Date of Circulation: ( To all National SIDS Contact Points and the OECD Secretariat) EXCH\ MANUAL\ 96 4 2. DOC/ May 1996 11 Annex 3 SIDS INITIAL ASSESSMENT PROFILE CAS No.

CHEMICAL NAME STRUCTURAL FORMULA CONCLUSIONS AND RECOMMENDATIONS [ The summary of properties and effects of the chemical and the result of the assessment on potential risk, and recommendations related to further work or action, as appropriate, together with the reasons which support it] EXCH\ MANUAL\ 96 4 2. DOC/ May 1996 12 Annex 4 FULL SIDS SUMMARY CAS NO: SPECIES PROTOCOL RESULTS PHYSICAL CHEMICAL 2.1 Melting Point ° C 2.2 Boiling Point ° C ( at kPa)

2.3 Density kg/ m3 2.4 Vapour Pressure kPa at ° C 2.5 Partition Coefficient ( Log Pow)

2.6 A. Water Solubility mg/ l at ° C B. pH at ° C pKa 2.12 Oxidation: Reduction Potential mV ENVIRONMENTAL FATE AND PATHWAY 3.1.1 Photodegradation In air T1/ 2 = hour 3.1.2 Stability in Water T1/ 2 = min 3.2 Monitoring Data In air = mg/ m3 In surface water= mg/ l In soil/ sediment= mg/ g In biota = mg/ g 3.3 Transport and Distribution Calculated ( Fugacity Level 1 type)

( local exposure) In Air % In Water % In Sediment % In Soil % In Biota %

3.5 Biodegradation ECOTOXICOLOGY 4.1 Acute/ Prolonged Toxicity to Fish LC50 ( 24 hr) = mg/ l, LC50 ( 48 hr) = mg/ l, LC50 ( 72 hr) = mg/ l, LC50 ( 96 hr) = mg/ l 4.2 Acute Toxicity to Aquatic Invertebrates Daphnia EC50 ( 24 hr) = mg/ l, EC50 ( 48 hr) = mg/ l,

4.3 Toxicity to Aquatic Plants e. g. Algae EC50 ( hr) = mg/ l NOEC ( hr) = mg/ l 4.5.2 Chronic Toxicity to Aquatic Invertebrates ( Daphnia) EC50s ( d) = mg/ l ( Reproduction) EC50s ( d) = mg/ l ( Growth) LC50s ( d) = mg/ l NOECs ( d) = mg/ l 4.6.1 Toxicity to Soil Dwelling Organisms LC50 ( d) = mg/ Kg NOEL ( d) = mg/ Kg 4.6.2 Toxicity to Terrestrial Plants EC50 ( d) = mg/ Kg, LC50 = mg/ Kg EC50 ( d) = mg/ Kg, LC50 = mg/ Kg EC50 ( d) = mg/ Kg, LC50 = mg/ Kg ( 4.6.3) Toxicity to Other Non Mammalian Terrestrial LD50 ( hr) = mg/ Kg EXCH\ MANUAL\ 96 4 2. DOC/ May 1996 13 CAS NO: SPECIES PROTOCOL RESULTS Species ( Including Birds)

TOXICOLOGY 5.1.1 Acute Oral Toxicity LD50 = mg/ Kg 5.1.2 Acute Inhalation Toxicity LC50 = mg/ m3 5.1.3 Acute Dermal Toxicity LD50 = mg/ Kg 5.4 Repeated Dose Toxicity NOEL = mg/ Kg 5.5 Genetic Toxicity In Vitro A. Bacterial Test ( Gene mutation) + or  ( With metabolic activation) + or  ( Without metabolic activation)

B. Non Bacterial In Vitro Test ( Chromosomal aberrations) + or  ( With metabolic activation) + or  ( Without metabolic activation)

5.6 Genetic Toxicity In Vivo + or

5.8 Toxicity to Reproduction NOEL = mg/ Kg ( General toxicity) NOEL = mg/ Kg ( Repro. Tox. parental) NOEL = mg/ Kg ( Repro. Tox. F1 generation)

5.9 Developmental Toxicity/ Teratogenicity NOEL = mg/ Kg ( General toxicity) NOEL = mg/ Kg ( Pregnancy/ litter) NOEL = mg/ Kg ( Foetal data)

5.11 Experience with Human Exposure [ Note] Data beyond SIDS requirements can be added if the items are relevant to the assessment of the chemical, e. g. corrosiveness/ irritation, carcinogenicity. EXCH\ MANUAL\ 96 4 3. DOC/ May 1996 1 4.3 Provisional Guidance for the Initial Assessment of Environmental Exposure*

4.3.1 Introduction 1. This document provides guidance for the application of simple models for the initial assessment of environmental exposure of High Production Volume ( HPV) chemicals for which a full SIDS is available, based mainly on the conclusions and recommendations of the OECD Workshop on the Application of Simple Models for Environmental Exposure Assessment ( Berlin, 11 13 December 1991).

2. The objective of the Workshop was to identify simple models which can be used for initial environmental exposure assessment of new and existing chemicals with limited data including indirect exposure to man via food and drinking water, in particular those models which can be used in the context of the OECD work on HPV chemicals. This means that the models should be applicable using data which are available in the SIDS. One further objective was to develop guidance for Member countries in using these models when they develop their recommendation related to the initial assessment of SIDS chemicals.

3. An exposure assessment consists of a source assessment and a fate and pathway assessment ( Ref. 38 and 16). In a source assessment, identification of emission source( s) and an estimation of release( s) from the source( s) are made by means of information on use categories of a chemical and emission factors generally. Exposure through the environment ( environmental exposure) is considered in a fate and pathway assessment. Then indirect exposure through food and drinking water is calculated based on these results. This document focuses on three issues in this procedure: emission factors and use categories, simple models for environmental exposure, and models for indirect exposure.

4. It should be noticed that the overall environmental exposure assessment should strive to conduct an assessment at the global level. Even though the exposure situation to a chemical might be different depending on local or national conditions, all calculations at these levels should be integrated in the global assessment.

5. Also it is important to consider a variety of emission sources and to include several sources in the assessment. To date, environmental exposure assessments dealt with by the SIDS Initial Assessment Meeting ( SIAM) almost always considered emission data from a single point source, e. g. one production site, though various sources such as other producers, subsequent processing independent of the producer, and produced product are considered to exist. When several sources cannot be considered qualitatively in the assessment, a more simple qualitative approach such as a scoring system might be considered.

6. Following the recommendations of the Berlin Workshop, diskettes with national models that were thought to be appropriate for initial assessment of HPV chemicals with full SIDS at the Workshop have been prepared and distributed separately with an explanatory note which includes manuals of each model ( Ref. 35, details in Ref. F). Also local and global reference models, which could be used in addition to and/ or in place of national models, have been developed based on the recommendations of the Workshop and have been distributed by means of a diskette ( Ref. 36 and 37, details in Ref. F).

7. In addition, Discussion Documents ( Ref. 14, 16, 18, 19) and Background Documents ( Ref. 20 22) prepared for the Workshop could be referred to whenever detailed information relating to the assessment procedure presented in this document is required. These documents were prepared on the basis of information on the procedures and the results of the application of ten Member countries' approaches on ten SIDS chemicals ( Ref. 1 13) and are included in Environment Monograph No. 67 ( Ref. 38).

8. Structure Activity Relationships ( SARs) for physical chemical properties important for exposure assessment were also addressed at the Workshop ( Ref. 17) and the report has been distributed separately as an Environment Monograph ( Ref. 39).

4.3.2 Emission Factors and Use Categories of Chemicals * This document was prepared by the OECD Secretariat in 1992 based on the OECD Workshop on the Application of Simple Models for Environmental Exposure Assessment, held in Berlin in December 1991. It has been updated to reflect comments by Member countries and agreements reached in the context of the OECD Existing Chemicals Programme up to mid 1994. EXCH\ MANUAL\ 96 4 3. DOC/ May 1996 2 9. Release of chemicals into the various environmental compartments and the quantities concerned are strongly dependent on the use of the chemical. Therefore, in an exposure assessment, the use pattern of a substance should be considered as a starting point when using any kind of exposure scenario. When high quality information and data are lacking, screening quality release assessments can be made by using a typical or average release scenario based on emission factors presenting a boundary estimate of release of chemicals. It should be noticed that the results of the source assessment are used as input data for models for environmental and indirect exposure assessment.

10. " Emission Factors and Use Categories" ( Ref. 14 and 38) present various approaches used in Member countries, and detailed information is provided in Ref 20. The tools mentioned in the documents will assist Member countries in developing release assessments, as well as allow them to understand the assessments of other Member countries. The summary report of the Working Group on this issue of the Workshop is attached to this document as Annex 1.

Necessary Information for Source Assessments 11. Initial exposure assessments can often be based on the SIDS Dossier. However, in order to improve the quality of the assessment, further information on exposure and use are considered to be necessary and elements of exposure information have been agreed and are included in the SIDS ( see Section 2.2).

12. In order to collect the necessary information, release reporting requirements such as a product register system would be a good source of information. In addition, manufacturers could provide more detailed information on chemical use and releases, and monitoring data could be collected intensively. Data from monitoring should be used as much as possible, in order to compare them with the results obtained from other methods such as emission scenario approaches.

Assessment Methods for Release of Chemicals 13. Approaches of Member countries for estimating releases of SIDS chemicals into water, which were discussed at the Workshop, are often conceptually similar. However, differences in values chosen for variables contained in release calculations frequently lead to widely varying release concentrations. This situation probably exists for other release scenarios that may be evaluated in the future. There is a clear need for Member countries to work more closely together to develop mutually compatible release estimation methods.

14. Releases should be assessed for the entire life cycle of SIDS chemicals. The life cycle of a chemical includes: EXCH\ MANUAL\ 96 4 3. DOC/ May 1996 3  manufacture or production;  processing or formulation;  industrial use;  private or consumer use;  recycling; and  disposal and treatment.

15. For commonly encountered release scenarios, estimates of releases can be presented in the form of the matrix shown in the Appendix to Annex 1 to this document, which shows releases as a fraction of production or use volume.

16. All SIDS release assessments should be extremely clear with regard to how they were developed and should, when possible, include:

 rationales, assumptions and data used to generate release estimates;  types of releases ( point source or diffuse);  release quantities;  media for release;  time dimensions of releases;  kinds of release estimates ( average or worst case); and  uncertainties associated with the estimates.

17. Release assessments address releases up through waste water treatment. Water releases of SIDS chemicals are estimated before and after waste water treatment.

18. The SIDS assessment efforts should be structured to avoid false negatives  incorrectly excluding chemicals of potential concern from further consideration, for example, by considering a worst case scenario.

19. An iterative approach to improving initial assessments may be needed on occasion.

4.3.3 Local Models and Global Models 20. The environmental exposure assessments are generally carried out by means of models and are based on information obtained by a source assessment, as well as on information on the properties of the chemical and on the environment for which estimations will be made. Application of local and global models for a chemical is considered depending upon production and use of the chemical, in order to discriminate local exposure and general exposure. In this document local models are those which are concerned with the environment close to the release site, and with a short time scale after the release. They can use environmental data which are generic, or they can use data from a real situation if such data are available. On the other hand, global models are those which are concerned with the longer term, steady state behaviour of a chemical and are multi media. The estimated concentrations of a chemical in the environmental media are used for comparison with " a low risk level of a chemical" derived from an effects assessment. An elaborated exposure assessment based on more precise and detailed information and/ or a refined effects assessment would be required in cases where estimated concentrations exceed the " low risk level of the chemical".

21. Diskettes which compile national and reference models could be used for the actual estimation of the concentration of a chemical ( see Ref. F).

22. " Local and Global Models" ( Ref. 16 and 38) introduces a procedure for SIDS initial assessment and the issues to be considered in an environmental exposure assessment. Reference models which would be used for the initial environmental exposure assessment are presented in the document, " Reference models which would be used for the Initial Environmental Exposure Assessment" ( Ref. 19 and 38). Outlines of national models and results of their application for ten SIDS chemicals are summarized in " Local and Global Models in Member countries" ( Ref. 21 and 38). " Potential Approaches for Developing Screening Level Environmental and Human Exposure Assessment for SIDS Chemicals" ( Ref. 22 and 38), which can be applied when sufficient information on the source and the environment are available, presents an approach taken by the US. The summary report of the Working Group is attached to this document as Annex 2.

Necessary Information for Models EXCH\ MANUAL\ 96 4 3. DOC/ May 1996 4 23. The physical chemical data available in the SIDS are generally sufficient for using local and global models used for the initial assessment. Information on degradation rates is generally missing in the SIDS although they are included implicitly. This might be a problem for global models. Also the release estimates in the previous section should be able to be used in the models.

Models Used in Initial Environmental Exposure Assessment 24. Three local models on a national scale for estimation of the concentration of a chemical in air phase, six for water phase ( including a simple dilution model which does not require PCs for calculation), and two for soil phase were submitted for distribution by Member countries. Eight of them, which are thought to be simple but appropriate for use for an initial assessment of HPV chemicals with full SIDS, are included in diskettes. Also four fugacity type global national models are available through diskettes.

25. As various modelling approaches are taken by Member countries, a set of four so called " reference models", namely the Screening Assessment Model System ( SAMS) which consists of three local models ( Water, Air and Soil) and one global model ( Fugacity Model, FUGMOD), have been developed. The basis and mechanisms considered have been agreed at the Workshop. They serve as a minimum assessment procedure, but Member countries could use them in addition to or in place of their own approaches. The choice of which of the three local models to use will be made on the basis of the compartments identified as receiving the release of the chemical. Detailed information on reference models is presented in Annex 2 to this document, and reference models developed are available through a diskette.

26. By using local models, Member countries should be able to have opportunities to adapt the input data to their own particular situation. The possibility of developing a reference scenario which represents generic local conditions should also be investigated. A conservative approach to the choice of generic parameters should be taken.

27. Even for a chemical used in closed systems,** estimation of the amount of the chemical that can be expected to reach the environment can be carried out. An approach presented in the MNSEM model based on the physical chemical properties can be considered as one of the methods that can be applied.

28. FUGMOD, which is the latest version of the Fugacity Level III model, is to be used as the basis of the global models. The default environmental parameters for this version also could be used in the assessment in addition to, or in place of, parameters for the environment of each country. This global reference model is available on a diskette.

29. Currently there are various models which can be identified for use in environmental exposure assessment. However, to date there is a lack of standardisation of selection of distribution models employed for the initial assessments. Harmonization in this field would be desirable.

30. Methods used, including any assumptions made, extra data required, and QSAR estimation adopted, should be transparent to others in order to undertake the assessment of HPV chemicals in a co operative way.

31. It is the responsibility of the user of the models to assess the effect of uncertainties in the data when estimation is carried out by the models.

4.3.4 Models for Indirect Exposure by Food and Drinking Water 32. Exposure of human beings is generally expressed as an average daily intake of a chemical per unit of body weight. In the initial indirect exposure assessment this average daily intake of a chemical is compared with the " low risk level of average intake", which is derived from the results of toxicity testing and other information. Models for indirect exposure by food and drinking water are used for estimation of the average daily intake using default values, the data for intake volume of food, drinking water and air, and concentrations of chemicals in the media. Therefore there is a close relation with environmental exposure models and indirect exposure models. Some models consist of both a model for ** A chemical used in closed system: a substance should only be considered to be used in closed systems if it remains within a reactor or is transferred from vessel to vessel through closed pipework and therefore accidental spillage is the only likely cause for human exposure or environmental contamination. EXCH\ MANUAL\ 96 4 3. DOC/ May 1996 5 environmental exposure and a model for indirect exposure in order to conduct an assessment in an integrated way. An elaborated exposure assessment would be required in cases where estimated intake exceeds the " safe level of average intake."

33. " Indirect Exposure of Human Beings to Organic Chemicals" ( Ref. 18 and 38) summarises the approaches of Member countries. Four national models which are compiled on the diskette could be used for estimation. Also estimation of indirect exposure could be done partly by reference models.

Necessary Information 34. Physical chemical data in the SIDS are thought to be sufficient for the models submitted by Member countries, but further data on the estimation of emission beyond data included in the SIDS are considered to be necessary.

Models 35. Four models ( CHEMCAN, CHEMFRANCE, MNSEM, and RISK) are adaptable to individual country needs and are available for those Member countries who wish to use them in their initial indirect exposure assessment of HPV chemicals to humans. All of them are available through diskettes. In addition, reference models could be used for partial estimation of indirect exposure.

36. Both local and global approaches should be used when circumstances indicate that this type of insight would be useful to the assessment.

37. The indirect exposure assessment should cover critical target groups such as children and elderly people.

38. Calculations for extreme dietary compositions such as high and low consumption of fish should be carried out if available information suggests this is important. EXCH\ MANUAL\ 96 4 3. DOC/ May 1996 6 Annex 1 Emission Factors and Use Categories of Chemicals ( Summary Report of Working Group I of the OECD Workshop held in Berlin in December 1991)

Objectives and Purpose of the Working Group 1. Environmental release estimation is the first step within the exposure assessment. Release estimates involve the identification of the sources and the receiving environmental media for each stage of the chemical's life cycle. Specific quantities released during these stages can be expressed as emission rates or emission factors. The objective of release assessments is to develop information that provides a starting point for estimating chemical concentrations in media of concern. Working Group I considered issues related to releases before and after waste water treatment. It was agreed that water releases of SIDS chemicals will be estimated before and after waste water treatment.

Information and Data Sources for Developing Release Assessments 2. The Discussion documents ( Ref. 14 and 15) and the Background documents ( Ref. 20, 24 and 29) developed for the Workshop were presented. The documents detail:

° databases containing chemical release information; ° sources for obtaining emission factors for chemicals; ° approaches for estimating releases used in the EC and US new chemicals programmes.

3. In addition, nine Member countries provided estimates of releases and exposures for nine selected SIDS chemicals. These submissions also provide insight into methods that numerous Member countries use to estimate chemical releases.

4. Most participants agreed that initial exposure assessments should be based on the SIDS dossier with the understanding that it may be necessary to get additional exposure information on chemicals of concern after the initial assessment. Participants from one Member country were concerned that initial assessment of SIDS chemicals may be impossible given the information in the SIDS dossier. Participants from a number of Member countries indicated they would assure that their assessments would be based on information beyond what is available in the SIDS Dossier. Participants from other Member countries expressed their anxiety that they may not have the resources to obtain additional information, though they have extensive dialogue with industry for each SIDS chemical. Therefore, they may prefer a screening assessment which uses only SIDS Dossier data or accepted worst case assumptions in order to complete the SIDS screening on a timely basis.

5. The Working Group recommended that Member countries take advantage of mandatory release reporting requirements or other data sources of several Member countries. Product registries are an example of this kind of relevant data. It was recommended that Member countries strive to use as much as possible monitoring data, such as that available in the literature and databases, whenever appropriate in their release and exposure assessments. Assessments based on monitoring data should be compared to estimates using other approaches. The Working Group recommended that release assessors should involve waste management officials in the development of their assessments. In addition, chemical manufacturers may be able to provide more detailed information on chemical use and releases. The Working Group was aware that the further downstream a release scenario was from manufacturing, the poorer the use information may be supplied by the manufacturer.

Life cycle Assessment and Relevant Emission Scenarios 6. There was agreement that releases should be assessed for the entire life cycle of SIDS chemicals. The life cycle of a chemical includes:

 manufacture or production;  processing or formulation; EXCH\ MANUAL\ 96 4 3. DOC/ May 1996 7  industrial use;  private or consumer use;  recycling;  disposal and waste treatment.

7. For commonly encountered release scenarios, estimates of releases may be based on working models and might take the form of the matrix shown in the Appendix to this Annex which shows releases as a fraction of production or use volume.

8. It was agreed that an iterative approach to improving initial assessments may be needed on occasion.

9. There was concern in the Working Group that many release estimating models are based on estimates of production or use volumes which are not necessarily of high quality.

Scope of SIDS Release Assessments 10. There was general agreement that all SIDS release assessments should be extremely clear with regard to how they were developed and should, when possible, include:

 rationales, assumptions and data used to generate release estimates;  types of releases ( point source or diffuse);  release quantities;  media for release;  time dimensions of releases;  kinds of release estimates ( average or worst case);  uncertainties associated with the estimates.

Results of Comparison of Release Estimating Methods for Selected SIDS Chemicals 11. The Working Group considered release and exposure estimates for the selected chemicals as submitted by nine Member countries. Member country approaches to estimating water releases of chemicals were often conceptually similar. However, differences in values chosen for variables contained in release calculations frequently lead to widely varying release concentrations. This situation probably exists for other release scenarios that may be evaluated in the future. There is a clear need for the Member countries to work more closely together to develop mutually compatible release estimating methods.

12. It was generally agreed that the SIDS assessment efforts should be structured to avoid false negatives  incorrectly excluding chemicals of potential concern from further consideration. False positives should be identified during the exposure assessment process.

Applicability of New Chemical Assessment Methods to the SIDS Programme 13. Patterns of the intended use are usually well known for new chemicals. For HPV chemicals, use patterns may not be easily identifiable. For some Member countries this means that assumptions, such as default values, may be more commonly relied on for HPV chemical assessment than for new chemical assessment.

Summary of Conclusions and Recommendations 14. Even though it was not possible for the Working Group to develop consensus decisions regarding the details on how to estimate releases for selected scenarios, there were many useful results. The most significant were:

14. a Many relevant release assessment tools were distributed to the participants through the Discussion documents and the Background Document. These tools will assist Member countries in developing release assessments as well as allow them to understand the assessments of other Member countries. Additional assessment methods, use category documents, and other materials not yet submitted from other Member EXCH\ MANUAL\ 96 4 3. DOC/ May 1996 8 countries should be exchanged through the OECD. The OECD should endeavour to expand the Working Group Background Document to include additional assessment tools available in other Member countries and make it available.

14. b There was agreement that releases should be assessed for the entire life cycle of SIDS chemicals. The lifecycle of a chemical includes:

 manufacture or production;  processing or formulation;  industrial use;  private or consumer use;  recycling;  disposal and treatment.

14. c There was agreement that all SIDS release assessments should be extremely clear with regard to how they were developed and should, when possible, include:

 rationales, assumptions and data used to generate release estimates;  types of releases ( point source or diffuse);  release quantities;  media for release;  time dimensions of releases;  kinds of release estimates ( average or worst case);  uncertainties associated with the estimates.

14. d Member country approaches to estimating SIDS chemical intermediate water releases, were often conceptually similar. However, differences in values chosen for variables contained in release calculations frequently lead to widely varying release concentrations. This situation probably exists for other release scenarios that may be evaluated in the future. There is a clear need for the Member countries to work more closely together to develop mutually compatible release estimating methods.

14. e Release assessments will address releases up through waste water treatment. Water releases of SIDS chemicals will be estimated before and after waste water treatment.

14. f For many use categories there are no adequate emission scenarios. Member countries should develop and share use category information and other assessment tools.

APPENDIX TO ANNEX 1 Industrial Category Use category / Function Release Estimates Applicable Steps of Life Cycle Water Air Soil Waste 1. Agricultural chemicals Fertilisers Pesticides Production Compounding Processing Use ( private) Recovery Pharmaceutical ( vet.) Production Compounding Processing Use ( private) Recovery 2.... EXCH\ MANUAL\ 96 4 3. DOC/ May 1996 9 ..

15....

 Diffuse  Local: point source ( fraction, time periods,...) EXCH\ MANUAL\ 96 4 3. DOC/ May 1996 10 Annex 2 Local and Global Models ( Summary Report of Working Group II of the OECD Workshop held in Berlin in December 1991)

Objectives 1. The objectives of the Working Group were to identify and recommend suitable environmental models for use in initial screening assessment. Appropriate models would provide estimates of concentrations in environmental compartments of concern ( Predicted Environmental Concentration, PEC). Additional information on mass balances, mass fluxes or residence times from the models would be valuable for a better understanding and evaluation of the fate and pathways of the chemicals. The models should be able to use release estimates from Working Group I and the data available in the SIDS.

Scope of the Models 2. A range of modelling approaches was used by Member countries in the estimates carried out in preparation for the workshop. These are summarized in Background Documents ( Ref. 21 and 22). It was obvious from the discussions in the Working Group that different Member countries had different methods which they would like to use. The approach agreed therefore was to find a set of models which would act as a minimum assessment procedure, but which Member countries could use in addition to, or in place of, their own approaches.

3. It was agreed that the Working Group should aim to recommend models which covered the range of spatial and temporal scales over which assessments are carried out. After discussion a set of four models was decided upon  three local models, each concerned with a single environmental phase ( Air, Water, Soil), and one global model. For the purposes of this document, local models are those which are concerned with the environment close to the release site, and with a short time scale after the release. They can use environmental data which is generic or they can use data from a real situation if such information is available. The choice of which of the three local models to use would be made on the basis of the compartments identified as receiving the release of the chemical. Global models are those which are concerned with the longer term, steady state behaviour of a chemical, and are multi media. The scale of those models favoured by the group was national or regional.

Description of Models 4. It was agreed at the beginning of the discussions that the aim would be to identify the key processes involved and the data requirements ( both for the chemical and the environment). As far as possible the chemical data should be available from the SIDS or through the SAR methods discussed in the Special Session on SAR. It was decided that only the basis of the models would be recommended and not actual models for use. The discussion was based on the Discussion Document ( Ref. 16 and 19). EXCH\ MANUAL\ 96 4 3. DOC/ May 1996 11 Local Models a. Water model i. Major processes: dilution.

ii. Optional processes: volatilization, degradation, adsorption.

iii. Chemical data: release rate ( mass/ time, mass/ site/ time), release concentrations and discharge flows, Henry's Law Constant, Bioconcentration Factor ( BCF), Organic Carbon Sorption Constant ( Koc).

iv. Environmental data: flow rates ( generic or site specific).

v. Remarks: Calculation of dilution is the minimum necessary. Member countries may then use the concentration obtained in order to calculate concentrations in sediment, biota etc. through the appropriate physical chemical data. They may also use the available data to indicate whether reductions in this concentration through degradation, volatilization are likely.

[ Note:

i. Major processes: the processes which should be considered in the Models. ii. Optional processes: the processes which can be considered optionally in the Models. iii. Chemical data: the physical chemical data of a chemical which are necessary for calculation by the Models as input data. iv. Environmental data: the data on the environment for which the calculation is carried out.]

b. Air model i. Major processes: dispersion, dilution.

ii. Optional processes: degradation, deposition.

iii. Chemical data: release rate ( mass/ time). No other data required for basic assessment; degradation and physical chemical data may be used to modify the assessment.

iv. Environmental data: source height, mixing layer height, meteorological parameters; for all these, generic or site specific information could be used.

v. Remarks: The calculation of dilution is the minimum necessary. The approach for calculation of concentrations is dependent on the type of release. For a point source, a local plume model should be used. A modification of this could be used to describe a larger area source, for example a city. For other types of source a box model may be more appropriate. Member countries should use their judgement in choosing which method to apply. The results required are the concentration in the plume where it first interacts with the ground or with a receptor of interest, or the distributed concentration in the box model. Degradation and physical chemical data may be used to indicate whether changes in the calculated levels are likely. They could also be used to estimate deposition rates for use as input into the soil model. c. Soil model i. Major processes: partitioning between water and soil; removal by degradation, leaching.

ii. Optional processes: volatilization, root uptake.

iii. Chemical information: Henry's Law Constant, Koc, degradation rate( s), deposition rate, concentration in sewage sludge.

iv. Environmental data: soil properties ( porosity, water content, organic carbon content, depth of root zone and surface layer ( see remarks)); meteorological properties ( rainfall, evaporation, or a water balance). EXCH\ MANUAL\ 96 4 3. DOC/ May 1996 12 v. Remarks: This situation is more complicated than the previous two models. Two possible release routes were considered: deposition from air, or application of sewage sludge containing the chemical. Member countries may consider other release routes if they so wish. It was agreed that concentrations were desired to assess effects on soil organisms and on possible levels in groundwater. Accordingly there are actually two versions of the same model that may be used here. For assessing effects on soil organisms, a model of only the shallow surface layer might be considered. For levels in groundwater, calculations would be carried out for soil to the depth of the root zone or below; the concentration in the leaching water would be then available for use in assessing groundwater concentrations. Different values for organic carbon content etc. could be used for the two cases. Values for the depths of the two layers, and the soil properties should be chosen by the Member countries ( generic or site specific). The possibility of volatilization affecting the estimated concentrations was considered, but it was felt that the routes of release had already taken this into account.

General Comments on the Local Models 5. Throughout these models there are opportunities for Member countries to adapt them to their own particular situations. Whilst it was agreed that this should be done where the data was available, it was felt by several of the participants that the application of a set of generic local conditions as a reference scenario would also be useful. It is recommended that the possibility of developing such scenarios be investigated. It is also recommended that Member countries take a conservative approach to the choice of generic parameters.

Global Model 6. Rather than derive a multi media model from basic processes, the group decided after discussion that the Mackay level III model should be used as the basis of the global model. However, this did not rule out the use of other models considering long term fate if a Member country had such models available.

7. As a number of versions of this model have been available over the years, it was agreed that it was important that all Member countries had the same basic model with which to work, if they wished to use this approach. The version chosen was that presented by Frank Wania ( University of Toronto) at the Workshop, and described in " Generic Models for Evaluating the Regional Fate of Chemicals" by D. Mackay et al. ( Chemosphere, in press 1992) ( Ref. 34). This should be adapted to model the environment of the Member country if this was possible, for example by using appropriate sizes for the compartments. If this was not possible, the default compartment sizes as presented in the article should be used. In line with the comment above on the local models, it was felt by many of the participants that it would be useful for each country to use these default values in addition to their own values if possible. In order to allow Member countries to modify the environmental parameters, development of a modified version of the computer program was necessary.

i. Chemical data required: physical chemical data from the SIDS data set; degradation rate data, release rate appropriate to the model used.

ii. Environmental parameters: compartment volumes, areas, densities, organic carbon content where appropriate. These are the parameters which users can input in the modified version.

iii. Remarks: Where parameters such as Koc, BCF are estimated from other data it is important that the method used is indicated. This is also the case for estimates of degradation rate. For the generic model, an appropriate input rate should be used, for example 1% of the total release in the OECD Member countries.

General Remarks 8. It is important when using the approaches indicated above that any assumptions made or extra data used are made clear, for example the reasons for choosing flow rates in the water model should be given. If SAR methods are used to estimate other data, the method used should be given. It is essential that the methods used are transparent to other Member countries.

9. The physical chemical data available in the SIDS are generally sufficient for these models. For some data it is necessary to use SAR methods. EXCH\ MANUAL\ 96 4 3. DOC/ May 1996 13 10. There is a general lack of information on degradation rates in the SIDS data set. This may not be important for the local models in the first instance, but it is an obvious problem for global models. Therefore the Working Group recommends that efforts be made to improve the provision of such data, whether through measurement or estimation.

11. Where there are uncertainties in the data used, the user should assess the effect these have on the concentration estimates. In addition it should be noted that there are some chemicals for which these methods are not suitable.

12. It is recommended that models based on the methods in this report should be developed and distributed to Member countries by the OECD Secretariat in time to perform the next round of assessment of HPV phase 1 chemicals. Member countries are invited to submit their own models to be distributed at the same time. EXCH\ MANUAL\ 96 4 3. DOC/ May 1996 14 Annex 3 Models for Indirect Exposure by Food and Drinking Water ( Summary Report of Working Group III of the OECD Workshop held in Berlin in December 1991)

1. The objectives of the Working Group were to identify and recommend suitable models for indirect human exposure assessment. It was generally agreed that such models cannot be considered separate from models used for estimating environmental concentrations. Therefore, discussions touched parts of the discussion in Working Groups I and II, especially concerning the scale on which indirect exposure of human beings is considered.

2. The main discussion point concerned the connection between environmental models and indirect exposure models. The exact process descriptions were seen as of minor importance, as they are more or less the same in most models.

Models presented 3. There were six models presented by the members of the Working Group.

3. a CHEMCAN 2 ( Canada, Ref. 1)

i. This is a global model based on Mackay Level III dividing Canada into 24 regions considering four primary ( air, water, soil, sediment) and four secondary compartments ( groundwater, coastal water, terrestrial plants and terrestrial animals).

ii. Indirect exposure of humans can be calculated from the concentrations in food but up to now it is not included in the model. Fine tuning of some pathways ( e. g. soil plant) has to be carried out.

3. b CHEMFRANCE ( France, Ref. 3)

This model is similar to CHEMCAN 2 dividing France in 12 regions.

3. c MNSEM ( Japan, Ref. 5 and 6)

This model is also similar to CHEMCAN 2, that means it is also based on Mackay Level III and it is specific for Japan. It calculates concentrations for all relevant compartments as well as the total daily intake for adults. Elimination according to first order kinetics can also be calculated.

3. d RISK ( Netherlands, Ref. 7)

RISK is a local model for a generic standard environment and is specific for average conditions in the Netherlands. It is a worst case approach for indirect exposure of humans, but can be modified to a realistic worst case. EXCH\ MANUAL\ 96 4 3. DOC/ May 1996 15 3. e US Approach ( Ref. 11 and 22)

It is a local model, generic or site specific, and refers to the situation in the US. EPA databases on emission patterns and stream flows are used. Certain pathways, e. g. exposure via cattle or crops, are not included and there is no automated version available, e. g. for a PC.

3. f HESP ( SHELL, ECETOC)

HESP is a site specific model for Hazard Assessment when there is soil pollution. For the exposure of humans ( adults as well as children) detailed information is given on the various routes ( inhalation, ingestion and dermal absorptions).

Evaluation of the Models 4. The following table shows the evaluation of each model.

Table: Evaluation of the Models NAME Scale Input data Data covered by SIDS CHEM FRANCE global, specific for France physical chemical emission estimates +

CHEMCAN 2 global, specific for Canada physical chemical emission estimates +

MNSEM global, specific for Japan physical chemical emission estimates +

RISK local, generic physical chemical emission estimates +

US Approach local, generic or specific physical chemical emission estimates +

HESP site specific physical chemical soil concentration +

5. For all models emission estimates or soil concentrations are necessary but not available from SIDS.

6. The structure of indirect exposure models as proposed in Figure 1 of the Discussion document ( Ref. 18) was agreed. One amendment is proposed by adding SEDIMENT as a pathway to FISH.

1 2 7 6 7 AIR SURFACE WATER SEDIMENT SOIL HUMAN BEINGS Groundwater Grass Fish Drinking Water Crops Cattle Meat Milk EXCH\ MANUAL\ 96 4 3. DOC/ May 1996 16 6 8 3 7 3 4 7 5 7 1 inhalation 2 bioconcentration water fish 3 bioconcentration soil plant 4 biotransfer to meat 5 biotransfer to milk 6 purification of drinking water 7 consumption 8 ingestion of soil Figure 1  Schematic Representation of the Indirect Exposure to Human Beings Conclusions 7. It was stressed that because certain target groups like children or elderly people behave differently from the average adult, it is important that such critical target groups be included in indirect exposure assessments. There may be also large differences between the exposure of communities which live near the source compared to the population as a whole.

8. All models except HESP are in fact environmental models which include modules/ methods for estimating human intake. This emphasizes the strong relationship with the local and global models as discussed in Working Group II. HESP is the only true human exposure model, developed for specific application. Four models namely CHEMCAN, CHEMFRANCE, MNSEM and RISK have been developed for specific regions. They are adaptable and, therefore, are available to those Member countries who wish to use them in their initial indirect exposure assessment of HPV chemicals to humans.

9. Both local and global approaches were thought to be important in order to obtain insight into the exposure of local and average populations. Both types of models are strongly recommended to be used, when circumstances indicate that this type of insight will be useful to the assessment. Similarly, to the extent warranted by other factors or information, it is recommended to carry out calculations for extreme dietary compositions, e. g. high and low consumption of fish, meat or vegetable.

10. It was considered that the US approach is not so easily adaptable and, therefore, is of limited use to other Member countries. HESP can be used only for specific purposes ( soil contamination) and is therefore out of scope for the initial exposure assessment of HPV chemicals of the OECD Existing Chemicals Programme. EXCH\ MANUAL\ 96 4 3. DOC/ May 1996 17 Annex 4 References A. Member Countries' Responses to the Questionnaire 1. Application of a Fugacity Based Model to the Estimation of the Environmental Fate of 10 Chemicals on the OECD SIDS List, J. Sitwell and D. M. Kane, National Health and Welfare ( Canada)

2. Environmental Exposure Assessment, Product Register Data on Ten Selected Substances, P. Andersen, National Institute of Occupational Health ( Denmark)

3. Environmental Behavior of Ten Organic Compounds, J. Devillers and D. Domine CTIS ( France)

4. Response from Germany, P. Greiner, Umweltbundesamt ( Germany)

5. Application of Simple Model for Environmental Exposure Assessment, K. Yoshida, Mitsubishi kasei Institute of Toxicological and Environmental Sciences ( Japan)

6. Multi Phase Non Steady State Equilibrium Model ( MNSEM) Version 1.4.5 Model Information, K. Yoshida, Mitsubishi kasei Institute of Toxicological and Environmental Sciences ( Japan)

7. Assessment of Environmental Concentrations and Risk Quotients for the Netherlands: Application of Simple Models, C. Toet, D. van de Meent, Th. E. M. ten Hulscher, K. D. van den Hout, National Institute of Public Health and Environmental Protection etc. ( the Netherlands)

8. Environmental Exposure Assessment, E. Hoygaard, State Pollution Control Authority ( Norway)

9. Initial Exposure Assessment of 10 HPV/ P1 Chemicals, Applying a Swedish Exposure Model ( Revised version), S. Fischer, National Chemicals Inspectorate ( Sweden)

10. Response from United Kingdom, P. J. Corcoran, Department of the Environment ( United Kingdom)

11. Engineering and Environmental Exposure Report for Ten High Production Volume SIDS Chemicals, ( US Environmental Protection Agency)

B. Request and Data on the Ten SIDS Chemicals 12. Data on ten selected SIDS Chemicals from HPV Form 1 ( OECD Secretariat)

13. Estimates of Ecotoxicity ( Aquatic Effects) and Bioaccumulation, Data of the Ten SIDS Chemicals ( the Netherlands)

C. Discussion Documents for the OECD Workshop held in Berlin in December 1991 14. Emission Factors and Use Categories of Chemicals ( for W. G. I) ( W. Penberthy, P. Greiner)

15. Memorandum: OECD Scheme for Estimating Rates of Removal in Waste Water Treatment ( for W. G. I  comments on Ref. 14 by the US) ( R. Boethling)

16. Local and Global Models ( for W. G. II) ( OECD Secretariat)

17. Application of SARs to the Estimation of Properties Important in Exposure Assessment, Fraunhofer  Institute ( for the Special Session) ( P. Degner, H. Jackel, M. Muller, N. Nendza, B. von Oepen, W. Klein)

18. Indirect Exposure of Human Beings to Organic Compounds ( C. Toet, S. Arai) EXCH\ MANUAL\ 96 4 3. DOC/ May 1996 18 19. Reference Models which would be used for the Initial Environmental Exposure Assessment ( for W. G. II) ( M. Matthies)

D. Background Documents for the OECD Workshop held in Berlin in December 1991 20. Emission factors and Use Categories of Chemicals ( for W. G. I) ( W. Penberthy, P. Greiner)

21. Local and Global Models ( for W. G. II) ( OECD Secretariat)

22. Potential Approaches for Developing Screening Level Environmental and Human Exposure Assessments for SIDS Chemicals ( for W. G. II) ( E. Bryan)

E. Additional References 23. OECD's Work on Investigation of High Production Volume Chemicals, OECD, 1991 24. Environmental Releases of Chemicals in Household Products, US EPA, Dec. 1991 25. Site Specific Surface Water Flows and REACH Number, US EPA, Dec. 1991 26. Stream Dilution Factor Programme Outputs for 40 Industrial Categories, US EPA, Dec. 1991 27. User's Guide to Probabalistic Dilution Model 3 ( PDM 3), US EPA, Dec. 1991 28. Probabalistic Dilution Model 3 ( PDM3), US EPA, Dec. 1991 29. A Model of Organic Chemical Fate in a Biological Wastewater Treatment Plant, B. Clark et al. University of Toronto, Oct. 1989 30. Comparison of different models for Environmental Hazard Classification of Chemicals, KEMI Report No. 9/ 89 31. Systems for Testing and Hazard Evaluation of Chemicals in the Aquatic Environment, A Manual for an Initial Assessment  ESTER, KEMI Report No. 4/ 88 32. Substances and Preparations Dangerous for the Environment, A System for Classification, Labelling and Safety Data Sheets, Final Report from a Nordic Working Group, Nordic Council of Ministers, 1990 33. Fugacity Models, D. Mackay et al., Practical Application of QSAR in Environmental Chemistry and Technology , June 1990, Klamer Academic Publication, pp. 433 461 34. Generic Models for Evaluating the Regional Fate of Chemicals, D. Mackay et al. ( Chemosphere, in press 1992)

35. The Explanatory Note for Diskettes Comprising National Models, OECD Secretariat, July 1992 36. Screening Assessment Model Systems (" SAMS", The Explanatory Note for Diskette of the Local Reference Models, Version 1.1), OECD Secretariat, December 1992 37. The Explanatory Note for Diskette of the Global Reference Model, OECD Secretariat, July 1992 38. Report of the OECD Workshop on the Application of Simple Models for Environmental Exposure Assessment, Environment Monographs No. 69, 1993 39. Application of Structure Activity Relationships to the Estimation of Properties important in Exposure Assessment, Environment Monographs No. 67, 1993 F. List of Diskettes and Documents Distributed to the SIDS Contact Points EXCH\ MANUAL\ 96 4 3. DOC/ May 1996 19 a. Reference Models and National Models ( ENV/ EHS/ SA/ fcl/ 92.40, 11th August 1992, and ENV/ EHS/ SA/ fcl/ 93.1, 11th January 1993)

· Diskettes of Reference Models (" Screening Assessment Model System ( SAMS)" Version 1.1 and " Fugacity Model ( FUGMOD)") · Two diskettes of National Environmental Exposure Models ( i. e. The Netherlands, UK, Canada, France and Japan) · Explanatory Note of a Diskette of the Global Reference Model ( FUGMOD) · Explanatory Note of a Diskette of the Local Reference Models ( SAMS Version 1.1) · Explanatory Note of Diskettes Comprising National Models b. Documents and Diskettes of the U. S. models ( ENV/ EHS/ SA/ fcl/ 92.41, 11th August 1992)

· A letter from Ms. E. Bryan to Rob Visser dated 23rd March 1992 · Models 1. STP ( Sewage Treatment Plant model or " Toronto model")  The diskette of " Water" includes STP 2. Water ( the following sub models)

A. Exposure from Airborne Release a. Turner model  Enclosure I of the letter: Document for Generic Turner Method for Estimated Exposure from Near Ground Releases to Air b. ISCLT model ( Industrial Source Complex Long Term model)  Enclosure II of the letter: Documentation for Generic ISCLT Method for Estimating Exposure form Elevated Release to Air B. Site specific Surface Water Release Calculation C. Industrial SIC Code Based Water Surface Water Calculation D. Drinking Water Exposure from Landfilled Chemicals  Enclosure III of the letter: Draft Guidelines for Groundwater Assessments for PMN Chemicals E. Chemical Removal from Adsorption Diskette  Water ( including above mentioned six models)  STP ( Toronto Model)  PMNPLUME Model 3. PMNPLUME  PMNPLUME Exposure Model Description and Use's Manual  The diskette of " Water" includes PMNPLUME 4. Probabilistic Dilution Model 3 ( PDM3)  Draft Report, Probabilistic Dilution Model 3 ( PDM3), Volume 1 and 2  Final report, User's Guide to PDM3  Diskettes " PDM3" ( 6 diskettes for a set) 1. Option 1 Estimated flows 2. Option 1 Measured flows, disk 1 of 3 3. do , disk 2 of 3 4. do , disk 3 of 3 5. PDM. EXE 6. Option 2 SIC code data 5. ReachScan EXCH\ MANUAL\ 96 4 3. DOC/ May 1996 20  ReachScan User's Manual  a diskette of ReachScan with Region 3 Stream Data 6. PCGEMS  PCGEMS User's Guide Release 1.0  Diskettes for PCGEMS ( 21 diskettes for a set) EXCH\ MANUAL\ 96 4 4. DOC/ May 1996 1 4.4 Provisional Guidance for the Initial Assessment of Occupational and Consumer Exposure*

4.4.1 Introduction 1. This document provides guidance for the initial assessment of the occupational and consumer exposure of High Production Volume ( HPV) chemicals for which a full SIDS is available, based mainly on the results of the OECD/ US EPA Workshop held in Orlando, Florida in February 1992. The results of the Workshop are published by the OECD as OECD Environment Monograph No. 70, Occupational and Consumer Exposure Assessments ( from now on referred to as " Monograph No. 70").

2. The objective of any occupational and consumer exposure assessment is to calculate a " realistic" Estimated Human Exposure ( EHE) level, expressed in terms of dose per unit weight, e. g. mg/ kg, based on data contained within the full SIDS Dossier for the " sponsored" chemical. This level can then be compared with the results obtained from conducting the Initial Assessment of Health Effects and a judgement made as to whether the chemical presents a cause for concern and the possibility of further action. For consistency within assessments, when calculating the human exposure level, in the absence of evidence to the contrary, there may be a need to standardise some of the appropriate physiological parameters. In this respect it is suggested to assume that:

( a) an adult weighs 70 kg; ( b) the respiratory volume is 10 m 3 ( i. e. 10,000 litres) per working day ( 8 hours); ( c) the consumer respiratory volume is 15 litres per minute.

3. Other factors, which should be obtained before assessing exposure, relate to the physical state of the chemical and its weight fraction in any product or formulation that is professionally used. If the chemical is also present in consumer products, an appropriate adjustment should be made to the EHE.

4.4.2 Occupational Exposure 4. For exposure via the inhalation route, some chemicals may have been assigned a national or company based occupational exposure limit ( e. g. TLV, MAK, MAC, OES, etc.), perhaps even further refined to encompass short term limits or ceiling values. Whenever possible these levels, preferably expressed as mg/ m 3 rather than p. p. m., should be used as the basis for calculating the EHE. It is important to compare these occupational exposure limits as the values may differ between Member countries. The toxicity and exposure data used and the date the limits were set should also be considered in the comparison.

5. In other cases actual monitoring data, both personal and background, may be available and can, after suitable statistical treatment ( e. g. geometric mean and standard deviation), be used in a similar manner. The overall procedure should be repeated for all the various production processes and uses made of the chosen chemical and, from a knowledge of frequency and duration of exposure, the results of the " worst case" highlighted. Again knowledge that technical or personal protective equipment is required may assist in formulating views. 6. However, for the majority of SIDS chemicals it is anticipated that " real" data will not be available and hence " estimation" methods will need to be used. Three such methods, as proposed by Germany, the UK and the USA, with varying levels of detail and from which the National SIDS Contact Points are free to choose, have been identified. These are attached to Monograph No. 70 as Annexes I III. They rely on a knowledge of similar production processes and use patterns and/ or on the physical chemical properties of the " sponsored" or surrogate chemical. Thus where " real" data are missing for the chosen chemical it may be possible to substitute data from another chemical meeting the criteria mentioned above. In all these methods the amount of detail and level of sophistication required for a " quantitative" estimation depends to some extent on the toxicity of the chemical. Therefore, the occupational exposure ( and consumer exposure) assessment should not be conducted in isolation. For example, a chemical showing low toxicity may require only qualitative, or at most semiquantitative exposure estimation. In those cases where a chemical is also incorporated into a consumer product, the occupational or professional exposure should be supplemented by the appropriate component of the consumer exposure assessment in calculating the overall EHE. The situation is not so clear cut regarding dermal exposure and only the model * This document was prepared by the OECD Secretariat in 1992 based on the results of the OECD/ US EPA Workshop held in Orlando, Florida, in February 1992. It has been updated to reflect comments by Member countries and agreements reached in the context of the OECD Existing Chemicals Programme up to mid 1994. EXCH\ MANUAL\ 96 4 4. DOC/ May 1996 2 used by the US EPA addresses this point. Indeed one of the conclusions of the Orlando workshop was that more work was needed in this area and that Member countries should share their experiences. Such information will be invaluable in updating this provisional guidance, for both occupational and consumer exposure.

Overview of Models for Estimating Occupational Exposure 7. The US EPA submission provides a number of model approaches whose applicability relies on some knowledge of production and use scenarios in the US ( e. g. the NIOSH National Occupational Exposure Survey). The identification of critical unit operations during manufacture and use leading to significant exposure scenarios allows a degree of specificity in the assessment. However, some reservations as to the applicability of the models, in circumstances of more modest resources or expertise, could restrict their use. ( See Annex I to Monograph No. 70.)

8. The UK HSE submission illustrates a possible approach based on a structured logic tree using analogous exposure data. Its recent development into a simple, validated " expert system" for screening purposes is attractive, particularly as the ultimate choice of exposure databases could be adapted to national needs. In the first instance the use of the UK National Exposure Database ( NEDB) could be a relevant tool in the development of this approach. The classifications based on physical and ( apparent) toxicological properties and containment levels will need careful definition for more general future use. ( See Annex II to Monograph No. 70.)

9. The German BAU submission offers a generally qualitative screening approach based on common knowledge of the exposure situations in different areas of use and on an example of " mass balance" calculations. This could be a particularly relevant screening tool when there was an early indication that a high degree of sophistication was unlikely to be warranted. ( See Annex III to Monograph No. 70.)

4.4.3 Consumer Exposure 10. Much of the foregoing can also be applied to the assessment of consumer exposure in that the objective, when combined with any possible occupational exposure, is to calculate an EHE, that " real" data is to be preferred, and that the toxicity of the chemical should be brought to bear on the level of detail required. Again for most SIDS chemicals, it is expected that " estimation" methods will be required and two have been identified. One of these, as used by the US EPA, is available on computer diskette. Although a synopsis is attached to Monograph No. 70 as Annex IV, further details of its use are best obtained from the incorporated files, most of which are " menu driven". The other one, a discussion paper from the Netherlands, is also attached to Monograph No. 70 as Annex V. Unlike the occupational setting where, to a greater or lesser extent, some exposure is bound to occur, there will of course be no requirement to undertake an exposure assessment if the chemical is not present in a consumer product. Product registers and inventories, etc. will need to be consulted, perhaps with assistance from other Member countries, to check if this is indeed the case. There may, however, be the need to incorporate other factors, such as presence in drinking water, in obtaining an overall EHE.

Overview Models for Estimating Consumer Exposure 11. Details of the method proposed by the US EPA are obtained from the diskette which contains the SCIES, AMEM, FLUSH and DERMAL procedures and explanatory documents. Both have been distributed to the SIDS Contact Points ( see the list in Reference as well as details in Annex IV to Monograph No. 70.)

· SCIES is a Screening level Consumer Inhalation Exposure Software program for the passive and active annual average inhalation exposure to components of consumer products.

· AMEM is an estimation model for assessing migration of a chemical from a polymer and the inhalation exposure.

· FLUSH is a program for estimating concentrations of chemicals in surface waters that may result from disposal of consumer products containing these chemicals into household wastewater and also provides estimates of human exposure from ingestion of drinking water and fish that may become contaminated by these household wastewater releases. EXCH\ MANUAL\ 96 4 4. DOC/ May 1996 3 · DERMAL is a program which allows estimation of dermal exposure, in terms of potential dose rate, for contact with ( 1) a film of liquid deposited on the skin, ( 2) dusts and powders, and ( 3) chemicals contained in or adhering to solid matrices.

A computer expert may need to be consulted on the AMEM program as a " maths co processor" is required.

12. The proposed model from the Netherlands in Annex V to Monograph No. 70 is self explanatory and allows one to input selected values or, in certain circumstances, to choose the " default" value.

4.4.4 Reporting 13. General guidance for preparing the report is given in the document entitled " Provisional Guidance for the Outline of the SIDS Initial Assessment Report" ( see Section 4.2), but it is worth re emphasizing that the approach used in obtaining any estimation of the EHE, including the underlying assumptions and uncertainties, should be sufficiently well explained to enable other interested parties to confirm the conclusions and respond effectively. Also as a reminder, it is requested that the use, or otherwise, made of this " provisional" guidance be highlighted so that future versions can be modified. Views of the users on the suitability of various " default" or other " standardised" values will also be welcome. EXCH\ MANUAL\ 96 4 4. DOC/ May 1996 4 Reference List of Diskettes and Documents for Consumer Exposure Assessment Distributed to the SIDS Contact Points ( ENV/ EHS/ AS/ fcl/ 92.4, 11th August 1992)

· A diskette of " Models for Consumer Exposure Assessment"

· An explanatory note for the diskette · Screening level Consumer Inhalation Exposure Software ( SCIES): Description and User's Manual, Version 3.0 ( Draft), USEPA · FLUSH User's Manual ( Final Draft Report), USEPA · Dermal Exposure Model Description and User's Manual ( Draft), USEPA · Methods for Assessing Exposure to Chemical Substances Volume 11, Methodology for Estimating the Migration of Additives and Impurities from Polymeric Materials, USEPA Annexes ( not reprinted here: to be found in OECD Environment Monograph No. 70, Occupational and Consumer Exposure Assessments, OECD, 1993)

Annex I Approaches for Developing Screening Quality Estimates of Occupational Exposure used by the US EPA's Office of Toxic Substances and their Applicability to the OECD SIDS Programme, US EPA, December 1992 Annex II The estimation of Occupational Exposure to Chemicals, HSE, UK Annex III Occupational Exposure Assessment for Selected SIDS Chemicals, BAU, Germany Annex IV Screening Level Consumer Exposure Assessment, US EPA Annex V Estimation of Consumer Exposures to Chemicals: Application of Simple Models, RIVM, the Netherlands EXCH\ MANUAL\ 96 4 5. DOC/ May 1996 1 4.5 Provisional Guidance for the Initial Assessment of Aquatic Effects*

4.5.1 Introduction 1. This document provides guidance for the initial assessment of aquatic effects of High Production Volume ( HPV) chemicals with a full SIDS. It is based mainly on the " Guidance Document for Aquatic Effects Assessment" ( Ref. 1), which was drafted initially by the Netherlands in the framework of the OECD Hazard Assessment Programme and is now published as OECD Environment Monograph No. 92. This Monograph is based on the reports of the following three Workshops:

 Application of Quantitative Structure Activity Relationships ( QSARs) to estimate ecotoxicity data ( Utrecht, 12 14 September 1990) ( Ref. 2);  Extrapolation of ecotoxicity data to the real environment ( Arlington, Virginia, 10 12 December 1990) ( Ref. 3);  Effects assessment of chemicals in sediment ( Copenhagen, 13 15 May 1991) ( Ref. 4)

2. These documents ( Ref. 1, 2, 3 and 4) can be referred to whenever detailed information relating to the assessment procedure presented in this document is required. In particular, examples of effects assessments in Ref. 1 are useful for understanding the procedure.

3. This guidance can be applied to soluble compounds; however, it may not be suitable for elements in the metallic state and for insoluble substances.

4. Recently, the European Commission has developed the Technical Guidance Document for risk assessment of new and existing chemicals ( Ref. 5), that includes detailed guidance for aquatic effects assessment.

4.5.2 Background to Aquatic Hazard Assessment 5. Environmental hazard assessment is defined as the assessment of the potential of a chemical to cause adverse effects on the environment and/ or man. Effects assessment can be defined as the identification and quantification of the potential adverse effects of chemicals on individuals, population or ecosystems by means of laboratory testing or field observations. In an assessment procedure, a comparison is made of the calculated " low risk" concentration where no unacceptable adverse effects on the ecosystem are expected ( i. e. Predicted No Effect Concentration, PNEC)** and the concentrations that are present in the environment, either measured or calculated ( i. e. Predicted Environmental Concentration, PEC).*** This comparison gives some insights into the risks that the chemical under study poses to human beings or to specific species in any environmental compartment.

6. Aquatic effects assessment of chemicals is a sequential process that may comprise three stages: initial, refined and comprehensive, where each stage depends on the type and quantity of information that is available.

7. In the initial aquatic effects assessment on which this document focuses, the impact of the chemical is generally assessed against only one or two representatives from each of three trophic levels by means of short term toxicity tests; i. e. using primary producers ( algae), primary consumers ( Daphnia) and predators ( fish). Refined effects assessments are based on chronic or sub chronic tests, whereas ( semi) field studies provide the basis for comprehensive effects assessments. Hence, the process of effects assessment goes through stages of imprecise to precise estimations of the concentration that will have no adverse effect on the ecosystem under consideration.

* This Provisional Guidance was first prepared by the OECD Secretariat in 1992 based on the results of three OECD Workshops ( see para 1). It has been updated to reflect comments by Member countries and agreements reached in the context of the OECD Existing Chemicals Programme up to April 1996.

** Maximum Tolerable Concentration ( MTC) is also used synonymously.

*** The methods which can be used to calculate environmental concentrations are addressed in " Provisional Guidance of Initial Assessment of Environmental Exposure" ( see Section 4.3). Diskettes comprising environmental exposure models for calculation of PECs are also available. It should be noted that all important emission sources should be clearly identified in determining PECs. EXCH\ MANUAL\ 96 4 5. DOC/ May 1996 2 8. Figure 1 presents an example of a scheme for an aquatic effects assessment. It includes not only the initial assessment procedure, but also refined and comprehensive assessment procedures which can be performed when information beyond that in SIDS is available.

9. Information available through databases and publications as well as from industry should be collected intensively. The data should then be evaluated by appropriate assessors, for example experts in the field of environmental chemistry and toxicology, before they are used for an environmental effects assessment. It is necessary to review the original publication to assess the data collected through databases. In the SIDS work, the data should be generated according to guidelines such as the OECD Test Guidelines using Good Laboratory Practice ( GLP) Principles. ( Criteria which could be used for evaluation of data is given in Section 3 of Ref. 1. Its summary, with some amendments, is attached as Annex 1 to this document.)

10. In an initial assessment based on the information obtained in the SIDS work, a set of assessment factors would be applied ( see Section 6 of Ref. 1). Also a QSAR approach using physical chemical properties is applicable for estimating the toxicity of chemicals on a case by case basis when no data or only data for one test species are available or when the measured data for a species is deemed to be unacceptable. This approach may also be used for estimating a PNEC value by the application with assessment factors ( see Section 7 of Ref. 1). For chemicals where additional information beyond the SIDS are available, the possibility of carrying out higher stages of assessments could be considered [ e. g. those based on field testing ( see Section 4 of Ref. 1), those by the extrapolation method ( see Section 5 of Ref. 1)].

11. In addition, indirect effects on birds and mammals ( see Section 8 of Ref. 1) and effects on benthic organisms ( see Section 9 of Ref. 1) of a chemical could be considered depending on the use and properties of the chemical.

12. When considering refinement of effect assessments or further testing, refinement of exposure assessment should also be considered. EXCH\ MANUAL\ 96 4 5. DOC/ May 1996 3 Figure 1  An Example of an Aquatic Effects Assessment Flow Scheme 1. Calculation of PNEC Data Collection and Evaluation ( Section 3)

Effects Assessment on Aquatic Organisms yes yes Beyond SIDS Field Data Use of Field Data PNEC for Selection Criteria Comprehensive no no ( Section 4) Assessment no yes Data on Chronic e. g. Extrapolation PNEC for Tox. on Multiple Method Refined Species ( e. g. five ( Section 5) Assessment or more different species)

Toxicity Data Assessment PNEC for on 1 or more yes Factors Initial Species ( Section 6) Assessment no yes QSAR QSAR Approach no ( Section 7)

Testing Note: Section numbers in brackets ( e. g. Section 3) refer to the appropriate Sections in Ref. 1.

2. Comparison of PNEC with PEC · PEC/ PNEC < 1  Chemicals of low current priority for further work · PEC/ PNEC ³ 1  Consideration of further work or actions ( post SIDS testing, detailed exposure analysis, indepth risk assessment or further risk management actions) EXCH\ MANUAL\ 96 4 5. DOC/ May 1996 4 4.5.3 Outline of Various Approaches to Aquatic Effects Assessment Assessment Factors 13. When only a limited data set is available for an initial assessment of a chemical, such as is the case for most SIDS chemicals, assessment factors can be used to adjust the effect concentration and to estimate a PNEC. However, assessment factors should be applied with care to acute data for substances which are suspected of having a specific mode of action, or which have a high log Pow or which significantly bioaccumulate.

14. Assessment factors may be used to extrapolate:  from the lowest chronic NOEC to the field situation;  from concentrations with acute effects to NOECs; and  to take account of inter species differences in sensitivity.

15. Several sets of assessment factors have been proposed to date. Table 1 summarises proposals from the OECD Arlington Workshop ( Ref. 1 and 3), the European Commission ( Ref. 5) and ECETOC ( Ref. 6). These factors can be modified under certain conditions ( e. g. an assessment factor of 1000 in the EU Technical Guidance Document can be lowered to 100 with certain evidence); however, such modifications of the factors are not explained here ( please see the references).

Table 1. Proposed Assessment Factors for Application to Aquatic Toxicity Data for Estimating a PNEC Available information applied Assessment factor applied to the lowest value ( modifications not included)

( a) OECD Workshop ( b) EU Technical Guidance Document ( c) ECETOC proposal One acute L( E) C50 for acute toxicity from one trophic level 1000

At least one acute**** L( E) C50 from each of three trophic levels of the base set ( fish, Daphnia and algae) 100 1000 200 One chronic NOEC ( either fish or Daphnia)  100

Two chronic NOECs from species representing two trophic levels ( fish and/ or Daphnia and/ or algae)  50 5 Chronic NOECs from at least three species ( normally fish, Daphnia and algae) representing three trophic levels 10 10 Field data or model ecosystems  case by case 1 **** In the EU Technical Guidance Document, " short term toxicity" and " long term toxicity" are used instead of " acute toxicity" and " chronic toxicity". EXCH\ MANUAL\ 96 4 5. DOC/ May 1996 5 16. With respect to the OECD Arlington Workshop proposals, a factor of 10 is suggested for each extrapolation step described in para 14. This approach is a modification of a method proposed by US EPA ( Ref. 7).

17. Assessment factors proposed in the EU technical Guidance Document depend on the properties of the chemical and the conditions of testing ( such as use of the most sensitive species). In a recent study ( Ref. 8), a factor of 100 between the E( L) C50 of acute toxicity and NOEC of chronic toxicity has been shown by measured data to be generally justifiable.

18. ECETOC's proposals are based on comparisons of toxicity data. An acute: chronic ratio of 40, a chronic: ecosystem ratio of 5, and an ecosystem: field ratio of 1 are suggested.

QSAR Approach 19. When experimental data are limited, QSARs are useful for estimating toxicities of chemicals. QSARs based on chemical classes are used widely ( for example Ref. 9). Proper selection and use of a model for a given chemical can be carried out on a case by case basis by using computerised systems such as US EPA ASTER ( Ref. 10) and ECOSAR ( Ref. 11). QSARs can also be applied to chemicals with a common mode of toxic action, such as narcosis where the mechanism is dependent on a chemical's hydrophobicity ( e. g. log Pow). It should be noted that QSARs are valid only for liquids at room temperature and for solids on which data on water solubility are available.

20. QSARs for chemicals with a common mode of toxic action were discussed in the OECD Utrecht Workshop for two classes, Class I ( inert chemicals, baseline toxicity) and Class II ( less inert chemicals) shown in Table 2. For a Class I chemical, QSARs may be used to establish whether the experimental toxicity of a chemical agrees with baseline toxicity. If so, then QSAR equations may be used to extend the data on fish, Daphnia and algae. For a Class II chemical, estimation by QSAR can be done for acute toxicity to fish although QSARs should not be used when reliable experimental data are available ( Ref. 2).

Table 2. Categorisation of Chemicals for QSARs for Approach by Common Mode of Action Class Structure Available QSARs Reliability Class I aliphatic alcohols, aliphatic ketones, aliphatic ethers, alkoxyethers, aliphatic halogenated hydrocarbons, saturated alkanes and halogenated benzenes ( only C, H, N, O, F, Cl, Br could be included) acute and chronic tox. to fish and to Daphnia magna, chronic tox. to algae ( for only nonpolar narcotics) concentration can be predicted Class II non or weakly acidic phenols, aromatic amines and anilines, aliphatic primary amines, weakly basic pyridines acute tox. to fish ( phenol and primary aromatic amines) a range can be predicted 21. A recent evaluation by the US and EC of QSARs used by the US EPA OPPT has demonstrated good agreement between predicted and measured toxicity for Daphnia and fish ( Ref. 12).

22. A PNEC may be derived from QSAR estimates in combination with or without experimental data by the application of assessment factors, using values similar to those proposed for experimental data.

23. QSAR can also be used to validate laboratory tests or to decide which further data are necessary.

Extrapolation Methods EXCH\ MANUAL\ 96 4 5. DOC/ May 1996 6 24. Extrapolation methods, which allow for different sensitivities of other, non tested, species within ecosystems, can be used to estimate a PNEC when chronic toxicity data are available. Three extrapolation methods, which require at least laboratory data on the chronic toxicity of a chemical to five or more different aquatic species, are available through a computer program ( Ref. 3).

( Semi) Field Test 25. If the results from testing using complex systems such as multi species laboratory systems, microcosms, experimental ponds and field trials are available, a comprehensive assessment should be considered. Although there are no internationally agreed protocols for ecosystem tests up to now, multi species tests have been developed by US EPA ( Ref. 13 and 14) and guidance for multi species studies has been developed by SETAC ( Ref. 15 and 16). Criteria for judging the applicability of these results for estimation of a PNEC in the comprehensive assessment are recommended in Ref. 1.

4.5.4 Aquatic Effects Assessments Procedure for SIDS Chemicals A. Evaluation of data used for the assessment 26. Before conducting an effects assessment, data should be evaluated for their adequacy. For example, it should be affirmed that the test and effect concentrations did not exceed the solubility limit. Test results using solvents should carefully be examined. Other criteria are mentioned in Section 3 of Ref. 1 or Annex 1 to this document.

B. Assessment possible when only SIDS data are available Assessment Factors 27. The experimental data on aquatic effects available from SIDS testing will include:  the fish acute test;  the Daphnia acute test;  the algal test ( usually acute data); and, possibly  the Daphnia chronic test ( in cases where there is concern about long term effects in the aquatic environment)

28. The recommended approach for estimating a PNEC with such a limited data set is to use assessment factors ( see paragraphs 13 18). Table 3 shows data which would be obtained from the SIDS Dossiers and the assessment factors which could be applied. The approach to the selection of an assessment factor is described below, taking current discussions into consideration. EXCH\ MANUAL\ 96 4 5. DOC/ May 1996 7 Table 3. Data in the SIDS Dossiers and Assessment Factors for Estimating an PNEC Case Data available Range of Assessment factor ( a) EC50 algae ( 72hr)

EC50 Daphnia ( 24 48hr acute test)

LC50 fish ( 96hr) 100  1000 ( b) NOEC Daphnia ( 14 21d chronic toxicity test)

NOEC algae ( 72hr)

[ NOEC fish ( chronic toxicity test)] 10  100 [ Note] 1. In case ( a), all three acute data are included in the SIDS. 2. In case ( b), NOECalgae is a SIDS element and NOECDaphnia may also be included in the SIDS for certain chemicals. NOECfish is available rarely.

29. When only acute toxicity data in the SIDS are available, an assessment factor of between 1000 and 100 is applied to the lowest L( E) C50 [ i. e. case ( a)]. A factor of 1000 is a conservative and protective factor and applied when only limited data are available, i. e. this value may be reduced to 100 if evidence is available to suggest that this may be a more appropriate factor. Such evidence would include:

( 1) availability of data from a wide variety of species including those which are considered to represent the most sensitive species;

( 2) information, from structurally similar compounds or QSAR, to suggest that the acute to chronic ratio is likely to be lower than that for many other compounds;

( 3) information to suggest that the chemical acts in a non specific or narcotic manner, with little inter species variation in toxicity; and ( 4) information to suggest that the chemical's release would be short term or intermittent, and the chemical would not be persistent in the environment;

30. When chronic toxicity data are available in addition to acute data, an assessment factor of between 100 and 10 is applied to the lowest NOEC [ i. e. case ( b)], taking the following situation into account:

( 1) If chronic NOEC is available from one or two species representing one or two trophic levels ( i. e. fish, Daphnia or algae), a factor of 100 or 50 is applied to the lowest NOEC. In this case, a PNEC value derived from chronic data should be compared to that derived from the lowest acute data. It is then the lowest value that is compared to the PEC.

( 2) If chronic NOECs are available from three species representing three trophic levels ( i. e. fish, Daphnia and algae), a factor of 10 is applied to the lowest NOEC. If there is convincing evidence that the most sensitive species has been tested, a factor of 10 may also be applied to the lowest NOEC from two species representing two trophic levels ( i. e. fish and/ or Daphnia and/ or algae).

31. Variation in the assessment factors applied should be clearly justified in the assessment report. EXCH\ MANUAL\ 96 4 5. DOC/ May 1996 8 QSAR Approach 32. In the SIDS Programme there is a preference for using measured data in effects assessment and in estimation of PNECs. However, if appropriate QSARs are available, they could be used and PNECs estimated by application of suitable assessment factors. A factor similar to that shown in Table 3 could be used. In this case the QSAR used and its reliability should clearly be indicated.

C. Assessment Possible When Data Beyond SIDS are Available Extrapolation Methods 33. It is considered that extrapolation methods for the estimation of a PNEC in a refined assessment will not be an option for most HPV chemicals because chronic NOEC values for at least five different species are required.

( Semi) Field Test 34. The results of ( semi) field studies including short term multi species trials and long term mesocosm trials are not thought to be available for many HPV chemicals. Where they are available and are considered appropriate, they provide the basis for a comprehensive effects assessment in combination with chronic toxicity data. The assessment factor to be used will need to be reviewed on a case by case basis.

D. Consideration of Indirect Effects Assessment and Assessment on Benthic Organisms 35. In addition to the effects assessments using pelagic aquatic organisms, assessments of indirect effects on birds and mammals and effects on benthic organisms ( Ref. 4) could be done if information on the chemical suggests possible hazard. However, these are thought to be beyond the scope of the initial assessment of HPV chemicals with SIDS. Some methods mentioned in Ref. 1 and Ref. 7, namely an approach using BCF for indirect effects and the equilibrium partitioning method for benthic organisms, could be considered. However, assessments carried out using only data available in SIDS may be very uncertain.

4.5.5 Outcome of the Initial Assessment 36. It should be stressed that all initial assessments in SIDS work should be extremely clear with regard to how they were developed, including approaches taken, any data used, and any assumptions made. Also data and estimations of exposure of a chemical which were used should be mentioned clearly. Examples in Ref. 1 are considered quite useful not only for understanding the assessment procedure but also for a model form of the report of the aquatic effects assessment.

37. If the conclusions of the initial assessment of a chemical suggest a possible risk to aquatic organisms, a more precise assessment by further testing, as well as elaborating exposure assessment, could be considered and proposed. For example, in cases where an estimated PNEC was derived from the results of acute toxicity tests and assessment factors, doing chronic tests with appropriate species ( e. g. most sensitive species in acute tests) would be considered as one of the possible further activities. Also if there is a possibility of indirect effects on birds and mammals or a possible hazard to benthic organisms, assessments on these could be considered and proposed for the next phase. EXCH\ MANUAL\ 96 4 5. DOC/ May 1996 9 Annex 1 Criteria for Evaluation of Data A. Octanol water Partition Coefficient 1. The octanol water partition coefficient ( Pow) should be examined carefully because it is very critical to the initial assessment of potential hazard. For example, determination of Pow by the shake flask method is not suitable for highly hydrophobic chemicals ( log Pow > 5). For those chemicals, the slow stirring method or generator column method can be used. It should also be noted that log Pow may not work for surfactants, polymers, inorganics, and organometalics.

B. Bioaccumulation 2. Data on bioaccumulation are principally used only for evaluating indirect effects of a chemical. They could be obtained through a QSAR equation by using Pow as well as by experiment. It should be noted that simple bioaccumulation QSARs often cannot predict the concentrations of extremely hydrophobic chemicals under field conditions. If more than one bioconcentration factor ( BCF) is available for the same species, the geometric mean for the species could be used; however, the test concentration should be taken into account. If BCFs are available for two or more species, the highest factor for a trophic level should be used. BCFs for algae, daphnids and fish should not be mixed and should be kept separate for each trophic level.

C. Aquatic Toxicity 3. Results of chronic toxicity tests are preferred for chemicals that have been shown to bioconcentrate/ bioaccumulate or are potentially bioaccumulative. For some of these chemicals, a 96 hour exposure in acute tests may not be sufficiently long. In any case, the water solubility of the test substance must be measured or predicted and the solubility limit must be compared to effect concentrations ( e. g. 96h LC50).

4. Interpretation of the data is important. For example, the key aspects of the study methods which affect study quality, such as measured or nominal concentration, control response, use of " insensitive" species, and water quality values, should be considered. Endpoints which have direct ecological relevance ( e. g. survival, growth, reproduction) should be given more weight than other endpoints ( e. g. biochemical parameters). Consideration of test species is also important; for example, in those cases where chronic studies have not been done with the most sensitive species in the acute tests.

5. If several toxicity data are available for one test species, the following rules may be applied:

 If these data are based on the same effect parameter ( endpoint) and the same time period, the geometric mean value should be used.  If different effect parameters or different exposure times within the same species are used, only the lowest value from the longest test time should be used taking into account the importance of the endpoints and the exposure periods in the various tests.  Data used for the extrapolation methods as described in Section 5 of Ref. 1 are restricted to NOEC values or geometric mean MATC values [ MATC = ( NOEC x LOEC) 1/ 2]. Results of chronic tests reporting only the lowest test concentration ( LOEC) might be included if they are converted to estimated NOEC values appropriately. For example, the equation: NOEC= LOEC/ 2 could be used in several cases. Regression methods also can be used for estimation. EXCH\ MANUAL\ 96 4 5. DOC/ May 1996 10 Annex 2 References 1. OECD Environment Monograph N0. 92, Guidance Document for Aquatic Effects Assessment, 1995 2. OECD Environment Monograph No. 58, Report of the OECD Workshop on Quantitative Structure Activity Relationships ( QSARs) in Aquatic Effects Assessment, 1992 3. OECD Environment Monograph No. 59, Report on the OECD Workshop on the Extrapolation of Laboratory Aquatic Toxicity Data to the Real Environment, 1992 4. OECD Environment Monograph No. 60, Report on the OECD Workshop on the Effects Assessment of Chemicals in Sediment, 1992 5. Technical Guidance Documents in Support of the Commission Directive 93/ 67/ EEC on Risk Assessment for New Substances and the Commission Regulation ( EC) N o 1488/ 94 on Risk Assessment for Existing Substances ( in print)

6. Technical Report No. 51, Environmental Hazard Assessment of Substances, European Centre for Ecotoxicology and Toxicology of Chemicals ( ECETOC), January 1993 7. Estimation of " concern levels" for concentrations of chemical substances in the environment, US EPA, OTS, Health and Environmental Review Division, Environmental Effects Branch, 1984 8. Heger, W., S. M. Jung, S. Martin, H. Peter; Acute and Prolonged Toxicity to Aquatic Organisms of New and Existing Chemicals and Pesticides. Chemosphere Vol. 31, No. 2, 2707 2726, 1995 9. Estimating Toxicity of Industrial Chemicals to Aquatic Organisms using Structure Activity Relationships, OTS, US EPA, 1988 10. ASTER ( Assessment Tools for the Evaluation of Risk), Scientific Outreach Program, US EPA, Environmental Research Laboratory Duluth, 1991 11. ECOSAR ( A Computer Program for Estimating the Ecotoxicity of Industrial Chemicals Based on Structure Activity Relationships.), OPPT, US EPA, 1994 12. OECD Environmental Monograph No. 88, US EPA/ EC Joint Project on the Evaluation of ( Quantitative) Structure Activity Relationships, 1994 13. Federal Register Vol. 52, No. 187, Sept. 28, 1987, pp 36334 to 36371.

14. Methods for Ecological Toxicology: A Critical Review of Laboratory Multispecies Tests. A. S. Hammons, Ed. Ann Arbor Science Publications, Inc./ The Butterworth Group, 1981.

15. Guidance Document on Testing Procedures for Pesticides in Freshwater Mesocosms, Society of Environmental Toxicology and Chemistry ( SETAC)  Europe, 1991 16. Workshop Report ( Workshop on Aquatic Microcosms for Ecological assessment of Pesticides, Wintergreen, Virginia, 6  12 October 1991), SETAC, February 17, 1992 EXCH\ MANUAL\ 96 4 6. DOC/ May 1996 1 4.6 Provisional Guidance for the Initial Assessment of Health Effects*

4.6.1 Introduction 1. This document provides guidance for the initial assessment of health effects of chemicals with a full SIDS, including suggestions for making decisions on any follow up testing if this is considered to be necessary. This document was first drafted based on relevant sections of the monographs of the International Programme on Chemical Safety ( IPCS). These monographs are listed in Annex 2 to this document and can be consulted for information about making fuller assessments of chemical substances.

2. Although the SIDS is the minimum requirement for making an initial assessment of High Production Volume ( HPV) chemicals in the OECD Existing Chemicals Programme, for many chemicals currently under consideration there will be data already available in excess of SIDS; these should, of course, be assessed and taken into consideration when developing conclusions and recommendations. However, in making the initial assessment of health effects, the elements in the SIDS which are relevant in this respect are:

· Acute Toxicity; · Repeated Dose Toxicity; · Genetic Toxicity; and · Reproduction/ Developmental Toxicity.

3. In the traditional assessment of repeated dose toxicity and reproduction/ developmental toxicity, Uncertainty Factors ( UF's) are used and the Estimated Level of Low Concern ( EDLC) is calculated from the No Observed Adverse Effect level ( NOAEL) or, when not available, the Lowest Observed Adverse Effect level ( LOAEL) derived from animal test results; however, since UF's are always chosen arbitrarily, it is often difficult for readers of assessment reports to understand the relevance of the factors used. Although this approach has been used for many years, there is no strong scientific evidence supporting its use. Therefore, at the 4th SIDS Initial Assessment Meeting in May 1996, participants agreed that UF's should not be included in assessment reports which are to be discussed and published in the OECD context.

4. Instead of using UF's and EDLC, N( L) OAEL or, if available, actual human data can be compared directly to the Estimated Human Exposure ( EHE) level. This approach, the so called " margin of safety" approach, is adopted in the EU Technical Guidance Documents for the implementation of the EC Regulation 793/ 93 and is described in this Provisional Guidance. Tentative general guidance for using UF's is attached as Annex 1 for possible use by Member countries in risk assessment at a national level. Both approaches have a similar end result. Whichever is used, it is important to consider both the effects and ( potential) exposure of each chemical in a case by case manner and to apply professional judgement by, for example, toxicologists and occupational hygienists when evaluating the adequacy of any tests and the interpretation of results.

* This document was first prepared by the OECD Secretariat based on the monographs of the IPCS. It has been updated to reflect comments by Member countries and agreements reached in the context of the OECD Existing Chemicals Programme up to May 1996. EXCH\ MANUAL\ 96 4 6. DOC/ May 1996 2 4.6.2 Acute Toxicity 5. In the assessment of the toxicity of a chemical, the determination of the acute toxicity is often the first step. It provides information on the health effects likely to arise from short term exposure at a relatively high dose. Substances are classified either on the basis of the approximate LD50 ( or LC50) value or a discriminating dose. Other information obtained from the acute toxicity test, such as types of effects observed, their time of onset, duration and severity, and shape of the dose response curve ( steep or shallow) are also useful in the hazard assessment ( and in the design of further studies).

6. When only acute oral data are available, the need to obtain data from tests by other routes should be considered in the light of the physical chemical properties of the chemical, the nature and magnitude of the results from the oral route study, the actual or potential routes of exposure, and the measured or estimated exposure level.

7. In the initial assessment of SIDS chemicals, data on acute toxicity will usually not lead to recommending action for follow up testing, although exceptional findings ( high lethality, neurotoxicity seen at low doses, etc.) may warrant such action.

8. When data on acute toxicity indicate that a chemical is ( very) toxic or harmful, this could lead to risk management activities, such as labelling or reduction of occupational exposure. In many cases, however, recommendations for such activities would not be needed for SIDS chemicals because where acute toxicity data were known, appropriate action would have already been taken.

4.6.3 Repeated Dose Toxicity 9. One of the main objectives of any repeated dose study with a duration of administration of normally at least 28 days is to obtain a value for the No Observed Adverse Effect level ( NOAEL), or the Lowest Observed Adverse Effect level ( LOAEL), based on which the estimated effect level of concern for humans will be considered. The NOAEL could also be used in identifying chemicals which could be candidates for further testing. The NOAEL is considered to be the highest daily dose or concentration of a substance at which there is no adverse alteration observed in the morphology, functional capacity, growth, development, etc. of the target. The LOAEL, on the other hand, is considered to be the lowest daily dose or concentration of a substance at which any of these adverse alterations is actually observed. In general, greater confidence for establishing an estimated effect level of concern is placed in a NOAEL than in a LOAEL; in a NOAEL obtained from a sub chronic study rather than one from a sub acute study; in a test which demonstrates a clear dose response relationship; and in a test in which the manifestations of toxicity are well defined. In principle, a NOAEL should be obtained in each repeated dose study and can be used as a marker for human effects. However, when a reliable dose response relationship is obtained, and a NOAEL cannot be estimated, a LOAEL could be used for this purpose.

10. As an alternative to this " classical" NOAEL approach, where feasible the so called " bench mark dose" approach could also be adopted. However, as this latter system uses the lower confidence limit of the dose corresponding to the lowest increase judged to be toxicologically significant in the incidence of an effect, and calculated on the basis of at least two dose levels showing an effect, it is anticipated that the number of repeated dose studies where adequate quantal or continuous information is available will be limited.

11. For the initial assessment of repeated dose toxicity, it might be useful to consider each route of potential human exposure ( oral, inhalation, dermal) separately assuming equal absorption rates when no specific data on actual absorption are available. If it is expected that exposure via several routes will occur, the total dose from all these routes should preferably be considered. EXCH\ MANUAL\ 96 4 6. DOC/ May 1996 3 12. What is considered to be an adverse effect is dependent on expert judgement. In those cases where an adverse effect is observed in, for example, a parameter which monitors an organ system, such as a clinical biochemical change in a measurement of liver function, more weight can be attributed to its significance if other observations for that organ system, such as necropsy findings and to a lesser extent organ weight difference, also indicate an adverse effect. In addition, the dose response of an adverse effect, i. e. the progression of a change in an organ system with the dose, is a factor which adds weight to the significance of the effect. Further aspects which are usually considered include: reversibility of the toxicity, severity of the effect, latency of the onset of the effect and the shape of the dose response curve.

13. For the screening of chemicals, the initial assessment can be conducted using an Estimated Human Exposure ( EHE) level and the N( L) OAEL. The EHE can be obtained by using the approaches described in the Provisional Guidance for the Initial Assessment of Environmental Exposure and of Occupational and Consumer Exposure ( see Section 4.3 and 4.4). If the EHE is larger than or equal to the N( L) OAEL, a hazard may exist and further testing or other activities should be considered. If the EHE is smaller than the N( L) OAEL, the magnitude of the N( L) OAEL/ EHE ratio, called " margin of safety", needs to be considered taking account of the following parameters:

· Difference in exposure ( route, duration, frequency and pattern) · The nature and severity of the effect · The dose ( concentration) response ( effect) relationship observed · The inter and intraspecies variability · The overall confidence in the database Expert judgement is required to weigh these individual parameters on a case by case basis.

14. As mentioned above, Uncertainty Factors ( UF's) have traditionally been used for initial assessment of repeateddose toxicity ( see Annex 1). To a large extent, both approaches can be considered equivalent in that they reflect the confidence of the assessor in the quality and relevance of the database for a particular endpoint. The approach used should be transparent and a justification should be provided by the assessor for the conclusion reached.

4.6.4 Genetic Toxicity 15. Testing for genetic toxicity is conducted so that chemicals may be assessed for their potential to cause transmissible damage to the genetic material of somatic cells ( with potential carcinogenic consequences) and germ cells ( which may result in heritable damage to the offspring). Unlike most other toxicological effects, genotoxic effects in vivo are generally assumed to have no exposure threshold. Thus an important factor to be taken into account when thinking about further testing and/ or risk reduction is whether or not human exposure occurs or may occur and, if so, which and how many humans are ( potentially) exposed and the circumstances of any such exposures rather than the levels.

16. It is also essential to differentiate between the in vitro tests which are primarily used to investigate intrinsic potential of chemicals to cause genetic damage and the in vivo tests which are often used to investigate if these intrinsic properties are expressed in whole animals, to confirm negative in vitro results and to study effects of metabolites. Where an in vivo study is not available it should be considered whether the activation system used in in vitro is adequate.

17. For the initial assessment, results of at least two tests for genetic toxicity will generally be provided in the SIDS. These are expected to include results of a point mutation test [ e. g. an in vitro Salmonella typhimurium, Reverse Mutation Assay, OECD Test Guideline ( TG 471)] and a chromosomal aberration test [ e. g. an in vitro Mammalian Cytogenetic Test ( TG 473) or an in vivo Micronucleus Test ( TG 474)].

18. Various different approaches are available to assist with the initial assessment of genetic toxicity ( see Tables 1, 2 and 3 for guidance proposed by the OECD, Japan and the EU respectively). The OECD approach ( Table 1) is the only one to consider the scenario where one of the two initial assessment tests is an in vivo study for clastogenicity. A somewhat more simplified approach, recommended by Japan, is summarised in Table 2. In some cases, the results of more than the two initial tests, even standardised in vitro or in vivo germ cell tests, may be available. The general approach, as recommended by the European Commission to be used for initial assessment based on the various patterns of results, is summarised in Table 3.

4.6.5 Reproduction/ Developmental Toxicity EXCH\ MANUAL\ 96 4 6. DOC/ May 1996 4 19. Reproduction toxicity represents any effect on fertility and reproduction that can adversely affect the continuation of the species. Developmental toxicity is any adverse effect induced during the developmental period, i. e. from conception through puberty. The major manifestations of developmental toxicity include death of the developing organism, structural abnormalities, altered growth and functional deficiencies. Developmental toxicity can be considered a component of reproductive toxicity, and often it is difficult to distinguish between effects mediated through the parents versus direct interaction with developmental processes.

20. Because of the nature of the observations and variety of classes of reproduction/ developmental toxicity, the following paragraphs describe in slightly more detail suggestions for the initial assessment of these studies. The organisation of the information for an assessment of reproduction and developmental toxicity is described in a number of OECD Test Guidelines related to these endpoints ( TG 414, 415, 416) and the guidelines for the Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test ( TG 422) and the Reproduction/ Developmental Toxicity Screening Test ( TG 421). For example, toxic response data should be considered by sex and dose and, when possible, be sub divided into reproductive and developmental effects. Reproduction effects would include, inter alia, altered fertility indices for males and females, effects on mating performance or other factors affecting reproductive function and, when related to the nursing capacity of the females, postnatal viability indices for the offspring or other postnatal signs of toxicity. Developmental effects, either as a consequence of maternal toxicity or as a direct effect on the developing organism, would include, inter alia, decreased numbers and percentages of live offspring per litter, and increased numbers and percentage of affected offspring ( male, female or combined) per litter. Data on maternal toxicity and on certain metabolic or kinetic observations need to be considered when determining the nature, severity and relevance of developmental toxicity.

21. Reproductive and developmental effects exhibit dose response relationships, and where these effects are not genotoxic ( e. g. heritable) thresholds are generally assumed to exist. It is thus possible to estimate exposure levels unlikely to produce effects in humans on the basis of a NOAEL obtained in an animal experiment, in a similar manner to that for repeated dose toxicity.

22. The occurrence of a dose level producing well defined toxicity is considered of crucial importance in reproductive toxicity studies. This is called for in the OECD Test Guidelines for both screening tests, 421 and 422. Tests in which toxicity is not observed should, therefore, not be considered as adequate tests unless the limit concentration of 1000 mg/ kg has been included.

23. In addition, useful information can be derived from the repeated dose toxicity study, e. g. pathology in the reproductive organs, if specific histological examination has been carried out and a comparison of dose response curves for such an effect between males and females could be made both in the repeated dose toxicity and the reproduction toxicity study.

24. For the reproduction toxicity endpoint:

· when a 90 day repeated dose study is available and is sufficiently documented with respect to studying effects in the reproductive organs and a developmental study is available, the requirements for the reproduction toxicity endpoint would be satisfied;

· when either a 90 day or 28 day repeated dose study is the only repeated dose study available, it is recommended that the reproduction/ developmental toxicity screening test ( e. g. TG 421) be carried out in order to satisfy the requirements for the reproduction toxicity endpoint; and · when a 90 day repeated dose study is available and demonstrates no effects on the reproductive organs, in particular the testes, then a developmental study ( e. g. TG 414) can be considered as an adequate test to complete information on reproduction/ developmental effect.

25. In the similar way to repeated dose toxicity, the " margin of safety" approach could be used for the initial assessment instead of using Uncertainty Factors ( UF's). Guidance for the use of UF's is described in Annex 1 to this document.

26. When considering the " margin of safety" for reproduction/ developmental toxicity, its magnitude can be compared to that of repeated dose toxicity. A relatively high " margin of safety" may be acceptable when severe or EXCH\ MANUAL\ 96 4 6. DOC/ May 1996 5 irreversible developmental effects occur at exposure levels below those that induce well defined parental toxicity; in other words when the test substance produces severe developmental effects that are not secondary to general toxicity. The same level of " margin of safety" may be acceptable when developmental toxicity is only observed at exposure levels that are also toxic to the parent animals. The same considerations for the repeated dose study should be addressed when considering " margin of safety" for reproductive/ developmental toxicity. An assessment of whether the effects seen in reproduction toxicity studies are secondary to general toxicity, or are specific reproductive effects, is important and expert judgement is necessary.

27. This concept of considering higher " margin of safety" for developmental effects when they occur in the absence of maternal toxicity than when observed at levels that are also toxic to the parent animals is generally accepted. However, individual Member countries may consider developmental toxicity in the presence of maternal toxicity of as great a concern as developmental toxicity seen in its absence.

4.6.6 Suggestions for Follow up Testing Repeated Dose Toxicity 28. If the estimated exposure level ( EHE) for a specific human population is larger than or close to the estimated effect level of concern calculated from a 28 day repeated dose study, a 90 day subchronic toxicity test ( TG 408, 411 or 413) could be conducted, depending on reliability of the exposure estimation. Information on exposure should be considered in detail before deciding if this is needed. In the subchronic toxicity test, a more detailed examination of effects observed in a 28 day study would be important. If the effects found in a 28 day repeated dose toxicity test are reason for concern, and substantial long term exposure is expected to occur, it might be more effective to consider undertaking a longer toxicity test with an exposure duration of at least six months. If there is sufficient justification for a study for " conventional" ( i. e. noncarcinogenic toxic effects of longer duration than 90 days, then it should be combined with a carcinogenicity bioassay. EXCH\ MANUAL\ 96 4 6. DOC/ May 1996 6 Reproduction/ Developmental Toxicity 29. If EHE is larger than or close to the estimated effect level of concern derived from reproduction/ developmental toxicity studies at a screening level, a One or Two Generation Reproduction Toxicity test ( TG 415 or 416), which could include peri and postnatal administration and/ or a Developmental Toxicity test ( TG 414), could be considered depending on the reliability of the dose response curve and the type of toxic effects seen. Follow up studies which are tailored to address a specific concern might also be appropriate. For example, foetal or birth weight reduction is often the only indicator of possible developmental toxicity and could be followed up in cases of concern by studies to evaluate postnatal viability, growth and survival through weaning. Studies in a second species might also be useful.

30. When deciding to conduct a follow up reproduction/ developmental toxicity study, information on exposure has to be taken into consideration. For example, for substances which have only been tested in a reproductive screening test ( e. g. TG 421 or 422) and substantial, widespread and/ or prolonged exposure is anticipated, serious consideration should be given to conducting definitive reproduction toxicity tests ( i. e. TG 415/ 416 and 414). Also SARs may be taken into account when considering further testing.

31. For both repeated dose and reproduction/ developmental toxicity, when more than one route is of concern, the route giving the greatest reason for concern could be chosen for a follow up test. Similarly, if the concern is for more than one observed effect, then any follow up test could be tailored to study that effect having the greatest concern. EXCH\ MANUAL\ 96 4 6. DOC/ May 1996 7 Table 1 OECD Proposals for the Initial Assessment for Genetic Toxicity Point mutation test in vitro Chromosomal aberration test in vivo Chromosomal aberration test Second in vivo test Action A Negative Negative No need for further testing B Negative Positive Positive Negative Positive Negative Candidate for in depth review Candidate for in depth review No need for further testing C Positive Positive Candidate for in depth review D Positive Negative Positive Negative Positive Negative Candidate for in depth review Candidate for in depth review No need for further testing E Negative Negative No need for further testing F Negative Positive Candidate for in depth review G Positive Positive Candidate for in depth review H Positive Negative Positive Negative Candidate for in depth review No need for further testing Note: This table assumes that the results from a point mutation ( e. g. Ames type) test, and an in vitro ( A to D) or an in vivo ( E to H) chromosomal aberration test, are available. The arrows indicate the proposed sequence of actions following these results. EXCH\ MANUAL\ 96 4 6. DOC/ May 1996 8 Table 2 Proposal by Japan for Initial Assessment of Genetic Toxicity Point mutation test in vitro chromosomal aberration test in vivo cytogenetic test Second* in vivo test Action  ve  ve No need for follow up test + ve + ve  ve + ve  ve + ve + ve  ve + ve  ve Candidate for risk reduction Candidate for risk reduction Candidate for risk reduction No need for follow up test * In vivo liver UDS test, mouse spot test, or gene mutation test with transgenic animals.

Note: Negative in both point mutation test and in vitro chromosomal aberration test does not need for followup test. While, chemicals that give positive results in both in vitro tests are candidates for risk reduction. Essentially any in vivo positive indicates the need for risk reduction activity. In order to negate positive in vitro data in vivo negative information from at least two different tissues will be needed.

Any positive in vivo ( also both in vitro positive) data might be negated by the negative data of in vivo germ cell test ( e. g. dominant lethal test or germ cell cytogenetic test) and also the negative data of long term carcinogenicity test. EXCH\ MANUAL\ 96 4 6. DOC/ May 1996 9 Table 3 Proposal by the European Commission for Initial Assessment of Genetic Toxicity · in vivo germ cell positive:

No further testing. Control measures necessary. Further information on exposure may be required to assess possibility of risk by reducing exposure.

· in vivo somatic cell positive:

Control measures as above. Consider testing for germ cell effects if not already done to an adequate standard.

· in vitro positive:

One somatic cell test in vivo conducted and negative:

Consider control measures. A second test should be conducted in vivo using a different somatic target tissue from the first.

· in vitro positive but no testing yet in vivo:

Consider control measures. Test in vivo in somatic cells, usually bone marrow.

· in vitro negative ( two adequate tests):

Consider further testing in relation to potential for human exposure, e. g. where there may be widespread consumer exposure to significant amounts of a substance, a third test, preferably, in vitro, may be considered necessary for added assurance. Structure Activity Relationships ( SAR) may be of use.

Note 1: The suggested approach is based on the assumption that any positive in vitro result should be tested in vivo. Also that when a chemical gives a positive result in somatic cells in vivo, there is no need for further testing for somatic cell effects in vivo, but testing for potential germ cell effects should be considered, and the chemical should be regarded as a potential human carcinogen.

Note 2: In order to " negate" positive in vitro data, in vivo data from at least two different tissues will be needed. A negative result in the first tissue ( invariably the bone marrow) will not ( under any circumstance that we can envisage) be adequate. EXCH\ MANUAL\ 96 4 6. DOC/ May 1996 10 Annex 1 Guidance for the Use of Uncertainty Factors Introduction 1. In the context of initial assessments, the Estimated Dose of Low Concern ( EDLC) on repeated dose toxicity and reproduction/ developmental toxicity can be derived by dividing a N( L) OAEL by an Uncertainty Factor ( UF) and compared to the Estimated Human Exposure ( EHE).

2. Uncertainty Factors ( UF's) mentioned in this Annex are used in the context of being equivalent to " safety factors", " assessment factors", etc., which are generally applied to results from animal experiments to increase the confidence that recommended exposure concentrations for humans, if realised, do not lead to adverse effects in the majority of people exposed. Thus, in general, the more relevant the available animal data are to the human situation, e. g. if the same exposure route is anticipated, the smaller the UF. These UF's are only guidance values for use in assessing consumer/ general public exposure. They are not intended for occupational exposure for which lower values may be appropriate.

3. UF's will not be used in the OECD context; however, the approach can be used for any considerations at a national level.

Uncertainty Factors for Repeated Dose Toxicity 4. Traditionally, factors of, for example, 10 x 10 for inter and intra species variations have been used. Intraspecies variation refers to the differences in sensitivity within the same species ( e. g. differences due to age), while interspecies variation refers to the differences in sensitivity between humans and animals. This has been a workable approach to deal with the uncertainties inherent in the extrapolation process, and is often based on the NOAEL from a study with an exposure duration of at least 90 days. However, the reliance on such pre determined values may be misleading in terms of the confidence placed in the test results. UF's are guidance values only, and consideration should be given to increasing or decreasing their value on a case by case basis depending on the confidence that can be placed in the value of NOAEL. Factors affecting this confidence are the duration of the study, the dose response relationships, the nature of the effects observed, the spacing between the doses, the quality of the toxicity data, and the type and severity of toxic effects observed. In one Member country, based on a 28 day test, in addition to an UF of 100, a factor of 10 is used to extrapolate to 90 day studies and an additional factor of 10 to extrapolate from such studies to long term studies.

5. The following ranges UF's are suggested for guidance when applied to the:

· NOAEL: 100 300/ 500 · LOAEL: 500 1500/ 2500 These UF's cover the values generally used in Member countries, which might also include the value for the consideration of the worst case. It should be realised that UF's are always arbitrarily chosen and are not supported by strong scientific evidence. EXCH\ MANUAL\ 96 4 6. DOC/ May 1996 11 Uncertainty Factors for Reproduction/ Developmental Toxicity 6. UF's which are suggested to obtain an EDLC for reproduction/ developmental toxicity may be different from those for repeated dose toxicity. The use of a relatively high UF is suggested when severe or irreversible developmental effects occur at exposure levels below those that induce well defined parental toxicity, in other words when the test substance produces severe developmental effects that are not secondary to general toxicity. The same UF may be applied when developmental toxicity is only observed at exposure levels that are also toxic to the parent animals. The same considerations that went into the selection of the UF for the repeated dose study should be addressed when selecting the UF for allocating an EDLC for reproductive/ developmental toxicity. An assessment of whether the effects seen in reproduction toxicity studies are secondary to general toxicity, or are specific reproductive effects, is important and expert judgement is necessary.

7. As in the case of repeated dose toxicity, an additional uncertain factor of 5 is suggested when a NOAEL cannot be obtained in the study and a LOAEL has to be used. Depending on the nature of the effects, the dose response relationship and the spacing between the doses in the study, an even higher factor might be used.

8. UF ranges which are suggested as guidance for the NOAEL are:

a) parental toxicity, impaired fertility and reproduction toxicity 100 300/ 500 b) NOAEL for developmental effects lower than the NOAEL for maternal toxicity 1000 3000/ 5000 c) NOAEL for developmental effects higher than, or equal to, the NOAEL for maternal toxicity 100 300/ 500 9. Again, they cover the values generally used in Member countries, which might also include the value for the worst case analysis. As stated for the UF's for repeated dose toxicity, it should be realised, however, that UF's are always arbitrarily chosen and although this approach has been used for many years it is not supported by strong scientific evidence .

10. This concept of using more stringent UF's for developmental effects when they occur in the absence of maternal toxicity than when observed at levels that are also toxic to the parent animals is generally accepted. However, individual Member countries may consider developmental toxicity in the presence of maternal toxicity of as great a concern as developmental toxicity seen in its absence. EXCH\ MANUAL\ 96 4 6. DOC/ May 1996 12 Annex 2 References 1. Relevant Monographs of the IPCS · Environmental Health Criteria document ( EHC) No. 6, Principles and Methods for Evaluating the Toxicity of Chemicals, 1978.

· Environmental Health Criteria document ( EHC) No. 70, Principles for the Safety Assessment of Food Additives and Contaminants in Food, 1987.

· Environmental Health Criteria document ( EHC) No. 104, Principles for the Toxicological Assessment of Pesticide Residues in Food, 1990.

· Environmental Health Criteria document ( EHC) No. 170, Assessing Human Health Risks of Chemicals: Derivation of Guidance for Health based Exposure Limit, 1994 2. Reference for " margin of safety" approach · Technical Guidance Documents in Support of the Commission Directive 93/ 67/ EEC on Risk Assessment for New Substances and the Commission Regulation ( EC) N O 1488/ 94 on Risk Assessment for Existing Substances, European Commission ( in print)

3. Reference for Uncertainty Factors · V. J. Feron, P. J. van Bladeren and R. J. J. Hermus, A Viewpoint on the Extrapolation of Toxicological Data from Animals to Man, Fd Chem Tox, Vol 28, No. 11, 783 789, 1990. EXCH\ MANUAL\ 96 5. DOC/ May 1996 1 5. OVERVIEW OF THE POST SIDS WORK*

Initial Assessment 1. In the various phases of the SID programme, information collected on chemicals is collated into SIDS Dossiers and reviewed by Member countries during the SIDS review process. As necessary, SIDS testing and/ or additional data gathering is recommended to complete the SIDS, thus enabling the chemical to have a full SIDS data package. Based on a full SIDS data, the SIDS Initial Assessment Report with any recommendations on future work or action as appropriate is developed by the Sponsor country and discussed at the SIDS Initial Assessment Meeting ( SIAM).

2. Based on an initial assessment of the effects and exposure data provided in the SIDS Dossier, each chemical can be described in light of the potential it presents for risk to man and/ or the environment ( including the extent of exposure and current risk reduction measures) and of the need for further work or action ( e. g. post SIDS testing, exposure analysis, indepth risk assessment, further risk management action). Given the various possible combinations, conclusions and recommendations could be written, for example, as follows:

( a) The chemical can be considered to present a low potential for risk to man and the environment. Thus, there is no current priority for undertaking post SIDS testing and/ or exposure analysis or an in depth assessment;

( b) The chemical may present a potential for risk to man and/ or the environment. Thus, there is a priority for undertaking post SIDS testing and/ or exposure analysis and/ or an in depth assessment to clarify the nature or extent of the potential risk;

( c) The chemical presents a potential for risk to man and/ or the environment. However, risk reduction measures currently in place in Member countries are considered adequate to control the risk. Thus, there is no current priority for further risk management action;

( d) The chemical presents a potential for risk to man and/ or the environment. Due to the exposure and/ or lack of current risk reduction measures, risk management actions might be necessary. These could range, as appropriate, from responsible care activities by the chemical industry to national or international risk reduction activities;

( e) Etc.

3. These conclusions and recommendations agreed at the SIAM are confirmed at the Steering Group on Existing Chemicals, and subsequently by the Joint Meeting.

4. Any further work mentioned in the example 2( b) will be considered as post SIDS work. As in depth risk assessment is normally undertaken under the auspices of IPCS, the following description will only cover other work, e. g. post SIDS testing, detailed exposure analysis.

Post SIDS Work 5. Post SIDS work is undertaken in the framework of the OECD Programme on HPV Chemicals, on chemicals identified at a SIAM. In some chases, suitable analogues may be picked up at the same time. This work can encompass:

( a) data collection or generation by further testing with a view to clarifying specific effects related issues. ( b) data collection or generation and subsequent analysis of more detailed exposure aspects, e. g. exposure with respect to targets, levels, frequency, duration, etc.

6. For both the options in paragraph 5, the recommendations from the SIAM will include: