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  **For Official Use**          **ENV/MC/CHEM/HCL(98)15/REV2**   

                                                                 
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| Organisation de Coopération et |           | **OLIS :**   | *       |
| de Développement Economiques   |           |              | *11-Sep |
|                                |           |              | -1998** |
+--------------------------------+-----------+--------------+---------+
| Organisation for Economic      |           | **Dist. :**  | *       |
| Co-operation and Development   |           |              | *15-Sep |
|                                |           |              | -1998** |
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| \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ |           |              |         |
| \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ |           |              |         |
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+--------------------------------+-----------+--------------+---------+
|                                | **Or.     |              |         |
|                                | Eng.**    |              |         |
+--------------------------------+-----------+--------------+---------+
| **ENVIRONMENT DIRECTORATE**    |           |              |         |
|                                |           |              |         |
| **CHEMICALS GROUP AND          |           |              |         |
| MANAGEMENT COMMITTEE**         |           |              |         |
+--------------------------------+-----------+--------------+---------+

+-----------------------------------------------------------------------+
| **Advisory Group on Harmonization of Classification and Labelling**   |
+-----------------------------------------------------------------------+
| **A HARMONIZED INTEGRATED HAZARD CLASSIFICATION SYSTEM FOR**          |
|                                                                       |
| **HUMAN HEALTH AND ENVIRONMENTAL EFFECTS OF CHEMICALS**               |
+-----------------------------------------------------------------------+
| **Eighth Meeting of the Advisory Group on Harmonization of            |
| Classification and Labelling Systems, 3rd-4th September 1998, to be   |
| held at the Château de la Muette, Paris, beginning at 10:00 am**      |
|                                                                       |
| **on 3rd September**                                                  |
+-----------------------------------------------------------------------+

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  **69035**                                     

                                                

  **Document complet disponible sur OLIS dans   
  son format d\'origine**                       

  **Complete document available on OLIS in its  
  original format**                             
  --------------------------------------------- -------------------------

This document comprises the Harmonized Integrated Hazard Classification
System for Human Health and Environmental Effects on Chemicals as agreed
by the 8th Advisory Group Meeting. It contains step 4 documents for
those end-points for which harmonized classification criteria have been
completed (i.e. skin and eye irritation/corrosion, contact sensitizers,
germ cell mutagenicity, carcinogenicity, reproductive toxicity, acute
toxicity and aquatic hazards to the environment).

**INTRODUCTION**

The production and use of chemicals is fundamental in the economic
development of all countries and, at the same time, it may pose a risk
to the health and well-being of all people and the environment if not
managed in a responsible manner. The primary objective of hazard
classification and communication systems is to provide information to
protect human health and the environment. One essential step leading to
the safe use of chemicals is the identification of the specific hazards
and the organisation of that information so that it can be conveyed to
users of chemicals in a form that is easy to understand. Measures can
then be taken to avoid or manage potential risks in circumstances where
exposure may occur. This is the fundamental rationale behind the hazard
classification and labelling of chemicals. It has traditionally led at
the national level to sector-specific regulations (transport, industry,
environment, health, agriculture, consumer products, occupational
health). Because of differences in use and exposure, hazard
classification systems usually vary between sectors. In some cases,
there is little or no consistency within sectors between different
countries.

In 1952, the International Labor Office (ILO) began a study of the
classification and labelling of dangerous substances which led in 1989
to a Resolution considering the harmonization of systems of
classification and labelling for the use of hazardous chemicals at work.

In 1953, the UN Economic and Social Council created the UN Committee of
Experts on the Transport of Dangerous Goods (UNCETDG) charged with
developing recommendations addressed to governments and international
organizations concerned with the regulation of the transportation of
dangerous goods; amongst other aspects, these Recommendations cover the
principles of classification and definitions of the classes of dangerous
goods. In 1956, the UNCETDG first published its UN Recommendations on
Transport of Dangerous Goods (UNRTDG) which were recently modified
(1997) for the tenth time. The UNRTDG are now included in the transport
legislation of many UN states and they are used by the International
Maritime Organisation (IMO), the International Civil Aviation
Organisation (ICAO) and other international bodies covering transport
modes. Thus land-sea-air transport is the only sector where
harmonization of hazard classification and labelling has been to a large
degree achieved.

The UN Conference on Environment and Development (UNCED) in 1992
identified the harmonization of classification and labelling of
chemicals as one of six action programs in Chapter XIX of UNCED Agenda
21. Its objective was: "a globally harmonized hazard classification and
compatible labelling system (GHS) including material safety data sheets
and easily understandable symbols, should be available, if feasible, by
the year 2000." It was recognized that, while a harmonized
classification system might be feasible, harmonized labelling may or may
not be appropriate or possible across all sectors, but that
compatability of labelling systems might be achievable.

UNCED identified the International Program on Chemical Safety (IPCS) as
the nucleus for international cooperation on Chapter XIX activities.
Under the umbrella of IPCS a Coordinating Group for the Harmonization of
Chemical Classification Systems (CG/HCCS) was established to promote and
oversee the work to develop a GHS. Later, the oversight of the work of
the CG/HCCS was provided by the broader Inter Organisational Programme
for the Sound Management of Chemicals - IOMC. As expressed in the
CG/HCCS Terms of Reference, the goals of international harmonization are
to:

-   enhance the protection of mankind and the environment by providing
    an internationally comprehensible system for hazard communication;

-   provide a recognized framework for those countries without an
    existing system;

-   reduce the need for testing and evaluation of chemicals;

-   facilitate international trade in chemicals whose hazards have been
    properly assessed and identified on an international basis.

**ORGANIZATIONAL CONTEXT FOR DEVELOPMENT OF THE GHS**

The first priority of the CG/HCCS was the development of a harmonized
classification system defining the hazards of various endpoints of
concern. The Organisation for Economic Cooperation and Development
(OECD) was identified as the Focal Point for work on human health and
environmental hazards, ILO/UNCETDG as the Focal Point for work on
physical hazards, and ILO as the Focal Point for work on Hazard
Communication. The CG/HCCS would integrate the harmonized classification
scheme with a harmonized hazard communication system to give an overall
Globally Harmonized Classification and labelling System (GHS).

**The OECD Advisory Group on Harmonization of Classification and
Labelling (AG-HCL)**

The AG‑HCL was formally established in 1994 by the Joint Meeting of the
OECD Chemicals Group and Management Committee to develop proposals for a
harmonized classification system for the hazards of chemicals to human
health and the environment. It based its work on the initial efforts of
an OECD Clearing House (1991-1993) on the Acute Human Toxicity and on
the Acute Aquatic Toxicity of chemicals.

In its work the AG‑HCL followed a set of general principles developed by
the IOMC‑GG/HCCS for the work on harmonization of the hazard
classification of chemicals, that specifically:.

a)  the level of protection offered to workers, consumers, the general
    public and the environment should not be reduced as a result of
    harmonizing the classification and labelling systems;

b)  the hazard classification process refers only to the hazards arising
    from the intrinsic properties of chemical elements and compounds,
    and mixtures thereof, whether natural or synthetic;

c)  harmonization means establishing a common and coherent basis for
    chemical hazard classification and communication, from which the
    appropriate elements relevant to means of transport, consumer,
    worker and environment protection can be selected;

d)  the scope of harmonization includes both hazard classification
    criteria and hazard communication tools, e.g. labelling and chemical
    safety data sheets;

e)  changes in all existing systems will be required to achieve a single
    globally harmonized system; transitional measures should be included
    in the process of moving to the new system.

f)  the involvement of concerned international organisations of
    employers, workers, consumers, and other relevant organisations in
    the process of harmonization should be ensured,

g)  the comprehension of chemical hazard information, by the target
    audience, e.g. workers, consumers and the general public, should be
    addressed;

h)  test data already generated for the classification of chemicals
    under the existing systems, should be accepted when reclassifying
    these chemicals under the harmonized system;

i)  a new harmonized classification system may require adaptation of
    existing methods for testing of chemicals;

j)  in relation to chemical hazard communication, the safety and health
    of workers, consumers and the public in general should be ensured
    while protecting confidential business information, as prescribed by
    the competent authorities.

The work of the AG-HCL was generally of three related kinds:

a)  Comparison of the major classification systems, identification of
    similar or identical elements and, for the elements which were
    dissimilar, development of a consensus on a compromise;

b)  Examination of the scientific basis for the criteria which define
    the end‑point of concern, gaining expert consensus on the test
    methods, data interpretation and level of concern, and then seeking
    consensus on the criteria. For some end-points, the existing schemes
    had no criteria and the relevant criteria were developed by the
    AG‑HCL;

c)  Where there was a decision-tree approach (e.g. irritation) or where
    there were dependent criteria in the classification scheme (acute
    aquatic toxicity), development of consensus on the process or the
    scheme for using the criteria.

The AG‑HCL proceeded stepwise in developing its harmonized
classification criteria. For each end‑point the following steps
undertaken:

[Step 1]{.underline}:

A thorough analysis of existing classification systems, including the
scientific basis for the system and its criteria, its rationale and
explanation of the mode of use. A Step 1 document is prepared and
amended as required after discussion by AG‑HCL

[Step 2]{.underline}:

A proposal for a harmonized classification system and criteria for each
class is developed. A Step 2 document is prepared and amended as
required after discussion by AG‑HCL

[Step 3]{.underline}:

\(a\) AG‑HCL reaches consensus on the revised Step 2 proposal; or

\(b\) After attempts at consensus building fail, the specific
non-consensus items

are identified as alternatives in a revised Step 2 proposal.

[Step 4]{.underline}:

Final proposal is submitted to the OECD Joint Meeting for approval and
subsequently to the IOMC CG‑HCCS for global implementation.

As experience with the use of the system is accumulated, and as new
scientific information emerges, the test methods, the interpretation of
the test data and the harmonized criteria *per se* may have to be
updated. Thus, international work will continue to be needed in the
future and, depending on the nature of the future international
instrument for the implementation of the GHS, decisions will have to be
made on the mechanism for carrying out the updating work in the future.

**GENERAL CONSIDERATIONS**

**Scope** **of the Harmonized Classification System**

The work on harmonization of hazard classification and labelling focuses
on a harmonized system for all chemicals and mixtures of chemicals. The
application of the components of the system may vary by type of product
or stage of the life cycle.

The classification system applies to pure chemical substances, their
dilute solutions and to mixtures of chemical substances. However, since
special considerations are needed to classify mixtures, an OECD Working
Group on Classification Criteria for Mixtures has begun its work to
address harmonization in this area.

One objective of the harmonized hazard classification system is for it
to be simple and transparent with a clear distinction between classes in
order to allow for "self classification" as far as possible. For many
end‑points the criteria are semi‑quantitative or qualitative and expert
judgement is required to interpret the data for classification purposes.
Furthermore, for some end‑points, e.g. eye irritation, a decision tree
approach is given as an example.

**Presentation of Criteria**

The current criteria for specific endpoints are presented as a series of
chapters in this paper. These chapters include a number of sections all
of which are relevant to classification decisions. Some chapters also
have an Appendix which, unless clearly indicated to the contrary, are
not part of the criteria and should be regarded as background
information only. For one endpoint (hazardous for the aquatic
environment) a separate Guidance Document is considered essential for a
good understanding and use of the system.

**Test Methods** **and Test Data Quality**

The classification of a chemical substance depends both on the criteria
and on the reliability of the test methods underpinning the criteria. In
some cases the classification is determined by a pass or fail of a
specific test, e.g. the ready biodegradation test, while in other cases,
interpretations are made from dose/response curves and observations
during testing. In all cases, the test conditions need to be
standardized so that the results are reproducible with a given chemical
substance and the standardized test yields "valid" data for defining the
end‑point of concern. In this context, validation is the process by
which the reliability and the relevance of a procedure are established
for a particular purpose.

Tests that determine hazardous properties which are conducted according
to internationally recognised scientific principles can be used for
purposes of a hazard determination for health and environmental hazards.
The GHS criteria for determining health and environmental hazards should
be test method neutral, allowing different approaches as long as they
are scientifically sound and validated according to international
procedures and criteria already referred to in existing systems for the
endpoint of concern and produce mutually acceptable data.

**Previously Classified Chemicals**

One of the general principles established by the IOMC‑CG‑HCCS states
that test data already generated for the classification of chemicals
under the existing systems should be accepted when classifying these
chemicals under the harmonized system thereby avoiding duplicative
testing and the unnecessary use of test animals. This policy has
important implications in those cases where the criteria in the GHS are
different from those in an existing system. In some cases, it may be
difficult to determine the quality of existing data from older studies.
In such cases, expert judgement will needed.

**Substances Posing Special Problems**

The effect of a substance on biological and environmental systems is
influenced, inter alia, by the physico chemical properties of the
substance and the way in which it is biologically available. Some groups
of substances present special problems in this respect, for example some
polymers and metals.

**Animal Welfare**

The welfare of experimental animals is a concern . This ethical concern
includes not only the alleviation of stress and suffering but also, in
some countries, the use and consumption *per se* of test animals. Where
possible and appropriate, tests and experiments that do not require the
use of live animals are preferred to those using sentient live
experimental animals. To that end, for certain end-points (skin and eye
irritation/corrosion) testing schemes starting with non-animal
observation/measurements are included as part of the classification
system. For other endpoints such as acute toxicity, alternative animal
tests, using fewer animals or causing less suffering are internationally
accepted and should be preferred to the conventional LD50 test.

**Evidence From Humans**

For classification purposes, reliable epidemiological data and
experience on the effects of chemicals on humans (e.g. occupational
data, data from accident data bases) should be taken into account in the
evaluation of human health hazards of a chemical. Testing on humans
solely for hazard identification purposes is generally not acceptable.

**Weight of Evidence**

For some hazard endpoints, classification results directly when the data
satisfy the criteria. For others, classification of a chemical is made
on the basis of the total weight of evidence. This means that all
available information bearing on the determination of toxicity is
considered together, including the results of valid in vitro tests,
relevant animal data, and human experience such as epidemiological and
clinical studies and well-documented case reports and observations.

The quality and consistency of the data are important. Evaluation of
substances related to the material under study should be included, as
should site of action and mechanism or mode of action study results.
Both positive and negative results are assembled together in a single
weight of evidence determination..

Positive effects which are consistent with the criteria for
classification in each chapter, whether seen in humans or animals, will
normally justify classification. Where evidence is available from both
sources and there is a conflict between the findings, the quality and
reliability of the evidence from both sources must be assessed in order
to resolve the question for classification. Generally, data of good
quality and reliability in humans will have precedence over other data.
However, even well-designed and conducted epidemiological studies may
lack sufficient numbers of subjects to detect relatively rare but still
significant effects, or to assess potentially confounding factors.
Positive results from well-conducted animal studies are not necessarily
negated by the lack of positive human experience but require an
assessment of the robustness and quality of both the human and animal
data relative to the expected frequency of occurrence of effects and the
impact of potentially confounding factors.

Route of exposure, mechanistic information and metabolism studies are
pertinent to determining the relevance of an effect in humans. When such
information raises doubt about relevance in humans, a lower
classification may be warranted. When it is clear that the mode or
mechanism of action is not relevant to humans, the substance should not
be classified.

Both positive and negative results are assembled together in the weight
of evidence determination. However, a single positive study performed
according to good scientific principles and with statistically and
biologically significant positive results may justify classification.

**BUILDING BLOCK APPROACH**

At various times during the development of harmonized classification
criteria, concerns have arisen concerning the way a harmonized
classification system might be used and whether it would meet the needs
of its various end‑users.

One of the consequences of the application of the classification system
is expressed in the IOMC CG/HCCS General Principle (c):

"harmonization means establishing a common and coherent basis for
chemical hazard classification and communication, from which the
appropriate elements relevant to means of transport, consumer, worker
and environment protection can be selected."

In the following chapters, sufficient sub-classes have been included
under some endpoints to accommodate the fundamental needs of the
existing systems. The application of the classification scheme may vary
according to the circumstances, type of product, a stage of the life
cycle of the chemical.

It is essential that the cut-offs be recognized as a fundamental basis
for the harmonized classification system. The use of different cut-offs
for any use of the classification system would be contrary to
harmonization.

**HARMONIZED SYSTEM FOR THE CLASSIFICATION OF CHEMICALS WHICH CAUSE
ACUTE TOXICITY**

**HARMONIZED CLASSIFICATION SCHEME FOR ACUTE TOXICITY**

+------------------+---------+---------+---------+---------+---------+
|                  | Class 1 | Class 2 | Class 3 | Class 4 | Class 5 |
+------------------+---------+---------+---------+---------+---------+
| Oral (mg/kg)     | 5       | 50      | 300     | 2000    | 5000\   |
|                  |         |         |         |         | See     |
|                  |         |         |         |         | d       |
|                  |         |         |         |         | etailed |
|                  |         |         |         |         | c       |
|                  |         |         |         |         | riteria |
+------------------+---------+---------+---------+---------+---------+
| Dermal (mg/kg)   | 50      | 200     | 1000    | 2000    |         |
+------------------+---------+---------+---------+---------+---------+
| Gases (ppm)      | 100     | 500     | 2500    | 5000    |         |
|                  |         |         |         |         |         |
| Note a           |         |         |         |         |         |
+------------------+---------+---------+---------+---------+---------+
| Vapours (mg/L)   | 0.5     | 2.0     | 10      | 20      |         |
|                  |         |         |         |         |         |
| Note a           |         |         |         |         |         |
|                  |         |         |         |         |         |
| Note b           |         |         |         |         |         |
|                  |         |         |         |         |         |
| Note c           |         |         |         |         |         |
+------------------+---------+---------+---------+---------+---------+
| Dusts and Mists  | 0.05    | 0.5     | 1.0     | 5       |         |
| (mg/L)           |         |         |         |         |         |
|                  |         |         |         |         |         |
| Note d           |         |         |         |         |         |
|                  |         |         |         |         |         |
| Note a           |         |         |         |         |         |
+------------------+---------+---------+---------+---------+---------+

Notes to the scheme:

a\. Conversion of existing inhalation toxicity data which have been
generated according to exposures

other than 4 hours should be according to the following formulae:

For dusts and mists: LC50 (4 hours) is equivalent to LC50 (x
hours)•(x/4).

For vapours: LC50 (4 hours) is equivalent to LC50 (1 hour)•(1/2).

b\. It is recognised that saturated vapour concentration may be used as
an additional element by some regulatory systems to provide for specific
health and safety protection (e.g. UN Recommendations for the Transport
of Dangerous Goods).

c\. It is recognised that for some chemicals the test atmosphere would
not just be a vapour but would consist of a mixture of liquid and vapour
phases, and for some chemicals the test atmosphere may consist of a
vapour which is near the gaseous phase. In these latter cases,
classification would be based on ppm as follows: Class 1 (100 ppm),
Class 2 (500 ppm), Class 3 (2500 ppm), Class 4 (5000 ppm). Work in the
OECD Test Programme should be undertaken to better define the terms
"dusts", "mists" and "vapours" in relation to the inhalation toxicity
testing.

d\. The values for dusts and mists should be reviewed to adapt to any
future changes to OECD Test Guidelines with respect to technical
limitation in generating, maintaining and measuring dust and mist
concentrations in respirable form.

**[Criteria for Class 5]{.underline}**

The criteria for Class 5 are intended to enable the identification of
substances which are of relatively low acute toxicity hazard but which,
under certain circumstances, may present a danger to vulnerable
populations. These substances are anticipated to have an oral or dermal
LD50 in the range of 2000-5000 mg/kg or equivalent doses for other
routes.

1\. The substance is classified in Class 5 if reliable evidence is
already available that indicates the LD50 or (LC50) to be in the range
of Class 5 values; or other animal studies or toxic effects in humans
indicate a concern for human health or an acute nature.

2\. The substance is classified in Class 5, through extrapolation,
estimation or measurement of data, if assignment to a more hazardous
class is not warranted, and

-   reliable information is available indicating significant toxic
    effects in humans; or

-   any mortality is observed when tested up to class 4 values by the
    oral, inhalation; or dermal routes; or

-   where expert judgement confirms significant clinical signs of
    toxicity, when tested up to Class 4 values, except for diarrhoea,
    piloerection or an ungroomed appearance, or

-   where expert judgement confirms reliable information indicating the
    potential for significant acute effects from the other animal
    studies.

Recognising the need to protect animal welfare, testing in animals in
Class 5 ranges is discouraged and should only be considered when there
is a strong likelihood that results of such a test would have a direct
relevance for protecting human health.

**HARMONIZED SYSTEM FOR THE CLASSIFICATION OF CHEMICALS WHICH CAUSE SKIN
IRRITATION/CORROSION**

**EXECUTIVE SUMMARY**

From a comparison of existing dermal irritation/corrosion classification
procedures currently in use, a harmonized system was formulated. It
includes an evaluation strategy of existing information and specific
testing for dermal effects. In developing potential harmonized positions
for dermal irritation/corrosion testing, two objectives have been kept
in mind: to define criteria for both corrosion and irritation
classification that are in the range of sensitivity of existing systems
and to have the possibility of subdividing effects into different
subclasses for those authorities that need them.

A single class is adopted for skin corrosion. Authorities wanting to
have up to three subclasses may subdivide the single corrosive class.
These subclasses are modeled after those currently in use in the United
Nations transport authority.

A single class is adopted for skin irritation. The classification
procedure draws upon those currently employed by the European Union
(EU). Erythema/eschar and edema are graded separately; an animal's mean
score from readings over the first three days after exposure must meet a
defined level to be positive; and at least 2 of 3 tested animals must be
positive for the test to be positive. Positive responses can also be
obtained using other, less common criteria. The proportion of test
substances expected to be positive by the proposed irritant class is
within the range of positives among existing classification systems; it
is somewhat higher than that of some of the current classification
systems but below those of other systems. Authorities wanting to have
two hazard classes can use both irritant and mild irritant classes.

**PURPOSE, BASIS AND APPLICABILITY**

The purpose of the document is to present a harmonized system of
classification for skin irritation and corrosion that can be agreed upon
and utilized internationally.

The harmonized classification system grew out of the major systems that
are currently employed. It is based on concepts already in effect and
does not deviate significantly from those currently in use.

The harmonized system for classification of skin irritation and
corrosion include elements that are harmonized and will be used by all
authorities as well as other categories that will be applied by only
some authorities (e.g., transport, pesticides).

**CLASSIFICATION CATEGORIES AND CRITERIA**

The harmonized system includes guidance for the use of initial
considerations, that is those data elements that are evaluated before
animal testing for dermal corrosion and irritation is undertaken. It
also includes hazard classes for corrosion and irritation.

**Initial Considerations**

Several factors should be considered in determining the corrosion and
irritation potential of chemicals before testing is undertaken. Existing
human experience and data including from single or repeated exposure and
animal observations and data should be the first line of analysis, as it
gives information directly referable to effects on the skin. In some
cases enough information may be available from structurally related
compounds to make classification decisions. Likewise, pH extremes like
[\<]{.underline} 2 and [\>]{.underline} 11.5, may indicate dermal
effects, especially when buffering capacity is known, although the
correlation is not perfect. Generally, such agents are expected to
produce significant effects on the skin. It also stands to reason that
if a chemical is highly toxic by the dermal route, a dermal
irritation/corrosion study may not be practicable since the amount of
test substance to be applied would considerably exceed the toxic dose
and, consequently, would result in the death of the animals. When
observations are made of dermal irritation/corrosion in acute toxicity
studies and are observed up through the limit dose, additional testing
would not be needed, provided that the dilutions used and species tested
are equivalent. In vitro alternatives that have been validated and
accepted may also be used to help make classification decisions.

All the above information that is available on a chemical should be used
in determining the need for in vivo dermal irritation testing. Although
information might be gained from the evaluation of single parameters
within a tier (e.g., caustic alkalies with extreme pH should be
considered as dermal corrosives), there is merit in considering the
totality of existing information and making an overall weight of
evidence determination. This is especially true when there is
information available on some but not all parameters. Generally, primary
emphasis should be placed upon existing human experience and data,
followed by animal experience and testing data, followed by other
sources of information, but case-by-case determinations are necessary.

A tiered approach to the evaluation of initial information should be
considered, where applicable (Figure 1), recognizing that all elements
may not be relevant in certain cases.

**Corrosion**

A single harmonized corrosion class is adopted using the results of
animal testing. A corrosive is a test material that produces destruction
of skin tissue, namely, visible necrosis through the epidermis and into
the dermis) in [\>]{.underline} 1 of 3 tested animals after exposure up
to a 4 hour duration. Corrosive reactions are typified by ulcers,
bleeding, bloody scabs and, by the end of observation at 14 days, by
discoloration due to blanching of the skin, complete areas of alopecia
and scars. Histopathology should be considered to discern questionable
lesions.

**Figure 1. TIERED TESTING AND EVALUATION OF DERMAL CORROSION AND
IRRITATION POTENTIAL**

**(see also the "Testing and Evaluation Strategy for Eye
Irritation/Corrosion")**

**\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_**

**[Step Parameter Finding Conclusion]{.underline}**

1a Existing human or animal ⇒ Corrosive Classify as corrosive ^a^

experience^g)^

⇓

Not corrosive or no

data

⇓

1b Existing human or animal ⇒ Irritant Classify as irritant ^a^

experience^g)^

⇓

Not irritant or no

data

⇓

1c Existing human or animal ⇒ Not corrosive or No further testing

experience irritant

⇓

No data

⇓

2a Structure-activity relationships or ⇒ Corrosive Classify as corrosive
^a^

structure-property relationships ^b^

⇓

Not corrosive or no

data

⇓

2b Structure-activity relationships or ⇒ Irritant Classify as irritant
^a^

structure-property relationships ^b^

⇓

Not irritating or no data

⇓

3 pH with buffering ^c^ ⇒ pH [\<]{.underline} 2 or [\>]{.underline}11.5
Classify as corrosive ^a^

⇓

Not pH extreme or no

data

⇓

4 Existing dermal data in ⇒ Yes Possibly no further testing

animals indicate no need for may be deemed corrosive/irritant

animal testing ^d^

⇓

No indication or no data

⇓

5 Valid and accepted in vitro dermal ⇒ Positive response Classify as
corrosive ^a^

corrosion test ^e^

⇓

Negative response or

no data

⇓

**Figure 1. (continued)** **TIERED TESTING AND EVALUATION OF DERMAL
CORROSION AND**

**IRRITATION POTENTIAL**

**\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_**

**[Step Parameter Finding Conclusion]{.underline}**

6 Valid and accepted in vitro ⇒ Positive response Classify as irritant
^a^

dermal irritation test ^f^

⇓

Negative response or

no data

⇓

7 In vivo dermal corrosion ⇒ Corrosive response Classify as corrosive
^a^

test (1 animal)

⇓

Negative response

⇓

8 In vivo dermal irritation ⇒ Irritant response Classify as irritant

test (3 animals total) ^h^

⇓

Negative response ⇒ No further testing

⇓

9 When it is ethical to perform ⇒ Irritant response Classify as irritant
^a^

human patch testing ^g^

⇓

Not as above ⇒ Nonirritant response No further testing

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_­­­\_­\_

a Classify in the harmonized class, below.

b Structure-activity and structure-property relationships are presented
separately but would be conducted in parallel.

c Measurement of pH alone may be adequate, but assessment of acid or
alkali reserve is preferable; methods are needed to assess buffering
capacity.

d Preexisting animal data should be carefully reviewed to determine if
in vivo dermal corrosion/irritation testing is needed. As examples,
testing may not be needed when a test material has not produced any
dermal irritation in an acute dermal toxicity test at the limit dose, or
produces very toxic effects in an acute dermal toxicity test. In the
latter case, the material would be classed as being very hazardous by
the dermal route for acute toxicity; it is moot whether the material is
also irritating or corrosive on the skin. It should be kept in mind in
evaluating acute dermal toxicity information that the reporting of
dermal lesions may be incomplete, testing and observations may be made
on a species other than the rabbit, and species may differ in
sensitivity in their responses.

e Currently there are no internationally accepted validated in vitro
methods of dermal corrosion, but a validation study on several methods
has just been completed.

f Presently there are no validated and internationally accepted in vitro
test methods for dermal irritation.

g This evidence could be derived from single or repeated exposures.
There is no internationally accepted test method for human dermal
irritation testing, but an OECD guideline has been proposed.

h Testing is usually conducted in 3 animals, one coming from the
negative corrosion test.

For those authorities wanting more than one designation of corrosivity,
up to three subclasses are adopted which divide up responses in the
corrosive class (Table 1): **subclass 1** \--where responses are noted
following up to 3 minutes exposure and up to 1 hour observation;
**subclass 2** \--where responses are described following exposure
between 3 minutes and 1 hour and observations up to 14 day; and
**subclass 3** \--where responses occur after exposures between 1 hour
and 4 hours and observations up to 14 days.

**Table 1.** **CORROSIVE CLASS AND SUBCLASSES**^a)^

+--------------------+-----------------+-------------------+----------+
| **Corrosive**      | **Potential     | **Corrosive in    |          |
|                    | corrosive**     | [\>]{.underline}  |          |
| **class**          |                 | 1 of 3 animals**  |          |
|                    | **subclasses**  |                   |          |
+--------------------+-----------------+-------------------+----------+
| (applies to        | (only applies   | **exposure**      | **obser  |
| authorities not    | to some         |                   | vation** |
| using subclasses)  | authorities)    |                   |          |
+--------------------+-----------------+-------------------+----------+
| corrosive          | corrosive       | [\<]{.underline}  | [\<]{.un |
|                    | subclass 1      | 3 minutes         | derline} |
|                    |                 |                   | 1 hour   |
+--------------------+-----------------+-------------------+----------+
|                    | corrosive       | \> 3 minutes \--  | [\<]{.un |
|                    | subclass 2      | [\<]{.underline}  | derline} |
|                    |                 | 1 hour            | 14 days  |
+--------------------+-----------------+-------------------+----------+
|                    | corrosive       | \> 1 hour \--     | [\<]{.un |
|                    | subclass 3      | [\<]{.underline}  | derline} |
|                    |                 | 4 hours           | 14 days  |
+--------------------+-----------------+-------------------+----------+

> a\. In case human data is considered, the use of human data is
> discussed under \"general considerations\", in the introductory
> chapter of the Harmonized Integrated Classification System.

**Irritation**

A single irritant class is adopted that (a) is centrist in sensitivity
among existing classifications, (b) recognizes that some test materials
may lead to effects which persist throughout the length of the test, and
(c) acknowledges that animal responses in a test may be quite variable.
The current EU 3-animal classification system is modified to generate
the proposed position. An additional mild irritant class is available
for those authorities that want to have more than one dermal irritant
category.

Reversibility of dermal lesions is another consideration in evaluating
irritant responses. When inflammation persists to the end of the
observation period in 2 or more test animals, taking into consideration
alopecia (limited area), hyperkeratosis, hyperplasia and scaling, then a
material should be considered to be an irritant.

Animal irritant responses within a test can be quite variable, as they
are with corrosion. A separate irritant criterion should be added to
accommodate cases when there is a significant irritant response but less
than the mean score criterion for a positive test. For example, a test
material might be designated as an irritant if 1 of 3 tested animals
shows a very elevated mean score throughout the study, including lesions
persisting at the end of an observation period of normally 14 days.
Other responses could also fulfill this criterion. However, the
responses should be ascertained as being the result of chemical
exposure. Addition of this criterion increases the sensitivity of the
classification system beyond that of the current EU system.

To counterbalance the increases in sensitivity of a designation of an
irritant position and to make room for a mild irritant class, the
endpoint mean score for a positive animal response is raised from
[\>]{.underline} 2.0 under the current EU system to [\>]{.underline}
2.3. From a training set of data, the proportion of positive tests for
the total data base decreases from 0.59 for the current EU system to
0.34. The exact proportion of positive test materials in the proposed
system is not known, but it would definitely be higher than 0.34 and,
thus, closer to the proportion of positives in the current EU system. In
addition, the proportion of positives will vary considerably with the
composition of materials being tested. From the training set, about 0.34
of the chemicals are in the mild irritant class, and the total is the
sum of the proportion of irritants and mild irritants, or 0.68 of the
chemicals.

A single **irritant** class is adopted using the results of animal
testing. Authorities (e.g., pesticides) also have available a less
severe **mild irritant** class. Several criteria distinguish the two
classes (Table 2). They mainly differ in the severity of dermal
reactions. The major criterion for the irritant class is that at least 2
tested animals have a mean score of [\>]{.underline} 2.3 -
[\<]{.underline} 4.0. For the mild irritant class, the mean score
cutoffs are [\>]{.underline} 1.5 - \< 2.3 for at least 2 tested animals.
Test materials in the irritant class would be excluded from being placed
in the mild irritant class.

**Table 2.** **IRRITANT CLASS AND SUBCLASS** ^a^

+-------------+--------------------------------------------------------+
| **Classes** | **Criteria**                                           |
+-------------+--------------------------------------------------------+
| *           | \(1\) Mean value of [\>]{.underline} 2.3 - \< 4.0 for  |
| *Irritant** | erythema/eschar or for edema in at least 2 of 3 tested |
|             | animals from gradings at 24, 48 and 72 hours after     |
| (applies to | patch removal or, if reactions are delayed, from       |
| all         | grades on 3 consecutive days after the onset of dermal |
| a           | reactions, or                                          |
| uthorities) |                                                        |
|             | \(2\) Inflammation that persists to the end of the     |
|             | observation period normally 14 days in at least 2      |
|             | animals, particularly taking into account alopecia     |
|             | (limited area), hyperkeratosis, hyperplasia, and       |
|             | scaling, or                                            |
|             |                                                        |
|             | \(3\) In some cases where there is pronounced          |
|             | variability of response among animals, with very       |
|             | definite positive effects related to chemical exposure |
|             | in a single animal but less than the criteria above.   |
+-------------+--------------------------------------------------------+
| **Mild      | Mean value of [\>]{.underline} 1.5 - \< 2.3 for        |
| Irritant**  | erythema/eschar or for edema from gradings in at least |
|             | 2 of 3 tested animals from grades at 24, 48 and 72     |
| (applies to | hours or, if reactions are delayed, from grades on 3   |
| only some   | consecutive days after the onset of dermal reactions   |
| a           | (when not included in the irritant class above).       |
| uthorities) |                                                        |
+-------------+--------------------------------------------------------+

> a\. In case human data is considered, the use of human data is
> discussed under \"general considerations\", in the introductory
> chapter of the Harmonized Integrated Classification System.

**HARMONIZED SYSTEM FOR THE CLASSIFICATION OF CHEMICALS WHICH CAUSE EYE
IRRITATION/CORROSION**

## EXECUTIVE SUMMARY

1\. In the following harmonized system for eye irritation/corrosion
hazard classification the collection of test guidelines and
classification schemes worked out by the EC, the tier scheme of the U.S.
regulators, the experiences of the German regulators based on the EU
chemicals notification procedure and the outcome of the \"OECD Workshop
on Harmonization of Validation Criteria for Alternative Tests /
Harmonization and Acceptance Criteria for Alternative Toxicological Test
Methods\" in Solna, Sweden (22nd -24th January, 1996) have been
considered.

2\. Also reflected are eye irritation/corrosion classification schemes
for chemicals which are in force in the member countries of the
Organisation for Economic Cooperation and Development, OECD (6), in the
European Economic Community, EU and the Canadian Pest Management
Regulatory Agency and the Canadian workplace system, WHMIS. Within the
transport sectors of the United Nations, UN, only dermal corrosivity is
taken into account; eye corrosivity or eye irritating properties are not
included within the "Orange Book" of the UN.

3\. The harmonized system includes an evaluation strategy of existing
information and specific testing for eye effects. In developing
harmonized positions for eye irritation/corrosion testing, three
objectives have been kept in mind:

-   to define criteria for both serious damage to eyes and eye
    irritation that are in the range of sensitivity of existing systems,

-   to have the option of subdividing effects in two parts for those
    authorities that need them, and

-   to avoid testing for local effects on eyes with skin corrosive
    substances.

4\. A single harmonized hazard group is defined for the classification
of serious damage to eyes. Serious damage to eyes is defined as severe
irreversible effects on the eye including not only corrosive effects
like destruction of cornea or conjunctivae but also persistent
indication of serious impairment of sight.

5\. A single harmonized hazard group is defined for the classification
of eye irritation that reverses within an appropriate observation time.
The proposed harmonized classification of reversible eye irritation
draws upon procedures currently employed by the European Union (EU) and
by regulatory authorities in the United States of America (USA) and in
Canada. Classified are local effects detected in a Draize test with
rabbits that reverse within 21 days after instillation of the substance
into the eye. Effects on the cornea, effects on the iris and
conjunctival erythema and edema are graded separately; an animal's mean
score from readings over the first three days after instillation must
meet a defined level to be positive, and at least 2 of 3 tested animals
must be positive for the test to be positive. The proportion of test
substances expected to be positive by the proposed harmonized system is
somewhat higher than that of the current EU system but less than that of
the current US and Canadian systems. Authorities wanting to distinguish
between mild and moderate eye irritants have the option to use a
subcategorization that considers the differences within the current
classification systems.

## PURPOSE, BASIS AND APPLICABILITY

6\. The purpose of the document is to present a harmonized system of
hazard classification for eye irritation, destruction of eye tissues and
other serious damage to tissues and function of eyes that can be agreed
upon and utilized by OECD Member countries.

7\. A tiered testing and evaluation scheme is presented that combines
preexisting information on local corrosivity and on eye irritation
(including data relating to historical human or animal experience) as
well as considerations on structure-activity relationships (SAR) or
structure-property relationships (SPR) and the output of validated *in
vitro* tests in order to avoid unnecessary animal testing.

8\. The harmonized hazard classification system grew out of the
currently employed systems within the OECD. It is based on concepts
already in effect and melds together a position that does not deviate
significantly from those currently in use.

9\. The proposals for classification of eye irritation and serious
damage of the eye include elements that are harmonized and will be used
by all authorities as well as optional subcategories that will be
applied by only some authorities (e.g., authorities classifying
pesticides).

## CLASSIFICATION CATEGORIES AND CRITERIA

10\. The harmonized system includes guidance for the use of initial
considerations, that is those data elements that are evaluated before
animal testing for eye damaging effects is undertaken. It also includes
hazard classes for local lesions on the eyes.

**Initial considerations / tier testing and evaluation strategy**

11\. Before there is any *in vivo* dermal or eye irritation/corrosion
testing all existing information on a test material should be reviewed.
Preliminary decisions can often be made from them as to whether an agent
is corrosive. If a test material can be classified, no testing is
required. A highly recommended way of evaluating existing information on
agents or of approaching new uninvestigated substances, is to utilize a
tier testing strategy for eye irritation/corrosion.

12\. Several factors should be considered in determining the eye damage
or irritation potential of chemicals before testing is undertaken.
Accumulated human and animal experience should be the first line of
analysis, as it gives information directly referable to effects on the
eye. In some cases enough information may be available from structurally
related compounds to make hazard decisions. Likewise, pH extremes like ≤
2 and ≥ 11.5, may indicate corrosive effects, especially when buffering
capacity is known. Such agents are expected to produce significant
effects on the eyes. Possible skin corrosion has to be evaluated prior
to consideration of eye irritation/corrosion in order to avoid testing
for local effects on eyes with skin corrosive substances. *In vitro*
alternatives that have been validated and accepted may be used to make
classification decisions.

13\. All the above information that is available on a chemical should be
used in determining the need for *in vivo* eye irritation testing.
Although information might be gained from the evaluation of single
parameters within a tier (e.g., caustic alkalies with extreme pH should
be considered as local corrosives), there is merit in considering the
totality of existing information and making an overall weight of
evidence determination. This is especially true when there is
information available on some but not all parameters. Generally, primary
emphasis should be placed upon expert judgement considering human
experience with the substance, followed by the outcome of skin
irritation testing and of well validated alternative methods. Animal
testing with corrosive substances should be avoided whenever possible.

14\. A tiered approach to the evaluation of initial information should
be considered, where applicable recognizing that all elements may not be
relevant in certain cases. The tiered approach explained in figure 1 was
developed with contributions from (inter)national centres and committees
for the testing and validation of alternatives to animal testing during
a workshop in Solna, Sweden.

**Figure 1: TESTING AND EVALUATION STRATEGY FOR EYE
IRRITATION/CORROSION**

**(see also the: "Testing and Evaluation Strategy for Skin
Irritation/Corrosion")**

+---+----------------------+---------------------+---------------------+
| 1 | Data relating to     | Severe damage to    | Category A          |
| a | historical human or  | eyes                |                     |
|   | animal experience    |                     | Category B          |
|   |                      | Eye irritant        |                     |
+---+----------------------+---------------------+---------------------+
|   | No or don't know     |                     |                     |
+---+----------------------+---------------------+---------------------+
| 1 | Data relating to     | Skin corrosive      | No evaluation of    |
| b | historical human or  |                     | effects on eyes;    |
|   | animal experience    |                     | deemed to be        |
|   |                      |                     | Category A          |
+---+----------------------+---------------------+---------------------+
|   | No or don't know     |                     |                     |
+---+----------------------+---------------------+---------------------+
| 1 | Data relating to     | Skin irritant       | No evaluation of    |
| c | historical human or  |                     | effects on eyes;    |
|   | animal experience    |                     | deemed to be        |
|   |                      |                     | Category B          |
+---+----------------------+---------------------+---------------------+
|   | No or don't know     |                     |                     |
+---+----------------------+---------------------+---------------------+
| 2 | SAR/SPR              | Severe damage to    | Category A          |
| a |                      | eyes                |                     |
+---+----------------------+---------------------+---------------------+
|   | No or don't know     |                     |                     |
+---+----------------------+---------------------+---------------------+
| 2 | SAR/SPR              | Eye irritant        | No evaluation of    |
| b |                      |                     | effects on eyes;    |
|   |                      |                     | deemed to be        |
|   |                      |                     | Category B          |
+---+----------------------+---------------------+---------------------+
|   | No or don't know     |                     |                     |
+---+----------------------+---------------------+---------------------+
| 2 | SAR/SPR              | Skin corrosive      | No evaluation of    |
| c |                      |                     | effects on eyes;    |
|   |                      |                     | deemd to be         |
|   |                      |                     | Category A          |
+---+----------------------+---------------------+---------------------+
|   | No or don't know     |                     |                     |
+---+----------------------+---------------------+---------------------+
| 3 | pH/acid or alkaline  | pH ≥ 11.5 or pH ≤ 2 | Category A          |
|   | reserve              |                     |                     |
|   |                      | (considering acid   |                     |
|   |                      | or alkaline         |                     |
|   |                      | reserve)            |                     |
+---+----------------------+---------------------+---------------------+
|   | 2 \< pH \< 11.5      |                     |                     |
|   |                      |                     |                     |
|   | (no buffering        |                     |                     |
|   | potential)           |                     |                     |
+---+----------------------+---------------------+---------------------+
| 4 | Other information    | Yes                 | No evaluation of    |
|   | indicating the       |                     | effects on eyes;    |
|   | material is a dermal |                     | deemed to be        |
|   | corrosive            |                     | Category A          |
+---+----------------------+---------------------+---------------------+
|   | No                   |                     |                     |
+---+----------------------+---------------------+---------------------+
| 5 | Is a valid *in       | No                  | Go to Step 6        |
|   | vitro* test          |                     |                     |
|   | available to assess  |                     |                     |
|   | severe damage to     |                     |                     |
|   | eyes                 |                     |                     |
+---+----------------------+---------------------+---------------------+
| 5 | *In vitro* test for  | Severe damage to    | Category A          |
| a | severe eye           | eyes                |                     |
|   | irritation           |                     |                     |
+---+----------------------+---------------------+---------------------+

+---+----------------------+---------------------+---------------------+
|   | Not a severe eye     |                     |                     |
|   | irritant             |                     |                     |
+---+----------------------+---------------------+---------------------+
| 6 | Is a valid *in       | but *in vitro* test | Go to Step 8        |
|   | vitro* test for eye  | for                 |                     |
|   | irritation available |                     | Go to Step 7        |
|   |                      | severe eye          |                     |
|   |                      |                     |                     |
|   |                      | irritancy was       |                     |
|   |                      |                     |                     |
|   |                      | negative            |                     |
|   |                      |                     |                     |
|   |                      | No                  |                     |
|   |                      |                     |                     |
|   |                      | in the absence of   |                     |
|   |                      |                     |                     |
|   |                      | any *in vitro* test |                     |
+---+----------------------+---------------------+---------------------+
|   | Yes                  |                     |                     |
+---+----------------------+---------------------+---------------------+
| 6 | *In vitro* eye       | Eye irritant        | Category B          |
| a | irritation test      |                     |                     |
+---+----------------------+---------------------+---------------------+
|   | No indication of eye |                     |                     |
|   | irritant properties  |                     |                     |
+---+----------------------+---------------------+---------------------+
| 7 | Experimentally       | Skin corrosive      | No evaluation of    |
|   | assess skin          |                     | effects on eyes     |
|   | corrosion potential  |                     |                     |
|   | (see Testing         |                     |                     |
|   | Strategy for Skin    |                     |                     |
|   | I                    |                     |                     |
|   | rritation/Corrosion) |                     |                     |
+---+----------------------+---------------------+---------------------+
|   | Not corrosive        |                     |                     |
+---+----------------------+---------------------+---------------------+
| 8 | 1 rabbit eye test    | Serious damage to   | Category A          |
|   |                      | eyes                |                     |
+---+----------------------+---------------------+---------------------+
|   | No serious damage    |                     |                     |
+---+----------------------+---------------------+---------------------+
| 9 | 1 or 2 further       | Eye irritant        | Category B          |
|   | rabbits              |                     |                     |
+---+----------------------+---------------------+---------------------+
|   | Not an eye irritant  |                     |                     |
+---+----------------------+---------------------+---------------------+

**Notes to the testing and evaluation strategy for eye irritation /
corrosion**

15\. Step 1a/b: Data relating to historical human or animal experience:
Preexisting information on eye irritation and skin corrosion are shown
separately because evaluation of skin corrosion has to be considered if
there is no information on local effects on eyes. Analysis of
preexisting experience with the chemical may identify both corrosion and
irritation potential for both dermal and ocular effects: i) Step 1a -
reliable determination of eye irritancy basing on human or animal
experience - depends on expert judgement: In most cases human experience
is based on accidental events and thus, the local effects detected after
an accident have to be compared with classification criteria created for
evaluation of animal test data. ii) Step 1b - evaluation of data on skin
corrosivity - skin corrosive substances should not be instilled into the
eyes of animals; such substances should be considered as corrosive to
the eyes as well. **(Category A)**

16\. Step 2a/b: SAR (Structure Activity Relationships) / SPR (Structure
Property Relationships) for eye irritation and skin corrosion are shown
separately but in reality would probably be done in parallel. This stage
should be completed using validated and accepted SAR/SPR approaches. The
SAR/SPR analysis may identify both corrosion and irritation potential
for both dermal and ocular effects: i) Step 2a - reliable determination
of eye irritancy only by theoretical evaluations - in most cases it will
only be appropriate for substances that are homologous to agents with
very well known properties. ii) Step 2c - theoretical evaluation of skin
corrosivity - skin corrosive substances should not be instilled into the
eyes of animals; such substances should be considered as corrosive to
the eyes as well. **(Category A)**

17\. Step 3: pH extremes like \<2 and \>11.5 may indicate strong local
effects, especially in combination with assessment of acid or alkaline
reserve (see annexed draft of a respective guideline), substances
exhibiting such physico-chemical properties should be considered as
corrosive to eyes. **(Category A)**

18\. Step 4: All attainable information should be used, including
probable human experience. But this information should be restricted to
that which pre-exists (e.g. the results of a dermal LD50 test or
historical information on dermal corrosion).

19\. Step 5: These must be alternative methods for the assessment of
severe eye irritation/corrosion or serious damage to eyes (e.g.,
irreversible corneal opacity) which have been validated in accordance
with internationally agreed principles and criteria (see "General
Considerations" of the Harmonized Intergrated Hazard Classification
System).

20\. Step 6: At present this step seems not be achievable in the near
future. Validated alternative methods for the reliable assessment of
(reversible) eye irritation need to be worked out.

21\. Step 7: In the absence of any other relevant information, it is
essential to obtain this via an internationally recognized
corrosion/irritation test before proceeding to a rabbit eye irritation
test. This must be conducted in a staged manner. If possible, this
should be achieved using a validated, accepted in vitro skin corrosivity
assay. If this is not available, then the assessment should be completed
using animal tests (see the skin irritation/corrosion strategy).

22\. Step 8: Staged assessment of eye irritation in vivo. If in a limit
test with one rabbit serious damage to eyes/severe eye
irritation/corrosion is detected no further testing is needed.

23\. Step 9: Only two animals may be employed for irritation testing
(including the one used for evaluation of possible severe effects) if
these two animals give concordant clearly irritant or clearly
non-irritant responses. In the case of different or borderline responses
a third animal is needed. Depending on the result of this three-animal
test, classification may be required or not.

24\. Where data needed for such a testing strategy cannot be required,
the proposed tier testing approach demonstrates a good guidance how to
organize existing information on a test material and to make a
weight-of-evidence decision about hazard assessment and hazard
classification - ideally without conducting new animal tests.

**Irreversible effects on the eye / serious damage to eyes**

25\. A single harmonized hazard class is adopted for substances that
have the potential to damage the eyes seriously. This hazard class -
CATEGORY A (irreversible effects on the eye) - includes the criteria
listed below. These observations include animals with grade 4 cornea
lesions and other severe reactions (e.g., destruction of cornea)
observed at any time during the test, as well as persistent corneal
opacity, discoloration of the cornea by a dye substance, adhesion,
pannus, and interference with the function of the iris or other effects
that impair sight. In this context, persistent lesions are considered
those which are not fully reversible within an observation period of
normally 21 days. Hazard classification: CATEGORY A also contains
substances fulfilling the criteria of corneal opacity ≥ 3 or iritis \>
1.5 detected in a Draize eye test with rabbits, because severe lesions
like these usually do not reverse within a 21 days observation period.

**IRREVERSIBLE EFFECTS CLASS**

**An eye irritant CATEGORY A (irreversible effects on the eye)** is a
test material that produces:

\- at least in one animal effects on the cornea, iris or conjunctiva
that are not expected to reverse

or have not fully reversed within an observation period of normally 21
days

and/or

\- at least in 2 of 3 tested animals a positive response of:

corneal opacity ≥ 3 and/or

iritis \> 1.5

calculated as the mean scores following grading at 24, 48 and 72 hours
after installation of the test material.

26\. The use of human data is discussed under "General Considerations"
in the introductory chapters of the Harmonized Integrated Hazard
Classification System for Human Health and Environmental Effects of
Chemicals.

**Reversible effects on the eye**

27\. A single category is adopted for substances that have the potential
to induce reversible eye irritation. This single hazard category
provides the option to identify within the category a sub-category for
substances inducing eye irritant effects reversing within an observation
time of 7 days.

28\. Those authorities desiring one single category for classification
of "eye irritation" may use the overall harmonized CATEGORY B
(irritating to eyes): others may want to distinguish between CATEGORY B
(irritating to the eyes) and CATEGORY B1 (mildly irritating to eyes).

**REVERSIBLE EFFECTS CLASS**

**An eye irritant CATEGORY B (irritating to eyes)** is a test material
that produces:

\- at least in 2 of 3 tested animals a positive response of:

corneal opacity ≥ 1 and/or

iritis ≥ 1, and/or

conjunctival redness≥ 2

conjunctival edema (chemosis) ≥ 2

calculated as the mean scores following grading at 24, 48 and 72 hours
after installation of the test material, and

\- which fully reverses within an observation period of normally 21 days

Within this category an eye irritant is considered **mildly irritating
to eyes (CATEGORY B1)** when the effects listed above fully reversible
within 7 days of observation.

29\. For those chemicals where there is pronounced variability among
animal responses, this information may be taken into account in
determining the classification.

**HARMONIZED SYSTEM FOR THE CLASSIFICATION OF CHEMICALS WHICH CAUSE
RESPIRATORY OR SKIN SENSITISATION**

**PURPOSE, BASIS AND APPLICABILITY**

1\. The purpose of the harmonised criteria for classification of
respiratory and dermal sensitisers is to give a common ground, which
could be used internationally, for the hazard classification of
sensitising properties of chemicals.

2\. The basis for the harmonised criteria are those criteria which are
currently in use in the OECD countries. Elements from these were
integrated so as to maintain a high level of protection and to form
harmonised criteria which could be agreed upon.

3\. The criteria should be applicable on the hazard classification of
chemicals irrespective of their end use.

**I. RESPIRATORY SENSITISERS**

**Definitions**

4\. A respiratory sensitiser is a substance that will induce
hypersensitivity of the airways upon inhalation of the substance.

**Classification Criteria**

5\. Substances shall be classified as respiratory sensitisers in
accordance with the criteria given below:

+-----------------------------------------------------------------------+
| -                                                                     |
|                                                                       |
| -   if there is evidence in humans that the substance can induce      |
|     specific respiratory hypersensitivity**,** and**/**or             |
|                                                                       |
| -   where there are positive results from an appropriate animal test. |
+-----------------------------------------------------------------------+

**RATIONALE FOR THE SYSTEM**

***Human evidence***

6\. Evidence that a substance can induce specific respiratory
hypersensitivity will normally be based on human experience. In this
context, hypersensitivity is normally seen as asthma, but other
hypersensitivity reactions such as rhinitis/conjunctivitis and
alveolitis are also considered. The condition will have the clinical
character of an allergic reaction. However, immunological mechanisms do
not have to be demonstrated.

7\. When considering the human evidence, it is necessary for a decision
on classification to take into account in addition to the evidence from
the cases:

-   the size of the population exposed

-   the extent of exposure.

8\. The evidence referred to above could be

-   clinical history and data from appropriate lung function tests
    related to exposure to the substance, confirmed by other supportive
    evidence which may include:

-   in vivo immunological test (e.g. skin prick test)

-   in vitro immunological test (e.g. serological analysis)

-   studies that may indicate other specific hypersensitivity reactions
    where immunological mechanisms of action have not been proven, e.g.
    repeated low-level irritation, pharmacologically mediated effects

-   a chemical structure related to substances known to cause
    respiratory hypersensitivity

-   data from positive bronchial challenge tests with the substance
    conducted according to accepted guidelines for the determination of
    a specific hypersensitivity reaction.

9\. Clinical history should include both medical and occupational
history to determine a relationship between exposure to a specific
substance and development of respiratory hypersensitivity. Relevant
information includes aggravating factors both in the home and workplace,
the onset and progress of the disease, family history and medical
history of the patient in question. The medical history should also
include a note of other allergic or airway disorders from childhood, and
smoking history.

10\. The results of positive bronchial challenge tests are considered to
provide sufficient evidence for classification on their own. It is
however recognized that in practice many of the examinations listed
above will already have been carried out.

***Animal studies***

11\. Data from appropriate animal studies which may be indicative of the
potential of a substance to cause sensitisation by inhalation in humans
may include:

\- measurements of IgE and other specific immunological parameters, for
example in mice

\- specific pulmonary responses in guinea pigs.

**EXPLANATORY NOTES**

12\. The mechanisms by which substances induce symptoms of asthma are
not yet fully known. For preventative reasons these substances are
considered as respiratory sensitisers. However, if on the basis of the
evidence mentioned in paragraph 8, it can be demonstrated that these
substances induce symptoms of asthma by irritation only in people with
bronchial hyperreactivity, they should not be considered as respiratory
sensitisers.

13\. At present recognised animal models for the testing of respiratory
hypersensitivity are not available. Under certain circumstances, animal
testing may be used, e.g. a modification of the guinea pig maximisation
test for determination of relative allergenicity of proteins. However,
these tests still need further validation.

14\. Some substances causing respiratory sensitisation may in addition
cause immunological contact urticaria and therefore should be considered
for classification as a contact sensitisers (see part II).

**II. CONTACT SENSITISERS**

**Definitions**

15\. A contact sensitiser is a substance that will induce an allergic
response upon skin contact.

**Classification Criteria**

16\. Substances shall be classified as contact sensitisers in accordance
with the criteria given below:

+-----------------------------------------------------------------------+
| -                                                                     |
|                                                                       |
| -   if there is evidence in humans that the substance can induce      |
|     sensitisation by skin contact in a substantial number of persons, |
|     or                                                                |
|                                                                       |
| -   where there are positive results from an appropriate animal test. |
+-----------------------------------------------------------------------+

**RATIONALE FOR THE SYSTEM**

17\. For classification of a substance evidence should include any or
all of the following:

\- Positive data from patch testing, normally obtained in more than one
dermatology clinic.

\- Epidemiological studies showing allergic contact dermatitis caused by
the substance. Situations in which a high proportion of those exposed
exhibit characteristic symptoms are to be looked at with special
concern, even if the number of cases is small.

\- Positive data from appropriate animal studies.

\- Positive data from experimental studies in man. (see General
Considerations, paragraph 21).

\- Well documented episodes of allergic contact dermatitis, normally
obtained in more than one dermatology clinic.

18\. Positive effects seen in either humans or animals will normally
justify classification. Evidence from animal studies is usually much
more reliable than evidence from human exposure. However, in cases where
evidence is available from both sources, and there is conflict between
the results, the quality and reliability of the evidence from both
sources must be assessed in order to resolve the question of
classification on a case-by-case basis. Normally, human data are not
generated in controlled experiments with volunteers for the purpose of
hazard classification but rather to confirm lack of effects in animal
tests as part of risk assessment. Consequently, positive human data on
contact sensitisation are usually derived from case-control or other,
less defined studies. Evaluation of human data must therefore be carried
out with caution as the frequency of cases reflect, in addition to the
inherent properties of the substances, factors such as the exposure
situation, bioavailability, individual predisposition and preventive
measures taken. Negative human data should not normally be used to
negate positive results from animal studies.

19\. If none of the above mentioned conditions are met the substance
need not be classified as a contact sensitiser. However, a combination
of two or more indicators of contact sensitisation as listed below may
alter the decision. This shall be considered on a case-by-case basis.

-   \- Isolated episodes of allergic contact dermatitis.

-   \- Epidemiological studies of limited power, e.g. where chance, bias
    or confounders have not been ruled out fully with reasonable
    confidence.

-   \- Data from animal tests, performed according to existing
    guidelines, which do not meet the criteria given in the section on
    animal studies but are sufficiently close to the limit to be
    considered significant.

-   \- Positive data from non-standard methods.

-   \- Positive results from close structural analogues.

**EXPLANATORY NOTES**

***Immunological Contact Urticaria***

20\. Substances meeting the criteria for classification as respiratory
sensitisers may in addition cause immunological contact urticaria.
Consideration should be given to classify these substances also as
contact sensitisers. Substances which cause immunological contact
urticaria without meeting the criteria for respiratory sensitisers
should also be considered for classification as contact sensitisers.

21\. There is no recognised animal model available to identify
substances which cause immunological contact urticaria. Therefore,
classification will normally be based on human evidence which will be
similar to that for skin sensitisation.

***Animal Studies***

22\. When an adjuvant type test method for skin sensitisation is used, a
response of at least 30% of the animals is considered as positive. For a
non-adjuvant test method a response of at least 15% of the animals is
considered positive. Test methods for skin sensitisation are described
in the OECD Guideline 406 (the Guinea Pig Maximisation test and the
Buehler guinea pig test). Other methods may be used provided that they
are well-validated and scientific justification is given.

23\. The mouse ear swelling test, MEST, and the local lymph node assay,
LLNA, appear to be reliable screening tests to detect moderate to strong
sensitisers. The LLNA or the MEST can be used as a first stage in the
assessment of skin sensitisation potential. In case of a positive result
in either assay it may not be necessary to conduct a further guinea pig
test.

24\. When evaluating animal data, produced by testing according to the
OECD or equivalent Guidelines for skin sensitisation, the rate of
sensitised animals may be considered. This rate reflects the sensitising
capacity of a substance in relation to its mildly irritating dose. This
dose may vary between substances. A more appropriate evaluation of the
sensitising capacity of a substance could be carried out if the
dose-response relationship was known for the substance. This is an area
that needs further development.

25\. There are substances that are extremely sensitising at low doses
where others require high doses and long time of exposure for
sensitisation. For the purpose of hazard classification it may be
preferable to distinguish between strong and moderate sensitisers.
However, at present animal or other test systems to subcategorise
sensitisers have not been validated and accepted. Therefore,
subcategorisation should not yet be considered as part of the harmonised
classification system. (See Background Information).

**APPENDIX**

**BACKGROUND INFORMATION**

1\. Categorisation of sensitisers accounting for differences in
sensitising capacity among substances would be a useful concept to
develop. It may be appropriate to allocate both respiratory and dermal
sensitizers to, for example, one of the following categories:

Category 1, Strong Sensitizer:

A strong sensitizer would be indicated by

-   a high frequency of occurrence and/or severity of occurrence within
    an exposed population or

-   a probability of occurrence of a high sensitization rate in humans
    based on animal or other tests.

Category 2, Sensitizer:

A low to moderate sensitizer would be indicated by

-   a low or moderate frequency or severity of occurrence within an
    exposed population or

-   a probability of occurrence of a low to moderate sensitization rate
    in humans based on animal or other tests.

2\. Some authorities currently categorise strong sensitizers. However,
at present, animal or other test systems to subcategorise sensitizers as
indicated above, have not been validated and accepted. Work is going on
to develop such models for the potency evaluation of contact allergens
(a), (b), (c) and (d).

**HARMONIZED SYSTEM FOR THE CLASSIFICATION OF CHEMICALS WHICH CAUSE
MUTATIONS IN GERM CELLS**

## PURPOSE, BASIS AND APPLICABILITY

The purpose of the harmonized scheme for the classification of chemicals
which may cause heritable mutations in germ cells in humans is to
provide a common ground which could be used internationally for the
classification of mutagens. All tests conducted according to validated
and internationally accepted test guidelines are acceptable for the
purpose of classifying substances.

To arrive at that classification scheme, test results are considered
from experiments determining mutagenic and/or genotoxic effects in germ
and/or somatic cells of exposed animals. Mutagenic and/or genotoxic
effects determined in *in vitro* tests may also be considered.

The system is hazard based, classifying chemicals on the basis of their
intrinsic ability to induce mutations in germ cells. The scheme is,
therefore, not meant for the (quantitative) risk assessment of chemical
substances.

## DEFINITIONS

The classification system is primarily concerned with chemicals which
may cause mutations in the germ cells of humans and these mutations can
be transmitted to the progeny. However, mutagenicity/genotoxicity tests
*in vitro* and in mammalian somatic cells *in vivo* will also be
considered in the sub-divisions of the classification system.

In the present context, commonly found definitions of the terms
mutagenic, mutagen, mutations and genotoxic are used, and a mutation is
defined here as a permanent change in the amount or structure of the
genetic material in a cell.

The term "mutation" applies both for heritable genetic changes that may
be manifested at the phenotypic level, and for the underlying DNA
modifications when known (including, for example, specific base pair
changes and chromosomal translocations). The term "mutagenic" and
"mutagen" will be used for agents giving rise to an increased occurrence
of mutations in populations of cells and/or organisms.

The more general terms "genotoxic" and "genotoxicity" apply to agents or
processes which alter the structure, information content, or segregation
of DNA, including those which cause DNA damage by interfering with
normal replication processes, or which in a non-physiological manner
(temporarily) alter its replication. Genotoxicity test results are
usually taken as indicators for mutagenic effects.

**CLASSIFICATION CATEGORIES AND CRITERIA**

The classification system comprises two different classes of germ cell
mutagens to accommodate the weight of evidence available. The two-class
system is described in the following.

+-----------------------------------------------------------------------+
| **[Class 1:]{.underline}**                                            |
|                                                                       |
| [Description]{.underline}: **Chemicals known to induce heritable      |
| mutations or to be regarded as if they induce heritable** **mutations |
| in the germ cells of humans.**                                        |
|                                                                       |
| [Class 1a:]{.underline}                                               |
|                                                                       |
| [Description:]{.underline} Chemicals known to induce heritable        |
| mutations in germ cells of humans                                     |
|                                                                       |
| [Criteria:]{.underline} Positive evidence from human epidemiological  |
| studies.                                                              |
|                                                                       |
| [Class 1b:]{.underline}                                               |
|                                                                       |
| [Description:]{.underline} Chemicals which should be regarded as if   |
| they induce heritable mutations in the germ                           |
|                                                                       |
| cells of humans.                                                      |
|                                                                       |
| [Criteria:]{.underline}                                               |
|                                                                       |
| -   PNumber range level0Number range level1Number range level2Number  |
|     range level3Number range level4Number range level5Number range    |
|     level6Number range level7ositive result(s) from *in vivo*         |
|     heritable germ cell mutagenicity tests in mammals; or             |
|                                                                       |
| -   Positive result(s) from *in vivo* somatic cell mutagenicity tests |
|     in mammals, in combination with some evidence that the substance  |
|     has potential to cause mutations to germ cells. This supporting   |
|     evidence may, for example, be derived from                        |
|     mutagenicity**/**genotoxic tests in germ cells *in vivo*, or by   |
|     demonstrating the ability of the substance or its metabolite(s)   |
|     to interact with the genetic material of germ cells; or           |
|                                                                       |
| -   Positive results from tests showing mutagenic effects in the germ |
|     cells of humans, without demonstration of transmission to         |
|     progeny; for example, an increase in the frequency of aneuploidy  |
|     in sperm cells of exposed people.                                 |
|                                                                       |
| **[Class 2]{.underline}:**                                            |
|                                                                       |
| [Description:]{.underline} **Chemicals which cause concern for man    |
| owing to the possibility that they may induce heritable mutations in  |
| the germ cells of humans.**                                           |
|                                                                       |
| [Criteria:]{.underline} Positive evidence obtained from experiments   |
| in mammals and/or in some cases from *in vitro* experiments, obtained |
| from:                                                                 |
|                                                                       |
| -   Somatic cell mutagenicity tests *in vivo*, in mammals; or         |
|                                                                       |
| -   Other *in vivo* somatic cell genotoxicity tests which are to be   |
|     supported by positive results from *in vitro* mutagenicity        |
|     assays.                                                           |
|                                                                       |
| > Nota Bene:                                                          |
|                                                                       |
| -   Chemicals which are positive in *in vitro* mammalian mutagenicity |
|     assays, and which also show chemical structure activity           |
|     relationship to known germ cell mutagens, should be considered    |
|     for classification as class 2 mutagens.                           |
+-----------------------------------------------------------------------+

**RATIONALE FOR THE PROPOSED SYSTEM**

Classification for heritable effects in human germ cells is made on the
basis of well conducted, sufficiently validated tests, preferably as
described in OECD Test Guidelines. Evaluation of the test results should
be done using expert judgement and all the available evidence should be
weighed for classification.

Examples of *in vivo* heritable germ cell mutagenicity tests are:

Rodent dominant lethal mutation test (OECD 478)

Mouse heritable translocation assay (OECD 485)

Mouse specific locus test

Examples of in vivo somatic cell mutagenicity tests are:

Mammalian bone marrow micronucleus test (OECD 474)

Mammalian bone marrow chromosome aberration test (OECD 475)

Mouse spot test (OECD 484)

Mammalian erythrocyte micronucleus test (OECD 474)

Examples of mutagenicity/genotoxicity tests in germ cells are:

A\) Mutagenicity tests:

Mammalian spermatogonial chromosome aberration test (OECD 483)

Spermatid micronucleus assay

B\) Genotoxicity tests:

Sister chromatid exchange analysis in spermatogonia

Unscheduled DNA synthesis test (UDS) in testicular cells

Examples of genotoxicity tests in somatic cells are:

Liver Unscheduled DNA Synthesis (UDS) in vivo (OECD 486)

Mammalian bone marrow sister chromatid exchanges (SCE)

Examples of in vitro mutagenicity tests are:

In vitro mammalian chromosome aberration test (OECD 473)

In vitro mammalian cell gene mutation test (OECD 476)

Bacterial reverse mutation tests (OECD 471)

The classification of individual substances should be based on the total
weight of evidence available, using expert judgement. In those instances
where a single well-conducted test is used for classification, it should
provide clear and unambiguously positive results. If new, well
validated, tests arise these may also be used in the total weight of
evidence to be considered. The relevance of the route of exposure used
in the study of the chemical compared to the route of human exposure
should also be taken into account.

**EXPLANATORY NOTES**

It becomes increasingly clear that the process of chemical-induced
tumorigenesis in man and animals involves (an accumulation of) genetic
changes in proto-oncogenes and/or tumour suppres*s*or genes of somatic
cells. Therefore, the demonstration of mutagenic properties of chemicals
in somatic and/or germ cells of mammals *in vivo* may have implications
for the potential classification of these chemicals as carcinogens (cf.
chapter "Harmonization of Classification Systems on Carcinogens").

**HARMONIZED SYSTEM FOR THE CLASSIFICATION OF CHEMICALS WHICH CAUSE
CANCER**

**PURPOSE, BASIS AND APPLICABILITY**

The purpose of the harmonized system for the classification of chemicals
which may cause cancer is to provide common ground which could be used
internationally for the classification of carcinogenic substances.

The scheme is applicable to the classification of all chemicals. The
system deals only with chemical substances. The application to
classification of preparations/products/mixtures should be considered as
a further step by the Working Group on Mixtures.

In common with other classification schemes, it is anticipated that the
general hazard, or primary indication of danger, is emphasised by means
of a symbol shown on the label and in the Safety Data Sheet. The more
specific hazard is represented by means of a standardized phrase. The
harmonization of hazard symbols and phrases is being addressed as a
separate issue by the IOMC Coordinating Group.

**DEFINITIONS**

The term \"carcinogen\" denotes a chemical substance or a mixture of
chemical substances which induce cancer or increase its incidence.
Substances which have induced benign and malignant tumours in well
performed experimental studies on animals are considered also to be
presumed or suspected human carcinogens unless there is strong evidence
that the mechanism of tumour formation is not relevant for humans.

Classification of a chemical as posing *a* carcinogenic hazard is based
on the inherent properties of the substance and does not provide
information on the level of the human cancer risk which the use of the
chemical may represent.

**CLASSIFICATION CATEGORIES AND CRITERIA**

For the purpose of classification for carcinogenicity, chemical
substances are allocated to one of two classes based on strength of
evidence and additional considerations (weight of evidence). In certain
instances route specific classification may be warranted.

+-----------------------------------------------------------------------+
| **CLASS 1:** **KNOWN OR PRESUMED HUMAN CARCINOGENS**                  |
|                                                                       |
| The placing of a chemical in Class 1 is done on the basis of          |
| epidemiological and/or animal data. An individual chemical may be     |
| further distinguished:                                                |
|                                                                       |
| **Class 1A: KNOWN** to have carcinogenic potential for humans; the    |
| placing of a chemical is largely based on human evidence.             |
|                                                                       |
| **Class 1B**: **PRESUMED** to have carci­nogenic potential for humans; |
| the placing of a chemical is largely based on animal evidence.        |
|                                                                       |
| Based on strength of evidence together with additional                |
| considerations**,** such evidence may be derived from human studies   |
| that establish a causal relationship between human exposure to a      |
| chemi­cal and the development of cancer (known human carcinogen).      |
| Alterna­tively, evidence may be derived from animal experiments for    |
| which there is sufficient evidence to demonstrate animal              |
| carcinogenicity (presumed human carcinogen). In addition**,** on a    |
| case by case basis, scientific judgement may warrant a decision of    |
| presumed human carcinogenicity derived from studies showing limited   |
| evidence of carcinogenicity in humans together with limited evidence  |
| of carcino­genicity in experimental animals.                           |
|                                                                       |
| **Classification:** Class 1 (A and B) Carcinogen                      |
|                                                                       |
| **CLASS 2:** **SUSPECTED HUMAN CARCINOGENS**                          |
|                                                                       |
| The placing of a chemical in Class 2 is done on the basis of evidence |
| obtained from human and/or animal studies, but which is not           |
| sufficiently convincing to place the chemical in Class 1.             |
|                                                                       |
| Based on strength of evidence together with additional                |
| considerations, such evidence may be from either limited evidence of  |
| carcinogenicity in human studies or from limited evidence of          |
| carcinogenicity in animal studies.                                    |
|                                                                       |
| **Classification:** Class 2 Carcinogen                                |
+-----------------------------------------------------------------------+

**RATIONALE FOR THE PROPOSED SYSTEM**

**Classification as Carcinogen** is made on the basis of evidence from
reliable and acceptable methods, and is intended to be used for
chemicals which have an intrinsic property to produce such toxic
effects. The evaluations should be based on all existing data,
peer-reviewed published studies and additional data accepted by
regulatory agencies.

**Carcinogen classification** is a one-step, criterion-based process
that involves two interrelated determinations: evaluations of strength
of evidence and consideration of all other relevant information to place
chemicals with human cancer potential into hazard classes.

**Strength of evidence** involves the enumeration of tumours in human
and animal studies and determination of their level of statistical
significance. Sufficient human evidence demonstrates causality between
human exposure and the development of cancer, whereas sufficient
evidence in animals shows a causal relationship between the agent and an
increased incidence tumours. Limited evidence in humans is demonstrated
by a positive association between exposure and cancer, but a causal
relationship cannot be stated. Limited evidence in animals is provided
when data suggest a carcinogenic effect, but are less than sufficient.
The terms \"sufficient\", and \"limited\" are used here as they have
been defined by the International Agency for Research on Cancer (IARC)
and are cited in the Background Information for this document.

**Additional considerations** (weight of evidence). Beyond the
determination of the strength of evidence for carcinogenicity, a number
of other factors should be considered that influence the overall
likelihood that an agent may pose a carcinogenic hazard in humans. The
full list of factors that influence this determination is very lengthy,
but some of the important ones are considered here.

The factors can be viewed as either increasing or decreasing the level
of concern for human carcinogenicity. The rela­tive emphasis accorded to
each factor depends upon the amount and coherence of evidence bearing on
each. Generally there is a requirement for more complete information to
decrease than to increase the level of concern. Additional
considerations should be used in evaluating the tumour findings and the
other factors in a case-by-case manner.

Some important factors which may be taken into consideration, when
assessing the overall level of concern are:

-   Tumor type and background incidence.

-   Multisite responses.

-   Progression of lesions to malignancy.

-   Reduced tumor latency.

Additional factors on which the evaluation may increase or decrease the
level of concern include:

-   Whether responses are in single or both sexes.

-   Whether responses are in a single species or several species.

-   Structural similarity or not to a chemical(s) for which there is
    good evidence of carcinogenicity.

-   Routes of exposure.

-   Comparison of absorption, distribution, metabolism and excretion
    between test animals and humans.

-   The possibility of a confounding effect of excessive toxicity at
    test doses.

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-   Mode of action and its relevance for humans, such as mutagenicity,
    cytotoxicity with growth stimulation, mitogenesis,
    immunosuppression.

**Mutagenicity.** It is recognized that genetic events are central in
the overall process of cancer development. Therefore evidence of
mutagenic activity *in vivo* may indicate that a chemical has a
potential for carcinogenic effects.

**EXPLANATORY NOTES**

The following additional considerations apply to classification of
chemicals into either Class 1 or Class 2. A chemical that has not been
tested for carcinogenicity may in certain instances be classified in
Class 1 or Class 2 based on tumour data from a structural analogue
together with substantial support from consi­deration of other important
factors such as formation of common significant metabolites, e.g. for
benzidine congener dyes.

The classification should take into consideration whether or not the
chemical is absorbed by a given route(s); or whether there are only
local tumours at the site of administration for the tested route(s), and
adequate testing by other major route(s) show lack of carcinogenicity.

It is important that whatever is known of the physico-chemical,
toxicokinetic and toxicodynamic properties of the substances, as well as
any available relevant information on chemical analogues, i.e. structure
activity relationship, is taken into consideration when undertaking
classification.

It is realised that some regulatory authorities may need flexibility
beyond that developed in the hazard classification scheme. For inclusion
into Safety Data Sheets positive results in any carcinogenicity study
performed according to good scientific principles with statistically
significant results may be considered.

Guidance on the importance of the different factors mentioned in 4.4.
has to be elaborated in order to indicate their effects or level of
concern.

The relative hazard potential of a chemical is a function of its
intrinsic potency. There is great variability in potency among
chemicals, and it may be important to account for these potency
differences. The work that remains to be done is to examine methods for
potency estimation. Carcinogenic potency as used here does not preclude
risk assessment. (See Background Information)

The proceed­ings of the recent WHO/IPCS working group to harmonized risk
assessment for carcinogenicity points to a number of scientific
questions arising for classification of chemicals e.g. mouse liver
tumours, peroxisome proliferation, receptor-mediated reactions,
chemicals which are carcinogenic only at toxic doses and which do not
demonstrate mutagenicity. Accordingly, there is a need to articulate the
principles necessary to resolve these scientific issues which have led
to diverging classifications in the past. Once these issues are
resolved, there would be a firm foundation for classification of a
number of chemical carcinogens.

Data already generated for classifying chemicals under existing systems
should be acceptable when reviewing these chemicals with regard to
classification under the harmonized system. Further testing should not
(normally) be necessary.

**APPENDIX**

**BACKGROUND INFORMATION**

**I. Evaluation of the Strength of Evidence for Carcinogenicity Arising
from Human and Experimental Data Adopted by the International Agency for
Research on Cancer (IARC)**

**Carcinogenicity in humans**

The evidence relevant to carcinogenicity from studies in humans is
classified into one of the following categories:

-   **Sufficient evidence of carcinogenicity:** The Working Group
    considers that a causal relationship has been established between
    exposure to the agent, mixture or exposure circumstance and human
    cancer. That is, a positive relationship has been observed between
    exposure and cancer in studies in which chance, bias and confounding
    could be ruled out with reasonable confidence.

-   Limited evidence of carcinogenicity: A positive association has been
    observed between exposure to the agent, mixture or exposure
    circumstance and cancer for which a causal interpretation is
    considered by the Working Group to be credible, but chance, bias or
    confounding could not be ruled out with reasonable confidence.

In some instances the above categories may be used to classify the
degree of evidence related to carcinogenicity in specific organs or
tissues.

**Carcinogenicity in experimental animals**

The evidence relevant to carcinogenicity in experimental animals is
classified into one of the following categories:

-   **Sufficient evidence of carcinogenicity:** The Working Group
    considers that a causal relationship has been established between
    the agent and an increased incidence of malignant neoplasms or of an
    appropriate combination of benign and malignant neoplasms in (a) two
    or more species of animals or (b) in two or more independent studies
    in one species carried out at different times or in different
    laboratories or under different protocols.

-   Exceptionally, a single study in one species might be considered to
    provide sufficient evidence of carcinogenicity when malignant
    neoplasms occur to an unusual degree with regard to incidence, site,
    type of tumour or age at onset.

-   **Limited evidence of carcinogenicity:** The data suggest a
    carcinogenic effect but are limited for making a definitive
    evaluation because, e.g., (a) the evidence of carinogenicity is
    restricted to a single experiment; or (b) there are unresolved
    questions regarding the adequacy of the design, conduct or
    interpretation of the study; or (c) the agent or mixture increases
    the incidence only of benign neoplasms or lesions of uncertain
    neoplastic potential, or of certain neoplasms which may occur
    spontaneously in high incidences in certain strains*.*

**II. Considerations of Potency for Labelling Limits**

4\. The considerations as laid out below were excerpted from the Report
of the Meeting of the Working Group on Harmonization of Classification
and Labelling of Carcinogens, Washington, DC, 17-18 October 1995.

**Purpose**

5\. The purpose of establishing a potency scheme to be used for
labelling of substances, preparations (mixtures) and contaminants is to
provide for practical mini­mum levels of carcinogens in substances for
which labelling would be required. It will result in labelling highly
potent materials more strictly and less potent materials less strictly.
A further purpose is to eliminate unnecessary labelling. In addition,
use of a potency scheme may encourage risk reduction through
purification of chemical substances or reformulating preparations.

**Background**

6\. A large number of chemicals have been classified as carcinogenic and
placed into various categories for labelling or other regulatory
purpose. Chemicals that have been identi­fied as carcinogenic may also
occur as compo­nents of preparations (mixtures), impurities or additives.
Gold and co‑authors (Environ Health Perspect 79: 259, 1989) calculated
doses from animal testing which result in tumours in half the dosed
animals (TD50 values span a range of more than eight orders of
magnitude. Most classification systems do not take into account the wide
range of potencies of these chemicals.

7\. Carcinogens are in some countries divided into three potency groups:
high, medium and low. Potency is in these instances determined using
dose-response data in the observed dosing range for laboratory animals.
Additional indicators of potency such as tumour site and species
specificity, or species differences in toxicokinetics may also be used.
Such potency groups are used to set upper limits for the classification
of substances as carcinogens and for the purpose of initiating
labelling. They have also been used for the classification and
determination of labelling provisions for preparations (mixtures) of
carcinogenic chemicals.

8\. Some countries have implemented a scheme where 0.1% is used as a
default limit value for labelling of substances and preparations
(mixtures) as carcinogens with sufficient data for carcinogenicity. In
these coun­tries chemicals with medium carcinogenic potency are labelled
if they occur in chemical substances at or above this level. Many
carcinogenic compounds fall into the medium range. Carcinogens with high
potency might be classified and labelled at lower levels and carcinogens
with low potency could be classified and labelled only when they occur
at higher levels. Some countries use 1% as a default limit value for low
potency carcinogens and for carcinogens with more limited data.

9\. Some regulatory authorities do not have the obligation to perform
potency determinations. If a chemical carcinogen is a candidate for a
potency rating outside of the default range, such chemicals should be
referred to an international group for its determination.

**Observations**

10\. The Working Group agreed that it would be useful to explore further
the concept of using potency to make labelling decisions. Initial
thoughts of the Working Group are presented here.

11\. Potency ranking of carcinogens should not be determined or refined
more precisely than by ten-fold factors in light of differ­ences in
species response, tumour types and the limits of standardization of test
proto­cols. In light of these points, a scheme for classification and
labelling purposes which separates carcinogens into potency groupings
serves the practical purposes listed above.

12\. The use of potency for establishing limits does not preclude the
ability of authori­ties to perform quantitative risk assessments of
exposures to carcinogenic substances for regu­latory purposes.

13\. Potency determinations should be based on well performed studies
which are peer reviewed, performed according to good laboratory
practices, or are deemed accep­table by regulatory authorities.

**HARMONIZED SYSTEM FOR THE CLASSIFICATION OF CHEMICALS WHICH CAUSE
REPRODUCTIVE TOXICITY**

**PURPOSE, BASIS, AND APPLICABILITY**

1\. The purpose of the harmonized system for the classification of
chemicals which may cause an adverse effect on reproduction in humans is
to provide a common ground which could be used internationally for the
classification of reproductive toxicants.

2\. The system is hazard based, classifying chemicals on the basis of
intrinsic ability to produce an adverse effect on reproductive function
or capacity, and/or on development of the offspring.

3\. The present system involves consideration of any substance-related
adverse effect on reproduction seen in humans, or observed in
appropriate tests conducted in experimental animals.

4\. The Explanatory Notes provide essential guidance and should be
regarded as an integral part of the Classification System.

**REPRODUCTIVE TOXICITY: DEFINITIONS**

5\. Reproductive toxicity includes adverse effects on sexual function
and fertility in adult males and females, as well as developmental
toxicity in the offspring. The definitions presented below are adapted
from those agreed at the IPCS/OECD Workshop for the Harmonisation of
Risk Assessment for Reproductive and Developmental Toxicity, Carshalton,
UK, 17-21 October, 1994 (OECD Monograph Series on Testing and Assessment
No. 17, 1998). For classification purposes, the known induction of
genetically-based inheritable effects in the offspring is addressed
elsewhere, since in the present classification system it is considered
more appropriate to address such effects under the separate end-point of
germ-cell mutagenicity.

6\. In this classification system, reproductive toxicity is subdivided
under two main headings:

**a). Adverse effects on reproductive ability or capacity**

7\. Any effect of chemicals that would interfere with reproductive
ability or capacity. This may include, but not be limited to,
alterations to the female and male reproductive system, adverse effects
on onset of puberty, gamete production and transport, reproductive cycle
normality, sexual behaviour, fertility, parturition, premature
reproductive senescence, or modifications in other functions that are
dependent on the integrity of the reproductive systems.

8\. Adverse effects on or via lactation can also be included in
reproductive toxicity, but for classification purposes, such effects are
treated separately (see paragraph 16). This is because it is desirable
to be able to classify chemicals specifically for adverse effect on
lactation so that a specific hazard warning about this effect can be
provided for lactating mothers.

**b). Adverse effects on development of the offspring**

9\. Taken in its widest sense, developmental toxicity includes any
effect which interferes with normal development of the conceptus, either
before or after birth, and resulting from exposure of either parent
prior to conception, or exposure of the developing offspring during
prenatal development, or postnatally, to the time of sexual maturation.

10\. However, it is considered that classification under the heading of
developmental toxicity is primarily intended to provide hazard warning
for pregnant women and men and women of reproductive capacity.
Therefore, for pragmatic purposes of classification, developmental
toxicity essentially means adverse effects induced during pregnancy, or
as a result of parental exposure. These effects can be manifested at any
point in the life span of the organism. The major manifestations of
developmental toxicity include (1) death of the developing organism, (2)
structural abnormality, (3) altered growth, and (4) functional
deficiency.

**CLASSIFICATION**

**Weight of Evidence**

11\. Classification as a reproductive toxicant is made on the basis of
an assessment of the total weight of evidence. This means that all
available information that bears on the determination of reproductive
toxicity is considered together. Included are such information as
epidemiological studies and case reports in humans and specific
reproduction studies along with sub-chronic, chronic and special study
results in animals that provide relevant information regarding toxicity
to reproductive and related endocrine organs. Evaluation of substances
chemically related to the material under study may also be included,
particularly when information on the material is scarce. The weight
given to the available evidence will be influenced by factors such as
the quality of the studies, consistency of results, nature and severity
of effects, level of statistical significance for intergroup
differences, number of endpoints affected, relevance of route of
administration to humans and freedom from bias. Both positive and
negative results are assembled together into a weight of evidence
determination. However, a single, positive study performed according to
good scientific principles and with statistically or biologically
significant positive results may justify classification (see also
paragraph 13).

12\. Toxicokinetic studies in animals and humans, site of action and
mechanism or mode of action study results may provide relevant
information, which could reduce or increase concerns about the hazard to
human health. If it can be conclusively demonstrated that the clearly
identified mechanism or mode of action has no relevance for humans or
when the toxicokinetic differences are so marked that it is certain that
the hazardous property will not be expressed in humans then a substance
which produces an adverse effect on reproduction in experimental animals
should not be classified.

13\. In some reproductive toxicity studies in experimental animals the
only effects recorded may be considered of low or minimal toxicological
significance and classification may not necessarily be the outcome.
These include for example small changes in semen parameters or in the
incidence of spontaneous defects in the foetus, small changes in the
proportions of common fetal variants such as are observed in skeletal
examinations, or in fetal weights, or small differences in postnatal
developmental assessments.

14\. Data from animal studies ideally should provide clear evidence of
specific reproductive toxicity in the absence of other, systemic, toxic
effects. However, if developmental toxicity occurs together with other
toxic effects in the dam, the potential influence of the generalised
adverse effects should be assessed to the extent possible. The preferred
approach is to consider adverse effects in the embryo/fetus first, and
then evaluate [maternal toxicity]{.underline}, along with any other
factors which are likely to have influenced these effects, as part of
the weight of evidence. In general, developmental effects that are
observed at maternal toxic doses should not be automatically discounted.
Discounting developmental effects that are observed at maternal toxic
doses can only be done on a case-by-case basis when a causal
relationship is established or refuted.

15\. If appropriate information is available it is important to try to
determine whether developmental toxicity is due to a specific maternally
mediated mechanism or to a nonspecific secondary mechanism, like
maternal stress and the disruption of homeostasis. Generally, the
presence of maternal toxicity should not be used to negate findings of
embryo/fetal effects , unless it can be clearly demonstrated that the
effects are secondary nonspecific effects. This is especially the case
when the effects in the offspring are significant, e.g. irreversible
effects such as structural malformations. In some situations it is
reasonable to assume that reproductive toxicity is due to a secondary
consequence of maternal toxicity and discount the effects, for example
if the chemical is so toxic that dams fail to thrive and there is severe
inanition; they are incapable of nursing pups; or they are prostrate or
dying.

**Hazard classes**

16\. For the purpose of classification for reproductive toxicity,
chemical substances are allocated to one of two classes. Effects on
reproductive ability or capacity, and on development, are considered as
separate issues.

> **[Class 1: KNOWN OR PRESUMED HUMAN REPRODUCTIVE OR DEVELOPMENTAL
> TOXICANT]{.underline}**
>
> This Class includes substances which are known to have produced an
> adverse effect on reproductive ability or capacity or on development
> in humans or for which there is evidence from animal studies, possibly
> supplemented with other information, to provide a strong presumption
> that the substance has the capacity to interfere with reproduction in
> humans. For regulatory purposes, a substance can be further
> distinguished on the basis of whether the evidence for classification
> is primarily from human data ([Class 1A]{.underline}) or from animal
> data ([Class 1B]{.underline}).
>
> **[Class 1A:]{.underline} KNOWN to have produced an adverse effect on
> reproductive ability or capacity or on development in humans. The
> placing of the substance in this class is largely based on evidence
> from humans.**
>
> **[Class 1B:]{.underline} PRESUMED to produce an adverse effect on
> reproductive ability or capacity or on development in humans. The
> placing of the substance in this class is largely based on evidence
> from experimental animals. Data from animal studies should provide
> clear evidence of specific reproductive toxicity in the absence of
> other toxic effects, or if occurring together with other toxic effects
> the adverse effect on reproduction is considered not to be a secondary
> non-specific consequence of other toxic effects. However, when there
> is mechanistic information that raises doubt about the relevance of
> the effect for humans, classification in Class 2 may be more
> appropriate.**
>
> **[Class 2: SUSPECTED HUMAN REPRODUCTIVE OR DEVELOPMENTAL
> TOXICANT]{.underline}**
>
> This Class includes substances for which there is some evidence from
> humans or experimental animals, - possibly supplemented with other
> information - of an adverse effect on reproductive ability or
> capacity, or on development, in the absence of other toxic effects, or
> if occurring together with other toxic effects the adverse effect on
> reproduction is considered not to be a secondary non-specific
> consequence of the other toxic effects, and where the evidence is not
> sufficiently convincing to place the substance in Class 1. For
> instance, deficiencies in the study may make the quality of evidence
> less convincing, and in view of this Class 2 could be the more
> appropriate classification.

**[EFFECTS ON OR VIA LACTATION]{.underline}**

> [Effects on or via lactation]{.underline} are allocated to a separate
> single class. It is appreciated that for many substances there is no
> information on the potential to cause adverse effects on the offspring
> via lactation. However, for substances which are absorbed by women and
> have been shown to interfere with lactation or which may be present
> (including metabolites) in breast milk in amounts sufficient to cause
> concern for the health of a breastfed child, should be classified to
> indicate this property hazardous to breastfed babies. This
> classification can be assigned on the basis of:
>
> \(a\) absorption, metabolism, distribution and excretion studies that
> would indicate the likelihood the substance would be present in
> potentially toxic levels in breast milk; and/or
>
> \(b\) results of one or two generation studies in animals which
> provide clear evidence of adverse effect in the offspring due to
> transfer in the milk or adverse effect on the quality of the milk;
> and/or
>
> \(c\) human evidence indicating a hazard to babies during the
> lactation period.

**BASIS OF CLASSIFICATION**

17\. Classification is made on the basis of the appropriate criteria,
outlined above, and an assessment of the total weight of evidence.
Classification as a reproductive or developmental toxicant is intended
to be used for chemicals which have an intrinsic, specific property to
produce an adverse effect on reproduction or development and chemicals
should not be so classified if such an effect is produced solely as a
non-specific secondary consequence of other toxic effects.

18\. In the evaluation of toxic effects on the developing offspring, it
is important to consider the possible influence of maternal toxicity.

19\. For human evidence to provide the primary basis for a Class 1A
classification there must be reliable evidence of adverse effect on
reproduction in humans. Evidence used for classification should ideally
be from well conducted epidemiological studies which include the use of
appropriate controls, balanced assessment, and due consideration of bias
or confounding factors. Less rigorous data from studies in humans should
be supplemented with adequate data from studies in experimental animals
and classification in Class 1B should be considered.

20\. Data already generated for classifying chemicals under existing
systems should be acceptable when reviewing these chemicals with regard
to classification under the harmonised system. Further testing should
not normally be necessary.

**EXPLANATORY NOTES**

**Maternal toxicity**

21\. Development of the offspring throughout gestation and during the
early post-natal stages can be influenced by toxic effects in the mother
either through non-specific mechanisms related to stress and the
disruption of maternal homeostasis, or by specific maternally-mediated
mechanisms. So, in the interpretation of the developmental outcome to
decide classification for developmental effects it is important to
consider the possible influence of maternal toxicity. This is a complex
issue because of uncertainties surrounding the relationship between
maternal toxicity and developmental outcome. Expert judgement and a
weight of evidence approach, using all available studies, should be used
to determine the degree of influence that should be attributed to
maternal toxicity when interpreting the criteria for classification for
developmental effects. The adverse effects in the embryo/fetus should be
first considered, and then maternal toxicity, along with any other
factors which are likely to have influenced these effects, as weight of
evidence, to help reach a conclusion about classification.

22\. Based on pragmatic observation, it is believed, that maternal
toxicity may, depending on severity, influence development via
non-specific secondary mechanisms, producing effects such as depressed
foetal weight, retarded ossification, and possibly resorptions and
certain malformations in some strains of certain species. However, the
limited number of studies which have investigated the relationship
between developmental effects and general maternal toxicity have failed
to demonstrate a consistent, reproducible relationship across species.
Developmental effects which occur even in the presence of maternal
toxicity are considered to be evidence of developmental toxicity, unless
it can be unequivocally demonstrated on a case by case basis that the
developmental effects are secondary to maternal toxicity. Moreover,
classification should be considered where there is significant toxic
effect in the offspring, e.g. irreversible effects such as structural
malformations, embryo/fetal lethality, significant post-natal functional
deficiencies.

23\. Classification should not automatically be discounted for chemicals
that produce developmental toxicity only in association with maternal
toxicity, even if a specific maternally-mediated mechanism has been
demonstrated. In such a case, classification in Class 2 may be
considered more appropriate than Class 1. However, when a chemical is so
toxic that maternal death or severe inanition results, or the dams are
prostrate and incapable of nursing the pups, it may be reasonable to
assume that developmental toxicity is produced solely as a secondary
consequence of maternal toxicity and discount the developmental effects.
Classification may not necessarily be the outcome in the case of e.g.
small reduction in fetal/pup body weight, retardation of ossification.

24\. Some of the end points used to assess maternal toxicity are
provided below. Data on these end points, if available, needs to be
evaluated in light of their statistical or biological significance and
dose response relationship.

> [Maternal Mortality]{.underline}: An increased incidence of mortality
> among the treated dams over the controls should be considered evidence
> of maternal toxicity if the increase occurs in a dose-related manner
> and can be attributed to the systemic toxicity of the test material.
> Maternalmortality greater than 10% is considered excessive and the
> data for that dose level should not normally be considered for further
> evaluation.

[Mating Index]{.underline} (no. animals with seminal plugs or sperm/no.
mated x 100)[^1]

[Fertility Index]{.underline} (no. animals with implants/no. of matings
x 100)[^2]

> [Gestation Length]{.underline} (if allowed to deliver)
>
> [Body Weight and Body Weight Change]{.underline}: Consideration of the
> maternal body weight change and/or adjusted (corrected) maternal body
> weight should be included in the evaluation of maternal toxicity
> whenever such data are available. The calculation of a adjusted
> (corrected) mean maternal body weight change, which is the difference
> between the initial and terminal body weight minus the gravid uterine
> weight (or alternatively, the sum of the weights of the foetuses), may
> indicate whether the effect is maternal or intrauterine. In rabbits,
> the body weight gain may not be useful indicators of maternal toxicity
> because of normal fluctuations in body weight during pregnancy.
>
> [Food and Water Consumption]{.underline} (if relevant): The
> observation of a significant decrease in the average food or water
> consumption in treated dams compared to the control group may be
> useful in evaluating maternal toxicity, particularly when the test
> material is administered in the diet or drinking water. Changes in
> food or water consumption should be evaluated in conjunction with
> maternal body weights when determining if the effects noted are
> reflective of maternal toxicity or more simply, unpallatibility of the
> test material in feed or water.
>
> [Clinical evaluations]{.underline} (including clinical signs, markers,
> hematology and clinical chemistry studies): The observation of
> increased incidence of significant clinical signs of toxicity in
> treated dams relative to the control group may be useful in evaluating
> maternal toxicity. If this is to be used as the basis for the
> assessment of maternal toxicity, the types, incidence, degree and
> duration of clinical signs should be reported in the study. Examples
> of frank clinical signs of maternal intoxication include: coma,
> prostration, hyperactivity, loss of righting reflex, ataxia, or
> laboured breathing.
>
> [Postmortem data]{.underline}: Increased incidence and/or severity of
> postmortem findings may be indicative of maternal toxicity. This can
> include gross or microscopic pathological findings or organ weight
> data, e.g., absolute organ weight, organ‑to‑body weight ratio, or
> organ‑to‑brain weight ratio. When supported by findings of adverse
> histopathological effects in the affected organ(s), the observation of
> a significant change in the average weight of suspected target
> organ(s) of treated dams, compared to those in the control group, may
> be considered evidence of maternal toxicity.

**Potency and cut-off doses**

25\. In the present scheme, the relative potency of a chemical to
produce a toxic effect on reproduction is not included in the criteria
for reaching a conclusion regarding classification. Nevertheless, during
the development of this scheme it was suggested that cut-off dose levels
should be included, in order to provide some means of assessing and
categorising the potency of chemicals for the ability to produce an
adverse effect on reproduction. This concept has not been readily
accepted by all member countries because of concerns that any specified
cut-off level may be exceeded by human exposure levels in certain
situations, e.g. inhalation of volatile solvents, the level may be
inadequate in cases where humans are more sensitive than the animal
model, and because of disagreements about whether or not potency is a
component of hazard.

26\. There has been interest in this concept to further consider it as a
future development of the classification scheme.

**Limit dose**

27\. Member countries appear to be in agreement about the concept of a
limit dose, above which the production of an adverse effect may be
considered to be outside the criteria which lead to classification.
However, there is disagreement between members regarding the inclusion
within the criteria of a specified dose as a limit dose. Some Test
Guidelines specify a limit dose, other Test Guidelines qualify the limit
dose with a statement that higher doses may be necessary if anticipated
human exposure is sufficiently high that an adequate margin of exposure
would not be achieved. Also, due to species differences in
toxicokinetics, establishing a specific limit dose may not be adequate
for situations where humans are more sensitive than the animal model.

28\. In principle, adverse effects on reproduction seen only at very
high dose levels in animal studies (for example doses that induce
prostration, severe inappetence, excessive mortality) would not normally
lead to classification, unless other information is available, e.g.
toxicokinetics information indicating that humans may be more
susceptible than animals, to suggest that classification is appropriate.
Please also refer to the section on Maternal Toxicity for further
guidance in this area.

29\. However, specification of the actual \'limit dose\' will depend
upon the test method that has been employed to provide the test results,
e.g. in the OECD Test Guideline for repeated dose toxicity studies by
the oral route, an upper dose of 1000 mg/kg unless expected human
response indicates the need for a higher dose level, has been
recommended as a limit dose.

**Animal and experimental data**

30\. A number of internationally accepted test methods are available;
these include methods for developmental toxicity testing (e.g., OECD
Test Guideline 414, ICH Guideline S5A, 1993), methods for peri- and
post-natal toxicity testing (e.g. ICH S5B, 1995) and methods for one or
two-generation toxicity testing (e.g. OECD Test Guidelines 415, 416).

31\. Results obtained from Screening Tests (e.g. OECD Guidelines 421 -
Reproduction/Developmental Toxicity Screening Test, and 422 - Combined
Repeated Dose Toxicity Study with Reproduction/Development Toxicity
Screening Test, )can also be used to justify classification, although it
is recognised that the quality of this evidence is less reliable than
that obtained full studies.

32\. Adverse effects or changes, seen in short- or long-term repeated
dose toxicity studies, which are judged likely to impair reproductive
ability or capacity and which occur in the absence of significant
generalised toxicity, may be used as a basis for classification, e.g.
histopathological changes in the gonads.

33\. Evidence from in vitro assays, or non-mammalian tests, and from
analogous substances using structure-activity relationship (SAR), can
contribute to the procedure for classification. In all cases of this
nature, expert judgement must be used to assess the adequacy of the
data. Inadequate data should not be used as a primary support for
classification.

34\. It is preferable that animal studies are conducted using
appropriate routes of administration which relate to the potential route
of human exposure. However, in practice, reproductive toxicity studies
are commonly conducted using the oral route, and such studies will
normally be suitable for evaluating the hazardous properties of the
substance with respect to reproductive toxicity. .However if it can be
conclusively demonstrated that the clearly identified mechanism or mode
of action has no relevance for humans or when the toxicokinetic
differences are so marked that it is certain that the hazardous property
will not be expressed in humans then a substance which produces an
adverse effect on reproduction in experimental animals should not be
classified.

35\. Studies involving routes of administration such as intravenous or
intraperitoneal injection, which may result in exposure of the
reproductive organs to unrealistically high levels of the test
substance, or elicit local damage to the reproductive organs, e.g. by
irritation, must be interpreted with extreme caution and on their own
would not normally be the basis for classification.

**HARMONIZED SYSTEM FOR THE CLASSIFICATION OF CHEMICALS WHICH CAUSE
TARGET ORGAN ORIENTED SYSTEMIC TOXICITY**

*(to be inserted here after approval by the Advisory Group and
subsequent endorsement by the Joint Meeting)*

**Purpose, basis and applicability**

**Definitions**

**Classification categories and criteria**

**Rationale for the proposed System**

**Explanatory notes**

**Literature**

***Background information***

**HARMONIZED SYSTEM FOR THE CLASSIFICATION OF CHEMICALS WHICH ARE
HAZARDOUS FOR THE AQUATIC ENVIRONMENT**

**PURPOSE, BASIS AND APPLICABILITY**

1\. The harmonized system for classifying chemical substances for the
hazards they present to the aquatic environment is based on a
consideration of the existing systems listed below. The aquatic
environment may be considered in terms of the aquatic organisms that
live in the water, and the aquatic ecosystem of which they are part. To
that extent, the proposal does not address aquatic pollutants for which
there may be a need to consider effects beyond the aquatic environment
such as the impacts on human health etc. The basis, therefore, of the
identification of hazard is the aquatic toxicity of the substance,
although this may be modified by further information on the degradation
and bioaccumulation behaviour.

2\. The proposed system is intended specifically for use with chemical
substances and is not intended at this stage to cover preparations or
other mixtures such as formulated pesticides. Its application to
mixtures is deferred to the OECD Working Group on Mixtures. While the
scheme is intended to apply to all substances, it is recognised that for
some substances, e.g. metals, poorly soluble substances etc., special
guidance will be necessary. A Guidance Document will thus be prepared to
cover issues such as data interpretation and the application of the
criteria defined below to such groups of substances. Considering the
complexity of this endpoint and the breadth of the application of the
system, the Guidance Document is considered an important element in the
operation of the harmonised scheme.

3\. Consideration has been given to existing classification systems as
currently in use, including the EU Supply and Use Scheme, the revised
GESAMP hazard evaluation procedure, IMO Scheme for Marine Pollutant, the
European Road and Rail Transport Scheme (RID/ADR), the Canadian and US
Pesticide systems and the US Land Transport Scheme. The harmonized
scheme is considered suitable for use for packaged goods in both supply
and use and multimodal transport schemes, and elements of it may be used
for bulk land transport and bulk marine transport under MARPOL 73/78
Annex II insofar as this uses aquatic toxicity.

**DEFINITIONS AND DATA REQUIREMENTS**

4\. The basic elements for use within the harmonized system are:

\- acute aquatic toxicity;

\- potential for or actual bioaccumulation;

\- degradation (biotic or abiotic) for organic chemicals; and

\- chronic aquatic toxicity.

5\. While data from internationally harmonized test methods are
preferred, in practice, data from national methods may also be used
where they are considered as equivalent. In general, it has been agreed
that freshwater and marine species toxicity data can be considered as
equivalent data and are preferably to be derived using OECD Test
Guidelines or equivalent according to the principles of GLP. Where such
data are not available classification should be based on the best
available data.

**Acute toxicity**

6\. Acute aquatic toxicity would normally be determined using a fish 96
hour LC~50~ (OECD Test Guideline 203 or equivalent), a crustacea species
48 hour EC~50~ (OECD Test Guideline 202 or equivalent) and/or an algal
species 72 or 96 hour EC~50~ (OECD Test Guideline 201 or equivalent).
These species are considered as surrogate for all aquatic organisms and
data on other species such as Lemna may also be considered if the test
methodology is suitable.

**Bioaccumulation potential**

7\. The potential for bioaccumulation would normally be determined by
using the octanol/water partition coefficient, usually reported as a log
Kow determined by OECD Test Guideline 107 or 117. While this represents
a potential to bioaccumulate, an experimentally determined
Bioconcentration Factor (BCF) provides a better measure and should be
used in preference when available. A BCF should be determined according
to OECD Test Guideline 305.

**Rapid degradability**

8\. Environmental degradation may be biotic or abiotic (e.g. hydrolysis)
and the criteria used

reflect this fact (Annex I). Ready biodegradation can most easily be
defined using the OECD biodegradability tests OECD Test Guideline 301
(A - F). A pass level in these tests can be considered as indicative of
rapid degradation in most environments. These are freshwater tests and
thus the use of the results from OECD Test Guideline 306 which is more
suitable for marine environments has also been included. Where such data
are not available, a BOD(5 days)/COD ratio \>0.5 is considered as
indicative of rapid degradation.

9\. Abiotic degradation such as hydrolysis, primary degradation, both
abiotic and biotic, degradation in non-aquatic media and proven rapid
degradation in the environment may all be considered in defining rapid
degradability. Special guidance on data interpretation will be provided
in the Guidance Document.

**Chronic toxicity**

10\. Chronic toxicity data are less available than acute data and the
range of testing procedures less standardised. Data generated according
to the OECD Test Guidelines 210 (Fish Early Life Stage), 202 Part 2 or
211 (Daphnia Reproduction) and 201 (Algal Growth Inhibition) can be
accepted. Other validated and internationally accepted tests could also
be used. The NOECs or other equivalent L(E)Cx should be used.

**CLASSIFICATION CATEGORIES AND CRITERIA**

11\. Substances classified under the following criteria will be
categorised as 'hazardous to the aquatic environment'. These criteria
describe in detail the classification categories detailed
diagramatically in Annex 2.

**Acute toxicity**

+-----------------------------------------------------------------------+
| **[Class: Acute I]{.underline}**                                      |
|                                                                       |
| Acute toxicity:                                                       |
|                                                                       |
| 96 hr LC~50~ (for fish) ≤1 mg/L and/or                                |
|                                                                       |
| 48 hr EC~50~ (for crustacea) ≤1 mg/L and/or                           |
|                                                                       |
| 72 or 96hr ErC~50~ (for algae or other aquatic plants) ≤1 mg/L.       |
|                                                                       |
| Class: Acute I may be subdivided for some regulatory systems to       |
| include a lower band at L(E)C~50~ ≤0.1 mg/L.                          |
+-----------------------------------------------------------------------+

+-----------------------------------------------------------------------+
| **[Class: Acute II]{.underline}**                                     |
|                                                                       |
| Acute toxicity:                                                       |
|                                                                       |
| 96 hr LC~50~ (for fish) \>1 - ≤10 mg/L and/or                         |
|                                                                       |
| 48 hr EC~50~ (for crustacea) \>1 - ≤10 mg/L and/or                    |
|                                                                       |
| 72 or 96hr ErC~50~ (for algae or other aquatic plants) \>1 - ≤10      |
| mg/L.                                                                 |
+-----------------------------------------------------------------------+

+-----------------------------------------------------------------------+
| **[Class: Acute III]{.underline}**                                    |
|                                                                       |
| Acute toxicity:                                                       |
|                                                                       |
| 96 hr LC~50~ (for fish) \>10 - ≤100 mg/L and/or                       |
|                                                                       |
| 48 hr EC~50~ (for crustacea) \>10 - ≤100 mg/L and/or                  |
|                                                                       |
| 72 or 96hr ErC~50~ (for algae or other aquatic plants) \>10 - ≤100    |
| mg/L.                                                                 |
|                                                                       |
| Some regulatory systems may extend this range beyond an L(E)C~50~ of  |
| 100 mg/L through the introduction of another class.                   |
+-----------------------------------------------------------------------+

**Chronic toxicity**

+-----------------------------------------------------------------------+
| **[Class: Chronic I]{.underline}**                                    |
|                                                                       |
| Acute toxicity:                                                       |
|                                                                       |
| 96 hr LC~50~ (for fish) ≤1 mg/L and/or                                |
|                                                                       |
| 48 hr EC~50~ (for crustacea) ≤1 mg/L and/or                           |
|                                                                       |
| 72 or 96hr ErC~50~ (for algae or other aquatic plants) ≤1 mg/L        |
|                                                                       |
| and the substance is not rapidly degradable and/or the log Kow ≥ 4    |
| (unless the experimentally determined BCF \<500).                     |
+-----------------------------------------------------------------------+

+-----------------------------------------------------------------------+
| **[Class: Chronic II]{.underline}**                                   |
|                                                                       |
| Acute toxicity                                                        |
|                                                                       |
| 96 hr LC~50~ (for fish) \>1 to ≤10 mg/L and/or                        |
|                                                                       |
| 48 hr EC~50~ (for crustacea) \>1 to ≤10 mg/L and/or                   |
|                                                                       |
| 72 or 96hr ErC~50~ (for algae or other aquatic plants) \>1 to ≤10     |
| mg/L                                                                  |
|                                                                       |
| and the substance is not rapidly degradable and/or the log Kow ≥4     |
| (unless the experimentally determined BCF \<500), unless the chronic  |
| toxicity NOECs are \> 1 mg/L.                                         |
+-----------------------------------------------------------------------+

+-----------------------------------------------------------------------+
| **[Class: Chronic III]{.underline}**                                  |
|                                                                       |
| Acute toxicity:                                                       |
|                                                                       |
| 96 hr LC~50~ (for fish) \>10 to ≤100 mg/L and/or                      |
|                                                                       |
| 48 hr EC~50~ (for crustacea) \>10 to ≤100 mg/L and/or                 |
|                                                                       |
| 72 or 96hr ErC~50~ (for algae or other aquatic plants) \>10 to ≤100   |
| mg/L                                                                  |
|                                                                       |
| and the substance is not rapidly degradable and/or the log Kow ≥4     |
| (unless the experimentally determined BCF \<500) unless the chronic   |
| toxicity NOECs are \>1 mg/L.                                          |
+-----------------------------------------------------------------------+

+-----------------------------------------------------------------------+
| **[Class: Chronic IV]{.underline}**                                   |
|                                                                       |
| Poorly soluble substances for which no acute toxicity is recorded at  |
| levels up to the water solubility, and which are not rapidly          |
| degradable and have a log Kow ≥ 4, indicating a potential to          |
| bioaccumulate, will be classified in this class unless other          |
| scientific evidence exists showing classification to be unnecessary.  |
| Such evidence would include an experimentally determined BCF \<500,   |
| or a chronic toxicity NOECs \>1 mg/L, or evidence of rapid            |
| degradation in the environment.                                       |
+-----------------------------------------------------------------------+

**RATIONALE FOR THE SYSTEM**

12\. The system for classification recognises that the core intrinsic
hazard to aquatic organisms is represented by both the acute and chronic
toxicity of a substance, the relative importance of which is determined
by the specific regulatory system in operation. Distinction can be made
between the acute hazard and the chronic hazard and therefore separate
hazard classes are defined for both properties representing a gradation
in the level of hazard identified. The lowest of the available toxicity
values will normally be used to define the appropriate hazard class(es).
There may be circumstances, however, when a weight of evidence approach
may be used*.* Acute toxicity data are the most readily available and
the tests used are the most standardised. For that reason, these data
form the core of the classification system.

13\. Acute toxicity represents a key property in defining the hazard
where transport of large quantities of a substance may give rise to
short-term dangers arising from accidents or major spillages. Hazards
classes up to L(E)C~50~ values of 100 mg/L are thus defined although
classes up to 1000 mg/L may be used in certain regulatory frameworks.
The Acute: Class I may be further sub-divided to include an additional
class for acute toxicity L(E)C~50~ ≤0.1 mg/L in certain regulatory
systems such as that defined by MARPOL 73/78 Annex II. It is anticipated
that their use would be restricted to regulatory systems concerning bulk
transport.

14\. For packaged substances it is considered that the principal hazard
is defined by chronic toxicity, although acute toxicity at L(E)C~50~
levels ≤1 mg/L are also considered hazardous. Levels of substances up to
1 mg/L are considered as possible in the aquatic environment following
normal use and disposal. At toxicity levels above this, it is considered
that the short-term toxicity itself does not describe the principle
hazard, which arises from low concentrations causing effects over a
longer time scale. Thus, a number of hazard classes are defined which
are based on levels of chronic aquatic toxicity. Chronic toxicity data
are not available for many substances, however, and it is necessary to
use the available data on acute toxicity to estimate this property. The
intrinsic properties of a lack of rapid degradability and/or a potential
to bioconcentrate in combination with acute toxicity may be used to
assign a substance to a chronic hazard class. Where chronic toxicity is
available showing NOECs \>1 mg/L, this would indicate that no
classification in a chronic hazard class would be necessary. Equally,
for substances with an L(E)C~50~ \>100 mg/L, the toxicity is considered
as insufficient to warrant classification in most regulatory systems.

15\. While the current system will continue to rely on the use of acute
toxicity data in combination with a lack of rapid degradation and/or a
potential to bioaccumulate as the basis for classification for assigning
a chronic hazard class, it is recognised that actual chronic toxicity
data would form a better basis for classification where these data are
available. It is thus the intention that the scheme should be further
developed to accommodate such data. It is anticipated that in such a
further development, the available chronic toxicity data would be used
to classify in the chronic hazard in preference to that derived from
their acute toxicity in combination with a lack of rapid degradation
and/or a potential to bioaccumulate.

16\. Recognition is given to the classification goals of MARPOL 73/78
Annex II which covers the transport of bulk quantities in ships tanks,
which are aimed at regulating operational discharges from ships and
assigning of suitable ship types. They go beyond that of protecting
aquatic ecosystems, although that clearly is included. Additional hazard
classes may thus be used which take account of factors such as
physico-chemical properties and mammalian toxicity.

**EXPLANATORY NOTES**

17\. The organisms fish, crustacea and algae are tested as surrogate
species covering a range of trophic levels and taxa, and the test
methods are highly standardised. Data on other organisms may also be
considered, however, provided they represent equivalent species and test
endpoints. The algal growth inhibition test is a chronic test but the
EC~50~ is treated as an acute value for classification purposes. This
EC~50~ should normally be based on growth rate inhibition. If only the
EC~50~ based on reduction in biomass is available, or it is not
indicated which EC~50~ is reported, this value may be used in the same
way.

18\. Aquatic toxicity testing by its nature, involves the dissolution of
the substance under test in the water media used and the maintenance of
a stable bioavailable exposure concentration over the course of the
test. Some substances are difficult to test under standard procedures
and thus special guidance will be developed on data interpretation for
these substances and how the data should be used when applying the
classification criteria.

19\. It is the bioaccumulation of substances within the aquatic
organisms that can give rise to toxic effects over longer time scales
even when actual water concentrations are low. The potential to
bioaccumulate is determined by the partitioning between n-octanol and
water. The relationship between the partition coefficient of an organic
substance and its bioconcentration as measured by the BCF in fish has
considerable scientific literature support. Using a cut-off value of log
P(o/w) ≥ 4 is intended to identify only those substances with a real
potential to bioconcentrate. In recognition that the log P(o/w) is only
an imperfect surrogate for a measured BCF, such a measured value would
always take precedence. A BCF in fish of \<500 is considered as
indicative of a low level of bioconcentration.

20\. Substances that rapidly degrade can be quickly removed from the
environment. While effects can occur, particularly in the event of a
spillage or accident, they will be localised and of short duration. The
absence of rapid degradation in the environment can mean that a
substance in the water has the potential to exert toxicity over a wide
temporal and spatial scale. One way of demonstrating rapid degradation
utilises the biodegradation screening tests designed to determine
whether a substance is \`readily biodegradable\'. Thus a substance which
passes this screening test is one that is likely to biodegrade
\`rapidly\' in the aquatic environment, and is thus unlikely to be
persistent. However, a fail in the screening test does not necessarily
mean that the substance will not degrade rapidly in the environment.
Thus a further criterion was added which would allow the use of data to
show that the substance did actually degrade biotically or abiotically
in the aquatic environment by \>70% in 28 days. Thus, if degradation
could be demonstrated under environmentally realistic conditions, then
the definition of \`rapid degradability\' would have been met. Many
degradation data are available in the form of degradation half-lives and
these can also be used in defining rapid degradation. Details regarding
the interpretation of these data will be further elaborated in the
Guidance Document. Some tests measure the ultimate biodegradation of the
substance, i.e. full mineralisation is achieved. Primary biodegradation
would not normally qualify in the assessment of rapid degradability
unless it can be demonstrated that the degradation products do not
fulfil the criteria for classification as hazardous to the aquatic
environment.

21\. It must be recognised that environmental degradation may be biotic
or abiotic (e.g. hydrolysis) and the criteria used reflect this fact.
Equally, it must be recognised that failing the ready biodegradability
criteria in the OECD tests does not mean that the substance will not be
degraded rapidly in the real environment. Thus where such rapid
degradation can be shown, the substance should be considered as rapidly
degradable. Hydrolysis can be considered if the hydrolysis products do
not fulfil the criteria for classification as hazardous to the aquatic
environment. A specific definition of rapid degradability is included as
Annex 1. Other evidence of rapid degradation in the environment may also
be considered and may be of particular importance where the substances
are inhibitory to microbial activity at the concentration levels used in
standard testing. The range of available data and guidance on its
interpretation will be provided in the Guidance Document.

22\. For inorganic compounds and metals, the concept of degradability as
applied to organic compounds has limited or no meaning. Rather the
substance may be transformed by normal environmental processes to either
increase or decrease the bioavailability of the toxic species. Equally
the use of bioaccumulation data should be treated with care. Specific
guidance will be provided on how these data for such materials may be
used in meeting the requirements of the classification criteria.

23\. Poorly soluble inorganic compounds and metals may be acutely or
chronically toxic in the aquatic environment depending on the intrinsic
toxicity of the bioavailable inorganic species and the rate and amount
of this species which may enter solution. A protocol for testing these
poorly soluble materials is being developed and will be covered further
in the special guidance.

24\. The system also introduces as \`safety net\' classification (Class:
Chronic IV) for use when the data available does not allow
classification under the formal criteria but there are nevertheless some
grounds for concern. The precise criteria are not defined with one
exception. For poorly water soluble organic substances for which no
toxicity has been demonstrated, classification can occur if the
substance is both not rapidly degraded and has a potential to
bioaccumulate. It is considered that for such poorly soluble substances,
the toxicity may not have been adequately assessed in the short-term
test due to the low exposure levels and potentially slow uptake into the
organism. The need for this classification can be negated by
demonstrating the absence of long-term effects, i.e. a long-term NOECs
\> water solubility or 1 mg/L, or rapid degradation in the environment.

25\. While experimentally derived test data are preferred, where no
experimental data are available, validated Quantitative Structure
Activity Relationships (QSARs) for aquatic toxicity and log Kow may be
used in the classification process. Such validated QSARs may be used
without modification to the agreed criteria, if restricted to chemicals
for which their mode of action and applicability are well characterized.
Validity may be judged according to the criteria established within the
USEPA/EU/Japan Collaborative Project. Reliable calculated toxicity and
log Kow values should be valuable in the safety net context. QSARs for
predicting ready biodegradation are not yet sufficiently accurate to
predict rapid degradation.

**ANNEX 1**

**RAPID DEGRADABILITY**

Substances are considered rapidly degradable in the environment if the
following criteria hold true:

a\) if in 28-day ready biodegradation studies, the following levels of
degradation are achieved;

\- tests based on dissolved organic carbon: 70%

\- tests based on oxygen depletion or carbon dioxide generation: 60% of
theoretical maxima

These levels of biodegradation must be achieved within 10 days of the
start of degradation which point is taken as the time when 10% of the
substance has been degraded.

or

b\) if, in those cases where only BOD and COD data are available, when
the ratio of BOD5/COD is ≥0.5

or

c\) if other convincing scientific evidence is available to demonstrate
that the substance can be degraded (biotically and/or abiotically) in
the aquatic environment to a level \>70% within a 28 day period.

**ANNEX 2**

**Classification Scheme for Substances Hazardous to the Aquatic
Environment**

<table style="width:100%;">
<colgroup>
<col style="width: 17%" />
<col style="width: 11%" />
<col style="width: 0%" />
<col style="width: 16%" />
<col style="width: 0%" />
<col style="width: 0%" />
<col style="width: 16%" />
<col style="width: 0%" />
<col style="width: 16%" />
<col style="width: 20%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="3"><strong>Toxicity</strong></td>
<td><strong>Degradability (note 3)</strong></td>
<td colspan="3"><strong>Bioaccumulation (note 4)</strong></td>
<td colspan="3"><strong>Classification categories</strong></td>
</tr>
<tr class="even">
<td><p><strong>Acute</strong></p>
<p><strong>(note 1)</strong></p></td>
<td><p><strong>Chronic</strong></p>
<p><strong>(note 2)</strong></p></td>
<td colspan="3"></td>
<td colspan="3"></td>
<td><strong>Acute</strong></td>
<td><strong>Chronic</strong></td>
</tr>
<tr class="odd">
<td><p><strong>Box 1</strong></p>
<p>value ≤ 1.00</p></td>
<td></td>
<td colspan="4"><strong>Box 5</strong></td>
<td colspan="2"><strong>Box 6</strong></td>
<td><p><strong><u>Class: Acute I</u></strong></p>
<p><strong>Box 1</strong></p></td>
<td><p><strong><u>Class: Chronic I</u></strong></p>
<p><strong>Boxes 1+5+6</strong></p>
<p><strong>Boxes 1+5</strong></p>
<p><strong>Boxes 1+6</strong></p></td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td colspan="4"></td>
<td colspan="2"></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><strong>Box 2</strong></td>
<td></td>
<td colspan="4"></td>
<td colspan="2"></td>
<td><strong><u>Class: Acute II</u></strong></td>
<td><strong><u>Class: Chronic II</u></strong></td>
</tr>
<tr class="even">
<td>1.00 &lt; value</td>
<td></td>
<td colspan="4">lack of rapid</td>
<td colspan="2">BCF ≥ 500 or,</td>
<td><strong>Box 2</strong></td>
<td><strong>Boxes 2+5+6</strong></td>
</tr>
<tr class="odd">
<td>≤ 10.0</td>
<td></td>
<td colspan="4">degradability</td>
<td colspan="2"><p>if absent</p>
<p>log Kow ≥ 4</p></td>
<td></td>
<td><p><strong>Boxes 2+5</strong></p>
<p><strong>Boxes 2+6</strong></p>
<p><strong>Unless Box 7</strong></p></td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td colspan="4"></td>
<td colspan="2"></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><p><strong>Box 3</strong></p>
<p>10.0 &lt; value</p></td>
<td></td>
<td colspan="4"></td>
<td colspan="2"></td>
<td><p><strong><u>Class: Acute III</u></strong></p>
<p><strong>Box 3</strong></p></td>
<td><p><strong><u>Class: Chronic III</u></strong></p>
<p><strong>Boxes 3+5+6</strong></p>
<p><strong>Boxes 3+5</strong></p></td>
</tr>
<tr class="even">
<td>≤ 100</td>
<td></td>
<td colspan="4"></td>
<td colspan="2"></td>
<td></td>
<td><strong>Boxes 3+6</strong></td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td colspan="4"></td>
<td colspan="2"></td>
<td></td>
<td><strong>Unless Box 7</strong></td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td colspan="4"></td>
<td colspan="2"></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><p><strong>Box 4</strong></p>
<p>No acute</p>
<p>toxicity <strong>(note 5)</strong></p></td>
<td><p><strong>Box 7</strong></p>
<p>value &gt; 1.00</p></td>
<td colspan="4"></td>
<td colspan="2"></td>
<td></td>
<td><blockquote>
<p><strong><u>Class: Chronic IV</u></strong></p>
</blockquote>
<p><strong>Boxes 4+5+6</strong></p>
<p><strong>Unless Box 7</strong></p></td>
</tr>
</tbody>
</table>

[Notes to the table:]{.underline}

Note 1a. Acute toxicity band based on L(E)C-50 values in mg/L for fish,
crustacea and/or algae or other aquatic plants (or QSAR estimation if no
experimental data)

Note 1b Where the algal toxicity ErC-50 \[ = EC-50 (growth rate)\] falls
more than 100 times below the next most sensitive species and results in
a classification based solely on this effect, consideration should be
given to whether this toxicity is representative of the toxicity to
aquatic plants. Where it can be shown that this is not the case,
professional judgement should be used in deciding if classification
should be applied. Classification should be based on the ErC-50. In
circumstances where the basis of the EC-50 is not specified and no
ErC-50 is recorded, classification should be based on the lowest EC-50
available.

Note 2a. Chronic toxicity band based on NOEC values in mg/L for fish or
crustacea or other recognised measures for long-term toxicity.

Note 2b. It is the intention that the system be further developed to
include chronic toxicity data.

Note 3. Lack of rapid degradability is based on either a lack of Ready
Biodegradability or other evidence of lack of rapid degradation.

Note 4. Potential to bioaccumulate, based on an experimentally derived
BCF ≥ 500 or, if absent, a log Kow ≥ 4 provided log Kow is an
appropriate descriptor for the bioaccumulation potential of the
substance. Measured log Kow values take precedence over estimated values
and measured BCF values take precedence over log Kow values.

Note 5. "No acute toxicity" is taken to mean that the L(E)C-50 is above
the water solubility. Also for poorly soluble substances, (w.s. \< 1.00
mg/L), where there is evidence that the acute test would not have
provided a true measure of the intrinsic toxicity.

**HAZARDOUS FOR THE TERRESTRIAL ENVIRONMENT**

*(no proposal available)*

**Purpose, basis and applicability**

**Definitions**

**Classification categories and criteria**

**Rationale for the proposed System**

**Explanatory notes**

**Literature**

***Background information***

**HARMONIZED SYSTEM FOR THE CLASSIFICATION OF MIXTURES**

*(no proposal available)*

**Purpose, basis and applicability**

**Definitions**

**Classification categories and criteria**

**Rationale for the proposed System**

**Explanatory notes**

**Literature**

***Background information***

**SCHEMATIC PRESENTATION OF THE INTEGRATED HAZARD SYSTEM FOR HUMAN
HEALTH AND THE ENVIRONMENT**

For the convenience and comparison of the various endpoints, the scheme
and criteria for classifying each toxic end‑point are presented in the
following diagram. The criteria have been drastically abridged and the
end‑point chapters should be consulted for the specific details.

+----------+----------+----------+----------+------------+----------+
| **EN     | **HAZARD |          |          |            |          |
| DPOINT** | CLASSES  |          |          |            |          |
|          | AND      |          |          |            |          |
|          | CR       |          |          |            |          |
|          | ITERIA** |          |          |            |          |
+----------+----------+----------+----------+------------+----------+
| **ACUTE  | Class 1  | Class 2  | Class 3  | Class 4    | Class 5  |
| TO       |          |          |          |            |          |
| XICITY** |          |          |          |            |          |
+----------+----------+----------+----------+------------+----------+
| **Oral** | 5        | 50       | 300      | 2.000      | C        |
|          |          |          |          |            | riteria: |
| (mg/kg)  |          |          |          |            |          |
+----------+----------+----------+----------+------------+----------+
| **       | 50       | 200      | 1.000    | 2.000      | -   In   |
| Dermal** |          |          |          |            | dication |
|          |          |          |          |            |     of   |
| (mg/kg)  |          |          |          |            |     sig  |
|          |          |          |          |            | nificant |
|          |          |          |          |            |          |
|          |          |          |          |            |   effect |
|          |          |          |          |            |     in   |
|          |          |          |          |            |          |
|          |          |          |          |            |    human |
+----------+----------+----------+----------+------------+----------+
| -        | 100      | 500      | 2.500    | 5000       | -   Any  |
|          |          |          |          |            |     m    |
| **Inha   |          |          |          |            | ortality |
| lation** |          |          |          |            |     at   |
|          |          |          |          |            |          |
| gas      |          |          |          |            |    Class |
| (ppm)    |          |          |          |            |     4    |
+----------+----------+----------+----------+------------+----------+
| -        | 0.5      | 2.0      | 10       | 20         | -   Sig  |
|          |          |          |          |            | nificant |
| vapour   |          |          |          |            |          |
| (mg/L)   |          |          |          |            | clinical |
|          |          |          |          |            |          |
|          |          |          |          |            |    signs |
|          |          |          |          |            |     at   |
|          |          |          |          |            |          |
|          |          |          |          |            |    Class |
|          |          |          |          |            |     4    |
+----------+----------+----------+----------+------------+----------+
| -        | 0.05     | 0.5      | 1.0      | 5          | -   Ind  |
|          |          |          |          |            | ications |
| **Inha   |          |          |          |            |     from |
| lation** |          |          |          |            |          |
|          |          |          |          |            |    other |
| du       |          |          |          |            |          |
| st/mists |          |          |          |            |  studies |
| (mg/L/4  |          |          |          |            |          |
| hrs)     |          |          |          |            |          |
+----------+----------+----------+----------+------------+----------+

+----------+----------+----------+----------+---+------------+---+----------+
| **EN     |          |          |          |   |            |   |          |
| DPOINT** |          |          |          |   |            |   |          |
+----------+----------+----------+----------+---+------------+---+----------+
|          | [Class   |          |          | [ |            | [ |          |
|          | 1]{.un   |          |          | C |            | C |          |
|          | derline} |          |          | l |            | l |          |
|          |          |          |          | a |            | a |          |
|          |          |          |          | s |            | s |          |
|          |          |          |          | s |            | s |          |
|          |          |          |          | 2 |            | 3 |          |
|          |          |          |          | ] |            | ] |          |
|          |          |          |          | { |            | { |          |
|          |          |          |          | . |            | . |          |
|          |          |          |          | u |            | u |          |
|          |          |          |          | n |            | n |          |
|          |          |          |          | d |            | d |          |
|          |          |          |          | e |            | e |          |
|          |          |          |          | r |            | r |          |
|          |          |          |          | l |            | l |          |
|          |          |          |          | i |            | i |          |
|          |          |          |          | n |            | n |          |
|          |          |          |          | e |            | e |          |
|          |          |          |          | } |            | } |          |
|          |          |          |          | : |            | : |          |
+----------+----------+----------+----------+---+------------+---+----------+
| **       | Des      |          |          | \ |            | \ |          |
| DERMAL** | truction |          |          | - |            | - |          |
|          | of       |          |          | R |            | R |          |
| **IRRIT  | dermal   |          |          | e |            | e |          |
| ATION/** | tissue:  |          |          | v |            | v |          |
|          | visible  |          |          | e |            | e |          |
| **COR    | necrosis |          |          | r |            | r |          |
| ROSION** | in at    |          |          | s |            | s |          |
|          | least    |          |          | i |            | i |          |
|          | one      |          |          | b |            | b |          |
|          | animal   |          |          | l |            | l |          |
|          |          |          |          | e |            | e |          |
|          |          |          |          | a |            | a |          |
|          |          |          |          | d |            | d |          |
|          |          |          |          | v |            | v |          |
|          |          |          |          | e |            | e |          |
|          |          |          |          | r |            | r |          |
|          |          |          |          | s |            | s |          |
|          |          |          |          | e |            | e |          |
|          |          |          |          | e |            | e |          |
|          |          |          |          | f |            | f |          |
|          |          |          |          | f |            | f |          |
|          |          |          |          | e |            | e |          |
|          |          |          |          | c |            | c |          |
|          |          |          |          | t |            | t |          |
|          |          |          |          | s |            | s |          |
|          |          |          |          | i |            | i |          |
|          |          |          |          | n |            | n |          |
|          |          |          |          | d |            | d |          |
|          |          |          |          | e |            | e |          |
|          |          |          |          | r |            | r |          |
|          |          |          |          | m |            | m |          |
|          |          |          |          | a |            | a |          |
|          |          |          |          | l |            | l |          |
|          |          |          |          | t |            | t |          |
|          |          |          |          | i |            | i |          |
|          |          |          |          | s |            | s |          |
|          |          |          |          | s |            | s |          |
|          |          |          |          | u |            | u |          |
|          |          |          |          | e |            | e |          |
+----------+----------+----------+----------+---+------------+---+----------+
|          | [        | [        | [        |   | \- Mean    |   | \- Mean  |
|          | Subclass | Subclass | Subclass |   | Draize     |   | Draize   |
|          | 1A]{.un  | 1B]{.un  | 1C]{.un  |   | score in 2 |   | score in |
|          | derline} | derline} | derline} |   | of 3       |   | 2        |
|          |          |          |          |   | animals:   |   |          |
|          | Exposure | Exposure | Exposure |   |            |   | of 3     |
|          | \< 3     | \< 1     | \< 4     |   | 2.3        |   | animals: |
|          | minutes  | hour     | hours    |   | [\         |   |          |
|          |          |          |          |   | <]{.underl |   | 1.5      |
|          | Obs      | Obs      | Obs      |   | ine}erythe |   | [\<]{.un |
|          | ervation | ervation | ervation |   | ma/eschar/ |   | derline} |
|          | \< 1     | \< 4     | \< 14    |   |            |   | e        |
|          | hour     | days     | days     |   | edema \<   |   | rythema/ |
|          |          |          |          |   | 4.0, or    |   |          |
|          |          |          |          |   |            |   | eschar/  |
|          |          |          |          |   | \-         |   | edema \< |
|          |          |          |          |   | persistent |   | 2.3      |
|          |          |          |          |   | in         |   |          |
|          |          |          |          |   | flammation |   |          |
+----------+----------+----------+----------+---+------------+---+----------+

+----------+----------+----------+-----------+------------+----------+
| **EYE    | [Cl      |          |           | [Class     |          |
| IRRIT    | ass]{.un |          |           | B]{.       |          |
| ATION/** | derline} |          |           | underline} |          |
|          | A        |          |           |            |          |
| **COR    |          |          |           | \-         |          |
| ROSION** | Irre     |          |           | reversible |          |
|          | versible |          |           | adverse    |          |
|          | damage   |          |           | effects on |          |
|          | to       |          |           | cornea,    |          |
|          | cornea,  |          |           | iris,      |          |
|          | iris,    |          |           | conjuctiva |          |
|          | con      |          |           |            |          |
|          | junctiva |          |           | \- mean    |          |
|          | 21 days  |          |           | Draize     |          |
|          | after    |          |           | score in 2 |          |
|          | exposure |          |           | of 3       |          |
|          | in at    |          |           | animals:   |          |
|          | least    |          |           |            |          |
|          | one      |          |           | corneal    |          |
|          | animal   |          |           | opacity:   |          |
|          |          |          |           | [\>]{.un   |          |
|          |          |          |           | derline}1, |          |
|          |          |          |           | iritis:    |          |
|          |          |          |           | [\>]{.un   |          |
|          |          |          |           | derline}1, |          |
|          |          |          |           | redness    |          |
|          |          |          |           | [\>]{.     |          |
|          |          |          |           | underline} |          |
|          |          |          |           | 2,         |          |
|          |          |          |           | chemosis:  |          |
|          |          |          |           | [\>]{.u    |          |
|          |          |          |           | nderline}2 |          |
+----------+----------+----------+-----------+------------+----------+
|          |          |          |           | [Subclass  | [        |
|          |          |          |           | B1:]{.     | Subclass |
|          |          |          |           | underline} | B2:]{.un |
|          |          |          |           |            | derline} |
+----------+----------+----------+-----------+------------+----------+
|          |          |          |           | reversible | re       |
|          |          |          |           | in 21 days | versible |
|          |          |          |           |            | in 7     |
|          |          |          |           |            | days     |
+----------+----------+----------+-----------+------------+----------+

+----------+-----------------------------------------------------------+
| **RES    | [Class 1]{.underline}:                                    |
| PIRATORY |                                                           |
| SENSITI  | \- evidence of specific respiratory hypersensitivity,     |
| SATION** | normally as asthma, or                                    |
|          |                                                           |
|          | \- positive results from animal test                      |
+----------+-----------------------------------------------------------+

+----------+-----------------------------------------------------------+
| **DERMAL | [Class 1:]{.underline}                                    |
| SENSITI  |                                                           |
| SATION** | \- evidence in humans of sensitisation by skin contact,   |
|          | or                                                        |
|          |                                                           |
|          | \- positive results from animal tests                     |
+----------+-----------------------------------------------------------+

+----------+---------------+---------------+---+---------------------------+
| **EN     | **HAZARD      |               |   |                           |
| DPOINT** | CLASSES AND   |               |   |                           |
|          | CRITERIA**    |               |   |                           |
+----------+---------------+---------------+---+---------------------------+
|          | [Class        |               |   | [Class 2:]{.underline}    |
|          | 1             |               |   |                           |
|          | ]{.underline} |               |   |                           |
|          |               |               |   |                           |
|          | known to      |               |   |                           |
|          | produce       |               |   |                           |
|          | heritable     |               |   |                           |
|          | mutations in  |               |   |                           |
|          | human germ    |               |   |                           |
|          | cells         |               |   |                           |
+----------+---------------+---------------+---+---------------------------+
| **GERM   | [Subclass     | [Subclass     | \ |                           |
| CELL     | 1A            | 1B            | - |                           |
| MUTAGE   | ]{.underline} | ]{.underline} | m |                           |
| NICITY** |               |               | a |                           |
|          | positive      | positive      | y |                           |
|          | evidence from | results in:   | i |                           |
|          | ep            |               | n |                           |
|          | idemiological | *- in vivo*   | d |                           |
|          |               | heritable     | u |                           |
|          | studies       | germ cell     | c |                           |
|          |               | tests         | e |                           |
|          |               |               | h |                           |
|          |               | in mammals    | e |                           |
|          |               |               | r |                           |
|          |               | \- human germ | i |                           |
|          |               | cell tests    | t |                           |
|          |               |               | a |                           |
|          |               | \- *in vivo*  | b |                           |
|          |               | somatic       | l |                           |
|          |               | mutagenicity  | e |                           |
|          |               | tests,        | m |                           |
|          |               |               | u |                           |
|          |               | combined with | t |                           |
|          |               | some evidence | a |                           |
|          |               | of            | t |                           |
|          |               |               | i |                           |
|          |               | germ cell     | o |                           |
|          |               | mutagenicity  | n |                           |
|          |               |               | s |                           |
|          |               |               | i |                           |
|          |               |               | n |                           |
|          |               |               | h |                           |
|          |               |               | u |                           |
|          |               |               | m |                           |
|          |               |               | a |                           |
|          |               |               | n |                           |
|          |               |               | g |                           |
|          |               |               | e |                           |
|          |               |               | r |                           |
|          |               |               | m |                           |
|          |               |               | c |                           |
|          |               |               | e |                           |
|          |               |               | l |                           |
|          |               |               | l |                           |
|          |               |               | s |                           |
|          |               |               |   |                           |
|          |               |               | \ |                           |
|          |               |               | - |                           |
|          |               |               | p |                           |
|          |               |               | o |                           |
|          |               |               | s |                           |
|          |               |               | i |                           |
|          |               |               | t |                           |
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|          |               |               | v |                           |
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|          |               |               | d |                           |
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|          |               |               | n |                           |
|          |               |               | m |                           |
|          |               |               | a |                           |
|          |               |               | m |                           |
|          |               |               | m |                           |
|          |               |               | a |                           |
|          |               |               | l |                           |
|          |               |               | s |                           |
|          |               |               | a |                           |
|          |               |               | n |                           |
|          |               |               | d |                           |
|          |               |               | s |                           |
|          |               |               | o |                           |
|          |               |               | m |                           |
|          |               |               | a |                           |
|          |               |               | t |                           |
|          |               |               | i |                           |
|          |               |               | c |                           |
|          |               |               | c |                           |
|          |               |               | e |                           |
|          |               |               | l |                           |
|          |               |               | l |                           |
|          |               |               | t |                           |
|          |               |               | e |                           |
|          |               |               | s |                           |
|          |               |               | t |                           |
|          |               |               | s |                           |
|          |               |               |   |                           |
|          |               |               | \ |                           |
|          |               |               | - |                           |
|          |               |               | * |                           |
|          |               |               | i |                           |
|          |               |               | n |                           |
|          |               |               | v |                           |
|          |               |               | i |                           |
|          |               |               | v |                           |
|          |               |               | o |                           |
|          |               |               | * |                           |
|          |               |               | s |                           |
|          |               |               | o |                           |
|          |               |               | m |                           |
|          |               |               | a |                           |
|          |               |               | t |                           |
|          |               |               | i |                           |
|          |               |               | c |                           |
|          |               |               | g |                           |
|          |               |               | e |                           |
|          |               |               | n |                           |
|          |               |               | o |                           |
|          |               |               | t |                           |
|          |               |               | o |                           |
|          |               |               | x |                           |
|          |               |               | i |                           |
|          |               |               | c |                           |
|          |               |               | i |                           |
|          |               |               | t |                           |
|          |               |               | y |                           |
|          |               |               | s |                           |
|          |               |               | u |                           |
|          |               |               | p |                           |
|          |               |               | p |                           |
|          |               |               | o |                           |
|          |               |               | r |                           |
|          |               |               | t |                           |
|          |               |               | e |                           |
|          |               |               | d |                           |
|          |               |               | b |                           |
|          |               |               | y |                           |
|          |               |               | * |                           |
|          |               |               | i |                           |
|          |               |               | n |                           |
|          |               |               | v |                           |
|          |               |               | i |                           |
|          |               |               | t |                           |
|          |               |               | r |                           |
|          |               |               | o |                           |
|          |               |               | * |                           |
|          |               |               | m |                           |
|          |               |               | u |                           |
|          |               |               | t |                           |
|          |               |               | a |                           |
|          |               |               | g |                           |
|          |               |               | e |                           |
|          |               |               | n |                           |
|          |               |               | i |                           |
|          |               |               | c |                           |
|          |               |               | i |                           |
|          |               |               | t |                           |
|          |               |               | y |                           |
+----------+---------------+---------------+---+---------------------------+

+----------+---------------+---------------+---+---------------------------+
|          | [Class        |               |   | [Class 2:]{.underline}    |
|          | 1]            |               |   |                           |
|          | {.underline}: |               |   |                           |
|          |               |               |   |                           |
|          | Known or      |               |   |                           |
|          | presumed      |               |   |                           |
|          | carcinogen    |               |   |                           |
+----------+---------------+---------------+---+---------------------------+
| **C      | [Sub Class    | [Sub Class    | \ |                           |
| ARCINOGE | 1A:           | 1B:           | - |                           |
| NICITY** | ]{.underline} | ]{.underline} | s |                           |
|          |               |               | u |                           |
|          | known human   | presumed      | s |                           |
|          | carcinogen    | human         | p |                           |
|          | based on      | carcinogen    | e |                           |
|          | human         | based on      | c |                           |
|          | evidence      | demonstrated  | t |                           |
|          |               | animal        | e |                           |
|          |               | ca            | d |                           |
|          |               | rcinogenicity | c |                           |
|          |               |               | a |                           |
|          |               |               | r |                           |
|          |               |               | c |                           |
|          |               |               | i |                           |
|          |               |               | n |                           |
|          |               |               | o |                           |
|          |               |               | g |                           |
|          |               |               | e |                           |
|          |               |               | n |                           |
|          |               |               |   |                           |
|          |               |               | \ |                           |
|          |               |               | - |                           |
|          |               |               | l |                           |
|          |               |               | i |                           |
|          |               |               | m |                           |
|          |               |               | i |                           |
|          |               |               | t |                           |
|          |               |               | e |                           |
|          |               |               | d |                           |
|          |               |               | e |                           |
|          |               |               | v |                           |
|          |               |               | i |                           |
|          |               |               | d |                           |
|          |               |               | e |                           |
|          |               |               | n |                           |
|          |               |               | c |                           |
|          |               |               | e |                           |
|          |               |               | o |                           |
|          |               |               | f |                           |
|          |               |               | h |                           |
|          |               |               | u |                           |
|          |               |               | m |                           |
|          |               |               | a |                           |
|          |               |               | n |                           |
|          |               |               | o |                           |
|          |               |               | r |                           |
|          |               |               | a |                           |
|          |               |               | n |                           |
|          |               |               | i |                           |
|          |               |               | m |                           |
|          |               |               | a |                           |
|          |               |               | l |                           |
|          |               |               | c |                           |
|          |               |               | a |                           |
|          |               |               | r |                           |
|          |               |               | c |                           |
|          |               |               | i |                           |
|          |               |               | n |                           |
|          |               |               | o |                           |
|          |               |               | g |                           |
|          |               |               | e |                           |
|          |               |               | n |                           |
|          |               |               | i |                           |
|          |               |               | c |                           |
|          |               |               | i |                           |
|          |               |               | t |                           |
|          |               |               | y |                           |
+----------+---------------+---------------+---+---------------------------+

+----------+--------------+----------------+---+---------------+----------+
| **REPROD | [Class       |                |   | [Class        | [Ad      |
| UCTIVE** | 1:]          |                |   | 2:            | ditional |
|          | {.underline} |                |   | ]{.underline} | Cl       |
|          |              |                |   |               | ass]{.un |
|          | known or     |                |   |               | derline} |
|          | presumed     |                |   |               |          |
|          | human        |                |   |               |          |
|          | reproductive |                |   |               |          |
|          | or           |                |   |               |          |
|          | d            |                |   |               |          |
|          | evelopmental |                |   |               |          |
|          | toxicant     |                |   |               |          |
+----------+--------------+----------------+---+---------------+----------+
| **TO     | [Class       | [Class         | s |               | effects  |
| XICITY** | 1A:]         | 1B             | u |               | on or    |
|          | {.underline} | :]{.underline} | s |               | via      |
|          |              |                | p |               | l        |
|          | known        | presumed       | e |               | actation |
|          |              |                | c |               |          |
|          |              |                | t |               |          |
|          |              |                | e |               |          |
|          |              |                | d |               |          |
|          |              |                | h |               |          |
|          |              |                | u |               |          |
|          |              |                | m |               |          |
|          |              |                | a |               |          |
|          |              |                | n |               |          |
|          |              |                | r |               |          |
|          |              |                | e |               |          |
|          |              |                | p |               |          |
|          |              |                | r |               |          |
|          |              |                | o |               |          |
|          |              |                | d |               |          |
|          |              |                | u |               |          |
|          |              |                | c |               |          |
|          |              |                | t |               |          |
|          |              |                | i |               |          |
|          |              |                | v |               |          |
|          |              |                | e |               |          |
|          |              |                | t |               |          |
|          |              |                | o |               |          |
|          |              |                | x |               |          |
|          |              |                | i |               |          |
|          |              |                | c |               |          |
|          |              |                | a |               |          |
|          |              |                | n |               |          |
|          |              |                | t |               |          |
+----------+--------------+----------------+---+---------------+----------+
|          |              |                |   |               |          |
+----------+--------------+----------------+---+---------------+----------+

  -------------- ------------ -----------------------------------------------------------
  **ENDPOINT**   **HAZARD     
                 CLASSES AND  
                 CRITERIA**   

  **TARGET ORGAN              (to come)
  ORIENTED                    
  TOXICITY**                  
  -------------- ------------ -----------------------------------------------------------

+----------+-------------------+-------------------+-------------------+
|          | [Acute Class      | [Acute Class      | [Acute Class      |
|          | 1:]{.underline}   | 2:]{.underline}   | 3:]{.underline}   |
|          |                   |                   |                   |
|          | acute toxicity ≤  | acute toxicity \> | acute toxicity \> |
|          | 1.00mg/L          | 1.00 but ≤        | 10.0 but ≤        |
|          |                   | 10.0mg/L          | 100mg/L           |
+----------+-------------------+-------------------+-------------------+
| *        | [Chronic Class    | [Chronic Class    | [Chronic Class    |
| *AQUATIC | 1:]{.underline}   | 2:]{.underline}   | 3:]{.underline}   |
| TO       |                   |                   |                   |
| XICITY** | acute toxicity ≤  | acute toxicity \> | acute toxicity \> |
|          | 1.00mg/L and lack | 1.00 but ≤        | 10.0 but ≤        |
|          | of ready          | 10.0mg/L and      | 100mg/L and acute |
|          | degradability     | acute toxicity ≤  | toxicity ≤        |
|          | and/or BCF ≥ 500  | 1.00mg/L and lack | 1.00mg/L and lack |
|          | or log Kow ≥ 4    | of ready          | of ready          |
|          |                   | degradability     | degradability     |
|          |                   | and/or BCF ≥ 500  | and/or BCF ≥ 500  |
|          |                   | or log Kow ≥ 4    | or log Kow ≥ 4    |
|          |                   |                   | unless no acute   |
|          |                   | unless no acute   | toxicity          |
|          |                   | toxicity          |                   |
+----------+-------------------+-------------------+-------------------+

  -------------- -----------------------------------------------------------
  **MIXTURES**   (to come)

  -------------- -----------------------------------------------------------

[^1]: ^1^ . It is recognised that this index can also be affected by the
    male

[^2]: ^1^