COMMISSION DIRECTIVE 94/79/EC of 21 December 1994 amending Council Directive 91/414/EEC concerning the placing of plant protection products on the market

KOMMISSIONENS DIREKTIV 94/79/EF af 21. december 1994 om aendring af Raadets direktiv 91/414/EOEF om markedsfoering af plantebeskyttelsesmidler

THE COMMISSION OF THE EUROPEAN COMMUNITIES,

KOMMISSIONEN FOR DE EUROPAEISKE FAELLESSKABER HAR -

Having regard to the Treaty establishing the European Community,

under henvisning til traktaten om oprettelse af Det Europaeiske Faellesskab,

Having regard to Council Directive 91/414/EEC of 15 July 1991 concerning the placing of plant protection products on the market (1), as last amended by Directive 94/43/EC (2), and in particular Article 18 (2) thereof,

under henvisning til Raadets direktiv 91/414/EOEF af 15. juli 1991 om markedsfoering af plantebeskyttelsesmidler (1), senest aendret ved direktiv 94/43/EF (2), saerlig artikel 18, stk. 2, og

Whereas Annexes II and III to Directive 91/414/EEC set out the requirements for the dossier to be submitted by applicants respectively for the inclusion of an active substance in Annex I and for the authorization of a plant protection product;

ud fra foelgende betragtninger:

Whereas it is necessary to indicate, in Annexes II and III, to the applicants, as precisely as possible, any details on the required information, such as the circumstances, conditions and technical protocols under which certain data have to be generated; whereas these provisions should be introduced as soon as available in order to permit applicants to use them in the preparation of their files;

Bilag II og III til direktiv 91/414/EOEF indeholder kravene til det dossier, ansoegere skal indsende med henblik paa henholdsvis optagelse af et aktivt stof i bilag I og godkendelse af et plantebeskyttelsesmiddel;

Whereas it is now possible to introduce more precision with regard to the data requirements concerning toxicological and metabolism studies on the active substance provided for in Section 5 of Part A of Annex II;

i bilag II og III maa ansoegerne saa praecist som muligt kunne se, hvilke oplysninger der kraeves, og der boer derfor gives en naermere beskrivelse af, under hvilke omstaendigheder og vilkaar og efter hvilke tekniske protokoller visse test skal udfoeres; saadanne praeciseringer boer gives, saa snart de foreligger, saa ansoegerne har mulighed for at benytte dem ved udarbejdelsen af deres dossier;

Whereas it is also now possible to introduce more precision with regard to the data requirements concerning toxicological studies on the plant protection product provided for in Section 7 of Part A of Annex II;

der kan nu gives flere praeciseringer med hensyn til datakravene i forbindelse med toksicitetstest og metabolismetest af det aktive stof, jf. afsnit 5 i del A i bilag II;

Whereas the measures provided for in this Directive are in accordance with the opinion of the Standing Committee on Plant Health,

det er ogsaa muligt at give flere praeciseringer med hensyn til datakravene i forbindelse med toksicitetstest af plantebeskyttelsesmidlet, jf. afsnit 7 i del A i bilag III;

HAS ADOPTED THIS DIRECTIVE:

de i dette direktiv fastsatte foranstaltninger er i overensstemmelse med udtalelse fra Den Staaende Komité for Plantesundhed -

UDSTEDT FOELGENDE DIREKTIV:

Article 1

Directive 91/414/EEC is amended as follows:

Artikel 1

1. in Part A of Annex II the section headed '5. Toxicological and metabolism studies on the active substance' is replaced by Annex I hereto;

I direktiv 91/414/EOEF foretages foelgende aendringer:

2. in Part A of Annex III the section headed '7. Toxicological studies' is replaced by Annex II hereto;

1) I del A i bilag II affattes afsnittet »5. Toksikologiske undersoegelser og metabolismeundersoegelser af det aktive stof« som angivet i bilag I til naervaerende direktiv.

3. Point 1.2 of the introduction to Annexes II and III is replaced by the following: '1.2 where relevant, be generated using test guidelines, according to the latest adopted version, referred to or described in this Annex; in the case of studies initiated before the entry into force of the modification of this Annex, the information shall be generated using suitable internationally or nationally validated test guidelines or, in the absence thereof, test guidelines accepted by the competent authority;'

2) I del A i bilag III affattes afsnittet »7. Toksikologiske undersoegelser« som angivet i bilag II til naervaerende direktiv.

4. in point 1.3 of the introduction to Annexes II and III, the following words are added at the end: 'in particular, when reference is made in this Annex to an EEC Method which consists in the transposal of a method developed by an international organization (e.g. OECD), Member States may accept that the required information is generated according to the latest version of that method if at the initiation of the studies the EEC Method has not yet been updated;'.

3) Punkt 1.2 i indledningen til bilag II og III affattes saaledes:

»1.2. skal i relevante tilfaelde fremskaffes ved at foelge de retningslinjer i den senest vedtagne version, som der er henvist til eller beskrevet i dette bilag; naar der er tale om test indledt inden ikrafttraedelsen af bilagets aendring, skal oplysningerne fremskaffes ved at foelgende passende internationalt eller nationalt validerede retningslinjer eller, saafremt saadanne ikke foreligger, retningslinjer godkendt af den kompetente myndighed«.

Article 2

4. I punkt 1.3 i indledningen til bilag II og III tilfoejes foelgende i slutningen:

Member States shall bring into force the laws, regulations and administrative provisions necessary to comply with this Directive by 31 January 1996. They shall immediately inform the Commission thereof.

»Navnlig i tilfaelde, hvor der i dette bilag henvises til en EOEF-metode, som bestaar i overfoersel af en metode, der er udviklet af en international organisation (f.eks. OECD), kan medlemsstaterne godkende, at de kraevede oplysninger fremskaffes efter den seneste version af paagaeldende metode, hvis EOEF-metoden ved testindledningen endnu ikke var ajourfoert«.

When Member States adopt these provisions, these shall contain a reference to this Directive or shall be accompanied by such reference at the time of their official publication. The procedure for such reference shall be adopted by Member States

Artikel 2

Article 3

Medlemsstaterne saetter de noedvendige love og administrative bestemmelser i kraft for at efterkomme dette direktiv senest den 31. januar 1996. De underretter straks Kommissionen herom.

This Directive shall enter into force on 1 February 1995.

Naar medlemsstaterne vedtager disse bestemmelser, henvises der deri til dette direktiv, eller de ledsages ved offentliggoerelsen af en saadan henvisning. De naermere regler for denne henvisning fastsaettes af medlemsstaterne.

Article 4

Artikel 3

This Directive is addressed to the Member States.

Dette direktiv traeder i kraft den 1. februar 1995.

Done at Brussels, 21 December 1994.

For the Commission

Artikel 4

René STEICHEN

Dette direktiv er rettet til medlemsstaterne.

Member of the Commission

Udfaerdiget i Bruxelles, den 21. december 1994.

Paa Kommissionens vegne

(1) OJ No L 230, 19. 8. 1991, p. 1.(2) OJ No L 227, 1. 9. 1994, p. 31.

René STEICHEN

Medlem af Kommissionen

ANNEX I

'5. TOXICOLOGICAL AND METABOLISM STUDIES

(1) EFT nr. L 230 af 19. 8. 1991, s. 1.(2) EFT nr. L 227 af 1. 9. 1994, s. 31.

Introduction

(i) The information provided, taken together with that provided for one or more preparations containing the active substance, must be sufficient to permit an evaluation to be made as to the risks for man, associated with the handling and use of plant protection products containing the active substance, and the risk for man arising from residual traces remaining in food and water. In addition, the information provided must be sufficient to:

BILAG I

- permit a decision to be made as to whether, or not, the active substance can be included in Annex I,

»5. TOKSICITETSTEST OG METABOLISMETEST

- specify appropriate conditions or restrictions to be associated with any inclusion in Annex I,

Indledning

- classify the active substance as to hazard,

i) De meddelte oplysninger skal sammen med dem, der er givet for et eller flere midler, som indeholder det aktive stof, vaere tilstraekkelige til, at der kan foretages en vurdering af risici for mennesker ved haandtering og brug af plantebeskyttelsesmidler, som indeholder det aktive stof, og risiko for mennesker paa grund af rester, der forbliver i foede og vand. Oplysningerne skal endvidere vaere tilstraekkelige til at

- establish a relevant acceptable daily intake (ADI) level for man,

- goere det muligt at traeffe beslutning om, hvorvidt det aktive stof kan optages i bilag I

- establish acceptable operator exposure level(s) (AOEL),

- specificere de relevante betingelser og begraensninger i forbindelse med optagelse i bilag I

- specify the hazard symbols, the indications of danger, and the risk and safety phrases for the protection of man, animals and the environment to be included in packaging (containers),

- anbringe det aktive stof i en fareklasse

- identify relevant first aid measures as well as appropriate diagnostic and therapeutic measures to be followed in the event of poisoning in man, and

- etablere en relevant acceptabel daglig indtagelse (ADI) for mennesker

- permit an evaluation to be made as to the nature and extent of the risks for man, animals (species normally fed and kept or consumed by man) and of the risks for other non-target vertebrate species.

- etablere AOEL('s): acceptable operator exposure level(s) (acceptabel eksponering af sproejtepersonale)

(ii) There is a need to investigate and report all potentially adverse effects found during routine toxicological investigations (including effects on organs and special systems such as immunotoxicity and neurotoxicity) and to undertake and report such additional studies which may be necessary to investigate the probable mechanism involved, to establish Noaels (no observed adverse effect levels), and to assess the significance of these effects. All available biological data and information which is relevant to the assessment of the toxicological profile of the substance tested, must be reported.

- bestemme faresymbolerne, farebetegnelserne og risiko- og sikkerhedssaetningerne med henblik paa beskyttelse af mennesker, dyr og miljoeet, som skal findes paa emballagen (beholderne)

(iii) In the context of the influence that impurities can have on toxicological behaviour, it is essential that for each study submitted, a detailed description (specification) of the material used, as mentioned under section 1 point 11 be provided. Tests should be conducted using active substance of that specification to be used in the manufacture of preparations to be authorized, except where radiolabelled material is required or permitted.

- identificere relevante foerstehjaelpsregler saavel som passende diagnostike og terapeutiske forholdsregler, der skal foelges i tilfaelde af forgiftning hos mennesker

(iv) Where studies are conducted using an active substance produced in the laboratory or in a pilot plant production system, the studies must be repeated using the active substance as manufactured, unless it can be justified that the test material used is essentially the same, for the purposes of toxicological testing and assessment. In cases of uncertainty, appropriate bridging studies must be submitted to serve as a basis for a decision as to the possible need for repetition of the studies.

- goere det muligt at vurdere arten og omfanget af risici for mennesker, dyr (arter, som mennesker normalt fodrer, holder eller fortaerer) og risici for andre hvirveldyrarter, der ikke er maalarter.

(v) In the case of studies in which dosing extends over a period, dosing should preferably be done using a single batch of active substance if stability permits.

ii) Der er behov for at efterforske og rapportere alle potentielt uheldige virkninger, der paavises under toksikologiske rutinetest (herunder virkninger paa organer og specielle systemer saasom immunotoksicitet og neurotoksicitet), samt at foretage og rapportere saadanne supplerende tester, som kan vaere noedvendige for at efterforske den mekanisme, der sandsynligvis er involveret, at etablere NOAEL's (no observed adverse effect levels) og at bedoemme betydningen af disse virkninger. Alle foreliggende biologiske data og oplysninger, som er relevante for vurderingen af det testede stofs toksicitetsprofil, skal rapporteres.

(vi) For all studies actual achieved dose in mg/kg body weight, as well as in other convenient units, must be reported. Where dosing via the diet is utilized the test compound must be distributed uniformly in the diet.

iii) I forbindelse med den indflydelse, som urenheder kan have paa toksikologiske egenskaber, er det vaesentligt, at der for hver meddelt test gives en detaljeret beskrivelse (specifikation) af det benyttede materiale, jf. afsnit I, punkt 11. Testene boer udfoeres med et aktivt stof, som har de specifikationer, der skal benyttes ved fabriksfremstillingen af de midler, som skal godkendes, undtagen naar der kraeves eller tillades radioaktivt maerket materiale.

(vii) Where, as a result of metabolism or other processes in or on treated plants, or as a result of processing of treated products, the terminal residue (to which consumers or workers as defined in Annex III, point 7.2.3 will be exposed) contains a substance which is not the active substance itself and is not identified as a metabolite in mammals, it will be necessary to carry out toxicity studies on these components of the terminal residue unless it can be demonstrated that consumer or worker exposure to these substances does not constitute a relevant risk to health. Toxicokinetic and metabolism studies relating to metabolites and degradation products should only be conducted if toxicity findings of the metabolite cannot be evaluated by the available results relating to the active substance.

iv) Naar der foretages test med brug af et aktivt stof fremstillet paa laboratoriet eller i et pilotanlaegsproduktionssystem, skal testene gentages med brug af det aktive stof som fremstillet paa fabrik, medmindre det kan begrundes, at det benyttede testmateriale i det vaesentlige er det samme med henblik paa toksikologisk afproevning og vurdering. Hvis der hersker usikkerhed, skal der indgives relevante »bridging studies«, som kan danne grundlag for en beslutning om det eventuelle behov for gentagelse af testene.

(viii) The way of administration of the test substance depends on the main exposure routes. In cases where exposure is mainly by the gas phase, it can be more appropriate to perform inhalation studies instead of oral studies.

v) Ved test, hvor doseringen straekker sig over en periode, foretages doseringen helst med en og samme batch af det aktive stof, hvis dets stabilitet tillader det.

5.1. Studies on absorption, distribution, excretion and metabolism in mammals

vi) Der skal for alle test rapporteres den faktisk opnaaede dosis i mg/kg legemsvaegt saavel som i andre bekvemme enheder. Hvis doseringen sker via foderet, skal testforbindelsen fordeles jaevnt i foderet.

Quite limited data, as described below and restricted to one test species (normally the rat) may be all that is required in this area. These data can provide information useful in the design and interpretation of subsequent toxicity tests. However, it must be remembered that information on interspecies differences may be crucial in extrapolation of animal data to man and information on percutaneous penetration, absorption, distribution, excretion and metabolism may be useful in operator risk assessments. It is not possible to specify detailed data requirements in all areas, since the exact requirements will be dependant upon the results obtained for each particular test substance.

vii) Hvis restkoncentrationen (som forbrugere eller arbejdere, jf. punkt 7.2.3 i bilag III, vil blive eksponeret for) som resultat af metabolisme eller andre processer i eller paa behandlede planter eller som resultat af forarbejdning af behandlede produkter indeholder et stof, der ikke er selve det aktive stof og ikke er identificeret som en metabolit hos pattedyr, vil det vaere noedvendigt at udfoere toksicitetstest paa disse bestanddele af restkoncentrationen, medmindre det kan paavises, at forbruger- eller arbejdereksponering for disse stoffer ikke udgoer en relevant sundhedsrisiko. Toksikokinetiske test og metabolismetest vedroerende metabolitter og nedbrydningsprodukter boer kun foretages, hvis metabolittens toksicitet ikke kan vurderes ud fra de foreliggende resultater vedroerende det aktive stof.

Aim of the test:

viii) Det afhaenger af de vigtigste eksponeringsveje, hvorledes teststoffet skal administreres. I tilfaelde, hvor eksponeringen vaesentligst sker i gasfasen, kan det vaere mere hensigtsmaessigt at foretage inhalationstest end orale test.

The tests should provide sufficient data to permit:

5.1. Test af absorption, distribution, udskillelse og metabolisme hos pattedyr

- an evaluation of the rate and extent of absorption,

Eventuelt kan ganske faa data som beskrevet nedenfor og begraenset til en enkelt testart (normalt rotten) vaere alt, hvad der kraeves paa dette felt. Saadanne data kan vaere nyttige for senere toksicitetstests design og fortolkning. Det maa imidlertid erindres, at oplysninger om forskelle arterne imellem kan vaere af afgoerende betydning ved ekstrapolering af data fra dyr til mennesker, og oplysninger om optagelse gennem huden, absorption, distribution, udskillelse og metabolisme kan vaere nyttige til vurdering af sproejtefoererrisiko. Det er ikke muligt at angive detaljerede databehov paa alle felter, da de eksakte krav vil afhaenge af de resultater, der er opnaaet for hvert enkelt teststof.

- the tissue distribution and the rate and extent of excretion of the test substance and the relevant metabolites,

Testens formaal

- the identification of metabolites and the metabolic pathway.

Testene skal give tilstraekkelige data til at muliggoere:

The effect of dose level on these parameters and whether results are different after single versus repeated doses, should also be investigated.

- en vurdering af hastigheden og omfanget af absorption

Circumstances in which required

- en vurdering af fordelingen i vaevet samt hastigheden og omfanget af udskillelse af teststoffet og de relevante metabolitter

A single dose toxicokinetic study in rats (oral route of administration) in at least two dose levels as well as a repeated dose toxicokinetic study in rats (oral route of administration) at a single dose level, must be conducted and reported. It may be necessary in some cases to perform additional studies on another species (such as goat or chicken).

- identificering af metabolitterne og den metaboliske reaktionsvej.

Test guideline

Desuden boer man undersoege virkningen af dosisniveauet paa disse parametre, og om resultaterne efter enkeltdoser er anderledes end efter gentagne doser.

Commission Directive 87/302/EEC of 18 November 1987 adapting to technical progress for the ninth time Council Directive 67/548/EEC on the approximation of laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances (1), part B, Toxicokinetics.

Omstaendigheder, hvorunder oplysningerne kraeves

5.2. Acute toxicity

Der skal foretages og rapporteres en toksikokinetisk test med enkeltdosis i rotter (oral indgift) med mindst to dosisniveauer saavel som en toksikokinetisk test med gentagen dosis i rotter (oral indgift) med et enkelt dosisniveau. Det kan i nogle tilfaelde vaere noedvendigt at foretage supplerende test i en anden dyreart (for eksempel ged eller kylling).

The studies, data and information to be provided and evaluated must be sufficient to permit the identification of effects following a single exposure to the active substance, and in particular to establish, or indicate:

Testretningslinjer

- the toxicity of the active substance;

Kommissionens direktiv 87/302/EOEF af 18. november 1987 om niende tilpasning til den tekniske udvikling af Raadets direktiv 67/548/EOEF om tilnaermelse af lovgivning om klassificering, emballering og etikettering af farlige stoffer (1), afsnit B, Toksikokinetik

- the time course and characteristics of the effects with full details of behavioural changes and possible gross pathological findings at post-mortem;

5.2. Akut toksicitet

- where possible mode of toxic action; and

De test, data og oplysninger, der skal meddeles og vurderes, skal vaere tilstraekkelige til, at man kan identificere virkningerne efter en enkelt eksponering for det aktive stof og navnlig at konstatere eller indicere:

- the relative hazard associated with the different routes of exposure.

- det aktive stofs toksicitet

While the emphasis must be on estimating the toxicity ranges involved, the information generated must also permit the active substance to be classified in accordance with Council Directive 67/548/EEC. The information generated through acute toxicity testing is of particular value in assessing hazards likely to arise in accident situations.

- virkingernes tidsforloeb og egenskaber med fuldstaendige detaljer om adfaerdsaendringer og eventuelle makropatologiske obduktionsfund

5.2.1. Oral

- om muligt, den toksiske virkningsmekanisme

Circumtances in which required

- den relative fare i forbindelse med de forskellige eksponeringsveje.

The acute oral toxicity of the active substance must always be reported.

Mens vaegten maa ligge paa at skoenne de involverede toksicitetsintervaller, skal de fremkomme oplysninger ogsaa goere det muligt at klassificere det aktive stof i overensstemmelse med direktiv 67/548/EOEF. De oplysninger, der fremkommer ved test af akut toksicitet, er af ganske saerlig vaerdi for vurdering af de farer, der sandsynligvis kan opstaa i tilfaelde af uheld.

Test guideline

5.2.1. Oral indgift

The test must be carried out in accordance with the Annex to Commission Directive 92/69/EEC of 31 July 1992 adapting to technical progress for the seventeenth time Council Directive 67/548/EEC on the approximation of laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances (2), Method B1 or B1 bis.

Omstaendigheder, hvorunder oplysningerne kraeves

5.2.2. Percutaneous

Det aktive stofs akutte orale toksicitet skal altid rapporteres.

Circumstances in which required

Testretningslinjer

The acute percutaneous toxicity of the active substance must always be reported.

Testen skal udfoeres efter metode B.1 eller B.1 a i bilaget til Kommissionens direktiv 92/69/EOEF af 31. juli 1992 om syttende tilpasning til den tekniske udvikling af Raadets direktiv 67/548/EOEF om tilnaermelse af lovgivning om klassificering, emballering og etikettering af farlige stoffer (2).

Test guideline

5.2.2. Indgift gennem huden

Both local and systemic effects must be investigated. The test must be carried out in accordance with Directive 92/69/EEC method B3.

Omstaendigheder, hvorunder oplysningerne kraeves

5.2.3. Inhalation

Det aktive stofs akutte perkutane toksicitet skal altid rapporteres.

Circumstances in which required

Testretningslinjer

The inhalation toxicity of the active substance must be reported where the active substance is:

Baade lokale og systemiske virkning skal undersoeges. Testen skal udfoeres efter metode B.3 i direktiv 92/69/EOEF.

- a gas or liquified gas,

5.2.3. Inhalation

- is to be used as a fumigant,

Omstaendigheder, hvorunder oplysningerne kraeves

- is to be included in a smoke generating, aerosol or vapour releasing preparation,

Det aktive stofs toksicitet ved inhalation skal rapporteres, hvis det aktive stof:

- is to be used with fogging equipment,

- er en gas eller flydende gas

- has a vapour pressure > 1 × 10-2 Pa and is to be included in preparations to be used in enclosed spaces such as warehouses or glasshouses,

- skal bruges som rygemiddel

- is to be included in preparations which are powders containing a significant proportion of particles of diameter > 50 µm (> 1 % on a weight basis), or

- skal indgaa i et middel, der danner roeg, aerosol eller damp

- is to be included in preparations to be applied in a manner which generates a significant proportion of particles or droplets of diameter < 50µM (> 1 % on a weight basis).

- skal bruges i en taagesproejte

Test guideline

- har et damptryk >1×10-2 Pa og skal indgaa i midler, der anvendes i lukkede rum som lagre eller vaeksthuse

The test must be carried out in accordance with Directive 92/69/EEC Method B2.

- skal indgaa i midler i pulverform med en signifikant andel af partikler med en diameter paa <50 µM (>1 % paa vaegtbasis) eller

5.2.4. Skin irritation

- skal indgaa i midler, der anvendes paa en maade, som giver en signifikant andel af partikler eller draaber med en diameter paa >50 µm (>1 % paa vaegtbasis).

Aim of the test

Testretningslinjer

The test will provide the potential of skin irritancy of the active substance including the potential reversibility of the effects observed.

Testen skal udfoeres efter metode B.2 i direktiv 92/69/EOEF.

Circumstances in which required

5.2.4. Hudirritation

The skin irritancy of the active substance must be determined except where it is likely, as indicated in the test guideline, that severe skin effects may be produced or that effects can be excluded.

Testens formaal

Test guideline

Testen vil vise det aktive stofs evne til at fremkalde hudirritation, herunder den potentielle reversibilitet af de observerede virkninger.

The acute skin irritation must be carried out in accordance with Directive 92/69/EEC Method B4.

Omstaendigheder, hvorunder oplysningerne kraeves

5.2.5. Eye irritation

Det aktive stofs hudirritationsevne skal bestemmes, undtagen naar det som angivet i testretningslinjerne er sandsynligt, at der kan fremkaldes alvorlige virkninger paa huden, eller at virkningerne kan udelukkes.

Aim of test

Testretningslinjer

The test will provide the potential of eye irritancy of the active substance including the potential reversibility of the effects observed.

Testen for akut hudirritation skal udfoeres efter metode B.4 i direktiv 92/69/EOEF.

Circumstances in which required

5.2.5. OEjenirritation

Eye irritation tests must be conducted except where it is likely, as indicated in the test guideline, that severe effects on the eyes may be produced.

Testens formaal

Test guidelines

Testen vil vise det aktive stofs evne til at fremkalde oejenirritation, herunder den potentielle reversibilitet af de observerede virkninger.

The acute eye irritation must be determined in accordance with Directive 92/69/EEC Method B5.

Omstaendigheder, hvorunder oplysningerne kraeves

5.2.6. Skin sensitization

Der skal foretages oejenirritationstest, undtagen hvis det som angivet i testretningslinjerne er sandsynligt, at der kan fremkomme alvorlige virkninger paa oejnene.

Aim of test

Testretningslinjer

The test will provide sufficient information to assess the potential of the active substance to provoke skin sensitization reactions.

Akut oejenirritation skal bestemmes efter metode B.5 i direktiv 92/69/EOEF.

Circumstances in which required

5.2.6. Hudsensibilisering

The test must always be carried out except where the substance is a known sensitizer.

Testens formaal

Test guideline

Testen vil give tilstraekkelige oplysninger til at vurdere det aktive stofs evne til at fremkalde overfoelsomhedsreaktioner paa huden.

The test must be carried out in accordance with Directive 92/69/EEC Method B6.

Omstaendigheder, hvorunder oplysningerne kraeves

5.3. Short-term toxicity

Testen skal altid foretages, medmindre stoffet vides at vaere sensibiliserende.

Short-term toxicity studies must be designed to provide information as to the amount of the active substance that can be tolerated without toxic effects under the conditions of the study. Such studies provide useful data on the risks for those handling and using preparations containing the active substance. In particular, short-term studies provide an essential insight into possible cumulative actions of the active substance and the risks to workers who may be intensively exposed. In addition short-term studies provide information useful in the design of chronic toxicity studies.

Testretningslinjer

The studies, data and information to be provided and evaluated, must be sufficient to permit the identification of effects following repeated exposure to the active substance, and in particular to further establish, or indicate:

Testen skal udfoeres efter metode B.6 i direktiv 92/69/EOEF.

- the relationship between dose and adverse effects,

5.3. Korttidstoksicitet

- toxicity of the active substance including where possible the Noael,

Testdesign for korttidstoksicitetstest skal vaere saaledes, at de giver oplysninger om den maengde aktivt stof, der kan tolereres uden toksiske virkninger under de givne testbetingelser. Saadanne test giver nyttige data om risici for dem, som haandterer og bruger midler, der indeholder det aktive stof. Korttidstest giver navnlig et vigtigt indblik i det aktive stofs eventuelle kumulative virkninger og risikoen for arbejdere, som kan vaere intensivt eksponeret. Desuden giver korttidstest oplysninger, som er nyttige for design af kroniske toksicitetstest.

- target organs, where relevant,

Testene og de data og oplysninger, der skal frembringes og vurderes, skal vaere tilstraekkelige til, at man kan identificere virkningerne efter gentagen eksponering for det aktive stof, og navnlig til senere at konstatere eller indicere:

- the time course and characteristics of poisoning with full details of behavioural changes and possible pathological findings at post-mortem,

- forholdet mellem dosis og uheldige virkninger

- specific toxic effects and pathological changes produced,

- det aktive stofs toksicitet, herunder om muligt NOAEL

- where relevant the persistence and reversibility of certain toxic effects observed, following discontinuation of dosing,

- i relevante tilfaelde maalorganer

- where possible, the mode of toxic action, and

- forgiftningens tidsforloeb og egenskaber med fuldstaendige detaljer om adfaerdsaendringer og eventuelle patologiske obduktionsfund

- the relative hazard associated with the different routes of exposure.

- fremkomne specifikke toksiske virkninger og patologiske forandringer

5.3.1. Oral 28-day study

- i relevante tilfaelde persistensen og reversibiliteten af visse observerede toksiske virkninger efter doseringsophoer

Circumstances in which required

- naar muligt, den toksiske virkningsmekanisme og

Although it is not mandatory to perform 28-day short term studies, they can be useful as range finding tests. Where conducted they must be reported, since the results could be of particular value in the identification of adaptive responses which can be masked in chronic toxicity studies.

- den relative fare i forbindelse med de forskellige eksponeringsveje.

Test guideline

5.3.1. Oral 28-dages test

The test must be carried out in accordance with Directive 92/69/EEC Method B7.

Omstaendigheder, hvorunder oplysningerne kraeves

5.3.2. Oral 90-day study

Selvom der ikke er pligt til at foretage 28-dages korttidstest, kan de vaere nyttige som »range finding tests«. Hvis de bliver foretaget, skal de rapporteres, da resultaterne kunne vaere af saerlig vaerdi for identifikationen af adaptive responser, som kan vaere maskeret i kroniske toksicitetstest.

Circumstances in which required

Testretningslinjer

The short-term oral toxicity (90 day) of the active substance to both rat and dog, must always be reported. Where there is evidence that the dog is significantly more sensitive and where such data are likely to be of value in extrapolating results obtained to man, a 12-month toxicity study in dogs must be conducted and reported.

Testen skal udfoeres efter metode B.7 i direktiv 92/69/EOEF

Test guidelines

5.3.2. Oral 90-dages test

Directive 87/302/EEC, Part B, sub-chronic oral toxicity test.

Omstaendigheder, hvorunder oplysningerne kraeves

5.3.3. Other routes

Det aktive stofs orale korttidstoksicitet (90 dage) i saavel rotte som hund skal altid rapporteres. Hvis der foreligger tegn paa, at hunden er signifikant mere foelsom, og hvis saadanne data sandsynligvis kan vaere af vaerdi for ekstrapolering af de opnaaede resultater til mennesker, skal der foretages og rapporteres en tolv-maaneders toksicitetstest i hunde.

Circumstances in which required

Testretningslinjer

For the assessment of operator exposure additional percutaneous studies may be useful.

Direktiv 87/302/EOEF, afsnit B, subkronisk toksicitet, oral indgift.

For volatile substances (vapour pressure >10-2 Pascal) expert judgment is required to decide whether the short term studies have to be performed by oral or inhalation exposure.

5.3.3. Andre administrationsveje

Test guidelines

Omstaendigheder, hvorunder oplysningerne kraeves

- 28-day dermal: Directive 92/69/EEC Method B9,

Supplerende perkutane test kan vaere nyttige til bedoemmelse af eksponering af sproejtepersonale.

- 90-day dermal: Directive 87/302/EEC, Part B, sub-chronic dermal toxicity study,

For flygtige stoffers vedkommende (damptryk >10-2 Pa) kraeves der ekspertbedoemmelse for at beslutte, om korttidstestene skal foretages ved oral eksponering eller ved inhalation.

- 28-day inhalation: Directive 92/69/EEC Method B8,

Testretningslinjer

- 90-day inhalation: Directive 87/302/EEC, Part B, sub-chronic inhalation toxicity study.

- 28 dage dermal: direktiv 92/69/EOEF, metode B.9

5.4. Genotoxicity testing

- 90 dage dermal: direktiv 87/302/EOEF, afsnit B, subkronisk toksicitet, optagelse gennem huden

Aim of the test

- 28 dage inhalation: direktiv 92/69/EOEF, metode B.8

These studies are of value in:

- 90 dage inhalation: direktiv 87/302/EOEF, afsnit B, subkronisk toksicitet, inhalation

- the prediction of genotoxic potential

5.4. Genotoksicitetstest

- the early identification of genotoxic carcinogens

Testens formaal

- the elucidation of the mechanism of action of some carcinogens

Disse test er af vaerdi for

To avoid responses that are artifacts of the test system, excessively toxic doses must not be used in either in vitro or in vivo assays for mutagenicity. This approach should be regarded as general guidance. It is important that a flexible approach is adopted, with selection of further tests being dependant upon interpretation of results at each stage.

- forudsigelse af genotoksisk potentiale

5.4.1. In vitro studies

- tidlig identificering af genotoksiske kraeftfremkaldende stoffer

Circumstances in which required

- klarlaegning af virkningsmekanismen hos visse kraeftfremkaldende stoffer

In vitro mutagenicity tests (bacterial assay for gene mutation, test for clastogenicity in mammalian cells and test for gene mutation in mammalian cells) must always be performed.

For at undgaa reaktioner, der er artefakter for testsystemet, maa der ikke anvendes alt for toksiske doser i mutagenicitetstest hverken in vitro eller in vivo. Denne fremgangsmaade boer betragtes som en generel retningslinje. Det er vigtigt, at der vedtages en fleksibel fremgangsmaade, hvor valget af yderligere test afhaenger af fortolkningen af resultaterne paa hvert trin.

Test guidelines

5.4.1. In vitro-test

Acceptable test guidelines are:

Omstaendigheder, hvorunder oplysningerne kraeves

Directive 92/69/EEC Method B14 - Salmonella Typhimurium reverse mutation assay

Der skal altid foretages mutagenicitetstest in vitro (bakterieforsoeg for genmutation, clastogenicitetstest i pattedyrsceller og genmutationstest i pattedyrsceller).

Directive 92/69/EEC Method B10 - in vitro mammalian cytogenetic test

Testretningslinjer

Directive 87/302/EEC, Part B - in vitro mammalian cell gene mutation test

Som eksempler paa acceptable test kan naevnes:

5.4.2. In vivo studies in somatic cells

Direktiv 92/69/EOEF, metode B.14 - Salmonella typhimurium tilbagemutationstest

Circumstances in which required

Direktiv 92/69/EOEF, metode B.10 - In vitro cytogenetisk test paa pattedyrsceller

If all the results of the in vitro studies are negative further resting must be done with consideration of other relevant information available (including toxicokinetic, toxicodynamic and physico-chemical data and data on analogous substances). The test can be an in vivo study or an in vitro study using a different metabolizing system from that/those previously used.

Direktiv 87/302/EOEF, afsnit B - Genmutationstest - pattedyrsceller in vitro

If the in vitro cytogenetic test is positive, an in vivo test using somatic cells (metaphase analysis in rodent bone marrow or micronucleus test in rodents) must be conducted.

5.4.2. In vivo-test i somatiske celler

If either of the in vitro gene mutation tests are positive, an in vivo test to investigate unscheduled DNA synthesis or a mouse spot test must be conducted.

Omstaendigheder, hvorunder oplysningerne kraeves

Test guidelines

Hvis samtlige resultater af test in vitro er negative, skal der foretages yderligere test under hensyntagen til anden tilgaengelig relevant information (inklusiv toksikokinetiske - toksikodynamiske - og fysisk-kemiske data og data om analoge stoffer). Testen kan vaere en in vivo-test eller en in vitro-test med benyttelse af et anderledes metaboliseringssystem end det/dem, der tidligere er benyttet.

Acceptable test guidelines are:

Hvis den cytogenetiske test in vitro er positiv, skal der foretages en test in vivo med brug af somatiske celler (metafaseanalyse i gnaverknoglemarv eller mikrokernetest i gnavere).

Directive 92/69/EEC Method B12 - Micronucleus test,

Hvis den ene af genmutationstestene in vitro er positiv, skal der foretages en test in vivo for at undersoege unscheduled DNA-syntese eller en musespottest.

Directive 87/302/EEC Part B - Mouse spot test,

Testretningslinjer

Directive 92/69/EEC Method B11 - In vivo Mammalian Bone-Marrow cytogenetic test, Chromosomal analysis.

Som eksempler paa acceptable test kan naevntes:

5.4.3. In vivo studies in germ cells

- Direktiv 92/69/EOEF, metode B.12 - Mikronucleustest

Circumstances in which required

- Direktiv 87/302/EOEF, afsnit B - Spottest - mus

When any result of an in vivo study in somatic cells is positive, in vivo testing for germ cell effects may be justified. The necessity for conducting these tests will have to be considered on a case by case basis, taking into account information regarding toxicokinetics, use and anticipated exposure. Suitable tests would need to examine interaction with DNA (such as the dominant lethal assay), to look at the potential for inherited effects and possibly make a quantitative assessment of heritable effects. It is recognized that in view of their complexity, the use of quantitative studies would require strong justification.

- Direktiv 92/69/EOEF, metode B.11 - In vivo cytogenetisk test paa knoglemarv fra pattedyr - kromosomanalyse

5.5. Long term toxicity and carcinogenicity

5.4.3. In vivo-test i kimceller

Aim of the test

Omstaendigheder, hvorunder oplysningerne kraeves

The long-term studies conducted and reported, taken together with other relevant data and information on the active substance, must be sufficient to permit the identification of effects, following repeated exposure to the active substance, and in particular must be sufficient to:

Hvis resultaterne af en test in vivo i somatiske celler er positive, kan test in vivo for kimcellevirkninger vaere berettigede. Noedvendigheden af at foretage saadanne test maa overvejes i det enkelte tilfaelde ud fra oplysninger om toksikokinetik, brug og forventet eksponering. Passende test ville indebaere, at man undersoeger interaktionen med DNA (for eksempel dominant letal test), betragter potentialet for nedarvede virkninger og om muligt foretager en kvantitativ vurdering af arvelige virkninger. Det anerkendes, at benyttelsen af kvantitative test paa grund af, at de er saa komplekse, vil kraeve staerk begrundelse.

- identify adverse effects resulting from exposure to the active substance,

5.5. Langtidstoksicitet og carcinogenicitet

- identify target organs, where relevant,

Testens formaal

- establish the dose-response relationship,

De langtidstest, der foretages og rapporteres, skal sammen med oevrige relevante data og oplysninger om det aktive stof vaere tilstraekkelige til, at man kan identificere virkningerne efter gentagen eksponering for det aktive stof, og navnlig tilstraekkelige til at

- identify changes in toxic signs and manifestations observed, and

- identificere uheldige virkninger efter eksponering for det aktive stof

- establish the Noael.

- identificere maalorganer, naar dette er relevant

Similarly, the carcinogenicity studies taken together with other relevant data and information on the active substance, must be sufficient to permit the hazards for humans, following repeated exposure to the active substance, to be assessed, and in particular must be sufficient:

- fastslaa forholdet mellem dosis og respons

- to identify carcinogenic effects resulting from exposure to the active substance,

- identificere forandringer i observerede tokiske tegn og manifestationer

- to establish the species and organ specificity of tumours induced,

- fastslaa NOAEL.

- to establish the dose-response relationship, and

Carcinogenicitetstestene skal ligeledes sammen med oevrige relevante data og oplysninger om det aktive stof vaere tilstraekkelige til, at man kan vurdere risici for mennesker efter gentagen eksponering for det aktive stof, og de skal navnlig vaere tilstraekkelige til at

- for non-genotoxic carcinogens, to identify the maximum dose eliciting no adverse effect (threshold dose).

- identificere kraeftfremkaldende virkninger som foelge af eksponering for det aktive stof

Circumstances in which required

- fastslaa arts- og organspecificitet af inducerede tumorer

The long-term toxicity and carcinogenicity of all active substances must be determined. If in exceptional circumstances, it is claimed that such testing is unnecessary, that claim must be fully justified, viz. toxicokinetic data demonstrates that absorption of the active substance does not occur from the gut, through the skin or via the pulmonary system.

- fastslaa forholdet mellem dosis og respons

Test conditions

- for ikke-genotoksiske kraeftfremkaldende stoffers vedkommende identificere den stoerste dosis, der ikke giver uheldig virkning (taerskeldosis).

A long-term oral toxicity and carcinogenicity study (two years) of the active substance must be conducted using the rat as test species; these studies can be combined.

Omstaendigheder, hvorunder oplysningerne kraeves

A carcinogenicity study of the active substance must be conducted using the mouse as test species.

Langtidstoksiciteten og carcinogeniciteten af alle aktive stoffer skal bestemmes. Hvis det i helt saerlige tilfaelde fremfoeres, at saadanne proever er overfloedige, skal en saadan paastand vaere fuldt underbygget, nemlig at toksikokinetiske data viser, at det aktive stof ikke absorberes fra tarmen, gennem huden eller via lungesystemet.

Where a non-genotoxic mechanism for carcinogenicity is suggested, a well argued case, supported with relevant experimental data, including that necessary to elucidate the possible mechanism involved, must be provided.

Testbetingelser

While the standard reference points for treatment responses are concurrent control data, historical control data, may be helpful in the interpretation of particular carcinogenicity studies. Where submitted, historical control data should be from the same species and strain, maintained under similar conditions and should be from contemporaneous studies. The information on historical control data provided must include:

En oral langtidstoksicitetstest og carcinogenicitetstest (to aar) af det aktive stof skal foretages med rotten som testart; testene kan kombineres.

- identification of species and strain, name of the supplier, and specific colony identification, if the supplier has more than one geographical location,

Der skal foretages en carcinogenicitetstest af det aktive stof med musen som testart.

- name of the laboratory and the dates when the study was performed,

Hvis der foreslaas en ikke-genotoksisk mekanisme for carcinogenicitet, skal der forelaegges en velargumenteret sag med relevante forsoegsdata, herunder saadanne som er noedvendige for at belyse den eventuelt involverede mekanisme.

- description of the general conditions under which animals were maintained, including the type or brand of diet and, where possible, the amount consumed,

Mens standardreferencepunkterne for behandlingsreaktioner er sideloebende kontroldata, kan historiske kontroldata vaere til hjaelp ved fortolkningen af visse carcinogenicitetstest. Naar der meddeles historiske kontroldata, boer de vaere fra samme art og stamme, der er holdt under samme betingelser, og de skal komme fra samtidige test. Oplysningerne om historiske kontroldata skal omfatte:

- approximate age, in days, of the control animals at the beginning of the study and at the time of killing or death,

- identifikation af art og stamme, leverandoerens navn og specifik koloniidentifikation, hvis leverandoeren har mere end en geografisk lokalisering

- description of the control group mortality pattern observed during or at the end of the study, and other pertinent observations (e.g. diseases, infections),

- laboratoriets navn og de datoer, hvor testen blev udfoert

- name of the laboratory and the examining scientists responsible for gathering and interpreting the pathological data from the study, and

- herunder fodertype eller -maerke og om muligt den indtagne maengde

- a statement of the nature of the tumours that may have been combined to produce any of the incidence data.

- kontroldyrenes omtrentlige alder (i doegn) ved testens paabegyndelse og paa aflivnings- eller doedstidspunktet

The doses tested, including the highest dose tested, must be selected on the basis of the results of short-term testing and where available at the time of planning the studies concerned, on the basis of metabolism and toxicokinetic data. The highest dose level in the carcinogenicity study should elicit signs of minimal toxicity such as slight depression in body-weight gain (less than 10 %), without causing tissue necrosis or metabolic saturation and without substantially altering normal lifespan due to effects other than tumours. If the long-term toxicity study is carried out separately, the highest dose level should elicit definite signs of toxicity without causing excessive lethality. Higher doses, causing excessive toxicity are not considered relevant to evaluations to be made.

- beskrivelse af mortalitetsmoenstret som observeret i kontrolgruppen i loebet af eller ved afslutningen af testen samt andre relevante observationer (for eksempel sygdomme, infektioner)

In the collection of data and compilation of reports, incidence of benign and malignant tumours must not be combined, unless there is clear evidence of benign tumours becoming malignant with time. Similarly, dissimilar, un-associated tumours, whether benign or malignant, occurring in the same organ, must not be combined, for reporting purposes. In the interests of avoiding confusion, terminology such as that developed by American Society of Toxicologic Pathologists (3), or the Hannover Tumour Registry (RENI) should be used in the nomenclature and reporting of tumours. The system used must be identified.

- laboratoriets navn og navn paa de videnskabsmaend, der udfoerer testen og er ansvarlige for at indsamle og fortolke de patologiske data fra testen

It is essential that biological material selected for histopathological examination includes material selected to provide further information on lesions identified during gross pathological examination. Where relevant to the elucidation of mechanism of action and available, special histological (staining) techniques, histochemical techniques and electron microscopic examinations, must be conducted and reported.

- en redegoerelse for arten af tumorer, der kan have vaeret kombineret for at give incidensdataene.

Test guideline

De testede doser, herunder den stoerste dosis, der testes, skal udvaelges paa grundlag af resultaterne af korttidstest og paa grundlag af dataene om metabolisme og toksikokinetisk, hvis saadanne data foreligger paa tidspunktet for planlaegning af de paagaeldende test. Det hoejeste dosisniveau i carcinogenicitetstesten boer vise tegn paa minimumstoksicitet som for eksempel en mindre svaekkelse af kropstilvaeksten (under 10 %) uden at foraarsage vaevsnekrose eller metabolisk maetning og uden at aendre livslaengden vaesentligt paa grund af andre virkninger end tumorer. Hvis langtidstoksicitetstesten foretages separat, boer det hoejeste dosisniveau vise definitive tegn paa toksicitet uden at foraarsage overdreven letalitet. Stoerre doser, der foraarsager overdreven toksicitet, betragtes ikke som relevante for de vurderinger, der skal foretages.

The studies must be carried out in accordance with Directive 87/302/EEC, part B, Chronic toxicity test, Carcinogenicity test or combined chronic toxicity/carcinogenicity test.

Ved indsamling af data og kompilering af rapporter maa forekomsten af godartede og ondartede tumorer ikke kombineres, medmindre der foreligger klart bevis for, at godartede tumorer med tiden bliver ondartede. Forskelligartede tumorer uden forbindelse, hvad enten de er godartede eller ondartede, som forekommer i samme organ, maa heller ikke kombineres med henblik paa rapportering. For at undgaa forvirring boer der benyttes terminologi som den, der er udviklet af American Society of Toxicologic Pathologists (3) eller Hannover Tumour Registry (RENI), i nomenklaturen for og rapporteringen af tumorer. Det skal oplyses, hvilket system der er benyttet.

5.6. Reproductive toxicity

Det er vaesentligt, at biologisk materiale udvalgt til histopatologisk undersoegelse omfatter materiale, der er udvalgt for at give yderligere oplysninger om laesioner, der er konstateret under den makropatologiske test. Hvis det er noedvendigt (og muligt) for at belyse virkningsmekanismen, skal der foretages og rapporteres specielle histologiske (farvnings-)metoder, histokemiske metoder og elektromikroskopiske undersoegelser.

Adverse reproductive effects are of two main types:

Testretningslinjer

- impairment of male or female fertility, and

Testene skal udfoeres efter direktiv 87/302/EOEF, afsnit B, kronisk toksicitetstest, carcinogenicitetstest eller kombineret kronisk toksicitets-/carcinogenicitetstest.

- impacts on the normal development of progeny (developmental toxicity).

5.6. Reproduktionstoksicitet

Possible effects on all aspects of reproductive physiology in both males and females, as well as possible effects on pre-natal and post-natal development, must be investigated and reported. If in exceptional circumstances, it is claimed that such testing is unnecessary, that claim must be fully justified.

De uheldige reproduktionsvirkninger falder i to hovedtyper:

While the standard reference point for treatment responses are concurrent control data, historical control data may be helpful in the interpretation of particular reproductive studies. Where submitted, historical control data should be from the same species and strain, maintained under similar conditions and should be from contemporaneous studies. The information on historical control data provided must include:

- forringelse af hanfertilitet eller hunfertilitet og

- identification of species and strain, name of the supplier, and specific colony identification, if the supplier has more than one geographical location,

- indvirkning paa afkommets normale udvikling (udviklingstoksicitet).

- name of the laboratory and the dates when the study was performed,

Eventuelle virkninger paa alle aspekter af reproduktionsfysiologien hos baade handyr og hundyr saavel som eventuelle virkninger paa udviklingen foer og efter foedslen skal undersoeges og rapporteres. Hvis det i helt saerlige tilfaelde fremfoeres, at en saadan test er overfloedig, skal paastanden vaere fuldt underbygget.

- description of the general conditions under which animals were maintained, including the type or brand of diet and, where possible, the amount consumed,

Mens standardreferencepunkterne for behandlingsreaktioner er sideloebende kontroldata, kan historiske kontroldata vaere til hjaelp ved fortolkningen af visse reproduktionstest. Naar der meddeles historiske kontroldata, boer de vaere fra samme art og stamme, som er holdt under samme betingelser, og de skal komme fra samtidige test. Oplysningerne om historiske kontroldata skal omfatte:

- approximate age, in days, of the control animals at the beginning of the study and at the time of killing or death,

- identifikation af art og stamme, leverandoerens navn og specifik koloniidentifikation, hvis leverandoeren her mere end en geografisk lokalisering

- description of the control group mortality pattern observed during or at the end of the study, and other pertinent observations (e.g. diseases, infections), and

- laboratoriets navn og de datoer, hvor testen blev udfoert

- name of the laboratory and the examining scientist responsible for gathering and interpreting the toxicological data from the study.

- beskrivelse af de generelle betingelser, som dyrene blev holdt paa, herunder fodertype eller -maerke og om muligt den indtagne maengde

5.6.1. Multi-generation studies

- kontroldyrenes omtrentlige alder (i doegn) ved testens paabegyndelse og paa aflivnings- eller doedstidspunktet

Aim of the test

- beskrivelse af mortalitetsmoenstret som observeret i kontrolgruppen i loebet af eller ved afslutningen af testen samt andre relevante observationer (for eksempel sygdomme, infektioner)

The studies reported, taken together with other relevant data and information on the active substance, must be sufficient to permit the identification of effects for reproduction, following repeated exposure to the active substance, and in particular must be sufficient:

- laboratoriets navn og navnet paa den videnskabsmand, der udfoerer testen og er ansvarlig for at indsamle og fortolke de toksikologiske data fra testen.

- to identify direct and indirect effects on reproduction resulting from exposure to the active substance,

5.6.1. Flergenerationstest

- to identify any enhancement of general toxic effects (noted during short-term and chronic toxicity testing),

Testens formaal

- to establish the dose-response relationship, to identify changes in toxic signs and manifestations observed, and

De rapporterede test skal sammen med de oevrige relevante data og oplysninger om det aktive stof vaere tilstraekkelige til, at man kan identificere virkningerne paa reproduktionen efter gentagen eksponering for det aktive stof, og de skal navnlig vaere tilstraekkelige til at

- to establish the Noael.

- identificere direkte og indirekte virkninger paa reproduktionen som foelge af eksponering for det aktive stof

Circumstances in which required

- identificere eventuelle oegede generelle toksiske virkninger (bemaerket under korttids- og kronisk toksicitetstest)

A reproduction toxicity study in rats over at least two generations must always be reported.

- fastslaa forholdet mellem dosis og respons

Test guideline

- identificere forandringer i observerede toksiske tegn og manifestationer og

The tests must be carried out in accordance with Directive 87/302/EEC, Part B, two-generation reproduction toxicity test. In addition organ weight of reproductive organs must be reported.

- fastslaa NOAEL.

Supplementary studies

Omstaendigheder, hvorunder oplysningerne kraeves

Where necessary for a better interpretation of the effects on reproduction and as far as this information is not yet available it could be necessary to perform supplementary studies in order to provide the following information:

Der skal altid rapporteres en test for reproduktionstoksicitet i rotter over mindst to generationer.

- separate male and female studies,

Testretningslinjer

- three segment designs,

Testene skal udfoeres efter direktiv 87/302/EOEF, afsnit B, reproduktionstoksicitetsundersoegelse i to generationer. Desuden skal organvaegten af reproduktionsorganerne rapporteres.

- dominant lethal assay for male fertility,

Supplerende test

- cross-matings of treated males with untreated females and vice versa,

Naar det er paakraevet for en bedre fortolkning af virkningerne paa reproduktion, kan det, saafremt saadanne oplysninger endnu ikke foreligger, vaere noedvendigt at foretage supplerende test for at fremskaffe foelgende oplysninger:

- effects on spermatogenesis,

- separate test af hanner og hunner

- effects on oogenesis,

- »three segment designs«

- sperm motility, mobility and morphology, and

- dominant letal test for hanfertilitet

- investigation of hormonal activity.

- krydsning af behandlede handyr med ubehandlede hundyr og omvendt

5.6.2. Developmental toxicity studies

- histopatologisk undersoegelse og organvaegt af reproduktionsorganerne

Aim of the test

- virkning paa spermatogenese

The studies reported, taken together with other relevant data and information on the active substance, must be sufficient to permit effects on embryonic and foetal development, following repeated exposure to the active substance, to be assessed, and in particular must be sufficient:

- virkning paa oogenese

- to identify direct and indirect effects on embryonic and foetal development resulting from exposure to the active substance,

- saedens motilitet, mobilitet og morfologi og

- to identify any maternal toxicity,

- undersoegelse af hormonaktivitet.

- to establish the relationship between observed responses and dose in both dam and offspring,

5.6.2. Udviklingstoksicitetstest

- to identify changes in toxic signs and manifestations observed, and

Testens formaal

- to establish the Noael.

De rapporterede test skal sammen med oevrige relevante data og informationer om det aktive stof vaere tilstraekkelige til, at man kan vurdere virkninger paa embryo- og fosterudvikling efter gentagen eksponering for det aktive stof, og de skal navnlig vaere tilstraekkelige til at

Furthermore, the tests will give additional information on any enhancement of general toxic effects of pregnant animals.

- identificere direkte og indirekte virkninger paa embryo- og fosterudvikling som foelge af eksponering for det aktive stof

Circumstances in which required

- identificere eventuel maternel toksicitet

The tests must always be carried out.

- fastslaa forholdet mellem observerede responser og dosis hos baade moderdyr og afkom

Test conditions

- identificere forandringer i observerede toksiske tegn og manifestationer og

Developmental toxicity must be determined both to rat and rabbit by the oral route. Malformations and variations should be reported separately. A glossary of terminology and diagnostic principles for malformations and variations must be given in the report.

- fastslaa NOAEL.

Test guideline

Testene vil desuden give supplerende oplysninger om eventuel oegning af generelle toksiske virkninger hos draegtige dyr.

The tests must be carried out in accordance with Directive 87/302/EEC, Part B, teratogenicity test - rodent and non-rodent.

Omstaendigheder, hvorunder oplysningerne kraeves

5.7. Delayed neurotoxicity studies

Testene skal altid foretages.

Aim of the test

Testbetingelser

The test shall provide sufficient data to evaluate if the active substance could provoke delayed neurotoxicity after acute exposure.

Udviklingstoksicitet skal bestemmes i baade rotte og kanin ved oral indgift. Misdannelser og variationer boer rapporteres saerskilt. Der skal i rapporten gives et glossar over terminologi og diagnostiske principper for alle misdannelser og variationer.

Circumstances in which required

Testretningslinjer

These studies have to be performed for substances of similar or related structures to those capable of inducing delayed neurotoxicity such as organophosphates.

Testene skal udfoeres efter direktiv 87/302/EOEF, afsnit B, teratogenicitetsundersoegelse i gnavere og ikke-gnavere.

Test guidelines

5.7. Test for forsinket neurotoksicitet

The test must be carried out in accordance with OECD Guideline 418.

Testens formaal

5.8. Other toxicological studies

Testen skal give tilstraekkelige data til at vurdere, om det aktive stof vil kunne fremkalde forsinket neurotoksicitet efter akut eksponering.

5.8.1. Toxicity studies of metabolites as referred to in the introduction point (vii)

Omstaendigheder, hvorunder oplysningerne kraeves

Supplementary studies, where they relate to substances other than the active substance, are not a routine requirement.

Disse test skal foretages for stoffer med lignende eller relaterede strukturer som dem, der kan medfoere forsinket neurotoksicitet, for eksempel organofosfater.

Decisions as to the need for supplementary studies must be made on a case by case basis.

Testretningslinjer

5.8.2. Supplementary studies on the active substance

Testene skal udfoeres efter OECD guideline 418.

In certain cases it can be necessary to carry out supplementary studies to further clarify observed effects. These studies could include:

5.8. Andre toksicitetstests

- studies on absorption, distribution, excretion and metabolism,

5.8.1. Toksicitetstest af metabolitter som omhandlet i indledningens nr. vii)

- studies on the neurotoxic potential,

Supplerende test, der vedroerer andre stoffer end det aktive stof, er ikke et rutinekrav.

- studies on the immunotoxicological potential,

Beslutninger om behovet for supplerende test skal traeffes i det enkelte tilfaelde.

- studies on other routes of administration.

5.8.2. Supplerende test af det aktive stof

Decisions as to the need for supplementary studies must be made on a case by case basis, taking into account the results of the available toxicological and metabolism studies and the most important exposure routes.

Det kan i nogle tilfaelde vaere noedvendigt at foretage supplerende test for bedre at klarlaegge observerede virkninger. Saadanne test kunne omfatte:

Studies required must be designed on an individual basis, in the light of the particular parameters to be investigated and the objectives to be achieved.

- undersoegelser af absorption, distribution, udskillelse og metabolisme

5.9. Medical data

- undersoegelser af det neurotoksiske potentiale

Where available, and without prejudice to the provisions of Article 5 of Council Directive 80/1107/EEC of 27 November 1980 on the protection of workers from the risks related to chemical, physical and biological agents at work (4), practical data and information relevant to the recognition of the symptoms of poisoning, and on the effectiveness of first aid and therapeutic measures have to be submitted. More specific references to the investigation for antidotal pharmacology or safety pharmacology using animals should be provided. Where relevant, the effectiveness of potential antagonists to poisoning, should be investigated and reported.

- undersoegelser af det immunotoksikologiske potentiale

Data and information relevant to the effects of human exposure, where available and of the necessary quality, are of particular value, in confirming the validity of extrapolations made and conclusions reached with respect to target organs, dose-response relationships, and the reversibility of toxic effects. Such data can be generated following accidental or occupational exposure.

- undersoegelser af andre administrationsveje.

5.9.1. Medicinal surveillance on manufacturing plant personnel

Beslutninger om behovet for supplerende test maa traeffes i det enkelte tilfaelde ud fra resultaterne af foreliggende toksicitetstest og metabolismetest samt de vigtigste eksponeringsveje.

Reports of occupational health surveillance programmes, supported with detailed information on the design of the programme, on exposure to the active substance and exposure to other chemicals, must be submitted. Such reports should, where feasible, include data relevant to the mechanism of action of the active substance. These reports shall, where available, include data from persons exposed in manufacturing plants or after application of the active substance (e.g.: in efficacy trials).

Testdesign skal vaere paa individuel basis ud fra de saerlige parametre, der skal undersoeges, og de maal, der skal naas.

Available information on the sensitization including allergenic response of workers and others exposed to the active substance, must be provided, and include where relevant details of any incidence of hypersensitivity. The information provided should include details of frequency, level and duration of exposure, symptoms observed and other relevant clinical information.

5.9. Medicinske data

5.9.2. Direct observation, e.g.: clinical cases and poisoning incidents

Uden at dette beroerer artikel 5 i Raadets direktiv 80/1107/EOEF af 27. november 1980 om beskyttelse af arbejdstagere mod farerne ved at vaere udsat for kemiske, fysiske og biologiske agenser under arbejdet (4), skal der meddeles data og oplysninger fra praksis om genkendelse af forgiftningssymptomerne og effektiviteten af foerstehjaelp og terapeutiske forholdsregler, saafremt saadanne data og oplysninger foreligger. Der boer gives mere specifikke henvisninger til undersoegelsen for antidotfarmakologi eller sikkerhedsfarmakologi med brug af dyr. Naar det er relevant, boer effektiviteten af potentielle antagonister ved forgiftning undersoeges og rapporteres.

Available reports from the open literature, relating to clinical cases and poisoning incidents, where they are from refereed journals or official reports, must be submitted together with reports of any follow-up studies undertaken. Such reports should contain complete descriptions of the nature, level and duration of exposure, as well as the clinical symptoms observed, first aid and therapeutic measures applied and measurements and observations made. Summary and abstract information is not of value.

Data og oplysninger om virkningerne af human eskponering er, naar de foreligger og er af fornoeden kvalitet, af ganske saerlig vaerdi for bekraeftelse af validiteten af foretagne ekstrapoleringer og konklusioner med hensyn til maalorganer, forholdet mellem dosis og respons og reversibiliteten af toksiske virkninger. Saadanne data kan fremskaffes efter eksponering ved uheld eller i en arbejdsmiljoesituation.

Where supported with the necessary level of detail, such documentation can be of particular value in confirming the validity of extrapolations from animal data to man and in identifying unexpected adverse effects which are specific to humans.

5.9.1. Laegetilsyn med personalet paa fabriksanlaeg

5.9.3. Observations on exposure of the general population and epidemiological studies if appropriate

Der skal indgives rapporter over programmer for bedriftssundhedsovervaagning bilagt detaljerede oplysninger om programmets udformning, eksponering for det aktive stof og eksponering for andre kemikalier. Saadanne rapporter boer om muligt omfatte data om det aktive stofs virkningsmekanisme. Rapporterne skal, naar der foreligger saadanne data, omfatte data om personer eksponeret i fabriksanlaeg eller efter anvendelse af det aktive stof (for eksempel i effektivitetsforsoeg).

Where available, and supported with data on levels and duration of exposure, and conducted in accordance with recognized standards (5), epidemiological studies are of particular value and must be submitted.

Foreliggende oplysninger om sensibilisering, herunder allergiske reaktioner hos arbejdere og andre, som eksponeres for det aktive stof, skal meddeles og naar relevant omfatte detaljer om eventuelle tilfaelde af overfoelsomhed. Oplysningerne boer omfatte detaljer om hyppighed, omfang og varighed af eksponering, observerede symptomer og andre relevante kliniske oplysninger.

5.9.4. Diagnosis of poisoning (determination of active substance, metabolites), specific signs of poisoning, clinical tests

5.9.2. Direkte observation, for eksempel kliniske tilfaelde og forgiftningstilfaelde

A detailed description of the clinical signs and symptoms of poisoning, including the early signs and symptoms and full details of clinical tests useful for diagnostic purposes, where available, must be provided and include full details of the time courses involved relevant to the ingestion, dermal exposure or inhalation of varying amounts of the active substance.

Rapporter fra den alment tilgaengelige litteratur om kliniske tilfaelde og forgiftningstilfaelde skal, hvis de kommer fra censurerede tidsskrifter eller officielle rapporter, indgives sammen med rapporter om eventuelle opfoelgningstest. Saadanne rapporter boer indeholde fuldstaendige beskrivelser af eksponeringens art, omfang og varighed samt de observerede kliniske symptomer, foerstehjaelp og terapeutiske foranstaltninger, der er anvendt, samt foretagne maalinger og observationer. Oplysninger i form af resuméer eller abstracts er vaerdiloese.

5.9.5. Proposed treatment: first aid measures, antidotes, medical treatment

Naar saadan dokumentation er stoettet af detaljer i fornoedent omfang, kan den vaere af ganske saerlig vaerdi for beskraeftelse af validiteten af ekstrapoleringer af data fra dyr til mennesker og til identificering af uventede uheldige virkninger, som er specifikke for mennesker.

The first aid measures to be used in the event of poisoning (actual and suspected) and in the event of contamination of eyes must be provided.

5.9.3. Observationer af eksponering af befolkningen i almindelighed og epidemiologiske undersoegelser, hvis relevante

Therapeutic regimes for use in the event of poisoning or contamination of eyes, including where available the use of antidotes, must be described in full. Information based on practical experience, where it exists and is available, in other cases on theoretical grounds, as to the effectiveness of alternative treatment regimes, where relevant, must be provided. Contraindications associated with particular regimes, particularly those relating to 'general medical problems' and conditions, must be described.

Hvis der foreligger epidemiologiske undersoegelser, som er underbygget af data om eksponeringens omfang og varighed og udfoert i overensstemmelse med anerkendte normer (5), er de af ganske saerlig vaerdi og skal meddeles.

5.9.6. Expected effects of poisoning

5.9.4. Diagnosticering af forgiftning (bestemmelse af det aktive stof, metabolitter), specifikke forgiftningssymptomer, kliniske test

Where known, the expected effects and the duration of these effects following poisoning must be described and include the impact of:

Der skal gives en detaljeret beskrivelse af de kliniske tegn og symptomer paa forgiftning, herunder de tidlige tegn og symptomer, samt - hvis de foreligger - fuldstaendige detaljer om kliniske test, som er nyttige til diagnosticeringsformaal, og materialet skal omfatte fuldstaendige detaljer om de involverede tidsforloeb med hensyn til indtagelse, hudeksponering eller indaanding af forskellige maengder af det aktive stof.

- the type, level and duration of exposure, or ingestion, and

5.9.5. Forslag til behandling: foerstehjaelp, antidot, laegebehandling

- varying time periods between exposure, or ingestion, and commencement of treatment.

De foranstaltninger til foerstehjaelp, der skal anvendes i tilfaelde af forgiftning (faktisk eller mistaenkt) og i tilfaelde af forurening af oejnene, skal anfoeres.

5.10. Summary of mammalian toxicity and overall evaluation

Terapeutiske foranstaltninger, der skal anvendes i tilfaelde af forgiftning eller forurening af oejnene, herunder brug af antidot, naar der er adgang hertil, skal beskrives noeje. Oplysninger baseret paa praktiske erfaringer, naar saadanne findes og er tilgaengelige, og ellers paa teoretisk grundlag om effektiviteten af alternative behandlinger skal naar relevant angives. Kontraindikationer i forbindelse med bestemte behandlinger, navnlig saadanne som vedroerer generelle helbredsproblemer og betingelser, skal beskrives.

A summary of all data and information provided under paragraphs 5.1 through 5.10, must be submitted, and include a detailed and critical assessment of those data in the context of relevant evaluative and decision making criteria and guidelines, with particular reference to the risks for man and animals that may or do arise, and the extent, quality and reliability of the data base.

5.9.6. Forventede virkninger af forgiftning

Where relevant, in the light of findings with respect to the analytical profile of batches of the active substance (paragraph 1.11) and any bridging studies conducted (paragraphs 5 (iv)), the relevance of the data as submitted to the assessment of the toxicological profile of the active substance as manufactured, must be argued.

De forventede virkninger og varigheden af saadanne virkninger efter forgiftning skal, hvis de er kendt, beskrives og omfatte betydningen af:

On the basis of an assessment of the data base, and the relevant decision making criteria and guidelines, justifications must be submitted for the Noaels proposed for each relevant study.

- eksponeringens eller indtagelsens art, omfang og varighed og

On the basis of these data scientifically reasoned proposals for the establishment of ADI and AOEL(s) for the active substance must be submitted.'

- forskellige tidsperioder mellem eksponering eller indtagelse og paabegyndelsen af behandling.

5.10. Resumé af pattedyrstoksicitet og generel vurdering

(1) OJ No L 133, 30. 5. 1988, p. 1.(2) OJ No L 383A, 29. 12. 1992, p. 1.(3) Standardized System of Nomenclature and Diagnostic Criteria - Guides for Toxicologic Pathology(4) OJ No L 327, 3. 12. 1980, p. 8.(5) Guidelines for Good Epidemiology Practices for Occupational and Environmental Research, developed by the Chemical Manufacturers Association's Epidemiology Task Group, as part of the Epidemiology Resource and Information Centre (ERIC), Pilot Project, 1991

Der skal indgives et resumé over alle data og oplysninger i henhold til punkt 5.1 til 5.10; det skal omfatte en detaljeret, kritisk vurdering af dataene i forbindelse med relevante kriterier for vurdering og beslutningstagning og retningslinjer med saerlig henvisning til risici for mennesker og dyr, der kan eller vil opstaa, samt datagrundlagets omfang, kvalitet og paalidelighed.

Naar det i lyset af resultater med hensyn til den analytiske profil af batcher af det aktive stof (punkt 1.11) og eventuelle »bridging studies« (punkt 5, nr. iv)) er relevant, skal de meddelte datas relevans for vurdering af det fabriksfremstillede aktive stofs toksicitetsprofil diskuteres.

ANNEX II

Ud fra en vurdering af datagrundlaget og de relevante kriterier og retningslinjer for beslutningstagning skal der gives begrundelse for foreslaaede NOAEL('s) for hver relevant test.

'7. TOXICOLOGICAL STUDIES

Der skal paa grundlag af disse data forelaegges videnskabeligt argumenterede forslag til fastsaettelse af ADI og AOEL('s) for det aktive stof.«

For proper evaluation of the toxicity of preparations sufficient information should be available on acute toxicity, irritation and sensitization of the active substance. If possible, additional information on mode of toxic action, toxicological profile and all other known toxicological aspects of the active substance should be submitted.

In the context of the influence that impurities and other components can have on toxicological behaviour, it is essential that for each study submitted, a detailed description (specification) of the material used, be provided. Tests must be conducted using the plant protection product to be authorized.

(1) EFT nr. L 133 af 30. 5. 1988, s. 1.(2) EFT nr. L 383A af 29. 12. 1992, s. 1.(3) Standardized System of Nomenclature and Diagnostic Criteria - Guides for Toxicologic Pathology(4) EFT nr. L 327 af 3. 12. 1980, s. 8.(5) »Guidelines for Good Epidemiology Practices for Occupational and Environmental Research« udarbejdet af Chemical Manufacturers Association's Epidemiology Task Group som led i pilotprojektet 1991 fra Epidemiology Resource and Information Center (ERIC).

7.1. Acute toxicity

The studies, data and information to be provided and evaluated, must be sufficient to permit the identification of effects following a single exposure to the plant protection product, to be assessed, and in particular to establish, or indicate:

BILAG II

- the toxicity of the plant protection products,

»7. TOKSICITETSTEST

- toxicity of the plant protection product relative to the active substance,

Der boer til korrekt vurdering af midlers toksicitet foreligge tilstraekkelige oplysninger om det indeholdte aktive stofs akutte toksicitet, irritation og sensibilisering. Om muligt boer der meddeles supplerende oplysninger om det aktive stofs toksiske virkningsmekanisme, toksicitetsprofil og alle andre kendte toksikologiske aspekter.

- the time course and characteristics of the effect with full details of behavioural changes and possible gross pathological findings at post-mortem,

Det er i forbindelse med den indflydelse, urenheder og andre bestanddele kan have paa toksikologiske egenskaber, vaesenligt, at der for hver meddelt test gives en detaljeret beskrivelse (specifikation) af det benyttede materiale. Der skal foretages test med brug af det plantebeskyttelsesmiddel, som skal godkendes.

- where possible the mode of toxic action, and

7.1. Akut toksicitet

- the relative hazard associated with the different routes of exposure.

De test, data og oplysninger, der meddeles og vurderes, skal vaere tilstraekkelige til, at man kan identificere virkningerne efter en enkelt eksponering for plantebeskyttelsesmidlet og navnlig til at konstatere eller indicere:

While the emphasis must be on estimating the toxicity ranges involved, the information generated must also permit the plant protection product to be classified in accordance with Council Directive 78/631/EEC. The information generated through acute toxicity testing is of particular value in assessing hazards likely to arise in accident situations.

- plantebeskyttelsesmidlets toksicitet

7.1.1. Oral

- plantebeskyttelsesmidlets toksicitet i forhold til toksiciteten af det aktive stof

Circumstances in which required

- virkningens tidsforloeb og egenskaber med fuldstaendige detaljer om adfaerdsaendringer og eventuelle makropatologiske observationsfund

An acute oral test should always be carried out unless the applicant can justify to the satisfaction of the competent authority that Article 3.2 of Council Directive 78/631/EEC can be invoked.

- om muligt den toksiske virkningsmekanisme og

Test guidelines

- den relevante fare i forbindelse med de forskellige eksponeringsveje.

The test must be carried out in accordance with Directive 92/69/EEC Method B1 or B1 bis.

Mens vaegten maa ligge paa at skoenne de involverede toksicitetsintervaller, skal de frembragte oplysninger ogsaa goere det muligt at klassificere plantebeskyttelsesmidlet i henhold til direktiv 78/631/EOEF. De oplysninger, der fremkommer ved akut toksicitetstest, er af saerlig vaerdi for bedoemmelse af de farer, der sandsynligvis kan opstaa i tilfaelde af uheld.

7.1.2. Percutaneous

7.1.1. Oral indgift

Circumstances in which required

Omstaendigheder, hvorunder oplysningerne kraeves

An acute percutaneous test should always be carried out unless the applicant can justify to the satisfaction of the competent authority that Article 3.2 of Council Directive 78/631/EEC can be invoked.

Der boer altid foretages en akut oral test, medmindre ansoegeren over for den kompetente myndighed kan godtgoere, at artikel 3, stk. 2, i direktiv 78/631/EOEF kan paaberaabes.

Test guideline

Testretningslinjer

The test must be carried out in accordance with Directive 92/69/EEC Method B3.

Testen skal udfoeres efter metode B.1 eller B.1a direktiv 92/69/EOEF.

7.1.3. Inhalation

7.1.2. Indgift gennem huden

Aim of the test

Omstaendigheder, hvorunder oplysningerne kraeves

The test will provide the inhalation toxicity to rats of the plant protection product or of the smoke it generates.

Der boer altid foretages en akut perkutan test, medmindre ansoegeren over for den kompetente myndighed kan godtgoere, at artikel 3, stk. 2, i direktiv 78/631/EOEF kan paaberaabes.

Circumstances in which required

Testretningslinjer

The test must be carried out where the plant protection product:

Testen skal udfoeres efter metode B.3 i direktiv 92/69/EOEF.

- is a gas or liquified gas,

7.1.3. Inhalation

- is a smoke generating formulation or fumigant,

Testens formaal

- is used with fogging equipment,

Testen vil vise toksiciteten for rotter ved indaanding af plantebeskyttelsesmidlet eller af den roeg, det udvikler.

- is a vapour releasing preparation,

Omstaendigheder, hvorunder oplysningerne kraeves

- is an aerosol,

Testen skal foretages, hvis plantebeskyttelsesmidlet:

- is a powder containing a significant proportion of particles of diameter <50 µM (> 1 % on a weight basis),

- er en gas eller flydende gas

- is to be applied from aircraft in cases where inhalation exposure is relevant,

- er en roegudviklende formulering eller et rygemiddel

- contains an active substance with a vapour pressure > 1 × 10-2 Pa and is to be used in enclosed spaces such as warehouses or glasshouses,

- bruges i taagesproejte

- is to be applied in a manner which generates a significant proportion of particles or droplets of diameter <50 µM (> 1 % on a weight basis).

- er et dampudloesende middel

Test guideline

- er en aerosol

The test must be carried out in accordance with Directive 92/69/EEC Method B2.

- er et pulver med en signifikant andel af partikler med en diameter paa >50 µm (>1 % paa vaegtbasis)

7.1.4. Skin irritation

- skal udbringes fra fly i tilfaelde, hvor inhalationseksponering er relevant

Aim of the test

- indeholder et aktivt stof med et damptryk paa >1×10-2 Pa og skal bruges i lukkede rum som lagre eller vaeksthuse

The test will provide the potential of skin irritancy of the plant protection product including the potential reversibility of the effects observed.

- skal anvendes paa en maade, som giver en signifikant andel af partikler eller draaber med en diameter paa <50 µM (>1 % paa vaegtbasis).

Circumstances in which required

Testretningslinjer

The skin irritancy of the plant protection product must be determined except where it is likely, as indicated in the test guideline, that severe skin effects may be produced or that effects can be excluded.

Testen skal udfoeres efter metode B.2 i direktiv 92/69/EOEF.

Test guideline

7.1.4. Hudirritation

The test must be carried out in accordance with Directive 92/69/EEC Method B4.

Testens formaal

7.1.5. Eye irritation

Testen vil vise plantebeskyttelsesmidlets hudirritationsevne, herunder den potentielle reversibilitet af de observerede virkninger.

Aim of the test

Omstaendigheder, hvorunder oplysningerne kraeves

The test will provide the protential for eye irritation of the plant protection product, including the potential reversibility of the effects observed.

Plantebeskyttelsesmidlets hudirritation skal bestemmes, undtagen hvis det som angivet i testretningslinjerne er sandsynligt, at der kan fremkaldes alvorlige hudeffekter, eller at effekter kan udelukkes.

Circumstances in which required

Testretningslinjer

Eye irritation tests must be conducted except where it is likely, as indicated in the test guideline, that severe effects on the eyes may be produced.

Testen skal udfoeres efter metode B.4 i direktiv 92/69/EOEF.

Test guideline

7.1.5. OEjenirritation

The eye irritation must be determined in accordance with Directive 92/69/EEC Method B5.

Testens formaal

7.1.6. Skin sensitization

Testen vil vise plantebeskyttelsesmidlets oejenirritationsevne, herunder den potentielle reversibilitet af de observerede virkninger.

Aim of the test

Omstaendigheder, hvorunder oplysningerne kraeves

The test will provide sufficient information to assess the potential of the plant protection product to provoke skin sensitization reactions.

Der skal foretages oejenirritationstest, undtagen naar det som angivet i testretningslinjerne er sandsynligt, at der vil blive udloest alvorlige virkninger paa oejnene.

Circumstances in which required

Testretningslinjer

The tests must always be carried out except where the active substance(s) or co-formulants are known to have sensitizing properties.

OEjenirritation skal bestemmes efter metode B.5 i direktiv 92/69/EOEF.

Test guideline

7.1.6. Hudsensibilisering

The tests have to be carried out in accordance with Directive 92/69/EEC Method B6.

Testens formaal

7.1.7. Supplementary studies for combinations of plant protection products

Testen vil give tilstraekkelige oplysninger til at vurdere plantebeskyttelsesmidlets evne til at fremkalde overfoelsomhedsreaktioner paa huden.

Aim of the test

Omstaendigheder, hvorunder oplysningerne kraeves

In certain cases it may be necessary to carry out the studies as referred to under points 7.1.1 to 7.1.6 for a combination of plant protection products where the product label includes requirements for use of the plant protection product with other plant protection products and/or with adjuvants as a tank mix. Decisions as to the need for supplementary studies must be made on a case by case basis, taking into account the results of the acute toxicity studies of the individual plant protection products, the possibility for exposure to the combination of the products concerned and available information or practical experience with the products concerned or similar products.

Der skal altid foretages test, undtagen hvis det aktive stof eller hjaelpestofferne vides at have sensibiliserende egenskaber.

7.2. Data on exposure

Testretningslinjer

7.2.1. Operator exposure

Testene skal udfoeres efter metode B.6 i direktiv 92/69/EOEF.

The risks for those using plant protection products depend on the physical, chemical and toxicological properties of the plant protection product as well as the type of the product (undiluted/diluted), and on the route, the degree and duration of exposure. Sufficient information and data must be generated and reported to permit an assessment of the extent of exposure to the active substance(s) and/or toxicologically relevant compounds in the plant protection product likely to occur under the proposed conditions of use. It must also provide a basis for the selection of the appropriate protective measures including personal protective equipment to be used by operators and to be specified on the label.

7.1.7. Supplerende test af kombinationer af plantebeskyttelsesmidler

7.2.1.1. Estimation of operator exposure

Testens formaal

Aim of the estimation

Det kan i nogle tilfaelde vaere noedvendigt at foretage de test, der omhandles i punkt 7.1.1 til 7.1.6, for en kombination af plantebeskyttelsesmidler, hvis deres etiket indeholder krav til brugen af plantebeskyttelsesmidlet sammen med andre plantebeskyttelsesmidler og/eller med adjuvanter som en tankblanding. Det maa i det enkelte tilfaelde besluttes, om der er behov for supplerende test ud fra resultaterne af de akutte toksicitetstest af de enkelte plantebeskyttelsesmidler, muligheden for eksponering for kombinationen af de paagaeldende midler samt foreliggende oplysninger eller praktisk erfaring med de paagaeldende eller lignende midler.

An estimation shall be made, using where available a suitable calculation model, in order to permit an evaluation of the operator exposure likely to arise under the proposed conditions of use.

7.2. Eksponeringsdata

Circumstances in which required

7.2.1. Eksponering af sproejtepersonale

An estimation of operator exposure must always be completed.

Risici for dem, der benytter plantebeskyttelsesmidler, afhaenger af plantebeskyttelsesmidlets fysiske, kemiske og toksikologiske egenskaber saavel som dets type (ufortyndet/fortyndet) og af eksponeringsvejen, -omfanget og -varigheden. Der skal frembringes og rapporteres tilstraekkelige data og oplysninger til, at der kan foretages en vurdering af omfanget af eksponering for det aktive stof (eller stoffer) og/eller for toksikologisk relevante forbindelser i plantebeskyttelsesmidlet, der sandsynligvis vil forekomme under de paataenkte brugsbetingelser. Samtidig skal der skabes grundlag for valg af passende beskyttelsesforanstaltninger, herunder personlige vaernemidler, som sproejtefoerere skal bruge, og som skal specificeres paa etiketten.

Estimation conditions

7.2.1.1. Skoennet eksponering af sproejtepersonale

An estimation shall be made for each type of application method and application equipment proposed for use of the plant protection product taking account of the requirements resulting from the implementation of the classification and labelling provisions of Directive 78/631/EEC for handling the undiluted or diluted product as well as the different types and sizes of containers to be used, mixing, loading operations, application of the plant protection product, the climatic conditions and cleaning and routine maintenance of application equipment.

Skoennets formaal

At first an estimation shall be made with the assumption that the operator is not using any personal protective equipment.

Der skal foretages et skoen, idet der om muligt benyttes en egnet beregningsmodel, for at give en vurdering af den eksponering af sproejtefoereren, der sandsynligvis kan ske under de paataenkte brugsbetingelser.

Where appropriate, a second estimation shall be made with the assumption that the operator is using effective and readily obtainable protective equipment which is feasible to be used by the operator. Where protective measures are specified on the label, the estimation will take these into account.

Omstaendigheder, hvorunder oplysningerne kraeves

7.2.1.2. Measurement of operator exposure

Der skal altid udarbejdes et skoen over eksponering af sproejtepersonale.

Aim of the test

Betingelser for skoen

The test shall provide sufficient data to permit an evaluation of the operator exposure likely to arise under the proposed conditions of use.

Der skal foretages et skoen for hver type udbringningsmetode og udbringningsudstyr, der foreslaas til anvendelse af plantebeskyttelsesmidlet, idet der tages hensyn til de krav, der foelger af gennemfoerelsen af klassificerings- og maerkningsbestemmelserne i direktiv 78/631/EOEF i forbindelse med haandtering af ufortyndede eller fortyndede produkter, samt de forskellige typer og stoerrelser beholdere, der skal bruges, blanding, paafyldningsbetingelser, udbringning af plantebeskyttelsesmidlet, vejrforholdene og hvis relevant rengoering og rutinevedligeholdelse af udbringningsudstyret.

Circumstances in which required

I foerste omgang foretages et skoen ud fra den antagelse, at sproejtefoereren ikke bruger personlige vaernemidler.

Actual exposure data for the relevant exposure route(s) must be reported where the risk assessment indicates that a health-based limit value is exceeded. This will, for example, be the case when the results of the estimation of operator exposure provided for under point 7.2.1.1 indicate that:

Naar relevant, foretages et andet skoen ud fra den antagelse, at sproejtefoereren bruger effektive vaernemidler, som let kan skaffes, og som sproejtefoereren sandsynligvis vil bruge. Hvis der paa etiketten er specificeret beskyttelsesforanstaltninger, skal disse tages i betragtning ved skoennet.

- the Acceptable Operator Exposure Level(s) (AOEL) established in the context of inclusion of the active substance(s) in Annex I, and/or

7.2.1.2. Maaling af eksponering af sproejtepersonale

- the Limit Values established for the active substance and/or toxicologically relevant compound(s) of the plant protection product in accordance with Council Directive 80/1107/EEC and Council Directive 90/394/EEC of 28 June 1990 on the protection of workers from the risks related to exposure to carcinogens at work (1),

Testens formaal

may be exceeded.

Testen skal give tilstraekkelige data til, at man kan vurdere den eksponering af sproejtefoereren, der sandsynligvis vil ske under de paataenkte brugsbetingelser.

Actual exposure data must also be reported when no appropriate calculation model or no appropriate data are available to do the estimation provided for under point 7.2.1.1.

Omstaendigheder, hvorunder oplysningerne kraeves

In cases where dermal exposure is the most important exposure route, a dermal absorption test or the results of a sub-acute dermal study, if not already available, may be a useful alternative test to provide data in order to refine the estimate provided for under point 7.2.1.1.

Der skal rapporteres faktiske data for den relevante eksponeringsvej (eller veje), hvis risikovurderingen indicerer, at en helbredsbaseret graensevaerdi er overskredet. Det vil for eksempel vaere tilfaeldet, hvis resultaterne af skoennet over eksponering af sproejtepersonale, jf. punkt 7.2.1.1, indicerer, at

Test conditions

- den acceptable eksponering af sproejtepersonale (AOEL('s)) fastlagt i forbindelse med optagelse af det aktive stof (eller stoffer) i bilag I kan blive overskrevet og/eller

The test must be done under realistic exposure conditions taking into account the proposed conditions of use.

- de graensevaerdier, der er etableret for det aktive stof og/eller toksikologisk relevante forbindelser i plantebeskyttelsesmidlet, kan blive overskredet, jf. direktiv 80/1107/EOEF om beskyttelse af arbejdstagere mod farerne ved at vaere udsat for kemiske, fysiske og biologiske agenser under arbejdet og Raadets direktiv 90/394/EOEF af 28. juni 1990 om beskyttelse af arbejdstagere mod risici for under arbejdet at vaere udsat for kraeftfremkaldende stoffer (1).

7.2.2. Bystander exposure

Der skal ogsaa rapporteres faktiske eksponeringsdata, hvis der ikke findes nogen passende beregningsmodel eller data til at foretage skoennet som omhandlet i punkt 7.2.1.1.

Bystanders can be exposed during the application of plant protection products. Sufficient information and data must be reported to provide a basis for the selection of appropriate conditions of use, including the exclusion of bystanders from treatment areas and separation distances.

I tilfaelde, hvor hudeksponering er den vigtigste eksponeringsvej, kan en dermal absorptionstest eller resultaterne af en subakut dermal test, hvis saadanne ikke allerede findes, vaere en nyttig alternativ test til at frembringe data, saa skoennet som omhandlet i punkt 7.2.1.1 kan forbedres.

Aim of the estimation

Testbetingelser

An estimation shall be made, using where available a suitable calculation model in order to permit an evaluation of the bystander exposure likely to arise under the proposed conditions of use.

Testen skal foretages under realistiske eksponeringsforhold under iagttagelse af de paataenkte brugsbetingelser.

Circumstances in which required

7.2.2. Eksponering af andre tilstedevaerende

An estimation of bystander exposure must always be completed.

Andre end sproejtepersonale kan blive eksponeret under udbringningen af plantebeskyttelsesmidler. Der skal rapporteres tilstraekkelige data og oplysninger til at danne grundlag for valget af passende brugsbetingelser, herunder udelukkelse af uvedkommende fra arealer under behandling og sikkerhedsafstande.

Estimation conditions

Formaal med skoennet

An estimation of bystander exposure must be made for each type of application method. The estimation shall be made with the assumption that bystanders do not use any personal protective equipment.

Der foretages et skoen, hvor der om muligt benyttes en passende beregningsmodel, saa man kan vurdere den eksponering af andre, der sandsynligvis kan ske under de paataenkte brugsbetingelser.

Measurement of bystander exposure may be required when estimates indicate a cause for concern.

Omstaendigheder, hvorunder oplysningerne kraeves

7.2.3. Worker exposure

Der skal altid udarbejdes et skoen over eksponering af andre tilstedevaerende.

Workers can be exposed following application of plant protection products, when entering treated fields or premises or handling treated plants or plant products on which residues remain. Sufficient information and data must be reported to provide a basis for the selection of appropriate protective measures, including waiting and re-entry periods.

Betingelser for skoen

7.2.3.1. Estimation of worker exposure

Der skal foretages et skoen over eksponering af andre tilstedevaerende for hver type udbringningsmetode. Skoennet skal foretages ud fra den antagelse, at uvedkommende ikke bruger personlige vaernemidler.

Aim of the estimation

Der kan kraeves maalinger af eksponering af andre tilstedevaerene, hvis skoennene indicerer, at der er grund til uro.

An estimation shall be made using where available a suitable calculation model, in order to permit an evaluation of the worker exposure likely to arise under the proposed conditions of use.

7.2.3. Eksponering af arbejdere

Circumstances in which required

Arbejdere kan blive eksponeret efter udbringning af plantebeskyttelsesmidler, naar de gaar ind paa behandlede marker eller i behandlede lokaler eller haandterer behandlede planter eller planteprodukter, som der sidder rester paa. Der skal rapporteres tilstraekkelige data og oplysninger til at danne grundlag for valget af passende beskyttelsesforanstaltninger, herunder vente- og re-entryperioder.

The estimation of worker exposure must always be completed.

7.2.3.1. Skoen over eksponering af arbejdere

Estimation conditions

Formaal med skoennet

An estimation of worker exposure must be made for each crop and task to be carried out.

Der foretages et skoen, hvor der om muligt benyttes en passende beregningsmodel, saa man kan vurdere den eksponering af arbejdere, der sandsynligvis kan ske under de paataenkte brugsbetingelser.

At first the estimation shall be made using available data on the exposure to be expected with the assumption that the worker is not using any personal protective equipment.

Omstaendigheder, hvorunder oplysningerne kraeves

Where appropriate, a second estimation shall be made with the assumption that the worker is using effective and readily obtainable protective equipment which is feasible to be used.

Der skal altid udarbejdes et skoen over eksponering af arbejdere.

Where appropriate, a further estimation shall be made using data generated on the amount of dislodgeable residues under the proposed conditions of use.

Betingelser for skoennet

7.2.3.2. Measurement of worker exposure

Der foretages et skoen over eksponering af arbejdere for hver afgroede og for hver opgave, der skal udfoeres.

Aim of the test

I foerste omgang foretages et skoen ved brug af foreliggende data om forventet eksponering ud fra den antagelse, at arbejderen ikke bruger personlige vaernemidler.

The test shall provide sufficient data to permit an evaluation of the worker exposure likely to arise under the proposed conditions of use.

Naar relevant, foretages et andet skoen ud fra den antagelse, at arbejderen bruger effektive vaernemidler, som let kan skaffes, og som er mulige at bruge under de givne betingelser.

Circumstances in which required

Naar relevant, foretages endnu et skoen ved brug af fremkomne data om maengden af »dislodgeable« rester under de foreslaaede brugsbetingelser.

Actual exposure data for the relevant exposure route(s) must be reported where the risk assessment indicates that a health-based limit value is exceeded. This will, for example, be the case where the results of the estimation of worker exposure provided for under point 7.2.3.1 indicate that:

7.2.3.2. Maaling af eksponering af arbejdere

- the AOEL(s) established in the context of inclusion of the active substance(s) in Annex I,

Testens formaal

and/or

Testen skal give tilstraekkelige data til, at man kan vurdere den eksponering af arbejdere, der sandsynligvis vil ske under de paataenkte brugsbetingelser

- the Limit Values established for the active substance and/or toxicologically relevant compound(s) of the plant protection product in accordance with Council Directives 80/1107/EEC and 90/394/EEC,

Omstaendigheder, hvorunder oplysningerne kraeves

may be exceeded.

Der skal rapporteres faktiske data for den relevante eksponeringsvej (eller veje), hvis risikovurderingen indicerer, at en helbredsbaseret graensevaerdi er overskredet. Det vil for eksempel vaere tilfaeldet, hvis resultaterne af skoennet over eksponering af arbejdere, jf. punkt 7.2.3.1, indicerer, at

Actual exposure data must also be reported when no appropriate calculation model or no appropriate data are available to do the estimation provided for under point 7.2.3.1.

- den AOEL (eller AOEL's), der er fastlagt i forbindelse med optagelse af det aktive stof (eller stoffer) i bilag I, kan blive overskredet og/eller

Where dermal exposure is the most important exposure route, a dermal absorption test, if not already available, may be a useful alternative test to provide data in order to refine the estimate provided for under point 7.1.3.1.

- de graensevaerdier, der er etableret for det aktive stof og/eller toksikologisk relevante forbindelser i plantebeskyttelsesmidlet, kan blive overskredet, jf. direktiv 80/1107/EOEF og direktiv 90/394/EOEF.

Test conditions

Der skal ogsaa rapporteres faktiske eksponeringsdata, hvis der ikke findes nogen passende beregningsmodel eller data til at foretage skoennet som omhandlet i punkt 7.2.3.1.

The test must be done under realistic exposure conditions taking into account the proposed conditions of use.

I tilfaelde, hvor hudeksponering er den vigtigste eksponeringsvej, kan en dermal absorptionstest, hvis en saadan ikke allerede findes, vaere en nyttig alterantiv test til at frembringe data, saa skoennet som omhandlet i punkt 7.2.3.1 kan forbedres.

7.3. Dermal absorption

Testbetingelser

Aim of the test

Testen skal foretages under realistiske eksponeringsforhold under iagttagelse af de paataenkte brugsbetingelser.

The test shall provide a measurement of the absorption of the active substance and toxicologically relevant compounds through the skin.

7.3. Optagelse gennem huden

Circumstances in which required

Testen skal give en maaling af absorptionen af det aktive stof og toksikologisk relevante forbindelser gennem huden.

The study must be conducted when dermal exposure is a significant exposure route and where the risk assessment indicates that a health-based limit value is exceeded. This will, for example, be the case where the results of the estimation or measurement of operator exposure provided for under points 7.2.1.1 or 7.2.1.2 indicate that:

Omstaendigheder, hvorunder oplysningerne kraeves

- the AOEL(s) established in the context of inclusion of the active substance(s) in Annex I,

Testen skal foretages, naar dermal eksponering er en signifikant eksponeringsvej, og hvis risikovurderingen indicerer, at en helbredsbaseret graensevaerdi er overskredet. Det vil for eksempel vaere tilfaeldet, hvis resultaterne af skoennet over eller maalingen af eksponering af sproejtepersonale, jf. punkt 7.2.1.1 eller 7.2.1.2, indicerer, at:

and/or

- den AOEL (eller AOEL's), der er fastlagt i forbindelse med optagelse af det aktive stof (eller stoffer) i bilag I kan blive overskredet og/eller

- the limit values established for the active substance and/or toxicologically relevant compound(s) of the plant protection product in accordance with Council Directives 80/1107/EEC and 90/394/EEC may be exceeded.

- de graensevaerdier, der er etableret for det aktive stof og/eller toksikologisk relevante forbindelser i plantebeskyttelsesmidlet, kan blive overskredet, jf. direktiv 80/1107/EOEF og direktiv 90/394/EOEF.

Test conditions

Testbetingelser

In principle data of an in vivo rat skin absorption study must be reported. If, when the results of the estimation using these in vivo skin absorption data are incorporated in the risk assessment, there remains an indication of excessive exposure, it may be necessary to perform an in vivo comparative absorption study on rat and human skin.

Principielt skal data fra en absorptionstest in vivo paa rottehud rapporteres. Hvis der, naar resultaterne af skoennene ved benyttelse af disse data fra absorptionstest in vivo indgaar i risikovurderingen, foreligger tegn paa for hoej eksponering, kan det vaere noedvendigt at foretage sammenlignende absorptionstest in vitro paa rottehud og menneskehud.

Test guideline

Testretningslinjer

Appropriate elements of OECD guideline 417 are to be used. For the design of the studies it may be necessary to take into account the results of the skin absorption studies with the active substance(s).

De relevante afsnit i OECD guideline 417 skal benyttes. Det kan til udarbejdelse af testdesign vaere noedvendigt at tage hensyn til resultaterne af hudabsorptionstestene med det aktive stof (eller stoffer).

7.4. Available toxicological data relating to non-active substances

7.4. Foreliggende toksikologiske data i forbindelse med ikke-aktive stoffer

Where available, a copy of the notification and the safety data sheet submitted in the context of Directive 67/548/EEC and Commission Directive 91/155/EEC of 5 March 1991 defining and laying down the detailed arrangements for the system of specific information relating to dangerous preparations in implementation of Article 10 of Council Directive 88/379/EEC (2) must be submitted for each formulant. All other available information should be submitted.'

Om muligt skal der for hvert hjaelpestof indgives en kopi af anmeldelsen og sikkerhedsdatabladet, som er indsendt i henhold til direktiv 67/548/EOEF og Kommissionens direktiv 91/155/EOEF af 5. marts 1991 om fastsaettelse i henhold til artikel 10 i Raadets direktiv 89/379/EOEF af de naermere bestemmelser for en saerlig informationsordning vedroerende farlige praeparater (2). Alle andre tilgaengelige oplysninger boer meddeles.

(1) OJ No L 196, 26. 7. 1990, p. 1.(2) OJ No L 76, 22. 3. 1991, p. 35.

(1) EFT nr. L 196 af 26. 7. 1990, s. 1.(2) EFT nr. L 76 af 22. 3. 1991, s. 35.«