. Kreysa (2010). ECVAM Technical Report on
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the framework of Directive 2003/15/EC (7th Amendment to the Cosmetics Directive). EC DG
JRC58991, EUR 24413 EN.
59
The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
60
Appendix I
Table 4 to Table 6 present the available data from endpoint study record (ESR) perspective
in detail. It shows the number of ESRs available in the registration dossiers to fulfil a specific
endpoint (column 1) for phase-in or non-phase-in substances (Column 2) in a given tonnage
band (Column 3). During the creation of study records in IUCLID5, the registrant can classify
them according to the purpose of that study record. Column 4 “Total ESR” shows the total
number of study records in the IUCLID 5 dossiers. The rest of the columns contain the
number of study records according to the classification assigned by the registrant:
• Column 5 “Experimental studies” contains the number of ESRs classified as
“experimental result” from the pick-list in the field “Study result type” (abbreviation:
ES)
• Column 6 “Testing proposal” shows the number of ESRs employed by the registrant
for the testing proposals. These are classified by the registrant as “experimental study
planned” from the pick-list of options in the field “Study result type” (abbreviation TP).
• Column 7 “Read-across” contains the number of ESRs classified by the registrant as
read-across from the pick-list of options in the field “Study result type” (abbreviation
RA).
• Column 8 “IUCLID flags to omit the study”: selected by the registrant to omit the
submission of the required data by choosing the appropriate option from those
available in the pick-list in the field called “data waiving”. These options are to be
used to indicate when testing does not appear to be: scientifically necessary;
technically not possible; or not necessary based on low exposure considerations
(abbreviation FO).
• Column 9 “Weight of Evidence” consists of the number of ESRs classified by the
registrant as weight of evidence in the “purpose flag” pick-list. All cases selected as
Weight of Evidence, were counted and not taken into account in more detailed
analysis (abbreviation WE).
• Column 10 “QSAR studies” has the number of ESRs classified by the registrant as
“(Q)SAR studies” from the pick-list of options in the field “Study result type”
(abbreviation QS).
• Column 11 “Miscellaneous” shows the number of ESRs classified by the registrant as
“other” from the pick-list of options in the field “Study result type” (abbreviation MS).
The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
Table 4: HH Endpoint Study Records (1 of 2)
1. Test type 2. Phase
3. Tonnage
band
4. Total ESR
5.
Experimental
Studies (ES)
%
6. Testing
Proposals (TP)
%
7. Read-across
(RA)
%
8. IUCLID flags
to omit the
study (FO)
%
9. Weight of
Evidence (WE)
%
10. QSAR
Studies (QS)
%
11.
Miscellaneous
Studies (MS)
%
Phase-In >1000 12874 7328 56.9 0 0.0 2756 21.4 1184 9.2 1116 8.7 11 0.1 479 3.7
Phase-In 100to1000 1649 988 59.9 0 0.0 342 20.7 178 10.8 113 6.9 3 0.2 25 1.5
Non-Phase-In >100 396 154 38.6 0 0.0 51 12.9 80 20.2 20 5.1 0 0.0 91 23.0
Phase-In >1000 5864 3724 63.5 0 0.0 1241 21.2 143 2.4 502 8.6 4 0.1 250 4.3
Phase-In 100to1000 797 560 70.3 0 0.0 164 20.6 17 2.1 43 5.4 1 0.1 12 1.5
Non-Phase-In >100 156 71 45.5 0 0.0 23 14.7 8 5.1 13 8.3 0 0 41 26.3
Phase-In >1000 3990 2000 50.1 0 0.0 818 20.5 633 15.9 383 9.6 7 0.2 149 3.7
Phase-In 100to1000 433 207 47.8 0 0.0 94 21.7 97 22.4 26 6.0 2 0.5 7 1.6
Non-Phase-In >100 112 26 23.2 0 0.0 13 11.6 53 47.3 5 4.5 0 0 15 13.4
Phase-In >1000 3020 1604 53.1 0 0.0 697 23.1 408 13.5 231 7.6 0 0.0 80 2.6
Phase-In 100to1000 419 221 52.7 0 0.0 84 20.0 64 15.3 44 10.5 0 0.0 6 1.4
Non-Phase-In >100 128 57 44.5 0 0 15 11.7 19 14.8 2 1.6 0 0.0 35 27.3
Phase-In >1000 329 252 76.6 0 0.0 39 11.9 2 0.6 35 10.6 0 0.0 1 0.3
Phase-In 100to1000 24 20 83.3 0 0.0 2 8.3 0 0.0 2 8.3 0 0.0 0 0.0
Non-Phase-In >100 1 1 100.0 0 0.0 0 0 0 0.0 0 0.0 0 0.0 0 0.0
Phase-In >1000 5216 3343 64.1 0 0.0 1113 21.3 216 4.1 402 7.7 5 0.1 137 2.6
Phase-In 100to1000 600 402 67.0 0 0.0 131 21.8 28 4.7 31 5.2 1 0.2 7 1.2
Non-Phase-In >100 157 72 45.9 0 0.0 23 14.6 14 8.9 7 4.5 0 0.0 41 26.1
Phase-In >1000 172 149 86.6 0 0.0 12 7.0 1 0.6 5 2.9 0 0.0 5 2.9
Phase-In 100to1000 27 19 70.4 0 0.0 6 22.2 0 0.0 2 7.4 0 0.0 0 0.0
Non-Phase-In >100 1 1 100.0 0 0.0 0 0 0 0.0 0 0.0 0 0.0 0 0.0
Phase-In >1000 4221 2714 64.3 0 0.0 884 20.9 219 5.2 279 6.6 0 0.0 125 3.0
Phase-In 100to1000 524 343 65.5 0 0.0 102 19.5 53 10.1 19 3.6 0 0.0 7 1.3
Non-Phase-In >100 140 63 45.0 0 0.0 16 11.4 15 10.7 7 5 0 0.0 39 27.9
Phase-In >1000 21 10 47.6 0 0.0 6 28.6 0 0.0 5 23.8 0 0.0 0 0.0
Phase-In 100to1000 4 4 100.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0
Non-Phase-In >100 3 0 0.0 0 0.0 0 0.0 0 0.0 2 66.6 0 0.0 1 33.3
Phase-In >1000 3754 2080 55.4 0 0.0 782 20.8 264 7.0 513 13.7 18 0.5 97 2.6
Phase-In 100to1000 488 283 58.0 0 0.0 119 24.4 0 0.0 72 14.8 3 0.6 11 2.3
Non-Phase-In >100 176 73 41.5 0 0.0 27 15.3 35 19.9 4 2.3 0 0.0 37 21.0
Phase-In >1000 10322 5908 57.2 0 0.0 2272 22.0 394 3.8 1245 12.1 5 0.05 498 4.8
Phase-In 100to1000 1745 1128 64.6 0 0.0 308 17.7 53 3.0 206 11.8 0 0.0 50 2.9
Non-Phase-In >100 351 180 51.3 0 0.0 36 10.3 32 9.1 10 2.8 1 0.3 92 26.2
Phase-In >1000 3533 1852 52.4 18 0.5 875 24.8 221 6.3 389 11.0 0 0.0 177 5.0
Phase-In 100to1000 596 366 61.4 2 0.3 128 21.5 26 4.4 60 10.1 0 0.0 14 2.3
Non-Phase-In >100 94 47 50.0 0 0.0 5 5.3 7 7.4 1 1.1 0 0.0 34 36.2
Phase-In >1000 3535 1121 31.7 150 4.2 840 23.8 904 25.6 428 12.1 4 0.1 88 2.5
Phase-In 100to1000 487 146 30.0 9 1.8 118 24.2 138 28.3 47 9.7 0 0.0 29 6.0
Non-Phase-In >100 156 41 26.3 7 4.5 11 7.1 64 41.0 6 3.8 0 0.0 27 17.3
Phase-In >1000 4217 1783 42.3 151 3.6 1254 29.7 460 10.9 451 10.7 7 0.2 111 2.6
Phase-In 100to1000 589 260 44.1 34 5.8 174 29.5 71 12.1 32 5.4 2 0.3 16 2.7
Non-Phase-In >100 121 36 29.8 13 10.7 12 9.9 40 33.1 4 3.3 0 0.0 16 13.2
Phase-In >1000 390 293 75.1 0 0.0 37 9.5 22 5.6 8 2.1 0 0.0 30 7.7
Phase-In 100to1000 41 22 53.7 0 0.0 2 4.9 10 24.4 7 17.1 0 0.0 0 0.0
Non-Phase-In >100 3 2 66.7 0 0.0 0 0.0 1 33.3 0 0 0 0.0 0 0.0
Phase-In >1000 3559 1377 38.7 2 0.1 992 27.9 530 14.9 434 12.2 7 0.2 217 6.1
Phase-In 100to1000 451 254 56.3 1 0.2 100 22.2 59 13.1 26 5.8 0 0.0 11 2.4
Non-Phase-In >100 29 4 13.8 0 0.0 7 24.1 14 48.3 0 0.0 0 0.0 4 13.8
7.0 Developmental toxicity
5.2 Genetic toxicity (in vivo)
9.0 Carcinogenicity
8.0 Toxicity to reproduction other
studies
1.0 Acute toxicity (all routes)
1.1 Acute toxicity (oral)
1.2 Acute toxicity (inhalation)
1.3 Acute toxicity (dermal)
2.1 Skin irritation (in vitro)
2.2 Skin irritation (in vivo)
3.1 Eye irritation (in vitro)
4.2 Skin sensitisation (in vivo)
3.2 Eye irritation (in vivo)
4.1 Skin sensitisation (in vitro)
5.1 Genetic toxicity (in vitro)
6.0 Toxicity to reproduction
61
The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
Table 5: HH Endpoint Study Records (2 of 2)
1. Test type 2. Phase
3. Tonnage
band
4. Total ESR
5.
Experimental
Studies (ES)
%
6. Testing
Proposals (TP)
%
7. Read-across
(RA)
%
8. IUCLID flags
to omit the
study (FO)
%
9. Weight of
Evidence (WE)
%
10. QSAR
Studies (QS)
%
11.
Miscellaneous
Studies (MS)
%
Phase-In >1000 10790 4546 42.1 104 1.0 3032 28.1 2033 18.8 709 6.6 9 0.1 357 3.3
Phase-In 100to1000 1333 538 40.4 32 2.4 355 26.6 262 19.7 101 7.6 0 0.0 45.0 3.376
Non-Phase-In >100 359 105 29.2 8 2.2 30 8.4 162 45.1 3 0.8 0 0.0 51 14.2
Phase-In >1000 1704 989 58.0 1 0.1 490 28.8 24 1.4 178 10.4 0 0.0 22 1.3
Phase-In 100to1000 266 152 57.1 1 0.4 79 29.7 2 0.8 32 12.0 0 0.0 0 0
Non-Phase-In >100 60 52 86.7 0 0.0 7 11.7 0 0 0 0 0 0.0 1 1.7
Phase-In >1000 296 198 66.9 0 0.0 53 17.9 27 9.1 17 5.7 0 0 1 0.3
Phase-In 100to1000 28 16 57.1 0 0.0 9 32.1 2 7.1 1 3.6 0 0 0 0.0
Non-Phase-In >100 9 4 44.4 0 0.0 4 44.4 1 11.1 0 0.0 0 0 0 0.0
Phase-In >1000 997 610 61.2 2 0.2 284 28.5 16 1.6 57 5.7 2 0.2 26 2.6
Phase-In 100to1000 84 64 76.2 0 0.0 18 21.4 0 0.0 2 2.4 0 0.0 0 0.0
Non-Phase-In >100 8 5 62.5 1 12.5 1 12.5 1 12.5 0 0.0 0 0.0 0 0.0
Phase-In >1000 2365 1025 43.3 28 1.2 1072 45.3 38 1.6 184 7.8 0 0.0 18 0.8
Phase-In 100to1000 303 136 44.9 15 5.0 129 42.6 4 1.3 14 4.6 0 0.0 5 1.7
Non-Phase-In >100 37 28 75.7 1 2.7 5 13.5 3 8.1 0 0 0 0.0 0 0
Phase-In >1000 276 129 46.7 2 0.7 103 37.3 28 10.1 12 4.3 0 0 2 0.7
Phase-In 100to1000 26 6 23.1 0 0.0 15 57.7 3 11.5 2 7.7 0 0 0 0.0
Non-Phase-In >100 3 0 0.0 0 0.0 3 100 0 0.0 0 0.0 0 0 0 0.0
Phase-In >1000 1366 682 49.9 8 0.7 541 39.6 27 2.0 77 5.6 0 0.0 31 2.3
Phase-In 100to1000 125 66 52.8 0 0.0 49 39.2 1 0.8 8 6.4 0 0.0 1 0.8
Non-Phase-In >100 8 7 87.5 0 0.0 1 12.5 0 0.0 0 0.0 0 0.0 0 0.0
Phase-In >1000 574 266 46.3 0 0.6 189 32.9 19 3.3 85 14.8 3 0.5 12 2.1
Phase-In 100to1000 94 42 44.7 0 0.0 31 33.0 1 1.1 15 16.0 0 0.0 5 5.3
Non-Phase-In >100 8 3 37.5 0 0.0 5 62.5 0 0 0 0 0 0.0 0 0
Phase-In >1000 40 20 50 0 0.0 7 17.5 13 32.5 0 0.0 0 0 0 0
Phase-In 100to1000 4 2 50 0 0.0 1 25 1 25 0 0.0 0 0 0 0.0
Non-Phase-In >100 0 0 0.0 0 0.0 0 0 0 0.0 0 0.0 0 0 0 0.0
Phase-In >1000 340 157 46.2 0 0.0 117 34.4 11 3.2 36 10.6 0 0.0 19 5.6
Phase-In 100to1000 39 16 41.0 0 0.0 13 33.3 1 2.6 9 23.1 0 0.0 0 0.0
Non-Phase-In >100 1 1 100 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0
Phase-In >1000 966 225 23.3 47 4.9 127 13.1 418 43.3 30 3.1 2 0.2 117 12.1
Phase-In 100to1000 154 29 18.8 14 9.1 11 7.1 59 38.3 9 5.8 0 0.0 32 20.8
Non-Phase-In >100 92 3 3.3 6 6.5 1 1.1 36 39.1 1 1.1 0 0.0 45 48.9
Phase-In >1000 893 47 5.3 3 0.3 4 0.4 810 90.7 11 1.2 0 0 18 2.0
Phase-In 100to1000 118 4 3.4 1 0.8 0 0 107 90.7 6 5.1 0 0 0 0.0
Non-Phase-In >100 66 0 0.0 0 0.0 3 4.5 61 92.4 1 1.5 0 0 1 1.5
Phase-In >1000 973 198 20.3 13 1.3 45 4.6 602 61.9 22 2.3 2 0.2 91 9.4
Phase-In 100to1000 92 5 5.4 1 1.1 0 0.0 81 88.0 3 3.3 0 0.0 2 2.2
Non-Phase-In >100 67 2 3.0 0 0.0 0 0.0 60 89.6 1 1.5 0 0.0 4 6.0
10.2.3 RDT subchronic
(inhalation)
10.3.1 RDT chronic (oral)
10.3.2 RDT chronic (dermal)
10.4.3 RDT other (inhalation)
10.3.3 RDT chronic (inhalation)
10.4.1 RDT other (oral)
10.4.2 RDT other (dermal)
10.1.1 RDT subacute+screening
(oral)
10.0 RDT (all routes, all
durations)
10.1.2 RDT subacute+screening
(dermal)
10.1.3 RDT subacute+screening
(inhalation)
10.2.1 RDT subchronic (oral)
10.2.2 RDT subchronic (dermal)
62
The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
63
Table 6: ENV Endpoint Study Records
1. Test type 2. Phase
3. Tonnage
band
4. Total ESR
5. Experimental
Studies (ES)
%
6. Testing
Proposals (TP)
%
7. Read-across
(RA)
%
8. IUCLID flags
to omit the
study (FO)
%
9. Weight of
Evidence (WE)
%
10. QSAR
Studies (QS)
%
11.
Miscellaneous
Studies (MS)
%
Phase-In >1000 798 336 42.1 12 1.5 197 24.7 0 0.0 204 25.6 25 3.1 24 3.0
Phase-In 100to1000 278 59 21.2 5 1.8 103 37.1 0 0.0 107 38.5 0 0.0 3 1.1
Non-Phase-In >100 20 14 70.0 0 0.0 3 15.0 0 0.0 1 5.0 0 0.0 2 10.0
Phase-In >1000 6942 3653 52.6 0 0.0 1400 20.2 124 1.8 983 14.2 147 2.1 635 9.1
Phase-In 100to1000 1405 684 48.7 0 0.0 384 27.3 12 0.9 227 16.2 18 1.3 80 5.7
Non-Phase-In >100 143 76 53.1 0 0.0 12 8.4 6 4.2 6 4.2 3 2.1 40 28.0
Phase-In >1000 3281 899 27.4 27 0.8 697 21.2 1113 33.9 296 9.0 141 4.3 108 3.3
Phase-In 100to1000 812 288 35.5 10 1.2 282 34.7 139 17.1 67 8.3 10 1.2 16 2.0
Non-Phase-In >100 101 14 13.9 0 0.0 3 3.0 66 65.3 6 5.9 2 2.0 10 9.9
Phase-In >1000 2007 216 10.8 4 0.2 128 6.4 1460 72.7 198 9.9 1 0.0 0 0.0
Phase-In 100to1000 350 57 16.3 0 0.0 36 10.3 145 41.4 101 28.9 0 0.0 11 3.1
Non-Phase-In >100 36 0 0.0 0 0.0 0 0.0 33 91.7 1 2.8 0 0.0 2 5.6
Phase-In >1000 495 129 26.1 0 0.0 16 3.2 84 17.0 212 42.8 0 0.0 54 10.9
Phase-In 100to1000 254 84 33.1 0 0.0 2 0.8 7 2.8 131 51.6 0 0.0 30 11.8
Non-Phase-In >100 0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0
Phase-In >1000 644 244 37.9 0 0.0 143 22.2 7 1.1 27 4.2 3 0.5 220 34.2
Phase-In 100to1000 129 18 14.0 0 0.0 26 20.2 1 0.8 7 5.4 3 2.3 74 57.4
Non-Phase-In >100 12 2 16.7 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 10 83.3
15.0 Toxicity to other above-ground
organisms
16.0 Additional ecotoxicological
information
11.0 Bioaccumulation (fish)
12.0 Short-term toxicity to fish
13.0 Long term toxicity to fish
14.0 Long term toxicity to birds
The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
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The Use of Alternatives to Testing on Animals for the REACH Regulation 2011
65