Commission Directive 2001/36/EC of 16 May 2001 amending Council Directive 91/414/EEC concerning the placing of plant protection products on the market (Text with EEA relevance)
Date: 2001-05-16
Institutions: European Commission
Subjects: exchange of information, marketing standard, microorganism, pharmaceutical product, plant health product

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I

(Acts whose publication is obligatory)

COMMISSION DIRECTIVE 2001/36/EC

of 16 May 2001

amending Council Directive 91/414/EEC concerning the placing of plant protection products on
the market

(Text with EEA relevance)

THE COMMISSION OF THE EUROPEAN COMMUNITIES,

(4)

Having regard to the Treaty establishing the European
Community,

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 Commission Directive
2001/28/EC (2), and in particular Article 18(2) thereof,

Whereas:

Annexes IIB and IIIB to Directive 91/414/EEC set out
the requirements for the dossier to be submitted by an
applicant respectively for the inclusion of an active
substance consisting of micro-organisms or viruses in
Annex I to that Directive and for the authorisation of a
plant protection product based on preparations of
micro-organisms or viruses.

information,

It is necessary to indicate, in Annexes IIB and IIIB to
applicants, as precisely as possible, any details on the
required
circumstances,
conditions and technical protocols, under which certain
data have to be generated; these provisions should be
introduced as soon as available in order to permit
applicants to use them in preparation of their dossiers.

such as

the

(1)

(2)

(3)

is now possible to introduce more precision with
It
regard to the data requirements as experience was
gained during the evaluation of several new active
substances consisting of micro-organisms. In particular
the areas of occupational health, consumer exposure,
environmental risk have been subject to major changes.

(5)

The Scientific Committee on Plants provided an opinion
which dealt with the principles associated with the use
of micro-organisms as plant protection products and the
Committee provided comments on an early draft of the
data requirements. The recommendations made by the
Committee in the opinion (3),
including the proposed
amendments to the text of the draft data requirements
were taken into account by the Commission.

(6)

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

HAS ADOPTED THIS DIRECTIVE:

Article 1

Annex II to Directive 91/414/EEC shall be amended as set out
in Annex I to this Directive.

Article 2

Annex III to Directive 91/414/EEC shall be amended as set out
in Annex II to this Directive.

It is appropriate to differentiate data requirements for
chemical
in some
substances and micro-organisms
respects, as several requirements, e.g. on some issues
concerning fate and behaviour in the environment and
residues, are specific to chemicals while others, such as
those on infectiveness, are specific to micro-organisms.

Article 3

Member States shall bring into force the laws, regulations and
administrative provisions necessary to comply with this
Directive by 1 May 2002 at the latest. They shall forthwith
inform the Commission thereof.

(1) OJ L 230, 19.8.1991, p. 1.
(2) OJ L 113, 24.4.2001, p. 5.

(3) Scientific Committee on Plants SCP/MICR/006 final.

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those provisions,

When Member States adopt
they shall
contain a reference to this Directive or be accompanied by
such a reference on the occasion of their official publication.
Member States shall determine how such reference is to be
made.

Article 5

This Directive is addressed to the Member States.

Done at Brussels, 16 May 2001.

Article 4

This Directive shall enter into force on the 20th day following
its publication in the Official
the European
Communities.

Journal

of

For the Commission

David BYRNE

Member of the Commission

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ANNEX I

Annex II to Directive 91/414/EEC is amended as follows:

(1)

The following point 2.4 is added to the introduction:

(cid:145)2.4. By way of derogation from point 2.1, for active substances consisting of micro-organisms or viruses,
tests and analyses done to obtain data on the properties and/or safety with respect to other aspects than
human health, may have been conducted by official or officially recognised testing facilities or
organisations which satisfy at least the requirements under points 2.2 and 2.3 of the introduction of
Annex III.(cid:146)

(2)

Part B is replaced by the following:

(cid:145)PART B

Introduction

(i)

Active substances are defined in Article 2(4) and include chemical substances and micro-organisms
including viruses.

This Part provides data requirements for active substances consisting of micro-organisms,
viruses.

including

For the purposes of Annex II, Part B, the term (cid:147)micro-organism(cid:148) is used and is defined as follows:

(cid:147)A microbiological entity, cellular or non-cellular, capable of replication or of transferring genetic
material(cid:148).

The definition applies to, but is not limited to, bacteria, fungi, protozoa, viruses and viroids.

(ii)

For all micro-organisms that are subject to application all available relevant knowledge and information
in literature should be provided.

The most important and informative information is obtained by the characterisation and identification of
a micro-organism. Such information is found in sections 1 to 3 (identity, biological properties and
further information) which form the basis for an assessment of human health and environmental effects.

Newly generated data from conventional toxicological and/or pathological experiments on laboratory
animals are normally required unless the applicant can justify, on the basis of the previous information,
that the use of the micro-organism, under the proposed conditions of use, does not have any harmful
effects on human and animal health or on groundwater or any unacceptable influence on the
environment.

(iii)

Pending the acceptance of specific guidelines at international
level, the information required shall be
generated using available test guidelines accepted by the competent authority (e.g. USEPA guideline (1));
where appropriate test guidelines as described in Annex II, Part A, should be adapted in such a way that
they are appropriate for micro-organisms. Testing should include viable and, if appropriate, non-viable
micro-organisms, and a blank control.

(iv) Where testing is done, a detailed description (specification) of the material used and its impurities,
according to the provisions of section 1, point 1.4, must be provided. The material used should be of
that specification that will be used in the manufacture of preparations to be authorised.

Where studies are conducted using micro-organisms produced in the laboratory or in a pilot plant
production system, the studies must be repeated using micro-organisms as manufactured, unless it can
be demonstrated that the test material used is essentially the same for the purposes of the testing and
assessment.

(1) USEPA Microbial Pesticide Test Guidelines, OPPTS Series 885, February 1996

(http://www.epa.gov/oppbppd1/biopesticides/guidelines/series885.htm).

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(v) Where the micro-organism has been genetically modified, as defined in Council Directive 90/220/EEC of
23 April 1990 on the deliberate release into the environment of genetically modified organisms (2), a
copy of the evaluation of the data concerning the assessment of risk to the environment, as stated in
Article 1(3) of Directive 91/414/EEC, has to be submitted.

(vi) Where relevant, data should be analysed using appropriate statistical methods. Full details of

the
statistical analysis should be reported (e.g. all point estimates should be given with confidence intervals,
exact p-values should be given rather than stating significant/non significant).

(vii)

In the case of studies in which dosing extends over a period, dosing should preferably be done using a
single batch of the micro-organism, if stability permits.

If the studies are not performed using a single batch of the micro-organism, the similarity of the
different batches has to be stated.

Whenever a study implies the use of different doses, the relationship between dose and adverse effect
must be reported.

(viii) If the plant protection action is known to be due to the residual effect of a toxin/metabolite or if
significant residues of toxins/metabolites are to be expected not related to the effect of the active
substance, a dossier for the toxin/metabolite has to be submitted in accordance with the requirements of
Annex II, Part A.

1.

IDENTITY OF THE MICRO-ORGANISM

The identification together with the characterisation of the micro-organism provides the most important
information and is a key point for decision-making.

1.1.

Applicant

The name and address of the applicant (permanent community address) must be provided, as must the name,
position, telephone and fax number of the appropriate person to contact.

Where, in addition, the applicant has an office, agent or representative in the Member State to which the
application for inclusion in Annex I is submitted, and if different, in the rapporteur Member State appointed
by the Commission, the name and address of the local office, agent or representative must be provided, as
must the name, position, telephone and fax number of the appropriate person to contact.

1.2.

Producer

The name and address of the producer or producers of the micro-organism must be provided as must the
name and address of each plant in which the micro-organism is produced. A contact point (preferably a
central contact point, to include name, telephone and fax number) must be provided, with a view to
providing updating information and responding to queries arising, regarding production technology, processes
and the quality of product (including where relevant, individual batches). Where, following inclusion of the
micro-organism in Annex I, there are changes in the location or number of producers, the information
required must again be notified to the Commission and the Member States.

1.3.

Name and species description, strain characterisation

(i)

(ii)

The micro-organism should be deposited at an internationally recognised culture collection and given an
accession number and these details must be submitted.

Each micro-organism that is subject to the application should be identified and named at the species
level. The scientific name and taxonomic grouping, i.e. family, genus, species, strain, serotype, pathovar
or any other denomination relevant to the micro-organism, must be stated.

It must be indicated whether the micro-organism:

(cid:151) is indigenous or non-indigenous at the species level to the intended area of application,

(cid:151) is a wild type,

(2) OJ L 117, 8.5.1990, p. 15.

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(cid:151) is a spontaneous or induced mutant,

(cid:151) has been modified, using techniques described in Annex IA, Part 2, and Annex IB to Directive

90/220/EEC.

In the latter two cases, all known differences between the modified micro-organism and the parent wild
strain must be provided.

iii)

Best available technology should be used to identify and characterise the micro-organism at the strain
level. The appropriate test procedures and criteria used for identification (e.g. morphology, biochemistry,
serology, molecular identification) must be provided.

iv)

Common name or alternative and superseded names and code names used during the development, if
any, must be provided.

(v)

Relationships to known pathogens should be indicated.

1.4.

Specification of the material used for manufacturing of formulated products

1.4.1.

Content of the micro-organism

The minimum and maximum content of the micro-organism in the material used for manufacturing of
formulated products, must be reported. The content should be expressed in appropriate terms, such as
number of active units per volume or weight or any other manner that is relevant to the micro-organism.

Where the information provided relates to a pilot plant production system, the information required must
again be provided to the Commission and the Member States once industrial scale production methods and
procedures have stabilised, if production changes result in a changed specification of purity.

1.4.2.

Identity and content of impurities, additives, contaminating micro-organisms

is desirable to have a plant protection product without contaminants

It
(including contaminating
micro-organisms), if possible. The level and nature of acceptable contaminants should be judged from a risk
assessment point of view, by the competent authority.

If possible and appropriate,
the identity and maximum content of all contaminating micro-organisms,
expressed in the appropriate unit, must be reported. The information on identity must be provided where
possible as outlined in Annex II, Part B, section1, point 1.3.

Relevant metabolites (i.e. if expected to be of concern to human health and/or the environment) known to be
formed by the micro-organism should be identified and characterised at different states or growth stages of
the micro-organism (see Annex IIB, Introduction, (viii)).

Where relevant detailed information on all components such as condensates, culture medium, etc. must be
provided.

In the case of chemical impurities that are relevant for human health and/or the environment, the identity and
maximum content, expressed in appropriate terms, must be provided.

In the case of additives, the identity and content in g/kg must be provided.

The information on identity of chemical substances such as additives must be provided as outlined in Annex
II, Part A, section 1, point 1.10.

1.4.3.

Analytical profile of batches

Where relevant, the same data as outlined in Annex II, Part A, section 1, point 1.11, have to be reported,
using the appropriate units.

2.

BIOLOGICAL PROPERTIES OF THE MICRO-ORGANISM

2.1.

History of the micro-organism and its uses. Natural occurrence and geographical distribution

Familiarity, interpreted as the availability of relevant knowledge of the micro-organism, should be presented.

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2.1.1.

Historical background

The historical background of the micro-organism and its use (tests/research projects or commercial use) must
be provided.

2.1.2.

Origin and natural occurrence

The geographical region and the place in the ecosystem (e.g. host plant, host animal, or soil from which the
micro-organism was isolated) must be stated. The method of isolation of the micro-organism should be
reported. The natural occurrence of the micro-organism in the relevant environment shall be given if possible
at strain level.

In the case of a mutant, or a genetically modified micro-organism (as defined in Annex IA, Part 2, and Annex
IB to Directive 90/220/EEC), detailed information should be provided on its production and isolation and on
the means by which it can be clearly distinguished from the parent wild strain.

2.2.

Information on target organism(s)

2.2.1.

Description of the target organism(s)

Where relevant, details of harmful organisms against which protection is afforded, must be provided.

2.2.2. Mode of action

The principal mode of action should be indicated. In connection with the mode of action it should also be
stated if the micro-organism produces a toxin with a residual effect on the target organism. In that case, the
mode of action of this toxin should be described.

If relevant, information on the site of infection and mode of entry into the target organism and its susceptible
stages should be given. The results of any experimental studies must be reported.

It should be stated by which way an uptake of the micro-organism, or its metabolites (especially toxins) may
occur (e.g. contact, stomach, inhalation). It must also be stated whether or not the micro-organism or its
metabolites are translocated in plants and, where relevant, how this translocation takes place.

In case of pathogenic effect on the target organism, infective dose (the dose needed to cause infection with the
intended effect on a target species) and transmissibility (possibility of spread of the micro-organism in the
target population, but also from one target species to another (target) species) after application under the
proposed condition of use shall be indicated.

2.3.

Host specificity range and effects on species other than the target harmful organism

Any available information on the effects on non-target organisms within the area to which the
micro-organism may spread shall be given. The occurrence of non-target organisms being either closely
related to the target species or being especially exposed shall be indicated.

Any experience of the toxic effect of the active substance or its metabolic products on humans or animals, of
whether the organism is capable of colonising or invading humans or animals (including immunosuppressed
individuals) and whether it is pathogenic shall be stated. Any experience of whether the active substance or its
products may irritate skin, eyes or respiratory organs of humans or animals and whether it is allergenic in
contact with skin or when inhaled shall be stated.

2.4.

Development stages/life cycle of the micro-organism

Information on the life cycle of the micro-organism, described symbiosis, parasitism, competitors, predators,
etc., including host organisms, as well as vectors for viruses, must be presented.

The generation time and the type of reproduction of the micro-organism must be stated.

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Information on the occurrence of resting stages and their survival time, their virulence and infection potential
must be provided.

The potential of the micro-organism to produce metabolites, including toxins that are of concern for human
health and/or the environment, in its different development stages after the release, must be indicated.

2.5.

Infectiveness, dispersal and colonisation ability

The persistence of the micro-organism and information on its life cycle under the typical environmental
conditions of use must be indicated. In addition, any particular sensitivity of the micro-organism to certain
compartments of the environment (e.g. UV light, soil, water) must be stated.

The environmental requirements (temperature, pH, humidity, nutrition requirements, etc.)
for survival,
reproduction, colonisation, damage (including human tissues) and effectiveness of the micro-organism must be
stated. The presence of specific virulence factors should be indicated.

The temperature range at which the micro-organism grows must be determined,
including minimum,
maximum and optimum temperatures. This information is of particular value as a trigger for studies of effects
on human health (section 5).

The possible effect of factors such as temperature, UV light, pH, and the presence of certain substances on the
stability of relevant toxins must also be stated.

Information on possible dispersal routes of the micro-organism (via air as dust particles or aerosols, with host
organisms as vectors, etc.), under typical environmental conditions relevant to the use, must be provided.

2.6.

Relationships to known plant or animal or human pathogens

The possible existence of one or more species of
the active and/or, where relevant,
contaminating micro-organisms known to be pathogenic to humans, animals, crops or other non-target
species and the type of disease caused by them shall be indicated. It shall be stated whether it is possible, and
if so, by which means to clearly distinguish the active micro-organism from the pathogenic species.

the genus of

2.7.

Genetic stability and factors affecting it

Where appropriate, information on genetic stability (e.g. mutation rate of traits related to the mode of action
or uptake of exogenous genetic material) under the environmental conditions of proposed use must be
provided.

Information must also be provided on the micro-organism’s capacity to transfer genetic material to other
organisms as well as its capacity to being pathogenic for plants, animals or man. If the micro-organism carries
relevant additional genetic elements, the stability of the encoded traits should be indicated.

2.8.

Information on the production of metabolites (especially toxins)

If other strains belonging to the same microbial species as the strain subject to the application are known to
produce metabolites (especially toxins) with unacceptable effects on human health and/or the environment
during or after application, the nature and structure of this substance, its presence inside or outside the cell
and its stability, its mode of action (including external and internal factors of the micro-organism necessary to
action) as well as its effect on humans, animals or other non-target species shall be provided.

The conditions under which the micro-organism produces the metabolite(s)
described.

(especially toxin(s)) must be

Any available information on the mechanism by which the micro-organisms regulate the production of the(se)
metabolite(s) should be provided.

Any available information on the influence of the produced metabolites on the micro-organism’s mode of
action should be provided.

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2.9.

Antibiotics and other anti-microbial agents

Many micro-organisms produce some antibiotic substances. Interference with the use of antibiotics in human
or veterinary medicine must be avoided at any stage of the development of a microbial plant protection
product.

Information on the micro-organism’s resistance or sensitivity to antibiotics or other anti-microbial agents must
be provided, in particular the stability of the genes coding for antibiotic resistance, unless it can be justified
that the micro-organism has no harmful effects on human or animal health, or that it can not transfer its
resistance to antibiotics or other anti-microbial agents.

3.

FURTHER INFORMATION ON THE MICRO-ORGANISM

Introduction

(i)

(ii)

The information provided must describe the intended purposes for which preparations containing the
micro-organism are used, or are to be used and the dose and manner of their use or proposed use.

The information provided must specify the normal methods and precautions to be followed in the
handling, storage and transport of the micro-organism.

(iii) The studies, data and information submitted, must demonstrate the suitability of measures proposed for

use in emergency situations.

(iv) The information and data referred to are required for each micro-organism, except where otherwise

specified.

3.1.

Function

The biological function must be specified from among the following:

(cid:151) control of bacteria,

(cid:151) control of fungi,

(cid:151) control of insects,

(cid:151) control of mites,

(cid:151) control of molluscs,

(cid:151) control of nematodes,

(cid:151) control of weeds,

(cid:151) other (must be specified).

3.2.

Field of use envisaged

The field(s) of use, existing and proposed, for preparations containing the micro-organism must be specified
from among the following:

(cid:151) field use, such as agriculture, horticulture, forestry, and viticulture,

(cid:151) protected crops (e.g. in greenhouses),

(cid:151) amenity,

(cid:151) weed control on non-cultivated areas,

(cid:151) home gardening,

(cid:151) house plants,

(cid:151) stored products,

(cid:151) other (specify).

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3.3.

Crops or products protected or treated

Details of existing and intended use in terms of crops, groups of crops, plants, or plant products protected,
must be provided.

3.4.

Method of production and quality control

Full information on how the micro-organism is produced in bulk must be provided.

to a continuous quality control by the
Both production method/process and product must be subject
applicant.
the
spontaneous
micro-organism and of the absence/presence of significant contaminants should be monitored. The quality
assurance criteria for the production should be submitted.

changing of major

the occurrence of

characteristics of

In particular,

The techniques used to ensure a uniform product, and the assay methods for its standardisation, maintenance
and purity of the micro-organism must be described and specified (e.g. HACCP).

3.5.

Information on the occurrence or possible occurrence of the development of resistance of the target
organism(s)

Available information on the possible occurrence of the development of resistance or cross-resistance of the
target organism(s) must be provided. Where possible, appropriate management strategies should be described.

3.6.

Methods to prevent loss of virulence of seed stock of the micro-organism

Methods to prevent loss of virulence of starting cultures are to be provided.

In addition, any method, if available, that could prevent the micro-organism from losing its effects on the
target species must be described.

3.7.

Recommended methods and precautions concerning handling, storage, transport or fire

A safety data sheet similar to that required for chemical active substances in Article 27 of Directive
67/548/EEC (3) must be provided for each micro-organism.

3.8.

Procedures for destruction or decontamination

In many cases the preferred or sole means of safe disposal of micro-organisms, contaminated materials, or
contaminated packaging, is through controlled incineration in a licensed incinerator.

Methods to dispose safely of the micro-organism or, where necessary, to kill it prior to disposal, and methods
to dispose of contaminated packaging and contaminated materials, must be fully described. Data must be
provided for such methods to establish their effectiveness and safety.

3.9.

Measures in case of an accident

Information on procedures for rendering the micro-organism harmless in the environment (e.g. water or soil)
in case of an accident must be provided.

4.

ANALYTICAL METHODS

Introduction

The provisions of
monitoring purposes.

this section only cover analytical methods required for post-registration control and

(3) See doc. 6853/VI/98, Concise outline report of the first peer review meeting on micro-organisms.

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Post-approval monitoring might be considered for all areas of risk assessment. This is particularly the case
when (strains of) micro-organisms that are non-indigenous to the intended area of application are considered
for approval. For analytical methods used for generation of data as required in this Directive or for other
purposes the applicant has to provide a justification for the method used; where necessary separate guidance
will be developed for such methods on the basis of the same requirements as defined for methods for
post-registration control and monitoring purposes.

Descriptions of methods must be provided and include details of equipment, materials and conditions used.
The applicability of any internationally recognised method must be reported.

As far as practicable these methods must employ the simplest approach, involve the minimum cost, and
require commonly available equipment.

Data on specifity, linearity, accuracy and repeatability, as defined in Annex II, Part A, points 4.1 and 4.2, are
also required for methods used to analyse micro-organisms and their residues.

For this section the following applies:

Impurities

Any component
(including contaminating micro-organisms and/or chemical
substances) other than the specified micro-organism, originating from the
manufacturing process or from degradation during storage

Relevant impurities

Impurities, as defined above, that are of concern for human or animal health
and/or the environment

Metabolites

include products

Metabolites
resulting from degradative and biosynthetic
reactions taking place within the micro-organism or other organisms used to
produce the micro-organism of interest

Relevant metabolites

Metabolites that are of concern for human or animal health and/or the
environment

Residues

Viable micro-organisms and substances produced in significant quantities by
the
these micro-organisms which persist
micro-organisms and are of concern for human or animal health and/or the
environment.

disappearance

after

the

of

On request the following samples must be provided:

(i)

samples of the micro-organism as manufactured;

(ii)

analytical standards of relevant metabolites (especially toxins) and all other components included in the
residue definition;

(iii)

if available, samples of reference substances for the relevant impurities.

4.1.

Methods for the analysis of the micro-organism as manufactured

(cid:151) Methods for the identification of the micro-organism.

(cid:151) Methods for providing information on possible variability of seed stock/active micro-organism.

(cid:151) Methods to differentiate a mutant of the micro-organism from the parent wild strain.

(cid:151) Methods for the establishment of purity of seed stock from which batches are produced and methods to

control that purity.

(cid:151) Methods to determine the content of the micro-organism in the manufactured material used for the
formulated products and methods to show that contaminating micro-organisms are

production of
controlled to an acceptable level.

(cid:151) Methods for the determination of relevant impurities in the manufactured material.

(cid:151) Methods to control the absence and to quantify (with appropriate limits of determination) the possible

presence of any human and mammalian pathogens.

(cid:151) Methods to determine storage stability, shelf-life of the micro-organism, if appropriate.

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4.2.

Methods to determine and quantify residues (viable or non-viable)

of:

(cid:151) the active micro-organism(s),

(cid:151) relevant metabolites (especially toxins),

on and/or in crop, in foodstuffs and feeding stuffs, in animal and human body tissues and fluids, in soil, in
water (including drinking water, ground water and surface water) and in air where relevant.

Analytical methods for amount or activity of proteinaceous products should also be included, e.g. by testing
exponential cultures and culture supernatants in an animal cell bioassay.

5.

EFFECTS ON HUMAN HEALTH

Introduction

(i)

(ii)

Available information based on the properties of the micro-organism and corresponding organisms
(sections 1 to 3), including health and medical reports may be sufficient for a decision whether the
micro-organism would cause health effects (infectious/pathogenic/toxic) in humans or not.

The information provided, taken together with that provided for one or more preparations containing
the micro-organism, must be sufficient to permit an evaluation to be made as to the risks for man,
directly and/or indirectly associated with the handling and use of plant protection products containing
the micro-organism, and the risk for man handling treated products, and the risk for man arising from
residual traces or contaminants remaining in food and water. In addition, the information provided must
be sufficient to:

(cid:151) permit a decision to be made as to whether, or not, the micro-organism can be included in Annex I,

(cid:151) specify appropriate conditions or restrictions to be associated with any inclusion in Annex I,

(cid:151) specify risk and safety phrases (once introduced)

for the protection of man, animals and the

environment to be included on packaging (containers),

(cid:151) identify relevant first aid measures as well as appropriate diagnostic and therapeutic measures to be

followed in the event of infection or another adverse effect in man.

(iii) All effects found during investigations should be reported. Investigations which may be necessary in
order to evaluate the probable mechanism involved, and to assess the significance of these effects, must
also be performed.

(iv)

For all studies actual achieved dose in colony forming units per kg body weight (cfu/kg), as well as in
other appropriate units, must be reported.

(v)

Evaluation of the micro-organism should be carried out in a tier-wise manner.

The first tier (Tier I) includes available basic information and basic studies, which have to be performed
the appropriate test
for all micro-organisms. Expert
judgment will be necessary to decide about
programme on a case-by-case basis. Newly generated data from conventional
toxicological and/or
pathological experiments on laboratory animals are normally required unless the applicant can justify,
on the basis of the previous information, that the use of the micro-organism, under the proposed
conditions of use, does not have any harmful effects on human and animal health. Pending the
acceptance of specific guidelines at international level, the information required shall be generated using
available test guidelines (e.g. USEPA OPPTS Guidelines).

Tier II studies must be conducted if tests under Tier I have shown adverse health effects. The type of
study to be performed depends on the effects observed in the Tier I studies. Before performing such
studies, the applicant shall seek agreement of the competent authorities on the type of study to be
performed.

TIER I

5.1.

Basic information

Basic information is required about the micro-organism’s potential to cause adverse effects such as ability to
colonise, to cause damage and to produce toxins and other relevant metabolites.

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5.1.1. Medical data

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) and Articles 5 to 17 of Council Directive 90/679/EEC of 26 November 1990 on the
protection of workers from the risks related to biological agents at work (5), practical data and information
relevant to the recognition of the symptoms of infection or pathogenicity and on the effectiveness of first aid
and therapeutic measures have to be submitted. Where relevant, the effectiveness of potential antagonists,
should be investigated and reported. Where relevant, methods to kill or render the micro-organism uninfective
must be indicated (see section 3, point 3.8).

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, virulence, and the reversibility of adverse effects. Such data can be generated following
accidental or occupational exposure.

5.1.2. Medical surveillance on manufacturing plant personnel

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

Special attention should be devoted to those whose susceptibility may be affected, e.g. pre-existing disease,
medication, compromised immunity, pregnancy or breast feeding.

5.1.3.

Sensitisation/allergenicity observations, if appropriate

Available information on the sensitisation and allergenic response of workers,
in
manufacturing plants, agricultural and research workers and others exposed to the micro-organism must be
provided, and include, where relevant, details of any incidences of hypersensitivity and chronic sensitisation.
The information provided should include details of frequency,
level and duration of exposure, symptoms
observed and other relevant clinical observation. Information should be given about whether workers have
been subjected to any allergy tests or interviewed about allergenic symptoms.

including workers

5.1.4.

Direct observation, e.g. clinical cases

Available reports from the open literature on the micro-organism or closely related members of
the
taxonomic group (relating to clinical cases), where they are from reference journals or official reports, must be
submitted together with reports of any follow-up studies undertaken. Such reports are of particular value and
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 of limited value.

If there are animal studies performed, reports relating to clinical cases can be of particular value in confirming
the validity of interpretations from animal data to man and in identifying unexpected adverse effects which
are specific to humans.

5.2.

Basic studies

In order to make it possible to correctly interpret the obtained results, it is of greatest importance that the
suggested test methods are relevant regarding species sensitivity, administration route, etc., and relevant from
a biological and toxicological point of view. The way of administration of the test micro-organism depends on
the main exposure routes to humans.

to
after
To evaluate medium-
micro-organisms, it is necessary to use the options provided in most of the OECD guidelines, to extend the
studies concerned with a recovery period (after which full macroscopic and microscopic pathology is to be

and long-term effects

sub-acute or

semi-chronic

exposure

acute,

(4) OJ L 327, 3.12.1980, p. 8.
(5) OJ L 374, 31.12.1990, p. 1.

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performed,
including an exploration for micro-organisms in the tissues and organs). This facilitates the
interpretation of certain effects and provides the possibility to recognise infectiveness and/or pathogenicity,
which in turn helps taking decisions on other issues such as the necessity to perform long-term studies
(carcinogenicity etc., see point 5.3), and whether or not to perform residue studies (see point 6.2).

5.2.1.

Sensitisation (6)

Aim of the test

The test will provide sufficient
information to assess the potential of
sensitisation reactions by inhalation as well as with dermal exposure. A maximised test has to be performed.

the micro-organism to provoke

Circumstances in which required (7)

Information on sensitisation must be reported.

5.2.2.

Acute toxicity, pathogenicity and infectiveness

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 micro-organism, and in particular to establish, or indicate:

(cid:151) the toxicity, pathogenicity and infectiveness of the micro-organism,

(cid:151) the time course and characteristics of the effects with full details of behavioural changes and possible

gross pathological findings at post-mortem,

(cid:151) where possible mode of toxic action,

(cid:151) the relative hazards associated with the different routes of exposure, and

(cid:151) blood analyses throughout the studies in order to evaluate the clearance of the micro-organism.

Acute toxic/pathogenic effects may be accompanied by infectiveness and/or more long-term effects which
cannot be observed immediately. With a view to health evaluation, it is therefore necessary to carry out
studies on the ability to infect in connection with oral intake, inhalation and intraperitoneal/subcutaneous
injection by test mammals.

During the acute toxicity, pathogenicity and infectiveness studies, an estimation of the micro-organism and/or
the active toxin clearance in the organs deemed to be relevant for microbial examination (e.g. liver, kidneys,
spleen, lungs, brain, blood and site of administration) must be performed.

The observations to be made should reflect expert scientific judgement and may include the micro-organism
numeration in all the tissues likely to be affected (e.g. showing lesions) and in the main organs: kidneys, brain,
liver, lungs, spleen, bladder, blood, lymphatic ganglia, gastrointestinal tract, thymus gland and lesions at the
inoculation site in the dead or moribund animals and at interim and final sacrifice.

The information generated through acute toxicity, pathogenicity and infectiveness testing is of particular value
in assessing hazards likely to arise in accident situations and consumer risks due to exposure to possible
residues.

(6) The available methods for testing dermal sensitisation are not suitable for testing micro-organisms. Sensitisation by inhalation is
most probably a greater problem compared with dermal exposure to micro-organisms but so far, there are no validated test
methods. Development of these kinds of methods is therefore of great importance. Until then, all micro-organisms should be
regarded as potential sensitisers. This approach also takes into consideration immuno-compromised or other sensitive individuals in
the population (e.g. pregnant women, new-born children or elderly).

(7) As a consequence of the absence of proper test methods all micro-organisms will be labelled as potential sensitisers, unless the
applicant wants to demonstrate the non-sensitising potential by submitting data. Therefore, this data requirement should be regarded
as not obligatory but optional, on a provisional base.

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5.2.2.1. A c u t e o r a l t o x i c i t y , p a t h o g e n i c i t y a n d i n f e c t i v e n e s s

Circumstances in which required

The acute oral toxicity, pathogenicity and infectiveness of the micro-organism must be reported.

5.2.2.2. A c u t e i n h a l a t i o n t o x i c i t y , p a t h o g e n i c i t y a n d i n f e c t i v e n e s s

Circumstances in which required

The inhalation toxicity (8), pathogenicity and infectiveness of the micro-organism must be reported.

5.2.2.3.

I n t r a p e r i t o n e a l / s u b c u t a n e o u s s i n g l e d o s e

The intraperitoneal/subcutaneous test is considered a highly sensitive assay to elicit in particular infectiveness.

Circumstances in which required

The intraperitoneal injection is always required for all micro-organisms, however, expert judgement may be
exercised to evaluate whether subcutaneous injection is preferred instead of intraperitoneal injection if the
maximum temperature for growth and multiplication is lower than 37 oC.

5.2.3.

Genotoxicity testing

Circumstances in which required

If the micro-organism produces exotoxins according to point 2.8, then these toxins and any other relevant
metabolites in the culture medium must also be tested for genotoxicity. Such tests on toxins and metabolites
should be performed using the purified chemical if possible.

If basic studies do not indicate that toxic metabolites are formed, studies on the micro-organism itself should
be considered depending on expert judgement on the relevance and validity of the basic data. In the case of a
virus the risk of insertional mutagenesis in mammal cells or the risk of carcinogenicity has to be discussed.

Aim of the test

These studies are of value in:

(cid:151) the prediction of genotoxic potential,

(cid:151) the early identification of genotoxic carcinogens,

(cid:151) the elucidation of the mechanism of action of some carcinogens.

It is important that a flexible approach is adopted, with selection of further tests being dependent upon
interpretation of results at each stage.

Test conditions (9)

Genotoxicity of cellular micro-organisms will be studied after breaking of
Justification should be provided on the method of sample preparation used.

the cells, wherever possible.

Genotoxicity of viruses should be studied on infectious isolates.

5.2.3.1.

I n v i t r o s t u d i e s

Circumstances in which required

Results of in vitro mutagenicity tests (bacterial assay for gene mutation, test for clastogenicity in mammalian
cells and test for gene mutation in mammalian cells) must be provided.

(8) An inhalation study may be replaced by an intratracheal study.
(9) As the present test methods are designed to be performed on soluble chemicals, it is necessary that the methods are developed so as

to become relevant for micro-organisms.

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5.2.4.

Cell culture study

This information must be reported for intracellular replicating micro-organisms, such as viruses, viroids or
specific bacteria and protozoa, unless the information from sections 1 to 3 clearly demonstrates that the
micro-organism does not replicate in warm-blooded organisms. A cell culture study should be performed in
human cell or tissue cultures of different organs. Selection can be based on expected target organs after
infection. If human cell or tissue cultures of specific organs are not available, other mammal cell and tissue
cultures can be used. For viruses, the ability to interact with the human genome is a key consideration.

5.2.5.

Information on short-term toxicity and pathogenicity

Aim of the test

Short-term toxicity studies must be designed to provide information as to the amount of the micro-organism
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 micro-organism.
In particular,
short-term studies provide an essential insight into possible cumulative actions of the micro-organism, 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.

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

(cid:151) the relationship between dose and adverse effects,

(cid:151) toxicity of the micro-organism including where necessary the NOAEL for toxins,

(cid:151) target organs, where relevant,

(cid:151) the time course and characteristics of the effects with full details of behavioural changes and possible

gross pathological findings at post-mortem,

(cid:151) specific toxic effects and pathological changes produced,

(cid:151) where

relevant
discontinuation of dosing,

the persistence

and reversibility of

certain toxic

effects observed,

following

(cid:151) where possible, the mode of toxic action, and

(cid:151) the relative hazard associated with the different routes of exposure.

During the short-term toxicity study, an estimation of the micro-organism clearance in the main organs must
be performed.

Investigations should be included for pathogenicity and infectiveness end points.

Circumstances in which required

The short-term toxicity (minimum 28 days) of the micro-organism must be reported.

The choice of test species has to be justified. The choice of study length depends on acute toxicity and
clearance data.

Expert judgement is required to decide what route of administration is preferable.

5.2.5.1. H e a l t h e f f e c t s a f t e r r e p e a t e d i n h a l a t o r y e x p o s u r e

Information on the health effects after repeated inhalatory exposure is considered necessary, particularly for
the risk assessment of the occupational setting. Repeated exposure might influence the clearance capacity (e.g.
resistance) of the host (human). Furthermore, for proper risk assessment the toxicity after repeated exposure
to contaminants, growth medium, co-formulants and the micro-organism needs to be addressed. It should be
kept in mind that the formulants in the plant protection product can influence the toxicity and infectiveness
of a micro-organism.

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Circumstances in which required

Information on the short-term infectiveness, pathogenicity and toxicity (respiratory route) of a micro-organism
is required, unless the information already provided is sufficient to assess human health effects. This can be
the case if it is demonstrated that the test material has no inhalable fraction and/or repeated exposure is not
expected.

5.2.6.

Proposed treatment: first aid measures, medical treatment

The first aid measures to be used in the event of infection and in the event of contamination of eyes must be
provided.

Therapeutic regimes for use in the event of ingestion or contamination of eyes and skin 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.

Information on resistance to antibiotics must be provided.

(END OF TIER I)

TIER II

5.3.

Specific toxicity, pathogenicity and infectiveness studies

In certain cases, it can be necessary to carry out supplementary studies to further clarify the adverse human
effects.

if results from earlier studies indicate that the micro-organism may cause long-term health
In particular,
effects, studies on chronic toxicity, pathogenicity and infectiveness, carcinogenicity and reproductive toxicity
must be carried out. Furthermore, where a toxin is produced, kinetic studies must be performed.

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. Before performing such studies, the applicant shall seek
agreement of the competent authorities on the type of study to be performed.

5.4.

In vivo studies in somatic cells

Circumstances in which required

If all the results of the in vitro studies are negative further testing must be done with consideration of other
relevant
information available. The test can be an in vivo study or an in vitro study using a different
metabolising system from that/those previously used.

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.

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.

5.5.

Genotoxicity (cid:151) In vivo studies in germ cells

Aim of the test and test conditions

See point 5.4.

Circumstances in which required

When any result of an in vivo study in somatic cells is positive, in vitro 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 other relevant information available including use and expected 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 recognised that in view
of their complexity, the use of quantitative studies would require strong justification.

(END OF TIER II)

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5.6.

Summary of mammalian toxicity, pathogenicity and infectiveness and overall evaluation

A summary of all data and information provided under points 5.1 through 5.5, 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.

It must be explained whether exposure of animals or humans has any implications for vaccination or
serological monitoring.

6.

RESIDUES IN OR ON TREATED PRODUCTS, FOOD AND FEED

Introduction

(i)

The information provided,
for one or more preparations containing the
micro-organism, must be sufficient to permit an evaluation to be made as to the risk for man and/or
animals, arising from exposure to the micro-organism and its residual traces and metabolites (toxins)
remaining in or on plants or plant products.

taken together with that

(ii)

In addition, the information provided must be sufficient to:

(cid:151) permit a decision to be made as to whether or not the micro-organism can be included in Annex I

to Directive 91/414/EEC,

(cid:151) specify appropriate conditions or restrictions to be associated with any inclusion in Annex I to

Directive 91/414/EEC,

(cid:151) where relevant, set maximum residue levels, preharvest intervals to protect consumers and waiting

periods, to protect workers handling the treated crops and products.

(iii)

For the evaluation of risk arising from residues, experimental data on levels of exposure to the residue
may not be required where it can be justified, that the micro-organism and its metabolites are not
hazardous to humans in the concentrations that could occur as a result of authorised use. This
justification can be based on open literature, on practical experience and on information submitted in
sections 1 through 3 and section 5.

6.1.

Persistance and likelihood of multiplication in or on crops, feedingstuffs or foodstuffs

A substantiated estimation of persistance/competitiveness of
the micro-organism and relevant secondary
metabolites (especially toxins) in or on the crop under the environmental conditions prevailing at and after
the intended use, taking into account in particular the information provided in section 2, has to be delivered.

the application shall state to which extent and on which basis it

Moreover,
the
micro-organism can (or cannot) multiply in or on the plant or plant product or during processing of raw
products.

is considered that

6.2.

Further information required

Consumers may be exposed to micro-organisms for a considerable time as a result of the consumption of
treated food commodities; potential effects on the consumers must, therefore, be derived from chronic or
semi-chronic studies, so that a toxicological end point, such as the ADI, can be established for risk
management.

6.2.1.

Non-viable residues

A non viable micro-organism is a micro-organism that is not capable of replication or of transferring genetic
material.

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If relevant quantities of the micro-organism or of produced metabolites, especially toxins, have been found to
be persistant in section 2, points 2.4 and 2.5, full experimental residue data as provided for in Annex II, Part
A, section 6,
if concentrations of the micro-organism and/or its toxins in or on the treated
foodstuffs or feedingstuffs are expected to occur in concentrations higher than under natural conditions or in
a different phenotypic state.

is required,

In agreement with Directive 91/414/EEC,
the conclusion concerning the difference between natural
concentrations and an elevated concentration due to treatment with the micro-organism, is to be based on
experimentally obtained data, and not on extrapolations or calculations using models.

Before performing such studies, the applicant shall seek agreement of the competent authorities on the type of
study to be performed.

6.2.2.

Viable residues

If
the
the information submitted according to point 6.1 suggests persistance of relevant amounts of
micro-organism in or on treated products, food or feed, possible effects on humans and/or animals must be
investigated, unless it can be justified from section 5, that the micro-organism and its metabolites and/or
degradation products are not hazardous to humans in the concentrations and of the nature that could occur
as a result of authorised use.

the conclusion concerning the difference between natural
In agreement with Directive 91/414/EEC,
concentrations and an elevated concentration due to treatment with the micro-organism, is to be based on
experimentally obtained data, and not on extrapolations or calculations using models.

The persistence of viable residues needs special attention if infectiveness or pathogenicity to mammals have
been found in sections 2.3, 2.5 or 5 and/or if any other information suggests a hazard to consumers and/or
workers. In this case the competent authorities may require studies similar to those provided for in Part A.

Before performing such studies, the applicant shall seek agreement of the competent authorities on the type of
study to be performed.

6.3.

Summary and evaluation of residue behaviour resulting from data submitted under points 6.1 and 6.2

7.

FATE AND BEHAVIOUR IN THE ENVIRONMENT

Introduction

(i)

Information on the origin, the properties, and the survival of the micro-organism and its residual
metabolites as well as its intended use form the basis for an assessment of environmental fate and
behaviour.

Experimental data are normally required unless it can be justified that an assessment of its fate and
behaviour in the environment can be performed with the information already available. This justification
can be based on open literature, on practical experience and, on information submitted in sections 1
through 6. The function of the micro-organism in environmental processes (as defined in section 2,
point 2.1.2) is of particular interest.

(ii)

The information provided, taken together with other relevant information, and that for one or more
preparations containing the micro-organism, must be sufficient to permit an assessment of its fate and
behaviour as well as that of its residual traces and toxins, where they are of significance for human
health and/or the environment.

(iii)

In particular, the information provided should be sufficient to:

(cid:151) decide whether, or not, the micro-organism can be included in Annex I,

(cid:151) specify appropriate conditions or restrictions to be associated with any inclusion in Annex I,

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(cid:151) specify the hazard symbols (once introduced), the indications of danger, and relevant risk and safety

phrases for the protection of the environment, which are to be included on packaging (containers),

(cid:151) predict the distribution, fate, and behaviour in the environment of the micro-organism and its

metabolites as well as the time courses involved,

(cid:151) identify measures necessary to minimise contamination of

the environment and impact on

non-target species.

(iv) Any relevant metabolites (i.e. of concern for human health and/or the environment) formed by the test
organism under any relevant environmental conditions should be characterised. If relevant metabolites
are present in or produced by the micro-organism, data as outlined under Annex II, Part A, point 7 may
be required, if all of the following conditions are met:

(cid:151) the relevant metabolite is stable outside the micro-organism, see point 2.8, and

(cid:151) a toxic effect of the relevant metabolite is independent of the presence of the micro-organism, and

(cid:151) the relevant metabolite is expected to occur in the environment in concentrations considerably

higher than under natural conditions.

(v) Available information on the relationship with naturally occurring wild type relatives should be taken

into account.

(vi) Before performing studies as referred to below, the applicant shall seek agreement of the competent
authorities on whether studies need to be performed and, if so, the type of study to be conducted. The
information from the other sections has, also, to be taken into account.

7.1.

Persistence and multiplication

Where relevant, appropriate information on the persistence and multiplication of the micro-organism, in all
environmental compartments has to be given, unless it can be justified that exposure of the particular
environmental compartment to the micro-organism is unlikely to occur. Special attention shall be given to

(cid:151) competitiveness under the environmental conditions prevailing at and after the intended use, and

(cid:151) population dynamics in seasonally or regionally extreme climates (particularly hot summer, cold winter

and rainfall) and to agricultural practices applied after intended use.

Estimated levels of the specified micro-organism in a time course after use of the product under the proposed
conditions of use shall be given.

7.1.1.

Soil

Information on viability/population dynamics should be reported in several cultivated and uncultivated soils
representative of soils typical of the various Community regions where use exists or is anticipated. The
provisions on choice of soil and its collection and handling, as referred to in Part A, point 7.1, Introduction,
have to be followed. If the test organism is to be used in association with other media, e.g. rockwool, this
must be included in the test range.

7.1.2. Water

Information should be reported on viability/population dynamics in natural sediment/water systems under
both dark and illuminated conditions.

7.1.3.

Air

In case of particular concerns for operator, worker or bystander exposure, information on the concentrations
in air might be necessary.

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7.2.

Mobility

The possible spread of
in relevant environmental
the micro-organism and its degradation products
compartments has to be evaluated, unless it can be justified that exposure of the particular environmental
compartments to the micro-organism is unlikely to occur. In this context, the intended use (e.g. field or
greenhouse, application to soil or to crops), life cycle stages, including occurrence of vectors, persistence and
the ability of the organism to colonise adjacent habitats are of particular interest.

The spread, the persistence and probable transport ranges need special attention if toxicity, infectiveness or
pathogenicity have been reported or if any other information suggests possible hazard to humans, animals or
to the environment. In this case the competent authorities may require studies similar to those provided for in
Part A. Before performing such studies, the applicant shall seek agreement of the competent authorities on the
type of study to be performed.

8.

EFFECTS ON NON-TARGET ORGANISMS

Introduction

(i)

(ii)

(iii)

(iv)

The information on identity, biological properties and further information in sections 1 to 3 and 7 is
central to the assessment of impact on non-target species. Additional useful information may be found
on fate and behaviour in the environment in section 7 and on residue levels in plants in section 6
which, together with information on the nature of the preparation and its manner of use, defines the
nature and extent of potential exposure. The information submitted in accordance with section 5 will
provide essential information as to effects to mammals and the mechanisms involved.

Experimental data are normally required, unless it can be justified that an assessment of effects on
non-target organisms can be performed with the information already available.

The choice of the appropriate non-target organisms for testing of environmental effects should be
based on the identity of the micro-organism (including the host specificity, mode of action and ecology
of the organism). From such knowledge it would be possible to choose the appropriate test-organisms,
such as organisms closely related to the target organism.

The information provided, taken together with that for one or more preparations containing the
micro-organism, must be sufficient to permit an assessment of the impact on non-target species (flora
and fauna), likely to be at risk from exposure to the micro-organism, where they are of environmental
significance. Impact can result from single, prolonged or repeated exposure and can be reversible or
irreversible.

In particular,
information, and that provided for one or more preparations containing it, should be sufficient to:

the information provided for

together with other

the micro-organism,

relevant

(cid:151) decide whether, or not, the micro-organism can be included in Annex I,

(cid:151) specify appropriate conditions or restrictions to be associated with any inclusion in Annex I,

(cid:151) permit an evaluation of short- and long-term risks for non-target species (cid:151) populations,

communities, and processes (cid:151) as appropriate,

(cid:151) classify the micro-organism as to biological hazard,

(cid:151) specify the precautions necessary for the protection of non-target species, and

(cid:151) specify the hazard symbols (once introduced), the indications of danger, and relevant risk and
safety phrases for the protection of the environment, to be mentioned on packaging (containers).

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(v)

(vi)

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There is a need to report all potentially adverse effects found during routine investigations on
environmental effects, to undertake and report, where required by the competent authorities, such
additional studies which may be necessary to investigate the probable mechanisms involved and to
assess the significance of these effects. All available biological data and information which is relevant to
the assessment of the ecology profile of the micro-organism must be reported.

For all studies, average achieved dose in cfu/kg body weight as well as in other appropriate units must
be reported.

It may be necessary to conduct separate studies for relevant metabolites (especially toxins), where these
products can constitute a relevant risk to non-target organisms and where their effects cannot be
evaluated by the available results relating to the micro-organism. Before such studies are performed, the
applicant shall seek agreement of the competent authorities on whether such studies need to be
performed and, if so, the type of study to be conducted. The information from sections 5, 6 and 7 has
to be taken into account.

(viii)

In order to facilitate the assessment of the significance of test results obtained, the same strain (or
recorded origin) of each relevant species should, where possible, be used in the various tests specified.

(ix)

Tests must be performed unless it can be justified that the non-target organism will not be exposed to
the micro-organism. If it is justified that the micro-organism does not cause toxic effects or is not
pathogenic or infective to vertebrates or plants, only reaction to appropriate non-target organisms must
be investigated.

8.1.

Effects on birds

Aim of the test

Information on toxicity, infectiveness and pathogenicity to birds must be reported.

8.2.

Effects on aquatic organisms

Aim of the test

Information on toxicity, infectiveness and pathogenicity to aquatic organisms must be reported.

8.2.1.

Effects on fish

Aim of the test

Information on toxicity, infectiveness and pathogenicity to fish must be reported.

8.2.2.

Effects on freshwater invertebrates

Aim of the test

Information on toxicity, infectiveness and pathogenicity to freshwater invertebrates must be reported.

8.2.3.

Effects on algae growth

Aim of the test

Information on effects on algal growth, growth rate and capacity to recover must be reported.

8.2.4.

Effects on plants other than algae

Aim of the test

Information on effects on plants other than algae must be reported.

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8.3.

Effects on bees

Aim of the test

Information on toxicity, infectiveness and pathogenicity to bees must be reported.

8.4.

Effects on arthropods other than bees

Aim of the test

Information on toxicity, infectiveness and pathogenicity to arthropods other than bees must be reported. The
selection of the test species should be related to the potential use of the plant protection products (e.g. foliar
or soil application). Special attention should be given to organisms used for biological control and organisms
playing an important role in integrated pest management.

8.5.

Effects on earthworms

Aim of the test

Information on toxicity, infectiveness and pathogenicity to earthworms must be reported.

8.6.

Effects on non-target soil micro-organisms

Impact on relevant non-target micro-organisms and on their predators (e.g. protozoa for bacterial inoculants)
should be reported. Expert judgement is required to decide whether additional studies are necessary. Such
decision will take into consideration the available information in this and other sections, in particular data on
the specificity of the micro-organism, and the expected exposure. Useful information may also be available
from the observations carried out in efficacy testing. Special attention should be given to organisms used in
integrated crop management (ICM).

8.7.

Additional studies

The additional studies might include further acute studies on additional species or processes (such as sewage
systems) or higher tier studies such as chronic, sub-lethal or reproductive studies on selected non-target
organisms.

Before performing such studies, the applicant shall seek agreement of the competent authorities on the type of
study to be performed.

9.

SUMMARY AND EVALUATION OF ENVIRONMENTAL IMPACT

A summary and evaluation of all data relevant to the environmental impact, should be carried out according
to the guidance given by the competent authorities of the Member States concerning the format of such
summaries and evaluations. It should 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 the
environment and non-target species that may or do arise, and the extent, quality and reliability of the data
base. In particular the following issues should be addressed:

(cid:151) distribution and fate in the environment, and the time courses involved,

(cid:151) identification of non-target species and populations at risk, and the extent of their potential exposure,

(cid:151) identification of precautions necessary to avoid or minimise contamination of the environment, and for

the protection of non-target species.(cid:146)

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ANNEX II

Annex III to Directive 91/414/EEC is amended as follows:

(1)

The following point 2.6 is added to the introduction:

(cid:145)2.6. By way of derogation from point 2.1, for active substances consisting of micro-organisms or viruses,
tests and analyses done to obtain data on the properties and/or safety with respect to other aspects than
human health, may have been conducted by official or officially recognised testing facilities or
organisations which satisfy at least the requirements under points 2.2 and 2.3 of the introduction of
Annex III.(cid:146)

(2)

PART B is replaced by the following:

(cid:145)PART B

Introduction

(i) This Part provides data requirements for the authorisation of a plant protection product based on

preparations of micro-organisms including viruses.

The term (cid:147)micro-organism(cid:148) as defined in the introduction of Annex II, Part B, also applies to Annex III,
Part B.

(ii) Where relevant, data should be analysed using appropriate statistical methods. Full details of the statistical
analysis should be reported (e.g. all point estimates should be given with confidence intervals, exact
p-values should be given rather than stating significant/non significant).

(iii) Pending the acceptance of specific guidelines at international

level, the information required shall be
generated using test guidelines accepted by the competent authority (e.g. USEPA guideline (1)); where
appropriate test guidelines as described in Annex II, Part A, should be adapted in such a way that they are
appropriate, non-viable
appropriate
micro-organisms, and a blank control.

for micro-organisms. Testing should include viable

and,

if

(iv) Whenever a study implies the use of different doses, the relationship between dose and adverse effect must

be reported.

(v) Where testing is done, a detailed description (specification) of

the material used and its impurities,

according to the provisions of section 1, point 1.4, must be provided.

(vi) In cases where a new preparation is to be dealt with, extrapolation from Annex II, Part B, could be
acceptable, provided that all the possible effects of the formulants and other components, especially on
pathogenicity and infectiveness, are also evaluated.

1.

IDENTITY OF THE PLANT PROTECTION PRODUCT

The information provided, taken together with that provided for the micro-organism(s), must be sufficient to
precisely identify and define preparations. The information and data referred to, unless otherwise specified, are
required for all plant protection products. This is with the view to identify if any factor could alter the
properties of the micro-organism as a plant protection product in comparison to the micro-organism as such,
which is treated in Annex II, Part B, to Directive 91/414/EEC.

1.1.

Applicant

The name and address of the applicant (permanent community address) must be provided as must the name,
position, telephone and fax number of the appropriate person to contact.

Where, in addition, the applicant has an office, agent or representative in the Member State in which the
authorisation is being sought, the name and address of the local office, agent or representative should be
provided, as should the name, position, telephone and fax number of the appropriate person to contact.

(1) USEPA Microbial Pesticide Test Guidelines, OPPTS Series 885, February 1996

(http://www.epa.gov/oppbppd1/biopesticides/guidelines/series885.htm).

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1.2.

Manufacturer of the preparation and the micro-organism(s)

The name and address of the manufacturer of the preparation and of each micro-organism in the preparation
must be provided as must the name and address of each manufacturing plant in which the preparation and
micro-organism are manufactured.

A contact point (preferable a central contact point, to include name, telephone and fax numbers) must be
provided for each manufacturer.

If the micro-organism originates from a producer from which data according to Annex II, Part B, had not been
submitted previously, detailed information on the name and species description, as required in Annex II, Part B,
section 1.3, and on impurities, as required in Annex II, Part B, section 1.4, have to be provided.

1.3.

Trade name or proposed trade name, and manufacturer’s development code number of the preparation
if appropriate

former and current

the
All
preparation referred to in the dossier as well as the current names and numbers must be provided. Full detail of
any differences must be provided. (The proposed trade name must not give rise to confusion with the trade
name of already authorised plant protection products.)

trade names and proposed trade names and development code numbers of

1.4.

Detailed quantitative and qualitative information on the composition of the preparation

(i) Each micro-organism that is subject to the application should be identified and named at the species level.
The micro-organism should be deposited at a recognised culture collection and given an accession number.
The scientific name must be stated, as well as the group assignment (bacteria, virus, etc.) and any other
denomination relevant to the micro-organism (e.g. strain, serotype). In addition, the development phase of
the micro-organism (e.g. spores, mycelium) in the marketed product shall be stated.

(ii) For preparations the following information must be reported:

(cid:151) the content of

the
micro-organism in the material used for manufacturing of plant protection products. These must
include the maximum, minimum and nominal content of the viable and non-viable material,

in the plant protection product and the content of

the micro-organism(s)

(cid:151) the content of formulants,

(cid:151) the content of other components (such as by-products, condensates, culture medium, etc.) and

contaminating micro-organisms, derived from production process.

The contents should be expressed in terms as provided for in Article 6(2) of Directive 78/631/EEC for
chemicals and appropriate terms for micro-organisms (number of active units per volume or weight or any
other manner that is relevant to the micro-organism).

(iii) Formulants must where possible, be identified either by their chemical name as given in Annex I to
in accordance with both IUPAC and CA
Directive 67/548/EEC, or,
nomenclature. Their structure or structural
the
formulants the relevant EC (Einecs or Elincs) number and CAS number where they exist, must be provided.
Where the information provided does not fully identify a formulant, an appropriate specification must be
provided. The trade name of formulants, where they exist, must also be provided.

formula must be provided. For each component of

if not included in this Directive,

(iv) For formulants the function must be given:

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(cid:151) adhesive (sticker)

(cid:151) antifoaming agent

(cid:151) antifreeze

(cid:151) binder

(cid:151) buffer

(cid:151) carrier

(cid:151) deodorant

(cid:151) dispersing agent

(cid:151) dye

(cid:151) emetic

(cid:151) emulsifier

(cid:151) fertiliser

(cid:151) odorant

(cid:151) parfume

(cid:151) preservative

(cid:151) propellant

(cid:151) repellent

(cid:151) safener

(cid:151) solvent

(cid:151) stabiliser

(cid:151) synergist

(cid:151) thickener

(cid:151) wetting agent

(cid:151) miscellaneous (specify).

(v)

Identification of contaminating micro-organisms and other components derived from production process.

Contaminating micro-organisms must be identified as outlined in Annex II, Part B, section 1, point 1.3.

Chemicals (inert components, by-products, etc.) must be identified as outlined in Annex II, Part A, section
1, point 1.10.

Where the information provided does not fully identify a component, such as condensate, culture medium,
etc., detailed information on the composition must be provided for each such component.

1.5.

Physical state and nature of the preparation

The type and code of preparation must be designated according to the (cid:147)Catalogue of pesticide formulation
types and international coding system (GIFAP Technical Monograph No 2, 1989)(cid:148).

Where a particular preparation is not defined precisely in this publication a full description of the physical
nature and state of the preparation must be provided, together with a proposal for a suitable description of the
type of preparation and a proposal for its definition.

1.6.

Function

The biological function must be specified from among the following:

(cid:151) control of bacteria,

(cid:151) control of fungi,

(cid:151) control of insects,

(cid:151) control of mites,

(cid:151) control of molluscs,

(cid:151) control of nematodes,

(cid:151) control of weeds,

(cid:151) other (must be specified).

2.

PHYSICAL, CHEMICAL AND TECHNICAL PROPERTIES OF THE PLANT PROTECTION PRODUCT

The extent to which plant protection products for which authorisation is sought comply with relevant FAO
specifications, as agreed by the Group of Experts on Pesticide Specification of the FAO Panel of Experts on
Pesticide Specifications, Registration Requirements and Application Standards, must be stated. Divergences from
FAO specifications must be described in detail, and justified.

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2.1.

Appearance (colour and odour)

A description of both the colour and odour, if any, and the physical state of the preparation, must be provided.

2.2.

Storage stability and shelf-life

2.2.1.

Effects of light, temperature and humidity on technical characteristics of the plant protection product

(i) The physical and biological stability of the preparation at the recommended storage temperature including
information on the growth of contaminating micro-organisms must be determined and reported. The
conditions under which the test has been performed must be justified.

(ii) Additionally in the case of liquid preparations, the effect of low temperatures on physical stability, must be
determined and reported according to CIPAC (2) Methods MT 39, MT 48, MT 51 or MT 54 as appropriate.

(iii) The shelf life of the preparation at the recommended storage temperature must be reported. Where shelf
life is less than two years, the shelf life in months, with appropriate temperature specifications, must be
reported. Useful information is given in GIFAP (3) Monograph No 17.

2.2.2. Other factors affecting stability

Effect of exposure to air, packaging, etc., on the product stability must be explored.

2.3.

Explosivity and oxidising properties

Explosivity and oxidising properties will be determined as defined in Annex III, Part A, section 2, point 2.2,
unless it can be justified that it is technically or scientifically not necessary to perform such studies.

2.4.

Flash point and other indications of flammability or spontaneous ignition

Flash point and flammability must be determined, as defined in Annex III, Part A, section 2, point 2.3, unless it
can be justified that it is technically or scientifically not necessary to perform such studies.

2.5.

Acidity, alkalinity and if necessary pH value

Acidity, alkalinity and pH will be determined as defined in Annex III, Part A, section 2, point 2.4, unless it can
be justified that it is technically or scientifically not necessary to perform such studies.

2.6.

Viscosity and surface tension

Viscosity and surface tension will be determined as defined in Annex III, Part A, section 2, point 2.5, unless it
can be justified that it is technically or scientifically not necessary to perform such studies.

2.7.

Technical characteristics of the plant protection product

The technical characteristics of the preparation must be determined to permit a decision to be made as to its
acceptability. If tests have to be performed, they must be done at temperatures compatible with survival of the
micro-organism.

2.7.1. Wettability

The wettability of solid preparations which are diluted for use (e.g. wettable powders and water dispersible
granules), must be determined and reported according to CIPAC Method MT 53.3.

(2) Collaborative International Pesticides Analytical Council.
(3) International Group of National Pesticide Manufacturers’ Associations.

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2.7.2.

Persistent foaming

The persistence of
according to CIPAC Method MT 47.

foaming of preparations to be diluted with water, must be determined and reported

2.7.3.

Suspensibility and suspension stability

(cid:151) The suspensibility of water dispersible products (e.g. wettable powders, water dispersible granules,
suspension concentrates) must be determined and reported according to CIPAC Method MT 15, MT 161 or
MT 168 as appropriate.

(cid:151) The spontaneity of dispersion of water dispersible products (e.g. suspension concentrates and water
dispersible granules) must be determined and reported according to CIPAC Methods MT 160 or MT 174 as
appropriate.

2.7.4. Dry sieve test and wet sieve test

In order to ensure that dustable powders have a suitable particle size distribution for ease of application, a dry
sieve test must be conducted and reported according to CIPAC Method MT 59.1.

In the case of water dispersible products, a wet sieve test must be conducted and reported according to CIPAC
Method MT 59.3 or MT 167 as appropriate.

2.7.5.

Particle size distribution (dustable and wettable powders, granules), content of dust/fines (granules), attrition and friability
(granules)

(i) The size distribution of particles in the case of powders, must be determined and reported according to

OECD Method 110.

The nominal size range of granules for direct application must be determined and reported in accordance
with CIPAC MT 58.3, for water dispersible granules in accordance with CIPAC MT 170.

(ii) The dust content of granular preparations, must be determined and reported according to CIPAC Method
MT 171. If relevant for operator exposure the particle size of dust must be determined and reported
according to OECD Method 110.

(iii) The friability and attrition characteristics of granules, must be determined and reported once internationally
agreed methods are available. Where already data are available they must be reported together with the
method used.

2.7.6.

Emulsifiability, re-emulsifiability, emulsion stability

(i) The emulsifiability, emulsion stability and re-emulsifiability of preparations which form emulsions, must be

determined and reported according to CIPAC Method MT 36 or MT 173 as appropriate.

(ii) The stability of dilute emulsions and of preparations which are emulsions, must be determined and

reported according to CIPAC Method MT 20 or MT 173.

2.7.7.

Flowability, pourability (rinsability) and dustability

(i) The flowability of granular preparations must be determined and reported according to CIPAC Method MT

172.

(ii) The pourability (including rinsed residue) of suspensions (e.g. suspension concentrates, suspo-emulsions),

must be determined and reported according to CIPAC Method MT 148.

(iii) The dustability of dustable powders must be determined and reported according to CIPAC Method MT 34

or another suitable method.

2.8.

Physical, chemical and biological compatibility with other products including plant protection
products with which its use is to be authorised

2.8.1.

Physical compatibility

The physical compatibility of recommended tank mixes must be determined and reported.

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2.8.2. Chemical compatibility

The chemical compatibility of recommended tank mixes must be determined and reported except where
examination of the individual properties of the preparations would establish beyond reasonable doubt that
there is no possibility of reaction taking place. In such cases it is sufficient to provide that information as
justification for not practically determining the chemical compatibility.

2.8.3. Biological compatibility

The biological compatibility of
tank mixes must be determined and reported. Effects (e.g. antagonism,
fungicidal effects) on the activity of the micro-organism after mixing with other micro-organisms or chemicals
must be described. The possible interaction of the plant protection product with other chemical products to be
applied on the crops under the expected condition of use of the preparation should be investigated, based on
the efficacy data. Intervals between application of the biological pesticide and chemical pesticides should be
specified, if appropriate, in order to avoid loss of efficacy.

2.9.

Adherence and distribution to seeds

In the case of preparations for seed treatment, both distribution and adhesion must be investigated and
reported; in the case of distribution according to CIPAC Method MT 175.

2.10.

Summary and evaluation of data presented under points 2.1 to 2.9

3.

DATA ON APPLICATION

3.1.

Field of use envisaged

The field(s) of use, existing and proposed, for preparations containing the micro-organism must be specified
from among the following:

(cid:151) field use, such as agriculture, horticulture, forestry and viticulture,

(cid:151) protected crops (e.g. in glasshouses),

(cid:151) amenity,

(cid:151) weed control on non-cultivated areas,

(cid:151) home gardening,

(cid:151) house plants,

(cid:151) stored products,

(cid:151) other (specify).

3.2.

Mode of action

The way by which uptake of the product may occur (e.g. contact, stomach, inhalation) or the pest controlling
action (fungitoxic, fungistatic action, nutrient competition, etc.) must be stated.

It must also be stated whether or not the product is translocated in plants and, where relevant,
translocation is apoplastic, symplastic or both.

if such

3.3.

Details of intended use

Details of the intended use, e.g. types of harmful organisms controlled and/or plants or plant products to be
protected, must be provided.

Intervals between the application of the plant protection product containing micro-organisms and chemical
pesticides, or a list with active substances of chemical plant protection products not to be used together with
the plant protection product containing micro-organisms on the same crop, should also be provided.

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3.4.

Application rate

For each method of application and each use, the rate of application per unit (ha, m2, m3) treated, in terms of
g or kg or l for the preparation and in terms of appropriate units for the micro-organism, must be provided.

Application rates shall normally be expressed in g or kg/ha or in kg/m3 and where appropriate in g or
kg/tonne; for protected crops and home gardening use rates shall be expressed in g or kg/100 m2 or g or
kg/m3.

3.5.

Content of micro-organism in material used (e.g. in the diluted spray, baits or treated seed)

The content of micro-organism shall be reported, as appropriate, in number of active unit/ml or g or any other
relevant unit.

3.6.

Method of application

The method of application proposed must be described fully, indicating the type of equipment to be used, if
any, as well as the type and volume of diluent to be used per unit of area or volume.

3.7.

Number and timing of applications and duration of protection

The maximum number of applications to be used and their timing, must be reported. Where relevant the
growth stages of the crop or plants to be protected and the development stages of the harmful organisms, must
be indicated. Where possible and necessary the interval between applications, in days, must be stated.

The duration of protection afforded both by each application and by the maximum number of applications to
be used, must be indicated.

3.8.

Necessary waiting periods or other precautions to avoid phytopathogenic effects on succeeding crops

Where relevant, minimum waiting periods between last application and sowing or planting of succeeding
crops, which are necessary to avoid phytopathogenic effects on succeeding crops, must be stated, and follow
from the data provided under section 6, point 6.6.

Limitations on choice of succeeding crops, if any, must be stated.

3.9.

Proposed instructions for use

The proposed instructions for use of the preparation, to be printed on labels and leaflets, must be provided.

4.

FURTHER INFORMATION ON THE PLANT PROTECTION PRODUCT

4.1.

Packaging and compatibility of the preparation with proposed packaging materials

(i)

Packaging to be used must be fully described and specified in terms of the materials used, manner of
construction (e.g. extruded, welded, etc.), size and capacity, size of opening, type of closure and seals. It
must be designed in accordance with the criteria and guidelines specified in the FAO (cid:147)Guidelines for the
Packaging of Pesticides(cid:148).

(ii) The suitability of the packaging, including closures, in terms of its strength, leakproofness and resistance to
normal transport and handling, must be determined and reported according to ADR methods 3552, 3553,
3560, 3554, 3555, 3556, 3558, or appropriate ADR Methods for intermediate bulk containers, and, where
for the preparation child-resistant closures are required, according to ISO standard 8317.

(iii) The resistance of the packaging material to its contents must be reported according to GIFAP Monograph

No 17.

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4.2.

Procedures for cleaning application equipment

Cleaning procedures for both application equipment and protective clothing must be described in detail. The
effectiveness of the cleaning procedure must be determined, using e.g. biotests, and reported.

4.3.

Re-entry periods, necessary waiting periods or other precautions to protect man, livestock and the
environment

The information provided must follow from and be supported by the data provided for the micro-organism(s)
and that provided under sections 7 and 8.

(i) Where relevant pre-harvest intervals, re-entry periods or withholding periods necessary to minimise the
presence of residues in or on crops, plants and plant products, or in treated areas or spaces, with a view to
protecting man or livestock, must be specified e.g.:

(cid:151) pre-harvest interval (in days) for each relevant crop,

(cid:151) re-entry period (in days) for livestock, to areas to be grazed,

(cid:151) re-entry period (in hours or days) for man to crops, buildings or spaces treated,

(cid:151) withholding period (in days) for animal feedingstuffs,

(cid:151) waiting period (in days), between application and handling treated products.

(ii) Where necessary, in the light of the test results, information on any specific agricultural, plant health or

environmental conditions under which the preparation may or may not be used must be provided.

4.4.

Recommended methods and precautions concerning: handling, storage, transport or fire

The recommended methods and precautions concerning handling procedures (detailed) for the storage, at both
warehouse and user level of plant protection products, for their transport and in the event of fire must be
provided. Where relevant, information on combustion products must be provided. The risks likely to arise and
the methods and procedures to minimise the hazards arising, must be specified. Procedures to preclude or
minimise the generation of waste or leftovers must be provided.

Where relevant, assessment has to be done according to ISO TR 9122.

The nature and characteristics of protective clothing and equipment proposed must be provided. The data
provided must be sufficient to evaluate the suitability and effectiveness under realistic conditions of use (e.g.
field or glasshouse circumstances).

4.5.

Measures in the case of an accident

Whether arising during transport, storage or use, detailed procedures to be followed in the event of an
accident, must be provided and include:

(cid:151) containment of spillages,

(cid:151) decontamination of areas, vehicles and buildings,

(cid:151) disposal of damaged packaging, adsorbents and other materials,

(cid:151) protection of emergency workers and bystanders,

(cid:151) first aid measures.

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4.6.

Procedures for destruction or decontamination of the plant protection product and its packaging

Procedures for destruction and decontamination must be developed for both small quantities (user level) and
large quantities (warehouse level). The procedures must be consistent with provisions in place relating to the
disposal of waste and of toxic waste. The means of disposal proposed should be without unacceptable influence
on the environment and be the most cost effective and practical means of disposal feasible.

4.6.1. Controlled incineration

In many cases the preferred or sole means to safely dispose of plant protection products and in particular the
formulants contained in it, contaminated materials, or contaminated packaging,
through controlled
incineration in a licensed incinerator.

is

The applicant must provide detailed instructions for safe disposal.

4.6.2. Others

Other methods to dispose of plant protection products, packaging and contaminated materials, where
proposed, must be fully described. Data must be provided for such methods, to establish their effectiveness and
safety.

5.

ANALYTICAL METHODS

Introduction

The provisions of
monitoring purposes.

this section only cover analytical methods required for post-registration control and

It is desirable to have a plant protection product without contaminants, if possible. The level of acceptable
contaminants should be judged from a risk assessment point of view, by the competent authority.

Both production and product must be subject to a continuous quality control by the applicant. The quality
criteria for the product should be submitted.

For analytical methods used for generation of data as required in this Directive or for other purposes the
applicant has to provide a justification for the method used; where necessary separate guidance will be
developed for such methods on the basis of the same requirements as defined for methods for post-registration
control and monitoring purposes.

Descriptions of methods must be provided and include details of equipment, materials and conditions used. The
applicability of existing CIPAC methods must be reported.

As far as practicable these methods must employ the simplest approach,
require commonly available equipment.

involve the minimum cost, and

For this section the following applies:

Impurities

Any component
(including contaminating micro-organisms and/or chemical
substances) other than the specified micro-organism, originating from the
manufacturing process or from degradation during storage

Relevant impurities

Impurities, as defined above, that are of concern for human or animal health
and/or the environment

Metabolites

include products

resulting from degradative and biosynthetic
Metabolites
reactions taking place within the micro-organism or other organisms used to
produce the micro-organism of interest

Relevant metabolites

Metabolites that are of concern for human or animal health and/or the
environment

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Residues

Viable micro-organisms and substances produced in significant quantities by
the
these micro-organisms which persist
micro-organisms and are of concern for human or animal health and/or the
environment.

disappearance

after

the

of

On request the following samples must be provided:

(i)

samples of the preparation;

(ii)

samples of the micro-organism as manufactured;

(iii) analytical standards of the pure micro-organism;

(iv) analytical standards of relevant metabolites and all other components included in the residue definition;

(v)

if available, samples of reference substances for the relevant impurities.

5.1.

Methods for the analysis of the preparation

(cid:151) Methods, which must be described in full, must be provided for the identification and the determination of
the content of the micro-organism in the preparation. In the case of a preparation containing more than
one micro-organism, methods capable of identifying and determining the content of each one should be
provided.

(cid:151) Methods to establish regular control of the final product (preparation) in order to show that it does not

contain other organisms than the indicated ones and to establish its uniformity.

(cid:151) Methods to identify any contaminating micro-organisms of the preparation.

(cid:151) Methods used to determine the storage stability and shelf life of the preparation must be provided.

5.2.

Methods to determine and quantify residues

Analytical methods for the determination of residues, as defined in Annex II, Part B, section 4, point 4.2, must
be submitted unless it is justified that the information already submitted according to the requirements of
Annex II, Part B, section 4, point 4.2, is sufficient.

6.

EFFICACY DATA

The provisions for efficacy data have already been adopted under Commission Directive 93/71/EEC (4).

7.

EFFECTS ON HUMAN HEALTH

For proper evaluation of the toxicity including potential for pathogenicity and infectiveness of preparations
sufficient information should be available on acute toxicity, irritation and sensitisation of the micro-organism. If
possible, additional information on mode of toxic action, toxicological profile and all other known toxicological
aspects of the micro-organism should be submitted. Special attention should be given to co-formulants.

While performing toxicology studies, all signs of infection or pathogenicity should be noted. Toxicology studies
should include clearance studies.

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 authorised. In particular, it must be clear that
the micro-organism used in the preparation, and the conditions of culturing it, are the same for which
information and data are submitted in the context of Annex II, Part B.

A tiered testing system will be applied to the study of the plant protection product.

(4) OJ L 221, 31.8.1993, p. 27.

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7.1.

Basic acute toxicity studies

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, and in particular to establish, or indicate:

(cid:151) the toxicity of the plant protection product,

(cid:151) toxicity of the plant protection product relative to the micro-organism,

(cid:151) the time course and characteristics of the effect with full details of behavioural changes and possible gross

pathological findings at post-mortem,

(cid:151) where possible the mode of toxic action, and

(cid:151) the relative hazard associated with the different routes of exposure.

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 Directive 78/631/EEC. The information
generated through acute toxicity testing is of particular value in assessing hazards likely to arise in accident
situations.

7.1.1. Acute oral toxicity

Circumstances in which required

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 Directive 78/631/EEC can be invoked.

Test guideline

The test must be carried out in accordance with Method B.1 or B.1 bis of Commission Directive 92/69/EEC (5).

7.1.2. Acute inhalation toxicity

Aim of the test

The test will provide the inhalation toxicity to rats of the plant protection product.

Circumstances in which required

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

(cid:151) is used with fogging equipment,

(cid:151) is an aerosol,

(cid:151) is a powder containing a significant proportion of particles of diameter < 50 micrometre (> 1 % on a

weight basis),

(cid:151) is to be applied from aircraft in cases where inhalation exposure is relevant,

(cid:151) is to be applied in a manner which generates a significant proportion of particles or droplets of diameter

< 50 micrometre (> 1 % on a weight basis),

(cid:151) contains a volatile component at greater than 10 %.

Test guideline

The test must be carried out in accordance with Method B.2 of Directive 92/69/EEC.

(5) OJ L 383, 29.12.1992, p. 113.

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7.1.3. Acute percutaneous toxicity

Circumstances in which required

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 Directive 78/631/EEC can be invoked.

Test guideline

The test must be carried out in accordance with Method B.3 of Directive 92/69/EEC.

7.2.

Additional acute toxicity studies

7.2.1.

Skin irritation

Aim of the test

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

Circumstances in which required

The skin irritancy of the plant protection product must always be determined, except where the formulants are
not expected to be skin irritant or the micro-organism is shown not to be skin irritant or where it is likely, as
indicated in the test guideline, that severe skin effects can be excluded.

Test guideline

The test must be carried out in accordance with Method B.4 of Directive 92/69/EEC.

7.2.2.

Eye irritation

Aim of the test

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

Circumstances in which required

The eye irritancy of the plant protection product must be determined, where the formulants are suspected to
be eye irritant, except where the micro-organism is eye irritant or where it is likely, as indicated in the test
guideline, that severe effects on the eyes may be produced.

Test guideline

The eye irritation must be determined in accordance with Method B.5 of Directive 92/69/EEC.

7.2.3.

Skin sensitisation

Aim of the test

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

Circumstances in which required

The test must be carried out where the formulants are suspected to have skin sensitising properties, except
where the micro-organism(s) or the formulants are known to have skin sensitising properties.

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Test guideline

The tests have to be carried out in accordance with Method B.6 of Directive 92/69/EEC.

7.3.

Data on exposure

The risks for those in contact with plant protection products (operators, bystanders, workers), depend on the
physical, chemical and toxicological properties of the plant protection product as well as the type of the
product (undiluted/diluted), formulation type, 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
plant protection product likely to occur under the proposed conditions of use.

In the cases where there is particular concern on the possibility of dermal absorption based on the information
for the micro-organism available in Annex II, Part B, section 5, or from the information provided for the
preparation in the present section of Annex III, Part B, further dermal absorption data can be necessary.

Results from exposure monitoring during production or use of the product must be submitted.

The abovementioned information and data must provide the basis for the selection of appropriate protective
measures including personal protective equipment to be used by operators and workers and to be specified on
the label.

7.4.

Available toxicological data relating to non-active substances

A copy of the notification and the safety data sheet submitted in the context of European Parliament and
Council Directive 1999/45/EC (6) 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 Directive 88/379/EEC (7) must be submitted for each formulant. All other
available information should be submitted.

7.5.

Supplementary studies for combinations of plant protection products

Aim of the test

In certain cases it may be necessary to carry out the studies as referred to under points 7.1 to 7.2.3 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 possibility for exposure to the
combination of the products concerned and available information or practical experience with the products
concerned or similar products.

the individual plant protection products,

7.6.

Summary and evaluation of health effects

A summary of all data and information provided under paragraphs 7.1 through 7.5, must be submitted, and
relevant evaluative and
include a detailed and critical assessment of
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 database.

those data in the context of

8.

RESIDUES IN OR ON TREATED PRODUCTS, FOOD AND FEED

The same provisions as detailed in Annex II, Part B, section 6, apply; the information required according to this
section has to be provided unless it is possible to extrapolate the residue behaviour of the plant protection
product on the basis of the data available for the micro-organism. Special attention should be paid towards the
influence of formulation substances on the residue behaviour of the micro-organism and its metabolites.

(6) OJ L 200, 30.7.1999, p. 1.
(7) OJ L 76, 22.3.1991, p. 35.

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9.

FATE AND BEHAVIOUR IN THE ENVIRONMENT

The same provisions as detailed in Annex II, Part B, section 7, apply; the information required according to this
section has to be provided unless it is possible to extrapolate the fate and behaviour of the plant protection
product in the environment on the basis of the data available in Annex II, Part B, section 7.

10.

EFFECTS ON NON-TARGET ORGANISMS

Introduction

(i) The information provided, taken together with that for the micro-organism(s), must be sufficient to permit
an assessment of the impact on non-target species (flora and fauna), of the plant protection product, when
used as proposed. Impact can result from single, prolonged or repeated exposure, and can be reversible, or
irreversible.

(ii) The choice of the appropriate non-target organisms for testing of environmental effects should be based on
the information on the micro-organism, as required in Annex II, Part B, and on the information on the
formulants and other components, as required by sections 1 to 9 of the present Annex. From such
knowledge it would be possible to choose the appropriate test organisms, such as organisms closely related
to the target organism.

(iii) In particular, the information provided for the plant protection product, together with other relevant

information, and that provided for the micro-organism, should be sufficient to:

(cid:151) specify the hazard symbols, the indications of danger, and relevant risk and safety phrases for the

protection of the environment, to be mentioned on packaging (containers),

(cid:151) permit an evaluation of

the short- and long-term risks for non-target species (cid:151) populations,

communities, and processes as appropriate,

(cid:151) permit an evaluation whether special precautions are necessary for the protection of non-target

species.

(iv) There is a need to report all potentially adverse effects

found during routine investigations of
environmental effects and to undertake and report such additional studies which may be necessary to
investigate the mechanisms involved and assess the significance of these effects.

(v)

In general, much of the data relating to impact on non-target species, required for authorisation of plant
protection products, will have been submitted and evaluated for the inclusion of the micro-organism(s) in
Annex I.

(vi) Where exposure data are necessary to decide whether a study has to be performed, the data obtained in

accordance with the provisions of Annex III, Part B, section 9, should be used.

For the estimation of exposure of organisms all relevant information on the plant protection product and
on the micro-organism must be taken into account. Where relevant the parameters provided for in this
section should be used. Where it appears from available data that the plant protection product has a
stronger effect
the plant
protection product have to be used for the calculation of relevant effect/exposure ratios.

the data on effects on non target organisms of

than the micro-organism,

(vii) In order to facilitate the assessment of the significance of test results obtained, the same strain of each
relevant species should where possible be used in the various specified tests for effects on non target
organisms.

10.1.

Effects on birds

The same information as provided in Annex II, Part B, section 8, point 8.1, has to be reported where it is not
possible to predict the effects of the plant protection product on the basis of the data available for the
micro-organism, unless it can be justified that exposure of birds is unlikely to occur.

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10.2.

Effects on aquatic organisms

The same information as provided in Annex II, Part B, section 8, point 8.2, has to be reported where it is not
possible to predict the effects of the plant protection product on the basis of the data available for the
micro-organism, unless it can be justified that exposure of aquatic organisms is unlikely to occur.

10.3.

Effects on bees

The same information as provided in Annex II, Part B, section 8, point 8.3, has to be reported where it is not
possible to predict the effects of the plant protection product on the basis of the data available for the
micro-organism, unless it can be justified that exposure of bees is unlikely to occur.

10.4.

Effects on arthropods other than bees

The same information as provided in Annex II, Part B, section 8, point 8.4, has to be reported where it is not
possible to predict the effects of the plant protection product on the basis of the data available for the
micro-organism, unless it can be justified that exposure of arthropods other than bees is unlikely to occur.

10.5.

Effects on earthworms

The same information as provided in Annex II, Part B, section 8, point 8.5, has to be reported where it is not
possible to predict the effects of the plant protection product on the basis of the data available for the
micro-organism, unless it can be justified that exposure of earthworms is unlikely to occur.

10.6.

Effects on soil micro-organisms

The same information as provided in Annex II, Part B, section 8, point 8.6, has to be reported where it is not
possible to predict the effects of the plant protection product on the basis of the data available for the
micro-organism, unless it can be justified that exposure of non target soil micro-organisms is unlikely to occur.

10.7. Additional studies

Expert judgement is required to decide whether additional studies are necessary. Such decision will take into
consideration the available information in this and other sections, in particular data on the specificity of the
micro-organism, and the expected exposure. Useful information may also be available from the observations
carried out in efficacy testing.

Special attention should be given to possible effects on naturally occurring and deliberately released organisms
of
the product with IPM should be taken into
consideration.

In particular the compatibility of

importance in IPM.

Additional studies might include further studies on additional species or higher tier studies such as studies on
selected non-target organisms.

Before performing such studies, the applicant shall seek agreement of the competent authorities on the type of
study to be performed.

11.

SUMMARY AND EVALUATION OF ENVIRONMENTAL IMPACT

A summary and evaluation of all data relevant to the environmental impact should be carried out according to
the guidance given by the competent authorities of
the Member States concerning the format of such
summaries and evaluations. It should include a detailed and critical assessment of those data in the context of

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relevant evaluative and decision making criteria and guidelines, with particular reference to the risks for the
environment and non-target species that may or do arise, and the extent, quality and reliability of the database.
In particular the following issues should be addressed:

(cid:151) prediction of distribution and fate in the environment, and the time courses involved,

(cid:151) identification of non-target species and populations at risk, and prediction of the extent of potential

exposure,

(cid:151) identification of precautions necessary to avoid or minimise contamination of the environment, and for the

protection of non-target species.(cid:146)