United Stales
Environmental Prelection
Agency
Office ol Prevention,
Pesticides, and Toxic Substance
Washington DC 20460
EPA743-R-94-001
March 1994
Office of Pollution Prevention and Toxics
x-xEPA
U.S. EPA/EC Joint Project on the
Evaluation of (Quantitative) Structure
Activity Relationships
'
* Heaci
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OS EPA / EC JOINT PROJECT
ON THE EVALUATION OF
(QUANTITATIVE) STRUCTURE ACTIVITY RELATIONSHIPS
July 1593
Final Report
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US EPA / EC JOINT PROJECT ON THE EVALUATION OF
(QUANTITATIVE) STRUCTURE ACTIVITY RELATIONSHIPS
Contents
1. Background 3
2. Project Design 5
2.1. Competent Bodies 5
2.2. Confidentiality , 5
• 2.3. How the project was organized 6
3. Pfytificjj(ion.i schemes in the EXT and in the US 7
3.1. Essential features of the notification scheme for new chemical
substances in the European Community 7
3.2. Essential features of the notification scheme for new chemical
substances in the United States 9
4. Results 13
4.1. Introduction 13
4.1.1. Evaluation criteria 13
4.1.2. Complicating factors 13
4.2. Detailed analysis of results 15
4.2.1. Physico-chemical and environmental fate parameters 15
4.2.1.1. Boiling point 15
4.2.1.2. Vapour pressure ' 16
4.2.1.3. Water solubility . 17
4.2.1.4. Partition coefficient 18
4.2.1.5. Biodegradation 20
4.2.1.6. Hydrolysis 21
4.2.1.7. Soil sorption 21
4.2.1.8. Photodegradation 21
4.2.2. Ecotox icity parameters 22
4,2.2.1. Toxieity to aquatic organisms 22
4.2.2.2. Classification "Dangerous for the Environment" 24
4.2.3. . lexicological properties/health effects • 27
4.2.3.1. Absorption 27
4.2.3.2. Acute toxieity 28
4.2.3.3. Irritation 31
4.2.3.3.i Skin irritation 31
4.2.3.3.ii Eye irritation 33
4.2.3.3.iii Respiratory irritation 36
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5.1
5.1.1.
5.
5.
5.
5.
5.
5.
.2.
.2.1
.2.2
.2.3
.2.4
.2.5
4.2.3.4. Sensitisation 36
4.2.3.5. Repeated dose toxicity 39
4.2.3.6. Mutagenicity 42
4.2.3.7. ..Other effects . 43
w
5. Overall conclusions 45
Conclusions: US perspective 45
Introduction/Overview 45
Results 45
Physico-chemical properties . 46
Biodegradability 47
Health effects . 48
_ Ecotoxicity .. " 50
Other considerations 51
5.1.3. • Summary 52
5.2. Conclusions: EC perspective S3
5.2.1. Introduction S3
5.2.2. Synopsis 53
5.2.2.1. Physico-chemical end-points 53
5.2.2.2. Biodegradation 53
5.2.2.3. Health effects 53
5.2.2.4. Ecotoxicity 54
5.2.3. Overview 54
ANNEX 1: US EPA and EC experts within this joint project
ANNEX 2: Companies which gave permission to use their substances data
within this project
ANNEX 3: Generic chemical descriptions of the chemicals in this project
ANNEX 4: Boiling point: comparison of lest results and predictions
ANNEX 5: Vapour pressure: comparison of test results and predictions
ANNEX 6: Water solubility: comparison of test results and predictions
ANNEX 7: Partition coefficient: comparison.of test results and predictions
ANNEX 8: Biodegradation: comparison of test results and predictions
ANNEX 9; Toxicity to fish: comparison of test results and predictions
ANNEX 10: Toxicity to Daphnia: comparison of test results and predictions
ANNEX 11: Toxicity to algae: comparison of test results and predictions
ANNEX 12: Acute oral toxicity: comparison of test results and predictions
ANNEX 13: Skin and eye irritation: comparison of test results and predictions .
ANNEX 14: Systemic toxicity: comparison of test results and predictions
ANNEX 15: Mutagenicity: comparison of test results and predictions
APPENDIX 1: Directive 67/548/EEC, sixth amendment
APPENDIX 2: EC summary notification dossier
APPENDIX 3: Annex VI to Directive 67/548/EEC
APPENDIX 4: Toxic Substances Control Act: premanufacture notification
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I. Background
In October 1989 the OECD organized, in the context of that organizations chemicals programme, a
workshop on notification schemes for new chemicals. The major objective of this meeting was to
review, in the light of the 1981 OECD Council Act on the Mutual Acceptance of Data, the notification
schemes applied by the Member Countries of the OECD. The 1981 Council Act recommended mat
countries require manufacturers/importers to supply a certain minimum pre-marketing data set (MPD)
before placing a new chemical substance on the market: the test data to be generated experimentally
using standard OECD testing guidelines.
From the information presented at the workshop, it was apparent that the majority of Member
Countries had introduced notification schemes based on the principle of an MPD although the content
of the testing package often diverged from that recommended in the Council Act. One notable
exception to this general tendency was, however, the United States of America where the notification
scheme for new chemicals established under the 1976 Toxic Substances Control Act (TSCA) did not,
a prjori. oblige manufacturers/importers to carry out testing before placing a new substance on the
market. Essentially, the scheme established under TSCA required the submission of available data,
often extremely limited, to the regulatory authority, in this case the Environmental Protection Agency
(EPA). Faced with this paucity of experimental data, the EPA were obliged to place increasing
reliance on techniques known collectively as (Quantitative) Structure Activity Relationships (Q)SAR,
in order to carry out a preliminary hazard/risk assessment of notified substances: (Q)SARs are
predictive methods which estimate the properties (activity) of a chemical e.g. melting point, vapour
pressure, toxicity and ecotoxicity, on the basis of its structure.
One of the most important recommendations from the OECD workshop was that an attempt be made
to evaluate the predictive power of the (Q)SAR, used by the EPA. It was in addition recommended
that this evaluation be achieved by applying the (Q)SAR methods to chemicals for which extensive
test data were already available and then comparing the properties predicted by SAR with the
properties observed from experimental testing.
In the European Community, a new chemicals notification scheme came into force in 1981 in
accordance with the rules laid down in Directive 79/831/EEC, being the sixth amendment to Directive
67/S48/EEC on the classification, packaging and labelling of dangerous substances. The notification
procedure required manufacturers/importers to submit a standardized data set (roughly similar to the
OECD MPD) with experimental data being generated according to prescribed test methods
(essentially equivalent to OECD test guidelines). By 1989, the EC notification scheme had been in
force for over 8 years and several hundred notifications had been received. The OECD workshop
therefore recommended that the predictive power of the (Q)SAR methods used by the EPA should be
evaluated against the data submitted on chemicals in the context of the notification scheme established
in the European Community. ........
The recommendations from the OECD workshop were therefore the starting point for the collaborative
project between the European Community and the United States of America, which is described in
this report. It must be emphasized that the scope of this project was limited to that defined by the
OECD workshop namely: an evaluation of the predictive power of the (Q)SAR techniques used by
the EPA in the context of the new chemicals notification scheme established under the Toxic
Substances Control Act. The project is not, and was not designed to be, an evaluation of QSAR
techniques in general.
N B. : New chemicals notification schemes in-the United Stales of America and the European Community.
In order to understand fully the design of the collaborative project, its implementation and the conclusions which
can be drawn from i(. it is essential to understand the details of the notification schemes as they are applied in
•the United States of America under the Toxic Substances Control Act and in the European Community under
Directive 67/,548/EEC as amended. Descriptions of ihe schemes are to be found in chapter 3 of this report.
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2. Project Design
2.1. Competent Bodies
In the United States of-America, the Agency responsible for processing the new chemicals
notifications and die body responsible for the realization of this collaborative project is die
Environmental Protection Agency.
In die European Community, each of die 12 Member Countries has designated national Competent
Authorities responsible for die implementation of die notification scheme established under Directive
67/548/EEC as amended. The Commission of die European Communities is also involved in die
implementation of die notification scheme as well as being responsible for ensuring co-ordination
between die Member States. For the purposes of this project, die Commission of die European
Communities was mandated by die national Competent Authorities to act as die contact point with die
EPA. For die detailed realization of die project die input from die EC was co-ordinated by die
Commission with advice and support from die national Competent Authorities.
Lists of die EPA and EC experts who were responsible for carrying out die detailed analyses upon
which this report is based, are included as Annex I.
2.2. Confidentiality
Directive 67/548/EEC, as amended, makes clear that die confidential data included in a notification
dossier can only be made available to the national Competent Authorities designated as being
responsible for implementing die Directive, and die European Commission. Within the national
Competent Authorities and die Commission only a restricted number of staff are allowed access to this
confidential information and extensive measures are taken to ensure die physical security of this
information.
Given die obligations imposed under the Directive, die confidential data submitted to die European
Authorities could not be made available to die EPA without die specific permission of die
manufacturers/importers who had submitted die notifications in Europe. Therefore, prior to die Stan
of. die project, die national Competent Authorities in die EC Member States wrote to all notifiers
asking for permission to release confidential data to die EPA for die purpose of this collaborative
project. It was made clear to die notifiers that the EPA had undertaken to accord die same degree of
protection to confidential data submitted under this project as they would to confidential business
information submitted as part of a new chemical notification under TSCA.
A total of 107 companies responded positively to die request made by die national competent
authorities. A list of these companies is attached as Annex 2 to this report. The EPA, die national
Competent Authorities and the European Commission would like to thank these companies for dieir
assistance without which this project could not have been carried out.
Confidential information, exchanged between die EPA and die European authorities was taken by hand
from die notification unit located in Direction General XI of die European Commission in Brussels
to die mission of the United States of America to die European Commission. From there die
information was transferred by diplomatic bag to the EPA in Washington. While in die EPA die data
were held in secure areas dedicated to the storage and processing of confidential business information.
At die end of die project, confidential documents supplied to die EPA were destroyed.
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2.3. How the project was organized
Discussions with EC notifiers regarding the release of confidential data to the US authorities were
completed by December 1990. All together, companies gave permission for information, on a total
of 125 substances to be included in the project. Chemicals were removed from the study if, for
example, they were on the origina! TSCA inventory or had been submitted undtr the US notification
scheme and had been accompanied by the equivalent of the MPD. This reduced the test set of
chemicals to a total of 144. The various use categories of substances notified under the EC scheme
were reasonably well represented in this set of 144. The dates of notification ranged from 1983 to
1990. For the US, however, the scarcity of polymers and the inclusion of pesticides and
pharmaceutical intermediates represents a somewhat atypical data set of chemicals and, as such, may
not have been as good a match with the US experience as could be desired.
In autumn 1991, DG XI of the European Commission communicated to the EPA the following
information in relation to each of the substances selected for the study :
- lUPACname
• CAS number (where available)
- physical form
- melting point
• use (where this was adequately described in the original dossier). . •
Prior to the dispatch of information, the Commission and the national competent authorities were
provided by the EPA with details of the (Q)SAR methods that the EPA would use during the
collaborative project.
The EPA treated this input data in exactly the same way that they would have treated data submitted
under the TSCA new chemicals notification scheme, applying (Q)SARs to predict the properties of
the chemical and carrying but a preliminary hazard assessment. For each substance the EPA drew up
a one/two page summary of their analysis. These summaries were delivered to DG XI of the EC
Commission in March 1992 and thereafter to the national competent authorities.
In April 1992, DG XI communicated the full test dossiers on each of the 144 substances to the EPA.
Between April 1992 and September 1992 the US EPA on the .one hand and the EC Member
States/Commission (DG XI) on the other reviewed and analysed the result of the study. Between 14-16
October 1992, a joint meeting of US and EC experts took place at the Umweltbundesamt in Berlin
to discuss the results of the project. Following that meeting, this final report was prepared for onward
transmission to the OECD.
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3. Notification schemes in the European Community and in the United States
3.1. Essential features of the notification scheme for new chemical substances in the European
Community
Overview/Legal basis
The new chemicals notification scheme is established within the framework of Directive 67/548/EEC
on the classification, packaging and labelling of dangerous substances. The notification scheme was
in fact introduced in the 6th amendment to the basic Directive (Directive 79/831/EEC) which came
into force in the EC Member States in 1981.1A copy of the sixth amendment is attached as Appendix
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The obligation to submit a standard notification dossier harmonised at the level of the EC faHs upon
any manufacturer or importer wishing to place a new substance pn the market in quantities greater
than 1 tonne per annum per manufacturer. (Notice that the EC scheme is a pre-marketing scheme and
not premanufacture as is the case in the United States.]
A "new substance* is defined as one that is not to be found on the European Inventory of Existing
Commercial Chemical Substances (E1NECS). EINECS contains over 100,000 chemicals on the EC
market before 18th September 1981.
Even if a chemical is new it may not need to be notified if it falls into one of the exempted product
sectors e.g. Pharmaceuticals, or substance classes e.g. polymers containing "old" monomers, which
are specified in Articles 1 and 8 of the Directive respectively.
Notifiers are required to submit a notification dossier relating to the substance as marketed, including
any impurities and additives necessary for keeping the substance stable but without separable solvent.
This means that the substance or entity assessed is very rarely a pure substance and indeed some of
the properties observed may be due to the impurities or additives present in the "substance". This
means that the assessment is made on the entity to which man or the environment will actually be
exposed rather than on the pure substance.
Information to be provided by the notifiers
Notifiers must submit a notification dossier including an extensive technical dossier containing the
results of the experimental testing carried out on the substance. The contents of the technical dossier
are laid down in Annex VII to the Directive. This standard testing package is known as the "base set"
test dossier. When the marketing levels for a substance reach 10 tonnes per annum per notification
the authorities may require further testing. When marketing levels reach 100 tonnes and 1 000 tonnes
per annum the notifier is required to carry out further testing. These obligatory supplementary testing
packages are known as the level 1 and level 2 testing packages respectively and are laid down in
Annex VIII to the Directive. ...
The testing methods to be used in carrying out testing of chemicals for the purpose of notification are
laid down in Annex V to the Directive.
The "base set" test package is approximately equivalent to the OECD Minimum Pre Marketing Data
Set (MPD) and the testing methods in Annex V are, for the majority of tests, equivalent to the
corresponding OECD test guidelines. Requiring testing according to agreed standard test methods has
the distinct advantage of facilitating comparison of substances.
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How does the notification scheme work ?
The notifier submits a notification dossier to the competent authority in the Member State where the
substance is manufactured or imported. Forty five days after the authority is in receipt of a dossier
which conforms to the Directive, the notifier can place the substance on the market anywhere la the
European Community. "
The authority receiving the notification prepares a summary dossier which is circulated through the
Commission in Brussels to the other eleven Member States (a copy of the summary dossier is attached
as Appendix 2).
The other Member States and the Commission can request the lead authority to make changes to the
dossier or ask the notifier for further information.
The essential feature to note about the notification scheme is that it is a de-centralized one: the lead
authority effectively takes the decision as to the acceptability of the notification dossier on behalf of
the rest of the Community. In order for this de-centralized approach to work effectively the degree
of flexibility/subjectivity which the system can tolerate is rather small: it is not one single group of
people which take the decisions but 12 different national authorities each acting alone with the
Commission playing the role of coordinator. This is one of the main reasons for the perceived
rigidity in the EC notification scheme which is based upon a fixed set of information which must be
supplied for each substance. This loss of flexibility is one of the costs to be paid for the benefit of
having a notification scheme which has worked effectively across 12 different countries for over 10
years.
Classification and Labelling
Directive 67/548/EEC as amended contains detailed and extensive rules for the classification and
labelling of dangerous substances. Substances are classified on the basis of objective, often vety
precise, criteria which are laid down in Annex'VI to the Directive (the version of Annex VI in force
at the time of this study is included as Appendix 3). The classification criteria are in turn based upon
the results of the tests carried out on the substance. The rules laid down in Annex VI also determine
whether the labelling of a substance should carry a pictogram/symbol indicating certain types of
danger and also whether the label should indicate certain standard phrases describing the risk of the
substance, so called R-phrases, as well as certain standard phrases describing how the substance can
be used safely, so-called S-phrases.
In addition to determining the labelling of a substance, the classification is the starting point for the
risk assessment in the European Community and also drives downstream legislation concerned with
aspects of risk management, e.g. worker protection.
As can be understood from the short description given above, classification and labelling, and in
particular classification, are central elements in the EC chemicals legislation. However, the criteria
for classification are often extremely precise, for example, substances are classified as 'very toxic"
if the acute oral LD50 is less than or equal to 25 mg per kilogram but as "toxic" if the value is above
25 mg but less than or equal to 200 mg per kilogram. Classification schemes which demand such a
high degree of precision to discriminate between substances allocated to one category or another
obviously demand a high degree of precision in the estimates made of the chemical's properties.
Experimental testing does generate precise values and even though this precision may be more
apparent than real, it does provide an effective basis for building an objective classification scheme.
(Q)SAR methods on the other hand usually generate less objective/precise estimates of chemical
properties, and therefore do not immediately lend themselves as input data constructing classification
schemes.
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3.2. Essential features of the notification scheme for new chemical substances in the Unjled
Staffs
Overview/Legal basis
Persons who plan to manufacture or import a new chemical substance for a commercial purpose are
required to provide the Environmental Protection Agency (EPA) with a premanufacture notification
(PMN) at least 90 days prior to the activity. Section 5 of the Toxic Substances Control Act (TSCA)
was designed to enable die Agency to review activities associated with manufacture, processing, use
and disposal of any new chemical substance before it enters the market place. If necessary, EPA is
empowered to take action to prevent unreasonable risks before they occur (pollution prevention at its
basic level). This is accomplished by requiring premanufacture reporting. |A copy of the relevant part
of the TSCA is attached as Appendix 4].
TSCA defines 'new chemical substances' as chemical substances not listed on the TSCA Chemical
Substance Inventor) and not otherwise excluded by the regulations. The Inventory includes chemicals
in commercial production between 197S and 1979, and any chemicals reviewed in the PMN program
which have subsequently been commercially produced. The Inventory currently contains over 70,000
chemical substances, of which over 7,500 substances have been added to the Inventory through the
submission of notifications of commencement to manufacture (NOCs) after those substances had
completed the PMN review process and were manufactured for commercial.purposes.
The PMN program has been in place since 1979 and, through fiscal year 1992, has reviewed over
21,500 notices. The Agency took action to protect health and the environment from potential risks
posed for over 1,800 of these new substances.
The PMN review process
EPA developed the PMN review process to meet the statutory mandate of TSCA §5. Under the US
Program, any person who intends to manufacture or import a new chemical substance is required to
provide to EPA available data on the chemical structure, production, use, release, exposure, and
health and environmental effects. However, section 5 does not require chemical companies to test
their new chemical substances tor potential toxic effects. Therefore. EPA's review (and 5(e)
regulatory actions) are often conducted in the absence of data. The Agency relies on Structure Activity
Relationships (SAR) to make predictions concerning the environmental fate and effects (health and
environmental) of PMN chemicals. Each PMN proceeds through a screening process to determine
whether more detailed review is required and to identify candidates for regulatory action. The
Structure Activity Team (SAT), made up of a muliidisciplinary group of experts, is responsible for
the initial assessment of fate and effects. EPA focuses on the relatively few new chemicals of greatest
concern-those which are structurally related to known toxic chemicals, and those about which little
is known..
a. Initial screen. PMN notices go through a multidisciplined initial review designed to ascertain
whether regulatory action on a more detailed analysis is warranted. Preliminary chemistry, Structure
Activity Relationship (SAR) analysis, exposure, and environmental fate, analyses are conducted.
b. .Use of SAR in hazard assessment. Given the qualitative and quantitative limitations of the test
data provided with PMNs (over half of all PMNs contain no test data), EPA has developed innovative
approaches to characterize the potential hazards associated with new chemical substances. The major
components of EPA's SAR-based approach to hazard analysis are the following:
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- critical review of submitted test data, if any, on the PMN chemical;
- identification and selection of potential analogues and/or prediction of key PMN metabolites,
followed by critical review of test data available on these chemicals;
- use of QSAR (Quantitative Structural Activity Relationships) methods when available and
applicable; and
• the experience and judgement of scientific assessors in interpreting, weighing, and integrating the
often limited information yielded by the above hazard analysis components.
The TSCA PMN reporting requirements can be compared with the European Community's (EC)
"preraarketing" notification requirements. As the terms indicate, premanufacture notification under
TSCA is required at an earlier point in the development of a chemical than is the case for the EC's
premarket notification procedure. Many of the information reporting requirements under die EC
directive are similar to those in TSCA with the major difference that the EC directive requires, as a
mandatory pan of the notification, a specified "base set" of health, environmental, and physical
chemical test data. Therefore, a minimum set of test data is available on premarket notification EC
chemicals, whereas the hazard assessment of TSCA PMN chemicals often starts out with fewer or no
data.
c. Cases completing their initial review are brought to the first regulatory decision meeting called
"Focus". At this meeting, the results of the Initial Screen analyses are presented and considered and
a decision rendered on each PMN case. The possible outcomes include: drop the case from review;
hold it over for more investigation (standard review); or move directly toward a regulatory outcome
for certain standard categories of chemicals. To date, the Agency has developed over 35 chemical
"categories of concern" to facilitate the new chemicals review process.
d. For chemicals which are not screened out early, the standard review includes:
- Conducting a chemistry analysis,
- Identifying structurally analogous substances,
- ' Searching the literature for toxicity data, .
- Analysing test data on the substance or analogous substances,.
- Analysing potential releases to the environment.
- Estimating exposures to' workers and the general population,
- Estimating potential concentrations in surface waters.
'- Investigating additional uses which could significantly alter exposure.
e. Cases completing standard review are taken to the PMN Disposition Meeting for a final decision.
The meeting can result in a decision to drop a case from further review, to regulate (and require
controls) under section 5(e) or 5(0 (see below), or to "ban" the substance pending the receipt and
evaluation of "upfront testing." *
f. If a regulatory decision to impose certain controls on the manufacture, process, use, distribution,
or disposal of a new substance is reached, EPA staff communicate and negotiate with the submitter:
Similarly, if "upfront* testing is recommended in face of banning the new substance, this decision is
also communicated to the submitter by EPA staff. . . .
g. Notice of Commencement (NOC) of Manufacture or Import. An NOC must be submitted within
30 days of commencement of commercial production of a chemical substance which has completed
the 90-day review period. The substance is then added to the TSCA Inventory.
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Regulating new chemical substances under TSCA
Section 5(e) and 5(0 of TSCA authorize EPA to prohibit or limit the manufacture, processing,
distribution in-commerce, use, and disposal of a new chemical substance if EPA makes the following
determinations: ...
a. Section S(e) findings:
- Available information on the substance is insufficient to permit a reasoned evaluation of its health
or environmental effects; and *
- (1) The manufacture, processing, distribution in commerce, use, or disposal of the substance may
present an unreasonable risk of injury to health or the environment (referred to as a "may present'
or risk-based determination); or
- (2) the substance will be produced in substantial quantities and (A) may reasonably be anticipated
to enter the environment in substantial quantities, or (6) there may be significant or substantial
human exposure (referred to as an "exposure-based" finding). An exposure-based review is
triggered by an estimated threshold production volume of 100,000 kilograms per year. For those
substances meeting significant or substantial human exposure criteria, chemical manufacturers may
be asked to perform some or all of the following tests on their PMN substance: an Ames assay,
an in vivo mouse micronucleus test, a 28-day (oral) repeat dose toxicity test and an acute oral
toxicity test. PMN substances meeting the environmental release criterion may be tested for algal
acute toxicity, daphnid acute toxicity, and fish acute toxicity. Additional elements of the exposure-
based testing policy may include environmental fate testing and, for PMN substances having
higher production volumes, developmental toxicity testing requirements.
b. Section 5(0 findings:
- There is a reasonable basis to conclude that the manufacture, processing, distribution in
commerce, use, or disposal of the substance will present an unreasonable risk of injury to human
health or the environment before a TSCA §6 rule can be issued to prevent the risk (referred to
as a "will present" determination):
- A section 5(0 rule, which limits activities involving a new substance, is a section 6(b) proposed
rule which is immediately effective upon proposal. A section 5(0 order prohibits all activities
involving the substance. (To date. EPA has issued 3 section 5(0 rules and no section 5(0 orders,
although a number of PMNs have been withdrawn from review after EPA notified the submitters
that the Agency intended to ban the substances)
c. Practices under section 5(e): "
To date, there have been five outcomes, depending upon the facts of the case, when EPA has made
a determination under section 5(e): * '
- The'company may withdraw the PMN.
- The company may develop toxicity information sufficient to permit a reasoned evaluation of the
health or environmental effects of the substance prior to the conclusion of the review period
("upfront" or "voluntary" testing). Where exposures or releases cannot be controlled pending
testing to address EPA's concerns, or the requested testing is relatively cheap and not very time-
consuming, this may be the only option available to the PMN submitter short of withdrawing the
• PMN.
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The company may develop and provide to EPA other information on the potential effects of the
substance or its analogues, the potential exposures, or both, which if accepted by the Agency,
would negate the potential unreasonable risk determination.
The company may, together with EPA, suspend the notice review period, and negotiate and enter
•into a section S(e) Consent Order. The Consent Order would permit limited manufacture,
processing, distribution in commerce, use, and disposal of the substance pending the development
of information. A Consent Order may contain a requirement that toxicity data be submitted to
EPA when a specified volume of the chemical has been produced. This production volume level
is set where EPA estimates that profits from the chemical will support the cost of testing.
The company may refuse to withdraw the PMN, negotiate a Consent Order with EPA, and/or
conduct up-front testing or develop other information. EPA would then unilaterally develop a
Proposed Order, under the procedures in section 5(e), to ban manufacture or import.
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4. Results
4.1. Inlroduclion
For this project, the test set of chemicals was comprised of a maximum of 144 substances (sometimes
fewer depending upon the end-point and the results available). Each substance was assigned a number
and is referred to in the report by means of that number. A short generic description of each substance
included in the project is given in Annex 3.
In the sections which follow, the results are generally presented in a summary fofln, not substance
by substance. However, detailed annexes presenting the results by end-point and by substance are
appended to the report.
4.1.1. Evaluation criteria
For each end-point, specific criteria were agreed between the US and EC experts for assessing the
"success", "failure', "hit-rate" of the (Q)SAR methods, e.g. for most physico-chemical and die
ecotoxicity data, agreement was defined as being reached, if the difference between measured and
predicted value did not exceed a factor of 10. In addition to these end-point, specific criteria the
following, more general, considerations were also taken into account in relation to each end-point.
- Can the predicted data be used on a one-to-one basis in the place of the test results foreseen in
the OECD Minimum Pre-Marketing Data Set (MPD) or other similar test based notification
schemes? .
Can the results of the predictive approach be used in the context of schemes for the classification
and labelling of chemicals, which employ predefined cut off values?
- If estimated values based on predictive methods are used instead of test data for the purposes of
preliminary hazard assessment, are the predictive methods sufficiently reliable in relation to each
end-point and what is the likelihood of false negatives in relation to each end-point?
- The OECD MPD and other test based systems for screening of new chemicals frequently do not
include important end-points. To what extent do predictive methods allow one to go beyond the
scope of fixed data sets and to assess additional end-points?
4.1.2. Complicating factors ,
Issues addressed with regard to each end-point are discussed in connection with, that end-point.
Nevertheless a number of common problems can be identified which complicated the comparison of
predicted and observed results in relation to all end-points.
Pure substances vs notified substances
In the EC notification scheme substances are notified essentially as they are marketed including
impurities but minus any separable solvent. This means that impurities or non-separable solvents may
contribute significantly to the observed properties. In contrast, the (Q)SAR methods are based OR pure
substances and impurities are only taken into account in the US system if the manufacturer is aware
of their existence/identity and reports this information to the EPA.
13
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For the above reason the (Q)SAR methods will often fail to predict properties which are due to the
presence of impurities.
Effect quantification .
Experimental data reported from the EC notification dossiers may display considerable variability
(extremely wide confidence limits). Furthermore, both predicted and experimental data were often
expressed as > n, or as < n or as ranges. In these cases agreements had to be reached end-point by
end-point as to how to make effective comparisons.
End-point selection
When considering properties such as acute aquatic toxicity or biodegradation the precise end-points
addressed by the experimental testing and the (Q)SAR predictive methods were sometimes different
e.g. 24 hour toxicity as opposed to 48 hour; 'ready biodegradability* as opposed to an estimate of the
time required for complete biodegradation. Again in such cases, agreement had to be reached on a
realistic basis for comparison.
Descriptive narrative assessment vs numerical data
(Q)SAR methods frequently generate predictions placing substances in concern categories such as low.
medium or high. Again agreement had to be reached as to how such predictions should be compared
with an objective value such as a numerical (e.g. 35 mg/kg bodyweight/day) Lowest Observed
Adverse Effect Level (LOAEL) in a 28-day repeated dose toxicity study.
Nominal vs measured concentrations
Test results for aquatic toxicity test, in the EC notification dossiers, particularly dossiers received
early in the life of the notification scheme, were.frequently based upon nominal rather than measured
substance concentrations. In such cases it is entirely possible that the predicted value for aquatic
toxicity generated by (Q)SAR is nearer to the "real value" than the result reported from the
experimental determination.
14
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4L2. Detailed analysis or results
A detailed description of the end-point by end-point comparison of the values predicted by (Q)SAR
and Ate values generated by experimental determination in the EC notification dossiers is given below.
For ease of presentation the abbreviations "EC" or "EPA' have been used as a convenient short-band
to identify die .approaches used in the European Community and the United States Environmental
Protection Agency respectively.
4.2.1. Physico-chemical and environmental fate parameters
4.2.1.1. Boiling point
For predicting the boiling point, the EPA experts use estimation methods, e.g. PCGEMS (Meissner's
method), data on analogues and'experimentally determined data obtained from the published literature
investigations. Impurities are in general neglected in the predictions. The application of the estimation
techniques was not possible for all the chemicals within this study.
Even though the toiling point is required for notified chemicals at "base set" level in the EC, for
many substances in this study experimentally determined boiling points were not available as it was
technically not possible to conduct the tests.
The boiling point is used to characterize the material, it is not directly used for risk or safety
evaluations. The boiling point may serve as an input parameter for estimating vapour pressure, if the
latter is unavailable from experiment.
On!y for 30 chemicals out of the 144 were measured/estimated boiling point values available for
comparison. The following criteria were applied for the analysis:
- for all values assigned with < n or > n the signs are deleted and the values are directly compared;
- the values are considered to be in agreement if the difference between calculated and measured
data does not exceed ± 50 degree C.
The comparison of the SAR and MPD data is given in Table 1; for detailed analysis of the boiling
point data see Annex 4.
TABLE 1: Comparison of hoilintt point dalu
Total
Agreement
Disagreement
N° of chemicals
30
IS
15
100
50
50
If the literature data were included in the analysis, an additional II chemicals would be added, for
which the US boiling points were all in agreement with the EC data. The agreement was below 50%
for solid substances.
15
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Conclusions •
The data set for analysis was very small, so only limited conclusions are possible. The toiling point
is not used directly in the hazard/risk assessment nor is it used in the classification schemes. On the
other, hand, the boiling point is a basic piece of information about a chemical which manufacturers
should normally be aware of; furthermore boiling point determination by testing is relatively
inexpensive. Thus, it is concluded that it is preferable, in the EC scheme, to continue to measure the
boiling point when it is technically possible to do so.
4.2.1.2. Vapour pressure
The vapour pressure of the chemicals under consideration is predicted by the EPA using methods
based on the Antoine equation or the Watson equation or by applying the PCNOMO-tecbnique. The
vapour pressure contributes indirectly to the EPA's risk assessment, as it is used as an input parameter
to the exposure and fate analysis.
Also within the EC risk assessment, the vapour pressure serves as a basic parameter for human health
and environmental exposure evaluation. Measured vapour pressure data are required at "base set" level
in the EC; however, calculation methods can be used according to Annex V for range finding
purposes, for justifying the non-performance of the test or for providing an estimate or limit value in
cases where the experimental method cannot be applied due to technical reasons (including where the
vapour pressure is very low) .
For 113 chemicals out of the 144 test chemicals measured data on vapour pressure were available, and
predictions were available for all chemicals. The predictions are given in the majority of the cases as
upper/lower bounds. In order to compare the SAR values with the measured data, all values were
converted to like units (torr). The following criteria for comparison analysis were applied :
- for all values assigned with < n or > n the signs are deleted and the values are directly compared;
- the lower limit is set at 10"* torr. All SAR and MPD values that are less than this value are
• arbitrarily set-to 10"* torr;
- the values are considered to be in agreement if they are within ± 1 log unit.
The results of the comparison of the SAR and MPD data are given in Table 2; the detailed analysis
of the vapour pressure data is to be found in Annex 5.
TABLE 2: Comparison of vapour pressure data
N" of chemicals J&
Total
Agreement (± 1 log unit)
Disagreement
- of these, predictions which
were not at all in agreement
(>3 log units difference)
113
71
42
123]
100
62.8
37.2
120]
16
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The data pairs which show big deviations were mure rigorously investigated: in some cases the
disagreement can be put down to the tact that the material used for the experimental determination
contained volatile impurities, whereas the predictions are carried out for the pure substance.
• -Conclusions c - - _.
*
The best agreement was observed between the PCNOMO estimates and the measured values. In
general the predictions tend to underestimate the vapour pressure. Assessing the deviations with
respect to chemical classes is not possible with the small data set available. Imprecise predictions of
very high or very low vapour pressure do not affect the overall assessment, but more precise values
are needed in the decision-relevant range. Vapour pressure contributes to the exposure portion of the
risk assessment in the EC and the US; however, it is not normally used for the purpose of classifying
chemicals within the EC classification scheme. Under/overstimation of vapour pressure can result in
an under/overestimation of the exposure associated with a chemical and thus contribute to an
under/overestimation of the risks. The majority of methods for the experimental determination of
vapour pressure are relatively inexpensive, and therefore notification schemes based upon testing will
probably continue to require experimental determination. Schemes based upon predictive methods may
need to be adjusted to foresee a more systematic approach to the experimental determination of this
parameter for some of the chemicals which are identified as being of concern on the basis of a
preliminary hazard/risk assessment.
4.2.1.3. Water solubility
The methods used by the EPA experts for predicting water solubility are based on log Pw values
(PCGEMS). However, most new chemicals do not match the application criteria of the available
QSARs, e.g. applicability recommended fur liquid substances or only for certain log PM ranges.
Within the EPA hazard/risk assessment scheme, water solubility serves as an input parameter for the
environmental fate analysis and ecotoxicity assessment. The lower prediction limit for fate and
ecotoxicity assessment is £1 pg/l; for some other purposes it may be around 1 mg/l. In cases of
concern, e.g. for chemicals with higher production volumes, measured water solubility is required.
In the EC, experimentally determined water solubility data, which.are required at "base set" level,
are also used in environmental exposure assessment; they may also contribute to the classification
"dangerous for the environment".
Measured numerical values were not available for 13 of the 144 chemicals, as their determination was
technically not possible, but in 6 cases out of the 13, qualitative test data were available which could
be used for comparison. In 4 further cases the SAR data cannot be used for the comparative analysis.
This means there were 133 data pairs for comparison. An additional problem affecting meaningful
comparison is the lack of precision in the data (both predicted and measured): many data, in particular
the majority of the predicted data, are given as ranges or upper/lower bounds, in case of measured
data the values given as bounds are mostty without an indication of detection limit. •
The following criteria were applied for the comparison analysis:
- for all values assigned with < n or > n the signs are deleted and the values are directly compared;
- for data given as ranges, the average is taken for comparison;
- the lower limit is set at 0.01 mg/l and the upper limit at 10,000 mg/l. All SAR and MPD values
that are less than the lower limit value, or above the upper limit value are arbitrarily set to 0.01
mg/l or 10,000 mg/t, respectively;
17
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- the values are considered to be in agreement if they are within ±'l log unit.
Results of the comparison between SAR and MPD data is given in Table 3, the detailed analysis of
water solubility data in Annex 6.
TABLE 3: Comparison of water solubility data
Total
Agreement (± I log unit)
Disagreement
N* of chemicals J6
133 100
90 67.7
43 32.3
A rigorous scientific analysis of the estimated and measured data for water solubility was not possible
due to the imprecise nature of both data sets. Tendencies of over or underestimation of water solubility
are not observed. A relatively high rate of disagreement is detected for low solubility values (<1
mg/1).
Conclusions
Water solubility is a significant parameter in risk assessment and might have a decisive impact on the
classification "dangerous for the environment". Under/overestimation of water solubility can result
in a under/overestimation of exposure and thus contribute to a under/overestimation of the risks. SAR
based predictions may not always be of sufficient reliability, especially in the range of low solubility,
i.e. < 1 mg/1, due to the complexity of factors influencing a chemical's water solubility. The
experimental determination of water solubility is relatively inexpensive, therefore notification schemes
based upon testing will probably continue to require experimental determination. Schemes based upon
predictive methods may need to be adjusted to foresee a more systematic approach to the experimental
determination of. this parameter for chemicals at higher production levels or which are identified as
being of concern for the aquatic environment on the basis of a preliminary hazard/risk assessment.
4.2.1.4. Partition
The partition coefficient is a key parameter to evaluate a chemical's impact on the environment.
Furthermore, its particular importance is underlined as, in the SAR methodologies, several- other
predictions, e.g. ecotoxicity/toxicity, are based upon it. The SAR prediction methods applied by the
EPA use the MedChem ClogP Software package; the respective estimations are based on a fragment
method. In cases of missing fragments, their values are estimated from expert knowledge. The upper.
prediction limit applied by the EPA for fate assessment is log P_ 26. For ecotoxicity assessment no
upper limit is considered for some chemical classes.
In the test driven, stepwise assessment scheme of the EC, the partition coefficient is also used in the
decision taking process on further testing (e.g. for bioaccumulation potential); in addition, the log Pm
contributes to the criteria for classification as "dangerous for die environment" within the EC
classification scheme: the log P,, value 3 represents the cut off value for decisions on further testing
and for classification. The EC notification scheme requires experimentally determined partition
•coefficient data at "base set" level. Nevertheless, Annex V recommends to estimate log P.. for
18
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deciding which of the experimental methods is appropriate, tor selecting appropriate test conditions
and for providing a calculated lug Pw in cases where the experimental methods cannot be applied for
technical reasons. Therefore, in a number of cases, only estimated values were available in the EC
dossiers. Those values were not taken into consideration for the comparative analysis of the
SAR/MPDdata. , .
«
Eighty two chemicals with both measured and predicted log P,. values are available for the
comparative study. The analysis included the application of the following criteria for comparison :
• for all values assigned with < n or > n, the values are directly compared;
- for values given as ranges, the arithmetic average is used; •
- the lower limit is set at log Pm — 0, all values that are below 0 are arbitrarily set to 0;
• the upper limit is set to log Pw = 6; all values above 6 are arbitrarily set to 6;
- the values are considered to be in agreement if they are within ± 1 log unit.
The results of the comparison of the S AR and MPD data are given in Table 4 , the detailed analysis
of log P»» is anached (see Annex 7).
TABLE 4: Comparison of partition coefficient data
N * of chemicals ,&
Total "82 100
Agreement (± 1 log unit) 50 61
Disagreement 32 39
- Overestimation 25 30.5 .
- Underestimation 7 8.5
Conclusions
The log P^ estimates are in general reasonably accurate. However, estimations are in poor agreement
for certain classes of compounds (e.g. dissociated compounds, charged compounds, surfactants,
chelating compounds, organometallics, organophosphorous compounds, compounds with unknown
fragment values, UVCB compounds) and are not applicable for them. Calculated log Pw values above
4 tend to overestimate. Calculations in the range of 0 - 2 possibly underestimate log P; however, the
data set available is too small for exhaustive analysis. The EPA calculation methods ace in general
successful at calculating log P values < 0.
The results of this exercise indicate thai the predictive methods for log ?„ may be of further
importance in the EC in future, i.e. submission of predicted log P,*, values by the notifiers instead of
measured data might be regarded as a possible option. However, the log Pw range around the value
3, which is of particular importance for the EC classification and stepwise risk assessment scheme,
will anyhow have to be taken into special consideration and may' continue to require experimental
determination as well as in the case of suspected underestimation.
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4.2.1.5. giodeyradation '
The data on this end-point were difficult to compare because different scales /definitions are used. The
biodegradation estimates are given in semi-quantitative terms, indicating the appropriate time for
complete degradation ("days", "days to weeks", "weeks", "weeks to months*, 'months" or "months
or longer", whereas the OECD-based standard 28-days tests, which are available in die EC at "base
set" level, result either in the decision "readily biodegradable" or "not readily biodegradable".
The EPA predictions concern biodegradabil ity in terms of primary and ultimate biodegradability using
structural analogies with previously studied chemicals. The applied estimation methods are based on
expert judgement. The biodegradation predictions are used within the EPA risk assessment scheme
as an important factor of the environmental fate analysis.
Biodegradation data are required in the EC for risk assessment and also for the classification
"dangerous for the environment".
115 substances were available tor comparison of predicted with experimental data. By relating
estimates of "days* and "days - weeks" to the definition "readily biodegradable", 5 of the 9 substances
experimentally determined as being readily biodegradable have been identified as such by the
predicting methods (=55.5%). The other 4 readily biodegradable substances are predicted to degrade
in "weeks', "weeks-months" or "months or longer". At the same time, for 4 substances which did not
pass the experimental criteria for ready biodegradahility, a rapid degradation was predicted ("days-
weeks"). In general, as the predictive methods indicated increasing time required for complete
degradation, the better they correlated with test results indicative of a lack of ready biodegradability.
The overall results of the comparative study are summarised in Table 5, the detailed analyses of the
data is to be found in Annex 8.
TABLE 5: Comparison of hiodegradation results
Test result
Total .
Readily biodegradable .
Not readily biodegradable
Prediction
correct
incorrect
107 (93%)
5
102
8(7%)
4
4
Conclusions
The EPA methods are likely to identify those substances which are not "readily biodegradable", i.e.
slowly degrading chemicals. However, they do not appear to work as well in identifying chemicals
which readily degrade. The use of biodegradation predictions as a tool for establishing suitable testing
strategies within a stepwise assessment scheme is considered a possible option for the future in die
EC. On the basis of the EPA results it appears that if the predicted biodegradability is "weeks" or
longer, testing for "readily biodegradability" would not be indicated. Instead a test for inherent
degradability or another suitable test that provides further information on the biodegradation process
should be carried out. If the predicted biodegradability is "days" or "days-weeks" corresponding to
"readily biodegradability", then a "ready biodegradability test" would be needed for confirmation.
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4.2.1.6. Hvdrolvsis
The EPA dossiers include data hydrolysis only if it is likely to occur. The applied estimation methods
evaluate the rate of hydrolysis if relevant (hydrolysable) functional groups are present in the molecule.
For few compound classes the HYDRO-programme is applied. Hydrolysis tests are not mandatory in
the EC at 'base set" level; for 41 of the chemicals included in this study hydrolysis data were given.
Only for 6 chemicals were both measured and predicted hydrolysis data available. A comparative
analysis of this end-point was therefore not carried out.
4.2.1.7. Soil Sorption
The environmental fate analysis carried out by the EPA includes in general the prediction of log K».
For the majority of the chemicals within this study log K« predictions were available. The applied
estimation.methods are mostly taxed on log P_, but they are of limited applicability. The fragment
method can be applied more widely, but it also does not satisfy all requirements.
Under the sixth amendment no tests on soil sorption are required in the EC; for notifications according
to the seventh amendment a screening test on adsorption/desorption will be mandatory. For this study
no test results were available for comparison.
4.2.1.8. Pholodeqradatinn
The environmental fate analysis of the EPA experts includes estimates of the photolysis of the
substance (direct and indirect) in water. Measured photolysis data are not required at "base set" level
and are therefore in general not available. A comparative study is not possible on the data available.
21
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422. Ecotoxicitv parameters
422.1. Toxicitv to aqualic organisms
For predicting aquatic toxicity approximately 300 SAR models ve available to the EPA experts for
various (about 100) chemical classes. The estimation methods are mostly based on log P^ only
calculated values of this latter parameter are used. Expert knowledge U required for die selection of
die appropriate SAR model. The selection is based on the chemical class, not on the mode of action.
The EPA's SAR predictions cover both acute and chronic toxicity for aquatic organisms. Fish,
daphnia, algae and, for some pesticid structures, also vascular plants are considered. For some
chemical classes, if log P.. is above 5 it is assumed that there are no acute toxic effects. Nevertheless,
for those substances, and similarly for chemicals for which no toxic effect is predicted at the water
solubility limit, chronic effects may still be substantial. The data on aquatic toxicity are used for risk
assessment and assignment of "level of concern".
la the EC according to the requirements of Directive 79/83I/EEC (sixth Amendment) at "base set"
level, normally only acute fish and daphnia studies are conducted. Chronic effects and effects on
species other than fish and daphnia, e.g. algae, are in general not addressed at this stage. The aquatic
toxicity data are used for risk assessment and for the classification "dangerous for the environment".
In several cases, the data were given as > n, < n or as NTS (Non Toxic at Saturation). LC/EC50 data
given as n. however, can be used because usually, the given limit will be regarded as a worst case estimate
of the toxicity. The analysis includes therefore those chemicals for which exact and "higher than*
(>n) effect concentrations are supplied: data presented as NTS are also included.
The comparative analysis is carried out applying the following criteria:
- for all values given as > n the numbers are directly compared without considering the signs;
- for data pairs with both values above 100 mg/l, no differentiation is made between the numerical
- values: the ratio of estimated/measured value therefore is 1;
- the values are considered to be in agreement if they are within ± 1 log unit;
- for data pairs in which one value is given as NTS and the other as a numerical value, the results
. • are assessed considering the water solubility: for a numerical value much higher than the water
solubility (> 100 mg/l) the SAR and experimental value are deemed to be in agreement; for effect
concentrations closer to the water solubility (< 100 mg/l) the two values are deemed to be
inconsistent with one another (disagree). • • - •.
The results of the comparative analyses are given in Table 6 (Toxicity to fish) and Table 7 (Toxicity
to daphnia, -the detailed analyses are given in the Annexes 9 and 10.
22
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TABLE 6: Comparison of data on toxicUv to fish
N° of chemjcals J6
Total .": . - . 130 . 100
Agreement 107 82.3
Disagreement 23 17.7
- Overestimation 14 10.8
• Underestimation 9 6.9
TABLE 7: Comparison of data on toxicitv to Daohnia
Total
Agreement
Disagreement .
- Overestimation
- Underestimation
N" of chemicals %.
127 100
90 70.9
37 29.1
20 . 15.7
17 13.4
Some of the differences in predicted and experimental toxicicy can be attributed to nominal instead of
measured concentrations, the use of solvents to enhance water solubility and to different test durations
(24/48 hr for daphnia). For only 5 chemicals were measured and predicted data on algae toxicity
available. In 4 cases, agreement between SAR/MPD data is observed (data: see Annex 11).
Conclusions
Information on aquatic toxicity is used both for risk assessment and for classification purposes.
Overall, SAR predictions of aquatic toxicity are quite good. For fish toxicity the predictions tend to
overestimate the toxicity. For daphnia over- and underestimations occurred at about the same rate.
Further effort is desirable to explain the cases where the reason for the underestimation (false negative
predictions) is not evident. Nevertheless, if used with the required caution, SAR predictions can be
very effective in the context of the US notification scheme.
The predictions are considered to represent a very useful future option to support the decision taking
process within a stepwise risk assessment scheme for carrying out toxicity tests.
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4.2.2.2. Classification "Dangerous for Hie Environment" . ,
The EC scheme for classification "dangerous fur the environment" is driven by toxicity,
biodegradability and/or bioaccumulation potential. For certain types of substances (those which show
low solubility in water) the water solubility may also be taken into account when determining the final
classification.
The EC classification criteria and the resulting risk phrases (R-phrases) for the aquatic environment
are as follows:
R SO: Very toxic to aquatic organisms
Acute toxicity: 96 far LC SO (for fish) <1 mg/l
or 48 hr EC 50 (for Daphnia) £1 mg/l
or 72 hr 1C SO (for algae) £1 mg/l
R 50: Very toxic to aquatic organisms
and
R 53: May cause long-term adverse effects in the aquatic environment
Acute toxicity: 96 hr LC 50 (for fish) 51 mg/l
or 48 hr EC 50 (for Daphnia) £l mg/l
or 72 hr 1C 50 (for algae) £1 mg/l
and the substance is not readily degradable
or the log ?„ 23.0.
R51: Toxic to aquatic organisms
and
R 53: May cause lung-term adverse effects in the aquatic environment
Acute toxicity: 96 hr LC 50 (for fish)
or 48 hr EC 50 (for Daphnia)
or 72 hr 1C 50 (tor algae)
and the substance is not readily degradable
or the log P*. £3.0.
I mg/l< LC 50 £10 mg/l
1 mg/l < EC 50 £10 mg/l
1 mg/l< 1C 50 £10 mg/l
R 52: Harmful to aquatic organisms
and
R 53: May cause long-term adverse effects in the aquatic environment
Acute toxicity: 96 hr LC 50 (for fish)
or 48 hr EC 50 (for Daphnia)
or 72 hr 1C 50 (for algae)
and the substance is not readily degradable.
10mg/l< LC 50 £100 mg/l
10mg/l< EC SO £100 mg/l
10mg/l< 1C 50 £100 mg/l
R 53: May cause long-term adverse effects in the aquatic environment
Substances not falling under the criteria above, but which, on the basis of the available evidence
concerning their persistence, potential to accumulate, and predicted or observed environmental fata
24
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and behaviour may nevertheless present a long-term and/or delayed danger to the structure and/or
functioning to the aquatic ecosystems.
E.g. poorly water soluble substances, i.e. substances with water solubility < I mg/1, will be covered
by this criteria if: a) they are not readily degradabte
b) and the log P.. £3.0.
Further details are to be tbund in the complete EC classification and labelling guide which is attached
as Appendix 3.
In this comparative study the EPA's quantitative predictions are used to classify the chemicals
according to the EC criteria. The results are compared to those classifications based on the measured
data. All 144 chemicals in the project*were classified for the comparison purpose on the data
available, independent of whether the data sets - both measured and predicted - were complete or not.
The comparison and the results are given in Tables 8 and 9.
TABLE 8: Comparison of classification "dangerous for Ihe environment" according to the
EC scheme bused on MPD vs SAR data
Classif.
based on
MPD data Total
Total 144
* Not classified
Classification based on SAR data
N.c.* RS3 RS2/53 R51/53
R50/53
44
32
14
26
26
R50
Not class.
R53
R52/53
R51/53
R50/53
R50
48
23
26
34
13
-
28
2
8
5 .
1
-
6
17
4
3
2
-
6
.
4
3
1
—
3
-
7
14
2
-
3
4
3
9
7
-
2
-
.
.
-
«•
TABLE 9: Result of the comparison of classification "dangerous for the environment*
Total
Agreement
Disagreement
- Overclassification
- Underclassification
Ne of chemicals %.
144 100
70 48.6
74 51.4
43 29.9
31 21.5
25
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Conclusions
The overclassifications can be considered acceptable as being conservative. The agreement of 78%
when including the overclassifications is encouraging, even though the underclassifications give cause
for concern since potentially dangerous substances may not be recognized.
The concordance in classification of chemicals "dangerous for the environment" is in general
reasonably good. However, for the purpose of classification within a legislative scheme, the use of
measured data is clearly preferable.
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4.23.
Toxlcolopcal properties/health effects
4.2.3.1. Absorption
The likely extent of absorption of a chemical via skin, lungs and gastro-intestinal tract is predicted by
the EPA experts on the basis of the physico-chemical properties of the chemical (particularly log Pw
which is usually a predicted value, and the physical form of the chemical). The initial opinion on this
basis may be modified in the light of any available test data on the chemical itself or on a closely
related structural analogue. Good, moderate, poor or no absorption will be predicted for each route
of exposure (dermal, inhalation and oral). '
The prediction of the likely extent of absorption following exposure by a particular route will be used
when taking decisions on whether the chemical may present an unreasonable risk to human health
and/or on testing requirements in the USA.
Absorption is not investigated in the base-set level testing in the EC, but whether any absorption has
occurred can be inferred to an extent from evidence of systemic toxicity in the acute and repeated dose
studies. It is less easy to decide that absorption has not occurred - the chemical may be well absorbed
and show no systemic toxicity in the particular test(s) already conducted. However, it may cause
adverse effects in other test systems not yet applied. Evidence of absorption (i.e. systemic effects) may
have an influence on the liming of further testing. When there is no evidence from the currently
available test data, the timing of further testing may be influenced by the likelihood of absorption
based on -the physico-chemical properties of the chemical and/or the extent of human exposure
expected;
Conclusions
There were too few studies conducted using the inhalation route for an accurate assessment of
concurrence between SAR calls tor absorption from the lungs and derived absorption estimates from
toxicity test results.
Based on the 136 chemicals for which dermal toxicity studies were available, it is considered that
acute derma] studies are inadequate to judge dermal absorption. There were too few 28-day studies
to serve as a basis for definitive judgement on dermal absorption calls.
The SAR calls for gastro-intestinal absorption were essentially in agreement with estimates based on
the oral toxicity test results: when they differed it was only in degree of absorption and not, with one
exception, giving a completely different assessment of whether or not a chemical was absorbed at.all.
For some chemicals, which were classified in the EC on the basis of their oral toxicity, the relatively
low extent of absorption predicted may be of some concern. However, none of these'chemicals were
predicted to have "no absorption" and thus would not have been dropped from EPA evaluations.
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4.2.3.2. Acute toxlcitv
Acute toxicity data are used to predict the potential effects in humans of a single exposure to a
chemical {e.g. during maintenance work or in an accident). They are also used to help in setting dose
levels for other toxicity tests.
Prediction of acute toxicity is not emphasised in the EPA evaluation of a new chemical which focuses
on long-term or sub-chronic effects. For the purposes of this project, however, predictions of acute
toxicity following oral administration were made. (There .were too few chemicals with data from
inhalation or dermal acute toxicity tests which were suitable for conducting comparisons of the two
approaches to evaluation.)
' The following criteria were used to rank chemicals on die basis of their oral LDSO values, and so
provide a means of comparing the predicted toxicity with that observed in the tests:
Oral LDSO
>2000
>1000 <2000
> 500 < 1000
> 50 < 500
< 50
Tpxicity
Low(L)
Low-Medium (L-M)
Medium (M)
Medium-High (M-H)
High (H)
These criteria give more categories of acute toxicity than are conferred by the EC classification system
(below), but the .same criterion (LD50 >2000 mg/kg) is used to differentiate chemicals of low
concern with regard to acute oral toxicity from those of some level of concern.
Oral LDSO fmp/kpl
>2000
> 200 <2000
> 25 < 200
< 25
EC classification
Not classified
Harmful
Toxic
Very toxic
Acute oral toxicity tests had been conducted on 142 chemicals (two chemicals had not been tested:
chemicals 4 and 107 are corrosive and react violently with water). A prediction of acute oral toxicity
had been made for all of the 142 chemicals which had been tested, plus the two which had not.
There were 21 chemicals for which the toxicity indicated by the test data differed from that predicted
(15%). Twenty of these were found to have greater acute toxicity than had been predicted, but for
fourteen of these there was overlap between the predicted and observed toxicity categories, (see Table
10). One chemical had lower toxicity than had been predicted (number 124).
28
-------
Twenty-one chemicals had been classified in the EC on the basis of their acute oral toxidty: twenty
of them are included in Table 10 and were predicted to have lower toxicity than was observed, though
for 14 there was an overlap between predicted arid observed toxicity categories. However, 18 of the
classified chemicals (12%) were predicted to be of "low" acute oral toxicity, and thus would
apparently be considered of low concern with regard to this end-point (false negatives). The classified
chemical which is not in Table 10 (number 281) was predicted, by analogy to data in the EPA
confidential data base, to have "medium" acute toxicity and this was observed (LDSO - 850 mg/kg).
Details of the oral toxicity predictions and test results are given for all chemicals in the project in
Annex 12.
Conclusions
Usinfc arbitrary criteria to compare LDSO values with descriptions of predicted acute oral toxicity,
there was a tendency to under-prediction of the level of toxicity for chemicals which, when tested,
were shown to have significant acute oral toxicity. However, the majority of the chemicals were
correctly predicted to be of low concern with regard to acute oral toxicity.
Predicted toxicity for 18 (12%) of the classified chemicals was "low", indicating that one-to-one
substitution of predictive methods for testing would result in chemicals being missed which are, in
fact, of some potential concern because of acute toxicity. It should be noted that two of these
chemicals had been classified as "Toxic if swallowed" (numbers 307 and 330).
In most cases there were overlaps between the predicted and the observed toxicity for the classified
chemicals, and between the toxicity predicted for the classified chemicals and those not classified.
Hence, the predictive methods could nut readily be used to classify chemicals within the context of
a scheme using pre-defined criteria.
Thus, this comparative study shows that the predictive methods can be used to identify correctly the
> 80% of a batch of 142 heterogeneous new chemicals which are of low acute toxicity. However, it
is of concern that some 12% of this set of chemicals did have an appreciable level of acute oral
toxicity which .was not predicted (false negatives). Because of this outcome, if assessment of acute
toxicity is an important consideration in a given evaluation scheme, the submission of test data will
be needed to assess this end-point adequately. This is especially so in instances where a quantitative
assessment of acute toxicity is needed.
29
-------
. Chemical
47
49
54
124
156
197
219
241
242
300
307
312
330
340
.360
370 '
413
425
436
441
443
LD50
1800
>200
<2000
1984
. 2300
_ 1800M
1960F
612
1670
585
520
1011
88
1774
104
1750
>1000
<2000
1400
1200
1650
899
450
320
- Label'
R22
R22
R22
. • -
R22
R22
R22
R22
R22
R22
R25
R22
R25
R22
R22
R22
R22
R22
R22
R22
R22
MPD tox2
L-M
L-M
L-M
L
L-M
M
L-M
M
M
L-M
*
M-H
L-M
M-H
L-M
L-M
L-M
L-M
L-M
M
M-H
M-H
SAR tox1
L
L
L
M
L
L
L
L
L
L
L
L
L
L
L
L
L
L
L
M
M
! See Appendix 3 for list of "R phrases".
1 See abbreviations above.
30
-------
4.2.3.3. ]p-itailor]
Knowledge of the potential for skin, eye and respiratory irritation is important when evaluating safe
handling practices for chemicals. Skin and eye irritation test data are used to predict the likelihood
that exposure of human skin or eyes to a chemical will result in adverse effects (corrosion or
irritation). An indication of the duration/reversibility of effects is also usually obtained.
There is not a test method for respiratory irritation in either the EC or the OECD set of accepted test
methods for the toxicity testing of chemicals.
Prediction of irritation is not usually part of the routine evaluation of new chemicals in the US, but
predictions were made for the purposes of this project, although EPA did not attempt to characterise
the degree of irritation. .
4.233.i Skin irritation
The criteria used for conducting the comparisons were to compute "primary irritation scores* from
the test data, by taking the average of the total erythema and oedema scores for both the 24 and 72
hour readings:
Primary irritation index
2 or less
>2to5
>6
The category "corrosive" was also used.
Irritant category
Mild/nil (low)
Moderate
Severe
In addition, chemicals were also considered according to whether they had been classified as
"Corrosive" or "Irritating to skin" in the EC.
Of the total of 144 chemicals in the project, there were 140 on which skin irritation tests had been
conducted. All 144 chemicals had been considered when predicting the potential for skin irritation as
a consequence of dermal exposure to the chemicals.
Correct predictions of low concern for skin irritation were made for 104 of the 122 chemicals
(including the untested polymer, chemical number 267) for which the test results indicated little or no
irritancy (83 % of the 122 chemical s: 73 % of the total number of chemicals in the project). There were
18 chemicals which were predicted to be irritating tu skin, but were found not to be irritant in the test
conducted, i.e. false positives. - .
The test results
-------
TABLE II: Comparison of predicted skin irrilancv with that observed
Chemical
4
49 *
53
107
118
182
192
194
222
235
237
278
370
373
425
436
437
443
Label1 ,
R35
R34
R38
R35
R34
R34
R34 .
R34
R38
R34
R38
R38
R34
R38
R34
R34
R38
R34
MPD result1
Corrosive4
Corrosive
Mod - S«v
Corrosive4
•
Corrosive
Corrosive
Corrosive
Corrosive4
Moderate
Corrosive
Low - Mod
Moderate
Corrosive
Moderate
Corrosive
Corrosive
Mod - Sev
Corrosive
SAR result
Acute
Irritant
Irritant
Acute
No comment
No comment
No comment
No comment
Irritant
No comment
Irritant
Irritant
Irritant
No comment
Irritant
No comment
Irritant
No comment
Agreement?
Yes
Yes
•Yes
Yes
False -ve
False -ve
False -ve
False -ve
Yes
False -ve
Yes
Yes
Yes
False -ve
Yes
False -ve
Yes
False -ve
See Appendix 3 for list of "R phrases".
According to the criteria above, using pi
Predicted relative to test-derived level ol
4 Chemicals not tested: EC assumed corrosivity based on physico-chemical properties.
1 According to the criteria above, using primary irritation score.
Predicted relative to test-derived level of skin irritancy.
The overall results for the comparison of SAR calls and MPD data for skin irritation are summarised
in Table 12. In this Table, MPD positive includes the three chemicals considered corrosive in the EC
on the basis of physico-chemical properties (chemicals 4, 107 and 194); and SAR negative includes
•the two chemicals tor which the prediction was "uncertain". Details of the data on skin irritation for
all chemicajs are to be found in Annex 13.
-------
TABLE 12: Overall results for skin inrkniion
MPD Positive
MPD Negative
SAR Positive
14 (10%)
18 (12.5%)
SAR Negative
8 (5.5%)
104 (72%)
Conclusions - skin irritation
Incorrect predictions were obtained for 18% of the chemicals: 12.5% were false positives and 5.5%
were false negatives-. The predictive methods used are not adequate for classification of chemicals
using a system based on severity of response and thus the test cannot be replaced on a one-to-one basis
by the predictive approach when knowledge of the potential for skin irritation/corrosion is needed.
4.23 J.ii Eve irritation
The criteria used to compare the test data with the SAR call for eye irritation could not be made on
a severity index as the SAR evaluations did not usually include this index. From the test data
summaries, a chemical was considered to produce significant eye irritation if redness, swelling or
corneal opacity persisted beyond seven days or if effects were not reversible by 21 days or corrosion
was reported. Eye testing was not conducted on chemicals with predictable corrosivity because of their
physico-chemical characteristics or, for some chemicals (see Table 13), if corrosive effects had been
recorded in a previously conducted skin test.
Classification according to the EC system (for which the criteria are a combination of scores and
duration of effects), on the basis of the results of the eye irritation studies, was obviously also
considered as indicating that the classified chemicals were eye irritants.
Of the total of 144 chemicals in the project, there were 140 on which eye irritation tests had been
conducted, three were predicted to be corrosive and one (number 267) could not be tested for technical
reasons. All 144 chemicals had been considered when predicting the potential for eye irritation as a
consequence of ocular exposure to the chemicals.
On the basis of the test results, 105 chemicals were considered to be of low concern for eye irritation,
as was chemical 267, which had not been tested. Correct predictions of low concern'were' made for
87 of these (83% of the "negative " chemicals. 60% of the total set of chemicals). The other 18 were
predicted by the EPA to be irritant i.e. they were false positives.
The 38 remaining chemicals were either corrosive (12 chemicals), or irritant according to the criteria
given above. The outcome of the comparisons between the predicted and test results for the classified
chemicals is given in Table 13, the detailed analysis foj all chemicals in the project is given in Annex
13.'
33
-------
TABLE 13:
Chemical
4
47
49
87
107
118
124
151
170
182
192
194
197
222
235
237
256
263
270
281
370'
425
Comparison of oredicted eye
Label1 MPD result1
R35
R41
R34
R41
R35
R34
R36
R36
R41
R34
R34
R34
R41
R36
R34
R36
R36
R36
R36
R36
R34
R34
Corrosive*
Severe
Corrosive
Severe
Corrosive'
Corrosive*
Irritant
Irritant
Severe
Corrosive
Corrosive
Corrosive*
Severe
Irritant
Corrosive*
• Irritant
Irritant
Irritant
Irritant .
Irritant
Corrosive*
Corrosive*
irrittyncy with tha{ observed
SAR result
Acute
Uncertain
Irritant
No comment
Acute
No comment
Irritant
Irritant
Irritant
Irritant
No comment
No comment
No comment
Irritant
No comment
Irritant
Irritant
Irritant
No comment
Irritant
Irritant
Irritant
Agreement1
Yes
False -ve
.Low
False -ve
Yes
False -ve
Yes
Yes
Yes
Low
False -ve
False -ve
False -ve
Yes
• False -ve
Yes
Yes
Yes
False -ve
Yes
Low
Low
34
-------
TABLE 13
Chemical
436
441
442
443
- continued
Label1 -"
R34
R41
R41
.R34
MPD result'
Corrosive*
Severe
Severe
Corrosive4
SAR result
No comment
Irritant
Irritant
No comment
Agreement3
False -ve
Yes
Yes
False -ve
1 See Appendix 3 for list of "R phrases"
2 According to the criteria given in the text
3 Predicted relative to test-derived result
4 Chemicals not tested: corrosivity assumed based on physico-chemical properties or results of skin
irritation study
From the comparisons given in Table 13, it can be seen that, for the 26 classified chemicals, 16 were
correctly predicted to be eye irritants and 10 were incorrectly assessed (false negatives).
The overall results for the comparison of-the SAR calls and the MPD test results are summarised in
Table 14.
TABLE 14: Overall results for_eve irritation
MFD Positive
MPD Negative
SAR Positive
26(18%)
18(13%)
SAR Negative
13 (9%)
87 (60%)
Conclusions - eve irritation
Incorrect predictions were made for 22% of the chemicals (9% were false negatives, 13% false
positives). As with skin irritation, predictive methods are not adequate for classification of chemicals
with regard to severity of the response and thus cannot replace test results on a one-to-one basis.
35
-------
4.2.3J.iii Pfspiratorv irritation
.New chemicals are not tested for respiratory irritation in the EC, but the potential for respiratory
respiration had been considered by the EPA predictors. -
Predictions of potential respiratory or mucous membrane irritation had been made for 9 (6%) of the
chemicals in this study.
General conclusions
The majority of this group of new chemicals was of low concern for skin (85%) and eye (74%)
irritancy. Thus, the extent to which an assessment can be made of the power of the predictive methods
to discriminate between chemicals on the basis of their skin or eye irritation potential is limited.
The majority (>80%) of the low concern chemicals were predicted co'rectly and 18% were
over-predicted for either or both of skin and eye irritancy. The latter observation means that for these
substances, the risk assessment would err on the side of caution but would lead to "over-labelling"
if the predictive methods replaced the tests.
The incidence of false negatives and the limitations in assessing severity of response are of some
concern and indicate that replacement of testing with prediction cannot yet be recommended with
confidence.
.Respiratory irritation is an important end-point which is not investigated in the MPD. It would be
prudent to take note of chemicals predicted to be respiratory irritants.
4.2.3.4. Sensitisalinn
Knowledge of the sensitising potential of chemicals is important when evaluating safe handling
practices.
Prediction of sensitisation is not usually pan of the routine evaluation of* a new chemical in the US.
but it was considered for this project.
In the EC, chemicals are tested for their skin sensitising potential. There is not an internationally
recognised test method for respiratory sensitisation. Classification of notified new chemicals as skin
sensitisers in the EC is based on the proportion of animals showing a positive response in a particular
test. In the EC, chemicals may be classified as respiratory sensitisers if they show close structural
similarity to known chemical respiratory sensitisers.
Skin sensitisation tests, mostly maximisation tests, were conducted on 137 of the chemicals in the
project. Twenty eight chemicals were classified as skin sensitisers (including one of those which had
not been tested). A further 18 induced some positive responses but the number of animals responding
was below the threshold for classification in the EC.
-------
Seventeen chemicals were predicted to be sensitisers; four of these were predicted to be respiratory
sensitisers and one was predicted to be a phbtosensitiser. Two were predicted not to be sensitisers.
For most of the chemicals there was no comment on skin sensitisation - this is equivalent to
considering the chemical of low concern/negative for this end-point.
For 108 chemicals (75% of the whole set in the project), both die test results and die predictions
indicated low concern for skin sensitisation.
The results of the comparisons of the test data and the predictions are given in Table IS for the 28
chemicals classified as skin sensitisers in the EC.
TABLE 15: . Comparison of results fitr chemicals classified as skin sensitisers
Chemical ' SAR Result and comments
47
76 +
96
118
133
173 +
194
196 . +
197
200
222 +
235 .
256 +
271 -: '
275
False negative
Agree
False negative
False negative
False negative
Agree
False negative NB: chemical not tested
Agree
False negative
False negative
Agree Chemical also classified and predicted as a
respiratory sensitiser
False negative
Agree - -
False negative
False negative
37
-------
TABLE 15 - continued
Chemical . . . SAR .
330 +
341 +
344
348
376 +
393
401
413
416
437
442
444
Result and comments •
Agree
Agree Chemical also classified and predicted as a
respiratory sensitiser
False negative
False negative
Agree
False negative
False negative
False negative
False negative
False negative
False negative
False negative
Five other chemicals were predicted by the US to be skin sensitisers: one did not have adequate test
data (240); two did induce some-positive responses in the tests conducted (253, 312} and two were
apparently false positive predictions (340, 364).
Two other chemicals were predicted to be potential respiratory sensitisers (69, 101).
For the set of comparable skin sensitisation data (140 chemicals) the comparisons in Table 16 can be
made. . • •-.-•-
TABLE 16: Overall results for skin sensitisation
MPD Positive
MPD Negative
SAR Positive
9 (6.5%)
SAR Negative
19 (13.5%)
108 (77%) .
includes two substances for which positive responses, below the threshold for classification, where
observed .in the tests
38
-------
Conclusions
The incidence of false negatives precludes use of the predictive methods to replace the tests on a
one-to-one basis or to classify chemicals for their skin sensitisation potential. However, the
concurrence of positive predictions with positive test results needs to be further assessed with a larger
set of chemicals as confidence in the ability to predict positives could perhaps replace testing of
chemicals predicted to be skin sensitisers.
For respiratory sensitisation, reliance is currently placed on predictive methods,.based on structure,
to classify new chemicals in the EC, and the unclassified substances predicted, in this project, to be
potential respiratory sensitisers should be re-evaluated in the EC with regard to classification.
It is not possible to comment on the single prediction of potential photossnsitisation. .
4.2.3.5. Repeated dose toxicitv
Repeated dose toxicity covers the adverse effects which may arise in humans exposed to a chemical
at frequent, regular intervals over a prolonged period of time, for example at their daily work. To
facilitate evaluation of safe handling practices for chemicals, it is important to have knowledge of the
potential systemic effects which may occur on repeated exposure.
In the EC, general effects on the whole animal and effects on tissues, organs and/or systems are
investigated. Special effects (e.g. neurotoxicity, reproductive toxicity, carcinogenicity) are investigated
in specific tests, but indications of potential reproductive toxicity, neurotoxicity or immunotoxicity
may be detected in repeated dose toxicity studies.
For most of the chemicals in this project only 28-day, and/or occasionally 90-day, study results were
available. In the EC study summaries used for this project, dose levels used, a description of toxic
signs, including clinical chemistry and haematology, gross and microscopic changes in a selected set
of tissues/organs, and NOEL, NOAEL, LOEL and LOAEL (no/low observed effect/adverse effect
level) values are usually included or can be deduced. In general, only effects of biological significance
are included and species specific effects (e.g. peroxisome proliferation and, in the more recent
summaries, male rat specific light hydrocarbon nephropathy) are not. Chemicals are classified for
repeated dose toxicity in the EC on the basis of adverse effects (of biological/human significance)
occurring at or below dose levels specified according to the route of exposure and the duration of the
study.
Predictions of repeated dose toxicity are particularly important in the US EPA evaluation process; with
identification of potentially toxic chemicals as the goal. Efforts are also made to assess potential'target
tissue/organ/system. -
Test data were not available for seven chemicals (3 corrosive chemicals, 2 polymers, 1 organoclay
and one chemical not tested in the light of test data available for another notified chemical, of very
similar structure). Two chemicals had been tested in 28-day inhalation studies and eight in dermal
28-^ay studies. For one of the latter group, a 90-day study had also been conducted. The remaining
127 chemicals had been tested using 28-day oral toxicity studies and three also had results available
from 90-day studies.
Eight chemicals had been classified in the EC on the basis of their repeated dose toxicity.
-------
The comparison of repeated dose toxicity test results with predicted toxicity was the most difficult to
do as interpretation of observed effects in terms of severity and significance is a matter of professional
judgement. The factors considered in the evaluation were the perceived seriousness of the toxic effect,
the number of organ-specific parameters affected, with microscopic pathology given the heaviest
weight, multiplicity of target organs, the toxic effect(s) at the LOAEL, the numerical value of the
NOAEL, dose-related effects and the spacing of the dose levels used.
The systemic toxicity data from the test results were scored as high, moderate or low using the
following general criteria (sometimes modified according to professional judgement):
Concern level
Low(L)
Moderate (M)
High (H)
Criteria.
No systemic toxicity (NOAEL 1 g/kg/day or more); only minor clinical signs
of toxicity; liver and/or kidney weight increase or clinical chemistry changes;
LOAEL >500mg/kg/day.
Organ pathology (gross and/or microscopic) with LOAEL 500 mg/kg/day or
less; clinical chemistry changes and organ weight changes at <500
mg/kg/day; NOAEL < 100 mg/kg/day.
Death, organ pathology (microscopic) at LOAEL 100 mg/kg/day or less;
multiple organ toxicity; NOAEL < 10 mg/kg/day.
"Split-levels" (L-M; M-H) were adjustments fur specific multiple organ toxicity, borderline effect
levels and professional judgement.
The outcome of the comparisons of repeated dose toxicity on the basis of concern level is summarised
in Table 17.
TABLE 17: Matrix analysis of systemic Coxicitv concern levels
SAR
L=M
M-H
MPD
L
L-M
M
M-H
H
62
23
11
3
1
10
11
1
1
0
5
2
5
2
0
0
0
1
3*
0
0
0
1
0
1*
* 1 chemical in each of these groups was corrosive and predicted to have acute effects
40
-------
One chemical (337) is not included in the matrix. It was M-H according to the test results, but there
was no prediction of repeated toxicity..
Sixty-two chemicals (43%) were considered of low concern both following testing and by the
predictive methods.
Twenty chemicals (14%) with greater than "low" concern were predicted to have the same level of
concern as was deduced from the test data using the criteria given above. This group included the two
corrosive chemicals which were predicted to have "acute" effects (numbers 4 and 107) and chemical
292 for which data were available from the product literature. •
The concern level was under-predicted for 42 chemicals (29%) though for 27 chemicals there were
overlapping concern levels from the test and predicted results; and 23 of these predicted to be of low
concern were only low-moderate from test results. For the other IS the concern level predicted was
at least one whole level lower than that deduced from the test data. Six of this sub-set of IS were
chemicals classified in the EC on the basis of repeated dose toxicity.
Toxicity concern was apparently over-predicted for 19 chemicals. However, the extent of repeated
dose toxicity testing of these chemicals was limited to 28-day studies (18 oral studies, 1 dermal). It
will be of interest, if/when 90-day, or longer, study data become available, to re-compare the
predicted toxicity with that found on testing.
Overall, the correct level of concern (according to the criteria given above) was predicted for S7%
of the chemicals, but was under-predicted fur 29%. Toxicity was apparently over-predicted for 13%
of the chemicals.
Details of the organ toxicity predictions and test results are given for all the chemicals in the project
in Annex 14.
Conclusions
Just over half (57%) of this group of 143 heterogeneous chemicals were correctly predicted to be
either of low concern (43 % of the total) or to have the same level of concern (14% of total) in relation
to repeated dose systemic toxicity. The concern level was apparently over-predicted for a further 13%,
but if/when longer-term studies are conducted the predicted effects may be induced.
•*
Under-prediction of the level of concern on the basis of repeated dose toxicity was noted for 42
chemicals (29% of the total), although for 23 of these, die test data indicated only low-moderate
concern and EPA predicted low concern. For IS chemicals, there was at least one whole "level of
concern" difference, and six of the eight classified chemicals were in this group.
On the basis of these comparisons, although fur 74% of the chemicals in this study, correct or near-
correct predictions of concern level were made, it is not considered possible to consider the predictive
methods as an adequate substitute tor conducting repeated dose toxicity testing of a
random/heterogeneous group of chemicals because of under-prediction of toxicity. As classification
of a chemical as dangerous following repeated exposure depends not only on the effects seen, but also
on the doses at which they occur, the predictive methods for repeated dose toxicity would not provide
a firm basis for classification.
41
-------
4.23.6 Mutaeenicitv
Chemicals which increase the incidence of mutations in the cells of exposed humans may thereby
increase the incidence of cancer (from mutations in somatic cells) or genetic defects in the offspring
(from mutations in germ cells). It is generally thought prudent to assume that there is no threshold
exposure level, below which exposure would give rise to only low concern, for chemical mutagens.
Thus, chemicals identified as mutagens are subject to stringent controls so that human exposure is
minimised.
Because of the serious and irreversible effects which may occur in humans exposed to chemical
mutagens, testing for mutagenicity usually employs a number of tests, in vitro and in vivo, which are
conducted either as a battery or (as in the. EC) in series. In the EC, all notified chemicals must, it it
is technically possible, be tested' in a bacteriological test for gene mutation and in a test in mammalian
cells for chromosomal effects at the "base-set" level of supply. Hie latter test may be either an in vitro
test or a test conducted in vivo. Maximised conditions are used, though short of conditions likely to
cause artefactual positive results; and in vitro tests are conducted both with and without exogenous
metabolic activation. Further testing is conducted to investigate in more detail positive test results, as
necessary, and/or as supply tonnages reach the trigger levels. Classification of chemicals on the basis
of mutagenicity is done according to criteria defined in Annex VI to the dangerous substances
Directive. Chemicals are not usually classified unless there is evidence of mutagenicity from tests
conducted in vivo, so positive in vitro test data will trigger the need for testing in vivo.
The EPA predictions for mutagenicity, based on e.g. chemical class, analogue data, likely metabolites,
alkylating potential, represent an overall for mutagenic potential. EPA also considers available data
concerning mutagenicity test systems and their sensitivity towards different classes of chemicals. Thus,
the criteria for comparing the predicted with the test results involved more than a simple comparison
of EPA predictions with the test data. In addition, the test results for a few (6, 4%) chemicals with
borderline responses were not always interpreted in the same way by the EPA and EC experts.
Tests had not been conducted on five of the 144 chemicals in the project - 3 for technical reasons
(chemicals 4 and 107 were corrosive and chemicals 267 was an insoluble polymer) and for the other
two (chemicals 1*94 and 445) data from analogues were considered acceptable. Predictions bad been
made for the first three (all were "low concern" for mutagenicity) but there were no test data to
compare them with. Thus, there were 141 data pairs for comparison. All of the 139 chemicals tested
had Ames test data and all had at least a result from one other study. The in vivo micronucleus test
occurred most frequently as the second study, and the in vitro chromosome aberration test was next
most common. Tests in E coli (always alongside the Ames test when the E coli test had been
conducted); in vivo chromosome aberration, nuclear anomaly and sister chromatid exchange (SCE)
tests and in vitro mammalian cell gene mutation assays, unscheduled DNA synthesis, and SCE tests
also occurred in this set of tests. Interestingly, for no chemical was there more than one positive test.
One hundred and twenty chemicals gave negative results in both a bacteriological (Ames) test and a
non-bacteriological test. Some of these chemicals also had negative results from gene mutation tests
in E coli and/or from other non-bacteriological tests. Two chemicals were assumed by analogy to
structurally similar chemicals to be negative and were not tested. Thus, following testing, 122
chemicals (85% of the chemicals in the project) were considered negative. SAR predictions of low
concertrfor mutagenicity were made for 107 chemicals in this group (88% of the MPD "negatives").
Depending on how the analysis is done "false positive" predictions were made for 14 (10% of total)
or 2 (1.4%) chemicals. A direct reading of the MPD results would lead one to conclude that there
•were 14 false positive predictions. However, EPA considers that positive results would be produced
if tests were performed using assay systems other than those used already to test the affected
42
-------
chemicals. The EPA conclusions are based on the existence of data on analogues (chemical or
mechanistic) indicating positive results in certain test systems. It will be of interest (and potential
importance) to see whether-the predictions of positive mutagenicity are fulfilled if further test data
become available. .
Six chemicals (4% of total) with positive test data were predicted "low" (false negatives) because of
absence of known positive data in analogues.
The test results (including, where appropriate, an indication of weak positive results), EPA predictions
and results of comparison are given in Annex 15 tor all of the chemicals in the project.
Conclusions
A nigh proportion of the chemicals in this project were negative for mutagenicity and a high
proportion of these were correctly identified by the EPA.
Although the number of test-positive chemicals was small, it is also of concern that six of them were
called low. The observation thai 123 of 142 data pairs (87%) were apparently correctly predicted thus
has to be seen in the light of the above comment. For this reason it would not be prudent at this time
to replace mutagenicity testing of new chemicals in the EC with the predictive methods used in the
US for PMN chemicals.
As the EC classification system for mutagenicity, as applied to notified new chemicals, depends
essentially on testing in vivo to investigate whether effects observed in vitro are expressed in vivo,
the predictive methods used here, which do not make this distinction, could not be used for
classification in the EC.
4.2.3.7. Other eflwts
A number of effects were considered using the predictive methods which had not yet been investigated
in the EC testing programme for the chemicals in this project i.e. reproductive.and developmental
toxicity, neurotoxicity and oncogenicity. For some chemicals, indications of some of these effects (e.g.
clinical signs of neurotoxicity; changes affecting the reproductive organs) may be reported for the
acute or repeated dose tests. Such reports were made for some chemicals in this project: five
chemicals had significant indications of potential reproductive toxicity (76, 151, 186. 200 and 292)
and reproductive toxicity was predicted fur chemicals 200 and 292 but not for the others
(developmental toxicity was predicted tor chemical 76). Signs of neurotoxicity were seen with six
chemicals (54, 268, 340, 342,431 and 434) and neurotoxicity was predicted for two of these (54 and
340). •
Adverse effects on reproduction and/or development were predicted by EPA for 51 chemicals (35%);
27 chemicals were predicted to be neurotuxic (19%) and 33 (23%) to be oncogenic.- This is of
particular concern as these potential effects are not specifically investigated in the initial testing of new
chemicals in the EC.
The health concerns for which the MPD data set does not provide data were analysed for number of
chemicals for which such concerns were expressed and the frequency of occurrence. Of the 144
chemicals. 66 (44%) had concerns that addressed health effects outside the scope of the MPO data set.
The breakdown by effect and frequency of occurrence is presented in Table 18.
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TABLE 18: Health concerns not addressed hv the MPD data set
Concern _ Number of chemicals % of Total chemicals
Oncogenicity 33 23
Developmental toxicity 46 32
Reproductive toxicity 13 - .9
Neurotoxicity 21 IS
Immunotoxicity 2
Photosensitisation 1
Lung 1
Respiratory sensitisation 1
This table indicates that potential adverse effects beyond those in the MPD were identified for a
substantial number of the chemicals, which implies that hazards and possibly risks may be
underestimated if these effects are not considered. There may be a need for early focused testing in
at least some of these cases.
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5.
Overall conclusions
£.1.' Conclusions: US perspective
5.1.1. Introduction/Overview
The purposes of the study were to compare the results obtained in assessing a series of European
Community (EC) new chemicals using two methods - the US SAR-based (Structure Activity
Relationships) approach and the EC's testing-based approach using the Minimum Pre-market Data
(MPD)- and to estimate the extent to which the US hazard1 conclusions on new chemicals might
change given a "base set" of test data. The study would also provide insights into the strengths and
weaknesses of specific SAR approaches and allow EPA to judge how well SAR works in other areas
of application, e.g., priority setting for existing chemicals and testing.
The results "of the study, as expected, were quite useful in judging many of the strengths and
weaknesses of the US approach, as well as determining the utility of MPD-type data in improving US
assessment capabilities. It must be pointed out, however, that as useful as the study was, there are
some limitations that must be considered in the overall evaluation of the exercise. These limitations
include: the small data set available, the end-points used for comparison were limited to the tests
included in the MPD data set, different approaches to ascertaining certain parameters, and indirect
measurement in some MPD data sets of one or more physical/chemical properties (i.e. extrapolation)
which may or may not give a "true" result. These limitations are discussed in more detail in the
following sections. However, taking into account these limitations, the MPD/SAR exercise served to
confirm that the SAR approach to screening new chemicals2 is useful and effective in identifying
chemicals that may be toxic and in need of further scrutiny for US regulatory purposes. However,
the SAR approach appears to have limitations in predicting physical/chemical properties under some
circumstances and in predicting the exact type and level of toxicity of the chemical, especially with
regard to general systemic (health) effects.
5.1.2. Results
The end-points that were assessed have been divided into four categories (physical/chemical
properties, biodegradability, health effects, and ecotoxicity) for discussion purposes and appear below.
S.I.2.1. Phvsico-chemical properties
The physical/chemical properties routinely predicted by the SAT are: log P,., boiling pomt/melting
point, water, solubility, vapour pressure. Henry's Law constant as well as the soil sorption coefficient
and the bioconcentration factor. The MPD data set contains either measured or calculated values for
log PW,, boiling point/melting point, water solubility, vapour pressure, and Henry's Law constant. Of
these properties, there were sufficient data pairs for meaningful comparison of log P.., vapour
pressure, and water solubility.
'This study examined hazard (or toxicity) predictions and did not examine exposure or risk issues,
other than to consider predictions of environmental fate.
7ln the US scheme, PMN chemicals are initially reviewed by EPA's Structure Activity Team
(SAT) which "screens" the chemicals to assess their fate and effects. For cases which are determined
to present potentially significant risk concerns, a more detailed assessment is prepared. The present
study compared the results of SAT (screening) assessments with the results of the MPD testing.
t
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For log Pw comparisons of the 144 chemicals, there were 35 for which either SAR and/or MPD data
were missing, additionally, a number of the MPD values were calculated or estimated which allowed
for a comparison of estimation methods, hut did not provide an opportunity to compare the US
estimated values with actual measured values. Applying a US/EC agreed upon standard of ± I order
of magnitude for 'good agreement," the overall agreement between the US estimates and the EC
measured values was around 60%. In analysing the 40% which were in disagreement, it became
apparent that the estimation techniques for log P«« were of limited value with certain classes of
chemicals (e.g., classes where all the molecular fragment constants have not been measured, ionic
compounds, organometalHcs, inorganics, and classes/compounds which are readily hydtolysed). For
those classes where the estimation techniques are appropriate, the agreement was acceptable and
predictive approaches were judged to provide a useful alternative to experimentally determining log
Pw. For chemicals where models are nut appropriate, experimental determination of log P.. is the
preferred method.
Vapour pressure comparisons presented a number of analytical problems. In the US PMN program
vapour pressures below 10'' torr are routinely considered "negligible" and not of concern for either
worker/consumer exposure or volatilization from the pure state. Thus estimated values of less than
10"J torr are in general not determined. The EC, however, considers vapour pressures relevant to 10*
torr and thus requires values to be provided. In order to adjust for the differing requirements, a set
of rules was generated and agreed to by the US and EC. Additionally, the vapour pressure for the EC
chemicals was measured on the substance "as marketed" in the EC (i.e., a mixture or formulation,
in many cases), whereas the US estimate was made for the pure chemical. The results of the analysts
showed that 63% of the US estimated values were in agreement (+.1 tog unit) with the measured EC
values. Of the 37% (42 chemicals) of the comparisons that were in disagreement, the disagreement
for 30 of the chemicals can be accounted for by the following reasons:
the "measured" vapour pressure value was extrapolated from a value measured at a higher
temperature which tends to overestimate the (rue actual atmospheric vapour pressure;
the pre-market substance tested contained a volatile solvent and/or impurities;
the substance decomposed during the measurement procedure;
the measured value reflected water which was being driven off by the measurement procedure;
vapour pressure was the lowest value measured and thus represents the upper limit rather that an
actual value.
The best agreement was observed between the PCNOMO estimates and the measured values. Overall.
however, vapour pressure estimates were judged to have marginal acceptability since the values were
both over- and underestimated by the US. As was stated previously, vapour pressure contributes to
the exposure poition of the risk assessment for new chemicals and over/under estimation can result
in an over/under estimation of the exposure associated with a chemical and thus contribute to an
over/under estimation of the risks. Thus incorrectly estimating vapour pressure may unnecessarily put
the worker/consumer at risk or burden the manufacturer with unnecessary constraints depending upon
the direction of the estimation error. Vapour pressure is a relatively inexpensive parameter to
measure, and as such, it may be more cost effective and less risky/burdensome to obtain experimental
data to confirm the estimated value in cases where vapuur pressure is an important contributor to the
risk projection.
Water solubility comparisons presented same similar problems to the vapour pressure comparisons.
In the US PMN program water solubilities below I mg/l are not routinely estimated, because
reasonably'accurate estimation of extremely low water solubilities is difficult. On the other hand, the
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EC data measure water solubilities of < 0.1 mg/l in many cases. In addition the EC measured value
is not necessarily done on the pure chemical but many times on the substance "as marketed," whereas
the US estimated, value is for the pure chemical. The results of the analysts showed that 68% of the
US estimated values were in agreement (± 1 log unit) with the measured EC values. Of the 32% of
the comparisons (43 chemicals) that were in disagreement, the disagreement for 26 of the chemicals
can be accounted for by the following reasons:
the "measured" value was not actually measured but reported as a lower limit of detection or
the lowest value measured:
the pre-market substance tested contained a solvent and/or impurities which complicated
interpretation of water solubility values;
•
. the measured value was measured spectrophotometrically;
the substance decomposed or reacted, with the water during the measurement procedure.
Overall the water solubility estimates were judged to have marginal acceptability since the values were
both over- and under-estimated by the US. Water solubility contributes to the hazard and exposure
portions of die risk assessment for new chemicals and over/under estimation can result in an
over/under estimation of the hazard/exposure associated with a chemical and thus contribute to an
over/under estimation of the risks. Thus incorrectly estimating water solubility may put the
worker/consumer unnecessarily at risk or burden the manufacturer with unnecessary constraints
depending upon the direction of the estimation error. Water solubility is a relatively inexpensive
parameter to measure, and as such, it may be more cost effective and less risky/burdensome to obtain
experimental data to confirm the estimated value in cases where the water solubility is an important
contributor to the risk projection.
5.1.2.2. Biodeprqdahility
Comparison of the US and EC biodegradability data was difficult due to the fundamental
incompatibility of the evaluation approaches used for assessing biodegradability. in the US versus the
EC. The US estimates biodegradability in terms of "days, weeks, or months" which refer to the
approximate amount of time (not half-lite) required for complete primary and ultimate biodegradation
of the chemical in aquatic environments. In contrast, the EC requires a laboratory test which evaluates
the "ready" biodegradability of chemicals. Thus, while chemicals that degrade easily in the EC testing
scheme would most likely be easily degraded in the environment, it is not necessarily true that
chemicals, not degraded in the EC tests would not be degraded under environmental conditions'which
is what the US approach attempts to predict. For the purposes of this exercise, chemicals that did not
pass the EC test, i.e. did not degrade under conditions of the test were considered to correspond to
the descriptors "weeks or longer" and ones that passed, i.e., degraded, were considered to correspond
to the descriptors "days," and "days to weeks" in the US scheme. Using these criteria, there was a
93% agreement between the US predictions and the EC test results.
The US scheme for predicting biodegradability aims for a realistic assessment of the ultimate fate of
a chemical under environmental conditions. In contrast, the EC testing scheme is designed to
determine ready biodegraJability under precise laboratory conditions. While the EC scheme may
provide more quantitative results, it can be argued that the .modelling by the US represents a more
realistic estimate albeit qualitative. Biodegradability testing under conditions that duplicate actual
environmental conditions may not be feasible either from a scientific or a cost perspective. Although
the MPD/SAR analysis has significant uncertainty due to the basic differences between the two
approaches,'the present US modelling scheme appears to be reasonably effective in predicting
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biodegradability that is consistent with experimentally derived results. However, given the uncertainty
in the analysis, in the instances for which fate is a major contributor to the overall risk projection, or
for classes .of chemicals where there is insufficient data for modelling, it is advisable to confirm the
prediction with appropriate testing.
5.1.2.3. Health effects
Although the EC requires that a base set of toxicity data be submitted with all their new chemicals,
the data are used principally to classify and label the chemicals according to a set scheme. Hits is in
contrast to the US practice where hazard information is evaluated and integrated with potential
exposure to ascertain risk. In addition, under the EC scheme additional testing on the new chemical
must be provided as production'grows (known as the "step system"). In the US, on the other hand,
if controls or testing requirements are not implemented before manufacture commences, the new
chemical authorities under TSCA no longer apply. Thus any controls or testing must be done under
TSCA's existing chemical provisions which carry a much heavier burden for the government. Thus
the emphasis on end-points tends to differ under the two schemes, with more weight given to acute
effects (i.e. lethal dose, eye and skin irritation and sensitisation) in the EC scheme and more attention
paid to long-term or sub-chronic effects in the US. with relatively little emphasis given to acute
effects. Nonetheless, because the US does not routinely predict acute effects for new chemicals (end-
points which are well represented in the MPD), but focuses its efforts on predicting long-term effects
(many of which are not covered by the MPD), the study was somewhat limited in its ability to
compare health hazard predictions with MPD results. These points will be discussed in more detail
below.
For the analysis of the comparison between predicted effects and test data, each end-point was
compared and analysed separately. An overall analysis was also done which attempted to compare the
US and EC "bottom line" health assessments for each chemical regardless of effect.
For acute effects the US predictions corresponded to the EC results between 78-88% of the time. Eye
irritation had the lowest correspondence between predicted and measured value and dermal irritation
had the highest. Nonetheless, irritation and sensitisation are not judged to be particularly amenable
to SAR analysis except for general classes; furthermore the tests for these .effects are, in general,
inexpensive. It seems reaspnable that if understanding of these effects is an important consideration
under a given scheme, then the submission of data is preferable to prediction. For acute toxicity, the
predictive approach worked reasonably well and is judged to be acceptable for screening purposes
(i.e., qualitative assessment).
Overall, for mutagenicity the US predictions corresponded to the EC results 94% of the time. Out of
144 data sets available for mutagenicity. 2! initially were in disagreement between the US prediction
and the EC results. Further analysis of the 21 revealed that three of the disagreements were due to
the use of inappropriate analogues by the US, two were due to lack of positive analogue data and
weak or marginal positive responses reported in the EC data, and four were due to the absence of
analogue mutagenicity data upon which to base SAR decisions. The remaining 12 may be MPD "false
negatives" caused by testing in assay systems known to be insensitive to specific classes of chemicals.
These 12 were called positive by the US due to analogue data reporting positive results in assay
systems known to be sensitive to chemicals in the specific classes. Six chemicals with positive results
were predicted "low" because of the lack of data on analogues and an absence of structural features
suggestive of mutagenic activity. These false negatives, while small in number, were of concern and
suggest that testing for this end-point should be considered in cases for which data on analogues are
•unavailable and exposures are projected to be at moderate or higher levels.
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For long term and sub-chronic effects, the US routinely predicts'systemic toxicity as we!! as
developmental and reproductive toxicity, neurotoxicity, and oncogenicity. The EC "base set* data
includes only a 28-day repeat-dose study which does not address the latter concerns. In order to
analyse the results of the study, systemic toxicity was assessed and then the concerns that fall outside
of the 28-day study were folded into the analysis to achieve an overall analysis of the US predictions.
Systemic toxicity, exclusive of developmental and reproductive toxicity, neurotoxicity, and
•oncogenicity, was analysed by comparing the US predictions (concern levels)1 for systemic toxicitv •
only with 'the MPD data; both were also scored according to seventy of effect which was
predicted/observed. The results of this analysis showed that for 57% of the 1384 chemicals assessed
the scores were identical and tor 43% the scores disagreed. Further analysis revealed that the US
tends to under-predict systemic toxicity (effects and/or severity) as observed in the MPD's 28-day
study (which, in itself, is judged to provide a reasonable approximation of sub-chronic toxicity for
most chemicals). For 27% of the chemicals, the US predicted a "tow" concern whereas the MPD 28-
day study supported a "low-moderate" or greater concern level. For 3% of the cases, the US
predicted some concern (i.e., low-moderate or greater) while the MPD results supported a higher level
of concern. For 14% of the cases, results of MPD testing supported a lower level of concern than
was predicted by the US; in 11 % of the cases the MPD supported a "low" concern whereas the US
predicted low-moderate or greater concern. Note, however, that while the comparison study suggests
a clear tendency to underestimate rather than overestimate the potential for systemic toxicity, the
magnitude of the difference between the US and EC calls was relatively small. • For example, in 23
of the 41 cases for which the US under-predicted the concern level, the MPD supported a "low-
moderate* concern whereas the SAR-based call was.for "low" concern while in 3 additional cases
where the US predicted "low-moderate" or greater concern, the MPD supported a one-step increase
in the concern level (e.g., "low-moderate" concern to "moderate" concern). This, nonetheless, is
interpreted as indicating that the US needs to exercise caution in interpreting systemic toxicity
predictions and should consider requiring a repeat dose test in cases where the projected exposures
are at moderate or higher levels.
When concerns not addressed by the MPD (i.e., developmental and reproductive toxicity,
neurotoxicity, and oncogenicity) were folded into the analysis, the US level of concern scores were
identical to the MPD scores 78% of the time. The chemicals for which non-MPD health concerns
were identified by the US were analysed to determined the nature and frequency of their occurrence.
Of the 143 chemicals, 66 had concerns identified by the US that suggested one or more health effects
beyond the scope of the MPD. The breakdown by predicted effect revealed that 32% of the chemicals
had developmental toxicity concerns, 23% had oncogenicity concerns, 15% had neurotoxicity
concerns, and 9% had reproductive toxicity concerns.
The large number of chemicals that were predicted to have effects not addressed by the MPD raises
the issue of possible improvements to the MPD. Although it may not be feasible to address
oncogenicity directly, the developmental, reproductive and neurotoxicity concerns could conceivably
be screened by use of a modified testing scheme. Thus, in designing a "base set" o'f testing, it may
be appropriate, given the relative frequency with which these potential effects were identified in this
study, to include testing to screen for these effects.
JThe concern levels employed by the US in assessing new chemicals (and used in this study) are
as follows: low, low-moderate, moderate, moderate-high, and high.
'Five of the chemicals were not tested in a 28-day study due to physical/chemical properties (e.g.,
pyrophoric) that rendered them unsuitable fur testing.
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When overall level of concern scores tor health effects are considered, (i.e., a bottom-line assessment
considering all effect areas), the trend towards under-prediction rather than over-prediction (which was
observed in the analysis of systemic toxicity outcomes) is still apparent. If the overall level of concern
scores are analysed similarly to the systemic toxicity scores, 11 % of the chemicals were identified by
the US as being of low concern whereas the MPD supported a low-moderate or greater concern based
on the MPD data, while an additional 8% were identified as being of low-moderate or greater concern
by the US while the MPD supported a higher level of concern. In contrast, for only 4% of die cases
did the MPD support an overall lower level of concern than had been projected by EPA. However,.
the scores for overall level of concern for health effects indicate a higher concordance between the
US and EC than scores that were seen in the systemic effects analysis, which is due in pan to the
inclusion of concerns expressed for other MPD end-points (e.g., mutagenicity) as well as effect end-
points outside the scope of the MPD "base set".
5.1.2.4. Etotoxicitv
When the EPA predicted fish and daphnid acute toxicity levels of concern were compared to the levels
of concern assigned to the MPD measured acute values, the agreement (± 1 order of magnitude) for
fish acute toxicity was 82% (107 chemicals) and for daphnid acute toxicity 71% agreed (90
chemicals). Tne number of chemicals in the EC data sets having fish and daphnid toxicity differed
from each other with 139 chemicals tested for fish toxicity and 137 chemicals'tested for daphnid
toxicity. For fish toxicity the US tended to over-predict toxicity rather than under-predict (11 % versus
7%); for 7% of the chemicals the US predicted a "moderate" level of concern1 whereas the MPD data
set supported a "low" concern, for 4% of the chemicals the US predicted a "high" concern and the
MPD data set supported a "low* concern, and for 5% of the chemicals the US predicted a "high*
level of concern and the MPD data set supported a "moderate" level of concern. Under-prediction
resulted in 6% of the chemicals having their fish toxicity scores raised from a "low" concern to a
"moderate" concern and 1% going from a "moderate" concern to .a "high" concern.
In contrast, tor daphnid toxicity over- and under-prediction of toxicity values occurred at about the
same rate (16% versus 13%). The greatest percentage of chemicals (15%) where the US prediction
was not supported by MPD data occurred with chemicals the US considered as "low" concern, while
the MPD data supported a "moderate" concern level. In only 3% of the cases were the daphnid
concern scores raised from a "low" concern to a "high" concern.
'For aquatic toxicity the concern levels are expressed as "high," "moderate," and "low"
according to the following criteria:
- Acute toxicity values < lmg/1 and/or chronic toxicity values <0.1mg/l receive a high
concern.
- Acute toxicity values from I tu I00mg/l and/or chronic toxicity values from 0.1 to lmg/1
receive a moderate concern.
- Acute toxicity values >100mg/l, chronic toxicity values > lmg/1, and cases where the
solubility is severely limited and no effects are anticipated at saturation receive a low concern.
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provide purity information for the product as marketed and any tesr data pertain to this product.
Although in only one case did this distinction result in a large disparity in predicted systemic toxicity
versus experimentally determined systemic toxicity, more subtle disparities may not be easily
discerned. Clearly, in the physical/chemical properties exercise, this difference in chemical substances
played a not insignificant role in differing results between predicted values and experimental values.
The study, however, suggests that the US should consider requiring purity tests for PMN chemicals
which are subjected to EPA-required testing. The purity analysis should be conducted on the new
chemical as produced via commercial production-processes (i.e., characterize the commercial chemical •
not a research and development (R&D) sample which may differ significantly from the commercial
substance).
Although the EC chemicals provided a wide range of chemical- classes, the number of chemicals in
each class and the classes themselves were not wholly representative of the numbers and classes that
are typically reviewed by the US. For example, the EC does not routinely review polymer chemicals,
so few polymers were included in the study. On the other hand, the EC scheme includes pesticide
active ingredients and Pharmaceuticals. In the US new chemicals scheme, such chemicals are reported
under TSCA-onty if they haveTSCA uses (e.g., industrial or consumer uses). Thus, pesticides and
Pharmaceuticals occurred with greater frequency in the MPD set of chemicals than would be expected
in a typical equivalent set of US new chemicals. Thus, the experience and expenise of the US new
chemical assessors was'not a "perfect fit" for some of the EC chemicals and the skewed frequency
of the classes of chemicals may have affected the US performance in this study.
Lastly, the data from the EC were available to the US only in summary form. The original data were
reviewed and a summary was prepared by the Competent Authority in the EC country of origin.
These summaries varied widely in the level of detail, so the US assessors were limited in their ability
to interpret results independently. While most likely not a limiting factor in the interpretation of
overall (qualitative) levels of concern, it may have been a factor in the quantitative determination of
the level of toxicity.
5.1.3. Summary
Looking at the overall results of the MPD/SAR study, it is interesting to note that .overall the
physical/chemical properties appear to be the most difficult to predict accurately, but are among the
most inexpensive to measure. On the other hand, predicting of health hazards appears reasonably
good, although there is an issue as discussed above, with the .prediction of systemic toxicity. Targeted
testing may offer a cost effective alternative to use of a standard test battery. US ecotoxicity
predictions appear to be reasonably accurate in assessing acute toxicity for fish and daphnia.
The MPD/SAR study provided a unique opportunity to gain insight into the strengths and weaknesses
of the SAR approach used by the US versus the MPD approach of the EC in assessing the* potential
fate and effects of new chemicals. Analysis of the results of this study have shown that while* the SAR
approach, has largely been successful in identifying chemicals of concern, the process could be
improved by selectively incorporating specific testing schemes into the process'. Results from such
schemes would serve two purposes: to gain insight into chemical toxicuies and to improve our
predictive capabilities. Improving predictive capabilities would result in bener hazard assessment for
new chemicals by providing a richer data base upon which to base predictions as to their fate and
effects. These enhanced capabilities would also serve to avoid questionable testing requirements and
thus spare manufacturers the cost of such testing while not compromising worker, consumer or
environmental safety. Such a focussed effort would provide valuable data while not presenting large
overall cost implications.
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provide purity information for the product as marketed and any test data pertain to this product.
Although in only one case did this distinction result in a large disparity in predicted systemic toxicity
versus 'experimentally determined systemic toxicity, more subtle disparities may not be easily
discerned. Clearly, in the physical/chemical properties exercise, this difference in chemical substances
played a not insignificant role in differing results between predicted values and experimental values.
The study, however, suggests that the US should consider requiring purity tests for PMN chemicals
which are subjected to EPA-required testing. The purity analysis should be conducted on the new
chemical as produced via commercial productionprocesses (i.e., characterize the commercial chemical
not a research and development (R&D) sample which may-differ significantly from the commercial
substance).
Although die EC chemicals provided a wide range of chemical classes, the number of chemicals in
each class and the classes themselves were not wholly representative of the numbers and classes that
are typically reviewed by the US. For example, the EC does not routinely review polymer chemicals,
so few polymers were included in the study. On the other hand, the EC scheme includes pesticide
active ingredients and Pharmaceuticals. In the US new chemicals scheme, such chemicals are reported
under TSCA only if they have TSCA uses (e.g., industrial or consumer uses). Thus, pesticides and
Pharmaceuticals occurred with greater frequency in the MPD set of chemicals than would be expected
in a typical equivalent set of US new chemicals. Thus, the experience and expertise of the US new
chemical assessors was not a "perfect fit" for some of the EC chemicals and the skewed frequency
of the classes of chemicals may have affected the US performance in this study.
Lastly, the data from the EC were available to the US only in summary form. The original data were
reviewed and a summary was prepared by the Competent Authority in the EC country of origin.
These summaries varied widely in the level of detail, so the US assessors were limited in their ability
to interpret results independently. While most likely not a limiting factor in the interpretation of
overall (qualitative) levels of concern, it may have been a factor in the quantitative determination of
die level of toxicity.
5.1.3. .Summary .
Looking at the overall results of the MPD/SAR study, it is interesting to note that overall the
physical/chemical properties appear to be the most difficult to predict accurately, but are among the
most inexpensive to measure.. On the other hand, predicting of health hazards appears reasonably
good, although there is an issue as discussed above, with the prediction of systemic toxicity. Targeted
testing may offer a cost effective alternative to use of a standard test battery. US ecotoxicity
predictions appear to be reasonably accurate in assessing acute toxicity for fish and daphnia....
The MPD/SAR study provided a unique opportunity to gain insight into the strengths and weaknesses
of the SAR approach used by the US versus the MPO approach of the EC in assessing die potential
fate and effects of new chemicals. Analysis of the results of this study have shown that while the SAR
approach has largely been successful in identifying chemicals of concern, the process could be
improved by selectively incorporating specific testing schemes into the process. Results from such
schemes would serve two purposes: to gain insight into chemical toxicities and to improve our
predictive capabilities. Improving predictive capabilities would result in bener hazard assessment for
new chemicals by providing a richer data base upon which to base predictions as to their fate and
effects. These enhanced capabilities would also serve to avoid questionable testing requirements and
thus spare manufacturers the cost of such testing while not compromising worker, consumer or
environmental safety. Such a focussed effort would provide valuable data while not presenting large
overall cost implications.
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5.2. Conclusions: EC perspective
This study has provided many useful insights into the strengths and weaknesses of die notification
scheme for new chemicals' established under Directive 67/548/EEC as amended. The results will be
taken into account in the preparation of any future modification to the MPD* or "base set" used for
the notification or chemicals marketed in quantities in excess of 1 tonne per annum. In addition to the
direct benefits which will result from the project, the study also allowed the Commission and the*
national authorities in the Member States to obtain a better understanding of the PMN system as
applied in the United States under TSCA. While the benefits which accrue from such improvements
in mutual understanding are less tangible and difficult to quantify, they are nonetheless real and will
certainly facilitate the development of a more global approach to chemicals control in-line with the
objectives set out in Chapter 19 of Agenda 21 of UNCED.
5.2.2. Synopsis
5.2.2.1. Phvsico-chemicat end-points
Of the three end-points which were adequately explored, the SAR methods performed best in relation
to log P,.. However, even for this end-point, the predictive methods could not be used with
confidence for all chemical groups. Given the relatively low cost of carrying out these tests, the results
of this project do not constitute a persuasive argument for introducing SAR into the "base set* as an
alternative to testing.
5.2.2.2. Biodejirndiilion
The SAR methods performed extremely well in relation to this end-point, and at the next revision of
the "base set", consideration should be given to allowing, under defined conditions, the estimation of
biodegradation using SAR.
5.2;2.3. Health effects
The SAR methods are not sufficiently developed in relation to the estimation of eye/skin irritation or
sensitisation. As knowledge about these end-points is an essential part of the EC notification scheme.
• testing for these parameters will continue. SAR techniques were, in contrast, relatively successful in
providing qualitative assessments of acute lethal toxicity, and the opportunity for building SAR into
a future battery of approaches - including SAR, in vitro tests and non LD50 animal tests -Should be
explored.
While the SAR methods displayed a tendency to underestimate sub-chronic 28-day, repeated dose
toxicity, in most cases this involved an underestimate of the severity of the effects rather than true,
"false negatives". At the present time, it is unlikely that the testing requirements for jub-
chronic/repeated dose toxicity in the "base set" will be modified. However, it is clear that the SAR
techniques provide an excellent additional tool for informing decisions about further testing either
immediately post "base set" or at level I/level 2. as foreseen in the Directive.
53
-------
With regard to mutagenicity, the results of this project would suggest that SAR could, in a future
revision of .the "base set", usefully be incorporated into a battery of approaches for evaluating the
tnutagenic potential of a new chemical. In particular, the issue of the apparent 'false negatives' given
by the current 'base set" testing package needs to be addressed.
The proportion of substances in the test sample which were predicted as being of concern in relation
to end-points not .covered by the 6th Amendment "base set", e.g. reproductive toxicity, developmental
toxicity, carcinogenicity and neurotoxicity is a considerable source of disquiet. The 7th Amendment
to the Directive does foresee the introduction into the "base set" of a screening test for reproductive
toxicity. In the light of this project, consideration should also be givea to addressing the other
"missing" end-points.
5.2.2.4. Ecotoxicitv
The SAR methods performed extremely well in predicting acute toxicity to fish and daphnia. They
also provided estimates of toxic effects e.g. algal toxicity, not addressed in the "base set" of the 6th
Amendment. As part of any future revision, the conditions under which SAR predictions of acute
toxicity to aquatic organisms could be integrated into the "base set", should be explored.
5.2.3. Overview
As indicated in the preceeding section, this project has identified a number of possibilities for making
greater use of SAR as pan of the "base set" testing package applied to new chemicals marketed in the
European Community. These possibilities will be explored in the preparation of any future revision
to the legislation. However, in contemplating any such revision, there are a number of factors which
should also be taken into account.
1) The EC system is operated in a decentralized manner across 12 different national authorities:
this figure will shortly be increased to 16 when the EFT A countries join the scheme in the
context of the Enlarged European Economic Area. This means that any approach to
notification has to be transparent and objective; Thus, while some SAR methods may be used
successfully by a group of highly skilled experts working together over many years in one
Agency, such an approach could nut work in the decentralized system applied in the EC. This
means that opportunities fur the (consistent) systematic introduction of SAR into the EC
scheme could only be considered where the predictive models could be applied objectively by
all agencies working within the decentralised system.
2) The EC Directive puts great importance on the classification of a chemical. The emphasis
given to classification is frequently misunderstood because the term classification is almost
invariably linked with the term labelling, thereby giving the impression that labelling is the
only purpose for which substances are classified : this impression is entirely false.
Classification means the allocation of a substance to one of a number of danger categories on
the basis of its intrinsic properties. The decision to allocate substances to a particular category
is based on a series of agreed and published criteria. Classification is therefore synonymous
with the term hazard/risk identification. Within the EC, classification is consequently the
foundation for hazard assessment and the recently agreed Commission Directive laying down
the general principles for the risk assessment of new chemicals, recognises classification as
providing the staning point tor hazard/risk assessment. Secondly, classification may also be
the basis for risk reduction: substances classified as carcinogens under the EC scheme are for
54
-------
3}
example subject to severe restriction in the work place under separate EC legislation. Finally.
classification is also the basis for the system of -hazard communication by means of
standardized labels which has been developed in the EC.
Given the critical importance of classification for the entire EC policy on chemicals, it is
essential that the current approach to classification on the basis of objective, transparent
criteria is not put into question by allowing the possibility of using SARs instead of test data.
Essentially this would mean that SARs could be only admitted :
if they were objective and reliable and
if they were able to generate precise quantitative estimations/predictions of test results which
could be incorporated* into classification schemes or
if notifiers accepted the principle that classification on the basis of SARs would be admitted
but escape from classification i.e. non-allocation to a danger category would not be allowed.
The EC notification scheme is directed towards the substance as marketed, including
impurities but excluding separable solvents and any non essential stabilizers. The notification
scheme is not concerned with purified substances nor is it concerned with formulated products
(preparations). While it is clear that the SARs used in this study have in many cases
performed very well, such predictive models are in the most part, based upon pure substances.
For SARs to be used in a systematic way in the context of the EC notification scheme would
require this important issue of impurities to be addressed.
55
-------
-------
ANNEX 1
US EPA AND EC EXPERTS ON SAR WITHIN THIS JOINT PROJECT
Expert* of the US EPA:
Charles Auer
BobBoethling
Michael C. Cimino
. Richard G. Clements
Diana Darling
Mary Henry
Leonard C. Keifer
Asa Leifer
J. Vincent Nabholz
Pauline Wagner
EC Experts:
Herbert Baumann, Bundesgesundheitsamt, Germany
Peter Bougeard, Health and Safety Executive, UK
Andreas Gies-Reuschel, Umweltbundesamt, Germany
Kornelia Grein, Commission of the European Communities
Petra Greiner, Umweltbundesamt, Germany
Bjorn Hansen, Commission of the European Communities
Jim Han, Commission of the European Communities
Joop Hermens, Research Institute of Toxicology, Netherlands
Derek lames, Health and Safety Executive, UK
Patricia Koundakjian, Health and Safety Executive, UK
Patrick Murphy, Commission of the European Communities
AM
-------
Jay Niemela, Danish Environmental Protection Agency, Denmark
Hans Opdam, TNO * Medical Biological Laboratories, Netherlands
Christine Reteuna, Ministere de rEnvironnement, France
Marine Reynier, INKS, France
John Vosser, Health and Safety Executive, UK
Al-2
-------
ANNEX 1
US EPA AND EC EXPERTS ON SAR WITHIN THIS JQINJ PROJECT
«
Experts of the US EPA:
Charles Auer
Bob Boethling
Michael C. Cimino
Richard G..Clements
Diana Darling
Mary Henry
Leonard C. Keifer
Asa Leifer
J. Vincent Nabholz
Pauline Wagner
EC Experts :
Herbert Baumann, Bundesgesundheitsamt, Germany
Peter Bougeard, Health and Safety Executive, UK
Andreas Gies-Reuschel, Umweltbundesamt, Germany
Kernel ia Grein, Commission of the European Communities
Petra Greiner, Umweltbundesamt, Germany
Bjdrn Hansen, Commission of the European Communities
Jim Hart, Commission of the European Communities
Joop Hennens, Research Institute of Toxicology, Netherlands
Derek James, Health and Safety Executive, UK
Patricia Koundakjian, Health and Safety Executive, UK
Patrick Murphy, Commission of the European Communities
AM
-------
lay Niemela, Danish Environmental Protection Agency, Denmark
Hans Opdam, TNO * Medical Biological Laboratories, Netherlands
Christine Reteuna, Ministers de rEnvironnement, France
Martine Reynier, INRS, France
John Vosser, Health and Safety Executive, UK .
Al-2
-------
ANNEX!
US EPA AND EC EXPERTS ON SAR WITHIN THIS JOINT PROJECT
Experts of the US EPA:
Charles Auer
Bob Boethling
Michael C. Cimino
Richard G. Clements
Diana Darling
Mary Henry
Leonard C. Keifer
Asa Leifer
J. Vincent Nabholz
Pauline Wagner
EC Experts :
Herbert Baumann, Bundesgesundheiisamt, Germany
Peter Bougeard, Health and Safety Executive, UK
Andreas Gies-Reuschel, Umweltbundesamt, Germany
Kornelia Grein, Commission of the European Communities
Petra Greiner, Umweltbundesamt, Germany
Bjorn Hansen, Commission of the European Communities
Jim Han, Commission of the European Communities
loop Hermens, Research Institute of Toxicology, Netherlands
Derek James, Health and Safety Executive, UK
Patricia Koundakjian, Health and Safety Executive, UK
Patrick Murphy, Commission of the European Communities
AM
-------
I
Jay Niemela, Danish Environmental Protection Agency, Denmark
Hans Opdam, TNO • Medical Biological Laboratories, Netherlands
Christine Reteuna, Ministere de J'Enviionnement, France
^
Manine Reynier, INKS. France
John Vosser, Health and Safety Executive, UK
Al-2
-------
ANNEX 1
US EPA AP^D EC EXPERTS ON SAR WITHIN TglS JOINT PROJECT
Experts of the US EPA:
Charles Auer
Bob Boethling
Michael C. Cimino
Richard G. Clements
Diana Darling
Mary Henry
Leonard C. Keifer
Asa Leifer
J. Vincent Nabholz
Pauline Wagner
EC Experts :
Herbert Baumann, Bundesgesundheitsamt, Germany
Peter Bougeard," Health and Safety Executive, UK
Andreas Gies-Reuschel, Umweltbundesamt, Germany
Komelia Grein, Commission of the European Communities
Petra Greiner, Umweltbundesamt. Germany
Bjflrn Hansen, Commission of the European Communities
Jim Han, Commission of the European Communities
Joop Hermens, Research Institute of Toxicology, Netherlands
Derek James, Health and Safety Executive, UK .
^
Patricia Koundakjtan, Health and Safety Executive, UK
Patrick Murphy, Commission of the European Communities
AM
-------
Jay Niemela, Danish Environmental Protection Agency, Denmark
Hans Opdamv TNO - Medical Biological Laboratories, Netherlands
Christine Reteuna, Ministere de rEnvironnement, France
Martine Reynier, INRS, France
John Vosser, Health and Safety Executive, UK
Al-2
-------
ANNEX 2
*
COMPANIES. WHICH CAVE PERMISSION TO USE THEIR SUBSTANCE'S DATA
WITHIN tHE US EPA/EC PROJECT ON SAR
3M •'•;' . . '
AGFAGEVAERT
AGFA GEVAERT AG
AH MARKS & Co Ltd
AKZO CHEMIE .
AKZO CH1M1CA SPA
AVCNDALE CHEMICAL COMPANY
BASF .
BENTONE-CHEMIE GmbH
BOEHRINGER INCELHE1M KG
BOEHR1NGER MANNHEIM GmbH '
BUSH BOAKE ALLEN Ltd
CECA
CHEMISCHE FABRJK STOCKHAUSEN GmbH
CHIMEX
CIBA GEIGY
CIBA GEIGY A/S
CIBA GEIGY DANMARK
CIBA GEIGY D&C
CIBA GEIGY GmbH
CIBA GEIGY INDUSTRIAL CHEMICALS
CIBA GEIGY MARIENBERG GmbH
CIBA-GEIGY PLASTICS .
CONTINENTAL PHARMA
CYANAMIDBV
DEUTSCHE EXXON CHEMICAL GmbH
DEVELOP DR. EISBE1N GmbH&Co
DOMUS IND. CHIM.
DOW CORNING Ltd
DSM CHEMICALS
DSM RESINS B.V.
DU PONT DE NEMOURS
DU PONT DE NEMOURS (DEUTSCHLAND) GmbH
E. MERCK
EN1CHEM SYNTHESIS
EPSON DEUTSCHLAND GmbH
EPSON FRANCE •
ERGAM RONEO
FARCHEMIA SRL
FORMICA
FRAT. LAMBERT!
FUJI HUNT
FUJI PHOTO FILM BV
GALVANOCOR (GB) Ltd
GOODYEAR CHEMICALS
GRACE SERVICE CHEMICALS GmbH
GREAT LAKE CHEMICALS (EUROPE)
A2-1
-------
HAAG TECHNO BV
HERCULES
HIMONT ITALIA SPA
HOECHSTAG
INTERNATIONAL PAINT p.i.c.
ISF
ISF SPA
JANSSEN PHARMACEUT1CA
KODAK PATHE
KRONOS SA/NV
LAGOR SPA PROD. CH.
LONZA FRANCE
LONZA ITALIA SPA
LONZA-WERKE GmbH WALDSHOT
LUBRIZOL FRANCE
LUBRIZOLLtd
LUPEROX GmbH/MAP
MERCK, SHARP & DOHME
MINOLTA CAMERA HANDELSGES.
MOBIL OIL Co Ltd
MONSANTO
MONTEDISON SPA
N L ABBEY CHEMICALS Ltd
OL1N HUNT
PALMAROLE
PANASONIC
PANASONIC DANMARK A/S
PANASONIC DEUTSCHLAND GmbH
PANASONIC ITALIA
POLAROID (EUROPA)
PROCTER AND GAMBLE LIMITED
Q 0 CHEMICALS INC
RHONE POULENC
RICOH EUROPE
RICOH FRANCE
RICOH NEDERLAND '
RIEDEL-DE HAEN AG
RWE-DEA AG FOR MINERALOL UNO CHEMIE
SANDOZ
SANDOZ HUNINGUE
SANDOZ ITALIA
SANDOZ PROD. CHIM. SPA
SANDOZ-QUINN PRODUKTE GmbH
SANDOZ SPA
SANOF1 CHIMIE
SCHERING AG
SCHERING AGROCHEMICALS Ltd
SCHLOETTER Ltd
SHELL CHIMI
SHELL NEDERLAND CHEMIE BV
STAUFFBR CHEMICAL
TESSENDERLO CHEMIE
TEXACO Ltd
A2-2
-------
TEXAS ALKYLS BELGIUM
TO. GOLDSCHMIDT AG
WACKER-CHEMIE GmbH
WIGG1NS-TEAPE
WINKELHORN A/S '
WWE. AUGUST HEYMANNS & Co
YAMANOUCHI IRELAND COMPANY, Ltd
A2-3
-------
-------
ANNEX 3
GENERIC EvTICAL DESCRIPTIONS OF THE CHEMICALS IN THIS
Chemical Description
4 . alkyl aluminium, halogenated complex
6 aryl dialkyl ammonium clay complex
16 . mixture of bis-(hydroxyalkylammonium) salts of fatty acids
17 reaction mixture of unsaturated fatty acids, imino-dialcohol and inorganic acid
21 complex haloaryl alkylamide
23 substituted alkali pyrazoline arylsulfonate
24 phenolic benzopyran derivative
26 substituted spiro bis-indane
37 ary! substituted alkyl dione
44 perhalo poly cyclic hydrocarbon
47 alkyl hydroquinone
49 phosphorodithionic aliphatic amine
SO halogenated polymer of polyalkylmethacrylate
S3 complex alkyl ester of a diaza-spiro carboxytic acid
54 thioaryl morpholine ketone
61 haloaryl acetanilide
68 halotriazine dye
69 halotriazine azo dye - •
70 • haloaryl anilide
76 mixture of aryl (substituted benzotriazote) esters of polyethylene glycol
78 * azo dye
79 aryl organo-nickel complex
A3-1
-------
Chemical Description
87 substituted phenol
96 azo dye
99 trialkoxy vinyl silane
101 halotriazine dye
102 bis-(dialkyl)aryl-substituted peralkyl phenol
_ •
106 bis-(bicycloalkyl) alkane
107 alkyl substituted siloxy aluminium
108 halogeoated alkylaryi silane
107 dialkyl carbonate
113 alkyl atkoxybenzene di-alkyl valerate
118 alkyl amino triazole
124 baloaryl silane substituted triazole
128 haloaryl substituted pyrazole .
133 pyrazole substituted with various aryls
144 alkoxy aryl quinoline
148 substituted polyaicomatic hydrocarbon
151 bisphenoi A derivative
1SS mixture of various substituted benzotriazoles
1S6 alkyl substituted aryl thiocarbamate
164 phosphothioalkylamide mixture
170 N-arylalkylamino acetophenone hydrochloride
173 - mixture of aryl tertiary amines
176 •_ alkylamino chain substituted with piperidine and triazine
182 calcium alkyl aryl sulfonate
186 haloaryl substituted triazole
A3-2
-------
Chemical Description
192
194
196
197
200
204
214
216
217
218
219
222
224
235
.237
239
240
241
242
253
256
263
265
267
268
mixture of esters of aikane phosphinic acid
pyrazole substituted with various aryls
halotriazine dye
haloalkylphenoxy aminoaryl aniline bydrochloride
halo substituted diaryl aikane
variously substituted haloacetanilide
partially quaternised arene tallow carbamate
substituted bis-(cycloalkene) iron
aryl pyrrolopyrroledione
cycloalkyl alkyl substituted xylene
haloalkoxy arene
aryl substituted alkylisocyanate
phenoxodiazine dye
alkyl aminoalkyl substituted benzothiazolethione
. alkoxy alkyl silane
alkylamino arene substituted balophthalide
halotriazine dye
alkyl pyridinium halide
alkyl pyridinium halide
thioalkyl cresol
amino acid amide
chromium azo dye
haloacetyl amino acid derivative
haloaryl-ketone polymer
alkylamino carboxylic acid, Cn(medium chain)halo-alkyl ester
A3-3
-------
Chemical Description
269 substituted alky! styrene polymer
* *
270 alkyl piperidine succinate
271 mixed sodium salts of aminocarboxylic acid
275 . nitroaryl azo dye
278 mixed isomers of a terpene carboxylate
281 . diaryl ketone
283/429 mixture of perbaloalkyltetraoxodecanates
286 halo alkyl alkoxy aryl sulfonamido substituted pyrazolo-triazol
t
287 alkyl aryl sulfonamide substituted indole
289 azo nitrobenzoate dye
291 azo dye
292 haloaryl alkyl silyl triazole
300 arylpropionate alkyl ester
307 haloalkoxy nitroaryl
309 .diary! substituted aryl diamine
312 alkyl diorsubstituted arytamine
318 azo dye, calcium salt
320 nickel complex of oxyiminopolyaryl
321 • substituted triazine trione
330 . carboxyalkyl amino acid
335 chromium azo dye, alkyl ammonium salt
336 aluminium tris alkylphosphonate
337 haloalkyl phosphate tri-ester
340 cyano-alkyl thiazole
341 thia lactam derivative
A3-4
-------
Chemical Description
342 alkylene carbonate
344 - arylacetoacetate alkanolamine salt »
348 aryl substituted urea
349 aryl substituted anthracenedione
354 alkyl alkoxyaryl carbamate
355 . methacrylic acid, aryl ester
360 aryl alkyl carboxylate
361 alkyl imidazolidine substituted halobenzoate
362 aryloxyalkyl tosylate
364 halotriazine azo dye
366 alkenyl substituted polysiloxane .
368 aikylalkoxy silane
369 ferric ammonium salt of carboxyalkyl amino acid derivative
370 haloalkene carbonate
373 ClO-terpene
376 condensation mtxtureofalkylphenol,fonnaldehydeandalkanethiol(alkylthioalkylaryl
substituted methylene bis-(alkylaryl))
379 branched alkene
. 381 substituted phenoxazine pigment .
383 ' aryl triazine trione
386 aryl alkenyl morpholine
393 . , alkyl amino acridindione
394 potassium salt of substituted amino acid
396 substituted imidazole
398 cycloalkyl alkoxy silane
.401 chiral aryl arylamide dibenzoyl tartrate
*
A3-5
-------
Chemical Description
406
411
413
414
415
416
417
420
421
425
431
436
437
439
441
442
443
444
445
446
451
472
aiyl glycidyl ether
halovyl azo dye, calcium salt
dialkyl ester of alkyl disulfide
hexahydro aromatic carboxylate. ammonium salt
pyrazole substituted arylsulfonamide
aryl substituted naphthyl ketone
spiro naphthoxazine
halo alkoxy benzophenone
aryl aminoalkenyl ester sulfone
alkylamino alkanol
haloaryl alkyl carbonate
alkylammonium alkylphosphonate
mixture of substituted thiadiazoles
sulfonated styryl biphenyl
alkyl substituted heterocyclic amine hydrochloride
sulfonated vtnylic acetamide
aza bicyclb alkane
heterocyclic ester of methacrylic acid
oopolymer of methacrylic acid and heterocyclic ester of methacrylic acid
aryl substituted thiazole
alkoxy alkyl ester of unsaturated carboxylic acid
alkoxyalkyl tetradecanoate
A3-6
-------
COMPARISON OF TEST RESULTS AND PREDICTIONS
Chem.
No.
9 6
16
"
21
23
24
26
37
44
47
1 49
'
MPD
Boiling point
ra
(decomposes)
f
nd
>225
(decomposes)
5
(decomposes)
175
(decomposes)
* nd
nd
nd
295(100kPa)
213-217
>210
(250Pa)
145
(decomposes)
300
(decomposes)
SAR
Boiling point
m
nd
>500
>soo
nd
>500
>500
-400
500
'
..
nd
nd
(decomposes)
Result
-
disagree
disagree
'
-
'
'
I
.
A4-I
-------
Chem.
No.
53
54
61
68
69
70
76
78
.79
87
96
.99
101
MPD
Boiling point
PC]
>260
349
nd
nd •
nd
>220(2Pa)
>400
nd
nd
nd
nd
2S8.5
nd
SAR
Boiling point
rci
nd
210
(Beilstein)
nd
nd
nd
nd
nd
nd
nd
350
nd
285
nd
Result
.. *
».
**
.*
"
™
~
"
•
•
—
-
igree
»
A4-2
-------
Cbem.
No.
102
106
*
107
108
110
113
118
124
128
133
144
148
151
MPD
Boiling point
rci
217(llPa)
>250
122 (O.OTkPa)
>300
215
238
)09(llPa)
(>275)
214
(decomposes)
nd
nd
322
(decomposes)
nd
255
(decomposes)
SAR
Boiling point
TO
nd
345
nd
. 200-300
378
570
>300
nd
>350
nd
nd
nd
420
Result
#
.
disagree
-
agree
disagree
disagree
agree
"*
*
~
"
~
disagree
A4-3
-------
Chan.
No.
. 155
156
164
170
173
176
182
186
192
-. 194
196
197
200
*
MPD
Boiling point
!°CJ
174(llPa)
129 (33.3Pa)
210-230
(decomposes)
>198
(decomposes)
.*
nd
nd
>360
(decomposes)
nd
216
nd
nd
nd
190 (93Pa)
SAR
Boiling point
[•C]
-
™
nd
nd
nd
nd
nd
nd
190
nd
nd
nd
374
(Beilstein)
Result
*
~
•
"
«
p.
*"
•f
agree
~
"
•
^
A4-4
-------
Chem.
No.
204
214
216
217_
218
219
222
224
235
237
239
,•
240
241
MPD
Boiling point
rci
230 (40Pa)
(decomposes)
160 - 170
(decomposes)
nd
«
nd
105 - 245
250
268
nd
335
177
nd
nd
>204
(decomposes)
SAR
Boiling point
rci
>400
nd
4
nd
nd
175 (10 torr)
(>350)
276
(Beil stein)
263
nd
nd
180
nd
nd
nd
'Result
agree
"
"
*
disagree
*
agree
*
•
agree
"
~
"
A4-S
-------
Chem.
No,
242
253
256
263
265
267
268
269
270
271
275
278
281
MPD
Boiling point
PC]
212*214
>178(llPa)
nd
od
nd
nd
197
>300
>400
160
(decomposes)
nd
>300
>300
SAR
Boiling point
I'CJ
nd
2416
(178, 0.083 ton)
nd
nd
nd
nd
. >400
nd
>400
(Beilstein)
2500
nd
351
(153-154. 0.1 torr)
(Lit. value)
318 - 320
(Beilstein)
Result
» '
agree
~
•
*
""
disagree
*•
•
disagree
•
*
:
A4-6
-------
Chem.
No.
283/
429
286
287
289
291
292
300
307
309
312
318
320
321
MPD
Boiling point
CC]
213
150
(decomposes)
210
(decomposes)
nd .
nd
>248
(decomposes)
300
266
> 170
(decomposes)
>171
(decomposes)
nd
nd
325
SAR
Boiling point
[°C]
210-215
(Beilstetn)
nd
nd
nd
nd
nd
336
nd
nd
nd
nd
(decomposes)
nd
Result
#
- .
•"
" .
*
~
*
agree
*
*
*
*
~
*
A4-7
-------
Chem.
No.
330 .
335
336
337
340
341
342
344
348
349
354
355
360
MPD
Boiling point
rci
>150
nd
nd
203
nd
nd
241
nd
nd
nd
nd
nd
360
(extrapol.)
SAR
Boiling point
fci
. nd
nd
nd
2330
(decomposes)
>463
247
nd
nd
nd
nd
nd
>400
Result
* 4
•
~
disagree
•
**
agree
*
m
~
™
"
agree
A4-8
-------
Chem.
No.
361
362
364
366
368
369
370
373
376
379
381
383
386
0
MPD
Boiling point
m
175 - 179
(13.3 Pa)
254
(decomposes)
nd
>400
188
nd
165
• 193 - 204
215.- 220
(start to decompose
at 191)
142 - 143
nd
nd
nd
SAR
Boiling point
I'C]
nd
>250
(1 torr)
nd
nd
190
nd
155
(Beilstein)
188
{Beilstein)
>500
143.5 144
(Beilstein)
nd
nd
(decomposes)
Result
.-
agree
•
"
agree
*
"*
""
disagree
" • •
*
."
™
A4-9
-------
Cheat.
No.
393
394
396
398
401
406
4".
413
414
415
41.6
417
420
MPD
Boiling point
CCJ
nd
nd
nd
246
nd
>300
nd
375
(decomposes)
>224
(decomposes)
>187
(decomposes)
nd
nd
SAR
Boiling point
ra
(decomposes)
(decomposes)
nd
nd
nd
nd
- nd
400
nd
>300
(decomposes)
nd
300-370
' Result
»
*
•
•
•
*
*
agree
*
disagree
™
~
*
A4-10
-------
Chem.
No.
421
425
431
436
437
439
441
442
443
444
445
446
451
472
MPD
Boiling point
rci
247
(decomposes)
222 - 226
188- 190
(133 Pa)
268
182
nd
nd
205
(decomposes)
134
335 •
nd
nd
93 - 193
(decomposes)
>300
(decomposes)
SAR
Boiling point
ra
nd
216
(decomposes)
(decomposes)
>300
nd
nd
nd
82.5 - 83
(Beilstein)
245
nd
nd
274
nd
Result
#
- -
agree
•
"
disagree
*
~
*
"*
disagree
-
"
disagree
*
A4-11
-------
-------
ANNEX S
VAPOUR PRESSURE: COMPARISON OF TEST RESULTS AND PREDICTIONS
Chem.
No,
4
6
16
17
21
23
24
26
37
• 44
47
49
50
r
MPD vapour
. pressure
5,200 Pa
39 torr
nd
<7Pa (25QC.
65°C)
5.25 x 10-2torr
7Pa (24°C,
65.5 °C)
5.25. 10-' torr
<0.1 Pa .
(<170eC)
[10-* torr at rt]
<0.01 Pa
7.5 x 10-5 torr
WPa
[10* torr]
ia*Pa
[10* torr]
3.27 Pa
0.0245 torr
133.2 Pa at 70°C
10*1 torr at rt
< lO"3 Pa
7.5 x 10-* torr
68 Pa
0.51 torr
nd
SAR vapour
pressure
ftorrl
< 10 J
-------
Chem.
No.
53
54
61
68
69
70
76
78
79
87
96
.•
99
101
f
MPD vapour
pressure
6.7 x 10-* Pa
[10* torr]
2 x 10-7 Pa
[10* torr]
<10Pa
7.5 x 10-J ton
nd
nd
•
4.8 x 10-* Pa
[10* ton]
nd
nd
6.04 x 10" kPa
4.53 x 10-J torr
nd
0.026 kPa
0.195 torr
nd
SAR vapour
pressure
rtorrl
S10*
[10*]
3.3 x 10-'
-------
Chem.
No,
102
106
107
108
110
113
118
124
128
133
144
148
151
,
MPD vapour
pressure
2.1(rukPa
[lO* torr]
0.024 Pa
1.8 x 10-* ton-
1.49 x 10-* kPa
1.12x 10-Jtorr
18 x lO* Pa
1.35 x 10-2 torr
1.03 x 10-J Pa
[\Q* torr]
2.6 x lO'5 Pa
[10-6 torr]
7.1 x 10* kPa
5.34 x 10's torr
3.3 x 10" Pa
2.47 x 10* torr
nd
9.6 x 10-7 kPa
[10* torr]
<2.6x ID'5 Pa
[10* torr]
nd
2.47 Pa (extrapol.)
1.85'x 10'2torr
SAR vapour
pressure
rtorrl
10-5
2.5 x 10" torr
<0.01
£0.023
io-5
<10*
[10*]
io-s
10*
no-6]
3K
3K
-------
Chem.
No.
155
156
164
no
173
176
182
186
192
• 194
196
197
200
*
MPD vapour
pressure
2.4 x 10* kPa
[10* torr]
0.07 Pa
5.25 x 10* torr
220 Pa
1.65 ton-
Las x 10* kPa
1.41 x 10*s torr
2.1 Pa
1.57 x 10-2 torr
9.6 x 10-" Pa
[10* torr]
747 Pa (extrapol.)
5.6 torr
8.9 x 10"'° kPa
[10* torr]
0.0085 kPa
6.37 x 10-2 torr
nd
nd
8.82 x 10-' Pa
[10* torr]
4 Pa
3.0 x 10"2 torr
SAR vapour
pressure :
ftorrl
<10*
[10*]
0.054
< 10-'
<1G*
SlO*
[10*]
-------
Chem.
No.
204
214
216
217
218
219
222
224
235
237
239
240
<«»
241
MPD vapour
pressure
1.1 x 10-7Pa
[10* torr]
• 0.6 x 10-1 Pa
[10* torr]
1 x lO'8 kPa
[10-* ton}
nd
10.2 x 10J Pa
7.65 x 10'1 torr
0.0067 mbar
5.02 x 10'3 ton
1.34 Pa
1 x 10J torr
nd
2.1xlO'3Pa
1.57 x 10-5 torr
0.31 kPa
2.32 torr
2.54 x 10-15 Pa
[10*1
nd
2.0 x 10"
1.6 x 10* torr
SAR vapour
pressure
Ftorrl
10-'
HO*)
-------
Chem.
No.
242
253
256
263
265
267
268
269
270
•- 271
275
278
281
t
MPD vapour
pressure
0.90 Pa
6.6 x 10*' ton
2 x 10-' Pa
[10*]
1.0 Pa
7.5xlO-Jtorr
nd
nd
nd
4.9 Pa
3.67 x 10'2 ton
2 x 10° ton
1.3x ia*Pa
[10* torr)
<0.01 kPa
7.5 x 10-2 torr
5.4 x 10-' Pa
[10* torr]
6.06 x 10-* Pa
4.54 x 10-* torr
4.3 x 10-1 Pa
3.22 x 10* ton
SAR vapour
pressure
rtonl
10-5
S1.5 x 10-7
[10*]
10*
<104
tlO4!
-------
Chem.'
No.
283/
429
286
287
289
291
292
300
307
309
312
318
320
321
. MPD vapour
pressure
4.5 Pa
3.37 x 10° torr
6.4 Pa (extrapol.)
4.8 x lO'2 torr
0.9 Pa (extrapol.)
6.7 x 10-J torr
<4.9 x ID'1 Pa
[10* torr]
nd
1.55 Pa
1.16x 10'7torr
1.7x 10-1
(1.27x lO^torr)
nd
8 x W Pa
6 x \0* torr
96.5 Pa
0.724 torr
nd
nd
2.9 x 10-7 Pa
[IO* ton]
SAR vapour
pressure
rtorrl
0.3
TIO?J
-------
Chcm.
No.
330
335
336 .
337
340
341
342
344
348
' 349
354
355
360
#
MPD vapour
. pressure
10* Pa
[10* torr]
1.5 Pa
l,13x 10-2torr
nd
3.67 x 10* Pa
2.75 x 10-6 torr
nd
nd
7.3 Pa
[5.5 torr]
nd
£0.2 Pa
1.5 x 10-1 torr
nd
2.2 x 10* Pa
1.65x10* torr
3.02 x 10* Pa
2.2 x 10* torr
1.8 x 10* Pa
1.35 x 10* torr
SAR vapour
pressure
ftorrl
<10*
[10*]
<104
[10*3
< 104
[10*]
4x 10*
<10'3
«io-«
[10*]
o.t
10* .
io-»
[10*]
-------
Chem.
No.
361
362
364
366
368
369
370
373
376
379
381
383
386
MPD vapour
pressure
<1CT7
[10* torr]
1.7 x 10-4 at 84*C
[10* torr/rt]
nd
10* at 100°C
[10* torr]
0.075 kPa
0.56 torr
0.01 kPa
7.5 x 10"2 torr
153.3
[1.15 torr]
- 558 Pa
4. 18 torr
65 Pa
0.487 torr
1140 Pa
8.55 torr
•lO'1
[10* torr]
5 x 10-» Pa
[lO* torr]
1.0 x 10* Pa/
9.7 x lO'7 Pa
[lO* torrl
SAR vapour
pressure
Jtorfl
10-7
[10*]
<10*
[10*]
£10*
<10*
[10*]
1.5
<10*
[10*]
4.1
2
-------
Chem.
No.
393
394
396
398
401
406
411
413
414
415
416
417
420
t
MPD vapour
pressure
•104 kPa
[10*]
2.6 x 10-5 Pa
1 10-* torr]
33 Pa ;
0.247 torr
6.8 Pa (40eC)
, 0.02 ton (rt)
<10Pa
7.5 x 10-2 torr
<2.5 x 10*
1.87x 10" torr
«10"kPa
[10" torr]
2.3 x 10" Pa
1.72 x 10" ton-
S^l x 10" Pa
3.91 x 10-6 torr
0,04 Pa
3 x 10* torr
<0.1Pa
7.5 x 10" torr
2.5 x Ifr3 Pa
1.87-x 10" ton
9.01 x 10" Pa
[10" torr]
SAR vapour
pressure
ftorrl
<10"
HO"]
•CIO*
[10*1
<10"
[10*]
0.04
< 10*10
[10"]
<104
[10"]
<10"
lio*\
<10"
[10"]
[10"]
[10"]
<10"
[10*]
-------
Chem.
No.
421
425
431
436
437
439
441
442
443
444
445
446
451
472
.»
MPD vapour
pressure
IPa
7.5 x 10-* torr
<10Pa
< 0.075 torr
£l.6x 104Pa
[10* torr]
3.1 x 10-2Pa
2.33 x KT4 torr
9600 Pa
72 torr
-------
-------
ANNEX 6
WATER SOLUBILITY! COMPARISON OF TEST RESULTS AND
PREDICTIONS
Chem.
No.
4
6
16
17
21
23
24
26
37
44
47
49
50
*
MPD water sol.
[mg/lj
reacts
(decomposes)
hydrophobia
> 700,000
[10,000]
100,000
[10,000]
<0.8
mixes with each
other in all ratios
17.2
0.1-0.5
1
<5
145.7
1,450
5.3 -J-/-3
SAR water sol.
fmg/I]
reacts
< 10'3
> 700,000
[10,000]
50,000
[10,000]
<0.01
-200,000
<0.15x 10'3
[0.01] .
<1.6x 10-5
[0.01]
1
0.01
<1
-100,000
[10,000]
-------
Chem.
No.
53
54
61 .
68
69
70
76
78
79
87
. 96
99
101
» '
MPD water sol.
[mg/1]
... nd
17.9
<0.05 .
145,000
[10,000]
> 48,000
[10,000]
30
7.7
<0.05
<0.03
4,040
< 500,000
[10,000]
reacts
32,000
[10,000]
SAR water sol.
[mg/1]
S0.1
500
<0.1
> 100,000
[10,000]
200,000
[10,000]
<2
<10
<1
<0.1
2,000
100,000
[10,000]
reacts
< 250,000
[10,000]
Difference
[± log units]
+ 1.4
+0.3
0
0
-1.1
+ 0.1
+ 1.3
+ 1.5
-0.3
0
-'
0
Result
-
disagree
agree
agree
agree
disagree
agree
disagree
disagree
• agree
agree
agree
agree
A6-2
-------
Chem.
No.
102 -
106
107
108.
110
113
118
. 124
128
133
144
148
151
MPD water sol.
[mg/1]
0.17
<0.2
reacts
0.19
<1
0.065
58
182
<10
2.3
<0.01
< 0.005
[0.01]
5.61
SAR water sol.
[mg/1]
'
-------
Chem. .
No.
155
156
164
170
173
176
182
186
192
• 194
196
197
200
9 *
MPD water sol.
[mg/1]
<0.3
13
39
69,190
[10,000]
,. _-....
nd
<10
<10
0.9
hydrolyses
479,000
[10,000]
> 300,000
[10,000]
8.2
0.071
SAR water sol.
[mg/1]
sUO4
10-100
<5
140,000
[10,000]
<3
<10
< 2,000
9
2,500
2100,000
[10,000]
> 200,000
[10,000]
<1000
0.0064
[0.01]
Difference
[± log units]
-1.4 .
+0.5
-0.9
0
-
0
+23
+ 1.0
-
0
0
+2.1
-0.8
. Result
disagree
agree
agree
agree
•
agree
disagree
agree
••
. agree
agree
disagree
agree
A6-4
-------
Chem.
No,
204
214
216
217
218
219
222
224
235
237
239
240
241
MPD water sol.
tmg/1]
0.27
<0.1
4.2 x 10J
<0.07
63+M
363
1.52
• 180,000
[10,000]
<10
(hydrolyses)
18
<0.01
299,000
[10,000]
4.55 x 106
[10,000]
SAR water sol.
[mg/1]
<0.1
<1000
<100
<100
<50
<1000
reacts
60,000
[10,000]
£0.1
18
(reacts)
S10'3
[0.01]
100,000-
200,000
[10,000]
> 100,000
[10,000]
Difference
[± log units]
-0.4
+4.0
•1.6
+3.1
-0.1
+0.4
-
0
-2.0
0
0
0
0
Result
agree
disagree
disagree
disagree
agree
agree
-
agree
agree
. agree
agree
agree
agree
A6-5
-------
Chem.
No.
242
253
256
263
265
267
268
269
270
. 271
275
278
281
*
MPD water sol.
[mg/I]
> 11/7 x 10*
[10,000)
<0.02
470,000
[10,000]
77,500
[10,000]
712,900
[10,000]
nd
2.3
3
730
5,000 - 10,000
<0.04
<30
3
SAR water sol.
[mg/I]
100,000
[10,000]
0.02
" 10,000 - 50,000
[10,000]
90,000-
100,000
[10,000]
1,000-5,000
<0.1
<5
3
1- 1000
<1000
0.2
*10
<10
Difference
[± log units]
0
«
0
0
0
-0.6
•-
-1-0.3
0
-
-0.9
+0.7
-0.4
+0.4
Result
agree
agree
agree
agree
agree
-
agree
agree
-
agree
agree
agree
agree
A6-6
-------
Chem.
No.
283/'
429
286
287
289
291
292
300
307
309
312
318
320
321
MPD water sol.
[mg/1]
<0.5
0.019
0.005 - 0.009
[0.01]
0.091
<60
37
56
16
0.022 - 0.042
214,000
[10,000]
53
< 0.007
[0.01]
57,000
[10,000]
SAR water sol.
[mg/1]
sio-J
[0.01]
100,000
[10,000]
<100
<10
5,000 - 15,000
Difference
[± log units]
-1.7
-0.3
+ 1.0
+0.04
-1.8
-
+ 1.2
+ 1.8
+1.5
0
+0.3
+3.0
0
Result
disagree
agree
agree
agree
agree
-
disagree
disagree
disagree
agree
agree
disagree
agree
A6-7
-------
Chem.
No.
330
335
336
337
340
341
342
344
348
349
354
• 355
360
MPD water sol.
[mg/1]
1570
n.d.
11,500
[10,000]
660
749
66
65,800
nd
. (subst. only stable
in aqu. solution)
0.053
<0.2
31
0.008
[0.01]
1410
SAR water sol.
[mg/l]
> 100,000
110,000]
<10
<100
<7
20,000
[10,000]
1,000- 10,000
80,000
200,000
<0.1
<0.1
<50
7.9 x 10*
[0.01]
500 - 1,500
Difference
[± tog units]
0.8
»
* .
-2.0
-2.0
+ 1.1
+ 1.9
+0.08
-
+0.3
-0.3
+0.2
0
-0.1
Result
agree
*
disagree
disagree
disagree
disagree
agree
-
agree
agree
agree
agree
agree
A6-8
-------
Chem.
No.
361
362
364
366
368
369
370
373
376
379
381
383
386
MPD water sol.
[mg/1]
0.153
4.6 - 4.9
> 300,000
[10,000]
11
14
479,000
[10,000]
nd
(decomposes)
12.7
0.04
1.45
<10'J
[0.01]
<0.03
19 pH5
18 pH7
16 pH9
SAR water sol.
[mg/1]
<10
<150
£200,000
[10,000]
•0.1
reacts
370,000
[10,000]
8,000.
5- 15
0.03
9
<0.01
-0.1
<300
Difference
[± log units]
+1.8
+1.5
0
-2.0
•
0
-
-0.1
-0.1
+0.8
0
+0.5
+ 1.2
Result
disagree
disagree
agree
disagree
-
agree
•
agree
agree
agree
agree
agree
disagree
A6-9
-------
Chem.
No.
393
394
396
398
401
406
41!
413
414
415
416
417
420
MFD water sol.
[mg/lj
0.6
1140x10'
[10,000]
61,400
[10,000]
hydrolyses
137.5
<0.01
< 0.0015
[0.01]
<0.03
3,300
£0.005
[0.01]
0.0048
10.01]
1.26 x 10*
[0.01]
1.6 pH5
1.4 pH7
1.5 pH9
SAR water sol. ,
[mg/1]
<10
•500,000
[10,000]
1,000 - 2,000
reacts
500 - 1,000
0.1
<0.1
1
100 - 10,000
<0.1
<0.1
<1
<10
Difference
[± log units]
+1.2
0
-0.8
-
0.7
+ 1
+1
+ 1.5
-0.5
+ 1.0
+ 1.0
+2.0
+0.8
Result
disagree
agree
agree
agree
agree
agree
agree
disagree
agree
agree
. agree
disagree
agree
A6-10
-------
Chem.
No.
421
425
431
436
437
439
441
442
443
444
445
446
451
472
*
MPD water sol.
[mg/1]
SOxlCT6
[0.01]
>990,000
[10,000]
0.078
<10*
0.012
480
9,550
6,210
nd
61 .'
<0.5
<0.02
20,000
[10,000]
16.2
SAR water sol.
[mg/lj
<1
200,000
110,000]
<0.1
<100
<1
5,000 - 50,000
*40,000
[10,000]
<; 10,000
1,000 - 10,000
100
< 1 (acid)
<0.001
[0-01]
10,000 - 50,000
[10,000]
<0.05
> Difference
[± log units]
-1-2.0
0
+0.1
-2.0
+1.9
+1.3
+0.02
+0.2
-
+0.2
+0.3
-0.3
0
-2.5
Result
. disagree
agree
agree
disagree
disagree
disagree
disagree
agree
-
agree
agree
agree
agree
disagree
A6-11
-------
-------
ANNEX?
PARTITION COEFFICIENT; COMPARISON OF TEST RESULTS AND
PREDICTIONS . .
Chem.
No.-
4
6
J6
17
21
23
24
26
37
44
47
49
SO
4.15
-4.68
4.28
4.74
CO
3.0
3.93
1.65
1.3
SAR
-log P«
nd
nd . .
<-2.5
nd
>6
nd
6.9
>6 (10.8)
2.5
nd
5.3
*6
nd
Difference
(± log units]
•
-2.5
•
+ 1.85
-
[4-1.72]
[+1.26]
™
*
+ 1.37
+4.35
m
Result
-
•
disagree
-
disagree
-
disagree
disagree
•
*
disagree
disagree
~
A7-1
-------
Cbem.
No.
53 .
54
61
68
69
70
76
78
79
87
96
99
101
MPD
to* P..
nd.
3.09
4.38
nd
nd
4.4
nd
nd
nd
2.02
nd
nd
nd
SAR
log P..
>6
2.71
>6 (9.2)
<-2.5
<-2.5
>6
nd
5.9
nd
2.1
<-2.5
nd
nd
*
Difference
l± log units]
-
-0.38
1+1.62]
~
*
+ 1.6
*
—
*
+0.08
•
*
"
Result
• . -
agree
disagree
•
~
disagree
•
f *
•
agree
"
™
•
A7-2
-------
Chem.
No.
102
106
107
108
110
113
118
124
128
133
144
148
151
MPD
log P_
nd
nd
nd
>5
nd
4.01
nd
2.46
.nd
3.6
5.8
nd
4.87
SAR
log P_
> 6 (14.4)
> 6 (6.94)
nd
-5
>6
> 6 (10.8)
6.8
1 -2
3.4
3.6
> 6 (11.8)
>6
5.3
Difference
[± log units]
-
~
~
0
~
[ + 1.99]
*
•0.96
m
0
[+0.2]
~
+0.43
. . Result
-
•
™
agree
"
disagree
*"
agree
*
agree
agree
~
agree
A7-3
-------
Cbem.
No.
155
156
164
17Q
173
176
182.
186
192
194
196
197
200
MPD
log P..
nd
4.65
3.0
-0.823 to -1.148
1.9/2.0
4.5
5.42
5.6
0.74
nd
nd
3.6
6.25
SAR
log P«
>6
3.7
-*
6
3.8
*6
.6(11.2)
4
<3.8
3.6
-1.8
1.8
>6(6.7)
Difference
l± log units]
V
-0.95
+3
4-0.98
+ 1.85
+ 1.5
1+0.58]
-1.6
+3.06
•
•
-1.8
[0]
Result
-
agree
disagree
agree
disagree
disagree
agree
disagree
disagree
* . .
• t •
disagree
agree
A7-4
-------
Chem.
No..
204
214
216
217
218
219
222
224
235
237
. 239
240
241
MPD
log P..
3.80
nd
nd
nd
3.84
1.65
nd
nd
nd
5.1
>3.29
nd
-2.76
SAR
logP.,
>6
>6
nd
2.5
4.1
2.3
reacts
nd
>6
nd
>6{12.9)
nd
[0]
Difference
[± log units]
+2,11
"
~
™
4-0.26
+0.65
*
"*
*
*
[2.711
~
0
Result
disagree
*
~
"
agree
agree
«*
™
*
~
disagree
~
agree
A7-5
-------
Cbem.
No.
242
2S3
256
263
265
267
268
269
270
271
275
278
281
MPD
log P..
-JM
nd
-1.3
. -2.36
<-2.5
nd
4.6
4.53
-I.I (pH7.65)
+0.55 6 (10.5)
<-2.5
<0
S-1.075
nd
*5.4
5.0
3
~S
4.3
5.2
5.2
Difference
[± log units]
10]
•f
*
10]
10}
10]
•
+0.8
+0.47
>1
*»
"
™
+ 1.25
+0.79
Result
agree
*
agree
agree
agree
*
agree .
agree
disagree
*
~
dis^ree
agree
A7-6
-------
Chem.
No.
2837 '
429
286
287
289
291
292
300
307
309
312
318
320
321
MPD
log Pw
nd
26
25
nd
nd
2.88
3.67
3.07
3.9
1.09
nd
nd
1.11 (pH2)
SAR
log P.
nd
>6
»6
5.5
>6
3.4
4.2
3.1
>6
<0
3-4
nd
-0.25
(missing fragment)
Difference
l± log units]
-
0
1
*
•
+0.52
+0.53
-0.03
+2.1
-1.09
"
•
-1.36
Result
-
agree
agree
-
-
agree
agree
agree
disagree
disagree
-
-
disagree
A7-7
-------
Cbem.
No.'
330
335
336 .
337
340
341
342
344
348
•'. 349
354
355
360
*
MPD
log P..
<-3
-3
<-l
3.05
0.492
nd
-0.0053
. nd
5.9
>7.24
2.89
1.92
1.04
SAR
log P^
-0.85
nd
nd
1.7 - 1.9
-o
<-2.5
0.55
<-2.5
>6(11.5)
>6
3.3
>6(8.0)
3.2
Difference
l± log units]
[0] .
*
*
-1.15
-0.49
*
0.55
• *
t-«-o.i]
[0]
+0.41
+4,08
+2.16
Result
,«
agree
""
•
disagree
agree
*
agree
«
agree
agree :
agwe
disagree
disagree
A7-8
-------
Chem.
No.
361
362
364
366
368
369
370
373
376
379
.381
383
«
386
*
MPD
log P«
4.85
2.3
nd .
3.7
4.3
<-2.5
nd
4.18
>.5.7
4.74
nd
nd
2.62 / 2.73
SAR
Jog P..
»6(>8)
3.0
<-2.5
nd
3.1
nd
4.9
4-4
>6(11.6)
4.2
nd
>6
3
Difference
[± log units]
l+l.IS]
+0.7
•
™
-1.2
**
"
+0.22
[+0.3]
-0.54
™
*
0.38
Result
disagree
agree
-
—
disagree
"
™
agree
agree
agree
•
*
agree
A7-9
-------
Chem.
No.
393
394
396
398.
401
406
411
413
414
415
416
417
420
MPD
log P..
nd
-2.46
*
-1,47
>2.7
-3.27 / 0.758
4.65
nd
nd
0.258
7
nd
5.1
3.38
SAR
. log P..
3.6
<-2.5
-2.4
3.3
nd
5.3
>6
>6
2-3.5
>6
»6
5.4
3.8
Difference
l± log units]
•
10]
10]
+0.6
*
+0.65
*
*
+2.5
[0]
"
+0.3
+0.42
Result
•
agree
agree
agree
*•
agree
"
. *
disagree
agree
~
agree
agree
A7-10
-------
Chem.
No.
421
425
431
436
437
439
441
442
443
444
445
446
451
472
»
MPD
logPw
*5
nd
4.7
nd
6.4
-1.98
1.37
-1.88
1.96
3.39'
nd
nd
2.63
>4.6
SAR
log P..
5.6
0.31
>6 (12.0)
3.5 - 4.6
»6(9)
2
2.18
i-2.5
1.16
3.68
nd
>6
0.99
> 6 (6.78)
Difference
[± log units]
+0.6
-
> + 1.3
-
10]
+3.98
+0.81
[OJ
-0.8
+0.29
"
•
1.64
+ 1.4
Result
agree
•
disagree
*
agree
disagree
agree
agree
agree
agree
™
"
disagree
disagree
A7-n
-------
-------
ANNEX!
J
BIOPECRAPATIQNi COMPARISON OF TEST RESULTS AND PREDICTIONS
.Chan.
No.
4
6
16
17
21
23
24
26
37
44
47
49
SO
.MFD
dm
(% Biodegndation]
od
(reacts)
ad
nd
(BOD/COD - 0.75)
od
(BOD/COD - 0.23)
0%
35%
(adsorption)
0%
7%
34%
6%
0%
40%
2%
SAR
data
reacts
weeks
days
flBOOC&S
or longer
(persistent)
months
months
weeks to months
months
or longer
(persistent)
weeks
months
or longer
(persistent)
weeks
weeks to
OBOfltuS *
months
or longer
(persistent)
Hawk
»
»
"
-
•gne
"
agree
•free
•free
agree
agree
agree
agree
AS-l
-------
Cbem.
No.
53
54
61
68
69
70
76
78
79
87
96
99
101
MPD
data
I* BKNMgmUUOOJ
od
1%
1.5%
10%
-10%
0%
12%
ud
(insoluble)
(BOD/COD - 0.01)
nd
Onsoluble)
DOB/COD • 0.03
100%
10%
82%
10%
SAR
data
mniyht
or loafer
(persistent)
weeks to
months
oootos
IBftfluH
or longer
(persistent)
months
or longer
/mi**mi*tmmS\
(persistent)
mfinitim
montns
or longer
(persistent)
months or
more
months
or longer
(persistent)
nd
(insoluble)
days to weeks
months
or longer
(persistent)
nd
months
or longer
(persistent)
Result
«
agree
agree
agree
agree
agree
agree
, •"
"
agree
agree
*
agree
A8-2
-------
No."
102
106
107
108
110
113
118
124
128
133
144
148
151
MPD
A*
{% Biod«gnd*k»)
4ft
Sft
nd
fflammiM* in air
deoomp with water
3%
n%
nd
(BOD/COD - 0.23)
5%
0%
4%
10%
0%
0%
4%
SAR
dstt
or longer
foenUtmri
or longer
(persistent)
reaction with Qi and
IM)
months
or loafer
(persistent)
days to weeks
weeks to months
weeks to months
nd
(probably slow)
months
months
or longer
(persistent)
weeks to months
months
or longer
(persistent)
weeks
Result
•few
•free
•
•free
•free
•
•free
• " "
•free
•free
•free
•free
•free
A8-3
-------
Chem.
No.
155
156
164
no
173
176
182
186
192
194
196
197
200
MPD
data
I* Biodegndation)
13%
11%
0%
27%
21%
6%
11%
0%
>80%
nd
0%
0%
0%
SAR
data
^-^_— t* f^k ^^MM^tVa
Weeo to IPOBml
»
weeks
noons
orkmger
(persistent)
weeks
nd
months
or longer
(persistent)
weeks
mouths
or longer
(persistent)
days to weeks
months
fponttis
months
or longer
(persistent)
weeks to months
Result
•grot •
disagree
agree
AfTQC
•
agree
agree
agree
agree
"
agree
agree
agree
A8-4
-------
Own.
No.
204
214
216
217
218
219
%X2
224.
235
237
239
240
241
MPD
data
1% Biodegradation)
0%
20%
26%
12%
1%
0%
0%
10%
7%
0%
21%
20%
5%
SAR
dab
or longer
(persistent)
weeks
od
months
or looser
(persistent)
weeks to months
weekt
•• n • ill •
IDODQU
• •••tha
^oomm
or longer
(penistent)
weeks to monthi
od
months
or longer
(persistent)
OVQDtuS
or longer
(persistent)
weeks
' Renh
T*
agree
w
tgree
agree
agree
agree
agree
agree
•
agree
agree
agree
At-5
-------
Chan.
No.
242
253
256.
263
265
267
268
269 -
270
271
275
278
281
MPD
.data
t% Biodegndation]
0%
4%
46%
0%
81%
nd
(insoluble)
70%
2*
16%
33%
0%
80%
1%
SAR
data
weeks
IQQOtBS
- days to weeks
flBOOuU
or longer
(persistent)
od
months
or longer
(penistent)
Dontiu
or longer
(penistent)
months
weeks to months
weeks to months
months
or longer
(penistent)
days to weeks •
nd
. Result
agree *
agree
disagree
agree
•
. •
disagree
•free
agree
agree
agree
agree
*
-------
Chem.
No.
2837
429
286
287
"289
291
292
300
307
309
312
318
320
321
MFD
dm
1% Biodegndttkm]
od
3%
2%
3%
6%
0%
2%
0%
6%
13%
35%
nd
34%
SAR
tea
months
or longer
(persistent)
month,
gjmTjifhg
or longer
(penisteot)
months
or longer
(persistent)
months
or longer
(persistent)
months
or longer
(persistent)
months
or longer
(persistent)
months
months
or longer
(persistent)
weeks
months
or longer
(persistent)
months ,
or longer
(persistent)
weeks to months
Renh
4» •
agree
agree
agree
agree
agree
agree
agree
agree
agree
agree
m
agree
A8-7
-------
No.
330
335
33$
337
340
341
342
344 .
348
349
354
355
360
MFD
Data
1% BtodegndationJ
21%
14%
10%
0%
5%
30%
62%
0%
2.5%
nd
5%
48%
8%
SAR
Biodegndatioo
Data
weeks to months
montfas
or longer
(persistent)
weeks
weeks
weeks
weeks to montfas
BIHI Ir .i,,, ,.
monuis
weeks
months
DODCDS
or longer
(persistent)
weeks
months
weeks
Result
•tree
agree
•tree
agree
agree
agree
disagree
agree
agree
"
agree
agree
agree
A8-8
-------
Chen.
Ifo.
961
362
364
366
368
369
370
373.
376
379
381
383
386
MPD
data
(% Bfcdegradation]
0%
S%
o*
0%
7%
19%
ad
(reacts with water)
20%
od (insoluble)
3%
10%
11%
0%
SAR
data
or looter
(persistent)
weeks to norths
jHfiialllft
or longer
(persistent)
•IIMaihfl
or longer
(persistent)
ad
weeks to months
••i n iitfc •
Dnoois
or longer
(persistent)
weeto
. weeks to months
nd
QtOOulft
or longer
(persistent)
months
or longer
(persistent)
months
' RMdt
agne
agrw
agree
agree
*
«fw«
»
agne
*
"
agree
agree
agree
.i.
AS-9
-------
hen.
.No.
393
394
396
398
401
406
411
413
414
415
416
417
420
»
MFD
data
Iff fltn Ammmm limit n M!
I* DKXiegfioiuonj
30%
0%
10%
100%
f
45%
4%
20%
74%
27%
8%
4%
15%
3%
SAR
data
mm^m^^m
moBBis
or longer
(peaisteot)
^UhM«aV*
nMmns
ad
nd
weeks to month*
— -*y •
HIPIUP^
or longer
(persistent)
months
or longer
(persistent)
MAA^^W Agk ^•kJ^M^tkM
weeo to monois
^••A^^M *^_ ••k^kflfeAL*
weea to mooms
inoninn
or longer
QMnistent)
months
or longer
(persistent)
months
or longer
(persistent)
weeks
. Result
agree
agree
"
*
agree
agree
agree
disagree
agree
agree
agree
agree
agree
AS-10
-------
Chem.
No.
421
423
431
436
437
439
441
442
443
444
445
446
451
472
*•
MFD
data
[% Biodegndatkm]
18%
30%
21%
0%
10.5%
0%
<3%
0%
20%
33%
od
(polymer)
10%
20%
100%
SAR
dtta
WMkS
days lo weeks
weeks
days to weeks
B¥>ntbS
months
or longer
(persistent)
weeks to months
weeks
weeks
weeks
months
or longer
(persistent)
months
days to weeks
days to weeks
Result
• * •
•pw
disagree
agree
disagree
agree
agree
•
agree
agree
agree
agree
•
agree
disagree
agree
AS-11
-------
-------
ANNEX 9
TOXICITY TO FISH. COMPARISON OF TEST RESULTS AND PREDICTIONS,
Ctam.
No.
4
6
16
17
21
23
24
26
37
44
47 ,
49
50
*
MPD
LC50 value
lmg/1]
nd
>500
>1000
S.I
nd
>2100
1.8
NTS
>2
nd
1.8-3.2
11
NTS
SAR
LC50 value
ln*/l]
>1QO
>ll
>100
>0.5
NTS
>100
o.os
. NTS
8.8
NTS
£0.32
30
NTS
Difference
[± tog units]
4H»
»
-1.7
10]
-l.OS
"
toi
-1.52
'"
0.64
m
•
0.43
™
Result
disagree
agree
disagree
•
agree
disagree
agree
agree
*
*
agr**
agree
ASM
-------
Chan.
No.
S3
54
61
68
69
70
76
78
79
87
96
99
101
MPD
LCSOvilue
(mg/lj
2.0
9.0
NTS
>500
>500
NTS
2.8
172.0
>1000
8.5
>500
>60
>500
SAR
LCSO value
(«gfl]
0.1
27.0
- NTS
>100
>IOO
NTS
NTS
0.3
NTS
21.0
MOO
>100
>100
Difference
[±10f lintel
•1.30
0.4«
"
(0)
(0]
•
"
-2.70
•
-0.40
(0)
0.23
10]
Remit
disagree
agree
agree
agree
agree
•free
disagree
distsree ,
agree
agree
agree
agree
agree
A9-2
-------
Chan.
No.
102
106
107
108
110
113
US
124
128
133
144
148
151
MPD
LCSO value
(mg/l)
NTS
>74
118
nd
0.1
NTS
>1000
1.1
16.9
>IOO
10-100
NTS
>100
NTS
>500
0.32
SAR
LC50 value
. ImgflJ
NTS
NTS
NTS
0.35
NTS
NTS
0.07
1.4
13.0
< 10.2
NTS
NTS
0.42
Difference
lilogunits]
•
*
•
0.54
—
*
-1.22
-1.10
•0.89
~
*
•
0.13
Remit
agree
acne
•
agne
agree
agree
disagree
disagree
. agree
™
agree
agree
agree
A9-3
-------
Chan.
No.
155
156
164
170
173
176
182
186
192
194
196
197
200
MPD
LCSO value
lmg/1]--
NTS
>100
4.7
NTS
>40
9.0
.•
1.5
7.3
2.2
0.43
71
10-100
>1000
0.46
NTS
>0.7
SAR
LCSO value
Img/1]
NTS
1.37 -
- NTS
7.1
*8.4
NTS
NTS
>0.l
S16
$10.2
>IOO
0.60
NTS
Difference
l± log unto]
•
•0.54
"
•0.10
0.75
*
•
-0.64
•
*
10]
0.11
•
Remit
* agree
agree
afree
agree
acne
disagree
disagree
agree
•
*
agree "
agree
agree
A9-4
-------
Chem.
No. .
204
214
216
217
218
219
222
224 .
235
•237
239
240
241
MPD
1X50 value
[mg/l]
NTS
>0.3
111.8
>100
220
6.6
17.7
0.83
>100
0.76
244
NTS
>500
1000
SAR
LCSO value
[ng/l]
NTS
0.38
NTS
>100
3.8
9.0
10.0
121.0
0.40
>!00
NTS
>100
>100
Difrereoce
[± tog units]
••
-2.S2
"
(01
-0.24
-0.30
1.08
10]
0.26
10]
•
10]
[0]
Result
agree
disagree
agree
agree
agree
agree
disagree
agree
agree
agree
agree
agree
agree
A9-5
-------
Cheat.
No.
242
253
256
263
265
267
268
269
270
271
275
278
281
MPD
LCSO value
(mm
874'
NTS
>100
>1000
53
>1000
nd
>500
NTS
>5I
47
83
8.5
1.03
SAR
LCSO value
(mg/l]
>IOO
NTS
• 1700
7
>1000
NTS
1.0
NTS
21
100
0.24
11
NTS
Difference
l± log unto]
(0)
*
10]
-0.89
0
*
-2.70
**
•0.40
0.32
•2.52
0.11
"
Result
•?
•free
«f«e
agree
•free
"
diitfree
agree
agree
agree
disagree
agree
disagree
A9-6
-------
§ 720.87
40 CFR Ch. I (7.1-90 Edition)
(A) The submitter asserts a claim of
confidentiality In accordance with this
paragraph.
(B) No claim for confidentiality of
the specific chemical identity as part
of a health and safety study has been
denied in accordance with Part 2 of
this Title or §720.90.
(II) Publication of a generic name on
the public Inventory does not create a
category for purposes of the Invento-
ry. Any person who has a bonafide
intent to manufacture or import a
chemical substance which Is described
by a generic name on the public Inven-
tory may submit an Inquiry to EPA
under { 720.25(b) to determine wheth-
er the particular chemical substance is
included on the confidential Invento-
ry.
(ill) Upon receipt of a request de-
scribed in S720.25(b). EPA may re-
quire the submitter which originally
asserted confidentiality for a chemical
substance to submit to EPA the infor-
mation listed In paragraph (b)OXUi)
of this section.
(iv) Failure to submit any of the in-
formation required under paragraph
(bXSXiii) of this section within ten
days of a request by EPA under this
paragraph is a waiver of the original
submitter's confidentiality claim. In •
this event, EPA may place the specific
chemical identity on the public Inven-
tory without further notice to the
original submitter.
(6) If a submitter asserts a claim of
• confidentiality under this paragraph.
EPA wili examine the generic chemi-
cal name proposed by the submitter.
(i) If EPA determines that the ge-
neric name proposed by the submitter
is only as generic as necessary to pro-
tect the confidential identity of the
particular chemical substance. EPA
will place that generic name on the
public Inventory.
(ii) If EPA determines that the ge-
neric name proposed by the submitter
is more generic than necessary to pro-
tect the confidential identity. EPA will
propose in writing, for review by the
submitter, an alternative generic name
that will reveal the chemical Identity
of the chemical substance to the maxi-
mum extent possible.
(Hi) If the generic name proposed by
P!PA
EPA will place that generic name on
the public Inventory. .
-------
Environmental Protection Agency
§720.95
will deny any claim of confidentiality
with respect to information included
in a health and safety study, unless
the information would disclose confi-
dential business information concern-
ing:
(1) Processes used in the manufac-
ture or processing of a chemical sub-
stance or mixture.
(2) In the case of a mixture, the por-
tion of the mixture comprised by any
of the chemical substances in the mix-
ture.
(3) Informaton which is not in any
way related to the effects of a sub-
stance on human health or the envi-
ronment, such as the name of the sub-
mitting company, cost or other, finan-
cial data, product development or mar-
keting plans, and advertising plans, for
which the person submits a claim of
confidentiality in accordance with
{ 720.80.
(b) Specific chemical identity—(I)
Claims applicable to period prior to
commencement of manufacture. A
claim of confidentiality for the period
prior to commencement of manufac-
ture or import for the chemical identi-
ty of a chemical substance for which a
health and safety study was submitted
must be asserted in conjunction with a
claim asserted under $ 720.85(a).
.«) Claims applicable to period after
commencement of manufacture or
import for commercial purposes. To
maintain the confidential status of the
chemical identity of a chemical sub-
stance for which a health and safety
study was submitted after commence-
ment of manufacture or import, the
claim must be reasserted and substan-
tiated in conjunction with a claim
under §720.85(b). in addition to the
questions set forth in $ 720.85(b)(3)(iv)
of this part, the submitter must
answer the following questions:
(i) Would disclosure of the chemical
identity disclose processes used in the
manufacture or processing of a chemi-
cal substance or mixture? Describe
how this would occur. In responding to
the question in 5 720.85(b)(3)(iv)(A),
explain what harmful competitive ef-
fects would occur from disclosure of
this process information.
(li) Would disclosure of the chemical
identity disclose the portion of a mix-
ture comprised by any of the sub-
stances in the mixture? Describe how
this would occur. In responding to the
question in i 720.85(bK3Xtv)(A). ex-
plain what harmful competitive ef-
fects would occur from disclosure of
this information.
(ill) Do you assert that disclosure of
the chemical identity is not necessary
to interpret any of the health and
safety studies you have submitted? If
so, explain how a less specific identity
would be sufficient to interpret the
studies.
(c) Denial of confidentiality claim.
EPA will deny a claim of confidential-
ity for chemical identity under para-
graph (b) of this section, unless:
(1) The information would disclose
processes used in the manufacture or
processing of a chemical substance or
mixture.
(2) In the case of a mixture, the in-
formation would disclose the portion
of the mixture comprised by any of
the substances in the mixture.
(3) The specific chemical identity U
not necessary to interpret a health
and safety study.
(d) Use of generic names. When EPA
discloses a health and safety study
containing a specific chemical identity,
which the submitter has claimed con-
fidential, and if the Agency has not
denied the claim under paragraph (c)
of this section, EPA will identify the
chemical substance by the generic
name selected under f 720.85.
(Approved by the Office of Management
and Budget under control number 2070-
0012)
§720.95 Public file.
All information submitted with a
notice, including any health and
safety study and other supporting doc-
umentation, will become part of the
public file for that notice, unless such
materials are claimed confidential. In
addition, EPA may add materials to
the public file, subject to subpart E of
this part. Any of the nonconffdential
material described in this subpart will
be available for public inspection in
the TSCA Public Docket Office, Rm.
NE-G004, 401 M St., SW.. Washing-
ton. DC. between the hours of 8 a.m.
and 4 p.m. weekdays, excluding legal
holidays.
AP4-22
-------
§720.102
(48 PR 21742. May 13,1983, a» amended at
53 PR 12523. Apr. 15.1988]
Subpart F—Comm«nc*m«nt of
Manufacture or Import
9720.102 Notice of commencement of
manufacture or Import
(a) Applicability. Any person who
commences the manufacture or import
of a new chemical substance for a non-
exempt commercial purpose for which
that person previously submitted a
section 5(a) notice under this part
must submit a notice of commence-
ment of manufacture or Import.
(b) When to report. (1) If manufac-
ture or import for commercial pur-
poses begins on or after the effective
date of this rule, the submitter must
submit the notice to EPA on. or no
later than 30 calendar days, after the
first day of such manufacture or
import.
(2) If manufacture or import for
commercial purposes began or will
begin before the effective date of this
rule, the submitter must submit the
notice by the effective date of this
rule.
(c) Information to be reported. The
notice must contain the following in-
formation: Specific chemical identity,
premanufacture notice number, and
the date when manufacture or import
commences. If the person claimed
chemical identity confidential in the
commencement notice, and wants the
.identity to be listed on the confiden-
tial Inventory, the claim must be reas-
serted and substantiated in accordance
with 5 720.85(b). Otherwise, EPA will
list the specific chemical Identity on
the public Inventory.
(d) Where to submit. Notices of com-
mencement of manufacture or import
should be submitted to: TSCA Docu-
ment Processing Center (TS-790), Rm.
L-100, Office of Toxic Substances, En-
vironmental Protection Agency, 401 M
St., SW.. Washington. DC 20460.
(Approved by the Office of Management
and Budget under control number 2070-
0012)
[48 PR 21742, May 13, 1983. as amended at
48 PR 41140, Sept. 13. 1983; 51 PR 15103.
Apr. 22.1986; 53 FR 12523. Apr. 15.1988]
' 40 CFR Ch. I (7.1-90 Edition)
Subpart 6—Compliance and
Inspections
B 720.120 Compliance.
(a) Failure to comply with any provi-
sion of this part is a* violation of sec-
tion 15 of the Act (15 UAC 2614).
(b) A person who manufactures or
imports a new chemical substance
before a notice is submitted and the
notice review period expires is in viola-
tion of section 15 of the Act even if
that person was not requied to submit
the notice under (720.22.
(c) Using for commercial purposes a
chemical substance or mixture which
a person knew or had reason to know
was manufactured, processed, or dis-
tributed In commerce In violation of
section 5 of this rule is a violation of
section 15 of the Act (15 U.S.C. 2614).
(d) Failure or refusal to establish
and maintain records or to permit
access to or copying of records, as re-
quired by the Act, is a violation of sec-
tion 15 of the Act (15 U.S.C. 2614).
(e) Failure or refusal to permit entry
or inspection as required by section 11
is a violation of section 15 of the Act
(15 U.S.C. 2614).
(f) Violators may be subject to the
civil and criminal penalties in section
16 of the Act (15 U.S.C. 2615) for each
violation. Persons who submit materi-
ally .misleading or false information in
connection with the requirements of
any provision of this rule may be sub-
ject to penalties calculated as if they
never filed their notices.
(g) EPA may seek to enjoin the man-
ufacture or processing of a chemical
substance in violation of this rule or
act to seize any chemical substance
manufactured or processed in viola-
tion of this rule or take other actions
under the authority of section 7 of
this Act (15 U.S.C. 2606) or section 17
or this Act (15 U.S.C. 2616). -
§720.122 Inspections.
EPA will conduct Inspections under
section 11 of the Act to assure compli-
ance with section 5 of the Act and this
rule, to verify that information sub-
mitted to EPA under this rule is true
and correct, and to audit data submit-
ted to EPA under this rule.
AP4-23
-------
Environmental Protection Agency Part'720, Appendix A
APPENDIX A—PuniAirorACTURE NOTICE FOR .New CHEMICAL SUBSTANCES
UnfMdStm.
PREMANUFACTURE NOTICE
FOR NEW CHEMICAL SUBSTANCES
fOTMtOt
DOCUMENT CONTROL OFFICER
OFFICE OF TOXIC SUBSTANCES, TS-7SS
U.S. E.F-.A.
401 M STREET, «W
WASHINGTON, D.C. 2OMO
AGENCY USE ONLY
tfi* total
Nottc
0«
•iMMbl
GENERAL INSTRUCTIONS
I tom «••>••
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NUMAN IKMtUM ANeiNWMeMIMMTAt.
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COMnMMTIAUTY CUUMt
You mtvciMn*nvinl(ym*tien in thto nolle* M«en
-------
Part 720f 'Appendix A
40 CFR Ch. 1 (7-1-90 EdHion]
f
CERTIFICATION
T —
MfffttMMlMl.
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> «Mtlofi A -•UBMITTill IDENTIFICATION
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AP4-2S
-------
Environmental Protection Agency
Part 720, Appendix A
Pwt I - GENERAL INFORMATION -
»*••
» *• m, ••* oa *• M* « *•«
•.Cfctttft
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AP4-26
-------
Fort 720, Appendix A
40 CFR Ch. 1 (7.1-90 edition)
Part I - GENERAL INFORMATION -
- CMCMtCALIDKNTITV INFORMATION -
1.
• MMWtf.1
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AP4-27
-------
Environmental Protection Agency
Part 720, Appendix A
Pert I - GENERAL INFORMATION -
* - CKKMICALIOINTITY INFORMATION -
M - i**** jff'|i<»^s*gy>*
CHmmm
«M
••vtfi*b.M
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AP4-28
-------
Part 720, Appendix A
40 CFR Ch. I (7-1-90 Edition)
Part I- OENERAL INFORMATION -
C-mOOUCTIOII. IMPOST. AND UK INFOHMATtQM
T.
Ml-l
III
III
O MM0a«iikW*|Mlll
i «f wy I
i. \mmtm •§»•> mim Mlnmiimi >m •
AP4-29
-------
Environmental Protection Agency
Part 720, Appendix A
- HUMAN EXPOSURE AND ENVIRONMENTAL RELEASE
•••Han A - INOUSTMIA1 ilTM CONTftOUID »Y THI8UMHITTIII
• **»•
•. MdMly-IMM MtMMMv M «• rt« « «Mth «• I
D M«i* Ml Oil Mi *X»
• D
AP4-30
-------
Part 720, Appendix A
40 CFR Ch. I (7-1-90 Edition)
P«tt II - HUMAN EXPOSURE AND ENVIRONMENTAL RELEASE -Continued
A - INDUSTRIAL SITES CONTROLLED SV THE SUBMITTER - C«mliurtd*
111 " ft"!?*?**
Ol *•• JMljiiijMin
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nlum «oeaM4 o k«'<*
-------
finvhronmvntol Protection Agency
Pad 720, Appendix A
P«rt II - HUMAN EXPOSURE AND ENVIRONMENTAL RELEASE - ConttniMMJ
• - iNDurntuL SITM CONTKOUID BY OTHIM
To*
*•«•*••!
AP4-32
-------
Port 7JO, AjppviMllx A
40 0* ffc. I (7-L90 edition)
Port III - LIST Of ATTACHMINTS
AP4-33
-------
-------
Chem.
No.
283/
42$
286
287
289
291
292
300
307
309
312
318
320
321
MPD
LCSO value
[mg/1]
NTS
>500
NTS
>100
NTS
>1000
NTS
>1000
NTS
>100
5.7
1.7
6.9
NTS
101
(89 - 128)
NTS
>500
NTS
>69
SAR
LCSO value
- lmg/1)
NTS
NTS
NTS
NTS
NTS
1.4
1.6
16.3
NTS
1500
NTS
NTS
375
Difference
I± tof units]
-
**
.
"
~
-0.60
-0.03
0.38
*
1.17
™
" '
0.73
Remit
acne
agree
agree
agree
agree
agree
agree
agree
agree
disagree
agree
agree
agree
A9-7
-------
Chem.
No..
330
335
336
337 *
340
341
342
344
348
349
354
355
360
MPD
LCSO value .
Ung/l)~
341
2.0
. >100
36
152
>500
480
>1000
NTS
>10
NTS
>500
8.3
NTS
>100
SAR
LC50 value
(mg/1)
>1000
NTS
7
4
£1000
>1000
>1000
>1000
NTS
NTS
£13.5
NTS
60
Difference
[±log unto]
"
m
-1.15
0.96
™
*
•
*
*
"
*
"
•0.22
M •
agfW
din|fw
dittfTM
agree
—
BftM
agree
agree
agree
agree
™
agree
agree
A9-8
-------
Qwm.
No.
361
362
364
366
368
369
370
373
376
379
381
383
386
MPD
LC50 value
(ng/11
NTS
>1000
>1.0
17.8.
NTS
>135
5
1671
114
>100
NTS
>IOO
0.72
NTS
>500
NTS
>67
3.4
SAR
LC50 value
(mg/l)
NTS
14
>100
NTS
>14.8
2190
0.9
1.5
NTS
1.5
NTS
NTS
S35.3
Difference
(±k>g units]
•
1.15
0.75
™
0.47
10]
-2.10
-1.82
•
0.32
™
™
T
Result
agree
disagree
agree
agree
agree
agree
disagree
disagre
agree
agree
agree.
agree
*
A9-9
-------
CI)60&*
No.
393
394
396
398
401
406
411
413
414
415
416
417
420
MPD
LC50 value
Iwg/iJ
100
>IOOO
> 1000
>100
f
77
NTS
NTS
>500
NTS
> 100
220
NTS
>100
NTS
NTS
>113
1.4
SAR
LCSOvtlue
tim/ll
3.8
>100
>1000
>11.5
90
NTS
NTS
NTS
2100
NTS
NTS
NTS
5.9
Difference
(±tof ante]
-1.42
10)
0
•0.94
0.07
"
*
*
[01
•
•
m
0.62
Remit
disagree
agne
agne
agree
agree
agne
agree
agne
agree
agree .
agree
agne
agne
A9-10
-------
Cbem.
No.
421
425
431
436
437
439
441
442
443
^n^
445
446
451
472
*
MPD
LCSO value
[IDE/1]
od
1113
NTS
>1000
2.7
NTS
546
1
>258
1 60
769
138
7.3
>100
NTS
>22
21
NTS
>100
SAR
LCSO value
(mi/I]
0.58
500
NTS
0.52
NTS
110
60
2100
99
4
>100
NTS
£135
NTS
Difference
l±4og units]
-
0
•
-0.72
•
0
-0.43
10}
0.15
-0.26
0
™
*
™
Result
- .
««ree
'agree
agree
agree
agree
agree
agree
agree
agree
agree
agree
~
agree
A9-I1
-------
-------
* ANNEX 10
TQX1C1TV TO DAFHNIA. COMPARISON OF TEST RESULTS AND PREDICTIONS
Chem. .
No.
4
6
16
17
21
23
24
26
37
44
47
*" 49
50
*
MPD
EC50 value
[mg/lj
nd
230
(96 hr)
1100
(48 hr)
1.2
(48 hr)
nd
680
(24 hr)
10
(24 hr)
NTS
(24 hr)
>2
(24 hr)
nd
2.9
(24 hr)
0.84
(48 hr)
NTS
(24 hr)
. SAR
ECSO value
(mc/l)
>100
>140
>100
>0.2
NTS
MOO
<0.73
.NTS
10
NTS
SQ.57
£30
NTS
Difference
[± log units]
-
-0.22
10)
-0.80
•
(0]
™
*•"
- 0.70
*
~
*
•
Retult
.
•free
agree
agree
•
agree
**
agree
agree
* *
~
•
agree
A10-1
-------
Chan.
No.
53
54
61
68
69
70
76
78
79
87
96
99
101
MPD
ECSO value
(mj/l)
131.7
(24 hr)
15.3
(24 hr)
NTS
(24hr) .
20.5
(24 hr)
395
(24 br)
NTS
4.0
(48 hr)
990
(24hr) .
>100Q
(24 hr)
25,5
(48 hr)
355
(24 hr)
>56
(48 hr)
>1000
(24 hr)
SAR
EC50 value
(mm
O.I
2.2
... NTS
>100
>100
NTS
NTS
0.1
NTS
8.1
100
£100
>100
Difference
{±log uaia)
-3.15,
•085
*
0.69
0.60
M
*
-4
^
-0.49
-0.55
*
101
•Rnalt
disagree
agree
agree
agree
agree
agree
disagree
disagree
agree
agree
agree
*
agree
A10-2
-------
Chan.
No.
102
106
107
108
110
113
118
124
128
133
144
148
151
MPD
ECSO value
fmg/1]
47
(24 br)
5.6
(24 hr)
Dd
1.83
(48 hr)
0.018-0.032
(48 hr)
365 (nominal)
(24 hr)
9.3
(24 hr)
5.4
(48 hr)
>100
.(24 hr)
5.35
(24 hr)
NTS
>5.3
(48 hr)
NTS
>7.8
8.0
(48 hr)
SAR
EC50 value
Jmg/lJ
NTS
NTS
>100
0.46
NTS
NTS
0.01
3.4
15.4
£0.93
NTS
NTS
0.36
Difference
t± log units]
*
*
*
0.60
*
"
-4
-0.20
-0.82
•*
"
"
-1,35
Remit
disagree
disagree
~
agree
disagree
agree
disagree
agree
agree
*
agree
agree
disagree
A10-3
-------
Chem.
No.
155
156
164
170
173
176
182
186
192
194
196
197
200
MPD
ECSO value
JmgflJ- .
4.1
(48 hr)
1.3
(48 hr)
16
(48hr)
53
04 hr)
5
(48 hr)
NTS
(24 hr)
1.5
(48 hr)
>50
801 .
(48 hr)
1.72
(48 hr)
>1000
0.01
(48 hr)
0.046
(48 hr)
SAR
ECSOvalue
lmg/1]
NTS
0.45
, NTS
1.8
i8.4
NTS
NTS
>0.1
S63.0
£0.93
>100
0.2
NTS
Difference
[± log units}
•
-0.46
••
-152
0.23
*
•*>
-2.70
w
"
[0]
1.30
*
**'
•disagree
HIM
diiagree
dlMffM
•free
•grce
disagree
distgnr
"
™
agree
disagree
disagree
AKM
-------
Chem.
No.
204
214
216
217
218
219
222
224
235
237
239
240
241
MPD
ECSO value
[rng/1]
NTS
>0.3
(4ghr)
220
(24 hr)
23
(24 hf)
MOO
(24 hr)
7.2
(48 hf)
39.2
(24 hr)
1.9
(48 hr)
>1000
4.1
(24 hr)
>1000
(48 ht)
NTS
>100
(24 hr)
37.2
(48 hr)
24
(48 hr)
SAR
ECSO value
(Olg/lJ
NTS
2
30
230
1.9
10
10
MOO
0.2
10
NTS
MOO
MOO
Difference
I± log units)
-'
-2.05
0.11
0.36
-0.59
•0.60
0.72
10}
-1.30
-2
"
-0.43
0.62
Remit
•free
disagree
agree
agree
agree
agree
agree
agree
disagree
disagree
«gf«
agree
agree
A10-5
-------
Chan.
No.
242
2S3
256
263
265
267
268
269
270
271
275
278
281
MPD
ECSO value
tot*}
21.1 -
(48 br)
NTS
>1000
(24 hr)
250
(24 hr)
16,940
(48 hr)
nd
900
(24 hr)
NTS
>3.7
(48 hr)
44
(24 hr)
93
(48 hr)
139.3
(24 hr)
0.53
(48 hr)
0.91
(48 hr)
SAR
' ECSO vthie
Imgfll
>IOO
NTS
90
17
>1000
NTS
O.I
NTS
9
50
0.42
11
NTS
Difference
I±k>f units)
0.67
<*
-1.05
-1.16
10)
"
• -4
"
•0.7
•0.27
-2.52
1.32
*
Result
•free
•free
jj——— — — _
cusagree
disagree
•free
•
disagree
agree
agree
agree
disagree
disagree
disagree
A IO-«
-------
I
Chem.
No.
283/
429
286
287
289
291
292
300
307
309
312
318
320
321
MPD
ECSO value
|mg/l|
NTS
>1000
(24 hr)
NTS
>100
(48 hr)
NTS
>IOOO
(24 hr)
NTS
>1000
(24 hr)
NTS
>100
(24 hr)
20.5
(24 hr)
25
(24 hr)
3.5
(24 hr)
NTS
>0.03
(48 hr)
39.7
(24 hr)
NTS
750
(48 hr)
NTS
70
(48 hr)
>100
(24 hr)
SAR
ECSO value
lmg/1]
NTS
NTS
NTS
NTS
NTS
3.4
1.7
17.4
NTS
1500
NTS
NTS
>100
bifference
(± log units]
-
*
"
*
*
•0.77
-1.16
0.70
"
1.59
~
• •
0
Result
agree
agree
agree
agree
agree
agree
disagree
agree
agree
disagree
agree
agree
agree
A10-7
-------
Clicm.
No.
330
335
336
337
340
341
342
344
34g
349
354
355
360
MPD
FC50 value
|mg/l| - .
• 44
(48 hr)
>1000
(24 hr)
140
. (24 hr)
. 13
(48 hr)
25
(48 hr)
36
(48 hr)
>1000
(48 hr)
>IOOO
(24 hr)
NTS
>IOOO
(24 hr)
6-15
(48 hr)
>30
(48 hr)
NTS
>1
(48 hr)
>IOO
(24 hr)
SAR
EC50 value
lmg/1]
>IOOO
NTS
. 50
40
*72
>1000
>IOOO
>IOOO
NTS
NTS
-------
Chem.
No.
361
362
364
366
368
369
370
373
376
379
381
383
386
MPD
ECSOvahie
[mg/l]
NTS
>1000
04 hr)
NTS
>1.0
(24 hr)
1.2 .
(24 hr)
1.63
(48 hr)
>5.7
(48 hr)
602
(48 hr)
125
(24 hr)
20.9
(48 hr)
NTS
. 172.8
(48 hr)
0.78
(48 hr)
NTS
>500
(48 hr)
NTS
>70
(24 hr)
48.9
(48 hr)
SAR
ECSO value
. |mg/l)
NTS
31.3
MOO
NTS
ilO
400
0.42
0.73
NTS
0.95
NTS
NTS
538. 1
Difference
[± tog units]
•
1.50
1.92
™
0.24
•0.18
-2.52
-1.52
*
0.08
™
*
*
Remit
agree
disagree
disagree
disagree
agree
agree
disagree
disagree
agree
agree
agree •
agree
™
A10-9
-------
Chan.
No.
393
394
396
398
401
406
411
413
414
415
416
417
420
MPD
ECSO value
lmg/1]
200
(48 hr)
890
(48 hr)
>1000
(24hr)
8.6
' (48 hr)
62
(48 hr)
NTS
NTS
>1000
(48 hr)
NTS
>4.8
(24 hr)
88
(48 hr)
NTS
>100
(24 hr)
NTS
> 0.0048
(24 hr)
NTS
1.1
(48 hr)
SAR
EC30 value
i«ng/ij
1.6
>100
• >1000
ilO
16
NTS
NTS
NTS
21SO
NTS
NTS
NTS
5.1
Difference
l± log unto)
•2.10
[0]
0
0.06
-0.58
*
•
~
0.23
"
"
•
0.66
Remit
disifree
agree
agree
agree
agree
•free
agree
agree
•free
agree
agree
agree
•tree
A10-10
-------
Chem.
No.
421
425
431
436
437
439
441
442
443
444
445
446
451
472
f
MPD
ECSO value
\mf\\
signs for toxtchy
52
(48 hr)
NTS
>1000
(24 hr)
19
(24 hr)
NTS
14
(48 hr)
>1000
70
(48 hr)
176
(24 hr)
146
(24 hr)
5.2
(24 hr)
>100
NTS
62
(24 hr)
111
(48 hr)
6.36
(48 hr)
SAR
EC50 value
(mB/l)
0.07
230
NTS
0.06
NTS
2100
10
2100
27
ml
>100
NTS
£1000
NTS
Difference
(±lof units]
•»
*»
-0.24
*
-2.52
~
(0]
-0.85
-0.24
-1.30
•
0
~
™
•
Result
•
agne
agree
disagree
agree
agree
agree
agree
disagree
•
agree
agree
"
disagree
AIO-11
-------
-------
ANNEX II
TOXICITY TO ALGAE; COMPARISON OF TEST RESULTS AND PREDICTIONS
ChHH.
N«.
110
219
2T1
366
451
MPD
' ECSOvalue
img/1]
NTS
9.4
9
NTS
>12
32
SAR
EC50 value
(mg/U
NTS
6
10
NTS
£10
Difference
[±bg units)
w
-0.19
0.04
*
w
Result
agree
agree
agree
agree
•
All-l
-------
-------
ANNEX 12
ACUTE QRAL. TOinClTYi COMPARISON OF TEST RESULTS AND
PREDICTIONS
Chan.
Ne.
4
6
16
17
21
23
24
26
37
44
47
49
SO
MFD
(UW)*
(High)
(R35)
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low-Moderate
-------
Chan.
No.
53
54
61
68
69
70
76
78
79
87
96
99
101
MPD
OaW)«
Low
UUWBMUUdeWB
(R22)
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
SAR
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
RMOlt
AgrM •
SAT low
(overtip)
Agne
Agree
Agree
Agree
Agree
Agree
Agree
Agree
Agree
Agree
Agree
A12-2
-------
Chen.
No.
102
106
107
108
110
113
118
124
128
133
144
148
151
MFD
(label)'
Low
Low
(High)
-------
Cham.
No.
155
156
164
170
173
176
182
186
192
194
196
197
200
MFD
(Ubd)«
Low
Low»ModerBte
(KB)
Low
Low
Low
Low
Low
Low
Low
Low
Low
Moderate
(R22)
Low
.SAR
Low
Low
; Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Remit
Agree
SARlov
(overlap)
Afree
Afne
Afree
Agree
Afree
Afree
Afree
Agree
Agree
SAR low
Agree
A12-4
-------
1
Chan.
Mo.
204
214
216
217
218
219
222
224
235
237
239
240
241
MPD
(Ubel)«
Low
Low
Low
Low
Low
Low-Moderate
(R22)
Low
Low
Low
Low
Low
Low
Moderate
-------
Chem.
No.
242
253
256
263
265
267
268
269
270
271
275
278
281
MPD
C«bel)V -
Moderate
(R22)
Low
; Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Moderate
(R22)
SAR
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Moderate
Ratult
SAR tow
Agree
A free
Agree
Agree
Agree
Agree
Agree
Agree
Agree
Agree
Agree
Agree concern
A12-6
-------
Chan.
No.
283/
429
286
287
289
291
292
300
307
309
.312
318
320
321
MFD
0abel)«
Low
Low
Low-
Low
Low
Low
Low-Moderate
-------
Own.
No.
330
335
336
337
340
341
342
344
348
349
354
355
360
MFD
(l*bd)«
Moftnto-Hifh
Low
Low
Low
Low-Moderate
Low
Low
Low
Low
Low
Low
Low
uuw-ifffUUflltBC
(R22)
SAR
Low
Low
... Low
Low
Low
Low
Low
Low
Low
Low
• Low
Low
Low
*..,
SAR low
Apt*
Afm
Afi*e
SAR low
(owl*)
Afree
Afrae
Afree
Afree
Afree
Afrae
Afree
SAR low
(overlap)
A12-S
-------
No.
361
362
364
366
368
369
370
373
376
379
381
383
386
MFD
QabaQ*
Low
Low
.Low
Low
Low
Low
Low-Moderate
-------
Own.
No.
303
394
396
398
401
406
411
413
414
•415
416
417
420
MFD
(UW)«
Low
Low
Low
Low
Low
Low
Low
Low-Moderate
(R22)
Low
Low
Low
Low
Low
SAR
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Kenfc
Agrtf '
Acne
Agree
Agree
Agree
Agree
Agree
SAR tow
(overlap)
Agree
Agree
Agree
Agree
Agree
A12-10
-------
Chem.
No.
421
425
431
436
437
439
441
442
443
444
445
446
451
472
MFD
(label)*
Low
-------
-------
ANNEX 13
SKIN AND EYE IRRITATION: COMPARISON OF TEST RESULTS AND
PREDICTIONS '
Cbem.
No.
4
6
16
17
21
23
24
26
37
44
47
49
50
»
SUa
MPD (label)1 SAR
(cor.)1
005)
DM ufllUit
not kriiant
Dot irritant
DOt uulUtt
slight
not irritant
not irritant
not irritant
not irritant
not irritant
corrosive
(R34)
DOt
irritant
cflfectt
predicted
DO
comment
DO
not irritant
no
slight
no
GOOUIMBOl
no
comment
slight
not irritant
?
irritant
irritant
Result
agree
•tree
•gree
agree
•tree
agree
agree
agree
agree
agree
agree?
agree
SAR high
Eye
MPD (label)1 SAR
(corr.)'
-------
Chem.
No.
S3
54
61
68
69
70
76
78
79
87
96
99
101
Skin
MPD OibdJ1 SAR
irritant
008)
not irritant
• |j* !•»!*•••*
DPI UIHMIH
flOt iiillaOt
not irritant
not irritant
not irritant
_4^ lj^ti^»*
not irriuuit
not irritant
not irritant
not irritant
not irritant
not irritant
• •- . - j.
imtant
DO
to
GQfl^BkOQt
no
frumimitt
_^--.^. t •••*••••»
not imtant
not irritant
DO
oommtttt
not untant
no
comment
no
comment
irritant
irritant
not irritant
Remit
agree
agree
agree
agree
agree
agree
agree
agree
agree
agree
SAR high
SAR high
agree
Eye
MPDQabel)* SAR
(irritant)*
not iirkant
m*tt * *-
DOI UIBBK
not irritant
not irritant
not irritant
not irritant
not irritant
not irritant
irritant
-------
Chan.
No.
102
106
107
108
110
113
118
124
128
133
144
148
151
MFD (label)
nottoitatt
not iiiilaul
(corr.)1
(R35)
not irritant
not irritant
not irritant
corrosive
(R34)
not. irritant
not irritant
not irritant
not irritant
not irritant
not irritant
Skin
f SAR
no
no
comment
,ff,rl,
eiiecu
predicted
no
comment
no
comment
no
comment
no
comment
irritant
not irritant
no
comment
not irritant
no
comment
not irritant
Result
agree
agree
agree
agree
agree
agree
SAR low
SAR nigh
agree
agree
agree
agree
agree
Eye
MPD (label)1 SAR
not liikaut
not irritant
(cotr.)1
(RJS)
not iiiUant
not irritant
not irritant
(corr.)1
(R34)
• irritant
not irritant
not irritant
not irritant
not irritant
irritant •
no
no
effects
predicted
no
JMMMMM^M^
commeni
no
no
COfllOMMEtt
no
comment
* •-
irritant
irritant
no
comment
not irritant
no
comment
irritant
Remit
agree
agree
•tree
agree
agiee
•free
SAR tow
agree
SAR high
'agree
agree
agree
agree
A13-3
-------
Chen.
No.
155
156
164
170
173
176
1S2
186
192
194
196
197
200
Skin
MFD (label)1 SAR
not irritant
not irritant
not irritant
not irritant
(irritant)^
•not ufiunt
corrosive
(R34)
M4^ l»ail<»^t
not irritant
.
corrosive
-------
Own.
No.
204
214
216
217
218
219
222
224
235
237
239
240
241
SUn
MPDQabey SAR
__^ g tj
OOt UfitBflt
^**^ i^MtftA^^
B0( UTuUK
oot irrlunt
not irritant
oot irrittnt
not irritant
t*mitmmt
uruant
(R38)
. slight
corrosive
(R34)
irritant
-------
fm
uian.
No.
242
253
256
263
265
267
268
269
270
271
275
278
281
MPDQabd;
not irritant
not iiiitaiit
not irritant
not irritant
not irritant
ND
not irritant
not irritant
.not irritant
not irritant
not irritant
irritant
(R38)
not irritant
Skin
i> SAR
no
no
t,-ia--,t
tmtant
not irritant
no
DO
comment
not irritant
irritant
no
comment
irritant
no
comment
1--U-— •
tmtant
not irritant
*-
agree
agree
SAR high
agree
agree
agree
agree
SAR high
agree
SAR high
agree
agree
agree
MPD(Ubd)* SAR Remit
not Ifiiiani
— ,,a *__ia— — A
•ot irritant
irritant
(R36)
irritant
(R36)
HOT irriulBt
ND
not irritant
not irritant
irritant
(R36)
not irritant
not irritant
(irritant)*
irritant
(R36)
no
no
irritant
tmtrttm mt
irritant
00
no
comment
irritant
irritant
no
-
irritant
no
• »a — ~
trntant
Xaal**^*
srntant
"agree
""*
agree
Ageree
agree
agree
SAR high
SAR high
SAR km
SAR high
agree
agree
agree
A13-6
-------
Chen.
No,
283/
429
286
287
289
291
292
300
307
309
312
318
320
321
Skin
MPDGabeiy SAR
mnt IflHlft.^
not UIUIK
not irritant
not initint
not irritant
not irritant
•4^ I«M£*AW*
not irritant
not irritant
not irritant
not irritant
oot irritant
not irritant
not irritant
not irritant
no
comment
not Irritant
. no
coimvtfiflij
no
comment
no
OOIDflSttft
mJld
no
oonuncnt
no
OOlttDlMtt
no
comment
no
comment
no
comment
no
comment
no
comment
. Remit
agree
agree
agree
agree
agree
agree
agree
agree
agree
agree
agree
agree
agree
Ejt .
MPDQabel? SAR Result
not irritant
not Uiltaut
not irritant
not irritant
not iiiitaut
not irritant
not iii but
not irritant
not irritant
not irritant
not irritant
not irritant
not irritant
no
irritant
no
comment
no
comment
uo
QOflUDCflt
mad
no
comment
no
GQflUDCflK
no
OORUAdlt
no
comment
no
conuhun
no
OODVDtttt'
no
comment
agree
SAR high
agree
agree
agree
agree
agree
agree
agree
agree
agree
agree
agree
A13-7
-------
Chem.
No.
330
335
336
337
340
341
342
344
348
349
354
355
360
Skin
MFD (label)1 SAR
no( irritant
not Irritant
not irritant
not irritant
not irritant
not irritant
not irritant
not irritant
not irritant
not irrittnt
not irritant
not irrittnt
not irritant
not irritant
no
no
no
no
irrittnt
no
no
comment
. BO
no
comment
no
comment
no
comment
irritant
Remit
agree
agree
.agree
agree
agree
SAR high
agree.
agree
agree
agree
agree
agree
SAR high
MPD^
(IrrittnQr
not irritant
M* *-
uiuaia
not irritant
(irritant)*
not iiiilaut
not irritant
not irritant
not irritant
not irrittnt
not Irritant
not irritant
(irritant)1
1 SAR Remit
Irritant
no
no
•
no
Mmmanf
no
comment
* - • —
irritant
no
comment
no
no
no
no
no
irritant
•free
agree
agree
ft-
SAR low
SAR high
agree
agree
agree
agree
agree
agree
agree
A13-*
-------
Chen.
No.
361 .
362
364
366
368
369
370
373
376
379
381
383
«
386
Skin
MPD0«beO» SAR
DM irritant
not irritant
not irritsnt
not irritant
not irritint
not irritant
corrosive
-------
Chan.
No.
393
394
396
398
401
406
411
413
414
415
416
417
420
421
Skin
MPDQabd? SAR
not irritant
not ittitint
not irritant
•light
not initint
not irritant
not irritant
not irritint
not irritant
not irritant
not irritant
not irritant
not irritant
not irritant
*
no
no
no
It *iain*
irritant
irritant
no
no
comment
no
comment
no
comment
no
no
comment
no
GQfftlVlfifH
no
comment
no
GOOUBMK
Remit
•pee
agree
agree
•free
SAR high
agree
agree
agree
agree
agree
agree
agree
agree
agree
ETC
MPD 0abeD» SAR Remit
(irritant?
not irritant
not irritant
alight
not irritant
not irritant
not irritant
not irritant
not irritant
not irritant
not irritant
not irritant
not irritant
not irritant
no
no
no
irritant
;„•*--,
irritant
no
comment
no
no
comment
no
comment
no
comment
no
no
comment
no
QomnttflC
no
comment
SAR low
»
•jree
agree -
agree
SAR Ugh
agree
agree
agree
tgree
agree
agree
agree
agree
agree
A13-IO
-------
Chan.
No.
425 .
431
436
437
439
441
442
443
444
445
446
451
472
MPD (label]
corrosive
-------
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-------
ANNEX IS
MUTACENIOTY! COMPARISON OF TEST RESULTS AND PREDICTIONS
Cheat.
No.
4
6
16
17
21
23
24
26
37
44
47
49
50
MPD result
in vitro
nd
Ssl -ve
Sal-ve
MCGM+ve
Sal +ve
MCGM -ve
Sal-ve
Sal-ve
Sal -ve
. Sal-ve
Sal-ve
Sal-ve
Sal-ve
Sal-ve
MCGM -ve
Sal-ve
' IVC-ve
MPD result
in vivo
nd
mnuc -ve
• nd
nd
mnuc -ve
mnuc -ve
mnuc -ve
mnuc -ve
mnuc -ve
mnuc -ve
mnuc -ve
nd
nd
SAR
0
0
0
0
0
0
0
0
L-M
0
0
0
0
Agreement?
?
Yes
No SAR low
No SAR low
Yes
Yes
Yes
Yes
No EC low
Yes
Yes
Yes
Yes
A15-I
-------
Chem.
No.
S3
54
61
68
69
70
76
78
79
87
96
99
101
MPD result
in vitro
Sal-ve
Sal weak -rve
MCGM -ve
Sal-ve .
IVC -ve
Sal -ve
IVC-ve
Sal-ve
E Coli -ve
Sal-ve
Sal -ve
UDS -ve
Sal-ve
Sal-ve
E Coli -ve
Sal -ve
IVC-ve
Sal-ve
E Coli -ve
Sal -ve
IVC-ve
Sal-ve
9
MPD result
in vivo
mnuc-ve
SCE-ve
NA-ve
nd
nd
mnuc -ve
mnuc -ve
mnuc -ve
mnuc -ve
mnuc -ve
nd
mnuc-ve
mnuc -ve
mnuc-ve
SAR .. .
0
equivocal
0
0
0
0
0
0
0
0
L-M
0
L-M
Agreement?
Yet
Ye*
Yei
Yet
Y*
Yes
Yes
Yes
Yes
Yes -
No EC low
Yes
No EC low
A15-2
-------
Chan.
No.
102
106
107
108
110
113
118
124
128
133
144
148
151
MPD result
to vitro
Sal -ve.
Sal-ve
E Coli -ve
nd
Sal-ve
Sal-ve
MCGM -ve
IVC-ve
Sal-ve
Sal-ve
Sal -ve
Sal -ve
Sal-ve
Sal-ve
MCGM -ve
IVC-ve
Sal-ve
Sal-ve
MCGM-ve
IVC-ve
MPD result
in vivo
mnuc-ve
nnuc-ve
nd
mouc -ve
mnuc -ve
mnuc-ve
NA -ve
mnuc -ve
mnuc -ve
CA-ve
mnuc -ve
nd
mnuc -ve
nd
SAR f
L-M
0
0
0
0
0
0
0
0
0
0
0
0
Agreement?
No EC tow
«
Yes
?
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
AI5-3
-------
Cbem.
No.
155
156
164
170
173
176
182
186
192
194
196
197
200
MPD result
in vitro
Sal-ve
Sal-ve
Sal-ve
SCE-ve
Sal +ve
Sal-ve
Sal -ve
Sal-ve
MCGM -ve
Sal-ve
. Sal-ve
E Coli -ve
od
Sal -ve
IVC weak +ve
Sal weak +ve
E Coli -ve
IVC-ve
Sal-ve
IVC -ve
• »
MPD result
in vivo
ramie -ve
mouc-ve
mouc-ve
mnuc-ve
mnuc-ve
nmue -ve
mnuc-ve
mnuc -ve
mnuc -ve
nd
mnuc-ve
nd
nd
SAR
0
0
0
0
0
0
0
0
0
0
L-M
L-M
0
, Agreement?
Yet
Yes
Yes
No SAR tow
Yf»
Yet
Yet
Yet
Yes
Yes
Yes
Yes
Yes
A15-4
-------
Chan.
No.
204
214
216
217
218
219
222
224
235
237
239
240
241
MPD result
in vitro
Sil-ve
Sal we
Sal weak +ve
MCGM -ve
IVC -ve
Sal -ve
Sal -ve
E Coli -ve
IVC-ve
Sal +ve
MCGM -ve
Sal -ve
Sal-ve
Sal -ve
Sal -ve
IVC-ve
Sal-ve
IVC -ve
Sal -ve
Sal-ve
IVC-ve
*
MPO result
in vivo
mouc-ve
ninic -ve
NA -ve
mpuc-ve
mnuc-ve
nd
mnuc-ve
mnuc -ve
mnuc-ve
mnuc -ve
nd
nd
mnuc -ve
nd
SAR
< . *
b
0
0
0
0
L-M
L-M
L-M
0
0
0
0
0
Agreement?
Yet
Yes
No SAR low
Yes
Yes
Yes
No EC tow
No EC low
Yes
Yes
Yes
Yes
Yes
A15-5
-------
Chem.
No.
242
253
256
263
265
267
268
269
270
271
275
278
281
MPD result
in vitro
Sal -ve
IVC-ve
Sal-ve
Sal-ve
Sal +ve
IV£ -ve
Sal-ve
IVC-ve
od
Sal-ve
Sal weak +ve
MCGM-ve
IVC-ve
Sal-ve
Sal -ve
IVC-ve
. Sal -f ve
IVC -ve
Sal -ve
SCE weak +ve ?
Sal-ve
*
MPD result
in vivo
nd
tnnuc-ve
mnuc -ve
mnuc-ve
od
nd
mnuc -ve
mnuc -ve
mnuc -ve
nd
mnuc -ve
mnuc -ve
mnuc -ve
SAR '• '
0
0
0
L-M
0
0
0
L-M
0
0
L-M
0
L
Agreement? .
Yes
Yes
Yes
Yes
~ Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
A15-6
-------
Chem.
No.
283/
429
286
287
289
291
292
300
307
309
312
318
320
321
MPD result
in vitro
Sal -ver
Sal-ve
Sal-ve
Sal -»-ve
IVC-ve
Sal-ve
Sal-ve
IVC-ve
Sal -ve
Sal +ve
E Coli -ve
Sal-ve
Sal +ve
MCGM -ve
Sal -ve
Sal-ve
Sal -ve
MPD result
in vivo
mnuc-ve
mnuc -ve
mnuc -ve
mnuc -ve
mnuc -ve
od
mnuc -ve
mnuc -ve
mnuc -ve
mnuc - ve
mnuc -ve
mnuc -ve
mnuc -ve
SAR *
0
0
0
L-M
L
0
0
L-M
0
L-M
0
0
M
Agreement?
Yet
*
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No EC low
A15-7
-------
Cbem.
No.
330 .
335
336
337
340
341
342
344
348
349
354.
355
360
MPD result
in vitro
Sal-ve
Sal +ve
MCGM-ve
Sal -ve
Sal -ve
MCGM -ve
IVC-ve
Sal-ve
IVC +ve
Sal-ve
Sal -ve
FVC -ve
Sal -ve
Sal -ve
Sal -ve
Sal-ve
IVC-ve
SCE -ve
Sal-ve
Sal -ve
IVC-ve
9
MPD result
in vivo
mnuc-ve
untie -ve
mnuc-ve
nd
mnuc -ve
mnuc -ve
mnuc -ve
mnuc -ve
mnuc -ve
mnuc -ve
mnuc-ve
mnuc -ve
nd
SAR
L-M
L-M
0
L-M
0
0
0
0
0
0
0
0
0
. Agreement?
No
Yes
Y«
No EC low
No SAR low
Yes
Yes
Yet
Yes
Yes
Yes
Yes
Yes
A15-8
-------
Chem.
No.
361
362
364
366
368
369
370
373
376
379
381
383
386
MPD result
in vitro
Sal-ve
IVC-ve
Sal weak +ve
Sal *ve
IVC +ve
Sal-ve
E Cbli -v«
Sal-ve
IVC-ve
Sal-ve
IVC +ve (art)
Sal-ve
Sal-ve
Sal -ve
IVC-ve
Sal-ve
IVC-ve
Sal -ve
Sal -ve
Sal -ve
E Coii -vc
. IVC-ve
MPD result
in vivo
nd
mnuc -ve
mnuc-ve
mnuc-ve
nd
mnuc -ve
mnuc -ve
mnuc -ve
nd
nd
mnuc -ve
mnuc -ve
mnuc -ve
SAR
- - *
0
L-M
0
0
0
0
0
0
0
L-M
0
0
0
Agreement?
Yet
Yet
No SAR tow
Yes
Yes
Yes
Yes
Yes
Yes
No EC low
Yes
Yes
Yes
A1S-9
-------
Chem.
No.
393
394
396
398
401
406
411
413
414
415
416
417
420
MPD result
in vitro
Sal -YC
Sal-ve
IVC-ve
Sal-ve
Sal -ve .
.•
Sal-ve
IVC v.weak +ve
. Sal-ve
IVC -ve
Sal-ve
Prival -ve
Sal-ve
Sal-ve
Sal -ve
Sal -ve
. Sal -ve
Sal-ve
ECoIi-ve
iVC-ve
MPD result
in vivo
CA-ve
nd
mnuc -ve
mnuc-ve
nd
od
mnuc -ve
mnuc -ve
mnuc -ve
mnuc -ve
mnuc -ve
mnuc -ve
nd
SAR
0
0
0
0
0
L-M
0
0
0
0
0
0
0
f Agreement?
Yet
Yes
Yes
Yes
Yes
No EC tow
Yes
Yes
Yes
Yes
Yes
Yes
Yes
AIS-10
-------
Chem.
No.
421
425
431
436
437
439
441
442
443
444
445
446
451
472
MPD mult
in vitro
Sal-ve
Sal-ve
IVC-ve
Sal -ve
IVC-ve
Sal-ve
Sal-ve
IVC-ve
Sal-ve
IVC-ve
Sal-ve
E Coli -ve
IVC-ve
Sal-ve
WC +ve
Sal-ve
Sal-ve
nd
Sal-ve
E Coli -ve
Sal-ve
E Coli -ve
IVC-ve
.. Sal-ve
*
MPD result
in vivo
nnuc -ve
nd
nd
CA-ve
mnuc -ve
nd
nd
nd
mnuc -ve
mnuc -ve
nd
mnuc -ve
mnuc -ve
mnuc -ve
SAX
0
0
0
0
0
0
L-M
L-M
0
L-M
0
0
0
f
0
Agreement?
Yes
* Yes
Yes
Yes
Yes
Yes
No EC low
Yes
Yes
No EC low
Yes
Yes
Yes
Yes
AI5-11
-------
Abbreviations: Sal * Salmonella (Ames) gene mutation test
mnuc * micronucleus test
MCGM «" any mammalian cell gene mutation test
IVC » iD_yJttQ chromosome aberration test
SCE » sister chromatid exchange test
UDS « unscheduled DNA synthesis test
NA = nuclear anomaly test
CA * chromosome aberration test
E coli « E coll gene mutation test
art * artefact
od « not done
0 or L « SAR prediction of low concern '
L-M « SAR prediction of low to modenta concern
M * SAR prediction of moderate concern
+ve » positive
-ve « negative
-------
No 1.259/10
Official Journal of the European Communing .
APPENDIX 1
15.10.79—
COUNCU. DIRECTIVE
of 18 September 1979
•maiding for the ttxth time Directive 67/548/EEC on the approximation, of ibe Uws.
regulations and administrative provisions relating to the dassificatioa, r^i"r«f and
labelling of dangerous substances
(79/831/EEQ
THE COUNCIL OF THE EUROPEAN COMMUNfTIES,
Having regard to the Treaty establishing the European
Economic Community, and in particular Article 100
Having regard to the proposal from the Commission,
Having regard .to the opinion of the European
Parliament (»),
Having regard to the opinion of
Social Committee (*),
the Economic and
Whereas to protect man and the environment against
potential risks which could arise from the placing on the
market of new substances, it » necessary to lay down.
appropriate measures and in particular to reinforce die
recommendations provided in Council Directive
67/548/EEC of 27 June 1967 on die approximation of
the laws, regulations and administrative provisions
relating to die classification, packaging and labelling of
dangerous substances (*), as last amended by Directive
75/409/EEC(«);
Whereas it is necessary for these reasons to amend
Directive 67/548/EEC which at die moment by an
adequate classification, packaging tad labelling of
dangerous substances protects the population and
principally die worker* using diem;
Whereas in order to control the effects on man and die
environment it is advisable that any new substance
placed on the market be subjected to a prior study by
the manufacturer or importer and a notification to die
competent authorities conveying mandatorily certain
information; whereas it is, moreover, important to
follow closely the evolution and use of new substances
placed on die market, and that in order to do this it is
necessary to institute a system which allows all new
substances to be listed;
Whereas, moreover, it is necessary, if the Directive is to
be properly applied, to draw up an inventory of
substances on the Community market by 18 September
1981;
Whems it is necessary to provide for measures making
h possible to introduce a procedure of notification to
one Member State which is dien valid .for die
Community; whereas, it is, moreover, necessary to
provide that dx measure* relating to d*e daisificarion
and Utfiltug of substances may be laid down at
wnefcas it is necessary to introduce measures tor the
packaging and provisional labelling of dangerous
substances not yet appearing in Annex I to Directive
67/548/EEC;
Whereas it is necessary to make die indication of safety
advice obligatory;
Whereas Article 2 of die abovementioned Directive
dattifirs mbttancri and preparations as toxic, harmful.
corrosive or irritant by dw use of general definitions;
whereas experience has shown dm it b necessary to
improve dus classification; whereas in die absence, at
die moment, of specifications necessary for allocation to
these classes, it seems appropriate to provide precise
criteria for classification; whereas in addition Article 3
of dte Directive provides for an evaluation of danger for
die environment and it is therefore necessary to
enumerate certain characteristics and parameters of
assessment, and to establish a phased study programme,
HAS ADOPTED THIS DIRECTIVE:
Article I
Articles 1 to 8 of Directive 67/548/EEC are hereby
replaced by die following, Articles:
(») OJ No C 30. 7.2.1977, p. 35.
P) OJ NoC 114,11.5.1977. p. 20.
(*) Oj No 196, It. 8.1967, p. 1.
f) OJ No L 1S3.14.7.1975. p. 22.
I
1. The purpose of this Directive is to approximate
the laws, regulations and administrative provisions
of die Member States on:
AP1-1
-------
IS. 10. 79
Official Journal of the European Communities
)k> 1259/11
(a) the notification of substances, and
fb) the classification, packaging and labelling of
substance* .dangerous in man and the
which are placed on the market in the Member
States.
least equivalent or Community notification
procedures or procedures which are not yet
harmonised;
(c) to substances which are already subject to
similar testing and notification requirements
under ousting Directives.
2. This Directive does not apply to the provisions
relating to:
(a) medicinal products, narcotics and radioactive
substances;
(b) the carriage of dangerous substance* by nil,
road, inland waterway, sea or air;
(c) foodstuffs or fecdingsnifft;
(d) substances in the form of waste'which are
covered by Council Directive 75/44Z/EEC of
15 July 1975 relating to waste (') and Council
Directive 78/319/EEC of 20 March 1978
relating to toxic and dangerous waste (*);
(e) substances in transit which are under customs
supervision provided they do not undergo any
treatment or processing.
3. Articles 15, 16 and 17 do not apply to the
provisions governing:
(a) containers which contain gases compressed.
liquefied or dissolved under pressure, excluding
aerosols which comply with the requirements of
Council Directive 75/J24/EEC of 20 May 1975
' on the approximation- of the bws of me
Member States relating to aerosol dispensers {');
(b) munitions and explosives placed on the market
with a view to producing a. practical effect by
. explosion or a pyrotechnic effect.
Article 2
1. For die purpose of this Directive:
(a) "substances" means chemical dements and their
compounds as they occur in the natural state or
as produced by industry, including any additives
required for the purpose of placing them on the
market;
(b) "preparations" means mixtures or
composed of two or more su
solutions
(c) "environment" means water, air and land and
their inter-relationship as well as relationship*
between them and any living organisms;
(d) "notification" means the documents whereby
the manufacturer or any other person
established in the Community who places a
substance on is own or in a preparation on the
market presents the requisite information to the
competent authority of a Member State. The
person so doing shall hereinafter be referred to
as "the notifier";
(e) "placing on the market" means supplying or
making available to third parties.
Importation into Community customs territory
shall be deemed to be placing on dx market for
the purposes of this Directive.
4. Articles 5, 6 and 7, in so far as they are
concerned with notification, do nut apply.
(a) — until six months after publication of the
inventory referred to in Article M (I), tu
substances plated on the market hrfmv
18 September 1981;
— six months after publication ol* the inventory
referred to in Article 13 (I), to substances
which appear in that inventory;
(b) to pesticides and fertilizers, in as for as they art-
subject to approval procedures which are at
2. The 'following substances and prcparati«im arc.
-." tviihin I hi- ituMitiiiK ol lhi\ Dircviivrt
{•) OJ No L m, IS. 7.1975. p. .W.
{») OJ No L 84. 3t. 3.197g.-p. 4X
(') OJ No I. 147, 9. 6. 1975. p. 40.
(a) explosive:
suhsunccs and preparations which may explode
under the effect of flame or which arc more
Mrn>iiivc ID shocks or friction than
lUnitntT'cnzenc;
(b) oxidizing:
substance!) and preparations which give n
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No L 259/12
OffidalI Journal of the European Communities
IS. 10. 79
(d) highly flammaHp;
and preparations which may
become hot and finally ouch fire in contact
WIQI air at ambient ttntperature without any
application of energy, or
—•• solid substances and preparations which
may readily catch fire afar brief contact
wtm a source of ignition and which continue
to bum or to be consumed afar removal of
die source of ignition, or
— liquid substances and preparations having a
flash point below 21 *C, or
— gaseous substances and preparations which
are flammable in air at normal pressure, or
— substances and preparations which, in
contact with water or damp air, evolve
highly- • flammable gases in dangerous
(c)
able:
liquid substances and preparations having a
flash point equal to or greater than 21 "C and
less than or equal to 55 *Cj
(f) very toxic
substances and preparations which, if they are
inhaled or ingested or if they penetrate me skin,
may involve extremely serious, acute or chronic
health risks and even dead); .
(g) toxic:
substances and preparations which, if they are
inhaled or ingested or if they penetrate the skin,
may involve serious, acute or chronic health
. risks and even .death;
(h) harmful:
substances and preparations which, if they are
inhaled or ingested or if they penetrate the skin,
may involve limited health risks;
(i) corrosive:
sub'tances and preparations which may, on
contact with living tissues, destroy them;
(j) irritant:
non-corrosive substances and preparations
which, through immediate, prolonged or
repeated contact with the skin or mucous
membrane, can cause inflammation;
(k) dangerous for the environment:
substances and preparations the use of which
presents or may present immediate or delayed
nsks for tne environment;
(I) carcinogenic:
'substances or preparations which, if they are
inhaled or ingested or if they penetrate the skin,
may induce cancer in man or increase its
(m)ieratogenic;
(n) mutagenic
Article J
I. Hw physico-chemical properties of the
substances and preparations shall be determined
according to the methods specified in Annex V (A);
their toxicity shall be determined according to die
specified in Annex V (B) and their
[ to those specified in Anno: V
(Q.
2. The real or potential environmental hazard shall
be assessed according to die characteristics set out in
Annexes VII and VIII, on die basis of any existing
tnternaoonaliy iccugimcd parameters*
3. The general principles of the classification and
laHrBing of substances and preparations «K«it be
applied according to me criteria in Annex VI, save
where contrary requirements for dangerous
preparations are specified in separate Directives.
Article*
1. The classification of dangerous substances
according to the degree of hazard and to die specific
nature of the risks involved shaD be based on die
categories laid down in Article 2 (2). For categories
(a) to (j) die substances shall be classified according
to the greatest degree of hazard, in accordance with
Article 16 (4).
2. The dangerous substances listed in Annex I
shall, where appropriate, "be given a rating enabling
die heal* hazard of preparations to be assessed.
The ratings shall be determined in accordance wim
die criteria established by a subsequent Council
Directive.
Article S
1. The Member Sates shall take all the measures
necessary to ensure that without prejudice to Article
8 substances cannot be placed on the- market on
their own or in preparations unless die substances
have been:
— notified to the competent authority of one of die
Member States in accordance with this
Directive,
— packaged and labelled in accordance with
Articles 15 to 18 and with die criteria in Annex
VI, and in accordance with die results of the
t provided for in Article 6.
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Official Joaratl of the European Communities
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2. The measure* referred toin the second indent of
paragraph 1 shall apply until dw substance at lined
in Annex I or until a decision not to list it hat been
takes in accordance with the procedure laid down
in Article 21.
Dangerous substances not yet appearing in Annex 1
•but included in die list referred to in An'de 13 (1)
or already on die market before 18 September 1981
must, in so far as the manufacturer whether or not
established in the Community may reasonably be
expected to be aware of their dangerous properties,
be packaged and provisionally labelled by the
manufacturer or his representative in accordance
win dw roles laid down in Article* 15 to 18 and
with the criteria in Annex VI.
Article 6
1. Without prejudice to Arrides 1 (4) and 8 (1),
any manufacturer or importer into the Community
of a ft***™* within dw meaning of dus Directive
shall be required to submit to the mm|icimt
authority referred to in Article 7 of the Member
State in which die substance is produced or into
which it is imported into the Community, at die
latest 45 days before the substance b placed on dw
market, a notification including:
— a technical dossier supplying the information
necessary for evaluating dw foreseeable risks,
whether immediate or delayed, which dw
substance may entail for man and die
environment, and containing at least the
* information and results of die studies rcfcired to
in Annex VII, together wid> a detailed and full
description of die studies conducted and of die
methods used or a bibliographical reference to
dwm, . '
— a declaration concerning die unfavourable
effects of die substance in terms of die various
uses envisaged,
— die proposed classification and labelling of die
substance in accordance widt diis Directive,
— proposals for any recommended precautions
relating to die safe use of the substance.
2. However, in die case of a substance which has
already been notified, die competent authority may
agree that the notifier of that substance may, for die
purposes of the technical dossier, refer to the results
of the studies carried out by one or more previous
notifiers, provided die latter have given their agree-
ment in writing.
3. If a substance is already listed in Annex I, dw
notifier need not present the declaration concerning
its unfavourable effects, dw proposed classification
and the proposals for any recommended precautions
relating to safe use. Furthermore, the notifier need
not supply the information required for the
technical dossier in Annex VII, widt dw
of points 1 and 1 of that Annex, if die
was originally notified at lean 10 year* previously.
4. Any notifier of a substance already notified shall
be required to inform die competent authority of:
— changes in dw annual or total quantities placed
on dw market by him in accordance win dw
tonnage range bud down in Aruwx VII, point
12.1,
new knowledge of the effects of the
on man and/or the environment of which he
may reasonably be cupected to have become
— new uses for which dw substance is placed on
dw market (widiin dw meaning of Annex VII,
point 2.1.2) of which he may reasonably be
expected to have become aware,
~~ any cnnngr in dw propemes icsulong oom a
modification of dw substance referred to in
Annex VU, point 1J.
5. The notifier sha£ altt be required to inform dw
competent audtority of dw results of dw studies
carried out in accordance widt Annex VIC.
Arffcfc 7
1. Member States shall appoint the competent
audtority or audtorities responsible for receiving dw
information provided for in Article € and examining
IB conformity win dw requirements of -the
Directive, and in particular:.
— dw notifier's proposed findings on any
foreseeable risks which dw substance may
entail,
— classification and labelling,
— die proposals for any recommended precautions
relating to safe use submitted by die notifier.
Moreover, if it can be shown to be necessary for dw
evaluation of the hazard which may be caused by a
substance, the competent authorities may:
— ask for further information and/or verification
tests concerning dw substances of which they
have been notified; this may also include
requesting the information referred to in Annex
VIII earlier than provided for dwrein,
— carry out such sampling as b necessary for
control purposes,
— take appropriate measures relating to safe use of
a substance pending the introduction of
Community provisions.
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Official Journal of the European Communing
IS. 10. 79
2. The procedure bid down in Article 21 shall be
followed in confinning or amending proposals for:
— classification,
— labelling, and
— the recommended precautionary measures
provided for in Annex VII, points 2.3, 2.4 and
2J.
3. Member Stan and the Commission shall ensure
that any information concerning commercial
exploitation or manufacturing is kept secret *
Artufe *
1. The substances listed below, shall be considered
as having been notified within die meaning of this
Directive when die following conditions are
fulfilled:
— polymerizatts, polycondensates and polyadducts
except those containing in combined form 2%
or more of any monomer unmarketed before
18 September 1981,
— substances for research and analysis purpose*, in
so far as they are placed on die market for the
purpose of determining their properties in
accordance with this Directive;
— substances placed on me market for research or
analysis purposes in quantities of less than one
tonne per year per manufacturer or importer
and intended solely for laboratories,
— substances placed on the market in quantities of
less than one tonne per year per manufacturer
provided that die manufacturer announces their
identity, labelling data and quantity to the
competent authorities of the Member States
where die substances are placed on the market
and complies with any conditions imposed by
those authorities.
However, substances placed on the market at the
research and development stage with a limited
number of registered customers, in quantities which
arc limited to the purpose of the research and de-
velopment but which amount to more than one
tonne per year per manufacturer, shall qualify for
exemption for a period of one year, provided that
the manufacturer announces their identity, labelling
data and quantity to the competent authorities of
each Member State where the manufacture, research
or development takes place and complies with any
conditions imposed by those authorities on such
research and development; after this period, these
substances shall be subject to notification. The
manufacturer shall also give an assurance that the
substance or the preparation in which it is incor-
porated will be handled by customers' staff only,
under controlled conditions, and will not be made
available to the public
2. The substances referred to in paragraph 1 must,
in so far as the manufacturer may reasonably be
expected to be aware of their dangerous properties,
be packaged and provisionally labelled by the
manufacturer or his representative in accordance
with the roles laid down in Articles 15 to 18 and
with die criteria imposed in Annex VI.
If labelling in accordance with die principles set out
in Article 16 is not yet possible, the label should
bear the warning: "Caution — substance not yet
fully tested".
3. Where a substance as referred to in paragraph 1,
labelled in accordance with the principles set out in
Article 16, is very toxic or toxic, die manufacturer
or importer of such a substance must transmit to the
competent authority any appropriate information as
regards Annex VII, points 23,2.4 and 2J.
Article 9
When a Member State has received the notification
dossier or additional information referred to in
Article 6 it shall forthwith send to the Commission
a copy of the dossier or a summary thereof together
with any relevant comments; in the case of the
further information referred to in Article 7 (1) and
the additional information or studies provided for in
Annex VIII, the competent authority shall notify the
Commission of the tests chosen, the reasons for
their choice, and the assessment of their results.
Article 10
1. On receipt of the copy of rhe miriltc.uion
dossier, the summary thereof or the additional
information sent by a Mcfnber State, the
Commission shall forward:
— the notification dossier or the summary thereof
to the other Member States.
— any other relevant information it has colli-aed
pursuant to this Directive to all Member States.
2.. The competent authority of any Member Sute
may consult direct the. competent authority which
received the original notification, or the
Commission, on specific detail •• <»* the data
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Official Journal o( die European Communing
No. L 259/15 —-
oonuined in the dossier required under this
Directive; it may also suggest that further tens or
information be requested. If the competent
authority which received the original notification
fails to comply with "the suggestions of other
authorities regarding further information or
amendments in die Rudy programmes provided for
in Annex VIII, it ahall give is reason* to die other
authorities concerned. Should it not be possible for
die authorities concerned to reach agreement and
should any one authority fed, on the basic of
detailed reasons, that additional information or
amendments in the study programmes are
nevertheless really necessary to protect man and the
environment, it may ask the Commission to take a
decision in accordance widi the. procedure laid
down in Article 21.
Artide 11
1. If he considers that there is a confidentiality
problem, the notifier may indicate the information
provided for in Article € which he considers to be
commerciaDy sensitive and disclosure of which
might harm him industrially or commercially, and
which he therefore wishes to be kept secret from all
persons other man die competent authorities and
the Commission. Full justification must be given in
such cases.
Industrial and commercial secrecy shall not apply
to:
— the trade name of the substance,
— physico-chemical dam concerning the substance
in connection with Annex VII, point 3,
— the possible ways of rendering die substance
harmless,
— the interpretation of the toxicological and
ecotoxicological tests and the name of the body
responsible for die tests,
— the recommended methods and precaution*
referred to in Annex VII, point 2.3 and the
emergency measure* referred to in Annex VII,
points 2.4 and 2.5.
If the notificr himself subsequently discloses
previously confidential information, he shall be
required to inform 'the competent authority
ardingly.
3. The name of a substance appearing in die list
provided for in Artide 13 (2) may be included in
encoded form where the competent authority to
which the notification has been submitted so
. requests because of die confidentiality problems' to
which publication of me name of the substance
would give rise, provided that die substance is not
classified as dangerous.
A substance may be included in the list in encoded
form for no longer than three years*
4. Confidential information brought to die
attention cither of die Commission or of a Member
State shall be kept secret.
in all
such information
— may be brought to the attention only of die
audiorities whose responsibilities are specified in
Artide 7 (1),
— may, however, when administrative or legal
proceedings involving sanctions are undertaken
for die purpose of controlling substances placed
on die market, be divulged to persons directly
involved ID
2. The authority receiving die notification shall
decide, on its own responsibility which information
is covered by industrial and commercial secrecy in
accordance with paragraph 1.
This Artide and Artide 12 shall not oblige a
Member State whose legislation or administrative
practices impose stricter limits for die protection of
industrial and commercial secrecy dian dtose bid
down in these Artides to supply information, where
the State concerned does not take steps to comply
with these stricter limits.
Article 12
The data supplied in accordance with Articles 9 and
10 (1) may be forwarded to the Commission and
die Member States in summary form.
in such cases and in die context of Article 10 (2),
die competent authorities of a Member State and
die Commission shall have access to the notification
dossier and the additional information at all times.
Article 13
I. The Commission shall, on the basis in particular
of information provided by the Member States,
draw up an inventory of substances on the
Community market by 18 September 1981.
In so doing it shall have regard to Artides 1 (4)
and 8.
The inventory **>"" P»v«-' the chemical name under
an internationally recognized chemical
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Official Journal of the European Communitiei
15. 10. 79
nomenclature (preferably IUPAQ, the CAS number
and die common name or ISO abbreviation, if any.
2. The Commission shall" keep a list of all
substances notified tinder din Directive.
3. The information and the form in which it is
recorded in die list and the inventory, together with
die criteria coveting die provision to the
Commission by the Member States of information
relating to the inventory, dull be determined in
accordance wim the procedure laid down in
Article 21.
Artidt 14
Annex I contains the list of substances classified in
accordance with Article 4 and any recommen-
dations relating to safe use.
Article 15
1. Member States shall take all necessary measures
to ensure that dangerous substances cannot be
placed on the market unless their packaging satisfies
the following requirements:
(a) it shall be so designed and constructed that its
contents cannot escape; this requirement shall
not apply where special safety devices are
prescribed;
(b) the materials constituting the packaging and
fastenings must not be susceptible to advene
attack by the contents, or liable to form harmful
or dangerous compounds with the contents;
(c) packaging and fastenings must be strong and
solid throughout to ensure that they will not
loosen and will safely meet the normal stresses
and strains of handling;
(d) containers fined with replaceable fastening
devices shall be so designed thai the packaging
can be repeatedly refastened without the
contents escaping.
2. -The Member States may also prescribe thai:
— packages shall initially be closed with a seal in
such a way that when the package is opened for
the first time the seal is irreparably damaged,
— containers with a capacity not exceeding three
. litres which contain dangerous substances
intended for domestic use shall have
child-resistant fastenings,
— containers with a capacity not exceeding one
litre which contain very toxic, toxic or corrosive
liquids intended for domestic use shall carry a
tactile warning of danger.
4
3. Any technical*" specificarions which may be
necessary with regard to the devices referred to in
paragraph 2 shall be adopted by the procedure in
Article 21 and shall 6e given in Annex IX, in
particular:
— in Annex IX
fastenings,
(A) relating to child-resistant
— in Annex IX (B) relating to tactile warnings of
danger.
Article H
• 1. Member States shall take all necessary measures
to ensure that dangerous substances cannot be
placed on the market unless the labelling on their
packaging satisfies the following requirements.
2. Every package shall show dearly and indelibly
the following:
—, die name of the substance,
— the origin of the substance,
— the danger symbol, when laid down, and
indication of danger involved in the use of the
substance,
— standard phrases indicating the special risks
arising from such dangers,
— standard phrases indicating the safety advice
relating to the use of the substance.
(a) The name of the substance shall be one of the
terms listed in Annex I; if this is not the case the
name must be given in accordance- with
internationally recognized nomenclature. •
(b) The indication of origin shall include the name
and address of the manufacturer, "the distributor
or the importer.
(c) The following symbols and indications of danger
are to be used:
— explosive:
an exploding bomb (E)
— oxidizing:
a flame over a circle (O)
— extremely flammable;
a flame (F)
— highly flammable:
a flame (F)
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Official Journal of the European Communing
Not 259/17
very toxic:
* skull and crew-bones (T)
4. When more than one danger symbol is assigned
to a substance:
—- toxic
a skull and cross-bones (T)
— harmful:
a St Andrew's oats (Xn)
— corrosive:
the symbol showing die damaging effect of
an acid (Q
— irritant: . •
. a St Andrew's cross (Xi)
The symbols must conform to those in Annex 11;
they shall be printed in black on an
orange-yellow background.
(d) The special risks involved in using the
substances shall be indicated by one or more of
die standard phrases which, in accordance with
die references contained in die list in Annex I,
are set out in Annex HI. In die case of a
substance not listen in Annex I, die reference to
die special risks attributed to die dangerous
substances shall comply with appropriate
indications given in Annex III.
The phrases "extremely flammable" or "highly
flammable" need not be indicated where they
repeat die wording of an indication of danger
used in accordance with (c) above.
(e) The safety advice relating to die 'use of die
: substances shall be • indicated by standard
phrases which, in accordance with die references
contained in the list in Annex I, are set out in
Annex IV.
The packaging shall be accompanied by the
safety advice required by die above paragraph
where it is materially impossible for this to be
given on the label or package itself.
In the case of a substance not listed in Annex I,
the safety advice relating to the dangerous
substances shall comply with appropriate
indications given in Annex IV.
(f) Indications such as "non-toxic", "non-harmful"
or any other similar indications must not appear
on the label or packaging of substances subject
to this Directive.
3. In die case of irritant, highly flammable,
flammable and oxidizing substances, an indication
of special risks and safety advice need not be given
where,the package docs not contain more dian
125 ml. This shall also apply in die case of die same
volume of harmful •substances not retailed to the
general public.
die obligation to indicate the symbol T makes
die symbols X and C optional, unless Annex I
includes provision to the contrary,
die obligation to indicate die symbol C makes
die symbol X optional,
die obligation to indicate die symbol E makes
die symbols F and O optional.
Article 17
1. Where die particulars required by Article 16
appear on a label, diat label shall be firmly affixed
to one or more surfaces of die packaging so diat
diese particulars can be read horizontally when die
package is set down normally. The dimensions of
die label shall be as follows:
Ctffaty oftkt ffdksgt
— not exceeding three litres:
(mmOtimttru)
if possible
at least 52 X 74
™* greater than duee litres
but not exceeding 50 litres: at least 74 X 105
— greater dian 50 litres but
not exceeding 500 litres: «least 105 x 148
— greater dian 500 litres:. at least 148 x 210
Each symbol shall cover at least one tenth of the
surface area of the label but not be less than 1 cm'.
The entire surface of the label shall adhere to the
package immediately containing the substance.
These dimensions are intended solely for provision
of the information required by this Directive and if
necessary of any supplementary health or safety
indications.
2. A label is not required where the particulars are
clearly shown on die package itself, as specified in
paragraph 1.
3. The colour and-presentation of die label — or,
in die case of paragraph 2, of the package — shall
be such diat the danger symbol and its background
stand out dearly from it.
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Official journal of the European Communities
15. 10. 79
4. Member States may make the placing on.the
market of dangerous substances in their territories
subject to the use of the official language or
languages in respect of the labelling thereof.
5. For the purpose of this Directive, labelling
requirements shall be deemed to be satisfied:
(a) in the case of an outer package containing one
or more inner packages, if the outer package b
labelled in accordance with international rules
on the transport of dangerous substance! and
the inner package or packages are labelled in
accordance with this Directive; •
(b) in the case of a single package, if such a package
is J*|>*HT^ in ifrvrrliinfT with international tules
on the transport of dangerous substances and
with Aridc 16 (2) (a), (b). (d) and (e).
Where dangerous
do
not leave the
territory of a Member State, labelling may be
permitted which complies with national rules
instead of with international rales on the transport
of dangerous suf
Article 19
1. Member States may:
(a) permit die labelling required by Article 16 to be
'applied in some other appropriate manner on
packages which are tidier too small or odierwise
unsuitable for labelling in accordance with
Artide 17 (1) and (2);
(b) by way of derogation from Articles 16 and 17
permit the packaging of dangerous substances
which are neither explosive, very toxic nor toxic
to be unlabeUed or to be labelled in some other
way if they contain such small quantities that
there is no reason to fear any danger to persons
handling such substances or other persons.
2. If a Member State makes use of the options
provided for in paragraph 1, it shall fonhwith
inform the Commission thereof.
ArtitUW
\. A Committee (hereinafter called "the
Committee") is hereby set up to adapt to technical
progress die Directives concerning the elimination
of technical barriers to trade in dangerous
substances and preparations. It shall consist of
representatives of die Member States, with a
Commission representative as chairman.
2. The Committee shall adopt its own rule* of
procedure.
Article 21
1. Where reference b made to the procedure laid
down in this Article, the matter shall be referred to
the Committee by in chatnnant ciilier on bis own
initiative or at the request of die representative of a
Member State.
2. The Commission representative shall submit a
draft of the measures to be adopted to the
Committee. The Committee shall give its view of the
draft widiin a time limit set by the chairman having
regard to die urgency of die matter. Decisions shaC
be taken by a majority of 41 votes, the votes of the
Member States being weighted as provided in Arride
148 (2) of the Treaty. The chairman shall not vote.
3. (a) The Commission shall adopt the proposed
measures if they are in accordance with the
opinion of the Committee;
(b) If the proposed measures are not in
accordance with the opinion of the
Committee, or if no opinion has been stated,
the Commission shall without delay submit
a proposal to the Council concerning the
measures to be adopted. The Council shall
act by a qualified majority;'
(c) If the Council has nor acted within three
months of the proposal being submitted to
it, the proposed measures shall be adopted
by the Commission.
Article 19
The amendments necessary for adapting the
Annexes, other than Annex VI, Part I and Annexes
VII and VIII, to technical progress, shall be adopted
in accordance with the procedure bid down in
Article 21.
Article 22
The Member States may not, on grounds relating to
notification, classification, packaging or labelling
within the meaning of this Directive, prohibit,
restrict or impede the placing on the market of
substances which comply with the requirements of
this Directive and the Annexes thereto.
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Article 13
1. Where a Member State hat detailed evidence
that a substance, although satisfying the
requirements of this Directive, constitutes a hazard
^pr man or OK enviiuument oy reason of IB
classification packaging or labelling, it may
provisionally prohibit the sale of that substance or
subject it to special conditions in its tcfncocy* It
shall immediately inform the Commission and die
other Member States of such action and give
reasons for in decision.
2. The Commission shall consult die Member
States concerned within six weeks, then give iot view
without delay and take die appropriate measures.
3. If die Commission considers that technical
adaptations to diis Directive are necessary, such
adaptations shall be adopted, either by die
Commission or by the Council, in accordance wirn
the procedure laid down in Article 21; in such case,
die Member State which has adopted safeguard
measures may maintain diem until die adaptations
enter into force.'
Article 2
Andes 9, 10 and 11 of Directive 67/548/EEC hereby
become Articles 24,25 and 26.
Article 3
Annex V to Directive 67/548/EEC is hereby replaced by
Annexes V to DC to this Directive.
Article 4
The following amendments shall be made to die
Directives listed below:
(a) Directive 73/173/EEC:
— replace 'Article 6' by''Article 16' in Article 5 (2)
(c),
— replace 'Article 8.c* by 'Article 21* in Articles 9
(2) and 10;
.
— replace 'Article 8c* by 'Article 21' in Articles 10
(3) and 11;
(c) Directive 78/63 I/EEC:
— replace 'Article 6' by 'Article 16* in Article 6 (2)
to.
— replace 'Article Be* by 'Article 21* in Ankles 10
(3) and 11.
. Article 5
1. No later than 18 September 1981 the Member
States shall implement die laws, regulations and
administrative provisions necessary to comply win
Andes 1 to 4, Article 5 (1) and Andes 6 to 14 of
Directive 67/548/EEC as amended by this Directive and
f^fl'l tiuonn ttkc C>onuiitt$B!OA thereof. «Mo utcr tbftn
18 September 1983 diey shall implement the laws,
FC£l!UOOn$ ftBfl •IQfmiUStfalQVC plWlSlOllS AffiGttaVy tO
comply with Article 5 (2) of Directive 67/548/EEC as
amended by diis Directive and shall inform die
Commission diereof.
2. No later than 18 September 1981 the Member
States shall adopt and publish die* laws, regulations and
administrative provisions necessary to comply with
Andes 15 to 23 of Directive 67/548/EEC as amended
by diis Directive, which shall enter into force on
18 September 1981.
3. During die transitional period, when diis Directive
is not yet in force in certain Member States, die
forwarding of die notification dossier and any other
information collected by the Commission as provided
for in Artide 10 (1) of Directive 67/548/EEC as
amended by diis Directive shall be effective in die case
of only those Member States in which die provisions of
Andes 5 to 8 of Directive 67/548/EEC as amended by
this Directive, relating to notification, are being applied.
Article 6
This Directive is addressed to the Member States.
Done at Brussels, 18 September 1979. .
for the Council
The frttident
M.O'KENXEDY
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No L 259/20
Official Journal of the European Consreimio'ct
15. 10.79
ANNEX V
A. METHODS FOR THE DETERMINATION OF PHYSICO-CHEMICAL PROPERTIES: for At
noord
1L METHODS FOR THE DETERMINATION OF TOX1OTY: for die record
C METHODS FOR THE DETERMINATION OF ECOTOXIOTY: for the record
ANNEX VI
GENERAL CLASSIFICATION AND LABELLING REQUIREMENTS FOR DANGEROUS
SUBSTANCES
P«tl
A. Save where odwrwise provided in the separate Directives on dangerous preparations, die substances
and preparations shall be classified as ven u i \ k, t< »xk- or harmful according lu ihe following criteria:
(a) daaaficanon as very toxic, toxic or harmful shall be effected by dcterminu)| the acute toxicitv
of die oomroerdal substance or preparaboo in animals, expressed in LDu or LCj, value* with
die following panmecen bang caltea as reference values:
•civ
Very toxic
Toxic
Harmful
£25
25to 200
200 to 2000
£50
50to 400
400 to 2 000
£05
05 to 2
2 to 20
(b) if facts show that for the purposes of classification it is inadvisable to use the LDH or LCM
values as a principal basis because rite substances or preparations produce other effects, the
substance* or preparaboo* shall be classified according to the magnitude of these effects. •
PanD .
»• ^~ Corrosion criteria: tor the record
— Irritation criteria: for the record
C If the facts show the existence of effero other dun the acute effects indicated by experiments with
animals, e.g. carcinogenic, mutagenic, allcrpcnic. sub-acute or chronic effects, the substances or
, • preparations shall he dasaftrd aixtmling to the magnitude of these effects.
D. Guide for the labelling of dangerous substances and criteria for the choice of phrases allocated to
dangerous substances indicating the special risks (R phrases) and die safety advice (S phrases): for
the record.
AP1-11
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15.10.79
Official journal of the European Communing
No L 259/21 —
ANNEX VII
INFORMATION REQUIRED FOR THE TECHNICAL DOSSIER fBASE SET) REFERRED TO IN
ARTICLE < (I)
When giving notification the manufacturer or anjr other pi
provide the information act out below.
If it is not technically possible or if it 4oc§ not appear
TetB mat be
international bodies where and) i
placing a subetapce on the market shall
to give HuofBeBotit the rcaaotis ehall be
brihe
The bodies carrying am the tern shall comptr win the principlei of apod i
When compktB. nudia and the rente obtained ate •ubnaad. it »hiU be anted that the CMC were
coodutitj win| the ntbttance to be markoed. Ik u>mpo«tion at At cmple sbaU be iixfcrind
In aou&on» die ocvctinoon of die BMSWO« mod or the reference to M^nnmliirtl oc i
"^pj"^ oMthod* «h«ll abo be mniaonfd in the technical doeeier, neeiher with dw name of tht boo>
or bodies ntpomible for owninf out the studies
.1.
1.1
1.1.1.
1.1.3.
U
U.I.
U.2.
U.3.
1J.4.
U.5.
1.4.
IDENTITY OF THE SUBSTANCE
Nine
Namet in the IUPAC nomenclature
Other turnes (utual name, trade name, abbreviation)
CAS number fif available)
Empirical and i
Degree of purity (%}
Nature of impurities, including uomen and bv*productt *'
Percentage of (significant) main impurities
If the substance contain* a stabilizing agent or an inhibitor or other additives, spedfy:
nature, order of magnitude: ...ppm; ...%
Spectral data (UV, IR, NMR)
Methods of detecnoB and deter nunatsoo
A full description of the methods used or die appropriate bibliographical references
2. INFORMATION ON THE SUBSTANCE
2.1. Proposed «*es
2.1.1. Trees of use
Describe: the function of the substance
the desired effects
AP1-12
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No L 259/22
Official Journal of the European Communii:
15. 10. 79
2.1 JL Reids or application with appradituu breakdown
W
2J.
2J.1.
— lumen and stilled trades ,
_ UK by the pubfe at large ,
(b) open system
— farmcn and dcilkd trades.
— me by the public at Urge ,
prodBCbon and/or
OfcraD production and/or imports in order of
and 5 000
of d* asricspand wes or fields of application
3 per for 1; 10; SO; 100; SOO; 1000
— fast 121
— thercafa
.tonnes/year
-tonnes/year
Production and/or imperil, brolcen dawn in aocordino? witfa 2.1.1 and 2.1J, expressed as t
— fimUi
— tbereafa
bandlinc
2JJ. transport
Z3.4. fire future of combustion pscs or pyiolysis, where propuicJ i
2J J. other dangers, pairicularly ehemieat rcaoion with water
2.4. FIIII igi ni) an •inn i in llir ran of arriilrmat ipilltir
i justify this)
2J.
Emergency meat
(e-g. poisoning)
i in the case of injury to
3. PHYSICO-CHEMICAL PROPERTIES OF THE SUBSTANCE
3.1. Metuog point
3-2. Boiling point
3J, Rcbute density
. «c :
3.4. Vi
3J. Sarfaccwmo
... Pa at.....
... Pa at
- M/m (™
t
-CJ
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15.10. 79
Official Journal of the European Communibes
Not 159/23
3.6. W««r solubility
3.7.
3.8.
3.10.
3.11.
3.12.
. mf/lim (..
...•Q
FaiMtabfliiy
Solvent — oil (to be specified)
.„ mf/1001 solvent
n-ocranol/waKT
Flashpoint
-.,,,„ -„„-...„--- *C D often cup n dosed nip
Flanmability (within dK meaning of the definition given in Aitide 2 (2} (e), (d) and (e))
Explosive properties (within the meaning of the definition given in Anide 2 (2) (•))
3.13. Ondmni propeiuu (within the meaning of ihe definidoo given in Anide 2 (2) (b))
4.1.4.
4.1.5.
TOX1COLOG1CAL STUDIES
Acttte unuaty
Administered orally
i, including in the organs .
4.
4.1.
4.1.1.
4.1.2.
4.1.3. Administered cutaneoudy (percutaneous absorption)
Eft
obi
Adminutend by inhalation
LCto»—.——„...__. (pprn) Durtoon of txpojun .
Effects observed, induing in the organs.
Jwun
Effects observed, including in the organs
Substances other than gates shall be administered via two routes at least, one of which
should be the oral route. The other route will depend on the intended use and on Ae
physical properties of die substance.
• Cases and volatile liquids should be administered hy inhalation (a minimum period of
• administration of four hours).
In all cases, observation of the animals should be carried out for at least '14 days.
Unless there are comra-indications, the rat it the preferred species for oral and inhalapon
experiments.
The experiments in 4.1.1, 4.1.2 and 4.1.3 shall be carried out on both male and female
subjects.
Skin irritation
The substance should be applied to the shaved skin of an animal, preferably an albino
rabbit;
Duration of exposure ._.—_..
t
hours
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No L 259/24
Official Journal of the European Communities
IS. 10. 79
4.1.6. Eye irritation
The rabbit is the preferred animal.
- .. Duration .of exposure ..._.»..«.........~.M». hours
4.1.7. Skin sensituarJoo
To be determined by a recognised method using a guinea-pig.
4J.
4J-2.
Snb-i
4.2.1. Sub-acute toxicity (28 days)
Effects observed on the animal and organs according to the concentrations used, including
dinical and laboratory invcsngatiom .—« _
Dose for which no toxic cflcLt is observed
A period of daily admiiMtrabon (five to seven days per week) for at least four weeks should
be chosen. The route of administration should be the must appropriate having regard to the
intended use, rhe acute toxiciiy and die physical and chemical properties of the substance.
Unless there are contra-indicabons, the rat is the preferred species for oral and inhalation
cxyci uiieiitSi
4J. Other effect.
4J.1. Mutagenicity (including carcinogenic pre-ur
leeningtttt)
4J.2. The substance should be examined during a series of two tests, one of which should be
bacteriological, with and without metabolic activation, and one non-bacteriological.
5. ECOTOXICOLOG1CAL STUDIES
V
5.1. Effects on orgaiutmi
5.1.1. Acute tonarr for fish
LC*. .._.. {pom) Duration of exposure determined in accordance with
Annex V(Q
Specie* selected (one or more)..— ......
5.1.2. Acute toxicity for daphnia
LCw. (ppm) Duration of exposure determined in accordance with Annex
V(Q * •
5.2. PcgiMatKm
— biodc
— abiotic ' •.
The BOD and the BOH/COD ratio nhiiuld be determined as a minimum
6.
6.1.
POSSIBILITY OF RENDERING THK SUBSTANCE HARMLESS
For industry/skilled trades
Tl.l. Possibility of recovery
6.1.2. Possibility of neutralization
6. 1.3. Possibility of destruction-.
^_ controlled discharge ..........
— incineration
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15.10. 79
Official Journal of the European Communito
No L 259/25
^™ WAKf punfittCKNl MMMMI
— othen „.„_-
FonfepibKcul
Pombibty of noovtry ...
Pooibilify.of neuttaloaooo
Pottbiliiy of dutnicDon:
•^ OOACtOliCo QlfCnAf|C *••»•*
— water parifioaon MMMU
API-16
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Ho L 259/26 Official Journal of the European Communion 15.10.79
ANNEX VIII
ADDITIONAL INFORMATION AND TESTS REQUIRED UNDER ARTICLE* (5)
Any pcnon who has notified a substance to a competent authority in accordance with die requirements
of Anide 6 of this Directive shall provide «(he request of die authority further information and carry
oat addhioaal tots M provided for in this Anno.
Tern shall be conducted according to methods rccogm*ed and recommended by die competent
1 bodies wt*tt Mich
The bodia carrying oat die tan shall comply with the principle* of food cunatt laboratory practice.
When complete studies and the result* obtained an submitted, it ihall be Haled d>ai the era w*f*
conducted using the iubetancr marketed. The composidon of die sample shall be indicated.
to addition the detcriptjon of dte methods used or the reference to standardised or imcniatianaUy
tftngnned methods shall also be mentianed in die teduucal dococr, together widi the name of the body
or bodiel mpocwblc for carrying oot die studies*
LEVEL 1
Taking mo account*
— current knowledge of the suheranor,
— known and planned uses,
— die result* of the tests carried out in the context of the hate set,
the competent authority may require the following additional studies where the quantity of a substance
placed on the market by a norjficr readies a level of 10 tonnes per year or a total of SO tonna and if the
conditions specified afar each of the tern are fulfilled in the case of that substance.
T^irftfftlnajral studies
— Fertility study (one species, one generation, male and female, most appropriate route of •
administration)
If there are equivocal findings in the first generation, study of a second generation is required.
It is also possible in this study to obtain evidence on leratogenicity.
If there are indications of teracogcnicity, full evaluation of teratogenic potential may require a study
in a second species.
— Teratology study (one species, most appropriate route of administration)
This study is required if teratogeniciry has not been examined or evaluated in the preceding fertility
study.
— Sub-dimnic and/or chronic toxititjr study, including special studies (ime species, male and female,
most appropriate route of adrnimstraiion)
If the results of the sub-acute study in Annex VII or other relevant information demonstrate the
need for further investigation, this may take the form of a more detailed examination of certain
effects, or more prolonged exposure, e.g. 90 days or longer (even up to two yean).
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IS. 10. 79
Official Journal of the European Communities
No L 259/27
The effects which would indicate the need for such a study caold include for example:
(a) serious or imunlink lesions; •
(b) * very low or absence of a *no effect' level;
(c) a dear. relationship hv eneanscal structure between the substance being studied and other
substance* which have been proved dangerous.
tad » vat to verify
— Additional mutagencsi> studies {including
A. If results of the mutagenesis ten* are negative, a test to verify
carcinogeneM screening are obligatory.
If the remits of the mutagenesis verification tew are abo negative, fmther mutagcneais tettt ate
not necessary at this level; if the results are positive, fonhcr rautagenout tens are to be carried
em («e B).
If the results of the eaiqnoe/nesis screening verification ten are aha negative, further
carcinogenesis screening verification tests are not necessary at this level; if the results an
positive further carcioogene*U taeening verificanon tests are to be carried out (see B).
B. If the result* of the mutagcnerii tern ate positive (a single positive test means positive), at least
. two verificanon tests are necessary at thn level. Both mutageneiii lew an '
screening tests should be considered here. A positive result of a cardnogenesu •
should lead to a earcinogfnnis study at this level
— Aa algal test: one species, growth inhibition ten.
— Prolonged tmticjty study with Daphina nugna (21 days, dun study should abo include
determination of the 'no-effect leveT for reproduction and the 'no-effect level* for lethality).
The conditions under which this seat is carried out shall be determined in accordance wufa the
procedure described in Arode 21 in the light of dw methods laid down in Annex V (Q for acute
voxicity tests with F/aphma.
— Test on a higher plant.
^~ Test on an eatthworin-
— Prolonged toxidiy study with fish (c£. Orytiw, Jordanefla, etc; at least a period of 14 days; thus
study should alto indude determination of the 'threshold level').
The conditions under which this test is carried out shall be determined in accordance with the
procedure described in Article 21 in the light of the methods adopted under Annex V (Q for acute
toxicity tests with fish. ' ~
— Tests for species accumulation; one species, preferably fish (e.g. Poecilla rcriculata).
— Prolonged biodegndatton study, if sufficient (bio)degradaiion has not been proved by the studies
laid down in Annex VII, another test (dynamic) shall be chosen with lower concentrations and with
a different inoculum (e.g. flow-through sysrem).
In any case, the norifier shall inform the competent authority if the quantity of a substance placed on
the market reaches a level of 100 tonnes per year or a total of 500 tonne*.
On receipt of such notification and if the requisite conditions are fulfilled, the competent authority,
within a time limit it will determine, shall require the above tests to be carried out unless in any
particular cane an alternative sdentifk study would be preferable.
LEVEL 2
. If die quantity of a substance placed on the market by a norifier reaches 1 000 twinn per year or a total
of 5 000 tonnes, the notiner shall inform the competent authority. The Utter shall then draw up a
programme of (tin to be carried out by the nod'fier in order to enable the competent authority tu
evaluate the risks of the substance for man and the environment.
AP1-I8
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NoL259/2S
Official Journal of the European Communing
15. 10. 79
tut mt pffoy>mmc nwl cover the foUowing •ipccii unlcM ncre we motn
mppomdb7cndeiice.dui it tbould AW be fallowed: .
, — - flume MMioiy mapi »
— tenitiiy mdy (tf. three-fcncnaon study); only if an effect on ieniliqr ba* bcei' ctnMiihed mt
levdl.
(noo^odtnt
mdy w verify temolagjr «wdy mi level t tad experiment
—
•dditiaaal to dw levd 1 Hudy, if effeca on enbrrat/foeanc*
— •a«e«ndfub-«ajwinxidtyiwdyon«ecoiK)^>eoei:oBlyif««uh»irflevd 1 audio indicate * need
lor Ait. Abo icwto n-ooanol/water partibon coefficient
' The route of the level 1 accumulation Mudy and the phyatocodienucal propernai may lead to a
latfMcalc Bow-throiyjh ML
'm~~ Prolonged toBEicity stuoy win Bin (mduduig npiooutliOii).
' Kudy (acute and tub-acute) with bird* (t^. quailt): if acnimulirioii factor is
greater rhan 100.
— Mfaiftp«i loxkity study with other organism* (if «*"» proves neeesaary).
— Ahtorpo^ —de*orpikinfBidywr«ilieiMbetai^
ANNEX fX
A. PROVISIONS RELATING TO CHILD-RESISTANT FASTENINGS: for the record
B. PROVISIONS RELATING TO TACTILE WARNINGS OF DANGER: for the record
API-19
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APPENDIX 2
SUMMARY Of NOTIFICATION DOSSIER OF A HEW
CHEMICAL SUBSTANCE
In accordance with Directive 79/831/EEC
(Article 9)
O.J. L 259. volume 22. 15 October 1979
1. Details of the Notification
Member State of notification:
Notification number:
Name of the substance (Trade name or other Identification name If the trade
name Is not available):
Date of notification:
This substance has already been notified under No.
(Lead number first, followed by all previous notification numbers):
2- • Hot Ifler/Manufacturer/Importer
NOTIFIED (Name and address):
Domestic manufacturer \
Importer
In case of Import:
Manufacturer (Name and address)
AF2-1
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3. Name to be Included in ELINCS
,°f the *uth°r'ty with regard to the publication of the trade
name/lUPAC name Is as follows:
Non-Dangerous Substances
Dangerous Substances
The IUPAC name
and trade name
The I UP AC name
and trade name
Only the trade name for
a period of . ... years
(maximum 3) \
The trade name only
for an Indefinite
period for reasons of __
commercial secrecy \ _ ! (C)
Only the trade
name until such
time as the substance
Is added to Annex 1
of the Directive \ \ (£)
AP2-2
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4. Classification ami Labelling
Lead competent authorities should state their format proposal for
classification and labelling with Justification (where necessary)
Classification
} '{ very toxic
\~~\ toxic
t*~"i harmful
\j corrosive
{"}' Irritant
I{ explosive
}~~8 extremely flammable
! ! /i/0/»/y flammable
!~! flammable
', ! carcinogenic
\ i terotogenic
} ! mutagenlc
8{ or otherwise dangerous to
man or the environment..
!~j not classified .
Labelling
Syabol(s) and Indication of danger(s) (In accordance with
Annex II of Directive 67/54a/E£C)
Risk phrases (In accordance with Annex III of Directive 67/548/EEC)
Safety phrases (In accordance with Annex IV of Directive 67/548/EK)
AP2-3
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5- Comments/Observations of the Competent Authority concerning the Notification.
. (including fnecompetent authority's acceptance of.orcomments on the
notifier's proposed classification and labelling (page 52). •
6. The following summary of the notification of a new chemical substance is
transmitted to the Commission of the European Communities In accordance with
Article 9 of Directive 79/831/EEC by
(member state)
There are ... annexes attached to this summary notification. They are
numbered In accordance with the corresponding entry number in this summary.
The items which the notifier wishes to have considered as confidential and
have been accepted as confidential by the competent Authority are properly
marked in this summary. .
The competent Authority accepts the reasons given by the notifier for not
supplying certain Information In accordance with the preamble to Annex VII
of Directive 79/831/EEC (comments are given where necessary).
Signature:
Signature:
Name and position of the
responsible Offidal(s):
Name and position of the
responsible Official(s):
AP2-4
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SUUUARY NOTIFICATION DOSSIER
FOR SUBSTANCES NOTIFIED IN CONFORM TY WITH
ARTICLE 6.1 OF DIRECTIVE 79/831/EEC ON THE
CLASSIFICATION. PACKAGING AND LABELLING OF
DANGEROUS SUBSTANCES
This summary notification dossier Is divided Into four sections.
A. Technical dossier supplying the Information necessary for evaluating the
foreseeable risks, whether Immediate or delayed, which the substance may entail
for man and the environment;
B. Declaration concerning the unfavourable effects of the substance In terms of
• the various uses envisaged;
C. Proposed classification and labelling of the substance In accordance with the
directive:
0. Proposals for any recommended precautions relating to the safe use of the
substance.
! When Information Is confidential, tick appropriate block. Where this block Is
\ absent or hatchered. confidentiality cannot be claimed for the corresponding
! data.
AP2-5
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}. i HMO
1.1.1 Names in the I UPAC nomenclature
001
Confident Itl
Enytish
1.1.2 Other names
- Trade name(s) (or other public ldentlfle.r(s)):
- Other names:
1777}
1.1.3 CAS number (if available, otherwise enter "Hot yet allocated")
1.2. Empirical and structural formula
I empirical formula (according to the Hill system, and the CAS system;
if different from Hill)
Hill:
CAS:
structural formula (if this formula cannot be given, please
comment) •
AP2-6
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1.3 Compos ft Ion of the substance
1.3.1 Degree of purity (percentage by weight)
002
Confidential
\ typical concentration
I .-••••
lower limit
upper limit
(Concentration of the Individual components If the substance Is a complex
reaction mixture)
1,3.2/7.3.3 Identity and percentage of Impurities. Including Isomers and by-
products
Confidential
IUPAC name. CAS number If available and percentage by
weight of significant Impurities (lower/upper limit)
'
'
•
f
-
_
1.3.4 Essential additives (stabilizing agents. Inhibitors, other additives):
Confidential
IUPAC name. CAS number If available, and mean
percentage by weight (lower /upper limit) and functions
•
9
ppm or %
•
.
\
AP2-7
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IDENTITY OF- THE SUBSTANCE
-3-
1.3.5 Spectra/ data
003
Confidential
(/V/v/s/b/e spectrum.- (Annex ...)
Spectrum: (Annex ...)
NUR Spectrum: (Annex ...)
Others (eg llass spectrum)
(Annex ...)
AP2-8
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Methods of detection end determination.
A brief description of the methods used to detect' and determine the
substances detailed under 1.1.I, 1.3.1. 1.3,3 and 1.3.4 or the appropriate
bibliographical references. . -
—, : : ; •__ Confidential
\Substance(s) determined I
Uethod
AP2-9
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2.1 PROPOSED USES
2.1.1 Types of use
00
5
Confidential
Use category:
Desired effects:
Detailed Information en
envisaged uses:
Form in which the notlfler Intends to place the substance on the market
~!substance as such
\ \substance In a preparation
Trade name of the preparatipn(s):
Nature of the preparation(s) (granulate, paste )i
Estimated maximum content of the substance
in the preparations):
AP2-10
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-o-
2.1.2 Fields of application with approximate breakdown
(e.g. industry, open system. 1OOX)
•
i
Industry. Closed Systems.
industry. Open Systems.
X !
X
Farmers and Skilled Trades. Closed Systems.
Farmers and Skilled Trades. Open Systems.
X
X
Public at large. Closed Systems,
Public at large. Open Systems.
X
X
AP2-11
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42 INFORMATION ON THS SUBSTANCE
-7-
00?
2.2 ESTIUATeD PRODUCTION IH AMD/OH IUPORTS TO THE UMBER STATE FOR EACH USE
MID FOR EACH FIELD OF APPLICATION (in tonnes per calendar year)
Confidential
2.2.1 PRODUCTION AMD/OR IMPORTS
Production \ ', Import |"~{
2.2.I.J for the balance of the calendar year of notification:
tonnes
2.2.7.2 For the next three years, estimated production or
Imports in tonnes per calendar year
19 .. :
19 .. :
19 .. :
2.2.2 Production and/or Imports broken down (In accordance with 2.1.1 and 2.1,2)
AP2-I2
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2.3 Recommended methods and precautions concern I rig'
008
2.3.1 Handling
2.3.2 Storage
2.3.3. Transport (Including International and national code number for
transport, eg UN. if available)
AP2-I3
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-9-
009
2.3.4 Fire (Including nature of combustion gases or pyrolysls)
Recommended extinguishing agents:
Products arising from burning or pyrolysls:
Protective equipment:
2.3.5 Other dangers, particularly reaction with water
other dangers
chemical reaction In combination with water
* Indicate If this Information derives from tests carried out on the
substance.
AP2-14
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A2 INFORUATION OH THC SUBSTAttCE
-II-
2-6 Composition of the tested substance
Oil
exact companion of the samples which were used to perform the tests In
3.1 to S.3 (the purity mat be within the ranges given in sections 1.3,1 -
1.3.4/ *
Batch HO.
Used for tests:
Composition^ 1^
I
It Is much to be preferred that all tests are conducted on the same batch.
However, where several batches are used the appropriate batch number
should be Indicated for each test; where only one batch Is described above
ft will be assumed unless Indicated to the contrary that all tests were
conducted on this batch. ^ .,
AP2-15
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2.4 emergency Measures In the case of accidental spillage
010
2.5
Emergency Measures In the case of Injury to persons (e.g. poisoning)
(First-aid measures, recommended treatment)
I fyes.-
Ingest Ion:
inhalation:
AP2-16
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"• A3- PHYSICO-CHCUICAL PttOPERTI£S
-12-
3.O nature of the substance
012
I. Colour -
2. Physical state at 20'C and 101.3 kPa
solid
liquid' gaseous
3. State (e.g. powder, viscous, crystalline, compact.particle size)
(Wtere the particle size distribution has been determined,
It should been given here and details of the test should
be given under Item 3.14)
3.1 netting temperature/Freezing temperature
•C
Method:
Body responsible for test i
Comments:
3.2 Bolting temperature
"C at 101.3 KPa.
Method:
Body responsible for test.
Comments:
AP2-I7
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3.3 Relative density
013
20
UethOd:
Body responsible for test;
Comments:
Vapour pressure
Pa at .... 'C
Pa at ...- " *c
Pa at ... *c (20 or 25'C) (estimated from data above)
Hethod:
Body responsible for test:
Comments:
AP2-I8
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3.S Surface tens/on (of aqueous solution)
O.H
mtt/m at 'C
Concentrat/on
nethod
Body responsible for test:
Comments:
mg/l
3.6 Hater solubility
mg/l at *C
at pH ...(If available)
Uethod:
Analytical method:
Body responsible for test:
Comments:
AP2-I9
-------
3 I'HYSIM-CHIMICAL
-15-
3.7 Fat solubility
015
my/100 g solvent at ... 'C
uethod:
Analytical method:
Body responsible for test:
Comments:
3.8 Partition coefficient n-octanol/water
log Pow
at ... *C
Method.:
Analytical method:
body responsible for test:
Comments:
AP2-20
-------
PHTSICO-CHEUiCM
-16-
3.9 Flash point
016
... *C; open cup ! ! ; closed cup J 1
Hethod (Including reference fe the specific, procedure used)
Body responsible for test.
Comments:
AP2-21
-------
-17-
Oi?
3.10 Flammablllty (within the meaning, of the definition given In article 2 (2)
(c). (d) ami
extremely flammable (Test Methods A9 / A2
In Annex V) \ ! yes ! ! no
highly flammable !~! yes j~! no
- pyrophorlc substance (A 13) \ ; yes '~~~l. no
- highly flammable solid substance (A 10) |~! yes j'*~j no
- highly flammable liquid substance (A 9) j~! yes !~! no
- highly flammable gas (A 11) :~! yes }~J no
- In contact with water or humid air. j"~j yes \~~~\ no
substance evolves highly flammable
gases in dangerous quantities (A12)
flammable (A9)
!_! yes \'_J no
Itethod(s):
Body responsible for test:
Comments:
AP2-22
-------
018
3.M
°f the
/„
I . . '
! explosive under Influence of a flame:
i
| • _
! more sensitive to shocks than m-dI nitrobenzene:
more sensitive to friction than m-aInitrobenzene:
\ _ lye* 5 _ ; no
|no
Uethod:
Body responsible for test:
{Comments:
3.12 Auto-flammablltty
Self Ignition temperature on heating
of Annex V)
.. 'C (Test Method A1S / A16
Method (Including reference to the specific procedure used In the
case of method A1S)
Body responsible for test:
Comments:
AP2-23
-------
3.13 Oxidizing properties (within the meaning of the tie f'l nit Ion given
oxidizing \ ! ! ! organic peroxide I }
yes no
•ax. burning rate of test mixture : ma/s
max. burning rate of reference mixture : mm/s
Method
Body responsible for test:
Comments:
3.14 Any additional physico-chemical properties, where available
(minimum Information: Property; Result; Test llethod; Body responsible
for the test: Comments)
AP2-24
-------
A4 • 7OXICOLOGICAL STUDIES
4.1 ACUte toxlclty
*.».» Administered orally
-20-
020
On the basis of the test results given below and In conformity with
the erf ten m given In annex VI of the Directive, the substance should
be:
classified as very toxic I !
•• "if-' ^__
classified as toxic ! t
classified as harmful j~{- ,
not classified !~{
Limit test !~{ yes !~! no
t050; mg/kg
95X confidence limits:
Slope of the dose-mortality curve:
Species/strain:
Vehicle:
Results:
\ number of
animals
dose
number of deaths
AP2-25
-------
TOXICOLOGICAL STUDIES
4.1.1 Administered orally (continued)
-21-
021
Signs of tox I city related to dose level used,time of onset and duration
Effects In organs (related to dose level):
AP2-26
-------
4.1.1 Administered orally (continued)
022
He the*:
Body responsible for test*
Commentsf
AP2-27
-------
4.1.2 Administered by Inhalation
023
On the basis of the test results given below and In conformity with
the criteria given In annex VI of trie Directive, the substance should
be: : _
Classified as very toxic \ _ J
classified as toxic \~\
classified as harmful
not classified _
Limit test !~! ye* i"""} no
LCSO: mg/l
95X confidence limits:
Slope of the concentration-mortal /ty curve:
Species/strain:
Exposure period: hours
Method of exposure:
*SS. _
Physical form of substance ', _ S {__! ] !
Uass median aerodynamic diameter (for liquid and solid aerosols):
Vehicle:
ll(j. aerosol
solid aerosol
Results: '
concentration
number of
animals
number of deaths
AP2-2S
-------
A*
SIUDIES
.2 Mm mistered try Inhalation (continued)
-24-
024
Signs of toxlclty related to concentration, time of onset ana duration
£ffects In organs (related to concentration):
Method}
AP2-29
-------
A4 TOXICOLOGICAL STUDIES
-25-
4.1.2 Administered by Inhalation (continued)
025
Body , ssponslble for teat:
Comments:
AP2-30
-------
Administered cutaneous IV
026
On the basis of the test results given be I a* and in conformity with \
the enter le given in annex VI of the Directive, the substance should t
be: • , __ • •
classified as very toxic \ _ }
classified as toxic {~|
classified as harmful |~{
not classified |~{
Limit test S~{ yes !~! no
95* confidence limits:
Slope of the dose-mortality curve:
Species/strain:
exposure period: hours
Type of dressing:
occiusive j^J semi-occtuslve
Vehicle.-
Results:
dose
\ number of \
animals \
number of deaths
AP2-31
-------
4.1.3 Administered cuteneously (continued)
02?
Signs of toxlclty related to dose level used.
time of onset and duration:
a) local:
b) systemic:
effects In organs (related to dose level):
AP2-32
-------
A4 TOXltOLOGICAi STUDIES
4.1.3 Administered cutaneou*/y (continued)
028
Itethod:
Body responsible for teat:
AP2-33
-------
M TOXICQLOGICAL STUDIES
-29-
4.1.5 SKIn Irritation
029
! on the basis of the test results given below and In conformity with the
] criteria given In Annex VI of the Directive the substance should be:
.
"'
classified as corrosive \ !
classified as Irritant \~\
not classified |~I
Species/strain:
number of animals:
Duration of exposure: hours
Amount of substance:
Type of dressing: oGCfuslvo }~!
Vehicle:
*
seml-occtujfye j~j
Reversibility of any observed effect:
Changes fully reversible within ... days
Changes not fully reversible within an observation
" period of ... days
Overall results:
* !
If 3 animals mean score*, maximum
or less animal n' value
1 \ 2 ', 3
erythema/ eschar \ !
i :
oedema \ \ \
\maxlmum Maximum value at the
\duratlon end of the observation
\of any period
'.effect
I
• _ . * •
i
i
* calculated on the basis of the scores at 24, 48. 72 h
for each animal
.. ,
if > 3 animals mean score '.maximum
\vain.f
I
erythema/eschar ',
*
}
oedema j
! !
\aaxlaua maximum -value at the
'.duration lend of the observation
\of any \perlod
leffect !
i i
i :
i :
t i
j s
1 1
1 1
** calculated on the basis of the scores at 24. 48. 72 h
for all animals.
AP2-34
-------
020
4.1.5 SKIn Irrltmtton (continued)
{ Other observations:
Botfy responsible for test:
Comments:
AP2-3S
-------
A4 TOXICOLOGICAL STUDIES
£ye irritation
-31-
031
On the basis of the test results given below and
In conformity with the
criteria given In Annex VI of the Directive the substance should be:
classified as Irritant J~!
not classified J~l
Species/strain:
number of animals:
Nature and amount of substance:
Reversibility of any observed effects.-
Changes fully reversible within ... days
Changes not fully reversible within an observation
period of ... days
&>fer at 1 results:
If 3 animals
or less
conjunct Iva/ redness
conjunct Iva/cheuosis
cornea
Iris
* ! \maxlmum
mean score maxlmum\duratlon
animal n' value 'of any
1 8 2 3 Select
-
maximum value at
the end of the
observation period
* calculated on the basis of the scores at 24, 48.
if * 3 animals
conjunct Iva/ redness
conjunct iva/chemosis
cornea
iris
** '< maxima*
mean score maximum duration
value of any
effect
72 h for each animal
\Uaximum value at
\ the end of the
[observation period
•
•
1
** calcuJated on the basis of the scores at 24. 48
. 72 h for all animals
AP2-36
-------
4.1.6 Eye Irritation (continued)
Other observations:
Method:
Body responsible for test:
Comments:
AP2-37
-------
A4 TOXICOLOGICM. STUDIES
-33-
033
4.1.7 SKln senslfixation
On the basis of the test results given below and In conformity with the
criteria given In Annex VI of the Directive the substance should be
classified as Irritant O
not classified J~j
Species/strain:
number of animals In test group:
number of animals In 'negative control group:
Maximum concentration not giving rise to Irritating effects In the
preliminary -test :
Concentrations of test material and vehicle used at each stage of
Induction :
b)
Concentrations of test material and vehicle used at each challenge
*>
Signs of Irritation during Induction:
Kesults:
{Challenge concentrations of
test substance (a.b.ctc. If
more than 1 concentration)
Number of animals
showing skin reactions
after
1st challenge
24 hr 48 hr
a)
Test group
b)
2nd challenge
24 hr 48 hr
NegatIve
control group
Number of animals showing evidence of sensltlzatlon at each challenge
concentration:
AP2-38
-------
34-
4.1.7 Skin sensltlzetlon (continued)
034
Ot/)er observations:
itet/xx* ftype or te»f J;
Body responsible for test:
Comments:
AP2-39
-------
A4 TOXICOLOGICAl STUDIES
4.2.1 Subacute toxlcity (Z8~day-test)
-35-
035
of the test results given below ~inS~nr^onfonnty with the
given In Annex VI of the Directive the substance should be
classified as toxic J~!
classlf led as harmful !~!
not classified S~!
Limit test
yes l_l no l_\
Dose or concentration at which no toxic effects were observed-
ug/Hg/day
mg/l/...h/day
Species/strain:
Route of administration:
Hethod of administration or of exposure:
Vehicle:
ttass median aerodynamic diameter (for liquid and solid aerosols):
Duration of exposure per day (inhalation or dermal) : hours
Dosing regime (5 or 7 days/week):
number of •animals, doses (concentrations) and group numbers:
d*
2
'Number of animals
I
'
• •
.
I Dose or concentration
AI*Z-«U
.
i Group number
1
2
3
4
5
6
7
• 9
3
4
5
. 6
*
-------
4.Z.I Subacute toxlclty (28 ft ays) (continue*)
036
Result* (In relation to dote levels/concentrations):
1) Clinical observations:
i) Laboratory findings:
3) Effects In organs:
AP2-41
-------
M TOXICOLOGICAL STUDIES
-37-
4.2.1 Subacute tax (city (28-dty-teat) (continued)
037
Dose or concentration at which no effect was observed
(If available) :
mg/Kg/day
ug/1/...Mday
Uethod:
Body responsible for teat:
Comments:
AP2-42
-------
TOXICOLOGICM. STUDIES
-38-
4.3 Uutmgenlclty
4.3.1 Bmctmrlologrcal'test
038
t Type of bacteria/strain:
\
\
\ Concentration range In the main test -
\ w/th metiooUc mctlvmtlon:
\
} without metabolic activation:
\
r
! Concentration of teat auoatanee observed to be toxic to bacteria
"a) In a preliminary teat: with metabolic activation!
without metabolic activation.-
b) In the main teat: with metabolic activation:
without metabolic motivation.-
Solvent:
Concentration of the teat tubstance resulting In precipitation:
Metabolic activation system.-
Observations:
Result: +
With metabolic activation J~j
Without metabolic activation !!
AP2-43
-------
•4.3.1 Bacteriological test (continued)
039
tietnext (type of test):
Booy responsible for tne test.
Commentsi
4.3.2 Non-bacteriological test In vitro
i Type of ceil used:
Concent rat I on range in the main test
with metabolic activation:
without metabolic activation:
Concentrations producing toxlclty:
a) In a preliminary test: with metabolic activation:
t>) In the main test
without metabolic activation:
: with metabolic activation.-
without metabolic activation-.
Vehicle:
exposure period: with metabolic activation:
without metabolic activation-.
Fixation time:
Metabolic activation system-.
AP2-44
-------
4.3.2 Hon-oecterlologlcal test In vitro (continued)
040
Observations:
Result: *
With metabolic activation J~J
Without metabolic activation |~l
O
Method (type of test)
Body responsible for the test;
Comments:
4.3.3 Hon-bacterlologlcal test In vivo
Species/strain:
Oose levels:
Doses producing toxlelty:
Number of animals at each dose level for each sacrifice time:
Route of administration:
Vehicle:
Sacrifice times (In hours);
AP2-45
-------
A4 TOXICOLOGICM. STUDIES
4.3.3 Non-bacterlological test In vivo (continued)
-41-
041
! Observations:
I . '
Result:
\ I
Method (type of test)
Body responsible for the test:
4.4 Additional toxicologies! tests
Minimum Information: end point Investigated; Description of the
essential features of the test methods; Results;
Test procedure used; Body responsible for the
test; Comments.
-------
5.) effects on organisms
S.I.I Acute toxic Ity for fish
042
Values In eg /-'
; 24fr I 48h \ 72h J
! "I'!T
observed effect concentration at 96ft mg/l
Species:
static test \ ! semi-static test } J flow-through teat I i
% loss In concentration of the test substance over test period:
Identity ana concentration of any auxiliary solvent or details of any
other aethod used for dispersal:
itater hardness:
uethoa (type of test}:
eoay responsible for the teat i
Coaaents:
AP2-47
-------
*J eiUfUXfCULOG'CVU. S/UD/fS
-43-
5.J.2 jtcute toxlclty for daphnla
043
Cone. In mg i~>
4th
Mo observetf effect concentration after 48rt mg/l
Species: Daphnl* magna \ ! Daphnla pulex \ !
X loss In concentration over test period:
Identity and concentration of any auxiliary solvent or details
of any-other method used for dispersal:
Water hardness:
net hod (.type of test):
Body responsible for the test-.
Comments:
AP2-48
-------
044
5.2 Degradation
5.2.0 Inhibition of mlcroblal activity (if available)
T
Type of test: aerobic }~!
anaerobic l^l
Duration of test -• hours
ICgQ at hours - mg/l
Ho observed effect concentration at hours
nethod (type of test):
Body responsible for "the test?
CommentsT
AP2-49
-------
5.2.1 Blodegradablllty
S.Z.I.1 Ready blodegradablllty
045
..... X degradation
Classification: readily biodegradable
Reference substance:
yes
Experimental Values
J
tost substance \reference substance
day
day
Degradation curve:
Blodeyradablllty (X)
100 -I
90 -
90 -
70 -
60 -
SO -
40 -
30 -
20 <-
10 -
0 -I
.5
10
IS
20
tim
AP2-50
25
(days)
30
-------
5.2.1.1 *e*tfy Biodegrettabllity (continued)
046
I uetnoo (type or test):
\
t
\ Boay responsible tor roe rest:
I commenTTT
AP2-S1
-------
S.2.1.2 BOD/COD
047
', Botly reports ibie for the test:
I BOD (S ttaya)
COD
BOD/COD :
0/0
g/g
(type of test):
comments:
5.2.2 Hydrolysis as a function of pH
PH
•
4,0
7.0
9.0
*
T in mC
*~va/ue In s*'
•
rl/2~va/«* In h.
AP2-52
-------
n4S 'ECOTOXICOLOGICAL STUDIES
-48-.
5.2.2 Hydrolysis as function of pH (continued)
048
Method:
Body responsible for the test:
Comments!
5.3 Any additional Ccotoxlcologlcal Testa, where available
ifor example: bloconcentratlon factor
mdsorptlon/desorptlon
photodegradatIon)
Minimus Information: end point Investigated; Description of the
essential features of the test method: Results;
Test procedure used; Body responsible for the
test: Comments.
AP2-53
-------
A6 POSSIBILITY OF AfM0£ff/#G THE SUBSTANCE HMULESS
6.1 for Industry/skilled trades
049
6.1.1 Possibility of recovery/recycling of the used substance
6.1.2 Possibility of neutralization (of any potentially hazardous effects)
6.1.3 Possibility of destruction (where special techniques are necessary
please Indicate)
Controlled discharge."
Incineration:
Hater purification system:
"Others :
AP2-S4
-------
,~ iv** toil. i n ur
IHt SUBSIANCt HMMLISS
6.2 For the public at large
6.2.1 Possibility of recovery/recycling of the us«rf substance
-50-
050
6.2.2 Possibility of neutrtllzttlon (of any potentially hazardous effects)
6.2.3 Possibility of destruction
Controlled discharge:
Incineration:
Water purification systt
Others:
AP2-55
-------
-51-
051
8 DECLARATION CONCERN!HG THE UNFAVOURABLE EFFECTS OH HAH AMD THE EHVIftOHUEHT
FOR THE VARIOUS USES SUV ISAGED
AP2-S6
-------
*052
PROPOSED CLASSIFICATION AMD LAKUIMG Of THE* SUBSTANCE IM ACCORDANCE HITH
DIRECTIVE 70/831/EEC FOLLOWING THE CRITERIA Of ANNEX VI PART lit
Classification
l~~l very toxic
O toxic
O htrmful
|~J corrosive
l~l Irritant
J~J oxidising
\~~\ extr*m/y flammable
•*
Labelling
i : highly flammable
O flammable
!~} carcinogenic
}~! teratogenlc
S~S mutagenlc
}~~i or otherwise dangerous to
man or the environment
IJ not classified
Symbol(s) and Indication of danger(s) (in accordance with
Annex II of Directive 67/S49/f£C)
Risk phrases (In accordance with Annex III of Directive 67/S48/EEC)
Safety phrases (In accordance with Annex IV of Directive 67/548/fEC)
AP2-57
-------
r
-S3-
053
0 PROPOSALS FOR AMY fffCOMffNOfD PRECAUTIONS RELATING TO THE SAFE USf Of TMF
SUBSTANCE
AP2-58
-------
17.91
APPENDIX 3
No L i*W45
ANNEX V
(IWi AM«M|*MI At *to M< ftot D 4 AMNH 1»I»
79/U1/E8Q
GtMnl
MIT I
fa Act
to cMM w w
^_
If
LD. « 1C.
1C.)
teai
T«oc
W- 2
2 -30
MVfMi
ictol to
ikfc
CVHMrHt HMr HMI CIMMwV Oi
1. GENERAL IHIVODUCnON
i CLASSIFICATION ON THE BASIS OF PHYSICO-CHEMICAL P
2.1.
Ji
2J.I.
ru.
tu.
2A4.
2iS.
CmniifM
Of VM|f((« ChfllCC flf fllk pfcfMtt
indiatiMi *f *^WK, choice e< mk
J. CLASStPICATION ON THE BASIS OF TOXICOLOGICAL PftOPEITIES
3.1.
XI
XII.
XU. Tone
XU. Htonftd
rmmmiml
XIA
XI*.
X17. . Other
AP3-1
-------
No L
Offidri Jowml «f *•
9.7.91
4.
. 4.1.
4i
ON nn MSB or snanc men ON HUMAN IOM.TM
Crium far riMiirnrina. litirade «|
-------
t. 7. 9t
Offieal Journal of fee
No L ISV47
GENERAL INTRODUCTION
14.
Ik*
U.
n» Annex MI out
M/37VEEC tad otter
riw |racnl principlM feiwniiag die dwificMiM Mid UtUinc «f
in Article 3 poMXwam 47/S4I/EEC mim Article 3 (J) cf Dine.
It it
TlM
of dw DiMdi«* Md of DMC** M/XWEBC OM
ThetabddnmdM
The bbel m*r tbo tern to drtw mention to i
Md we nwhbtc in other
! product MoiMMiM Mulct*
IA IV
yhG
•>j> dflMid. 1W
of «fl
M» KMy IB bt fand to dw
iMMdl Ml I^AIlfllMMl bv Mrtho^ M^ hA^M^i ^^ d^M H^^^
infaiMKio* it eo«»fattd by tht i
| the one Mid fa Ih*
i «f «M IMW tMUvhtd in the CMMMfer *l» • MpaMMt far plKM| riw
the tudc «»mc ol the prepxttion. dit iadk«>i«» «l die cfacmial mnn ndfori
toutMV for «Mipl« the mute of pVeviaw teM, MMomttioa Ptquiied by intiintiiiinil
MtOtBlMlOH QCflVCO lfMH pffWDDCU
to Dura* «7/54*/BBC Pot
tMafitdinAanaV
' MV b* Med for
(w* Cfcapw f);
AP3-3
-------
No L 190/49
Offickl JourtMl of the Bnrapew Communitk.
9,7.91
I — if it concern deie on heekh effects, by dw eppUation of the i
. V IB dw Dhacd* eod/or by dw application of dw OMmmieoil method niened at to
••Ankle J (Q M at & of Dhoahe tt/STf/BEC,
pMomfaa. bydw eoplkirioii of dw OMmodonel owdwd lefaned a»in Ankle 10) a o»
la) of Dwoafre tt/37f/EEC
MM* CMomnf J»r ptlftrmtiut if mmimml mo
tt cmbuah cxpei
the protection of
Tht yeifarownct of
Dimrive M/«0»/BBC
Appticmbo* of *• g«M*
AMI b Mbjta »
M«d for
•uetafdw
c^prcoMdoridwhHwLPordApMpoetHleoeoenMytftoaoeidKdwcriO^ffwofardw
of enoboHA f**0 flak phiMe* hi I-*-1 IB Hi* 3J.I w T?* end *** 'i"" 4end 5 foe
ooJy.f^onmpte.rtewffirirmniiart.faj.lomoMimpfr
ceo be
•WM pMpmttOUt vVt Ottly Ml tO IMF
IBC CBlWIM
ferM of Minnh tbdl kt Hbicci to dw I
to Ornate 7S/324/BBC
i eetov fail feed life} of i
IJJ. Aoolkuioo of Ikt g«id« critcrii for MOMMCM
Tbc jiitoet cimk m o* joltMi Anna i
fcAmctV.lo
dw lot OMlhedi cmploynl with
ABOCT V «nd d* wltt «p«eifii J «thit Anno far omrmmim oV
Criltri*.
if MOJMMW
tmmmtfent
Apjonence
•*«*
mi
tantac en impurity or an eddidw which fa cteified ei
heeU be deetfed « a cerdaofen end hMed «ith 145 if dw
^» ODfeCT QIC ODoftCCAUVDQB Of UiC URplMliy Of OW oMoltlW SpCCoMffl M nfWR I» Of
of 0,1 % «hm dw hopunty or dw eoditnc eppeen m Amws 11
ttout (Hooewr w dw cete of eAotoi this geaeal nde don not apply oatil •
M been find to Anna L Subeaoca wtiidt hmc odwuee bopofibei
be rhJMifiid and UbeUed eccoidim ea the principles in Ankle S (2ft or
of 0,1 % wheie dw hopority or dw additive does not eooeer M Aooez L .
•« an impurity or «dditiw *nicb i* daoificd M •
m pan of • pupiHtiOB. the picpaiaiioo «haU be &*&* [* • catcfaapii i andebelkd %id»
K.45 ooJy vtofM we coiiCaTinntioii of Ibf cwcniOfctMC tutpumy or
boo,
If dw infomMMa rcgerdiot dw caitmofeak impurity or edditne on dw hbel of dw eobetenee hi
himffawot la eneble dw nwmiftcMrer of • ptepention M euty out dw daeufieMion oad tabd-
Knf comedy, dwipenon OMebbcbed withio dw Community lespeittible for ph«ii)( dw euboMcc
•MdacAiief. dw importer or dw dteibwer. iheU eupply, opoo
l mi If a^Oeble. oppomieet loforowdeo eooot d
of dw
AP3-4
-------
*.?. »l • OificM Journal of the Buiopcm Communkiei Not IW49
•. *
I7J. Application of the guide critcri* for preparation* .
The Midtooe criwit M ott io Ail Anne* ttt ittfMty oppttctMt when the del* MOMUDOO lint
of the ahrtt of Clipirr 4 hy which oofr the eoimmiaiiil •ethod ii ipaliEoMt. to.
f be i
coied •• Aooes * MO ow won cpecwieo M dMt Aoocv lor oetoroBiotojf OK
If ihe iMtUi BUMBI nv 8Mmcd vy •ppiyii^ die conviniiofitl nMOiod ivictfto 10 MI Afiicit ^ (Q
of Difcctivc M/379/EEC. rtw mdmdud conccmrMion limits » bt MMd «e eieho^enaMtoAoncsiondMboMofdM
criKrit of Aooei I « Dinette M/37VEEC. • extended by Dinette N/4C2/HBC
mmd ft tfuaitmrnli
The loVelline, of mA pnpmitoiii mm be to coofatmity with the Bionbiooi of Article 7 <
dtof to the tooaMoni tonown to Ankk 3 of Dinette U/379/BEC However, to cntoto
the tohroiatioo an the hbd of the preparation m toniffioeiit to ooihle othi
ift we it •• • coipriioitflC of OMit own pivpuMioii^) 10 CMiy out Oht oMHfittiiOM MM WMl-
: far pWMit At ttijintl piiiniMim «« Iht fl-wkct, vhcikcr ii bt Ac i
hbtflttii of the new preparation. Tha da
otoctof tfie new prepintion on the nurhet to oooiply vioi
•I/37J/EEC <
X CLASSIFICATION ON THE BASIS OF PHYSICO-CHEMICAL PROPERTIES
The MM nMthodj nbxtof w CRpkMte, oodiiiiic ood flonmable propertiei toctoded to Annex V
by the M oMhoai (nco M Aooa V. then Midi
io the Bmrd dwjr orettnt, M ioy. to time hjodliog the
to other
CeiKtio for doiiificotioo, choice of lymhob. todkojioB of do^or mmA choice of ride
phnooi
IB the CMC of prepewtiooi, the oriteri* referred io in Article 3 (2) of Dircctne MA37J/EEC need
io be token into conjidtnuon.
lil. Eiploiivc
Sutotoncei Md pnpiritioni AM be dMiificd « eipteww eod owgned the lyinbol *ff eod the
to 10 tor to the mb«Mea oad prepimioM tie eaploite m ptoced on the oiorhtt One tak |ihion
• ofc%*ary. it • to be ipecified oo the boo* of (he followiof:
AW-5
-------
No L 1W/50
Official Journal of the European Communitic
9. 7. 91'
tL2 took of explosion by shock, friction, fire or other
111
of ignition" -
foxide* but excepting the* set
1) Extreme risk of explosion by shock, fricbon. fire or other sources of ifnician
— Substances and preparations which aic particularly stnikiu tuck at picric acid saka.
PETN and certain undiluted organic peroxides such a* dibentoyt puuiidt.
Oxidiiing
Substances and preparations dial! be classified at enduing and assigned the symbol t>* and the
indication of danger 'oxidising' in accordance with the remits of the tots given in Annex V. One
risk phrase it obligatory, it it 10 be specified on the basis of the ten mute but subject t* the"
lollowing:
Kll Highly
-Organic
other
Rl Contact with
— OdM
fire
which have flammable properties even when not in contact with
fire
Bttuic nit Of CwMMMv QM (Hit v
with
tf Explosive wben mimed with combustible material
— Other substance* and preparations which become explosive when mixed with
2111. Ktmtrkt tmamimf /tntiaVr
Organic ptroxidct ate datsified at dangerous on the basis of their structure (e«. R-O-O-H;
R..OO-R4. In general terms, organic peroxides shall be classified aa oxidising, and labelled at
under 212, unktt:
— tests carried out in accordance with the methods given in Annex V show the organic peroxide.
in the fern in which it is placed on the market, to have explosive properties, aa under 211. or
— the organic peroxide it so diluted or phlegmalised to the point where it it no longer explosive.
Extremely flammable
I pveptraiiont tnall be classified as exttcmcly flemmsole snd assigned QIC symbol
F+ and the indication of danger extremely flammable m accordance with the results Of the
tests given in Annex V. The risk phrase shall be assigned in accordance with the following
R12 Extremely flammable
— Lio>d Mhttmc«t tad preparauoni which have • Oath point lower than 0*C and a
boiling point (or in case of a boiling range the initial boiling point) lower than or coual
»3S'C
214. Highly flammable
fi- ,, _ -i |
and assigned the symbol
Subttsneet and preparations shall be classified at highly
and the indication of danger 'highly flammable' in accordance with the results of the teats given
in Annex V. Risk phrases shall be assigned in accordance with the following criteria:
R I? Spontaneously flammable in sir
^~ jubtrtncas and preparations which may become not and finally catch file i
with air « ambient temperature without any input of energy.
Rll Highly flammable
with a
source of ignition and which continue to bum or to be consumed after lemoval of the
source of ignition.
— Liquid substances and preparations having a Oath point below 21 *C but which arc not
and pfepantiont which are flammable in air at normal
AP3-6
R 42 Extremely
-------
t-7r»i
Official Journal of the
No L IM/51
R 13 ExtfHMiy RMIMMNC W[|llrilM Jffl
• vtMH put oil CM ntnuEt In liquefied fam*
R15 Oimn with wHf
•§ in
ia air at
klflklM m -*-•-
•Wy aMBMBjie MM*
which, in contact with wner or damp air.
w» of OM MM per
115.
per hour.
SuUuncet Mid preparation* thatt be daiiifad it flammable m accordance with the iquta ol the
«M> gnw « Annti V. The risk pbnic thill be m»f** bi •cicwdiiicr nth the critem
RIO
Md km dm •» «H to 5S*C
H IMS P0MI
4| • tah point e^Mt 10 «r fiattr ihM 21 *C
21 *C Md Im *M or «qari to 55 *C «w* MI be
•at m tar My «»PP
K few risk* 10 dwae handling ihete preparations or to other
Other physico-chemical properties
point •oval lo or
V
is no
phrMii thtf be tttigncid ID
pitptr
ficd by wrwe of lil to UJ tbwe or by Chtpieit 3.4 «nd 5 beta*. M MOMMC* •fehihe Me.
untif coMpiMtion of Aiuwx Q •
arw.
K 4 FOCTHJ ^^y WMIVC ttpMMVC. flMttttlC
for •uhmnco aad tut pemiom which m«y fafm itiuitht qyloem flxttak ckrimi^n, €4.
'picnc icidt Hypfcuic tcid.
K5 Heatin| owy ctuw n caplorion
vkh tMie ihM IW% Mcraftn.
PC* QWIVMlly VMttMC lUMCAHCCI MM pfCpCfMHMIS HOI CUMRMQ M CTpJOtHC, C^. pCfdl-
kMkteid > 30%.
Explosive with or vrilhoM contact with «r
For wbttMCM Md preptntiom which «t UMttbte M tnibieiu
R7 Miy
For
•no
R14 Reacts vMemly with
unium attraebloride.
violently
,e«.M«yl chloride, alkali
Kl( Explore when cuied with ondiBn|
Per aubiances Md ptrpanaont which letct expkMr«eh; with an
afeni. c*. red
Rll In Me. may form fitmnubl«/«ploir*c vapour-air
«w prepanooM not MI tncaMeivct daiaiHaa ea
•emt which arc fltmmabte in ait.
•ammabte, which
Kl»M*T form
Par
' diediyl cthei, l,44ianii
AP3-7
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No L 110/52
Official Journal of the European Communio*.
I. 7. 91
tat pripirationi not in themaelvct daaHfiid at i
d«t w the toot «f
. A 44 IB* of
Ptopeitie* ia poetic* if
which would
•nder aufficient confinement. For egample, centra
captaively if heated in a tMd dram do not aho* thai effect if heated in ant-enon*.
3.
XI.
3.U.
For other additional ri»k phmcs tec 3i7.
CLASSIFICATION ON THE BASIS OF TOXtCOlOGICAL KOFOCTIES
•ad tone,, turn effect* of the**
•BCCOfcapOMfei
Uadeou
r to nubble K>
ia pMCtioc AM the t
E fffeft of IttbttMUCt Mil
I itn 01 by *c lOBlkMioa of Ik*
(J) of DiitciiM I«3»>/B8C*M Mdt inlmianiaoJp*.
t& fllCV IDKlCHy Ml MHHk IMMVVHt *BVB Oil HHH 900910 PC
be Med to
oUbt
»MAnid*3
XIO.
[ with me UtowMg criteria which lake IMO
r • ib)0e mioiiiia •«« 1
i for acute motif* (lethal and mveniblc effecti
cated in Fart t A of Anne* VI and under 3J.J 10 XU are to be
r XU to SX4 m tt be uted;
(e) for cotmnc and MMM «fMen. the oiMria under 3.J-J and 3X4 « » be «Md;
(d) far •cMiiiiinf «0ecn. the criteria undet XU » XZ4 « » be vied;
efkeo). law criteria in
(t) far tpecific efiem on bcahb fcatciaoteaic, mutfuuc and
Chapter 4 an to be 'need.
XIJ.
for heahh it carried out:
(t) en the baab of the coiMcMioml method nfemd 10 in Aitide 3 (J) of Diitonc M/37f/EEC
— either taken from Anna I w Dmcti«e o7/MI/EEC
— or bom Annex 1 to Directive tt/379/EEC where the
appear in Aaoei 1 w Diiecme o7/S4l/EEC or appear m k without
\ or when npenmcuial data tee avaHabk* accoedtno, to the cnteno dean
ding the cuonootnk. miMfenk and teratot«aic praptnici lefened to under XUfe) which
nun be evthMcd by the conventional method refencd to in Article 3 (J Q to (q) of Ducctne
U/379/EEC
Whichever method it vied for the evaluation of the danfer of a eecpaiation. all the
effects on heahh M defined in Anne* I to Directive M/37f/EEC moot be taken into
XM. Vhenthe
dity far man in thai the tent ttfkcc in an appmnioti way, the
AP3-S
-------
t.7.tl
OfScbl Joutml of the European Cotntnunhip
No L 1M/53
Crittfto tat cJMtlfieMlon, choke of lymboU, iadicMioe of
ptutttt
M.
XU. Very toiic
r. choice of (We
i wry tone end eeafMd UK fywboi TV and the
iadicetion of deiujer Swy leak* fa accofdanc* vkfa the criteria fnca to PHI I of Ann** VI. M
tpedfied brio*.
Risk phiates dull be He^acd in iccoidwMe with the feUoiriaf. criteria:
V«y nicif
~ Acute taocky
ID. on!, at: < 25mf/kj
Very noc fa contact wkh tUn
— Acute toncof MMki
LO. denial, at ot nbbit: < JB«|ftf
KM V«ty IOBC by
tC.i
nt: < O^l^/litK per 4 houn
ft 39 0 Dmftr of veiy uncut mcvenMe
— Soonf. evidence Hut incvcmble dam*fe otbef than the cffcca icfemd w in ChapMr 4
« Kkrty ID be ceiaid by a tinfle npoeure by an appMBtim lOMe. genenUy in dw
dote n*|e (tec tte 3.U io4 34 J).
301. Toiic
eMten of daHjer Wk' in •tcofdtiiet «idi the crimki frwa in hit I of Anno VI, m
below. IUA Bluwa ihau be ejMgMd in
R25TOMC if iwdlovrd
— Acute MKici
LD.onO.nt: 15 < LO. <
ft 24 Todc> contact wttufcui
•^ Acute KMucily Msultt
LOM dennil, nt or tmbbii: 50 < ID. < 400 nc/k|
ftZ3Tonc by Mktlatioii
— AMH taaicky mute
1C. inhalMioB. ttt: «4 < LC» < ZHf/Um per 4 ham
ft 39 n Dufet of ««y teriuut umeaMe cfhco
— Sum*, evidence (hat imvenibk duufe other OHM dw effect* tdened » fa ClMoirr 4
it likely w be cawed by • tingle expeeure by an appcopnate IOUK. |tn«tmuy in «MJ
••oowAMnttoiwo oovc mifv |v wvo 3»U MM ^u^
R4I D DMpr of Mrioui daaaft to health by
— SerioM damafc (dear n
k Ukdy k> be cowed by n|ii«iiJ
Submnces «* etanBed « Icttt •§ lane when tbcte cffeca Me observed « It** of «ot order of
lawf 0*. (en-fold) ihtn iboie MI out tor R 41 w 3O3.
ij*ot,"j»M07. iMoW KM/27/11, tSrumm.
t J»/U. RW/1VJ4. B3f/13/25. Rlt/KOS, 13*010401
*MU be MM* : 1»«. 1JW27.
wd: IJMS,
1410)0401.
AP3-9
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No L IN/54
Official Journal of the European Communities
I. 7. 91
3i3. Harmful
Substance* and preparations shall be dawned as harmful and assigned the symbol TCn* and-**
indication of winger ^harmful' in accordance with the criteria given in Part I of Annex VI. as
•pacified bete*. Risk phrases dull be assigned in accordance with the following criteria:
R 22 Harmful if swaUowed
— Acute micky results
LO.onl.nt: 200 < LO. < 2000mg/kg
R 21 Harmful in contact with skin
— Acute touchy tenths
ID. dermal, nt or rabbit: 400 < LO. < lOOOmg/kg
K20 rbnafid by
— Acute
LC. inhalation. M: 2 < LC. < 20 mg/lim per 4 hour*
R40 0 Poarible risk of srreversiMc cffectt
— Strong evidence that irreversible damagi
b likely to be
abovementioncd
i tne effects Nvemd to in
by a tiafle cspame by M tpproptutt IOMC. fenenlly M «hc
no|c (tec ado J.U and 3.1 J).
K 42 Mfty OMMt wttBtiinttKNi by ifuuudon
— If ptactk^ evidence it awaibbk which ahowt the
apabk of indueinC a temkiaatiftii teaction in hwnam by inhalation, at
would be opccMd (torn the mpowe of a flenenl
1141
lobe
to ncakh by ntnlognid
«ipitfic«ice) k likely to be
or morphological change which hm
by fepeeied or paosonged cxposuse by
Substance* tM daanfied at lent at hi
of:
nhil when nV
efkctt are obwned at levels of dx order
— wal. M' < JOmgfti (bodywetglK) per day.
— dermal, nt or nbbit < I00nn/k| (bed)«eifht) per day.
— inhalaiion, tat < OJIS am/litre per t hourt per day.
Time- guide vahies can apply directly when arvere lesions ha
in a
days) Wncity test- When interpreting the results of a sub-acme (2S days) tonciiy teat i
figure* should be tnocated aopraimitery three told. If a chrank (two yean) losicity tM is avai-
lable it should be evaluated on a caM-by-casc basil. U remits of studies of more dnn
are available, then nose from the study of the longest duration should normally be wed.
3.2.4. Comments regarding the vie of R4t
Use of this risk phrase refcts to the specific range of biological effects within the
below. It should be noted that the terms m not identical » the defirutiom of harmful and
in Article 2 (2) (g) and (h) of Danacm* C7/54S/EEC For aaaliesticn of dm risk
damage to health is to be considered w include death, dear fun.
are irreversible. It it abo importanl to consider not only specific severe changes m a single
or biological system but abo generalited changes of a fess severe nature involving several erg.
or severe changes fat general health statin.
BCMIflf WoCtOCi vSWVC IS CVIOCftOC
the following guidelines:
types of <
old be maife to
n
!• At^kff mm tmrntfef^mW s
R40/22, t4tOiai. K4Mt/21.
*4t/2X R 41/20/11. R4l/aBm. It 41/11
R4C/IO/2I/12.
AP3-IO
i ah* bt «Hrf: R 4*/M, R 4f/Sl.
d be mtt t R 4VM. R 4(711.
-------
i. 7. »l Official Journal of the European Cornmurutiei No L 110/55
I. Evidence Jndiciling thM K4I should be applied: '
(b) B Major functional changes in the central ot peripheral nervous systems, including sight.
bearing and Ac teote of swell, aasessed by chnical observations or oeher atvioaesate
pi) Major fuDcaoiuJ changes in ether organ eysamu (far exampk the lung).
(c) Any consistent changes » dinical bioctuiniiuy.
indicate feverc organ dysfunction, tiaematowgkal disturbances are considered IB be patoJcu-
tuty important if die evidence suggests AM they are due to dicuand bone marrow produc-
tion of blood edb.
(d) Severe
ides
tun
Widcspitsd or MWC fMOQ^ lib^M w gntty^^
nentivc opacky (ftf.
msis in die kidney.
fiiO
the myoaidHiHi or dying beck of • nerve) or in Mem celt pnp'ulMioni (tf.
hypoptnm of the bone Burrow).
The tbovr evidence
2. Evidence indicMint HIM R 41 (hould not be applied.
The use of this risk phrase it restricted to •aeriout damage to health by prolonged expotufc'. A
{Uttify the yw of R 4t. ilww cffcctf Mt fclcvMii vbcn MttwpMif 10 dnctMMw • no"Cfiiot level
fof • chciiifCii MibttaUicc. BKaUnpln of wnl nxuiiMttUd ctmuM WDICB would *wt MMBMly
justify cUuificttioo with R 4S. irrespective of their statistical
*•
(a) clinical observation* or changes in bodywefghl gain, food consumption or water mtake, which
may have some leaacelogKal impoctaace but which do not, by thcmscht*. indicate '
(b) »m*ll chan(a in clinical biochemistry. heemMolofy or urioalytis panairnis which m of
doubtful or mininal toncotofical importance;
(c) chanfet in orftn weights with no evidence of or|M dysfunction;
(d) adsptattve retpontei (c«. Bucrooha|c mifration in the lung, liver hypertrophy and enzyme
induction, byptrplaitk reipomes to uritaats). Local cffeco on the skin produced by repealed
dermal application of a tubstance whihc arc wore appropriately dowfied with X M •imtMMf
to skin';
fe) wheic a specMs^pocific nieclianaini of affirciiy ipf* specific ttieojooiic pot«ways) hoi been
3J-5. Corrosive
A substance or a preparation is considered to be corrosive if, when it is applied to healthy iotect
animal skin, it produces full thickness destruction of skin tissue on M least one animal during the
test for skin irritation cited in Annex V or during an equivalent method or if die results can be
predicted, for example from, strongly acid or alkaline reactions. Classification can be bated on the
results of validated rn eif/re tests.
The'substance or preparation shall be classified as corrosive and assigned the symbol XT and die
indication of danger 'corrosive'. Risk phrases shall be aarigned in accordance with die foUowing
criteria •
ft 35 Causes severe bums
—' If. when applied to healthy intact animal akin. Ml Aickneai destruction of akin
occurs as a result of up to three minutes exposure, or if this rcank can be predicted
AP3-11
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No L IK/56
Official Journal of the European Communities
•-7.fi
9.34
— If. when applied to healthy i
aaimal skin, Ml thickness destruction of tkin tissue
occur* m a result of up 10 low how* MBQSISM. or if this MMh can be
iit Irritant
•XT aod the indicKipo of
I. Inflammation of the tkin
Irritant' M
the sjrrtol
Inflammation of the skin which finiiu lor at hut 24 boun aftet an iiimsim petiod of MO 10
sour _ hours and corresponds SO QIC following values determined on tne rabbit j
cumcouf ifricttioa me method ckcd in Anitev V :
— the mean *-lue of tfre tcocct far either eiythemi md etchar
CMC? 40 QIC MUOTW ItMtQ, M IWI Off
•— a—.-
«^*» Off, m UK
In both ca*e* »D aeotw M each of the leading OOM* (24. 41 and 72 houn) far M effect
Tie foUowfof mk phme shad be tM«|ned in
• M Irriutmi to tkin '"
— It when
period*
with the ctMeria
to hcahby intact animal skin for up so four hours, significant i
and which persists lor 24 houri or snore after the end of the <
Inflammation • significant if the mean value of the scores is two or
eschar formation or oedema formation. The same shall be the <
I* if the aeore tor either erythema and ndiir formation or
observed in two or more animals is equivalent so tne value of two or more*
2. Ocular
*
uid tonwpond to the Mlowinf «K*» drnmincd on the nbbit *coonlifi| IB the eye initebon
mt method csted in Annex V;
fw^^wj|msfag|| JfOff lj|l ffaf OHilBth tHmfdi It
— the mean value of dte scores for each type of Ic
. one of the following:
. ^" cornel opeotytwo of owe*
— iris lesion one or more.
— redness of osajunctivae *,* or snore,
— oedema of conjunctivae (chemosis) two or more, or
— in the case where the Annex V test has been completed wMg.three animals, either cornea
opacity, iris lesion, redness of conjunctivae or oedema of conjunctivae (cbemosis) equivalent to
observed in two or
In both cases all scores at each of the reading times (24.41.72 bows) and for an effect should be *
used in calculating the respective mean values.
The following risk phrases shall also be assigned in accordance with the criteria, given:
RJ6 Irritating to eyes
— If. when applied to the eye of the animal, significant ocular lesions are caused and which
persist for 24 hours or more after instillation of the test material
Ocubr lesions arc significant if the means of the scores have any of the values: Cornea opacity
equal to or greater than 2 but less than 3: iris lesion equal to or greater than I but not greater
man 1.5; redness of the conjunctivae equal to or greater than 24: oedema of the conjunctivae
(chemom) equal to or greater than 2. The same shall be the case where the test has been
completed using three animals if the lesions, on two or more animals, are equivalent to any of the
2 and far redness of conjunctivae the value should be equal to or greater than 2,5.
AP3-12
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I. 7. fl
Official Journal oi the European Community
No L IM/S7
R4I Q Risk of scriout
— If when applied to Ac eye of the «nim»l severe ocular lesions an'caused «id which
•re present 24 bean or more after imtiltaiaa of the tat
Ocular litinm arc sewn if Ac
g( Ac starts have My at Ac
Cornea opacity equal to or greater Aan 3; iris ksion greater Aan IJ. The same shall be the
where At tot has been completed using ARC animals if Aete Moos, on two*or '
have say of Ac values:
to or fleeter Aan 3; iris lesion equal w 2.
It 43 M*y cause semination by skin contact
— If practical experience shows Ac substances Mkd prepmtioos to be optbk o( inducuit
• miiiimton Miction in m wbtuntMl number of penom fay «kin conuct. or on Ac
U the OM of Ac «dfu«em type Ml mcAo4 far dun tcMMiwioA deaOcd in AnaciVorio Ac
CMC of oAcr •dJMwM-type ten meAoA, a myoiut of 01 Iced M % of Ac oninab it cootUmd
pocitixt. for «ry oAcr Ml ncAod • tooomc of « ICM IS * of Ac CMMI* • contMknrf poii-
Imc.
SO7.
R37 4rtiMin| to mpiiMory lyMcm
^^ SuOOIMICCl dM DfCpMMlOM
bn«d Mrmtlly on pnctiol ob«f notion.
Other toiicoto|ictl propcrtict
•cnoui Miuiiion 10 Ac ittpiioiofy
Additions! risk phrases shall be assigned to substances and prepsmiom classified by virtue of
12.1 to 3ia sbovc and/or Chapter* 4 and S, in accordance wiA Ac following criteria (based on
experience obtained during compilation of Annex I):
R 39 Contact with water Uberstts toxic gas
For substances end preparations which in contact with water or damp air. evolve very mud
MS in potentially dangerous amounts, C£. aluminium phosphide, phosphor*
R31 Contact with adds liberatet tone fas
for aabtanea and preparationi which natt with ocidt to e»ohn *o«k |
, Cf. aodhMi ttypochloritc. barium potywlphidc. For fubttancei vied by immbtr*
of At teneral public. Ac uat of S 50 (do not mix with (w be specified by Ac man*
facurerg would be
1132 Contact with acidt liberate* very toaic |ai
For Mbmncct and ptcpaniiom which react with acids to evolve very toiK |ssci in
ntM tmountt; c«. nln of hydrogen cyanide, sodium aside. For substance* used by
member! of Ac cenenl public. Ac IMC of S 50 (do net mix with (to be specified by
Ac manufacturer)) would be mote suitable.
833 Danger of cumulative effects
Mcumulation in Ac human body U likely and may
For substances and prep)
cause some concern which, however, is net sufficient to justify Ac use of R 41.
Mgned to substances of Annex I and preparation* which wet* likely to cause damage
10 health by prolonged exposure or which were likely to be retained and Acn accumulated within
Ac human body. Now to be progressively replaced when appropriate by R4I.
When substances labelled with R 33 are present in preparations, R33 shall be included in the
label at all concentrations where a label h required by Ac Directive on dangerous preparation*.
For other risk phrases see 2JU.
O Ihe ot KM or'ft J5 pnchioa the M of It41.
AP3-13
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No L ISO/SB
Official Journal of the European Communities
I. 7. 91
4. CLASSIFICATION ON THE BASIS OF SPECIFIC EFFECTS ON HUMAN HEALTH
4*1» IftllOOUCtlOBi • ' .
4.1.1. This chapter sets out the procedure for the ctassifkation of swhstanm whkh may have dw tMaca
4J i If i manufacturer or bit representative lus into
enable which indie
i that*
4.1 J.
4.1.4.
4.1J.
4.14.
42.
42.1.
should be classified and labelled in accordance with the criierii given in 4.2.1, 4£2 or **?. he or
hit representative shall provisionally bbel the substance in accordance with these criteria, tmleas
the conclusions retched by the appication of the criteria mentioned in 3JLI to 3.U indicate the
rof .•
The manufacturer or his representative shall submit as soon as possible a document summarising
all relevant information to one Member State m which the substance is placed on the market
This summary document should include a bibliography containing all relevant references, inch-
Furthermore, a manufacturer or his icprcsemative who has new data which am setevem to the
dassificabon and labelling of a substance in accordance with the criteria given in 4A|, 4i2 or
42J, shall submit this data as soon as possible so one Member State in which the nasianii is
placed on the market.
In order to obtain as quickly as possible a harmonised classification for the rnmmimirf by the
procedure defined in Article 21 of Directive o7/54t7EEC. Member States which have
information available justifying the classification i
for classification and labelling, to the Commission as soon as possible.
The Commission will forward to the i
i the classification and I
«»*
that it receives. Any Member State may ask the Commission for the information h has itCMvod.
Any Member State which has good reason so believe that the suggested classification and boeUing
is inappropriate as far as the carcinogenic, mutsfmic Or teratogmk effects ate concerned shall
notify the Commission thereof.
Thei
ng applied by a manufacturer or his representative shall i
n valid until
the tony into force of a decision on the inclusion or non-inclusion of the substance concsinsd in
Annex I. .
Criteria for classification, indication of danger, choice of risk phrases
Csrcinogenic substances
For the purpose of classification and labelling, and having regard to the current state of know-
ledge, such substances are divided into three categories:
Category 1
Substances known to be carcinogenic to man. There is sufficient evidence to establish a causal
Miocintfton between QIMIWI cxpOMifc to s MbMince MM roc oevtiO|iment 41 CMICW.
Category 2
Substances which should be regarded as U they are carcinogenic to man. There ia sufficient
evidence to provide a strong presumption that human exposure to a substance may reauh in the
development of cancer, generally on the basis of:
— appropriate long-term animal studies.
— other relevant information.
Category 3
Substances which cause concern lor man owing to possible carcinogenic effects but in respect of
which the available information is not adequate for making a satisfactory assessment There is
some evidence from appropriate animal studies, but rhia is insufficient so place the i
AP3-14
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S. 7. 91
Official Jounui of the European
No L ISO/59
44.1.1. The fallo*iat symbols and specific risk ptinm apply:
Catagnrifi 1 and2:
T; R4S may can
d.for
Hywhcni
.as dust, vapour or fumes, (other routes of exposure e{. by swallowing or in contact •ilk
akin do not present any carcinogenic risk), the following symbol and specific risk phraae should
be used:
T;R4« may
Category 3:
Xn; It 40 possible risk of irreversible effects
•IjyjL CnffJiTfrytiff ittpnbiut Ac otcyBiiiiyioo M
The placiti| of * substance into category I it done on dw basis of epidcmiologkal data; placing
into categories 2 and 3 is based prinurily on animal experiments.
uldbt
avMlabte or desr pettuve evidence m one species, together with nipponing rrirkan Mdi as
ijenororiciiy d*u, metiboUc o? bioctiemkal studio, induction of benign nnnourv atructtnl rcb-
tieaship *i& OIBCT kaovn csicinofcns, or data from epidemiokfical studies tuggadng an •tnri
Category 3 actually
(a) wbatances «hkh are veil inwettifated but far which the evidence of a tumour-inducing effects
is insufficient for ckssifkation in category 2. Additional experiments would not be expected to
yield further relevant tnformaiion with mpect to classification.
(b) substances which are insuffkiefidy nmsiigaied. The avaibble data are inadequate, but they
raise concern for man. This classification b provisional; further experiments arc necessary
before a final decision can be made.
For a distinction btfwttn categories 2 and 3 the arguments listed below are relevant which reduce
the significance of experiments] tumour induction in view of possible human exposure. These
arguments, especially in combination, would lead in most cases » classification in category 3,
even Plough tumouA have been induced in animals:
— carcinogenic effects only at very high dose level* exceeding the 'mawtmat tolerated dote'. The
maximal tolerated dose is characterized by toxic effect* which, although not yet reducing
lifespan. go along with physical changes such as about 10 % retardation in weight gain.
— appearance of tumours, especially at high dote levels, only in particular organs of certain
known to-be susceptible to a high tpc
— appearance of tumour*, only at the site of application, in very sensitive tot systems 1ft, If. or
sx. application of certain locally active compounds), if the particular target is not relevant to
— lack of guiutuaicir/ in short-term tens m rir» and la ri/ru,
— eiistsnet of a secondary mechanism of action with the implication of a practical threshold
above a certain dose level («.g. hormonal cffets on target organs or on mechanisms of physiol-
ogical regulation, chronic stimulation of cell proliferation).
— existence of a species-specific mechanism of tumour formation (e{. by specific metabolic
pathways} irrelevant for man.
Fors
•gory 3 and no classification arguments ate relevant which
tor man •
— a substance should not be classified in any of the categories if the mechanism of experimental
tumour formation m clearly identified, with good evidence that this process cannot be extnpo-
MtCO tt) flUUI.
— H the only available tumour data are liver tumours in certain sensitive strains of mice, without
my other supplementary evidence, the substance may not be classified in any of the catego-
particular attention should be paid to cases where the only available
occurrence of ooaplaims at sites and in strains where they ace well known to occur
with • Bittta ifi
AP3-1S
-------
No L in/60
Official Journal of the European Comnrfnitics
I. 7. f I
4JEJL Mutagenic subtUBcet . . »
4X2.1. Par the purpotti of cUerificarion MM! labelling, and tuning itganf w Ike
lodge, wdi tuhoitBfffi «• divided iMp dmc catefonet:
Category I: .
Suhattncei known le be
There to sufficient evidence to eatabliin • cauttl
•nd htfMable genetic
Category 2:
; which should be regarded a* if they ate mutagenic to
«• •ufncMM w^FtoCwMMt o> IMNBMMM •
^ odwr peievint
Subwttnccf which CMBM concern for IAM ovinf lo pi
•dies, but this »JMuffirirntto place the
that it evidence
»CMt«oiy2.
The foUowiai tjrmbob end tpecific ride pome* apply:
I :
T; K4« mty CTUK huiable |eneuc
Xn; R 46 any <*uw berittblc |eoc*nUHC
GonflMim Rfuoinf DW cMCfonuojOii of
Definition of tmm:
. iauhin| in • ctenje of Ac phcnotypk
involve • tingle feiwi • block of
or* whole chi
! of the gcnrbc material in an erga-
i of dw orgumm. The tHrraiinnt aMy
may be a comenucncc of effecn on iingk ONA beta (point mutation*) or of latge
including deMont, within die gene. Effect* on whole chranoaoraei may in* "
munctical change*. A mutation in dw gem eeU* in aexually Mproducing ofganian* May be
It Motud DC nocc« BMC wWbwttnon tat dcMiliccI M •wutw^jctwi vivn •pccifac ICICMBCC
fcneik dtmtge. However, die type of rauto Indinf lo ulimifiriiinn of cbemictli in MUfBry
m*»ucoo
-------
8. 7. 91
Official Journal of the European Communities
No L ISO/61
Category 2: ...
To place a substance in category 2 . positive results are needed from assays showing (a) mutagenic
effects, or (b) other ccthiUi interactions relevant to mutagenicity. in germ cells of mammal* in
rim, or (c) muttgenic effects in somatic cells of mammals in rim in combination with dear
evidence that the substance or a relevant metabolite reaches the germ cells.
«
Vith respect to placement in category 2, at present the following methods are appropriate:
2(a) In rim germ cell mutagenicity essays:
— specific locus mutation test.
— heritable tnnslocatkxi test.
— dominant lethal mutation test.
Thete assay* actually demonstrate the appearance of affecte
ping embryo.
progeny or a defect in (he develo-
2 (b) In rim essays thawing relevant interaction with germ cdb (usually DNA):
— assays for chmmeaomal abnormalities, a* detected by cytogenetic
aneuploidy. caused by mabegregation of chromosomes.
— tett for Mtn chromatid exchanges (SCE't),
— UK for unscheduled DNA synthesis (UDS),
— assay of (covalent) binding of mutagen to germ cell DNA.
— assaying other kinds of DNA damsge.
These assays provide evidence of a more or lets indirect nature. Positive results in these assays
would normally be supported by positive results from in rim somatic cell mutagenicity assays, in
mammals or in man (tee under category 3. preferably methods as under 3 (aft.
2(c) tn rim assays showing mutagenk effects in somatic ceils of mammal* (sec under 3 (a)), in
combination with toncokinetic methods, or other methodologies capable of BemoiiitiBting
that the compound or a relevant metabolite teaches the germ cell*.
For 2 (b) and 2 (c). positive result* from host-mediated assays or the demonstration of
unequivocal effects in in riln assays can be considered as supporting evidence.
Category 3 •
To place a substance in category 3, positive results are needed in assays showing (a) mutagenic
effects or (b) other cellular interaction relevant to mutageniciry, in somatic cells in mammals in
rim. The latter especially would normally be supported by positive result* from in riln mutage-
nicity assays.
For effect* in somatic ecus in rin at present the following methods ace appropriate:
3 (a) In five somatic cell mutagenicity assays:
— bone marrow micionuclcus tett or metaphase analysis,
—metaphase analysis of peripheral lymphocytes,
— mouse coat colour spot test.
3 (b) /* rim somatic cell DNA interaction assays:
— test for SCE't in somatic cells,
, — test for UDS in somatic cells,
— assay for the (covalem) binding of mutagen to somatic cell DNA,
— assay for DNA damage, eg. by alkaline edition, in somatic cells.
Substances showing positive results only in one or more in rirra mutagenicity assays should
normally not be classified. Their further investigation using m rim aasayt, however, b strongly
indicated. In exceptional eases, eg. for a substance showing pronounced responses ia several in
s*r* assays.'for which no relevant in rim dan ate available, and which
known mutagem/carcinogens. classification in category 3 could be
APM7
-------
_ No L ISO/fit
O«ici»l Journal of the European Communities
"1. 7.
4JJ. Ttratof«nic
*
4U.I. Par the fwrpoar cf riaaaificniBn and tebeUu*. tad bran* itfaid to die
C~tory I
a>be
That
Oatfory 2
riMuldbt npided a* if they MC
IHMC M Mlficmtt tvMmcv tt ptovitiv
to dw
I
T; * 47 my c*wc bink Meet*
CMtiOiy 2
X*; »47 My CHM bkdi Mem
Fr«c«d»r« f«r the cl«»»ific*iioa of prtptrtiioat ceacer»in| ipccific «fl«cit on
i ttlptCt 10 PME CfMlCU MM MK
U/379/EEC (the KmiB «l conetwntian ww cidm m Anna I w dia Diitctmt. or M Annex I»
Dinarvc II/179/EBC wbtft the wbtMnor or **m»ncci under «oosiikaoea do not fffttr in
Annex I or appear in it
5.1.
CLASSIFICATION ON THE BASIS OF ENVHONMENTAL EFFECTS
The primary objectwt of dnnlyifi|
to dw nuaidi thi
HNCI
mvinnmeni it to «lett dx uter
Alt»eu|h the pn*em critem crier «o
imiitaneoM^ or
constkueM my n«fc from Mil nictation and mictobuna tp
The crimN MI out brio* fellow
tnCy MV flWttOOBCO* I*W KM
tidMcd and dw MfennMion dern«d fcom
bat
nimfinrion any Mquug additioml 4** <
« ten mrdMdi art out in Annex V. in to fa at
far dw tm* act* irlemd to in AMMB VII an?
nay be iniulficitni far an appropriate riaarifici
erived horn level I (Annex VIII) or other oojum-
•wy be aubject 10 Mview in At lj|hi of other new
For die putpom of rlaarificaticn and (abdlint and twvint. itfird ID die CIHICM atatt of I
kd|e tueh fubftanen aic divided into wo jtoupi according to dwir acute and/or loay-onm
tffccti fa aquatic aymmi or dieir acme and/or loaj^erre ttttett m noiKo^aik tyiteiM. In addi-
bon diotr Mbnanca* rtiMifiiil aooocdin( ID the critena aft out wder U.I.I. and 5A2 «OI be
Diiocij** CTtSWSK
AP3-18
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t.7.91
Official Journal of the European Communinc*
No L 1MJ/C3
SA
SJ.U
5X1.1.
Criteria for dMaiftoation, indication of oVwgcr. choice of risk pbraaea
Aqnatic environment
^ J .-^ML1- *- .
aa VanSjervUi KMT
the foUowiog criteria:
0*<*d mrijncif ride porn** ia
R SO Very awuc M aquatic ocpnbnu
tad
R S3 May cause long-term advene effects in the aquatic environment
Aorn lorieity:
M br LC. (lor fkh) < I mf/Uuc
•c 4t hr EC. (Cor Dtpknb) < I m|/liuc
oi 71 hr 1C.D (fv «lfM) < > ««*«
Mid the wbtanct it net itadtly dtfnd*M» (")
or the k« Po« (tof
BCF < 100)
i cocfficienr) > M (uolm gbe
. It SO Very tone to •quMk
Acott
H hi LC* (for GA) < I «|/te*
or 4< hr EC. (lor IXphnU) < I
or 72 hr
RSI Tone to *qurtic
tod
R S3 M*y CMNC toot-term advene eHtett in dtc aqiiMk enviromaenl
< LC.
< EC.
< 1C.
10 nif/litn
tonck*: H hr LC. (for fith) I »*Aitr«
or 41 hr EC. (for Dapiuu*} I wgrtitre
or 72 hr IC.D (k>r *lt*) 1 rn|/Ii«
•fid die mUuncc if MI readily defradabk (~)
or thelofPow > 3jO (unlm the esperimcoially determined BCF < 100)
Subatawei chi« be danified M dangerous for die environment HI accordance with the cmcra an
out below. Rttfc phnan (halt ato be ani|ncd in accordance with the Thif criterion applies
unless there exim additional scientific evidence concerning degrada-
tion and/or toncity sufficient to provide an adequate assurance that
neither the substance nor to degradation otoduea -ill consitute a
poumtial long-term and/or delayed dancer to the aquatic environment.
. m^ma**M»Kn^atS4in:tCt«m^t*e^terpiM-trvit**i
of c***tr nil be artgiicil » their *ua*anc«.
D Wht» it aa bt dcmaMUKtd in the tmt of aigMv cotcwitd •AaMcet *at alfit gJO«4 is uOAil
a noMDMi in light inwwitv. own the 7Ih 1C, far atgat shaoat aot ht a**4 M a BB* a>
nUawwat art cantom* mdiK eeendaMr if tat
(A) V ia H-dty biodigndiiiM mditi th* talkwiag lewis at
- ia IBM band upa* Awhtd arga^c canm: ?»%.
— m IBM BWid upM eavpa atpMan at carbaa dianOt g«i«r«l>o«: *»% ot o«
/Hate levels of
bioi>r|r»d»»ioiiaxi»ibciefcifwd»iny» |Q 4iv« al tht
, U < el ott mUa»c. att am devaatd.
ii o*ea •
att4.
Oft
(Q ff
it miUOt la
thai ox
kc drgnde4 (Waoodrf
AP3-19
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No L 1M/64
Official Journal of the European Communities
t.7. 91
Such additional acientific evidence ihould normally be baaed on *M
(Annex VIIQ. or audio of courvtlcm value, and could include:
® a proven potential m degrade tapidty in dM aquatic environment;
JM} on •botoce of duonic aaiictty enodi at a OBBjcoottattoo of IJ0 Wffvu^, cf» a
crMCt concenttaoon or a^reoMf tnan IJD wtf/vXK ocMfnuBpcl tn a pOMonaoB tOMW
fob or Daphnia.
At lean one of dM tattowmf, phmes:
R 52 Harmful W aquatic
It S3 Mcy
effects HI the M|IM(IC
Submnca not (aUm| wider tttt
in dm dMier, but «hidi o* ike km of Ac
•vuttMc CVMNAGV COdfOWiwm Ibcif iOKiciiyi
*br dw
f») they M M mdily
(M die tog Pow > 3J»
BCf < 100V
"ifradai
city NfBcieM » provide kn tfeqimt MJUIMU tk
prodMds will combtuie • ponnriri to«t*ienn owt/or 4dqr*d dtrigtr ID dM
Such xidiiioMl KitMiGc evidence ihould MOMlly be bved on dte MOM* nouind « level 1
(Anne* VlltX or Mudia of •quhmUnt veluc. MM) could include :
to w^noc npioly in UK
(ii) n •btcAC* of dHonk Haidiy effecn M the Mhtbilitjr liwk. tf. • i
tndoa of |tcMer tbtn • MUbility Mow determined w • pioloojed teaotMj «udy with fefe or
5Z2. Non-«^nmtic eavironmcnt
Subwncc* «MI be dMtififd M dtnfeioia lor the eaviroamcmn
At lent one of the foBovim pbmei rtaW be Mnpicd m
RM Tone to Bon
RSS Tone
-------
Official Journal ot the European Community No L 1MW
4. CHOICE OF SAFETY ADVICE PHRASES
4.1.
with the fallowing general criteria. In addition, for certain preparations, safety advice
Annex II H Directive M/37V/EEC Whenever the manufacturer is mentioned in C
IClCfi SO DM pCftQA mpOBltPft -lot pUCiflJ tDC MMMHCC Of jWlpMltlOlt OR UM
SI K«fhtM*f
— Applicability:
•^ Vfffy tOKK MM IOKIC WDMtllCM WtQ ptCpVfWUNKMk
— Criteria for use:
— Recommended for very toxic and toaic substance* and piepanjtions Kfc
by members of the general public.
S 2 Kttf Mrr •/ mw» •/ fbiUm
-Applicability:
— All dangerous substances and preparations.
— Criteria for use:
— Obligatory only for all dangerous substances and preparations likely to be used by
members of die general public or likely to be used in places to which the general
public have access unless there is no reason to fear any danger particularly to chil-
dren.
S 9 Kttf M « r*W
- Applkabuity
•™~ Organic yfc»^»n.—••
— Other dangerous substances and preparations having • boiling point < 40 *C
— Criteria for use:
— Obligatory for organic peroxides unless S47 is used.
— Recommended for other dangerous substances and preparations having a bailing
point < 40 *C
S4 Kttp fiimj /rm living fMrtm
-Applicabiliiy:
'— Very toaic and tone substance* and preparations.
— Criteria for use:
— Normally limited to very toxic and toxic substances and preparations when desirable
to supplement S I); for example when then is an inhalation risk and the substance
or preparation should be stored awey from Irvie^ quartm. 1>c advice is not tswended
to preclude proper use of the substance or preparation in living quarters.
S3 Kttf ntiitnu tatdtr... (appropriate liquid to be specified by die manufacturer)
— Applicability:
^^ Spontaneously flammable ffltiii substances and nnfjsTatffifit
— Criteria for use:
— Normally limited to special cases. e.g. sodium.
AP3r21
-------
No L ISO/66
Official Journal of the European Communit*
I. 7. f i
S6 Kttf «*4rr... (inert g*t to be specified by the manufacturer) "
— Applicability:
— Diagram rabttancct MM! prepMKmm which muM be kept under an
— Criteria for uct : . . : '
— Normally limited to special catcs. e,g. certain otgi
57 Kttf nmtimtr tigbfy
-Applicability:
••••• SUMtBACW Mid pICpMMNNV VniCo CUI
fltiHimMf oc ktftMy ftMMBiUc VIDOMK*
— Subtunca and preparation* which in contact with
ft , , *, i ^^.^^^^j^
••WIvMfe mmBCIy
give off highly How-
Criteria let MM :
— OMifaiory for Mganic permodes in the combintooa of S 3/7/9.
— Recommended for the other fiddi of application
Si Kttp nmuimtr Jry
-Applicability:
— Subnanfn and preparation! which may react violently with
— 5ub«tancei and preparations which on contact with
— Substance* and pitparaiioni which, on contact with
— Criteria far not:
— Normally limited to the field* of application mentioned above when
reinforce warnings given by R 14. R 15 in particular, and R 29.
S 9 Kttf «MMJMT in * wtll-vtnltltltd flma -
— Applicability.:
neccMary to
— Volatile tubcunces and preparatio« which may fr»* off very toxic, lone or narmful
— Eiutmdy flammable or highly flammable liquids and
— Critcrii for ua*:
— Obligatory for organic peroxides in the combination S 3/7/>.
— Recommended for volatile substance* and preparations which may give off very
toxic Or harmful vipoyca.
— Recommended for extremely flammable or highly flammable liquids or gate*.
S 12 Do net kttp ll* m«Mi**r tt»M
-Applkabiliry:
— Submneet and preparations which will by gmng off gam or
bunt the container.
~ Criteria for mt:
— Normally limited to the (oecial e
AP3-22
beUaMcw
-------
1. 7. f i Official Journal of ihc European Communibcf No i. 110/67
. *
S S3 JtMp mmy /nm f994 AM «W
«••> Vccy iQatiCt MQQC vtftd IWIHIIUJ Mnt&vicci UM
-.Criteria far MM:
wncii Mien tuoMwico «uw pnpuMiQAi AR bk£ly 10 DC mwd by
of the feneia! public
$14 JCa*«a^)hOT... (incompatible «••«««•» 10 be indicated by the
... -AppBcability:
— Orfouc |Mioaidtl
— Criteria far MM:
— Obtjfawry far and normally limiiad to organic pcfoodc*. How
acepoJOfwl caua when incompatibility it likdy a» produce a particular riik.
SIJ
i WM pfvpwMions vnicli Buy occpinpOK or vtucb my met
•ly iMder ibe dfcet of he*.
— Oterit far me:
Kmitcd la tpccial CMC*. «4- meoomtB, but MM mjfnH if riik phntcs
RJ hmalittdy bee*
S U JC«y «•«)• /MM «MIMM •/ igmitii* — M
•> __________________ .*-...
*""'» cmmiciy
— Crittife lot
— Rcenmncadcd far Ihc tubiuncei end prepmtiom mentioned tbew but mat
•ugned if mk phnta R2. R3 and/oc R 5 have iliMdy beta
S 17 JC«^ ***J fr»m ttmlnulMt m*uri*l
-AppliabOiiy:
prcpiinioiu which miy farm «pto»iin or $pen«nc«M*ly
VRII coffibtMtiDic nuicrul.
— Criteri* far INC :
— AvwUbk far UK in iptcitl cam, c«. n cmpbaue R I and R >.
S II H«*4lt m*d tft» A»MfWr trilk t*n
— Applk»bilify:
— Sutaaacet and prcparatioM liable to produce an
-------
NO i in/ci
Official Journal of the European Cooimitiutie*
S.7. tl
Sll Vftm *»*f *• *# «•**
_ ApplMbility:
— Critrn* for me :
_ Normally United w tptcial
S 22 />» ••»
— AppUcebOity:
_ All «>W dtafcrou*
— Crkera ferwie:
•ad
far (how
(•Me to form tohalaMc dun, and when it it neccnwy M dnw the
»»* IP inbibcinii riato not eaenriontd in the riik phiMtt *kieh fc«»
>«ftbt
S23
faewrrr)
KB rick phnatt. in p«t>-
to be Of irifiid by tbe •omt-
— Cracm far «K:
when it • nccoMy to 4mr Ac MKmiea tt the «t« w
rifki not mentioned b the ritk phntn vhick hnt IB b* mt&td.
R42.
tacepiioMJ am M craphMitc tueh ifak phntM. la pjitioiUr lo *mtfti*iu
for
be wed by
of the
M the farm of
S14
— All
_ Recommended when it fe nccacuy to dnw the attention*! the wer to akin <
risk* not Mentioned in the rak phnte* which have to be aicribed. Itowtwit. nwy be
ouch rnk phinet, in puticuUt to emphniae R43.
S 25 AvtH a»iMl milt
— App»w«bilit)r:
or irrittot
_ N.
i to which 4* rtak pbfMe It M bet obekiy been
AP3-24
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t. 7. f J Official Journal of the European Comn>i|niti«« No L IKVC9
S27 T«*f tff imm*i*ittj mil
— Vcvy •CHOC, tone 0r UNJOIIVC
— Criteria far oat:
— Obb>«y lor organic ,
jBiprbTd by ihf ikin uid for cottoahic MOMMCM Mid ptcpacMiofti vnlcM aafcty
phme S M can be ccmidend wfficicm by tacit
S 21 4/fer «Ml«r •«'/* AX MU^ immudimttij aift flntf tf... (M be tpcrifed by ** w«i-
-Apptobfl-y:
^ Vcty ton^ tone w cwrauvc MMMACW mo
— Ciwmfatw:
lor the MibHMicc* Mitf pKpuMtom OKMioocd ibovc.
•fata ««rr • net the tno« ippfopriMc rintttif Butt.
S 29 £» Mf ««99 ran
^« EfltRBKfy Of n^hiy RMiimblc
Criieni lor w«:
for dwic nrnmcly or highly Ounmabt* liqwidi which are nmniieible
«ich «mr. Tfc« iMrmion « w moid •eadcnii (««. fire aplotioii) WK| KM 10
S 30 Mrrrr J^ «/rr M
— SubitintM end pwpwMioM «bkh met violcnlly with WHM.
— Crittrn for me:
— Morally limited to tpccnl CMC* (««. wlphuric *cid) Md any be laed, • tppro-
priMC. ID |ive the ckwtn potable informMion. cither lo cmphtsitt R 14 or M m
dtmudvc to R 14.
S 33 T»kt fnaxMMrj mttutmt atmintl a flit
— Eaicmely or highly flunnubk wbMMMM nd prepenUOM.
— Criteria for MM:
— Recommended for wbMMcet and prepuMiom wed in industry which do Mt •booth
moiaure. Vbtutlly never uitd for mbmncri ond prepuMKMU a placed on the
market tor ute by member* of the fencta! public.
S34 XiW /*** **J frictit*
_.«ppUeabi»ry:
— Exploinc Mbatancet and preptmioM.
— Criteria for oae:
-. OM«am« for and normally limited t» nplotive organic pemidci.
AP3-2S
-------
No L ISO/70
Official Journal of the European Cmamuniticf
S. 7. f I
535 Ttit mmttiifl mm* iu «Mi*iMr muat or Japvtd if in m tfft my
• —Applicability:
— Veiy tone and ink
— Criteria far we:
— OblifMOryfO/Cntol*
IDT «ny
M* Kkdy M be wed by
of At
S36 Vttr tuiuUt fnuait
- Appl«6i%:
— Critrri* for we:
tow ic w CMVOHVC^ MM/ of
d tMOy •bioAcd by the thin, oad/or
— iMbfe » diaiafe health by pmlon|*d
S37
— V«y lone. mac. batmhil or
— OlfMUC
— CriKritfatMt:
S3* if not OMd («<. «is fencnl pubUc}.
. wt*n R 31 if MX (bows on tb* bbd.
S 31 /• aur •/ aumfficiail vnlibui** wMr miuMt ntfinmj tjmifmatt
umc
^•^ Vciy
— CtiKm for
— Normally limited to (pedal ene* imorviaf the we of *ny tone or Woe
•wo pvcpMvlioctt MI inoutfiy or M
S3S Phrr tj»tf*n prettafo*
- AppUojbflity:
i and pepanooM. jnchiding Mm* which fh« liie to ritk of
to die eye*.
— Vety (one and «o»ie MibManccs tad piepaiHioM
— Criteri* for we:
for orjMic [niuiiiitn at the fitmHnettim S37/39.
particular when there it t risk of tphthinj.
— Normally limited to exceptional oat* tor wty tone and tone eubttincei and pupa
f«>oat,«faetetlimiiaiUof«pledi^eodtheyeMlifceryttbeea«ilyiBWfbedby
dwricm.
AP3-26
-------
g. 7. f i Official JeMiMl of the Bmopeaii Communitka No L 1W71
$40 1% dM» tttfUtr mmd mil *•/«» flMfcM«MMrf •> lAu mnitnMl *tf...(io be aperi6ed by
•t ____.Jt._-~ ___ h '
— AH
— OteriaforMe:
IB be a aaJMbte dunainj »nd »faei» k k important far tuihh
•nd/or Mfcijr IJMUIU to provide • wainf on ifac UbcL
$41 /• MM •/A" *»&»r tsfi*ti»m 4» •« kn*lbt fitmtt
— Criteria for Me:
$42 Dariui f*mig*ti9mAprmyi»g MMr atiltUt ntfirmlttj t^ttifmtmt (tppropcutc wordim IB
* —
oc
; md prrpAnbom iatoMftcd for wch we but vbicb m«y
•Cmtb MM MWfy Of QIC UMff MBlm pfOpCf pRCMUMMtt MV IMBCA.
— Cmtm for IMC
^" ••
•"**' ITVI iiiiiiy
$43 /•«
die rak add:, New <*e water)
— Criteria for OK:
— OWiipMry lor mfa«uitc«i end pttpmttoiu which in cwiuct whh wMer or 4*mp «it.
cvohrc h^irjr B*mnublc (MC*.
lor «Mncmeiy Ibmnuble. k^hly flUnnuUe »d flunouble
, |wciicwwrty VMVI ttwy MC OMMIMCMVC vini
$44 //T» /w/ «•••// utk mtditml *4vi« (riwv the Ubd where powblc)
— Crimit for OK:
— Obli|Mor)r for die Mhttances and prepantiont rnenlioned above when need in
mouftry ano noc bfcely 10 be uavo by AMinbeit of the feoeiv pubiid
$45 l» «t* if *ecUt*t tr i/j»n fad HmnrH ittk mtJital Wtwr imm»4i*tttj (ihow dw labri
e)
-Applkabniry:
^ Vny tone lUbumcei MO pveptnoont.
— Crittria for «at:
for «be «aty lone tubatanori and prcparationi
— Obbjatory for tone aubatancet and pfeparatioat mentiened above when likdy •> be
wed by amnben of the gencnl public
AP3-27
-------
No L IN/72
Official Jounut of the European Communities
•. 7.
$4*
tut
«M**i**r «r
— Ml daiujeiow «ibMance» and preparationi ether than thoie which a*e tone or «riy
tone. .
— Criteria for we :
— Obligatory for *U dangerow wbftancci and pi«p«»tioM i
likely to be wed ky member* of the |e
ilolear
•ny danger from swallowing, particularly by children.
S47 Kttf M itmftrmtHTt MI cMfMfiiif... *£ (to be specified by the manufaouier}
— Substance* and .preparatioru which become wtsaMe at a certain
— Criteria for we:
— Normally limited 10 ipecial cue* (e*. certain organic petoaieVa).
541 Kttf wnud wak... (appropriate materiel ID be specified by the
— Applicability:
— Substances and preparations which may become very aenaiuve «o spark*, fricboa or
impact if allowed to dry out.
— Criteria for we:
^» Normally limited 10 apffial cases, cf. niliuti ttuloan
$49 Kttf M/T i* /*r trigiiuil aniaintr
-Applicability:
— Substances and patparnioni sensing to catalytk dccompeaibon.
— Criteria for we:
— Substances and preparations aemitive W catalytic decomposition ««. certain organic
S50 D» *M mix with... (to be specified by the manufacturer)
— Applicability:
—• Substances and preparations which may react with the specified product 10 evolve
very tone or mic gases.
— Organic peroxide*.
— Criteria for we:
tdibi
which we likely to
^ Rccoriiiiiciided for mbmnccs infl pfepifitions mei
be wed by members of the fenenl public, when it b a better •hciMthw to R 31 or
R32.
— OMifitory with ceruin perondei which imy five violem reaction with accekiamt
S Jl Utt only in tnHrt*titatt4 ettat
— Applk*bility:
— Subttancei and preparatiom likely IB or intended w produce «*pom, duct*, •pray*.
fume*, man. etc. which five me 10 mhttorion mki or to • fire or emplowon riifc.
— Criterit for we:
— Recommended when we of S Jt would not be appropriate. Thw important when
wch fubmnce* and prepamioni Me likely to be wed by mernbei* of the feocnl
AP3-28
-------
I. 7. f I
Official Journal of the European Communities
No l> IM/7J-
«JL
S 52 M»f
imrritr tat •* 4*ijp tmrftut *nmi
tandp,
-Applicability:
— Volatile, very so*ic,»o«ic*nd hi
— Criteria far MM :
— Recommended when damage 10 hetWi to likely to be caused by pi
n these substances by rcnon of their volatilization {torn large treated surface* in ike
noiM of other encMsco puces where petsoM congregate*
S 53
— svM*rft into drmimt *r the mqustit t*ri-
mmtnt.
— ApplicabiUty and criteria foe use :
— Recommended for tubsumcM which are very toiic. awk or htrmful to tquatic orgt-
nbm or tubttancei which mty catne long-term *d*ene effects for which treatment
technique* are available.
— Recommended when such substances are used in industry.
SS6 Dt met Jiubarfi inl» 4raint «r iht nvin»mtml, Jiifott u mm «»/6#riW teatlt nflttlion
— Applicability and criteria for use :
— Recommended for subuances which we very lone or toxic to aquatic orguiisms or
which msy cnne long-term adverse effects in the aquatic environment.
S 5? Utt
numimmnu l» «r*Mf tnr»i**mt*l*l nmt*mi*atioM
'— Appliobilily snd criteria for use:
— Recommended for substances which are very mk or tone to aquatk organisms and
pankularly for subiunces which may cause long-term advene effects in the aquatic
or non-aquatic environment.
. — Substance* snoc to flora, fauna, soil or other organiiatt.
— Recommended when such substance* are used in industry.
AP3-29
-------
No L ISO/74
Official Journal of the European Conuntraitie*
9.7.91
S It T» **
«*
— Applicability Mid criteria tot me :
•Of WOwttftCtt WBttCA HV ^gfy tOMCa, tUHH Off iMftttilll
which nuy cause long-atrm advene tfltca in die nan looitic or'
— Recommended for suhatanfft tome to Aon. fauna, bees or other
S 59 Xrftr it m*imf*amnrA*tptitr ftr i*frmuli»* «i tmvtry/ntfrinf
— Applicability and criteria for use:
— Obligatory for substance* dangerous for dw ozone layer.
— Recommended for substances which aic toxic so Bon. fauna, soil
• «fiecis in
e/«
S «0 Tfcir m*ttri*l
iu CMMMMT «tu>
— Applicability and critni* for ute :
— TOi phinw •hodd be wed in place of S 51 in <
— fctcomnicnded for wbttanon which art *ny lone,
iitttnt or aubatanco which may came luuf IKI
or humful to aquatic «p>
ia the i
7.
7.1.
7.2.
LABELLING
Wlbcn § iubittiict off pitpmtioii Im been diitifi*o tkic Appfopcuit Ubd it oVnbtfnitiMNl with
icfemcc to the Mquimnciili of Article U of Direom 47/J4I/EEC (7J/I3I/EEQ and Aftkk 7
of Direowe U/379/EEC for wbHancti and pifpHationi nn»tcii»tly. IMf KCtion cxptetnt how
f&c laocl ts octcrnincd ano\ tn paftictilar» fives a^iioanK on how 10 chooac ihc appioptiatv risk
and lafcty phiaic*.
The label of a fubctance or a pc«p»iauoa atoidd be derived from dw load
offyMboh,
faf DIC OCUfmilUltKNl Of BMt (j^j^pngj 0| ^mp,|> ^•^•j u^llCIIIOItV Of ^jgjjBjf •
(b) the ckfernitfiaKioii md fin*) choice of Che phfMCt indkorini pfUtKuter ritki (R-phnm);
f£l the wtetemumtioii 0110 niul CAOioe of IMF p|hjgB|gg ncbCKMif tntff Mtvicc ^^pbiMct} i
(d) the final choice of die name or namei which will appear on dw label.
Choice of R-phraaec
For MUtancei, K-phmct will be ariecud accoidinf lo die followiag criteria and pnoritia:
(a) in ihe cate of heahb effeeH:
(0 R-phn
idin| to dw catefory of danfer illuftmed by a tymbol — dwte phmet
mutt appear on dw label;
(ii) R-phme* cormpondiitf to other categoriei of danger which are not • illtntnced by a
lymbol by virtue of Article l< (4) of Dtcectmc C7/54I/EEC;
(b) in dw caw of danger arising fiom physico-chemical peopeitits:
— the criteria described tinder 7.2.1 (a) above are applicable, except that the risk phttses
•extremely flammable' or -highly flammable' need not be indicated when they repeal die
wording of die indication of danger used with a symbol;
(c) in die case of danger for dw environment:
10 dw .
^•» Thftf phiMCS oiuM ttttyttt m
AP3-30
-------
7. 9| Official Journal at the European Community No L IJO/75
ihelt^^
in the cat* of dangers which give me to beaUi effects:
110 *e natjory of danger atomed by a lyiulul la ccmia
UK R-BtaM must be adapted according to the Mbks of Annex I n Dinah*
Mow "
far the assignment of the preparation to a danger category must appear on d>e label;
fji) R-phiam which toumimid »the other categories of danger which have been attributed
» the constiiuenit but which are not Olustnted by a cymbal by virtue of Article 7 fd) of
Directive M7379/EEC:
(b) in the caae of dangers arising from phytico-chemkaJ
— the criiem dctdfted voder 7i2 M •*» •»•««>««. «««P« *« *• •**
fhmntble' or Tij|hh; flimnuble* need wx be Miattd wh«e they Kfctt the
the mdicttioA ftf deafer MM) «*fc • lymbol.
74. Final choice of risk a*d witty
Although the final choice of the most appropriate risk and safety phrases it primarily governed by
the need to give all necessary information, consideration should alto be given » the daaty and
impact of the label. With darby in -mind, the necessary information thould be e»yiutid in a
7J.I. litk phr»»ei
At • fcaenl lule, opolyinf to wbtttnct* «itd piepMliont. • m«mman of low R-phiMc* dull
•uffke to dcKribe the titk; brihi* pucpoie (he combined phmei teed in Annei III tlull be
•Cftided « tm&* phnm. However, the mndwd phratet MUM cewtf *tl the principal htMtdi
•noeitud with the prrpBntton. ,
However, where there » * need to ideniify cnviioomenti) buanb t4ditionil R-ptuoiet stuU be
7Ji Sifety phraies
The find choice of niety phnwf aunt hwc ref»nJ w the risk phmet indieMed on the bbd ond
to the intended ate of the (wtetnce or prepmiion :
— nfeiy phmet which |iwt ebwioui oMce in ichtion to mk phntct en fenemlty omitted from
Ac tebel irnkH uted w give pwticuUr cmpncMi to • specific «imin|,
•"*• cctuun tutty phiMHi ^4* * *» hwt pwticiiltn' fclcwuKic tv MDMVACCS wia
intended lo be uMd by the public, other phmet hive penfculu irfewicc to penont M work.
Phntet fhould be choteti with the intended vie m view.
^* ptnicuur Mtcntion mutt be jmen, in the cincNce of telety phnueit to rJie foreseen conoitiont
of use of cetMin tubtttnces and prepmnoiw, eg. tpnying or other terotel effects,
— MI |enenl rale. » nuximum of four S-phntn th*ll toHice to formubte the most ipproprwu
tifety advice ; for this purpose the combined phrases listed in Annex IV snail be retarded as
single phrates,
— in the ease of danger M the environment a minimum of one and a maximum of lour
S-phratn should be used.
— tome R-phrasei become superfluous if a catend selection is made of S-phnsc* and «ice-we«»a,
S^hram which obriously cormpond to R^htaan will appear on the label oaty U it it
mtended M emphatiae a specific warning.
AP3-31
-------
No L ISO/76
Officwl Journal of the European Communities
I. 7. 91
7A.
7J.
MIM(«) to be dttpUyerf on tb* label:
«**
me
to M.
A) lOf MCptfetfiOM*
the choice of dw aMnet to be diepbyed on dw bbet
Directive M/379SBEC
the nto of Anide 7 0) |E) of
which M imtniti tot the
far placing them on dw
by turn t» be
rhec*meof
•My identify eaefety tfae<
far the
be of the type
of*
oil of.
ofl.
It • important t» temcmbtr diet Aaoex U of Dinette M/379VEEC hot (pedal
toncernini the lebeUinf of certain
«.
1.1.
SPECIAL CASES: SUBSTANCES
Itae wteonm tit dMified in Anne* I to Dinette <7/54«VEEC or dull be dMificd to *ccor-
«UKX with Ankle 5 (1) of Dinctiw «7/S4l/EEC How«cf, taeae ot that
dtonfied in eccoidMcc widi Aiock 2 of Dinar* C7/54I/EBC 4o oat ptami «
kethh by wlwlKion, b|e«iM of conact with «ktn in the fcmu it. whkh they «t pieced on dw
da not itquice e kM Kcordini to Ankle l< of dUi Diiean*. Havcvet,
hich sbaald hwe tppeMtd oa the lebri thill be tMnunea' w the wet by
•0 dw
for pleant the metal on die aaerket.
f. SPECIAL CASES: PREPARATIONS
— the rMluation of the physico-chemical properties,
— die evaluation of beahh heard*.
•.1.1. Evaluation of physico-chemical properties
9.1.1.1. FUmmtMitj
of dmc
ue deteimiacrf in •ecocdwcc widi Ankle 3 (2) of
Diiccthc M/379/EBC *ccoraui| to the acthodi ipecified in Put A of Aaan V to Dircctm
•7/541/EEC HMec ptepemioni will be doHfied •ccordias to dw icwhi of the lem CMiicd OIK
end with lopect to the criterie of Animc V end to the criwii of the bbclliqt gwde. Howem. by
derogtiion, in the ce«e where ftteoui ptepemiom are praduced to order in smell OBMWUI. the
e*e|Mee4»imiCumc*abee*t^^
The expression of die gaseous mature
A.F, + ... + A.F. + ... A.F. + B,I, + ... B.I.
where: A. and B, arc the molar bacuoM
; . P. flammable (as
l« incA ftt
n number of inert ,
. B flllflkDCiT Ol MMtt .
can be tnntformed b a form where all the li (inert pees) are expressed by a «iircffen equivalent
vainf a coefficient Ki and where the equivalent content of inHammabk (as A'< is i
'4 - A. x (.
ICO
(A.+K3J
AP3-32
-------
i.7. 91
Official Journal of the European Cotnmuniaei
No L 110/77
Bv wing die value of the maximum content of flaminabk gas which, in « mixoii* with nitrogen,
gives • composition which it not flammable in air (To), the following explosion can be
i < I
The pi mixture i* flammable if die value of the above exyreoMon it gftaur Ihah one and the
P-P-A^. i. *~JG-» kfri-iy •.,—ia.. t-rf A- fi.— o .•> _ . .. -t. ^- -r-^nn)
according to die
Coefficients of equivalency (Ki)
The value* of the cotftkicatt of equivalency Ki, between ih« {AMI |«m and atttofea and die
whits of the mudniira coniemi of fUmimbto fM fTd) my be found in Ttbict 1 *nd 2 of the
ISO SttadHd ISO/DIS
OMMK*I of thinmihk |BI (To)
Ifce wlue of Ibc naximttin coaim of (Imairfilf f» (W) my bt found w Table 2 of At ISO
Sundud ISO/DIS IOIJ4. When a Td wlue far t flammable pi doc* am •ppew in the above
anwfeitdKramfpomliAclo^eipfotm^
ofTcivOlbiMtttlttfty
The tgpmrion above can be uatd a> allow M •ppfopriMe labeUiof of f«M«ui _
ooimu. it ifaouU not be tefudcd M • amhod for itylaring aperuBtfuaban for the
of
fviihenMOM. din ttpceation fhct no fafonnttMO M •> wheAer • mtztmt cenuinui(
an| aaiei can be ptcparcd talely. Vhen «aa«nttiin
The BBteNion above will pit tefiabk rouhi only if the flammable fata do not influence
each ether at
-------
No L ISO/79
Official Journal of die European Communitki
I. 7. 91
effect!
diteJiBtmoU^igrtttonfoflKahh^
eMkiatian of the health haw* it made Mcoitfaf» *•
**
Labelling
I to Diisctfre ll/J7»/EICTiblei I A n VI A. when the fa^o) cniuidcrcd aie
CMIttdcnNl 10 W ffCMoCO VMA
•> che nquiicincMi of Aflkfe 3
M/JWEEC
wtatoliom i«|e«iOB or contact *Mi ikw io dw
_,
With «rf
jhould it
COMMISSION STATEMENT
grnic, muttgcnic « ie»«egenk effect*
ek 21 of Di«cti« 47/541/EEC it »
by M«nbe« St.«. uid luving
in
AP3-34
-------
§717.19
tion of records must be submitted. The
reporting period will be specified by
the letter or notice but in no case will
such reporting period be less than 45
days from the date of the letter or the
effective date of the notice.
(c) How to report. When required to
report, firms must submit copies of
records (preferably by certified mall)
to: Document Processing Center (TS-
790) Rm. Lr-100, Office of Toxic Sub-
stances, Environmental Protection
Agency, 401 M St.. SW.. Washington.
DC 20460. ATTN: 8(c) Allegations.
(Approved by the Office of Management
and Budget under control number 2070-
0017)
148 PR 38187. Aug. 22, 1983, as amended at
49 PR 23183. June 5. 1984: 52 PR 20084.
May 29.1987: 53 FR 12523. Apr. 15.19881
8717.19 Confidentiality.
(a) Any person submitting copies of
records may assert a business confi-
dentiality claim covering all or part of
the submitted information. Any infor-
mation covered by a claim will be dis-
closed by EPA only as provided in pro-
cedures set forth at Part 2 of this title.
(b) If no claim accompanies a docu-
ment at the time it is submitted to
EPA. the document will be placed In
an open file available to the public
without further notice to the respond-
ent.
(c) To asset a claim of confidential-
ity for information contained in a sub-
mitted record, the respondent must
submit two copies of the document.
(1) One copy must be complete. In
that copy, the respondent must indi-
cate what information, if any. is
claimed as confidential by marking the
specific information on each page with
a label such as "confidential", "propri-
etary", or "trade secret" and briefly
state the basis of the claim.
(2) If some information is claimed as
confidential, the respondent must
submit a second copy of the record.
The second copy must be complete.
except that all information claimed as
confidential in the first copy must be
deleted.
(3) The first copy will be for Internal
'use by EPA. The second copy will be
placed in. an open file to be available
APPENDIX 4
40 CFR Ch. I (7-1-90 Edition)
(4) Failure to furnish a second copy
when information is claimed as confi-
dential in the first copy will be consid-
ered a presumptive waiver of the claim
of confidentiality. EPA will notify the
respondent b.y certified mail that a
finding of a presumptive waiver of the
claim of confidentiality has been
made. The respondent will be given 30
days from the date of receipt of notifi-
cation to submit the required second
copy. If the respondent fails to submit
the second copy within the 30 days,
EPA will place the first copy in the
public file.
PART 720— PREMANUFACTURE
NOTIFICATION
Svbpart A— C*n«rvl Previttau
Sec.
720.1 Scope.
720.3 Definition*.
Subpart B—Appflcabllity . .
720.22 Persons who must report.
720.25 Determining whether a chemical
substance Is on the Inventory.
720.30 Chemicals not subject to notifica-
tion requirements.
720.36 Exemption for research and devel-
opment.
72048 Exemptions for test marketing.
720.40 General.
720.45 Information that must be Included
In the notice form.
720.50 Submission of test data and other
data concerning the health and environ-
mental effects of a substance.
720.57 Imports.
Svbpart D— DUpodtiofl of N«tfa»
720.60 General.
720.62. Notice that notification is not re-
quired.
720.65 Acknowledgment of receipt of a
notice; errors In the notice: incomplete
submissions; false and misleading state-
ments.
720.70 Notice In the FEDERAL Rcoisna.
72075 Notice review period.
720.78 Recordkeeping.
Swfepmt E—CwtfidMtMlty «rw» PwMie AOMI
to InfOfNiotiwi
720.80 General provisions.
7*o.*s fihrnniml Identity.
AP4-I
-------
Environmental Protection Agency
§ 720.3
Sec.
720.87 Categories or proposed categories or
uses of a new chemical substance.
730.90 Data from health and safety stud-
ies.
720.95 Public file. ' ' .
Ivbport F—Commencement ef Momrfectvre er
720.102 Notice of commencement of manu-
facture or import.
Swbpart G—Compliance end Inspection!
720.120 Compliance.
720.122 Inspections.
APPENDIX A—PKniANDPAcnntE Nonce FOR
NEW CHEMICAL SOMTANCES
AUTHORITY: 15 U.S.C. 2604.2607. and 2613.
. SOURCE: 48 PR 21742. May 13.1983. unless
otherwise noted.
Subport A—General Previsions
1720.1 Scope.
This part establishes procedures for
the reporting of new chemical sub*
stances by manufacturers and import*
ers under section 5 of the Toxic Sub-
stances Control Act. 15 U.S.C. 2604.
The rule defines the persons and
chemical substances subject to the re-
porting requirements, prescribes the
contents of section 5 notices, and es-
tablishes procedures for submitting
notices: The rule also establishes EPA
policy regarding claims of confiden-
tiality for, and public disclosure of.
various categories of information sub-
mitted in connection with section 5 no-
tices.
(Approved by the Office of Management
and Budget under control number 2070-
0012) . .
6720.3 Definitions.
(a)(l) For the purposes of this part.
the terms "cosmetic." "device."
"drug." "food," and "food additive"
have the meanings contained in the
Federal Food, Drug, and Cosmetic Act,
21 UJ5.C. 321 et teg., and the regula-
tions issued under it. In addition, the
term "food" includes poultry and poul-
try products, as defined in the Poultry
Products Inspection Act, 21 U.S.C. 453
et teg.; meats and meat food products,
•s defined in the Federal Meat Inspec-
tion Act. 21 U.S.C. 60 et teg.; and eggs
and egg products, as defined in the
Egg Products Inspection Act. 21 UJS.C.
1033 et teg.
(2) The term "pesticide" has the
meaning contained in the Federal In-
secticide, Fungicide, and Rodenticide
Act, 7 U.S.C. 136 et teg. and the regu-
lations issued under it
(3) The terms "byproduct material."
"source material." and "special nucle-
ar material" have the meanings con-
tained in the Atomic Energy Act of
1954.42 U.S.C 2014 et teg. and the reg-
ulations issued under it.
(b) "Act" means the Toxic Sub-
stances Control Act, 15 U.S.C. 2601 et
teg.
(c) "Article" means a manufactured
item (1) which is formed to a specific
shape or design during manufacture,
(2) which has end use functlon(s) de-
pendent in whole or in part upon its
shape or design during end use. and
(3) which has either no change of
chemical composition during its end
use or only those changes of composi-
tion which have no commercial pur-
pose separate from that of the article
and that may occur as described in
§ 720.36(g)(5), except that fluids and
particles are not considered articles re-
gardless of shape or design.
(d) "Byproduct" means a chemical
substance produced without a separate
commercial intent during the manu-
facture, processing, use, or disposal of
another chemical substance or mix-
ture.
(e) "Chemical substance" means any
organic or inorganic substance of a
particular molecular Identity, includ-
ing any combination of such sub-
stances occurring in whole or in part
as a result of a chemical reaction or
occurring in nature, and any chemical
element or uncombined radical, except
that "chemical substance" does not in-
clude:
(1) Any mixture.
(2) Any pesticide when manufac-
tured, processed, or distributed in com-
merce for use as a pesticide.
(3) Tobacco or any tobacco product.
(4) Any source material, special nu-
clear material, or byproduct material.
(5) Any pistol, firearm, revolver.
shells, or cartridges.
(6) Any food, food additive, drug.
cosmetic, or device, when manufac-
AP4-2
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§720.3
tured, processed, or distributed in com-
merce for use as a food, food additive.
drug, cosmetic, or device.
U) "Commerce" means trade, traffic.
transportation, or'other commerce (1)
between a place in a State and any
place outside of such State, or (2)
which affects trade, traffic, transpor-
tation, or commerce between a place in
a State and any place outside of such
State.
(g) "Customs territory of the United
States" means the 50 States, Puerto
Rico, and the District of Columbia.
, (h) "Director" means the Director of
the EPA Office of Toxic Substances.
(i) "Distribute in commerce" means
to sell in commerce, to introduce or de-
liver for introduction into commerce.
or to hold after introduction into com-
merce.
(J) "EPA" means the UJ5. Environ
mental Protection Agency.
"Health and safety study" or
"study" means any study of any effect
of a chemical substance or mixture on
health or the environment or on both.
including underlying data and epide-
miologies! studies, studies of occupa-
tional exposure to a chemical sub-
stance or mixture, toxicologies!, clini-
cal, and ecological, or other studies of
a chemical substance or mixture, and
any test performed under the Act.
Chemical Identity is always part of a
health and safety study.
(1) Not only is information which
arises as a result of a formal, disci-
plined study Included, but other infor-
mation relating to the effects of a
chemical substance or mixture on
health or the environment is also in-
cluded. Any data that bear on the ef-
fects of a chemical substance on
health or the environment would be
included.
(2) Examples Include:
(i) Long- and short-term tests of mu-
tagenicity, carclnogeniclty, or terato-
genlcity; data on behavioral disorders:
dermatoxicity; pharmacological ef-
fects; mammalian absorption, distribu-
tion, metabolism, and excretion; cumu-
lative, additive, and synergistlc effects;
acute, subchronlc, and chronic effects;
and structure/activity analyses.
(U) Tests for ecological or other envi-
ronmental effects on invertebrates.
fish, or other animals, and plants. In-
AP4-3
' 40 CFR Ch. I (7-1-90 edition)
eluding: Acute toxiclty tests, chronic
toxlclty tests, critical life stage tests.
behavioral tests, algal' growth tests.
seed germination tests, plant growth
or damage tests, microbial function
testa, bioconcentraUon or bioaccumu-
latton tests, and model ecosystem (ml-
croouaiT*) studies.
(ill) Assessments of human and envi-
ronmental exposure. Including work-
place exposure, and impacts of a par-
ticular chemical substance or mixture
on the environment, including surveys.
tests, and studies of: Biological, photo-
chemical, and chemical degradation;
air. water, and soil transport; biomag-
nificatlon and bioconcentraUon; and
chemical and physical properties. e.g..
boiling point, vapor pressure, evapora-
tion rates from soil and water, octa-
nol/water partition coefficient, and
water solubility.
(iv) Monitoring data, when they
have been aggregated and analyzed to
measure the exposure of humans or
the environment to a chemical sub-
stance or mixture.
(v) Any assessments of risk to health
and the environment resulting from
the manufacture, processing, distribu-
tion In commerce, use. or disposal of
the chemical substance.
(1) "Importer" means any person
who Imports a chemical substance. In-
cluding a chemical substance as part
of a mixture or article, into the cus-
toms territory of. the United States.
"Importer" includes the person pri-
marily liable for the payment of any
duties on the merchandise or an au-
thorized agent acting on his or her
behalf. The term also includes, as ap-
propriate:
(1) The consignee.
(2) The importer of record.
(3) The actual owner if an actual
owner's declaration and. superseding
bond has been filed in accordance with
19 CFR 141.20; or
(4) The transferee, if the right to
draw merchandise in a bonded ware-
house has been transferred in accord-
ance with Subpart C of 19 CFR Part
144. (See "principal Importer.")
(m) "Impurity" means a chemical
substance which is unintentionally
present with another chemical sub-
stance.
-------
Environmental Protection Agency
(n) "Intermediate" means any chem-
ical substance that is consumed, in
whole or in part, in chemical reactions
used for the intentional manufacture
of another chemical substances) or
mixture(s). or that is intentionally
present for the purpose of altering the
rates of such chemical reactions.
(o) "Inventory" means the list of
. chemical substances manufactured or
processed in the United States that
EPA compiled and keeps current
under section 8(b) of the Act.
(p) "Known to or reasonably ascer-
tainable by" means all information in
a person's possession or control, plus
all information that a reasonable
person similarly situated might be ex-
pected to possess, control, or know.
(q) "Manufacture" means to produce
or manufacture in the United States
or import into the customs territory of
the United States.
(r) "Manufacture or import for com-
mercial purposes" means:
(I) To import, produce, or manufac-
ture with the purpose of obtaining an
immediate or eventual commercial ad-
vantage for the manufacturer or im-
porter, and includes, among other
things, "manufacture" of any amount
of a chemical substance or mixture:
(i) For commercial distribution, in-
cluding for test marketing.
Cil) For use by the manufacturer. In-
cluding use for product research and
development or as an intermediate.
(2) The term also applies to sub-
stances that are produced colnciden-
tally during the manufacture, process-
ing, use, or disposal of another sub-
stance or mixture, including byprod-
ucts that are separated from that
other substance or mixture and impu-
rities that remain in that substance or
mixture. Byproducts and impurities
without separate commercial value are
nonetheless produced for the purpose
of obtaining a commercial advantage.
since they are part of the manufacture
of a chemical substance for commer-
cial purposes.
(s) "Manufacture solely for export"
means to manufacture or import for
commercial purposes a chemical sub-
stance solely for export from the
United States under the following re-
strictions on activities in the United
States:
§720.3
(1) Distribution in commerce to limit-
ed to purposes of export or processing
solely for export as defined in < 721.3
of this chapter.
(2) The manufacturer or Importer.
and any person to whom the substance
to distributed for purposes of export or
processing solely for export (as de-
fined In 1721.3 of this chapter), may
not use the substance except In small
quantities solely for research and de-
velopment In accordance with 1720.36.
"Manufacturer" means a person
who Imports, produces, or munuffKr-
tures a chemical substance. A person
who extracts a component chemical
substance from a previously existing
chemical substance or a complex com-
bination of substances to a manufac-
turer of that component chemical sub-
stance. A person who contracts with a
manufacturer to manufacture or
produce a chemical substance to also a
manufacturer If (1) the manufacturer
manufactures or produces the sub-
stance exclusively for that person, and
(2) that person specifies the identity
of the substance and controls the total
amount produced and the basic tech-
nology for the plant process.
(u) "Mixture" means any combina-
tion of two or more chemical sub-
stances if the combination does not
occur In nature and to not. in whole or
In part, the result of a chemical reac-
tion; except "mixture" does include (1)
any combination which occurs. In
whole or in part, as a result of a chem-
ical reaction if the combination could
have been manufactured for commer-
cial purposes without a chemical reac-
tion at the time the chemical sub-
stances comprising the combination
were combined, and if all of the chemi-
cal substances comprising the combi-
nation are not new chemical sub-
stances, and (2) hydrates of a chemical
substance or hydrated ions formed by
association of a chemical substance
with water, so long as the nonhydrat-
ed form to Itself not a new chemical
substance.
(v> "New chemical substance" means
any chemical substance which to not
included on the Inventory.
(w) "Nontoolated Intermediate"
means any Intermediate that to not in-
tentionally removed from the equip-
ment in which it to manufactured, in-
AP4-4
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§ 720.3
eluding the reaction vessel In which 11
Is manufactured, equipment which Is
ancillary to the reaction vessel, and
any equipment through which the
chemical substance passes during a
continuous now process, but not In-
cluding tanks or other vessels in which
the substance Is stored after its manu-
facture.
(x) "Person" means any natural
person, firm, company, corporation.
joint-venture, partnership, sole propri-
etorship, association, or any other
business entity, any State or political
subdivision thereof, any municipality.
any interstate body, and any depart-
ment, agency or instrumentality of the
Federal Government.
(y) "Possession or control" means in
possession or control of the submitter,
or of any subsidiary, partnership in
which the submitter is a general part-
ner, parent company, or any company
or partnership which the parent com-
pany owns or controls, if the subsidi-
ary, parent company, or other compa-
ny or partnership is associated with
the submitter in the research, develop-
ment, test marketing, or commercial
marketing of the chemical substance
in question. (A parent company owns
or controls another company if the
parent owns or controls 50 percent or
more of the ether company's voting
stock. A parent company owns or con-
trols any partnership in which it Is a
general partner). Information is in-
cluded within this definition If it is:
(1) In files maintained by submit-
ter's employees who are:
(1) Associated with research, develop-
ment, test marketing, or commercial
marketing of the chemical substance
in question.
(ii) Reasonably likely to have such
data.
(2) Maintained In the files of other
agents of the submitter who are asso-
ciated with research, development.
test marketing, or commercial market-
ing of the chemical substance in ques-
tion in the course of their employment
as such agents.
(z) "Principal importer" means the
first importer who, knowing that a
new chemical substance will be im-
ported rather than manufactured do-
mestically, specifies the identity of the
chemical substance and the total
40 CFR Ch. I (7-1.90 Edition)
amount to be Imported. Only persons
who are Incorporated, licensed, or
doing business In the United States
may be principal importers.
(aa) "Process" means the prepara-
tion of a chemical substance or mix-
ture, after Its manufacture, for distri-
bution In commerce (1) In the same
form or physical state as, or In a dif-
ferent form or physical state from,
that in which ft was received by the
person no preparing such substance or
mixture, or (2) as part of a mixture or
article containing the chemical sub-
stance or mixture.
(bb> "Processor" means any person
who processes a chemical substance or
mixture.
(cc) "Small quantities solely for re-
search and development" (or "small
quantities solely for purposes of scien-
tific experimentation or analysis or
chemical research on, or analysis of.
such substance or another substance,
including such research or analysis for
the development of a product") means
quantities of a chemical substance
manufactured, imported, or processed
or proposed to be manufactured, im-
ported, or processed solely for re-
search and development that are not
greater than reasonably necessary for
such purposes.
(dd) "State" means any State of the
United States and the District of Co-
lumbia, the Commonwealth of Puerto
Rico, the Virgin Islands, Guam, the
Canal Zone. American Samoa, the
Northern Mariana Islands, and any
other territory or possession of the
United States.
(ee) "Technically qualified individ-
ual" means a person or persons (1)
who, because of education, training, or
experience, or a combination of these
factors, is capable of understanding
the health and environmental risks as-
sociated with the chemical substance
which is used under his or her supervi-
sion, (2) who Is responsible for enforc-
ing appropriate methods of conducting
scientific experimentation, analysis, or
chemical research to minimize such
risks, and (3) who is responsible for
the safety assessments and clearances
related to the procurement, storage.
use. and disposal of the chemical sub-
stance as may be appropriate or je-
AP4-5
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- Environmental Protection Agency
quired within the scope of conducting
a research and development activity.
(ff) "Test data4' means data from a
forma! or Informal test or experiment.
including Information concerning the
objectives, experimental methods and
materials, protocols, results, data anal-
yses, recorded observations, monitor-
'Ing data, measurements, and conclu-
sions from a test or experiment.
(gg) "Test marketing" means the dis-
tribution In commerce of no more
than a predetermined amount of a
chemical substance, mixture, or article
containing that chemical substance or
mixture, by a manufacturer or proces-
sor, to no more than a defined number
of potential customers to explore
market capability in a competitive sit-
uation during a predetermined testing
period prior to the broader distribu-
tion of that chemical substance, mix-
ture, or article in commerce.
-------
§720.30
, 40 CFR Ch. I (7-1-90 Edition)
or an infrared spectrum of the particu-
lar chemical substance, or if such data
do not resolve uncertainties with re-
spect to the identity of the chemical
substance, additional or alternative
spectra or other data to Identify the
substance.
(3) If an importer cannot provide all
the information required by para*
graph (bX2) of this section because It
is claimed confidential business infor-
mation by its foreign manufacturer or
supplier, the foreign manufacturer or
supplier may supply the information
directly to EPA.
(4) EPA will review the Information
submitted by the proposed manufac-
turer or Importer under this para-
graph to determine whether it has a
oona fi&e intent to manufacture or
import the chemical substance. If nec-
essary, EPA will compare this informa-
tion either to the information request-
ed for the confidential chemical sub-
stance under 1710.7(eX2Xv) of this
chapter or the information requested
under 1720.85(bX3Xili).
(S) If the proposed manufacturer or
importer has shown a oona /We intent
to manufacture or import the sub-
stance, and provide sufficient unam-
biguous .chemical identity information
so EPA can make a conclusive determi-
nation of the chemical substance's In-
ventory status, EPA will search the
. confidential Inventory and inform the
proposed manufacturer or importer
whether the chemical substance Is on
the confidential Inventory.
(6) If the chemical substance is
found on the confidential Inventory,
EPA will notify the person(s) who
originally reported the chemical sub-
stance that another person has dem-
onstrated a oona fide Intent to manu-
facture or import the substance and
therefore was told that the chemical
substance is on the Inventory.
(7) A disclosure of a confidential
chemical Identity to a person with a
oona flde Intent to manufacture or
Import the particular chemical sub-
stance will not be considered a public
disclosure of confidential business in-
formation under section 14 of the Act.
(8) EPA will answer an inquiry on
whether a particular chemical sub-
stance is on the confidential Inventory
within 30 days after receipt of a com-
plete submission under paragraph
.<
(c) Any new chemical substance
which will be manufactured or Import-
ed in small quantities solely for re-
search and development under
1720.36.
(d) Any new chemical substance
which will be manufactured or import-
ed solely for test-marketing purposes
under an exemption granted under
1720.38.
(e) Any new chemical substance
manufactured solely for export if,
when the substance is distributed in
commerce:
(1) The substance is labeled in ac-
cordance with section 12(aXl)(B) of
the Act.
(2) The manufacturer .knows that
the person to whom the substance is
being distributed intends to export it
or process it solely for export as de-
fined in 17214 of this chapter.
(f) Any new chemical substance
which is manufactured or imported
under the terms of a rule promulgated
under section 5
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Environmental Protection Agency
the component substances extracted
from the byproduct.)
The chemical substances de-
scribed below; (Although they are
manufactured for commercial pur-
poses under the Act. they .are not man-
ufactured for distribution in com-
merce as chemical substances per se
and have no commercial purpose sepa-
rate from the substance, mixture, or
article of which they are a part.)
(1) Any impurity.
(?) Any byproduct which is not used
for commercial purposes.
. (3) Any chemical substance which
results from a chemical reaction that
occurs incidental to exposure of an-
other chemical substance, mixture, or
article to environmental factors such
as air. moisture, mlcrobial organisms.
or sunlight.
(4) Any chemical substance which
results from a chemical reaction that
occurs incidental to storage or disposal
of another chemical substance, mix-
ture, or article.
(5) Any chemical substance which
results from a chemical reaction that
occurs upon end use of another chemi-
cal substance, mixture, or article such
as an adhesive, paint, miscellaneous
cleanser or other housekeeping prod-
uct, fuel additive, water softening and
treatment agent, photographic film.
battery, .match, or safety flare, and
which is not itself manufactured or
imported for distribution in commerce
or for use as an intermediate.
' (6) Any chemical substance which
results from a chemical reaction that
occurs upon use of curable plastic or
rubber molding compounds, inks.
drying oils, metal finishing com-
pounds, adhesives. or paints, or any
other chemical substance formed
during the manufacture of an article
destined for the marketplace without
further chemical change of the chemi-
cal substance except for those chemi-
cal changes that occur as described
elsewhere in this paragraph.
(7) Any chemical substance which
results from a chemical reaction that
occurs when (1) a stabilizer, colorant.
odorant, antioxidant, filler, solvent.
carrier, surfactant, plastidzer, corro-
sion inhibitor, antifoamer or de-
foamer. dispersant. precipitation in-
hibitor, binder, emulslfier, deemulsl-
§720.36
fier. dewaterlng agent, agglomerating
agent, adhesion promoter, flow modi-
fier, pH neutralizer. sequesterant, co-
agulant, flocculant. fire retardant, lu-
bricant, chelating agent, or quality
control reagent functions as intented.
or (ii) a chemical substance, which is
intended solely to impart a specific
physlochemical characteristic, func-
tions as intended.
<8) Any nbnisolated intermediate.
(i) Any chemical substance which is
manufactured solely for non-commer-
cial research and development pur-
poses. Non-commercial research and
development purposes include scientif-
ic experimentation, research, or analy-
sis conducted by academic, govern-
ment, or Independent not-for-profit re-
search organizations (e.g., universities,
colleges, teaching hospitals, and re-
search institutes), unless the activity
is for eventual commercial purposes.
(48 PR 21742. May 13,1*83. at amended at
51 PR 15101. Apr. 22.19861
§720.36 Exemption for research and de-
velopment
(a) This part does not apply to a
chemical substance if the following
conditions are met:
(1) The chemical substance is manu-
factured or Imported only in small
quantities solely for research and de-
velopment.
(2) The manufacturer or importer
notifies all persons In Its employ or to
whom it directly distributes the chem-
ical substance, who are engaged In ex-
perimentation, research, or analysis on
the chemical substance, including the
manufacture, processing, use. trans-
port, storage, and disposal of the sub-
stance associated with research and
development activities, of any risk to
health. Identified under paragraph (b)
of this section. Which may be associat-
ed with the substance. The notifica-
tion must be made In accordance with
paragraph (c) of this section.
(3) The chemical substance is used
by. or directly under the supervision
of. a technically qualified individual.
(b)(l) To determine whether notifi-
cation under paragraph (aX2) of this
section is required, the manufacturer
or importer must review and evaluate
the following information to deter-
AP4-8
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§ 720.36 :
mine whether there is reason to be-
lieve there is any potential risk to
health which may be associated with
the chemical substance:
(1) Information In its possession or
control concerning any significant ad-
verse reaction by persons exposed to
the chemical substance which may
reasonably be associated with such ex-
posure.
(II) Information provided to the
manufacturer or Importer by a suppli-
er or any other person concerning a
health risk believed to be associated
with the substance.
(Ill) Health and environmental ef-
fects data In its possession or control
concerning the substance.
(lv) Information on health effects
which accompanies any EPA. rule or
order issued under sections 4, 5, or 6 of
the Act that applies to the substance
and of which the manufacturer or im-
porter has knowledge.
(2) When the research and develop-
ment activity is conducted solely in a
laboratory and exposure to the chemi-
cal substance is controlled through
the Implementation of prudent labora-
tory practices for handling chemical
substances of unknown toxlclty. and
any distribution, except for purposes
of disposal. Is to other such laborato-
ries for further research and develop-
ment activity, the Information speci-
fied In paragraph (bXl) of this section
need not be reviewed and evaluated.
(For purposes of this paragraph, a lab-
oratory Is a contained research facility
where relatively small quantities of
chemical substances are used on a
non-production basis, and where ac-
tivities involve the use of containers
for reactions, transfers, and other han-
dling of substances designed to be
easily manipulated by a single individ-
ual.)
(cXl) The manufacturer or Importer
must notify the persons identified in
paragraph (aX2) of this section by
means of a container labeling system,
conspicuous placement of notices in
areas where exposure may occur, writ-
ten notification to each person poten-
tially exposed, or any other method of
notification which adequately informs
persons of health risks which the
manufacturer or Importer has reason
to believe may be associated with the
40 CFR Ch. I (7.L90 Edition)
substance, as determined under para-
graph (bX 1) of this section.
(2) If the. manufacturer or importer
distributes a chemical substance man-
ufactured or Imported under this sec-
tion to persons not In its employ, the
manufacturer or Importer must In
written form:
(1) Notify those persons that the
substance Is to be used only for re-
search and development purposes.
(11) Provide the notice of health risks
specified In paragraph CcXl) of this
section.
(3) The adequacy of any notification
under this section Is the responsibility
of the manufacturer or Importer.
A chemical substance Is not
exempt from reporting under this part
if any amount of the substance, in-
cluding as part of a mixture, is proc-
essed, distributed In commerce, or
used, for any commercial purpose
other than research and development,
except where the chemical substance
Is processed, distributed in commerce,
or used only as an Impurity or as part
of an article.
(e) Quantities of the chemical sub-
stance, or of mixtures or articles con-
taining the chemical substance, re-
maining after completion of research
and development activities may be:
(1) Disposed of as a waste in accord-
ance with applicable Federal, state.
and local regulations, or
(2) Used for the following commer-
cial purposes:
(1) Burning it as a fuel.
(U) Reacting or otherwise processing
it to form other chemical substances
for commercial purposes, including ex-
tracting component chemical sub-
stances.
(f) Quantities of research and devel-
opment substances existing solely as
impurities in a product or incorporat-
ed into an article, in accordance with
paragraph (d) of this section, and
quantities of research and develop-
ment substances used solely for com-
mercial purposes listed In paragraph
(e) of this section, are not subject to
the requirements Of paragraphs (a).
(b). and (c) of this section, once re-
search and development activities
have been completed.
(g) A person who manufactures or
imports a chemical substance in small
AP4-9
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Environmental Protection Agency
quantities solely for research and de-
velopment is not required to comply
with the requirements of this section
if the person's exclusive Intention is to
perform research and development ac-
tivities solely for the purpose of deter-
mining whether-the substance can be
used as a pesticide.
[81 PR 15102. Apr. 22,1036]
1720.38 Exemptions for test marketing
(a) Any person may apply for an ex-
emption to manufacture or import a
new chemical substance for test mar-
keting. EPA may grant the exemption
if the person demonstrates that the
chemical substance will not present an
unreasonable risk to injury to health
or the environment as a result of the
test marketing.
(b) Persons applying for a test-mar-
keting exemption should provide the
following Information:
(1) All existing data regarding
health and environmental effects of
the chemical substance. Including
physical/chemical properties or. In the
absence of such data, a discussion of
toxiclty based on structure-activity re-
lationships (SAR) and relevant data
on chemical analogues.
(2) The maximum quantity of the
chemical substance which the appli-
cant will manufacture or Import for
test marketing.
(3) The maximum number of per-
•sons who may be provided the chemi-
cal substance during test marketing.
(4) The maximum number of per-
sons who may be exposed to the chem-
ical substance as a result of test mar-
keting, including information regard-
Ing duration and route of such expo-
sures.
(5) A description of the test-market-
ing activity, including Its length and
how it can be distinguished from full-
scale commercial production and re-
search and development. '
(c) In accordance with section
5(hX6) of .the Act, after EPA receives
an application for exemption under
this section, the Agency will file with
the Office of the Federal Register a
notice containing a summary of the in-
formation provided in the application,
to the. extent it has not been claimed
confidential.
§720.40
(d) No later than 45 days after EPA
receives an application, the Agency
will either approve or deny the appli-
cation. Thereafter. EPA will publish a
notice in the FEDERAL Ruumt ex-
plaining the reasons for approval or
denial.
In approving an application for
exemption. EPA may impose any re-
strictions necessary to ensure that the
substance will not present an unrea-
sonable risk of injury to health and
the environment as a result of test
marketing.
(Approved by the Office of Management
and Budget under control number 2070-
0012)
Subport C—Notice Form
9720.40 General.
(a) Ute of the notice form. Each
person who is required by Subpart B
to submit a notice must complete, sign.
and submit a notice containing the in-
formation in the form and manner set
forth in EPA Form No. 7710-25 * under
Appendix A of this part. Except as
otherwise provided in Subpart C, each
notice must be submitted with all ref-
erenced attachments. The information
on the form and all attachments
(unless the attachment appears in the
open scientific literature) must be in
English. All Information submitted
must be true and correct.
(b) When to submit a notice. Each
person who is required to submit a
notice must submit the notice at least
90 calendar days before manufacture
or import of the new chemical sub-
stance for commercial purposes begins.
(c) Where to submit a notice.- Each :
person who submits a notice must
submit it to the address listed on the
notice form.
(d) General notice requirements.
Each person who submits a notice
must provide the information de-
scribed in ft 720.45 and specified on the
notice form, to the extent such infor-
mation is known to or reasonably as-
* Copies may be obtained from: Industry
Assistance Office (TS-7M). Office of Toxic
Substances, Environmental Protection
Agency. 401 M St., SW.. Washington. DC
20460.
12ft
AP4-10
-------
§ 720.40
certainable by the submitter. In ac-
cordance with {720.50. the notice
must also Include any test data in the
submitter's possession or control and
descriptions of other data which are
known to or reasonably ascertainable
by the submitter and which concern
the health and environmental effects
of the new chemical substance.
(e) Agency or joint submissions. (1)
A manufacturer or importer may des-
ignate an agent to submit the notice.
Both the manufacturer or Importer
and the agent must sign the certifica-
tion on the form.
(2) A manufacturer or importer may
authorize another person, (e.g.. a for-
eign manufacturer or supplier, or a
toll manufacturer) to report some of
the information required In the notice
to EPA on its behalf. If separate por-
tions of a joint notice are not submit-
ted together, the submitter should in-
dicate which information will be sup-
plied by another person and identify
that person. The other person must
submit the Information on the appro-
priate part of the notice form. The
manufacturer or importer and any
other person supplying the informa-
tion must sign the certification provid-
ed on their respective notice forms.
(3) If EPA receives a submission
which does not include information re-
quired by this rule, which the submit-
ter indicates that it has authorized an-
other person to provide, the notice
review period will not begin until EPA
receives that information.
(f) New information. During the
.notice review period, if the submitter
possesses, controls, or knows of new In-
formation that materially adds to.
changes, or otherwise makes signifi-
, cantly more complete the information
included In the notice, the submitter
must that information to the address
listed on the notice form within ten
days of receiving the new information.
but no later than five days before the
end of the notice review period. The
new submission must clearly identify
the submitter and the notice to which
the new information is related. If the
new information becomes available
during the last five days of the notice
review period, the submitter must im-
mediately inform its EPA contract for
that notice by telephone.
40 CFR Cft. I (7-1-90 Edition)
(g) Chemical substances subject to a
section 4 test rule. U) Except as pro-
vided In paragraph (g>(3) of this sec-
tion, If (1) A person intends to manu-
facture or import a new chemical sub*
stance which Is subject to the notifica-
tion requirements of this part, and (ID
The chemical substance is subject to a
test rule promulgated under section 4
of the Act before the notice is submit-
ted, section 5(bXl) of the Act requires
the person to submit the test data re-
quired by the testing rule with the
notice. The person must submit the
data In the form and manner specified
in the test rule and in accordance with
f 720.50. If the person does not submit
the test data, the submission is Incom-
plete and EPA will follow the proce-
dures in 1720.65.
(2) If EPA has granted the submitter
an exemption under section 4(c) of the
Act from the requirement to conduct
tests and submit data, the submitter
may not submit a notice until EPA re-
ceives the test data.
(3) If EPA has granted the submitter
an exemption under section 4(c) of the
Act and if another person previously
has submitted the test data to EPA.
the exempted person may either
submit the test data or provide the fol-
lowing information as part of the
notice:
(1) The name, title, and address of
the person who submitted the test
data to EPA.
(ii) The date the test data were sub-
mitted to EPA.
(iil) A citation for the test rule.
(iv) A description of the exemption
and a reference'identlfying It.
(h) Chemical substances subject to a
section $(bK4) rule. (1) If a person (1)
intends to manufacture or import a
new chemical substance which is sub-
ject to the notification requirements
of this part and which is subject .to a
rule Issued under section 5(bK4)vf the
Act: and (ii) is not required by a rule
issued under section 4 of the Act to
submit test data for the subst&nce
before the submission of a notice, the
person must submit to EPA data de-
scribed In paragraph (h)(2> of this sec-
tion at the time the notice is submit-
ted.
(2) Data submitted under paragraph
-------
Environmental Protection Agency
which the person submitting the
notice believes show that the manu-
facture, processing, distribution in
commerce, use and disposal of the sub*
stance, or any combination of such ac-
tivities, will not present an unreason-
able risk of injury to health or the en-
vironment.
(Approved by the Office of Management
and Budget under control number 2070-
0012)
1720.45 Information that mutt be includ-
ed in the notice form.
Bach person who submits a notice
must include the information specified
in the notice form to the extent it is
known to or reasonably ascertalnable
by the submitter. However, no person
is required to include information
which relates solely to exposure of
human or ecological populations out-
side of the United States. The notice
form requires the following informa-
tion relating to the manufacture, proc-
essing, distribution in commerce, use,
and disposal of the new chemical sub-
stance:
(a)(l) For substances whose composi-
tion can be represented by a definite
structural diagram (Class 1 sub-
stances), the notice must provide the
chemical name (preferably Chemical
Abstracts Service (CAS) or Interna-
tional Union of Pure and Applied
Chemistry (IUPAC) nomenclature),
the molecular formula, CAS Registry
Number (if available), and a structural
diagram.
(2) For chemical substances that
cannot be fully represented by a struc-
tural diagram (Class 2 substances), the
notice must provide the chemical
name, the CAS Registry Number (if
. available), and molecular formula. The
notice must Identify the immediate
precursors and reactants by name and
CAS Registry Number (if the number
Is available). The notice must include
a partial or incomplete structural dia-
gram if possible. Chemical names for
such substances should be developed
according to the guidelines in the
TSCA Chemical Substance Inventory,
Initial Inventory, Volume 1.
(3) For polymers, the notice must
identify monomers and other reac-
tants used in the manufacture of the
polymer by chemical name and CAS
§720.45_
*
Registry Number (if available). The
notice must indicate the typical per-
cent of each monomer and other reac-
tant In the polymer (by weight per-
cent of total polymer); the maximum
residual of eacfi monomer present in
the polymer; and a partial or Incom-
plete structural diagram, if possible.
The notice must provide estimates of
the minimum number-average molecu-
lar weight of the polymer and the
amount of low weight species below
500 and below 1.000 molecular weight
and describe how the estimates were
obtained.
(b) The impurities anticipated to be
present in the substance by name,
CAS Registry number, and weight per-
cent of the total substance.
(c) Known synonyms or trade names
of the new chemical substance.
(d) A description of the byproducts
resulting from the manufacture, proc-
essing, use, and disposal of the new
chemical substance.
(e) The estimated maximum amount
to be manufactured or imported
during the first year of production and
the estimated maximum amount to be
manufactured or imported during any
12-month period during the first three
years of production.
(f) A description of intended catego-
ries of use by function and application,
the estimated percent of production
volume devoted to each category of
use. and the percent of the new sub-
stance In the formulation for each
commercial or consumer use.
(g> For sites controlled by the sub-
mitter
(1) The identity of sites where the
new substance will be manufactured.
processed, or used.
(2) A process description of each
manufacture, processing, and use oper-
ation which Includes a diagram of the
major unit operations and chemical
conversions, the identity and entry
point of all feedstocks, and the points
of release of the new chemical sub-
stance.
(3) Worker exposure information, in-
cluding worker activities, physical
form of the new substance to which
workers may be exposed, the number
of workers, and the duration of activi-
ties.
AP4-I2
-------
§72030
(4) Information on release of the
new substance to the environment, In-
cluding the quantity and media of re-
lease and type of control technology
used. '
(h) For sites not controlled by the
submitter, a description of each type
of processing and use operation involv-
ing the new chemical substance. In-
cluding Identification of the estimated
number of processing or use sites, situ-
ations in which worker exposure to
and/or environmental release of the
new chemical substance will occur, the
number of workers exposed -and the
duration of exposure, and controls
which limit worker exposure and envi-
ronmental release.
9 720.50 Submission of test data and other
data concerning the health and envi-
ronmental effects of • substance.
(a) Test data on the new chemical
substance in the possession or control
of the submitter. (1) Except as provid-
ed in paragraph (d) of this section.
each notice must contain all test data
in the submitter's possession or con-
trol which are related to the effects on
health or the environment of any
manufacture, processing, distribution
in commerce, use. or disposal of the
new chemical substance or any mix-
ture or article containing the new
chemical substance, or any combina-
tion of such activities. This includes
test data concerning the new chemical
substance In a pure, technical grade,
or formulated form,
(2) A full report or standard litera-
ture citation must be submitted for
the following types of test data:
(i) Health effects data.
(ii) Ecological effects data.
(iii) Physical and chemical proper-
ties data.
(iv) Environmental fate characteris-
tics.
(v) Monitoring data and other test
data related to human exposure to or
environmental release of the chemical
substance.
(3Xi) If the data do not appear in
the open scientific literature, the sub-
mitter must provide a full report. A
full report includes the experimental
methods and materials, results, discus-
sion and data analysis, conclusions,
*nd the name and address
' 40 CFR Ch. I (7-1.90 Edition)
of the laboratory that developed the
data.
- (ii) If the data appear In the open
scientific literature, the submitter
need only provide.a standard litera-
ture citation. A standard literature ci-
tation includes author, title, periodical
name, date of publication, volume, and
page numbers.
(4X1) If a study, report, or test is in-
complete when a person submits a
notice, the submitter must identify
the nature and purpose of the study;
name and address of the laboratory
developing the data: progress to date;
types of data collected; significant pre-
liminary results; and anticipated com-
pletion date.
(10 If a test or experiment is com-
pleted before the notice review period
ends, the person must submit the
study, report, or test to the address
listed on the notice form, as specified
in paragraph (a)(3Ki) of this section.
within ten days of receiving it. but no
later than five days before the end of
the review period. If the test or experi-
ment is completed during the last five
days of the review period, the submit-
ter must immediately inform its EPA
contact for that notice by telephone.
(5) For test data in the submitter's
possession or control which are not
listed in paragraph
-------
Environmental Protection Agency
ture or article containing the new
chemical substance, or of any combi-
nation of such activities:
(I) Any data, other than test data. In
the submitter's possession or control.
(II) Any data, including test data,
* which are not in the submitter's pos-
session or control, but which are
known to or reasonably ascertainable
by the submitter. For the purposes of
this section, data are known to or rea-
sonably ascertainable by the submitter
if the data are known to any of its em-
ployees or other agents who are associ-
ated with the research and develop-
ment, test marketing, or commercial
marketing of the substance.
(2) Data that must be described In-
clude data concerning the new chemi-
cal substance In a pure, technical
grade, or formulated form.
(3) The description of data reported
under this paragraph must include:
(i) If the data appear In the open sci-
entific literature, a standard literature
citation, which includes the author,
title, periodical name, date of publica-
tion, volume, and pages.
(U) If the data are not contained in
the open scientific literature, a de-
scription of the type of data and sum-
mary of the results. If available, and
the names and addresses of persons
the submitter believes may have pos-
. session or control of the data.
(4) All data described by this para-
graph are subject to these require-
ments, regardless of their age, quality.
or results; and regardless of. whether
they are complete at the time the
notice Is submitted.
(c) [Reserved]
(d) Data that need not be submit-
ted—(1) Data previously submitted to
EPA. (i) A person need not submit any
data previously submitted to EPA with
no claims of confidentiality if the
notice includes the office or person to
whom the data were submitted, the
date of submission, and. if appropri-
ate, a standard literature citation as
specified In paragraph of this section.
(3) Non-UA. exposure data. This
part does not require submission of
any data which relates only to expo-
sure of humans or the environment
outside the United States; This does
not exclude nonexposure data such as
data on health effects (Including epi-
demiological studies), ecological ef-
fects, physical and chemical proper-
ties, or environmental fate characteris-
tics.
[48 PR 81742. May 13. 1983. u amended at
51 PR 15102. Apr. 22.1986]
9 720.57 Imports.
(a) Except as otherwise provided in
this section, the provisions of this Sub-
part C apply to each person who sub-
mits a notice for a new chemcial sub-
stance which he or she Intends to
import for a commercial purpose. In
addition, each importer must comply
with this section.
(b) EPA wUl hold the principal Im-
porter, or the importer that EPA de-
termines must submit the notice when
there Is no principal importer under
1720.22(bM2), liable for complying
with this part, for completing the
notice form and for the completeness
and truthfulness of all Information
which It submits.
Subpart D—Disposition of Notices
If 720.60 General.
This subpart establishes procedures
that EPA will follow in reviewing no-
tices.
9 720.62 Notice that notification is not re-
quired.
When EPA receives a notice, EPA
will review it to determine whether
the chemical substance Is subject to
the requirements of this part. If EPA
determines that the chemical sub-
stance is not subject to these require-
ments, EPA will notify the submitter
that section 5 of the Act does not pre-
vent the manufacture or import of Use
AP4-14
-------
§720.65
substance and that the submission is
not a notice under this part.
(Approved by the Office of Management
and Budget under control number 2070-
0012)
9720.65 Acknowledgment of receipt of •
notice; errors in the notice; Incomplete
submissions; false and misleading
statements.
(a) Notification to submitter. EPA
will acknowledge receipt of each
notice by sending the submitter a
letter that identifies the premanufac-
ture notice number assigned to the
new chemical substance and the date
on which the review period begins.
The review period will begin on the
date the notice is received by the
Office of Toxic Substances Document
Control Ofilcer. The acknowledgment
does not constitute a finding by EPA
that the notice, as submitted, is in
compliance with this part.
(b) Errors in the notice. (1) Within
30 days of receipt of the notice. EPA
may request that the submitter
remedy errors in the notice. The fol-
lowing are examples of such errors:
U) Failure to date the notice form.
(ii) Typographical errors that cause
data to be misleading or answers to
any questions to be unclear.
. (ill) Contradictory Information.
(iv) Ambiguous statements or infor-
mation.
(2) In the request to correct the
notice. EPA will explain the action
which the submitter must take to cor-
rect the notice.
(3) If the submitter fails to correct
the notice within 15 days of receipt of
the request, EPA may extend the
notice period under section (S)(c) of
the Act. in accordance with § 720.75(c>.
Incomplete submissions. (1) A
submission is not complete, and the
notification period does not begin, if:
(i) The wrong person submits the
notice form.
(ii) The submitter does not sign the
notice form.
(iii) Some or all of the information
in the notice or the attachments are
not in English, except for published
•scientific literature.
(iv) The submitter does not use the
notice form.
' 40 CFR Ch. I (7-1-90 Edition)
(v) The submitter does not provide
information that is required by section
S(dXlKB) and (C) of the Act and
1720.50.
(vi) The submitter does not provide
information required on the notice
form and by 1720.45 or indicate that it
is not known to or reasonably ascer-
tainable by the submitter.
(vii) The submitter does not submit
a second copy of the submission with
all confidential information deleted
for the public file, as required by
i 720.80(b)(2).
(viii) The submitter does not include
any information required by section
5(b)U) of the Act and pursuant to a
rule promulgated under section 4 of
the Act. as required by 1720.40(g).
(ix) The submitter does not submit
data which the submitter believes
show that the chemical substance will
not present an unreasonable risk of
injury to health or the environment, if
EPA has listed the chemical substance
under section 5(b)(4) of the Act. as re*
quired in 1720.40(h).
(2 Hi) If EPA receives an incomplete
submission, the Director, or his or her
delegate, will notify the submitter
within 30 days of receipt that the sub-
mission is incomplete and that the
notice review period will not begin
until EPA receives a complete notice.
(U> If EPA obtains additional infor-
mation during the notice review period
that indicates the original submission
was incomplete, the Director, or his or
her delegate, may declare the submis-
sion Incomplete within 30 days after
EPA obtains the additional informa-
tion and so notify the submitter.
(3) The notification that a submis-
sion is incomplete under paragraph
(c)(2) (i) or (ii) of this section will in-
clude:
(DA statement of the basis of EPA's
determination that the submission is
incomplete.
(ii) The requirements for correcting
the incomplete submission.
(Hi) Information on procedures
under paragraph (c)(4) of this section
for filing objections to the determina-
tion or requesting modification of the
requirements for completing the sub-
mission.
(4) Within ten days after receipt of
notification by EPA that a submission
AP4-15
-------
Environmental Protection Agency
is incomplete, the submitter may file
written objections requesting that
EPA accept the submission as a com*
plete notice or modify the require-
ments necessary to complete the sub*
mission:
(5X1) EPA will consider the objec-
tions riled by the submitter. The Di-
rector, or his or her delegate, will de-
termine whether the submission was
complete or Incomplete, or whether to
modify the requirements for complet-
ing the submission. EPA will notify
the submitter In writing of EPA's re-
sponse within ten days of receiving the
objections. -
(U) If the Director, or his or her del-
egate, determines, in response to the
objection, that the submission was
complete, the notice review period will
be deemed suspended on the date EPA
declared the notice Incomplete, and
will resume on the date that the
notice is declared complete. The sub*
mltter need not correct the notice as
EPA originally requested. If EPA can
complete Its review within 90 days
from the date of the original submis-
sion, the Director, or his or her dele-
gate, may inform the submitter that
the running of the review period will
resume on the date EPA originally de-
clared It incomplete.
(Ill) If the Director, or his or her del-
egate, modifies the requirements for
completing the submission or concurs
with EPA's original determination, the
notice review period will begin when
EPA receives a complete notice.
(d) Materially false .or misleading
statements. If EPA discovers at any
time that person submitted materially
false or misleading statements in the
notice. EPA may find that the notice
was incomplete from the date it was
submitted, and take any other appro-
priate action.
1720.70 Notice in the Federal Refitter.
(a) Filing of FEDERAL REGISTER
notice. In accordance with section
5(d)(2) of the Act, after EPA receives a
notice, EPA wiU file with the Office of
the Federal Register a notice Includ-
ing the Information specified in para-
graph (b) of this section.
(b) Contents of notice. (I) In the
public interest, the specific chemical
identity listed In-the notice will be
§ 720.75
published in th*e FEDERAL REGISTER
unless the submitter has claimed
chemical identity confidential. If the
submitter claims confidentiality, a ge-
neric name will be published In accord-
ance with 8 720.85(aK3).
(2) The categories of use of the new
chemical substance will be published
as reported in the notice unless this
Information Is claimed confidential. If
confidentiality Is claimed, the generic
information which is submitted under
( 720.87(5) will be published.
(3) A list of data submitted in ac-
cordance with 1720.50(a) will be pub-
lished. In addition, for test data sub-
mitted in accordance with § 720.40(g),
a summary of the data will be pub-
lished.
(4) The submitter's Identity will be
published, unless the submitter has
claimed It confidential.
1720.75 Notice review period.
(a) Length of notice review period.
The notice review period specified in
section 5(a) of the Act runs for 90 days
from the date the Document Control
Officer for the Office of Toxic Sub-
stances receives a complete notice, or
the date EPA determines the notice is
complete under i 720.65(c>. unless the
Agency extends the period under sec-
tion 5(c) of TSCA and paragraph (c) of
this section.
(b) Suspension of the running of the
notice review period. (DA submitter
may voluntarily suspend the running
of the notice review period If the Di-
rector or his or her delegate agrees. If
the Director does not agree, the review
period will continue to run. and EPA
will notify the submitter. A submitter
may request a suspension at any time
during the notice review period. The
suspension must be for a specified
period of time.
(2) A request for suspension may be
made in writing to the TSCA Docu-
ment Processing Center (TS-790), Rm.
L-100, Office of Toxic Substances. En-
vironmental Protection Agency. 401 M
St.. SW.. Washington. DC 20460. The
suspension also may be made orally.
Including by telephone, to the submit-
ter's EPA contact for that notice. EPA
will send the submitter a written con-
AP4-16
-------
§720.78
firmation that the suspension has
been granted.
(1) An oral request may be granted
for 15 days only. To obtain a longer
suspension, the Document Control Of*
fleer for the Office of Toxic Sub-
stances must receive written confirma-
tion of the oral request. The notice
review period is suspended as of the
date of the oral request.
(ii) If the submitter has not made a
previous oral request, the running of
the notice review period is suspended
as of the date of receipt of the written
request by the Document Control Of-
ficer for the Office of Toxic Sub-
stances.
(c) Extension of notice review
period. (1) At any time during the
notice review period, EPA may deter-
mine that good cause exists to extend
the notice review period specified in
paragraph (a) of this section.
(2) If EPA makes such a determina-
tion, EPA will:
(i) Notify the submitter that EPA is
extending the notice review period for
a specified length of time, and state
the reasons for the extension.
(ii) Issue a notice for publication in
the FEDERAL REGISTER which states
that EPA is extending the notice
review period and gives the reasons for
.the extension.
(3) The initial extension may be for
a period of up to 90 days. If the initial
extension is for less than 90 days, EPA
may make additional extensions. How-
ever, the total period of extensions
may not exceed 90 days for any notice.
(4) The following are examples of
situations in which EPA may find that
good cause exists for extending the
notice review period:
.(1) EPA has reviewed the notice and
.determined that there is a significant
possibility that the chemical substance
will be regulated under section 5(e) or
section 5(f) of the Act, but EPA is
unable to initiate regulatory action
within the initial 90-day period.
(ii) EPA has reviewed the submission
and is seeking additional information.
(iii) EPA has received significant ad-
ditional information during the notice
review period.
(iv) The submitter has failed to cor-
rect a ntftice after receiving EPA's re-
quest under { 720.65(b).
40 CFR Ch. I (7-1-90 Edition)
. #
(d) Notice of expiration of notice
review period. EPA will notify the sub-
mitter that the notice review period
has expired or that EPA has complet-
ed its review of the notice. Expiration
of the review period does not consti-
tute EPA approval or certification of l
the new chemical substance, and does /
not mean that EPA may not take reg-'
ulatory action against ttosubstancein
the. future. After expiration of the
statutory notice review period. In the
absence of regulatory action by EPA
under section 5(e), 5(l) Persons who manufacture or
import a chemical substance under
AP4-17
-------
Environmental Protection Agoncy
1720.36 must retain the following
records: '' •
(i) Copies of, or citations to. informa-
tion reviewed and evaluated under
1720.36(b)(l) to determine thfe need to
make any notification of risk.
' (ID Documentation of the nature
and method of notification under
1720.36(0(1) Including copies of any
labels or written notices used.
(ill) Documentation of prudent labo-
'•atory practices used instead of notifi-
cation and evaluation under
|720.36(b>(2).
(iv) The names and addresses of any
persons other than the manf acturer or
importer to whom the substance Is dis-
tributed, the Identity of the substance
to the extent known, the amount dis-
tributed, and copies of the notifica-
tions required under § 720.36(c)(2).
These records are not required when
substances are distributed as impuri-
ties or incorporated into an article, in
accordance with paragraph (d) of this
section.
(2) A person who manufactures or
imports a chemical substance under
1720.36 and who manufactures or Im-
ports the substance in quantities
greater than 100 kilograms per year
must retain records of the identity of
the substance to the extent known.
the production volume of the sub-
stance, and the person's disposition of
the substance. The person is not re-
quired to maintain records of the dis-
position of products containing the
substance as an impurity or of. articles
incorporating the substances.
(3) Records under this paragraph
must be retained for 5 years after they
are developed.
(c) Any person who obtains a test-
marketing exemption under this part
must retain documentation of infor-
mation in the application and docu-
mentation of compliance with any re-
strictions imposed by EPA when it
granted the application. This informa-
tion must be retained for five years
from the final dflte of manufacture or
import under the exemption.
(Approved by the Office of Management
and Budget under control number 2070-
0012)
C48 PR 21742, May 13. 1983: 48 FR 33872.
July 26. 1983. as amended at 51 FR 15102.
Apr. 22.1986]
§720.80
. *
Subpori E—Confidentiality and Public
Access to Information
0 720.80 General prorl«loi«.
(a) A person may assert a claim of
confidentiality for any Information
which he or she submits to EPA under
this part.
(b) Any claim of confidentiality
must accompany the Information
when it is submitted to EPA.
(1X1) For Information submitted on
the notice form, the clalm(s) must be
asserted on the form in the manner
prescribed on the notice form.
(11) When a person submits informa-
tion in an attachment, the claim(s)
must be asserted in the attachment as
described on the notice form.
(2) The person must submit two
copies of each notice form and any at-
tachments if any Information is
claimed confidential.
(i) One copy of the form and attach-
ments must be complete. In that copy,
the submitter must mark the informa-
tion which is claimed confidential in
the manner prescribed on the notice
form.
(ii) The second copy must be com-
plete except that all information
claimed as confidential In the first
copy must be deleted. EPA will place
the second copy in the public file.
(ill) If the submitter does not pro-
vide the second copy, the submission is
incomplete and the notice review
period does not begin to run until EPA
receives the second copy, in accord-
ance with i 720.65(c)U )(vi>.
(c) EPA will disclose information
that is subject to a claim of confiden-
tiality asserted under this section only
to the extent permitted by the Act.
this subpart, and Part 2 of this title.
(d) If a notice submitter does not
assert a claim of confidentiality for in-
formation at the time it is submitted
to EPA. EPA may make the informa-
tion public and place it in the public
file without further notice to the sub-
mitter.
(Approved by the Office of Management
and Budget under control number 2070-
0012)
AP4-IS
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§ 720.85
6720.85 Chemical identity.
(a) Claims applicable to the period
prior to commencement of manufac-
ture or import (IXi) A person who
submits information to EPA under
this part may assert a claim of confi-
dentiality for the chemical identity of
the new chemical substance. This
claim will apply only to the period
prior to the commencement of manu-
facture or Import for commercial pur-
poses. A submitter may assert this
claim only if the submitter believes
that public disclosure prior to com-
mencement of manufacture or Import
of the fact that anyone intends to
manufacture or import the specific
chemical substance for commercial
purposes would reveal confidential
business information.
(ii) If the notice Includes a health
and safety study concerning the new
chemical substance and if the claim
for confidentiality with respect to the
chemical identity is denied in accord-
ance with i720.90(c). EPA will deny a
claim asserted under this paragraph.
(2) Any person who asserts a claim
of confidentiality for chemical Identity
under this paragraph must provide
one of the following items at the time
the notice is submitted:
(i) The generic name which was ac-
cepted by EPA in the prenotice consul-
tation conducted under paragraph
(a)(3) of this section.
(ii) One generic name that Is only as
generic as necessary to protect the
confidential chemical Identity of the
particular chemical substance. The
name should reveal the specific chemi-
cal identity to the maximum extent
possible. The generic name will be sub-
ject to EPA review and approval at the
time a notice of commencement is sub-
mitted. .
(3)(i) Any person who intends to
assert a claim of confidentiality for
the chemical identity of a new chemi-
cal substance may seek a determina-
tion by EPA of an appropriate generic
name for the substance before submit-
ting a notice. For this purpose, the
person should submit to EPA:
(A) The chemical identity of the
substance.
(B) A 'proposed generic name(s)
which in only as generic as necessary
to nrotect the, confidential chemical
AP4-19
40 CFR Ch. I (7-1-90 Edition)
identity of the new • chemical sub-
stance. The name(s) should reveal the
chemical identity of the substance to
the maximum extent possible.
(11) Within 30 days. EPA will inform
the submitter either that one of the
proposed generic names is adequate or
that none Is adequate and further con-
sultation Is necessary.
(4) If a submitter claims chemical
identity to be confidential under thii
paragraph, and if the submitter com-
plies with paragraph (aX2) of this sec-
tion. EPA will issue for publication in
the FEDERAL REGISTER notice described
in i 720.70 the generic name proposed
by the submitter or one agreed upon
by EPA and the submitter.
(b> Claims applicable to the period
after commencement of manufacture
or import. (1) Any claim of confiden-
tiality under paragraph (a) of this sec-
tion Is applicable only until the sub-
stance is manufactured or imported
for commercial purposes and becomes
eligible for inclusion on the Inventory.
To maintain the confidential status of
the chemical identity when the sub-
stance Is added to the Inventory, a
submitter must reassert the confiden-
tiality claim and substantiate the
claim In the notice of commencement
of manufacture required uner
§720.102. A submitter may not claim
the chemical indentity confidential for
the period after commencement of
manufacture or import unless the sub-
mitter claimed the chemical identity
confidential for the period prior to
commencement of manufacture or
import under paragraph (a) of this
section.
(2)(i) A person who believes that
public disclosure of the fact that
anyone manfactures or imports the
new chemical substance for commer-
cial purposes would reveal confidential
business information may assert a
claim of confidentiality under this
paragraph.
(il) If the notice includes a health
and safety study concerning the new
chemical substance, and if the claim
for confidentiality with respect to the
chemical identity is denied in accord-
ance with f 720.90(c). EPA will deny a
claim asserted under this paragraph.
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Environmental Protection Agency
(3) Any person who asserts a confi-
dentiality claim for chemical Identity
must:
(1) Comply with the requirements of
paragraph (a)(3) of this section re-
tarding submission of a generic name.
(U) Agree that EPA may disclose to a
person with a bona flde Intent to man-
ufacture or import the chemical sub-
stance the fact that the particular
chemical substance is Included on the
confidential Inventory for purposes of
notification under section 5
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