experience in preparation of technical dossier

Maristella RubbianiIstituto Superiore di Sanità

RomaItaly

20/04/23 1TAIEX Belgrade

IntroductionSome info related to applicationSome info related to dossierSome info related to what’s going on


Who can apply for authorisation?

Application for authorisation shall be made by, or on behalf of, the natural person or legal entity responsible for the first placing the product on the market.


ApplicantThe applicant may be either native or foreign

but shall have a permanent office within the European Union, Norway or Switzerland.

If the applicant is not the manufacturer of the product or its active substance, he has to present a letter of access providing him the right to represent his principal in matters concerning the product or the active substance.


Applicant may be The future authorisation holder or a company or person who handles practical issues of the

application on behalf of future authorisation holder(s).

Authorisation holder is person/entity to whom the

decision on authorisation is issued to. Responsibility for the placing on the product on the

market, classification and labelling etc. always lies on the authorisation holder.

Please note that different MS may have different interpretations on the applicant, i.e. they may require that application shall always be made by the future authorisation holder.


When to apply for authorisation?


Specific issuesIf a product contains more than one active

substance the deadline for the product application is the one set out in the latest of the inclusion directives relating to its active substances

If a product belongs to several product types, authorisation for each product type shall be applied for separately at the deadline determined by the inclusion of the active substance.


Important !If no application for the authorisation of a

biocidal product is submitted by the given deadline the product shall be phased out of the market in 6 months from this deadline for the application.


Phasing outThe 6month deadline for the phasing out of

products not supported refers to the first placing on the market.

For subsequent storage, marketing, use and disposal of existing stocks different periods of grace applies depending on MS


Specific casesProducts that are not on the market: If you intend to start to place on the market a new biocidal product with active substance(s) which is already included in Annex I for the relevant product type there are no binding deadlines for submitting the application for authorisation. Placing the product on the market is not allowed before authorisation.

Products containing new active substances: If you intend to start to place on the market a biocidal product with a new active substance which is not yet included in Annex I procedures are according to the Art 11 of the BPD. Only after Annex I inclusion the product can be authorised. Application may be submitted at any time. Placing the product on the market is not allowed before authorisation.

Uses of active substances in product types not notified : and therefore not included in the review programme of existing active substances are treated the same way as products containing new active substances.


Before preparing application In addition to the status of the active substances in

Annex I there are a few other things to consider before preparing an application for a biocidal product:

Make sure that you consider the right product type with respect to the use purpose and pattern of your biocidal product.

Further information about scope of the BPD is compiled by the European Commission in the Manual of Decisions (MoD), http://ec.europa.eu/environment/biocides/manual.htm


??????????If you have any doubts as to whether your

products or active substances are biocides or to which product type they belong to take contact to the CA.


Technical equivalenceCheck that the active substance of your

product is technically equivalent to the one covered by the Annex I inclusion directive.

This means that the active substance has to be so similar in purity, impurities and possible isomers that the active substance evaluation for the Annex I inclusion is still applicable.


Technical equivalenceIn case of similarity, an access to the data

package used for the inclusion of the active substance or equivalent data is needed.

If the active substance is not considered equivalent corresponding data on the active substance as submitted for the Annex I active substance is needed.

The CA makes the final decision on the equivalence based on the data submitted by the applicant.


Guidance on technical equivalence is available at:

http://ihcp.jrc.ec.europa.eu/our_activities/health-env/risk_assessment_of_Biocides/


EvaluationConsider carefully the use purpose and

pattern of your product. Does the risk and efficacy assessment

conducted with the representative product in the active substance evaluation for the Annex I inclusion directive apply to the use of your product and there are no further elements to be taken into account in the product phase?


Evaluation of efficacyApplicants should always consider if the

efficacy data meet the requirements. If not, further data and risk assessment are

necessary. The applicant is responsible for providing

further data and the outstanding risk assessment for the product


General requirements for documentation

The application consists of application forms and the dossier.

The applicant is responsible for providing the required information and for including the study reports and other documents needed.

The evaluation of the data by the applicant will form the basis of the evaluation by the CA.


FormatThe MS and the European Commission have

agreed that the information included in dossiers on biocidal products should be submitted in a standard format .

The format is the same in whichever MS the dossier is submitted.

This will make it easier for the applicants to know exactly what must be done and what a dossier must contain.


Application forms

Application form consists of two parts. The whole form isavailable at the European

Register for Biocidal Products (R4BP). The first part of the application form for

authorisation of a biocidal product is made via the R4BP.

The register is maintained by the European Commission.

The application form is available in all of the EU official languages.


The R4BPIn the R4BP the applicant fills in the details

on the applicant and the product. The applicant has to indicate in which MS he

applies for the first product authorisation and in which EU/EEA countries mutual recognition.

Furthermore, the applicant is requested to indicate in which MS the product is already on the market.

R4BP: https://webgate.ec.europa.eu/env/r4bp/


TimingThe product may only stay on the market of a

particular MS without interruption if this MS is indicated in the application form generated via the register and submitted to all of these MS by the deadline of the application.

The second part of the application form is a word document which contains further details about the product and the type of application.


Dossier

Product dossier consists of data and documents

In addition, proposal for Safety Data Sheet (SDS) and proposal for labelling in the official languages shall be presented by the applicant


How is the Dossier structured?

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Doc II-AEffects Assessmenta.s.

Doc II-BEffects and Exposure Ass. b.p.(s)

Doc. II-C Risk Ass. Use of A.S. in B.P.(s)

Doc. II Risk Assessment

Doc. IEvaluation/AssessmentReport1

Document III-BStudy Summariesb.p.(s) 2)

Document III-AStudy Summariesa.s.2)

1) To include: I.1 Subject Matter I.2 Overall Summary and ConclusionsI.3 Proposal for Decision Annex I Inclusion;List of end points; List of abbreviations

Initial check for completeness of dossiers

CAs' Report

2) To append: Reference lists

TNsG on Preparation of Dossiers

Doc. IV-B: Test Reports b.p.(s)

Doc. IV-A: Test Reports a.s.

Doc II-AEffects Assessment a.s.

Doc II-BEffects and Exposure Ass. b.p.(s)

Doc. II-C Risk Ass.Use of a.s. in b.p.(s)

Document III-BStudy Summariesb.p.(s)2)

Doc III-AStudy Summariesa.s.2)

1) To append: List of end points List of abbreviationsCheck for completeness

Summary Dossier

2) To append: Reference lists

Doc. II Risk Assessment

Complete Dossier

Doc. IOverall Summary and Assessment1)

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Table 2. Data requirements for active substances and biocidal products. BPD Annex number Chemical active substances (a.s.) and products (b.p.) Core data for a.s. II A Annex 2 Core data for b.p. II B Annex 1 Additional data for a.s.

III A Annex 2

Additional data for b.p.

III B Annex 1

Biological active substances (a.s.) and products (b.p.) Data for a.s. IV A Annex 4 Data for b.p. IV B Annex 3

Data requirements Data requirements for the biocidal active substances and products are listed in Annexes II-IV of the BPD


Submission of the application

Application should be sent to CA


The structure of the dossier documentation required for the application for authorisation of a biocidal product, provided that the active substance is listed in

Annex I. Doc. IVA or LoA*: Test and Study Reports a.s.(s)

Doc. IVB or LoA*: Test and Study Reports b.p.** Doc IIB or LoA* - Effects Assess.** - Exposure Assess. - Efficacy Assess. for Biocidal Prod.2) Doc II-A or LoA* Effects and exposure Ass. Active Subst.(s)2) Doc. II-C Risk Characterisation for Biocidal Product Doc. II Risk and Efficacy Assess. Doc. I Overall Summary and Assessment1) Document III-A or LoA* Study Summaries Active Substance(s)2) Document III-B or LoA*: Study Summaries Biocidal Product2) 1) To append: List of end points 2) To append: Reference lists List of abbreviations Check for completeness Summary Dossier Complete Dossier * LoA = Letter of access ** In the case of applications for registration of low-risk products, the effects assessment is

confined to data on the active substance(s) only. In general, the data to be provided in Doc. IV-B and III-B are limited.


Technical requirements:

one paper copy of the whole application (application forms, Doc I – IV, Safety Data Sheet (SDS), draft labels, use instructions, Summary of Products Characteristics (SPC)).

Docs I-II must be MS Word-documents or MS Word-compatible.

Doc III i.e. study summaries must be either in IUCLID 5 or Word-documents

one electronic copy of the whole application on CD-rom


Language

SDS, draft label and use instructions must be available in national languages SPC, in national languages Other documents are accepted also in English. If the application is for an authorisation, which is to be used later for the purpose of mutual recognition, it is recommended that the dossier is submitted in English.


General principles on the submission of experimental studies The applicant shall submit to the CA all data

on physicalchemical properties, toxicological, environmental fate and ecotoxicological effects, efficacy and other properties of the chemical that is necessary for the assessment of the conditions for authorisation.


TNsGThe Technical Notes for Guidance (TNsG) on

Data Requirements describes the data needed which was originally set by Annexes II and III of the BPD.

MS specific data may be required in some cases (e.g. country specific exposure data, data related to specific resistance phenomena).


ReportsThe original study reports shall be attached

to the application. However, the original study reports (Doc IV)

and the study summaries (Doc III) are not required if the applicant has a written proof of his right to refer to them in his application (letter of access, LoA) and these documents have already been submitted either for the evaluation of the active substance for Annex I or in another application for product authorisation.


AppendicesThe appendices of the application shall be

numbered using the codes in the TNsG on Data Requirements 7.

If several studies are related to one item, they should be distinguished by lower case letters following the appendix number (e.g. 6.1.1a, 6.1.1b).


MethodsStudies must be conducted and reported either

according to the methods mentioned in the Council Regulation 440/2008 on test methods or according to the OECD (Organisation for Economic Cooperation and Development) guidelines for testing of chemicals.

The main rule is that studies must also comply with the principles of Good Laboratory Practice (GLP) and the study report shall contain a certificate of this.

Further guidance on GLP is given in the TNsG on Data Requirements, Chapter 6 6.


Animal welfareThe processing of the application will

continue after the supplementary data has been presented.

The BPD encourages limiting the duplication of testing on vertebrate animals, whenever possible.


Attention!According to this principle, before starting a

new test, literature searches should be conducted and the other owners of the required documentation should be consulted in order to find out, whether the available information is sufficient for the reliable evaluation of the possible hazards of the chemical


Sharing dataIn order to receive the contact details of

other data owners the applicants are invited to contact the CA.

If information is available, but it is inadequate, the scope of the additional studies required will be considered on a case-by-case basis.


Information and data requirements Core data and additional data

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Core data• always required• read across feasible• BPD Annex IIA for active substance • BPD Annex IIB for biocidal product• BPD Annex IV A for fungi, micro-organisms and viruses • BPD Annex IV B for biocidal product with fungi, micro-

organisms and viruses

Additional data• Required under certain circumstances: product type,

exposure/intended uses, characteristics of substance/product• BPD Annex IIIA for active substance• BPD Annex IIIB for biocidal product

20/04/23 TAIEX Belgrade

Information and data requirements Core data IIA and IIB

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• Applicant

• Identity

• Physical and chemical properties

• Analytical methods for detection and identification

• Effectiveness against target organisms and intended uses

• Exposure (ESD + monitoring)

• Toxicological and metabolic studies: acute, irritation, sensitisation, (sub)chronic, CMR

• Ecotoxicolgical studies: fate and behaviour, acute toxicity fish/invertebrate/algae, inhibition of microbiological activity, bio-concentration


Information and data requirements Additional data IIIA and IIIB – example

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Additional data

Annex IIIA for substance, IIIB for product, e.g.

o if indications of neurotoxicty from other studies neurotoxicity ⇒endpoints

o if necessary ⇒ mechanistic studies (es: placental passage)

o if available medical data⇒

o private area and health area disinfectants chronic aquatic toxicity⇒

o Veterinary hygiene products with possible release to manure storage facility anaerobic biodegradation, acute toxicity to plants.⇒


waivingIf it is not technically possible or scientifically

justifiable to submit the required information or carry out the required studies, or if the studies are not conducted according to the guidelines referred above, then the reasoning must be given in the application.

If such justifications are not given, or if the application is otherwise insufficient, the CA will ask the applicant to submit the missing information and studies.


Information and data requirements Waiving

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• For each endpoint necessary according to BPD Annexes IIA/IIB/IIIA/IIIB at least one acceptable study or a justification for non-submission of data (= waiving) has to be submitted

• Waiving arguments• Technically not possible to perform (es: 2nd gen.

anticoagulants)• Sufficiently valid other existing data available

• Read across to another similar substance or product• Other scientifically acceptable method, calculation

method, alternative study, literature study

• Study scientifically not necessary, e.g. Biodegradability of inorganic chemicals, eye irritation for skin

corrosive substance …

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Information and data requirements Waiving

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• Study not necessary due to limited exposure and toxicity profile:

Level of exposure: MOE > 1000 to rep. dose studies that cannot be waived

Frequency of exposure: < 12 x per year

Duration of exposure: < 3 months per year

AND

Low toxicological concern, e.g.

if subchronic studies in rodents and non-rodents are without indication of substance-related effects at the limit dose level – waive chronic toxicity studies

if no developmental effects in first species and no developmental or reproductive effects in 2-generation study – no developmental study in second species

• for further details see: TNsG on data requirements (chapter 1, 1.3.)

• actual practice: increasing flexibility, largely depending on “expert judgment”20/04/23

Which methods are available for toxicological hazard assessment and how much it costs ?

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€sub-acute oral (OECD 407) 40 500sub-acute inhalative (OECD 412) 71 400sub-chronic oral (OECD 408) 110 000Sub-chronic inhalative (OECD 409) 132 000Fertility 2 generation (OECD 416) 250 000Teratogenicity (OECD 414) 68 000Toxicokinetics (OECD 417) 75 600Chronic toxicity (OECD 452) 395 000Chronic toxicity/carcinogenicity (OECD 453) 767 000Fish acute toxicity (OECD 203) 6 000Fish early life stage (OECD 210) 39 000

More than 1 Million Euro are necessary for testing a single new biocidal substance.

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Animal Welfare Considerations:

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More than 3000 Animals are necessary for the evaluation of one biocidal substance

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Which studies are used for risk assessment? The key study concept

For each endpoint necessary according to BPD Annexes IIA/IIB/IIIA/IIIB at least one acceptable study or a justification for non-submission of data has to be submitted

If more than one study is submitted for an endpoint one key study should be defined: study regarded as sufficient and adequate for risk assessment

Key studies should bethe study with the most sensitive species and endpoint

= lowest NOAEL or ECGLP and test guideline-conform

each study’s value to the risk assessment has to be judged individually

detailed study summaries have to be provided just for key studies



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• Several studies can be considered as key studies for the same endpoint, e.g. when

data are available on several species or different routes of exposure or if different results are observed in valid tests

several studies compensate the deficiencies of each other?



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• Flexibility is necessary

All data for key studies should be of an acceptable quality, but flexibility is necessary for studies with deficiencies, if they are crucial or support special risk assessment aspects;

this would apply to all carcinogenicity, mutagenicity and reproductive toxicity studies with “positive” results

this could apply to literature data, studies on mechanisms of action, other non-guideline or non-GLP studies

• For further details to the key study concept see TNsG on Dossier Preparation and Study Evaluation, Part I: Chapter 4.2


What defines the validity of data? Reliability TNsG risk assessment, part I, 3(2), p86

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o exact description of the test substances, including the impurities

o OECD or Annex V method or complete method description

o in case not accepted OECD or Annex V method:o proper test set up: like control groups, exclusion of unspecific

effects, concentration range, replicate number ...o eventually supported by other literature data, QSARo if approximate value for the specific endpoint is sufficient for risk

assessment

o Good Laboratory Practice


What defines the validity of data? Relevance TNsG risk assessment, part I, 3(2), p86

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o proper species

o knowledge of toxicokinetics and metabolism (does not exclude extrapolation to human)

o route of exposure relevant for population and exposure scenario

o substance tested = substance supplied

o dose-response established (where possible)

o for in vitro data, QSAR: could established correlation to in vivo endpoint


What defines the validity of data? Klimisch scoring system• Each study submitted has to be classified according

to Klimisch scoring system:

1 = reliable without restrictions: generated according to generally valid and/or internationally accepted testing guidelines

2 = reliable with restrictions: test parameters documented do not totally comply with the specific testing guideline, but are sufficient for risk assessment

3 = not reliable

4 = not assignable: not sufficient experimental details, e.g. abstracts or secondary literature (books, reviews, etc.)

1 and 2 can be considered for risk assessment

3 or 4 can be considered limited or no value for risk assessment 5120/04/23 TAIEX Belgrade

Can data from literature be used? The applicant has to submit a survey of the available

literature on the effects of the biocide

The respective literature data are considered as additional, complementing for risk assessment

Only in justified cases some core endpoints could be covered without an appropriate standard, GLP study, but with literature data only BPD Article 8 (8) and (9)

Also legal property and copy rights have to be respected

The same holds true for other public available information like study summaries and evaluations from EPA, WHO, …


Can data from literature be used?Pro´sAvoid animal testingSafe costs (for applicant)Independent data, generated by scienceIn line with “weight of evidence evaluation”

(REACH approach)Con´sIdentity of active substance often unclearNo GLPScarce description of methods


What is the difference between Data Protection and Confidentiality?

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Data Protection (Art 12 of 98/8/EC)

• ensures that data can be used for registration/authorisation only by

o companies who own the data, oro those holding a letter of access

• allows industry to recover costs for Annex I/IA inclusion and authorisation of the biocidal product• public available data not protected • does not prejudice the use of data by EC, Scientific Committees (Art 27), MS

• for a defined period of time

• release of information does not affect the status of data protection! (e.g. regulations on the freedom of access to information on the environment)

Confidentiality (Art 19 98/8/EC)

• protects commercially sensitive results of R&D of companies

o technical details of the manufacturing processo details of full product formulation (composition)o names and addresses of test laboratories, sites and personnelo individual medical details (animal welfare)

• for indefinite period of time

• should only be made known to CA and EC, not on web



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Data Protection List in CA-report for Annex I inclusion Doc. 1.4

Data Confidentiality List in CA-report for Annex I inclusion Doc. 2.a



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Data Protection

• New active substances, Art 12 (1b)

15 years from the date of first inclusion in Annex I or IA

• Existing active substances, Art 12 (1c)

10 years from 14.05.2000

- except where information is already protected under existing national rules relating to biocidal products – national data protection period remains valid up to max. 14. May 2010

10 years from the date of first inclusion in Annex I/ IA

Product : 10 year from the first authorization

Confidentiality: indefinite time period20/04/23 TAIEX Belgrade

'letter of access' means

an original document, signed by the data owner or its representative, which states that the data may be used by the competent authorities, the European Chemicals Agency, or the Commission for the purpose of evaluating an active substance or granting an authorisation;


How is the Risk Assessment structured?

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• Templates provided in TNsG Dossier Preparation were developed as basis for IUCLID 5.1 version

•since old IUCLID 4 version is not adequate for biocides evaluation it should have been used in parallel to word doc III for priority list 1 and 2, but only few Member States sticked to this requirement ( 2nd ReviewR, Annex IV).

Use of IUCLID


How is the Risk Assessment structured?

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• IUCLID 5 will be free of charge

• IUCLID 5 will replace doc III level

• is a data-base file and therefore a significant improvement compared to word files!

• still under discussion, if mandatory already for priority list 3 or only for priority list 4

• new OECD html study summaries will be directly loadable

• will be standard also for chemicals evaluation under REACH

• for details see: http://ecb.jrc.it/reach-it_informatics/

Use of IUCLID


What questions are addressed to test evaluation? Substance tested identical to the substance

produced for the market? • Same quantity and quality of impurities?

Study carried out according to OECD standard method?• If not, are the deviations critical?• Are the validity criteria of the method met? – e.g.

mortality rates, body weight lossStudy carried out under Good Laboratory Practice

(GLP) conditions?• If not is the study nevertheless reliable? Was other

quality assurance system in place?

Is it possible to derive a NOAEL? (see ECETOC TR N. 85)

Is there a difference between test and control groups? Statistically, biologically significant?


What questions are addressed to test evaluation?

• Is the difference an effect of treatment?

Dose –response? Due to outlier? Precision of endpoint? Within historical control range? Biological plausibility?

• Is the treatment related effect adverse?

Alteration of general function of test organism or organ/tissue affected? Is it secondary to other adverse effects? Is it an adaptive response? Transient? Severity? Isolated effect or expected change with other parameters – in parallel or in time line? Consequence of specific animal model?


What questions are addressed to test evaluation?

Was the tested dose range appropriate?

Are the study- results in line with the finding of other studies?

Interspecies differences?

Which results are relevant for C&L?

Are scientific arguments for waiving or read across of data acceptable?


Some key elements for biocidal product evaluation:

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Is active substance within submitted product identical to active substance evaluated within CA-report?• if not – no authorisation/registration

Letters of access available for all key studies from the active substances defined in the CA reports?• if not – no authorisation/registration

Hazard evaluation for product has to be carried out based on acute toxicity data for the product and on the integrated long term toxicity data of the active substances and substances of concern

Is efficacy assessment complete? • for a.s. evaluation just a minimal efficacy evaluation was

required


Some key elements for biocidal product evaluation:

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Is exposure assessment of the representative product relevant and sufficient for intended use of submitted product?• if not – exposure assessment needs to be amended

Can some of the restrictions defined in document I of CA-report of the active substance be cancelled due to new data/information and evaluation?

Are other restrictions necessary due to new data/information or evaluation?

CA-report and possibly Annex I criteria of active substance need to be updated with new data/information and evaluation

CA-report for product with specific restrictions has to be compiled


What data and dossier structure are required for national authorisation or registration of biocidal products?

Summary Dossier Biocidal Product

• 98/8/EC, Art 8(2) the data – or the appropriate letters of access - covering annex IIA and IIIA and IIB and IIIB have to be submitted

• 98/8/EC Annex IIA (10) and IIB (10): summary and evaluation of the data submitted

• Structure? – no obligation to use Frauenhofer Formats (in contrast to Annex 1 inclusion- Comm. Reg. 2032/2003 Annex 4)

CA-Report Biocidal Product

• 98/8/EC Art 8(10) the MS has to generate a file containing at least:

• A copy of application

• A record of the administrative decision taken by the member state concerning the application and the dossier submitted

• A summary of the application and dossier submitted



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Deviations from standard product evaluation:

• for low risk products/ Art. 2(1b), containing• only active substance(s) listed in Annex IA

o full data requirements for AS and BP (similar to Annex I incl.)o but not classified as CMR, sensitising, bioaccumulating, not readily

biodegradable/ Art 10 (1)o concentration limits, other specific conditions may be attached to

Annex IA listing• and no substance(s) of concern/ Art. 2(1e)

o any substance other than the active substanceo which has inherent capacity to cause adverse effectso is present/produced in effect sufficient concentration in BP

⇒ product registration • reduced data requirements/ Art 8(3)

no (eco)tox; but identity, uses, efficacy, analytics, classification, safety data sheets

• faster decision: 60 days20/04/23 TAIEX Belgrade


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• for frame formulations/ Art. 2(1j)• specifications for a group of biocidal products with same use• must contain the same active substances of the same specifications,

and • their composition must present only variations from a previously

authorised product which do not affect the level of risk associated with them and their efficacy

• are established by MS/ Art 3(4)either on request of an applicant or on the CA owns initiative

⇒ no difference for mother substance/product ⇒ reduced data requirements for frame formulation- product/ Art 8(5)⇒ 60 days for frame formulation product authorisation/ Art 3(4)



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• Mutual recognition/ Article 4• active substance is on Annex I/IA• Annex I inclusion criteria are met by product• product already authorised/registered in other MS possibly with

additional restrictions• summary of dossier and copy of first authorisation submitted

⇒ authorisation/registration within 120/60 days after submission for mutual recognition

⇒ deviating restrictions only in case of deviating abundance of target species or tolerance or resistance compared to MS with first authorisation/registration

⇒ commission procedure in case of disagreement of MS with first authorisation


FeesRanging from 10.000 to 354.000 EUR for

active substance evaluation and from 1.000 to 70.000 for product authorisation.

Up to 1 million to be paid for a substance supported in 13 product-types.


Some useful guidance documents

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European Chemicals Bureau; http://ecb.jrc.it/biocides/Technical Guidance Documents (TGD) on risk assessmentTechnical Notes for Guidance

for human exposure assessment for biocidesfor Annex I inclusion for data requirementsfor product evaluation

OECD, http://www.oecd.orgTest GuidelinesSeries on Testing and Assessment /Adopted Guidance and Review Documents

International Conference on Harmonisation (ICH)ICH Guidelines, Safety topics, http://www.ich.org/cache/compo/276-254-1.html


Some useful guidance documents

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DG Health and Consumer Protection, Plant Health Guidance Documents

http://europa.eu.int/comm/food/plant/protection/resources/publications_en.htm

European Food and Safety Agency (EFSA)EPCO – manuals

http://www.efsa.europa.eu/it/science/praper/praper_guidance.html

European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC); http://www.ecetoc.org/

Technical Reports, Monographs, Special Reports

Word Health Organisation–International Programm on Chemical Safety; http://www.who.int/ipcs/methods/en/

Methods for Chemical Assessment


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Thank you for your attention!

20/04/23