La rivoluzione REACH

74
Costanza Rovida REACH Mastery - Como La rivoluzione REACH 23 maggio 2014

Transcript of La rivoluzione REACH

Page 1: La rivoluzione REACH

Costanza Rovida

REACH Mastery - Como

La rivoluzione REACH

23 maggio 2014

Page 2: La rivoluzione REACH

Costanza [email protected]

Center for Alternatives to Animal Testing – Europe (CAAT-Europe)University of Konstanz

La rivoluzione REACH

23 maggio 2014

Page 3: La rivoluzione REACH
Page 4: La rivoluzione REACH
Page 5: La rivoluzione REACH

Article 1

Aim and scope

1. The purpose of this Regulation is to ensure a high

level of protection of human health and the

environment, including the promotion of alternative

methods for assessment of hazards of

substances, as well as the free circulation of

substances on the internal market while enhancing

competitiveness and innovation

Page 6: La rivoluzione REACH

Article 1

Aim and scope

1. The purpose of this Regulation is to ensure a high

level of protection of human health and the

environment, including the promotion of alternative

methods for assessment of hazards of

substances, as well as the free circulation of

substances on the internal market while enhancing

competitiveness and innovation

Page 7: La rivoluzione REACH

List of requiredendpoints,

according toREACH

RegulationPhysico-chemical

information

Page 8: La rivoluzione REACH

List of requiredendpoints,

according to REACH Regulation

Toxicologicalinformation

Page 9: La rivoluzione REACH

List of requiredendpoints,

according toREACH

Regulation:Ecotoxicological

information

Page 10: La rivoluzione REACH
Page 11: La rivoluzione REACH

IUCLID fields to be completed

Page 12: La rivoluzione REACH

Guidelines on Information Requirements

Page 13: La rivoluzione REACH

TOTAL of 34 FILES !!! (How many thousands of pages?)

Guidelines on Information Requirements

Page 14: La rivoluzione REACH

ECHA Practical Guides

1. How to report in vitro data2. How to report Robust Study Summary3. How to report Weight of Evidence4. How to report waiving5. How to report (Q)SARs6. How to report read across and categories

http://echa.europa.eu/doc/press/na_10_16_practical_guides_20100409.pdf

Page 15: La rivoluzione REACH

Article 1

Aim and scope

1. The purpose of this Regulation is to ensure a high

level of protection of human health and the

environment, including the promotion of alternative

methods for assessment of hazards of

substances, as well as the free circulation of

substances on the internal market while enhancing

competitiveness and innovation

Page 16: La rivoluzione REACH

Articolo 13

Page 17: La rivoluzione REACH

REACH Regulation

ANNEXES VII-XBefore new tests are carried out to determine the properties listed in thisAnnex, all available in vitro data, in vivo data, historical human data, datafrom valid (Q)SARs and data from structurally related substances (read-across approach) shall be assessed first

ANNEX XIGeneral rules for adaptation of the standard testing regime set out in annexes VII to X

ANNEXES VII-X – Column 2Specific rules for adaptation from column 1

Page 18: La rivoluzione REACH

Annex XITESTING DOES NOT APPEAR SCIENTIFICALLY NECESSARY• Use of existing data• Historical human data

PRO and CONS

Studies are often very poor describedNo analytical identification of the substanceNo identification of the impurities……………..………………

Page 19: La rivoluzione REACH

Annex XI - Weight of EvidenceThere may be sufficient Weight of Evidence from several independent sources of information leading to the assumption/conclusion that a substance has or has not a particular dangerous property, while the information from each single source alone is regarded insufficient to support this notion.

• newly developed test methods

• not yet included in the test methods referred to in

Article 13(3)

• different studies with the same reliability, no key study,

but consistent to assess the end point

Page 20: La rivoluzione REACH

Annex XI - (Q)SARQUALITATIVE OR QUANTITATIVE

STRUCTURE-ACTIVITY RELATIONSHIP ((Q)SAR)

PRO and CONS

Applicability domainFit the purpose“Poor” training data setsDifficulties in reporting……………..………………

Page 21: La rivoluzione REACH

Annex XI - Grouping and Read AcrossGROUPING OF SUBSTANCES AND READ-ACROSS APPROACH

Two approaches:

GROUPING IN CATEGORIES (HPV-SIDS approach)chemical similaritiesfunctional groupsphysical chemical propertiescommon environmental fatecommon metabolites

READ ACROSS FROM SIMILAR SUBSTANCESa specific end-point can be assessed with a result on a similar substancedifferent end point can be assessed from different substances

Page 22: La rivoluzione REACH

Pavia – 7 maggio 2011

Annex XI

ALTERNATIVE METHODS (ECVAM activities)

http://tsar.jrc.ec.europa.eu/

Reduction of animals: Sensitisation

Acute oral toxicity

Acute aquatic toxicity

Developing screening metods that can support the reliability of a category

or a read across

Page 23: La rivoluzione REACH

Pavia – 7 maggio 2011

Annex XI

GROUPING OF SUBSTANCES AND READ-ACROSS APPROACH

Two approaches:

GROUPING IN CATEGORIES (HPV-SIDS approach)

chemical similarities

functional groups

physical chemical properties

common environmental fate

common metabolites

READ ACROSS FROM SIMILAR SUBSTANCES

a specific end-point can be assessed with a result on a similar

substance

different end point can be assessed from different substances

Page 24: La rivoluzione REACH

Pavia – 7 maggio 2011

Annex XI

SUBSTANCE-TAILORED EXPOSURE-DRIVEN TESTING

Testing in accordance with sections 8.6 and 8.7 of Annex VIII, Annex IX and

Annex X may be omitted, based on the exposure scenario(s) developed in

the Chemical Safety Report

PERFORM a Chemical Safety Assessment complete with Exposure

Scenarios even if the substance is NOT DANGEROUS

CONS: Companies are often not cooperative even if they save money

Page 25: La rivoluzione REACH

In vitro methodsIn vitro toxicity testing is the scientific analysis of the effects of toxic chemical substances on cultured bacteria or mammalian cells. In vitro (literally 'in glass') testing methods are employed primarily to identify potentially hazardous chemicals and/or to confirm the lack of certain toxic properties in the early stages of the development of potentially useful new substances such as therapeutic drugs, agricultural chemicals and direct food additives that may or may not taste good.

In vitro assays for xenobiotic toxicity are recently carefully considered by key government agencies (e.g. EPA; NIEHS/NTP; FDA), mainly due to a societal movement to reduce the use of animals in research, and a desire to better assess human risks. There are substantial activities in using in vitro systems to advance mechanistic understanding of toxicant activities, and the use of human cells and tissue to define human-specific toxic effects.

www.answers.com

Page 26: La rivoluzione REACH

I metodi alternativi: che cosa sono

Principio delle 3R:Reduction = RiduzioneRefinement = MiglioramentoReplacement = Sostituzione

Russell, W. M. S. and Burch, R. L. 1959. The principles of humane experimental technique

Page 27: La rivoluzione REACH

Direttiva EU 63/2010

Sostituisce la vecchia Direttiva EEC 86/609 con una maggiore attenzione al benessere animale e un esplicito riferimento alle 3RMaggiore controllo e rigore sugli esperimenti

Page 28: La rivoluzione REACH

Element Dir 86/609/EEC Dir 2010/63/EU

Ambito di applicazione Vertebrati. Vertebrati, cefalopdi, Feti

Compliance with the Three Rs Yes Yes

Project evaluation No Yes

Project authorisation (Yes/No) Yes

Housing and care standards guidelines bindingstandards

Main differences between the current & the new Dir

Page 29: La rivoluzione REACH

Element Dir 86/609/EEC Dir 2010/63/EU

Project follow-up (Yes) Yes

- Retrospective assessment No Yes

Non-technical summaries No Yes

Severity classification No Yes

Ispezioni periodiche Yes Obbligatorie

Main differences between the current & the new Dir

Page 30: La rivoluzione REACH

Shell Fish Biotoxins

Mouse bio-assay

Page 31: La rivoluzione REACH
Page 32: La rivoluzione REACH

Shell Fish Biotoxins

Metodo in vitro

Page 33: La rivoluzione REACH

Confronto metodo in vitro e in vivo

0

20

40

60

80

100

120

140

1 7 13 19 25 31 37 43 49 55 61 67 73 79 85 91 97 103 109 115 121 127 133 139 145 151 157

µg

ST

X e

q/1

00

g

correlative sample number

In vitro Assay Mouse Bioassay

17.2% 52.6% 80.0%

Page 34: La rivoluzione REACH

In vitro methodsIn vitro toxicity testing is the scientific analysis of the effects of toxic chemical substances on cultured bacteria or mammalian cells. In vitro (literally 'in glass') testing methods are employed primarily to identify potentially hazardous chemicals and/or to confirm the lack of certain toxic properties in the early stages of the development of potentially useful new substances such as therapeutic drugs, agricultural chemicals and direct food additives that may or may not taste good.

In vitro assays for xenobiotic toxicity are recently carefully considered by key government agencies (e.g. EPA; NIEHS/NTP; FDA), mainly due to a societal movement to reduce the use of animals in research, and a desire to better assess human risks. There are substantial activities in using in vitro systems to advance mechanistic understanding of toxicant activities, and the use of human cells and tissue to define human-specific toxic effects.

www.answers.com

Page 35: La rivoluzione REACH

IN VITRO METHODS

Validated methods:Skin corrosion/irritationSkin absorptionEye corrosion/irritation (partially)Screening for genotoxicity and mutagenicity (partially)Acute Toxicity (partially)

Pre-validation methods:SensitisationCarcinogenic potentialReproductive toxicity (embryotoxicity)

Page 36: La rivoluzione REACH

In vitro methods: Skin sensitisation

LOCAL LYMPH NODE ASSAYDays 1, 2 & 3Apply Chemical

Day 6 - Inject H-Thymidine3

5 hours LaterRemove Lymph Nodes

Make CellSuspension

Determine H-ThymidineIncorporation by LiquidScintillation Counting

3

Page 37: La rivoluzione REACH

In vitro approach to Skin sensitisation

Page 38: La rivoluzione REACH

SKIN Sensitisation

DPRA (Direct Peptide Reactivity Assay):

OECD 406 (Guinea pig): 2,000€OECD 429 (LLNA, traditional test): 3,500€OECD 442b (LLNA, BrdU-ELISA): 2,700€

Page 39: La rivoluzione REACH

Pavia – 7 maggio 2011

Strategy: sensitisation

MO

Test with OECD TG 428

Skin Absorption ≥ 0.1% Skin Absorption < 0.1%

MX2

LLNA positive

(Strong)

Negative

No classification as skin sensitiser

Positive

Classified as skin sensitiser H317Read Across

Metal salt Metal oxide

Page 40: La rivoluzione REACH

Pavia – 7 maggio 2011

Strategy: sensitisation

IN VITRO STUDIES : An example on how to assess doubtful sensitization

results on a basic dye supporting also exposure pattern.

No study available on both Oxalate and Chloride forms of the dye

Demonstration that the two salts are equivalent is missing

There is concern about the skin sensitisation potential

Negative result in an old study (1984)

Positive in a even older human patch test (1966)

• A new study performed on both salts is required

• A new study to confirm the sensitisation property is required

Page 41: La rivoluzione REACH

Pavia – 7 maggio 2011

ITS proposal:

1. Skin absorption assessment: OECD TG 428

2. In vitro sensitisation: U937 method, which passed the pre-validation

and has just started the official validation at

ECVAM (European Centre for Validation of

Alternative Methods)

RATIONALE

Skin Absorption: Only adsorbed substances can cause skin sensitisation

The results can be also exploited as a comparison between

the two salts

Sensitisation: a POSITIVE results is accepted (Annex XI:positive results

from a suitable in vitro test can be accepted)

a NEGATIVE result is also accepted: (peer review literature)

Strategy: sensitisation

Page 42: La rivoluzione REACH

Pavia – 7 maggio 2011

COSTS:

OECD TG 428, in GLP:

2,700 €/per substance

4,320 € for the two salts when tested simultaneously

U937

Performed for free at the University of Milan, as the validating committee

needs new substances to test

The final result will be confidential and will not be published

(LLNA in vivo method):

7,200 €/per substance

10,800 € for both salts when tested simultaneously

Strategy: sensitisationoss

Page 43: La rivoluzione REACH

Pavia – 7 maggio 2011

Strategy: full dossier

In vitro studies to assess the category of nickel compounds and verify the

representative substance to take the existing data in Read Across

BIOACCESSIBILITY BASED READ ACROSS ASSESSMENT OF NICKEL

COMPOUNDS: INHALATION TOXICITY

Sample ID Code(s)2 CAS No.

Ni

Content

(%)3

Interstitial

Bioaccessibility

(% Ni/g sample)4

Lysosomal

Bioaccessibility

(% Ni/g sample)4

Acute Toxicity

(inhalation LC50,

mg/L)5

Ni Sulfate Hexahydrate N58-72 10101-97-0 22 12.80 21.35 2.48

Ni Oxide Green N9/N46 (N126) 1313-99-1 77 (81) 0.10 0.82 >5.08

Ni Sub-Sulfide N129 (N18) 12035-72-2 61 (70) 3.60 26.20 1.14

Ni Hydroxy Carbonate N128 (N109) 12122-15-5 49 (49) 1.65 47.206 >2.09 (F); 0.25 (M)7

Ni Chloride Hexahydrate N98 7791-20-0 25 8.10 25.056 NC

Ni Acetate Tetrahydrate N103 6018-89-9 24 10.90 24.856 NC

Ni Sulfamate

TetrahydrateN104 13770-89-3 18 8.60 18.306 NC

Ni Hydroxide N106 12054-48-7 54 0.02 55.80 NC

Ni Oxide Black N105 1313-99-1 75 0.56 24.50 NC

Ni Sulfide N97 16812-54-7 59 1.08 25.95 NC

Page 44: La rivoluzione REACH

Pavia – 7 maggio 2011

Strategy: full dossier

BIOACCESSIBILITY BASED READ ACROSS ASSESSMENT OF NICKEL

COMPOUNDS: ORAL SYSTEMIC TOXICITY

Sample ID Code1 CAS No.

Ni Content

(%)2

Bioaccessibility (%

Ni content

released)3

In Vivo Acute

Toxicity (oral LD50,

mg/kg/bw)4

Ni Sulfate Hexahydrate N58-72 10101-97-0 23 90.55% 362

Ni Oxide Green N9/N46 1313-99-1 77 0.33% >11000

Ni Oxide Green N112 1313-99-1 81 <LOD5 >11000

Ni Sub-Sulfide N18 12035-72-2 70 22.65% >11000

Ni Chloride Hexahydrate N98 7791 -20-0 25 89.85% 500

Ni Acetate Tetrahydrate N 103 6018-89-9 24 88.50% 550

Ni Hydroxy Carbonate N109 121 22-1 5-5 49 84.30% 2000

Ni Sulfamate

TetrahydrateN 104 13770-89-3 18 83.40% 1098

Ni Hydroxide N106 12054-48-7 54 26.30% 5000

Ni Oxide Black N105 131 3-99-1 75 29.60% 9990

Ni Sulfide N97 1681 2-54-7 59 9.75% NC6

Ni Fluoride Tetrahydrate7 N111 13940-83-5 32 82.35% 310

Page 45: La rivoluzione REACH

Pavia – 7 maggio 2011

European projects

OSIRIS

Optimised Strategies for Risk Assessment of Industrial Chemicals through

Integration of Non-Test and Test Information

http://www.osiris-reach.eu/

Page 46: La rivoluzione REACH

Pavia – 7 maggio 2011

Improvements

With the first dossiers many data have been generated, that can be used to

improve also the reliability of predictions models in the next years

More in vitro metods will be developed / validated

Multidisciplinary approach within the working groups

Will ECHA be ready?

Page 47: La rivoluzione REACH

An example for a Strategy

IN VITRO STUDIES : An example on how to assess doubtful sensitization results on a basic dye supporting also exposure pattern.

No study available on both Oxalate and Chloride forms of the dye

Demonstration that the two salts are equivalent is missing

There is concern about the skin sensitisation potential

Negative result in an old study (1984)Positive in a even older human patch test (1966)

• A new study performed on both salts is required• A new study to confirm the sensitisation property is required

Page 48: La rivoluzione REACH

ITS proposal:

1. Skin absorption assessment: OECD TG 4282. In vitro sensitisation: THP-1 method, which passed the pre-validation

and has just started the official validation at ECVAM (European Centre for Validation of Alternative Methods)

RATIONALE

Skin Absorption: Only adsorbed substances can cause skin sensitisationThe results can be also exploited as a comparison between the two salts

Sensitisation: a POSITIVE results is accepted (Annex XI:positive results from a suitable in vitro test can be accepted)a NEGATIVE result is also accepted: (peer review literature)

Page 49: La rivoluzione REACH

COSTS:

OECD TG 428, in GLP:2,700 €/per substance4,320 € for the two salts when tested simultaneously THP-1 Performed for free at the University of Milan, as the validating committee needs new substances to test

(LLNA in vivo method):7,200 €/per substance10,800 € for both salts when tested simultaneously

Page 50: La rivoluzione REACH

In vitro methods: Strategy

INTELLIGENT = INTEGRATED

Existingdata

Weight ofEvidence

In vitro dataGOOD SENSE!

Exposureassessment

Readacross

Categories

In silicodata

Page 51: La rivoluzione REACH

Validation modular approach

Test definition

Within-lab. variability

Transferability

Between-lab.variability

Predictive capacity

Applicability domain

Minimum performance standards

Reprodu-cibility

Relevance

“Standardised”

“Suitable/Adequate”

“Validated”

“Equivalent”

Hartung et al. ATLA 2004, 32:467-472

Page 52: La rivoluzione REACH
Page 53: La rivoluzione REACH

OECD Member Countries

Countries/Economies Engaged in Working

Relationships with the OECDOECD

Page 54: La rivoluzione REACH

428 Skin Absorption: In Vitro Method

430 In Vitro Skin Corrosion: Transcutaneous Electrical Resistance Test (TER)

431 In Vitro Skin Corrosion: Human Skin Model Test

432 In Vitro 3T3 NRU Phototoxicity Test

435 In Vitro Membrane Barrier Test Method for Skin Corrosion

437 Bovine Corneal Opacity and Permeability Test Method for Identifying Ocular Corrosives and Severe Irritants

438 Isolated Chicken Eye Test Method for Identifying Ocular Corrosives and Severe Irritants

439 In Vitro Skin Irritation: Reconstructed Human Epidermis Test Method

471 Bacterial Reverse Mutation Test

472 Genetic Toxicology: Escherichia coli, Reverse Assay

473 In Vitro Mammalian Chromosome Aberration Test

474 Mammalian Erythrocyte Micronucleus Test

476 In Vitro Mammalian Cell Gene Mutation Test

477 Genetic Toxicology: Sex-Linked Recessive Lethal Test in Drosophilia melanogaster

479 Genetic Toxicology: In Vitro Sister Chromatid Exchange assay in Mammalian Cells

480 Genetic Toxicology: Saccharomyces cerevisiae, Gene Mutation Assay

481 Genetic Toxicology: Saccharomyces cerevisiae, Mitotic Recombination Assay

482 Genetic Toxicology: DNA Damage and Repair, Unscheduled DNA Synthesis in Mammalian Cells In Vitro

483 Mammalian Spermatagonial Chromosome Aberration Test

487 In Vitro Mammalian Cell Micronucleus Test

OECD Methods

Page 55: La rivoluzione REACH

428 Skin Absorption: In Vitro Method

430 In Vitro Skin Corrosion: Transcutaneous Electrical Resistance Test (TER)

431 In Vitro Skin Corrosion: Human Skin Model Test

432 In Vitro 3T3 NRU Phototoxicity Test

435 In Vitro Membrane Barrier Test Method for Skin Corrosion

437 Bovine Corneal Opacity and Permeability Test Method for Identifying Ocular Corrosives and Severe Irritants

438 Isolated Chicken Eye Test Method for Identifying Ocular Corrosives and Severe Irritants

439 In Vitro Skin Irritation: Reconstructed Human Epidermis Test Method

471 Bacterial Reverse Mutation Test

472 Genetic Toxicology: Escherichia coli, Reverse Assay

473 In Vitro Mammalian Chromosome Aberration Test

474 Mammalian Erythrocyte Micronucleus Test

476 In Vitro Mammalian Cell Gene Mutation Test

477 Genetic Toxicology: Sex-Linked Recessive Lethal Test in Drosophilia melanogaster

479 Genetic Toxicology: In Vitro Sister Chromatid Exchange assay in Mammalian Cells

480 Genetic Toxicology: Saccharomyces cerevisiae, Gene Mutation Assay

481 Genetic Toxicology: Saccharomyces cerevisiae, Mitotic Recombination Assay

482 Genetic Toxicology: DNA Damage and Repair, Unscheduled DNA Synthesis in Mammalian Cells In Vitro

483 Mammalian Spermatagonial Chromosome Aberration Test

487 In Vitro Mammalian Cell Micronucleus Test

OECD Methods

Page 56: La rivoluzione REACH

OECD 437 BCOP Test

H318 Causes serious eye damage

Page 57: La rivoluzione REACH

Un esempio di una strategia

IN VITRO STUDIES : Un esempio di come una strategia in vitro è statautilizzata per la valutazione di un risultato dubbio sulla sensitization e per avere maggiori dati sull'esposizione.

Nessuno studio disponibile su entrambi i Sali in commercio del colorante (Ossalato e cloruro)

Mancanza di una dimostrazione che i due Sali fossero equivalenti

Dubbio che potesse essere allergenicoRisultato negativo in uno studio molto vecchio (1984)Risultato positivo in un human patch test ancora più vecchio (1966)

• Necessario uno studio da fare contemporaneamente sui due sali• Necessario uno studio per decidere sulla skin sensitisation

Page 58: La rivoluzione REACH

ITS proposal:

1. Skin absorption assessment: OECD TG 4282. In vitro sensitisation: THP-1 method, che ha già passato la fase di pre-

validation and ed è in corso di validazione ufficiale a ECVAM (European Centre for Validation of Alternative Methods)

RATIONALE

Skin Absorption: Solo le sostanze che vengono assorbite possono provocareallergie. Il risultato può essere utilizzato come base per ilconfronto tra i due sali

Sensitisation: un risultato POSITIVO è accettato (Annex XI: positive results from a suitable in vitro test can be accepted)un risultato NEGATIVO è accettato lo stesso (peer review literature)

Page 59: La rivoluzione REACH

Non si conosconoSono più difficili da applicareSpesso sono più costosiNon si è sicuri che vengano accettatiSi è sempre fatto in un altro modo

Altex 27, 3/10

Page 60: La rivoluzione REACH

… Approccio avanzato, ma ancora con impostazione classica…

Page 61: La rivoluzione REACH

The reproductive cycle

Courtesy of Michael Schwarz

Page 62: La rivoluzione REACH

Use of bovine gametes for reproductive toxicity testing

bovine ovaries

2 cm

bovine oocytes

Endpoint: % Metaphase II

Chemicalexposure (24h) during IVM

In vitro maturation (IVM) of bovine oocytes

Endpoint: % 2Pronuclei

In vitro fertilisation (IVF) of bovine oocytes

Chemicalexposure (20h) during IVF

IVM, 24 h

Page 63: La rivoluzione REACH

Coltura di cellule

embrionali staminali

dall’embrione alle cellule staminaliconcepimento blastocisti (5 giorni)

Page 64: La rivoluzione REACH

Developmental Toxicity

Acute Toxicty

Stem Cell Toxicity Approach

Page 65: La rivoluzione REACH

performanceconfidence

in vivo relevance

validationpredictive

Page 66: La rivoluzione REACH

QIVIVE Quantitative in vitro in vivo extrapolation

Target cells: permeability, transport, metabolic competenceExtracellular space: proteins, lipids, pH, plastic, other cellsExposure (concentration x time)

Page 67: La rivoluzione REACH

Modelli PBPK

Page 69: La rivoluzione REACH

Biologic

Inputs

Normal

Biologic

Function

Morbidity

and

Mortality

Cell

Injury

Adaptive Stress

Responses

Early Cellular

Changes

Exposure

Tissue Dose

Biologic Interaction

Perturbation

Low DoseHigher Dose

Higher yet

(Courtesy of Mel Andersen)

A New Paradigm: Activation of Toxicity Pathways

Page 70: La rivoluzione REACH

Progetto ToxCast

Page 71: La rivoluzione REACH

Toxicity PathwaysA cellular response pathway that, when sufficiently perturbed, is expected to result in an adverse health effect.

Set Chemicals Assays Endpoints Completion Available

ToxCast Phase I 293 ~600 ~1100 2011 Now

ToxCast Phase II 767 ~600 ~1100 03/2013 10/2013

ToxCast Phase IIIa 1001 ~100 ~100 Just starting 2014

E1K (endocrine) 880 ~50 ~120 03/2013 10/2013

Tox21 8,193 ~25 ~50 Ongoing Ongoing

Page 72: La rivoluzione REACH

Effect of Concentration Response on Polypharmacology

72

Pentachlorophenol

Page 73: La rivoluzione REACH
Page 74: La rivoluzione REACH

“Non sopravvive chi è più forte o

più intelligente, ma chi

reagisce più velocemente ai

cambiamenti”

Charles Darwin