Opinion of the Scientific Committee on Toxicity, Ecotoxicity and the Environment (CSTEE) on the "Technical guidance document in support of the Directive 98/8/EC concerning the placing of biocidal products on the market: Guidance on data requirements for active substances and biocidal products - Final version, 7 December 1999" - Opinion expressed at the 13th CSTEE plenary meeting, Brussels, 4 February 2000.
Summary
The CSTEE welcomes the
regulation of biocidal products
as expressed in the Directive
98/8 EC and the present
Technical Guidance Document.
The most important points that
the CSTEE wants to raise are
the following:
The testing requirements consist of a common core data set and an additional data set. According to the CSTEE's opinion, it would have been preferable with a smaller common core data set for identification of human health hazards. The demand for additional tests would then depend on the anticipated possibility for human exposure and the outcome of the core data set. The test strategy for identification of human health hazards would in that case be more similar to the approach for environmental effects. However, as the test strategy is already decided upon, the criteria for waiving of common core data requirements for human health effects should be more elaborated. For those product categories where the human exposure is very low or of short duration, the testing requirements for chronic toxicity, carcinogenicity and 2-generation reproduction toxicity should be reassessed. The opposite is observed for the ecotoxicological part, and some tests should be required in all cases.
This document only deals
with the effects part of risk
assessment, whereas exposure
assessment and complete risk
assessment will be described in
other technical notes for
guidance. It will be important
to include consideration of the
formation and fate of
metabolites in the
environmental risk assessment
of biocidal products.
The CSTEE recommends
that the Biocidal Products
Directive be revised within a
short time frame in order to
remove scientific
inconsistencies (such as the
testing requirements for fungi,
micro-organisms and viruses as
if they were chemical entities
(Annex IVA) or the requirement
for carcinogenicity testing in
a non-rodent species).
Introduction - terms of
reference
The European Parliament
and the Council on 16 February
1998 adopted Directive 98/8/EC,
concerning the placing of
biocidal products on the
market. The directive covers 23
product types, grouped in 4
main groups, i.e.
disinfectants, preservatives,
pest control products and other
products such as antifouling
paints. Only active substances
that are listed in Annex 1, 1A
or 1B (positive lists) of the
Directive will be authorised
for use in biocidal products.
The Commission is
developing different guidance
documents to facilitate the
day-to-day implementation of
the Directive. The document
submitted to the CSTEE for
opinion is a document related
to the data requirements for
active substances and biocidal
products, that aims to give
detailed and practical guidance
on which studies and other data
are required when applying for
authorisation according to the
Directive. The general question
originally presented to the
CSTEE was the following:
"In the light of the
provisions of the Biocidal
Products Directive 98/8/EC does
the Scientific Committee
believe that the TNG on data
requirements for active
substances and biocidal
products is appropriate to
carry out a proper risk
assessment for the active
substances and relevant
biocidal products?"
The question posed
should literally be answered by
a no, since the document mainly
deals with the effects part of
risk assessment. However, the
CSTEE has been informed that
procedures for risk assessment
including exposure assessment
will be covered in one of the
other guidance documents. Thus,
the CSTEE interprets the
question to mean if the data
requirements are appropriate to
carry out a risk assessment if
satisfactory exposure
assessments are provided. This
interpretation has been
confirmed by a representative
from DG Environment and the
original general question was
reworded as follows
(ENV.E2/WC/jv D(99) of 25
November 1999):
In the light of the
provisions of the Biocidal
Products Directive 98/8/EC does
the Scientific Committee
believe that the TNsG on data
requirements for active
substances and biocidal
products is appropriate to
identify the hazards of active
substances and biocidal
products?
General Comments
The general structure of
the Biocidal Products Directive
builds on the Council Directive
91/414/EEC on Plant Protection
Products (pesticides). This may
be understandable given that
many pesticides may also be
used as biocides. However, the
exposure scenarios with respect
to humans may be quite
different when biocides are
compared to pesticides. For
instance, biocides are
generally not used on plants
for human consumption. Further,
human exposure to many biocides
will be short-term and/or
intermittent. Thus, simply
duplicating pesticide test
requirements for biocides does
not seem warranted.
Ideally, the CSTEE would
have recommended a test
strategy for identification of
human health hazards which had
been exposure driven. The need
for extensive toxicological
testing should be dictated by
the level, frequency and
duration of exposure. This
would have been accomplished by
a tiered approach to testing
with a smaller common core,
similar to the tiered scheme
for testing for environmental
effects.
The CSTEE realises that
the plans for implementing the
Biocidal Products Directive are
far advanced and that the
Technical Guidance Document has
been agreed upon by experts
representing regulatory
authorities in Member States.
In this document the common
core data is regarded as a
minimum requirement. However,
waiving of the data
requirements is possible in
certain cases. The CSTEE will
therefore give specific
comments to the waiving
process, rather than argue for
a tiered test strategy for
human health effects.
Testing resources should
be spent effectively addressing
the most important concerns for
possible health effects. Also,
it is difficult to envisage how
adhering to the present test
requirements will avoid a
possible conflict with the
requirement that the amount of
animal testing shall be
minimised.
The CSTEE is aware of a
proposal from The Netherlands
and the United Kingdom calling
for the development of
operational predictive exposure
models for use in the
authorisation of biocidal
products. The CSTEE strongly
endorses this proposal, since
exposure models will be an
essential part in the future
risk assessment of exposure to
biocidal products. Such models
will presumably also be of
great utility in the waving
process with respect to testing
requirements for identification
of human health hazards, as
well as for the tiered testing
system for environmental
effects assessment.
For the assessment of
environmental hazards, the
guidance document mostly
follows the Technical Guidance
Document on industrial
chemicals (existing and
notified substances). For
biocides, the exposure
scenarios for the
identification of the
environmental risk could be
related to those used, for
example, for pesticides, for
industrial chemicals or for
veterinary drugs.
The CSTEE considers it
very difficult to include in a
single scheme, general guidance
for all of the different types
of biocides (23 categories).
Depending on the extremely
different emission and use
patterns which could occur for
the various biocidal products,
the risk assessment procedures
(which are to be defined in
another document) could be
quite different. Therefore, the
data requirements should be
such as to allow for the proper
kind of risk assessment (i.e.
local, regional or continental)
for any specific biocidal
product category. The final
data requirements should be
revised after the exposure
scenarios are developed.
The potential for
bioconcentration/bioaccumulation
is mentioned in the proposal,
however, the likelihood for
biomagnification through
aquatic and terrestrial food
chains is not really
considered.
For chemicals with a
high/medium persistence and
potential for
bioconcentration/bioaccumulation,
the notifier should also
provide additional information
on the food chain transfer
potential of the active
substance. Mammalian and fish
toxicokinetic studies could
provide the basis for modelling
the biomagnification potential.
Additional studies using oral
and/or combined exposures
should be required for aquatic
as well as terrestrial
organisms.
Although the title of
the document is given as
"Technical Guidance Document",
the body of the text uses the
term "Technical Notes for
Guidance".
Specific Comments
Given the complexity of
the Biocides Directive and the
very many scientific issues
presented in the Technical
Guidance Document, a lack of
discussion does not necessary
mean that the CSTEE is in
agreement with all detailed
statements. The CSTEE has
concentrated its comments on
what is felt being the more
important issues.
The CSTEE recognises the
important revision activity
which has been initiated on the
Technical Guidance Document
regarding risk assessment of
industrial chemicals, in which
also biocides are included.
Chapter 1. Introduction to
and general guidance on data
requirements
1.2. Expert judgement.
The CSTEE agrees that
expert judgement could be
needed in some cases, as
mentioned in the document.
Nevertheless, in order to
ensure transparency, some
procedures should be carefully
specified and detailed.
Deviations from these generic
scenarios should be clearly
justified.
1.3. Use of QSAR data
In order to minimise
experimental testing, the use
of QSAR may also be suggested.
However, when using QSAR data
it must be considered that
these products are
intentionally designed to
produce effects on living
organisms, and therefore
similarity in the chemical
structure alone cannot be
accepted, and care must be
taken to use QSAR information
obtained from chemicals with a
similar mode of action.
Moreover, in order to take into
account the higher level of
uncertainty of predicted data
in comparison to experimental
data, different rules (i.e.
stricter application factors
and triggers) should be applied
to QSAR information.
1.4. Waiving
It must be remembered that long-term toxicological tests were developed in order to reveal structural and functional effects occurring after exposure of experimental animals for most of their life-span. The development of such effects needs either a long-term accumulation of the toxic entity in the body, a long-term accumulation of molecular/biochemical tissue change or both. Thus, testing for long-term toxicity in animals as models for human hazard is mainly relevant in those situations where human exposure is longer-term; an exception being potent genotoxicants which may act as carcinogens after short-term exposure. The CSTEE considers that the set of conditions which must be met for waiving are too restrictive. Certain specific conditions are also unclear, such as the condition that the general public shall not be exposed. There is an obvious need for good exposure data in order to decide under which use and exposure conditions one is able to waive long-term toxicological tests.
The term "expressive
toxicokinetics" in the last
bullet point must be a
misnomer.
Regarding points 4.2,
4.3 and 4.4 there may be a
possibility for waiving for the
sub-chronic toxicity study in
the second animal species, the
teratogenicity study in the
second animal species and the
carcinogenicity studies in both
species. However, no mention of
the possibility of waiving for
chronic toxicity and
2-generation reproductive
toxicity is presented here,
although this is stated in the
biocidal products directive and
pointed out in section 6.5
(chronic toxicity) and section
6.8 (reproductive toxicity),
respectively.
1.5 Testing of
metabolites
The document does not
give specific recommendations
on metabolites, and indicates
that proposals will be produced
in the future, after
considering the document that
is currently under discussion
for plant protection products.
The CSTEE recognises the
similarity between plant
protection products and certain
biocide types when addressing
the relevance of metabolites;
however the draft document
mentioned under point 1.5. has
not been submitted to the CSTEE
and therefore the relevance of
this document cannot be
addressed. In any case, clear
guidance on metabolite's
relevance, the testing strategy
and data requirement for
relevant metabolites is
essential for a proper hazard
and risk assessment of
biocides. The relevance of
metabolites should not be based
only on their amount, but also
on their potential biological
activity.
Chapter 2, part A. Common
core data set for active
substances
5. Effectiveness against
target organisms
The issue of
effectiveness against target
organisms is outside the remit
of this opinion and the tasks
of the CSTEE.
6. Toxicological and
metabolic studies
The testing requirements are essentially the same as for pesticides, and they must be regarded as sufficient for proper hazard identification concerning human health, together with any additional data needed according to chapter 3. However, from a scientific standpoint we question if all the toxicological tests are needed for all product categories. Both from a use and exposure perspective and considering the very large number of chemicals that will have to be tested, a tiered approach would have been a better alternative. A base set of tests similar to that for new industrial chemicals is judged to have been appropriate to carry out the hazard assessment for many compounds in product categories where the human exposure is very low/of short duration. The need for tests for chronic toxicity, carcinogenicity, teratogenicity and 2-generation reproductive toxicity would then have been assessed with regard to the possibility for higher/prolonged human exposure as well as findings in the base set, and from needs for environmental effects assessment.
The need for long-term
testing may be illustrated from
requirements laid down in the
field of pharmaceuticals.
According to international
harmonisation of testing
requirements for
carcinogenicity, this is
normally only required when the
expected clinical use is
continuous for at least 6
months.
Metabolism studies. If
the parental compound is the
toxic one, it might be enough
to determine the major
metabolic pathways.
Nevertheless, for
bioaccumulating chemicals, the
information submitted should
always be enough for a proper
quantitative assessment of the
potential for bioaccumulation
and biomagnification through
the food chain.
6.7 Carcinogenicity
study.
There is an error in
that the Directive requires
that carcinogenicity studies
should be carried out in
another mammalian species in
addition to the rodent. Such
studies are normally performed
in the rat and mouse,
occasionally in the hamster,
very seldom in monkeys and
never in dogs.
6.8.1.Teratogenicity
test.
Testing in the rabbit
might be sufficient in most
cases. Testing in a second
species (the rat) should be
dictated by the outcomes of the
rabbit study and the rat
reproductive study(ies).
7. Ecotoxicological
profile
Toxicity test on
terrestrial organisms. The use
of the equilibrium partitioning
method to estimate the
potential risk for terrestrial
(soil) organisms is not
considered appropriate for
chemicals which are
biologically active, and
therefore possess specific
mechanisms of action on certain
living organisms.
In addition, the lack of
direct release on the soil
surface does not mean absence
of exposure for soil organisms.
Transfer of chemicals among
environmental compartments
(i.e. water to soil via
irrigation; air to soil via
deposition) represents indirect
routes that are relevant unless
a rapid degradation in the
receiving compartment can be
expected.
Therefore, toxicity test
with soil organisms
(micro-organisms, soil and/or
ground dwelling invertebrates,
plants) should be requested as
a general rule. Only, when no
direct release to soil must be
expected and a rapid
degradation in water and/or air
could be predicted, these tests
should not be conducted.
Fate and behaviour in
the environment. The biotic
degradation studies
(ready/inherent degradation)
included in the core data set,
do not provide information on
the metabolites that can be
formed. The incorporation of
toxicity tests during and/or at
the end of the degradation
studies is considered a proper
tool for the evaluation of
relevant (toxic) metabolites.
The core data set should
include a degradation pathway
for the molecule in water, soil
and air, but the required
studies (aerobic and anaerobic
degradation in soil,
water/sediment studies,
simulation tests) are only
considered as additional
assays.
If the ecotoxicological
profile must include all
relevant metabolites (i.e.
those representing more than
10% of the applied dose) the
core data set should allow a
proper identification of
relevant metabolites.
Testing strategy for
fresh, brackish and marine
water. The use of appropriate
organisms for toxicological
testing in the different
aquatic environments should be
better defined. In some cases,
freshwater species that can be
used in the marine environment
are indicated, but the
possibility of using marine
species in the brackish
environment should be better
clarified by defining salinity
thresholds. A definition of
"brackish waters" is required
as well as clarification for
the testing conditions for the
brackish environment.
In line 941, a reference
to the "quality of water" is
included. The CSTEE considers
that the sentence should be
amended to include the quality
of water and other
environmental resources.
The sentence under lines
1068-1069 is not clear. It is
obvious that the relationship
between dose and adverse effect
must be reported in any case,
even for single-dose tests.
Lines 1070-1073. The use
of the same strain of organisms
for ecotoxicological studies
everywhere in Europe is
practically impossible. For
higher organisms it could be
enough to use reference
substances, as normally
suggested in testing
guidelines.
Under point 7.4.1.1
testing on one freshwater and
one marine fish species should
be considered as the minimum
requirement when several
aquatic compartments are
expected to be contaminated.
Under point 7.4.1.2,
considering the complexity of
the marine ecosystem, a testing
strategy including tests on at
least two different taxonomic
groups of invertebrates, for
example arthropods and
molluscs, and organisms living
in water and sediments, should
be suggested at least for
chemicals likely to be
discharged in the marine
environment unless the core
data set demonstrate that the
substance is of very low
toxicity for invertebrates.
10. Summary and
evaluation
This section is the
hazard and effects assessment
of the active substances. Since
this important section is
intended to include a risk
assessment involving the active
substance, such as describing
NOAELs, MOS, PECs and PNECs, it
would have been relevant to
review also the guidance
documents on risk assessment
and on guidance for inclusion
into Annex 1
Chapter 2, part B. Common
core data set for biocidal
products
6. Toxicological studies
(acute toxicity, skin and eye
irritation, skin sensitisation)
6.6. Information related
to the exposure of the biocidal
product. As this information
will be very important in the
overall evaluation, guidance
should be given for exposure
assessment. (A reference is
given to the report "Assessment
of human exposures to
biocides", not submitted to the
CSTEE). As stated previously,
exposure assessment of the
biocidal product ideally should
be done first, as the outcome
is relevant for deciding on
which common core, or
additional, toxicological data
should be included for biocidal
products and active substances.
7. Ecotoxicological data
The document only
presents very general
statements on the need of
ecotoxicological testing on
biocidal products. More
guidance is required on when
the formulation should be
suspected to influence the fate
and/or the ecotoxicological
properties of the active
substance. Alternatively, a
general requirement of a
limited set of ecotoxicity
tests should be required for
the formulation, unless it can
be demonstrated that the
information on the active
substance is enough to conduct
the risk assessment.
10. Summary and
evaluation
At present, information
provided by the document does
not allow for a risk
assessment. The first sentence
should be changed as follows:
"This section will be the risk
assessment of the biocidal
product".
Guidance for the risk
assessment of the biocidal
product is said to be given in
a guidance document not
submitted to the CSTEE.
Chapter 2.5. Product type
specific data set regarding
ecotoxicological profile,
including environmental fate
and behaviour
The specific testing
requirements for different
product types, either in part A
or in part B, as well as in the
overview table, must be
considered as a preliminary
indication, and must be
carefully revised in relation
to emission scenarios.
For products to be used
in fish farming it is important
that degradation studies in
marine waters be included
(7.1.2.4), in addition to
studies that demonstrate
partition of a chemical
compound between water and
sediment. For persistent
compounds which partition to
the sediment it is also
necessary to include effect
studies in relation to sediment
living and feeding organisms.
The same requirements should
apply to product type 17:
piscicides. For areas where the
use patterns indicate that the
biocides may reach the soil
compartment it is necessary to
require degradation studies in
soil. Mobility can be assessed
from adsorption data, however
degradation in soil requires
separate studies for risk
assessment. It is not
sufficient with tests to
elucidate easy degradation to
do a risk assessment.
Part A. Additional data
set and guidance for active
substances
A better description of
the different product-types and
of use and emission patterns is
needed in order to avoid
misunderstandings. For example
for Product type 1: Human
hygiene products, it is stated
that the release is usually
diffuse. What does this really
mean? Pollution sources may be
point sources or diffuse
sources. In this case the major
emission patterns seem to be
point sources (i.e. domestic
sewage). If "diffuse" means use
in closed and controlled
systems, not likely to attain
the environment, this could
justify the need for no
supplementary testing, but it
should be better clarified. The
same considerations apply to
Product types 4, 5, 20 and 22.
Exposure data for e.g.
product type 1: human hygiene
biocidal products, type 2:
private area and health area
disinfectants and type 4: food
and feed area disinfectants are
highly relevant also for the
human health risk assessment.
Part B. Additional data
set and guidance for active
products
An anaerobic degradation
study is requested for
substances expected to reach
animal manure. However, the
degradation conditions in
animal manure are expected to
be different from those
produced under the standard
soil anaerobic degradation
study. A specific test for
degradation in manure should be
requested.
Chapter 3, Part A.
Additional data and guidance
for active substances
The outline of this
chapter is difficult to follow.
It would benefit from an
introduction, explaining why
and when additional data may be
required.
6. Toxicological and
metabolic studies
It should be considered
to reduce the common core data
set and instead increase the
number of additional data in
order to make optimal use of
animal testing, yet reducing
the number of animals as much
as possible.
6.9 Neurotoxicity study,
third bullet point. In
situations were there also is
exposure to pregnant females
and infants, a developmental
neurotoxicity study (draft OECD
guideline 426) may be
considered.
7. Ecotoxicological
profile
Risk for sediment
dwelling organisms. The
document includes guidance on
the toxicity tests that should
be conducted, but no clear
specifications on when these
toxicity tests should be
required. Proper criteria and
trigger values are required, as
well as the assessment factors
and comparisons between the
laboratory toxicity data and
the time-related exposure
expected to be found in the
real environment.
Guidance on appropriate
test methods. Some of the
recommended guidelines are very
specific and not generally
available. These guidelines
have not been included in the
documents presented to the
CSTEE and therefore it is not
possible to comment on the
appropriateness of these
guidelines.
Figure 1. The
biodegradation testing strategy
covers the fate, but not the
route of degradation.
Figures 2 and 3.1,
Appendices 1 and 2: Includes
decisions based on the final
risk characterisation and
therefore the document does not
present enough information for
a proper assessment.
Figure 3.2: Is not
acceptable, because the risks
for soil organisms should not
be estimated from data on
aquatic organisms.
Figure 4: Should include
the risk for food-chain
biomagnification.
Chapter 3, Part B.
Additional data and guidance
for biocidal products
This part would also
benefit from an introduction.
6. Toxicological data
No comments.
7. Ecotoxicological data
No additional comments.
Chapter 4. Data requirements
for substances of concern
No comments.
Chapter 5. Data requirements
for active substances and
biocidal products in regard to
simplified procedures
No comments.