Post on 19-Mar-2018
Life-Edesia meeting 10-11 December 2014
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Last news from ECHA on alternative methods
in compliance with the REACH: the Read-
Across
Maria Teresa Russo
Centro Nazionale Sostanze Chimiche
Istituto Superiore di Sanità
Roma
REACH regulation2
REACH is the Regulation on Registration, Evaluation, Authorisation
and Restriction of Chemicals. It entered into force on 1st June 2007. It
streamlines and improves the former legislative framework on chemicals
of the European Union (EU).
Two of the major aims are:
1. To ensure high protection of human health
2. To promote alternative methods
Besides the possible adaptations of the standard information
requirements (based on the specific conditions listed in column 2 of
Annexes VII to X or on the more general conditions given in Annex XI
of the regulation), REACH provides the registrant also with the
possibility to submit information from non-animal tests.
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2) Promoting alternatives methods:
• comparing substances with similar ones;
• grouping them together into logical
categories;
• specialized computer modelling (QSAR
toolbox);
• bringing together a weight of evidence;
• and non-animal tests (for example, in vitro
studies using cells rather than animals)
REACH keeps the number of animal tests to
an essential minimum
1) The principle of data sharing introduced
by REACH----Reliable and adequate studies
must not be repeated.
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• comparing substances with similar ones
• grouping them together into logical
categories
By using this adaptation, registrants do not
need to test their substance(s)
one-by-one to fulfil their information
requirements
This strategy allows to avoid unnecessary
animal testing
READ ACROSS
The second report under Article 117(3) of the REACH Regulation shows
that registrants make use of alternative testing methods and strategies.
Building categories and predicting substance properties by read-across is
the most widely used method. In fact up to 75% of the analyzed dossiers
contains read-across at least for one endpoint (*).
Moreover, where possible the in vitro tests are used by the registrants: (*)
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The feedback of the registrants
(*) second report under Article 117(3) published on the 2 June 2014
ECHA’s database
by 1° October 2013
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Relative proportions of the principal options to fulfil information
requirements for human health endpoints for the substances
(phase-in, at or above 100 tonnes per year and at or above 1 000tonnes per year, 3 662 substances).
Read across is applied to all Human health endpoints
Data from: second report under Article 117(3) published on the 2 June 2014
Legend
ES – Experimental studies
WE – Weight of evidence
RA – Read-across
QS – (Q)SAR
TP – Testing proposal
FO – Flags to omit study
NR – Not reported
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Read across is applied to Environmental endpoints
Relative proportions of the principal options to fulfil information
requirements for environmental endpoints for the substances (phase-in,
at or above 100 tonnes per year and at or above 1 000 tonnes per year,
3662 substances)
Data from: second report under Article 117(3) published on the 2 June 2014
Read-across developments
REACH provides the possibility to adapt a standard
requirement for a test by read-across (Ax XI, 1.5)
Registrant is responsible for building the case
ECHA and the MSs are responsible for the evaluation
Need for a structured approach – Read-across
Assessment Framework (RAAF)
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9 History:
• RAAF discussed at ECHA in 1st WS in 2011
• ECHA further developed RAAF
• First Inclusion of refinements. E.g. More types of
read-across covered (Scenarios)
• Further refinements of RAAF in the last WS,
October 2014
Read-across Assessment Framework (RAAF)
RAAF is a tool for the assessment of read-across by ECHA
toxicologists
It is not guidance for registrants!
However, knowledge about how ECHA assesses read-across
helps registrants to prepare better-focused read-across
proposals.
10WHY THE RAAF?
• It allow the assessors to addresses the scientific
aspects of read-across in a structured and
consistent way;
• To guide the expert to focus on the scientific
aspects that are deemed crucial by ECHA;
• To create a systematic grading of cases based
on scientific credibility, thus indicating
limitations in reasoning and in supporting
evidence.
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Tier I = Administrative screening
Tier II = structure and rules to facilitate a
consistent scientific assessment
Cases cannot be accepted using
only a Tier-I assessment!
TWO TIERS for RAAF
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Tier II
structure and rules of RAAF
13Read-across always requires a convincing scientific
explanation.
It should be shown why structural differences between
source and target:
• Either do not influence an effect originating from
their common structural features,
• Or do so in a regular manner resulting in a regular
pattern (i.e. trend).
Basic principles
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Scientific explanation can be:• An explanation why read-across is possible in
explicit mechanistic terms.
• A causal relationship demonstrated by a trend
between an independent variable and a
dependent variable (property to read-across).
• Both, an explanation in mechanistic terms
and a trend are used to show that read-across is
possible.
Structural similarity as such is never
sufficient! (See also Maggiora et al., 2014*);
Small structural differences can have a strong
and often unexpected impact on toxicity.
A Challenge: Prediction by read-across
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•The enantiomers of the valproic acid analogue 2-n-propyl-4-pentynoic acid (4-yn-VPA): asymmetric synthesis and
highly stereoselective teratogenicity in mice
Regulatory Toxicology and Pharmacology 56 (2010) 67–81 .
•Hauck RS, Nau H. Pharm Res. 1992 Jul;9(7):850-5.
•IARC (http://www.inchem.org/documents/iarc/suppl7/naphthylamine1.html),
(http://www.inchem.org/documents/iarc/suppl7/naphthylamine2.html)
•The comparative toxicity of chlorinated dibenzo-p-dioxins in mice and guinea pigs. McConnell E.E. et al. (1978)
Toxicology and Applied Pharmacology 44: 335-356
Minor differences in chemical structure may lead to
significant differences in the properties of the substance
161. External exposure to different substances (source and
target) results in internal exposure to the same toxic
substances, due to chemical or biological conversion,
and thereby the same toxicity;
(External different exposure- the same toxic internal
exposure)
2. External exposure to different substances (source and
target) results in internal exposure to different
substances, which, nevertheless do not differ in toxicity.
(External different substances- the internal exposure is to
different substances with the same toxicy)Or a special case of the second basic type:
2a The potentially sensitive organ/tissue cannot be reached by
source and target due to their common structural
characteristics.
No absorption, complete binding, etc.
Scientific explanations of the RAAF
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Types of read-across in the RAAF
Type depends on the scientific explanation and
whether the:
• analogue approach (scenario 1 and 2)
or
• category approach (scenario 3, 4 and 5)
applies.
The RAAF distinguishes five basic types of
read-across.
These are called: SCENARIOS.
one source to one target
from several sources to one target
Each read-across proposal is expected to be covered
by only one of these five scenarios.
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Structure of RAAF
During the assessment crucial scientific aspects have to be
addressed for each scenario, because they determine the
validity of the read-across.
SCENARIO-ASSESSMENT ELEMENTS (AEs)
For each AE the assessor has to select one of a number of
predefined options that represents a possible opinion on the AE.
The options depend on the AE. Different AEs often have
different options.
AEs -Assessment Options (AOs)
Each AO is linked to a predefined numerical score.
The AO and the associated score indicates the
strength/weakness of the case as regards the considered AE
Assessment Options----Scores
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Accepted cases
Highest score: 5 = No
appreciable extra
uncertainty; case
succeeds with flying
colours.
Middle score: 4 =
Average extra
uncertainty.
Lowest score: 3 =
Highest allowable extra
uncertainty.
Rejected cases
Highest score: 2 = Based
on the information
provided, the case has to
be rejected, but
additional information
might lead to acceptance.
Lowest score: 1 = It is
not expected that
additional information
can lead to acceptance.
Scores and decisions
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RAAF provides:
• A structured approach ensuring consistency;
• a tool to reject or accept the read-across
case;
• an improved systematic documentation of the
assessment;
• A better indication of scientific robustness and
uncertainty of the read-across.
Outcomes of the RAAF
21 • Property to property read-across (e.g. across endpoints)
• Negative versus positive read-across (In cases where
absence of toxicity is being predicted, the read-across
justification should contain as many lines of evidence as
possible, including QSAR predictions, toxicokinetic
information, etc.)
• Bias – e.g. omitted category members
• Test on real cases, use in Substance Evaluation
The goal of illustrative case studies could serve to develop
a series of ‘guiding principles’ that would be helpful to
both the regulated and regulators
Elements to be discussed and future activity for RAAF
ECHA announced the publication in the
appropriate format of the RAAF in 2015
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Considerations on the use of predictive models
The information from the individual tools was combined with a weight of
evidence approach and the expert knowledge, the result is a better prediction of
the potential toxicity.
The combination use of the existing data and modelling approach improve
the predictivity.
The CAESAR developmental toxicity
model is a QSAR based model
Is a system which reports
structural alerts relating to
developmental, teratogenic
and testicular toxicity.
It is a profiler that determine the potential for
oestrogen receptor binding. They are associated with
endocrine distruption and may act as iniziating event,
eliciting reproductive or developmental toxicity
effects.
Is the approach used to generate
categories of compunds based on
structural similarity approach from
which a read-across estimate of
toxicity could be made
The in silico- in vitro integrated approach of LIFE-Edesia is a winning strategy
*M. Hewitt, C.M. Ellison, S.J. Enoch, J.C. Madden, M.T.D.
Cronin, Reproductive Toxicology 30 (2010) 147–160
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Thanks for your attention!
24 Scenarios
1: taget and sorce are converted in the same
toxicant
2: taget and sorce are converted in different
toxicant with the same effect
3:read across is based only on the analysis of trend,
no scientific explanation is present
4: read is across based on the analysis of trend, a
scientific explanation confirms the trend
5: is a group without a trend for the effect to be
read across. This means that a scientific
explanation makes clear that the target will do the
same.
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• Leads the assessor to aspects of the read-across deemed
crucial (assessment elements);
• Provides options for each of these aspects (assessment
options);
• Asks the expert to form an opinion on the R-A as
regards to the aspects of the R-A under consideration;
• Asks the expert to select one of the options based on
this opinion;
• Links the options with a quality/uncertainty
indicator(score) for the considered aspect;
• The aspects with the lowest quality indicator
determines the overall outcome of the assessment of
the R-A case (weakest-link principle).
What “does” the RAAF?