M0355008/1786Q/10/11/00

EUROPEAN COMMISSION DG ENV

Towards the establishment of a priority

list of substances for further evaluation of
their role in endocrine disruption
- preparation of a candidate list of substances
as a basis for priority setting

FINAL REPORT
(Incorporating corrigenda to final report dated 21 June 2000)

BKH Consulting Engineers, Delft, The Netherlands

in association with
TNO Nutrition and Food Research, Zeist, The Netherlands

Delft, 10 November 2000

Head Office Offices in:
P.O. Box 5094, 2600 GB Delft
The Netherlands
Tel. :+31(0)15 262 52 99 Bangladesh
Fax: +31(0)15 261 93 26 Chile, Colombia
E-mail [email protected] Kenya
Visiting address: Poortweg 10, Delft India, Sri Lanka
COLOPHON

client : European Commission DG ENV

project : Endocrine disrupting substances (man-made chemicals)
project number: M0355008
report : Towards the establishment of a priority list of substances for
further evaluation of their role in endocrine disruption:
- preparation of a candidate list of substances as a basis for priority
setting. Final report (incorporating corrigenda to final report dated
21 June 2000)
report volume : 29 pages (exclusive Annexes)
authors : Ch. Groshart, P.C. Okkerman ([email protected])
team leader : I. van der Putte
date of submission: 10 November 2000
authorisation: (I. van der Putte, team leader)
Contents Page

PREFACE............................................................................................................................................................III

ABBREVIATIONS ............................................................................................................................................. IV

EXECUTIVE SUMMARY................................................................................................................................... 1

1 INTRODUCTION ........................................................................................................................................ 5
1.1 BACKGROUND ............................................................................................................................................ 5
1.2 OBJECTIVES AND SCOPE OF THE CURRENT PROJECT .................................................................................... 6
2 PROJECT APPROACH.............................................................................................................................. 7
2.1 STEP 1: REVIEW OF EXISTING LISTS AND OTHER SOURCES OF INFORMATION .............................................. 9
2.1.1 Inventory of lists and literature ......................................................................................................... 9
2.1.2 Development of a database on endocrine disruption ........................................................................ 9
2.2 STEP 2: SELECTION OF HIGHLY PERSISTENT AND/OR HPV SUBSTANCES................................................... 10
2.3 STEP 3: PRELIMINARY EVALUATION OF SCIENTIFIC EVIDENCE OF ED-RELATED EFFECTS ......................... 11
2.4 STEP 4: PRELIMINARY EVALUATION OF EXPOSURE TO HUMANS AND WILDLIFE ........................................ 12
2.4.1 Literature research and processing of data .................................................................................... 13
3 RESULTS.................................................................................................................................................... 14
3.1 WORKING LIST OF SUBSTANCES ................................................................................................................ 14
3.2 FIRST SELECTION: HIGH PRODUCTION VOLUME CHEMICALS AND PERSISTENT CHEMICALS ....................... 15
3.3 SECOND SELECTION: EVIDENCE OF ENDOCRINE DISRUPTION .................................................................... 15
3.4 THIRD SELECTION: HIGH MEDIUM OR LOW EXPOSURE CONCERN .............................................................. 17
4. CONCLUSIONS AND RECOMMENDATIONS ................................................................................... 25
4.1 CONCLUSIONS........................................................................................................................................... 25
4.2 RECOMMENDATIONS................................................................................................................................. 28
5 REFERENCES ........................................................................................................................................... 29

I
CONTENTS OF ANNEXES

Annex 1 Candidate list of 553 substances

Annex 2 Background documents

Annex 3 Contacted organisations

Annex 4 Framework of the database

Annex 5 Effect parameters included in the database

Annex 6 List of 146 substances evaluated in the Expert meeting

Annex 7 Human health and wildlife relevant data on endocrine disruption included in the database
on the 146 substances evaluated in the Expert meeting

Annex 8 Human health and wildlife relevant data on endocrine disruption included in the database
on the remaining substances.

Annex 9 Working list of 564 chemicals with their literature source

Annex 10 List of 564 substances with their selection criteria

Annex 11 References of studies and reports on endocrine disruption incorporated in the database

Annex 12 Scientific evidence used in the Expert meeting for the evaluation of the 146 selected
substances

Annex 13 List of 146 substances with endocrine disruption categorisations prepared in the Expert
meeting

Annex 14 Summary profiles of chemicals with information on use, production, emission,

monitoring and legal status

Annex 15 List of 66 substances with categorisation high, medium or low exposure concern

II
PREFACE

BKH Consulting Engineers (Delft, the Netherlands) has been commissioned by the European
Commission by letter of 1 February 1999 to conduct a study on endocrine disruption
focusing on man-made chemicals. This is a first step towards the establishment, by the
Commission, of a priority list of substances for further evaluation of their role in endocrine
disruption. Project co-ordinators for the EC are Mrs K. Tierney, Dr H. Nover and Mr D.
Klein. The project was carried out in association with TNO Nutrition and Food Research
Institute (Zeist, the Netherlands). The project team included Mrs C.P. Groshart, Mr P.C.
Okkerman, Mrs G.J. Folkers-Gerritsen, Mr W.B.A. Wassenberg (BKH), Dr R.F. Witkamp,
Dr E.M. de Groene, and Dr C.J.M. Arts (TNO). Project co-ordinator for BKH is Dr I. van
der Putte. A stakeholder meeting with representatives from government, NGOs and
industry, was held on the 27th May 1999. A meeting with experts in the field of endocrine
disruption was held on 27th and 28th September 1999.
It should be noted that the results of this study will be used as a basis for consultation by the
Commission. This consultation process constitutes the second step in the establishment of a
priority list of substances for further evaluation of their role in endocrine disruption, as
outlined in the Commission Communication to Council and European Parliament on a
Community Strategy for Endocrine Disrupters (COM (1999)706).
ABBREVIATIONS

AHH Aryl Hydrocarbon Hydroxylase

BUA Bundes Umwelt Amt (Germany)
CAS Chemical Abstract Service
CEFIC European Chemical Industry Council
ED Endocrine disrupting
EPA Environmental Protection Agency
HPV High Production Volume
IUCLID International Uniform Chemical Information Database
NGO Non-Governmental Organisation
QSAR Quantitative Structure Activity Relationship
RIVM National Institute of Public Health and the Environment, The Netherlands
RIZA/RIKZ Institute for Inland Water- and Wastewater management / Institute for Coastal
and Marine Management, The Netherlands
SMILES Simplified Molecular Input Line Entry System (a code for the Structure of the
Chemical)
WHO World Health Organisation
DES Diethylstilbestrol

IV
EXECUTIVE SUMMARY

In recent years effects have been reported in animal species and human beings that are
attributed to the influence of certain substances on hormonal systems.
As announced in the Communication from the Commission to the Council and the European
Parliament on a Community Strategy for Endocrine Disrupters (COM(1999)706 final), a
priority list of substances is to be established to further evaluate their role in endocrine
disruption. The objective of the present study is to prepare a candidate list of substances, on
the basis of available information for specific selection criteria, which can be used in this
priority-setting exercise.

The following steps have been taken in the study:

STEP DESCRIPTION RESULTS

1. Review of existing lists and other sources of 564 substances

information

2. Selection of highly persistent and/or HPV 146 substances

substances

3. Preliminary evaluation of scientific evidence 66 substances

of ED-related effects (35 clustered substances)

4. Preliminary evaluation of exposure to humans 60 substances

and wildlife (29 clustered substances)

In Figure I the project approach and its outcome are presented schematically.

The starting point of the study is a working list, compiled from the lists of suspected
endocrine disrupting chemicals drawn up by various organisations as well as from an up-to-
date literature search. The working list was presented and discussed at a stakeholder meeting
with representatives of government, industry and NGOs.
For the working list consisting of 564 substances scientific evidence on endocrine disruption
was gathered. A further analysis was made for a number of 146 High Production Volume
chemicals and/or highly persistent substances.
A panel of experts in the field of endocrine disrupting effects of substances on human health
and wildlife categorised these 146 substances on the basis of the available evidence into
three categories:

Category 1. At least one study providing evidence of endocrine disruption in an

intact organism. Not a formal weight of evidence approach.

Category 2. Potential for endocrine disruption. In vitro data indicating potential for
endocrine disruption in intact organisms. Also includes effects in-vivo
that may, or may not, be ED-mediated. May include structural analyses
and metabolic considerations

Category 3. No scientific basis for inclusion in list or no data1

1
Category 3 also consisted of substances with insufficient data.

1
The outcome of the expert meeting was that on the basis on available data on endocrine
disruption, 66 substances are to be categorised into category 1, 51 substances into category 2
and 29 in category 3. The category 3 substances included 18 substances with no or
insufficient data and 11 substances that had scientific evidence for exclusion from the
working list of 564 chemicals.

For a further categorisation of category 1 into substances having high, medium and low
exposure-concern summary profiles were prepared with physico chemical properties,
production, emissions, use, exposure and monitoring data. Special attention was given to
possible exposure of vulnerable groups.

The following guidelines were used:

High exposure concern Human exposure is expected, due to environmental
concentrations and those in food or consumer products, also
taking into consideration exposure of vulnerable groups
And/Or
Wildlife exposure is expected, due to use and emission
patterns, and the chemical is persistent and bioaccumulative

Medium exposure concern Human exposure is not expected

And
Wildlife exposure is expected, due to use and emission
patterns, but the chemical is readily biodegradable and not
bioaccumulative

Low exposure concern No human exposure

And
No wildlife exposure

After a detailed evaluation 60 (29 chemical groups) of the 66 chemicals (35 chemical
groups) in category 1 are considered as substances having high exposure concern and
evidence on endocrine disruption. This group of 60 substances includes substances such as
DDT, PCBs, organo-tins and dioxins as well as chemicals such as styrene, phthalates and
some pesticides.

A number of 11 substances have been excluded from the initial working list of 564
substances because there was no scientific basis for inclusion in the list. The candidate list
consists therefore of 553 substances sorted into three groups, as shown in Table I.

The list is also open to change. As new information becomes available, chemicals may either
be removed from or added to the list.
.

2
Figure I Schematic overview of the project steps and theresults

Inventory
STEP 1

Working list
564

STEP 2 Selection on HPV and/or highly

persistence

HPV and/or Highly Not HPV and not highly No data on

persistent persistent persistence
146 213 205
Group III Group III

STEP 3 Evaluation of ED-related effects

Evidence of Potential evidence No scientific basis for

endocrine effects of endocrine in inclusion in list or
66 effects no data
51 29
Group II

No data Excluded from

working list
18 11
Evaluation of exposure
STEP 4 concern to human and wildlife Group III

High exposure Medium exposure Low exposure

concern concern concern
60 4 2
Group I Group II Group III

3
Table I. List of candidate substances summary of work to date

GROUP I
Selection criteria Number of substances Listing

Highly At least one study High concern in 60 See Annex 1.

persistent showing endocrine terms of human (29 chemical groups)
disruption in an and wildlife
And/or intact organism exposure
(Category 1)
HPV

GROUP II
Selection criteria Number of substances Listing

At least one study Medium 4 See Annex 1.

showing endocrine concern in
Highly disruption in an terms of human
persistent intact organism and wildlife
(Category 1) exposure
And/or

HPV Potential for endocrine disruption 51

(Category 2)

GROUP III
Selection criteria Number of substances Listing

Highly At least one study Low concern in 2 See Annex 1.

persistent showing endocrine terms of human
disruption in an and wildlife
And/or intact organism exposure
(Category 1)
HPV

No sufficient data (Category 3) 18*

Not HPV and not highly persistent 213

Not HPV and no data on persistence 205**

* Excluding 11 Substances that have been excluded from the candidate list because of data giving
no basis for inclusion in the list (Category 3)
** No Smiles notations were readily available for QSAR estimations on persistence.

4
1 INTRODUCTION

1.1 Background

Since the outcome of the book Our stolen future (Colborn, et al, 1996) and the BBC
documentary Assault on the Male (Deboray Cadbury) the health effects of many man-
made chemicals are again in the centre of interest. There is growing public concern about a
range of man-made chemicals, which are suspected of interfering with the endocrine systems
of both humans and wildlife, so-called endocrine disrupters. Possible adverse effects of
endocrine disrupters include cancers, behavioural changes and reproductive abnormalities.
The effects of endocrine disrupters are the greatest during foetal development and in
juveniles. Effects on reproduction and the immune system have been reported for fish,
alligators, seals and birds.

The threat of impairment of human reproductive function and the impact on health and
reproduction of wildlife as a result of exposure to endocrine-active substances in the diet and
in the environment is a topic receiving increasing attention. During the last years, numerous
studies have been performed, reviewing the health impact of "endocrine" disrupters. There is
conclusive evidence for effects on wildlife, but the evidence for effects on humans are
varying and sometimes contradictory. It is still unclear whether the presence of
environmental pollutants could lead to actual exposure of the human population to such an
extent that human reproductive function could be adversely affected. To address the concern
of the public, in December (2-4) 1996 a European workshop on Endocrine-disrupters was
held by the European commission (DG XII), the European Environmental Agency, the
European Centre for Environment and Health and the World Health Organisation with
scientists and policy-makers from all over the world. The result of this workshop was that
there is a call for action to reduce uncertainties and risks concerning reproductive health due
to endocrine disrupters.

Various organisations have published lists of suspected endocrine-disrupters. It was decided

to conduct a more in depth investigation into such lists in order to ascertain and assess the
reliability of the selection criteria used to establish the lists and to include information on the
sources, uses of such chemicals and the pathways in human and wildlife exposure. In
December 1999 a Communication from the Commission to the Council and the European
Parliament on a Community Strategy for Endocrine Disrupters (COM(1999)706 final) was
published. As announced in the Communication this study serves as a first step in
establishing a priority list of substances for further evaluation of their role in endocrine
disruption.

The priority list will be used, inter-alia,

- to identify substances for priority testing once agreed test methods become available,
- to identify substances which can be, or are already being addressed, under existing
Community legislation covering hazard identification, risk assessment and risk
management,
- to identify gaps in knowledge on aspects such as dose/response relationships,
sources/pathways of exposure and epidemiological studies of cause/effect relationships
which will help guide further research and/or monitoring efforts, and
- to identify specific cases of consumer use, for example, the case of potentially more
vulnerable groups of consumers such as children, for special consideration from a
consumer policy point of view.

5
1.2 Objectives and scope of the current project

The objectives of the study are:

1 to identify selection criteria and produce a working list of substances associated with endocrine
disruption;
2 to quantify the production volumes and to identify the sources/uses and pathways of human
and wildlife exposure for these chemicals;
3 to prepare a candidate list grouped according to available information on selection criteria.

The following working definitions of endocrine disrupters or suspected endocrine disrupters

served as a basis for the project:
- An endocrine disrupter is an exogenous substance or mixture that alters function(s) of the
endocrine system, and consequently, causes adverse health effects in an intact organism, or its
progeny, or (sub)populations (IPCS);

- A potential endocrine disrupter is an exogenous substance or mixture that possesses properties

that might be expected to lead to endocrine disruption in an intact organism, or its progeny, or
(sub)populations (IPCS).

Two classes of endocrine disrupters can be distinguished:

1 'Natural' hormones which include oestrogen, progesterone and testosterone found naturally in
the body of humans and animals, and phytoestrogens, substances contained in some plants
such as alfalfa sprouts and Soya beans which display oestrogen-like activity when ingested by
the body;
2 Man-made substances which include

- Synthetically-produced hormones, including those hormones which are identical to natural

hormones, such as oral contraceptives, hormone replacement treatment and some animal
feed additives, which have been designed intentionally to interfere with and modulate the
endocrine system; and
- Man-made chemicals designed for uses in industry such as in some industrial cleaning
agents, in agriculture such as in some pesticides, and in consumer goods such as in some
plastic additives. It also includes chemicals produced as a by-product of industrial processes
such as dioxins, which are suspected of interfering with the endocrine systems of humans
and wildlife.

The present project is focused on man-made chemicals.

6
2 PROJECT APPROACH

The project was carried out in four steps as shown in Table 2.1.
The first step in the project was the creation of a working list of substances associated with
endocrine disruption. This working list was compiled from lists of suspected endocrine
disrupters from different organisations and countries as well as from an up-to-date literature
search. Three further steps were followed applying different selection criteria and expert
evaluations.
- A first selection was made after consultation of stakeholders applying criteria on production
volume and persistence.
- A second selection was made after consultation of experts in the field of endocrine
disruption. Substances were selected on the basis of scientific evidence.
- The third and last selection was based on criteria related to exposure of vulnerable groups,
environmental behaviour and monitoring data.

Table 2.1 Project steps

STEP DESCRIPTION

1. Review of existing lists and other sources of information

2. Selection of highly persistent and/or HPV substances

3. Preliminary evaluation of scientific evidence of ED-related effects

4. Preliminary evaluation of exposure to humans and wildlife

In Figure 2.1 the project steps are presented schematically.

7
Figure 2.1 Schematic overview of the project steps

Inventory
STEP 1

Working list

STEP 2 Selection on HPV and/or highly

persistence

HPV and/or Highly Not HPV and not highly No data on

persistent persistent persistence

Group III Group III

STEP 3 Evaluation of ED-related effects

Evidence of Potential evidence No scientific basis for

endocrine effects of endocrine in inclusion in list or
effects no data

Group II

No data Excluded from

working list

Evaluation of exposure
STEP 4 concern to human and wildlife Group III

High exposure Medium exposure Low exposure

concern concern concern

Group I Group II Group III

8
2.1 Step 1: Review of existing lists and other sources of information

This step included the following activities:

- Inventory of lists and literature;
- Development of a database on endocrine disruption.;

2.1.1 Inventory of lists and literature

The inventory was carried out as follows:

a) An inventory of available lists of potential endocrine disrupters and suspected endocrine
disrupters from various organisations was made to prepare a working list. For this purpose
background documents on which these lists were based, were collected (Annex 2). In these
background documents, drawn up by governmental and non-governmental organisations, the
problem was brought to the attention of the public and the lists of suspected endocrine
disrupters were given.
Additionally substances that could potentially be associated with endocrine disruption from
the primary literature and in reviews, and that were not yet on the working list, were added.

b) The collection of literature from key experts, review documents and a literature search to
include the most recent references not covered by the review documents. In review
documents (such as WHO- EHC reports) all literature on certain chemicals is collected and
in most cases also evaluated.
Key experts from national focal points, branch organisations and non-governmental
organisations were contacted for information by email and fax. Some were contacted directly
by personal interviews. In Annex 3, an overview is given of the contacted organisations.
Background documents were used for backtracking and retrieving primary literature sources.
Review documents from WHO: Environmental Health Criteria and EU risk assessments
were collected. Furthermore databases like IUCLID, ISIS and AQUATOX were used as
sources of information.
A literature search to retrieve references, not yet covered by the review documents was
carried out for almost all chemicals in on-line databases like DIMDI-TOXCAS, TOXLINE,
TOXBIO, IPA and in Environmental ROUTENET (Internet: www.csa.com). The search was
based on the CAS number or, if not available, on the chemical name. Only chemicals such as
DDT and PCB, which were assessed in many studies, were not included in the literature
search. References retrieved from the literature search were selected on their title and the
publication years 1997 and 1998.
Primarily the data are based on the review documents, but data from original sources have
also been added and if original sources became available for the data from the review
documents, these data have been checked.

2.1.2 Development of a database on endocrine disruption

A database was developed including all substances from the working list with the available data
on endocrine disruption. The database only includes information on experiments from primary
publications or from background and review documents with sufficient experimental
information (like the background documents UBA98, SEPA98 and WHO Environmental Health
Criteria). In Annex 4, the framework of the database is given.

It should be noted that chemicals have been added to the working list on the basis of data on
endocrine disruption according to the evaluated literature. Furthermore the database contains
positive as well as negative test results: data on experiments that show evidence of endocrine
disruption related effects (positive) and data on experiments showing no evidence of endocrine
related effects (negative).

9
 The database contains references and background information on experiments with a wide range
of effects that are in some way linked to endocrine disruption. Information on human health
relevant and wildlife relevant endocrine disrupting effects were collected. Human health
relevant endocrine disrupting effects were mainly in vivo experiments with rats, mice, and
monkeys, in vitro experiments with human cancer cells and a restricted number of
epidemiological studies. Wildlife experiments were mainly in vivo laboratory and field
experiments with fish, birds, amphibians, insects, crustaceans and molluscs. The main effects
included are effects on reproduction, reproductive organs, hormone levels and fertility cycles.
Additionally information was included on experiments testing effect parameters like thyroid and
pituitary hormone levels, effects on hatching and development of offspring and the influence of
Ca-metabolism on eggshell thinning. In Annex 5, an overview is given of the identified
endocrine disruption related effect parameters, included in the database.

It should be emphasised that descriptions of the working mechanisms of these effects are, in
most cases, not available. Furthermore, there is a clear difference in the extent and the
seriousness of the effect, which, in most cases, can only be made evident by relating it to a
substance like DES or estradiol, for which the seriousness of the effects are more clear.
Moreover, there is a variety of testing methods applied to test and evaluate the chemicals. These
are not yet based on internationally accepted methods, which are still under development.

In addition to the database, a summary was prepared with the rationale of the different
organisations for the selection of substances on lists. The information not only includes the
evidence on endocrine disruption given by these organisations but also information on
bioaccumulation, persistence and legal status. This information is available as a background
document at the European Commission.

2.2 Step 2: Selection of highly persistent and/or HPV substances

A stakeholder meeting with representatives of governments, industry and NGOs was held at
27th May 1999. At the stakeholder meeting it was decided to narrow down the number of
chemicals to be evaluated and to install an expert panel in order to evaluate the available data.
The first selection of chemicals was based on high production volume (HPV) and/or
persistence. Both parameters were chosen as an indicator of exposure probability. This is
explained by the assumption that human and environmental exposure to a chemical is more
likely when this chemical is produced in high quantities or in case this chemical is persistent in
the environment. The metals were all selected because these elements persist in the
environment.

The selection of high production volume chemicals was based on the HPV list from
Regulation (EEC) No. 793/93 on chemicals with a production volume of more than 1000 tonnes
per year. For selection of persistent chemicals, Quantitative Structural Analysis Relations
(QSAR) based on the Syracuse Biodegradation programme is used as a first indication of the
persistence of a substance. Two models were used: the linear regression method and the
ultimate degradation method (Syracuse program, 1997). These models used the CAS number
and the SMILES notation (structure of the chemical) as data entry. The linear regression method
leads to the definition of classes of biodegradation probability. Substances with a
biodegradation probability of >0.5 are expected to biodegrade rapidly. Substances with a
probability of <0.1 are expected to biodegrade slowly.
The ultimate degradation model predicts the time for ultimate degradation (complete
mineralisation) of a substance. This model is based on the results of a survey of 17
biodegradation experts that were asked to evaluate 200 chemicals in terms of the time required
to achieve ultimate biodegradation. The substances were rated to time units: 5 = hours; 4 = days;
3 = weeks; 2 = months; 1 = more than months. The results were averaged per substance and

10
 formulated to 36 fragments and molecular weight parameter like the probability estimation on
linear regression. Substances that take more than months (level 1) to biodegrade, combined with
a biodegradation probability of <0.1 are considered highly persistent. Substances not fulfilling
both criteria are not considered to be highly persistent.
In Annex 6 the list of chemicals selected on basis of HPV and persistence is presented.

2.3 Step 3: Preliminary evaluation of scientific evidence of ED-related effects

At the expert meeting a panel of experts (organisations listed in Annex 3) on endocrine

disruption with respect to human health and wildlife were asked to evaluate all available
information to categorise the selected group of substances. The information, that was available
to the experts, consisted of experimental data taken up in the database, including the
publications and reports from which the data in the database were derived, plus information
from industry (A summary of all data on endocrine disruption in the database is presented in
Annex 7 and 8). For the evaluation the experts took a precautionary approach: All data were
evaluated, but more weight was given to positive data. The following criteria were used to
categorise the selected chemicals:

Category 1. At least one study providing evidence of endocrine disruption in an

intact organism. Not a formal weight of evidence approach.

Category 2. Potential for endocrine disruption. In vitro data indicating potential for
endocrine disruption in intact organisms. Also includes effects in-vivo
that may, or may not, be ED-mediated. May include structural analyses
and metabolic considerations

Category 3. No scientific basis for inclusion in list or no data

The lists of chemicals were distributed among groups of experts according to their specialisation
in Human health and Wildlife, respectively. Each group prepared categorisation proposals based
on the available background information and presented the results in the panel meeting in which
a final categorisation was determined.

The experts used the following guidelines and criteria:

- All experimental data were taken into consideration (both positive and negative test results);
- In case reliable in-vivo evidence for endocrine disruption was available, the respective
substance was categorised into category 1;
- In case less reliable in-vivo evidence for endocrine disruption was available (for example in
case of contradictory test results), the respective substance was categorised into category 2;
- In case only in-vitro evidence for endocrine disruption was available with positive test
results, the respective substance was categorised as category 2;
- Substances with no data but closely related to substances categorised as category 1 were
categorised into category 2
- Substances with no data but closely related to substances categorised as category 2 were
categorised into category 2
- Substances with no evidence for endocrine disruption or no data and not related to category 1
or 2 substances were categorised into category 3.

It should be emphasised that category 3 contains two groups of substances:

- Substances with sufficient data for evaluation, which are not considered to be endocrine
disrupters;
- Substances with no or insufficient data available.
At the expert meeting it was decided to combine both groups of substances in one category.

11
2.4 Step 4: Preliminary evaluation of exposure to humans and wildlife

In this Step the category 1 chemicals were further evaluated to identify their concern for
exposure. Categorisation into high, medium and low concern was based on qualitative criteria,
because in this stage it was not possible to derive representative exposure concentrations nor
approved (No) observed endocrine disrupting effect concentrations.

Exposure concern is especially referring to the exposure of vulnerable groups such as

(breastfeeding) infants and medical patients, but also to the exposure of wildlife such as
sediment living organisms and top predators.

The following guidelines were used:

High concern Human exposure is expected, due to environmental concentrations and
those in food or consumer products, also taking in consideration
exposure of vulnerable groups
And/Or
Wildlife exposure is expected, due to use and emission patterns, and the
chemical is persistent and bioaccumulative

Medium concern Human exposure is not expected

And
Wildlife exposure is expected, due to use and emission patterns, but the
chemical is readily biodegradable and not bioaccumulative

Low concern No human exposure

And
No wildlife exposure

For the different levels of exposure concern the following chemical properties are identified:

Chemicals with high exposure concern are:

- Chemicals intentionally or unintentionally applied in food products or cosmetics;
- Chemicals applied in residential areas (e.g. herbicides for weed control on pavements);
- Chemicals in consumer products causing direct or indirect exposure (such as additives in
food packaging materials or toys for children);
- Chemicals emitted in the environment and considered being persistent;
- High production volume chemicals emitted in the environment and considered being
bioaccumulative;

Chemicals with medium exposure concern are:

- High production volume chemicals with no human exposure, emitted in the environment
and although not considered as persistent or bioaccumulative, but observed in
environmental compartments;

Chemicals with low exposure concern are:

- Chemicals not causing human exposure nor wildlife exposure.

12
2.4.1 Literature research and processing of data

The literature research already performed for Step 1 was also used for the evaluation in Step 4.
Furthermore for most of the selected chemicals, review documents were used, like:
- Environmental Health Criteria of the WHO/IPCS,
- the IUCLID database,
- Swedish EPA report (Olsen, 1998),
- two German BUA reports (Gulden, 1998) and Bruhn, 1998),
- CEFIC information, received at the expert meeting,
- Fraunhofer report on monitoring data (Fraunhofer, 1999),
- TemaNord report (TemaNord, 1996)
- EU risk assessments (e.g. on phthalates and PBDEs),
- Dutch RIVM criteria documents,
- Dutch RIZA/RIKZ water system surveys.

Use was made of reports and documents sent to BKH by experts and handbooks, including the
Pesticides Manual (Worthing, 1987) and the Merck index (1999).

Based on the gathered information a summary profile was made. In this profile the reason for
selection is presented per chemical or group of related chemicals. Furthermore data on the
chemical characteristics (including bioaccumulation and biodegradation), use, production
volumes, exposure and emissions, vulnerable use/groups and environmental concentrations are
included.

13
3 RESULTS

3.1 Working list of substances

The working list is a compilation of 12 existing lists, including a number of sub-lists derived
from national authorities and non-governmental organisations. This information and an
overview of the selection criteria as applied by the various organisations to obtain the 12 lists
used to draw up the working list, are presented in a background document (BKH, 2000). The list
was supplemented with substances with literature evidence on endocrine disruption, leading to a
working list of 564 substances. The list includes 175 analogues and metabolites of DDT, PCB,
bisphenols, dioxins and furans, which are handled as individual substances. The complete
working list is given in Annex 9. In the database all retrieved data on endocrine disrupting
activity of substances on the working list are included. Note that natural and synthetically-
produced chemicals are excluded from the working list as these substances are not within the
scope of this study.

The individual chemicals on the working list have been clustered into 18 groups of pesticides,
18 groups of industrial chemicals, 1 group of metals and other substances, respectively. The 38
groups are presented in Table 3.1.

Table 3.1. Groups of chemicals and number of substances per group

No Groups Number of substances per group
Pesticides
1 Benzamidazoles 2
2 Carbamates 6
3 Chlorinated cyclodienes and camphenes 17
4 Chlorophenoxy compounds 5
5 DDT, derivatives and metabolites 28
6 Dicarboximides 5
7 Dinitroanilides 3
8 Dithiocarbamates 9
9 Hexachlorocyclohexane and Isomers 4
10 Hydroxybenzonitrils 2
11 Linuron, diuron and derivatives - metabolites 6
12 Methoxychlor and derivatives 9
13 Organo phosphorpesticides 28
14 Pyrethrins 1
15 Pyrethroids 12
16 Pyrimidines and pyridines 3
17 Triazines and triazoles 21
18 Other pesticides 27
Industrial chemicals
19 Alkylbenzenes and styrenes 5
20 Chlorophenols and benzenes 7
21 Alkylphenols and derivatives 71
22 Chlorinated paraffins (CPs) 3
23 Phthalates 19
24 Phenylsiloxanes 10
25 Phenylhydroxyphenylmethanes 2
26 Bisphenols 46
27 Triphenylmethane-derivatives 10
28 Diphenylpropane-derivatives 5
29 Biphenyls 5
30 Polychlorinated biphenyls (PCB) 63
31 Brominated and polybrominated biphenyls and biphenyl 5
ethers (PBBs and PBDEs)
32 Polychlorinated terphenyls (PCT) 2
33 Naphthalenes and derivatives 8
34 Polycyclic Aromatic Hydrocarbons (PAH) 16

14
 No Groups Number of substances per group
35 Dioxins 16
36 Furans 22
Metals
37 Metals 29
38 Other substances 32
Total 564

3.2 First selection: High production volume chemicals and persistent chemicals

At the stakeholder meeting it was decided to prepare a first selection of substances from the
working list to be evaluated by experts. As selection criteria were recommended to use
production volume and/or persistence. It should be noted that biodegradation QSAR
calculations were not used for metals, therefore all metals on the working list were included.
More details on the selection are given in Annex 6. The results of the selections are summarised
in Table 3.2.

Table 3.2: The number of substances that are selected and evaluated
Filter criteria: Number of substances
A: HPV 74 (incl. 6 metals and 1 persistent)
B: Highly persistent 51 (incl. 1 HPV)
C: Metals 29 (incl. 6 HPV)
First selection (A+B+C) 146
Remaining substances 418
All listed man made chemicals 564

The database contains 1657 records on Human health relevant endocrine disrupting effects and
448 records on Wildlife endocrine disrupting effects, for 359 and 106 substances, respectively.
The database includes both positive and negative test results.

146 substances were evaluated at the expert meeting. The list of substances is presented in
Annex 6 with per substance the number of positive and negative test results in the database and
information on production volumes and persistence.

A substantial group of substances (205) were not included in the first selection of 146
substances, because a smiles notation was not readily available and no QSAR calculation on
persistence could be made. In Annex 10 all chemicals are listed with their selection criteria.

3.3 Second selection: Evidence of endocrine disruption

The experts evaluated information from the database plus the available primary sources plus the
information presented by CEFIC.
A summary of all endocrine disruption effects data (included in the database) on substances
evaluated by the experts, is presented in Annex 7. A summary of all endocrine disruption data
(included in the database) of the remaining substances is presented in Annex 8. A complete
reference list of all publications and reports in the database is given in Annex 11.

In Annex 12 and 13 the results of the discussions at the expert meeting are presented. The
scientific evidence used by the experts for the evaluation of the selected substances is presented
in Annex 12. In Annex 13 the results of the categorisation per chemical are given. In Table 3.3
these results are summarised. Based on the human health data 42 substances were categorised as
category 1, 70 as category 2 and 35 as category 3. Based on wildlife data 29 substances were

15
 categorised as category 1, 22 as category 2 and 64 as category 31. Data on wildlife were
available in a minor extent. This may account for the higher number of substances categorised
as category 3. For the final categorisation of the substance the category of both human health
and/or wildlife giving the strongest evidence for endocrine disruption, was used. Finally 66 of
the 146 evaluated chemicals were categorised as category 1, 51 as category 2 and 29 as
category 3 of which 18 had insufficient data to exclude them from the list and 11 were excluded
from the list. These substances are excluded: aluminium, cadmium, copper oxychlor, copper
sulfate, lead, mercury, methylmercury, phenol, fenthion, DIDP (a phthalate) and ethylene
glycol.

Table 3.3 The summarised results of the expert meeting: number of substances in
category 1, 2 or 3.
Categorisation based on Category 1 Category 2 Category 3

Human data 42 69 35
Wildlife data 29 22 64
All data 66 51 29*
* 18 chemicals with no or insufficient data

The 66 category 1 substances consist of 8 groups of tributyltins, tetrabutyltins, tripropyltins,

triphenyltins, chlordanes, DDTs, dioxins/furans and PCBs, respectively and 27 individual
chemicals, total 35 category 1 chemical groups.
The list contains substances, like chlordane, kepone, mirex, toxaphene, DDT,
hexachlorobenzene, organo tins, PCBs, polychlorinated dibenzodioxins and furans, as well as
substances like styrene, resorcinol, phthalates and pesticides like maneb, metam natrium, thiram
and zineb.

It should be noted that no in vivo experiments were available for 1,2,3,7,8-Pentabromo-

dibenzofuran. For 1,2,3,7,8-Pentachloro-dibenzodioxin only effects on the induction of hepatic
AHH are available. Nevertheless these substances were categorised as category 1 substances by
the experts, based on the similarity with 2,3,7,8-Tetrachlorinated dibenzodioxin.

The experts selected the category 1 substances on a wide range of endocrine disrupting effects
as presented in Table 3.4. The main effects were effects on uterus-, testes-, prostate weight or
other sex organ weights, effects on sperm development, vaginal opening, imposex, effects on
thyroid hormone levels or synthesis, and neuroendocrine pituitary effects.

For some substances epidemiological studies have been used as evidence:

Kepone Disturbances in sperm in workers at a pesticides factory;

Resorcinol Changes in goitrogenic activity in workers;
PBB Hypothyroidism among PBB workers;
Styrene Elevation of prolactin levels and enhanced TRH stimulated prolactin secretion in
Female styrene-exposed workers at a styrene factory.

1
Wildlife effects on 32 chemicals (PCBs, dioxins/furans and PBBs) were not evaluated due to lack of resources.

16
 Table 3.4 Endocrine Disrupting effects observed in category 1 substances (: Increase; : Decrease)
Name Effects

Chlordanes (2)* Testicular toxicity

Kepone (Chlordecone) Sperm development
Mirex Testis descent
Toxaphene Thyroid tumours
DDTs (3)* Oestrus cycle ; Ovulation Eggshell thickness ; Uterus weight
Vinclozolin Testis weight ; Testosterone levels ; Sexual potency ; Sex organs
malformation.
Maneb Thyroid hormone synthesis
Metam Natrium Neuroendocrine Pituitary effects
Thiram Thyroid hormone synthesis
Zineb Thyroid hormone synthesis
Gamma-HCH Lindane Testis weight ; Vaginal opening ; Uterus weight
Linuron Sex organs weight
Amitrol Thyroid hormone synthesis
Atrazine Pseudopregnancies ; Estrous cycle irregular; Androgen receptors
Acetochlor Thyroid hormone levels
Alachlor Thyroid hormone levels
Nitrofen Thyroid effects
Hexachlorobenzene Testicular effects; Ovarian effects; Testosterone levels
Tributyltin compounds (18)* Imposex
Triphenyltin (2)* Imposex
Tri-n-propyltin (TPrT) Imposex
Tetrabutyltin (TTBT) Imposex**
4-tert-Octylphenol Vaginal opening ; Uterus weight
Phenol, nonyl- Uterus weight ; Testis weight ; Vitellogenin level
Butylbenzylphthalate (BBP) Testes weight ; Sperm production ; Testosterone levels
Di-(2-ethylhexyl) phthalate (DEHP) Testes weight ; Sex organs weight ; Sperm production ;
Testosterone levels ; Ovarian weight
Di-n-butylphthalate (DBP) Testicular atrophy; Prostate atrophy
Bisphenol A Skewed sex ratio; Prostate size ; Prolactin secretion ; Persistent
vaginal cornification; Vaginal opening
PCBs (9)* Thyroid effects; Uterus weight ; Endometriosis; Progesterone
receptors ; Uterus weight ; Uterus weight ; T4 plasma levels ;
Estrous cycle length
PBBs = Brominated Biphenyls Thyroid hormone levels ; Sex hormone levels
Dioxins/Furans (3)* Hepatic AHH induction ; Uterus weight ; Sperm number ; Thyroid
effects; Neoplasms ***
3,4-Dichloroaniline Androgen synthesis
4-Nitrotoluene Uterus weight
Styrene Prolactin secretion ; Pituitary effects
Resorcinol T4/T3 metabolism ; Thyroid effects
* In between brackets the number of individual substances of the group, is given.
** Tetrabutyltin is debutylated to TBT in both vertebrates and invertebrates. Therefore same effects as TBT
*** Due to structural analogy all 2,3,7,8-substituted congeners have been categorised in category 1

3.4 Third selection: High medium or low exposure concern

The category 1 chemical groups (35) with evidence for endocrine disrupting effects were
evaluated in greater detail concerning exposure. Substances that were closely related were
handled together in one summary profile. The summary profiles gives an overview of the
physical and chemical properties, bioaccumulating potential and degradation in the
environment, as well as an overview of the use, production volumes, emissions and monitoring
data on the substances. Based on this information a conclusion is drawn about the concern this
chemical group presents. The summary documents are given in Annex 14.

In Annex 15 the results of the detailed evaluation per chemical group are summarised. In Table
3.5 the results of the detailed evaluation is summarised.

17
Table 3.5 Number of substances with high, medium or low exposure concern
High concern Medium concern Low concern
Number of chemicals/ chemical 29 4 2
groups

Of the 29 chemical groups that have been categorised as high concern for exposure chemical
groups such as DDT, PCBs, dioxins, and organo-tins are included. Other chemical groups
included are the phthalates (BBP, DBP and DEHP), the pesticides chlordane, chlordecone,
HCB, lindane, linuron, mirex and toxaphene and the industrial chemicals bisphenol A and
PBBs. Other pesticides that are categorised as having high concern for exposure are acetochlor,
alachlor, maneb, thiram, metam natrium, zineb, vinclozolin and atrazine. In addition styrene,
3,4-dichloroaniline and resorcinol are included. However it should be noted that the information
on which the categorisation of styrene is based is fairly old and exposure conditions may have
changed. The information on resorcinol is also limited. In table 3.6 the information on which the
chemical groups are categorised as having high, medium and low concern for exposure, is
summarised.

18
Table 3.6 Information on chemical groups with high, medium and low concern for exposure.

Substance Concern HPV Concerned use Human exposure Wildlife Soluble Persistent Bioaccumulation Mea- Observed in Remark
exposure Sured environment
Acetochlor High Yes Herbicide also on food Food, workers Moderately Not persistent Not bioaccumulated No No Exposure should
crops (slightly) be checked
Alachlor High Yes Herbicide also on food Food, workers Moderately Not persistent Not bioaccumulated ( Yes Yes Exposure should
crops slightly) be checked
Atrazine High Yes Herbicide on food Food, workers, soil Moderately Persistent Not bioaccumulated Yes, Yes
crops and alongside alongside roads: water
roads and uncultured children and
land food
BBP High Yes Softener and plasticizer Toys: children; moderately Not persistent Bioaccumulates Yes Yes, water
in toys, packaging cosmetics, carpet, based on log Kow
material, vinyl floor wall paper, paint but metabolised and
tiles, vinyl foams and excreted
carpet backing, in
cosmetic industry
Bisphenol A High Yes Resin in plastic dental Food; teeth moderately Persistent Not bioaccumulative Yes Yes
fillings, teeth coating children;
especially of children; production workers
packaging as coating in
food cans
Chlordane High No Insecticide mostly on Found in mother poorly Persistent Bioaccumulation Yes Yes in mother Should be checked
non-food crops; milk observed milk if chlordane is still
forbidden in EU and found in mother
US milk and what the
source is.
Chordecone High No Fungicide, insecticide Insect traps, human Poorly Persistent Bioaccumulation Yes Yes in food, Relatively old
on some food crops milk: children; observed biota and information,
and in insect traps food and mother milk should be checked
(ants) production workers if uses are still
there and if still
measured in
mother milk and
food

19
Substance Concern HPV Concerned use Human exposure Wildlife Soluble Persistent Bioaccumulation Mea- Observed in Remark
exposure Sured environment
DBP High Yes Plasticizer and softener Numerous poorly Low to Bioaccumulated only Yes Yes, water and
in toys; carpet backing; exposure medium at low trophic levels biota
also in hair spray, nail possibilities: food persistent
polish, glue, coatings (through
on cellophane, packaging), toys,
cosmetics and as a cosmetics, dental
solvent in polysulfide fillings, glue,
dental impression textiles for all
materials, perfumes groups and
and as textile production workers
lubricating agent
DDT High Yes Insecticide against Widespread Widespread poorly Persistent Bioaccumulated Yes Yes
sickness forbidden in persistence in persistence in
EU, USA and Japan environment, biota, environment and
but still used in some mother milk and biota
countries food
DEHP High Yes Plasticizer in toys and Children through poorly Persistent Bioaccumulation Yes Yes
in tubes and bags used shewing on toys observed
for blood transfusion and patients
and other medical
equipment
Dichloroanilin High Yes Intermediate (closed Indirectly through Through Good Not readily Not bioaccumulated Yes Yes
e (3,4-) system); also linuron and diuron industrial biodegradable
metabolite of linuron which are used on wastewater and
food. as metabolite of
linuron
HCB High Yes Fungicide on seeds and Found in humans, Found in Poorly Persistent Bioaccumulation Yes Yes in cows
food crops; Severely fish and cows environment and observed milk and fish
restricted in the EU but milk biota; exposure
still used in some parts through
of the world production at
Long range transport industrial
wastewater
Lindane High Yes Insecticide on seed and Long range Through Poorly Inherently Bioaccumulation Yes Yes, biota
soil before food crops transport seen; wastewater at biodegradable observed (fish), water
are planted found in fish (food) production and systems
through
application on
soil and seeds

20
Substance Concern HPV Concerned use Human exposure Wildlife Soluble Persistent Bioaccumulation Mea- Observed in Remark
exposure Sured environment
Linuron High Yes Herbicide on food Food At production medium Inherently Not bioaccumulated Yes Hardly
crops (wastewater) and biodegradable; observed and if
application metabolite 3,4- observed
DCA around
detectielimit;
however 3,4-
DCA is
measured
Maneb High Yes Fungicide on fruit and Food At production Poorly Degraded to Not bioaccumulated No No, but the
food crops (wastewater) and metabolites metabolites
application whereunder ETU has been
ETU found
Metam- High Yes Fungicide on soil Food At production Very good Expected to Not bioaccumulated No No, but
natrium before culturing, (wastewater) and degrade metabolite
nematicide, herbicide application quickly, MITC MITC has been
also found
Mirex High No Insecticide (ants), as a Food (fish, meat) At production poorly Persistent Highly Yes Yes found in Information on
polymer and as a flame and found in (wastewater) and bioaccumulated humans, meat, uses in EU are very
retardant. Limited use human mother milk application fish, food crops limited
for agricultural and mother
purposes milk
PBB High No Flame retardants Exposure through At production Poorly to Persistent Most are Yes Yes in biota
workers at (wastewater) and medium bioaccumulated and
production site at the waste biomagnified
stage.
PCBs High No In past used in Exposure indirectly Emission at poorly Persistent Bioaccumulation Yes Yes in biota,
electrical equipment, through food (fish), production and at observed humans and
heath-transfer systems, and mother milk by the waste stage mother milk
hydraulic systems, in emission through
plastics, coats, glues, the waste stage
paints etc.; PCB are
severely restricted and
banned; still available
through existing
products

21
Substance Concern HPV Concerned use Human exposure Wildlife Soluble Persistent Bioaccumulation Mea- Observed in Remark
exposure Sured environment
Dioxins/ High No Forming during Exposure through Exposure poorly Persistent Highly accumulating Yes Yes in food
Furans combustion (municipal emission at through emission (fish, meat,
waste incineration), production and at at production and dairy products)
metal production, waste stage at waste stage and mother
paper and pulp (incineration); in (incineration) milk
production, food and mother
chlorophenols and milk
herbicides
Resorcinol High Yes Used in the Exposure through Exposure Very good Readily Not bioaccumulated Yes Yes, but only Little information
manufacture of skin, Exposure through emission biodegradation in effluents and available
adhesives, dyes, in through emission at at production and wastewater,
pharmaceutical production and at at waste stage cigarette smoke
preparations (for skin) waste stage; and wood
tanning, dyes, inhalation of wood smoke.
cosmetics, as topical and cigarette
antipruric and smoke
antiseptic
Styrene High Yes Used in closed Food (flavoring Exposure moderately Readily Not bioaccumulated Yes Yes in food, air Based on old
systems; used in agent; packaging); through emission biodegradable and water information; not
chemical industry, toys; at production and (partly old clear in how far the
paints, lacquers, Exposure through at waste stage data) uses are still the
varnishes, paper, pulp emissions from same.
and board and in production and use;
polymers: polystyrene, emitted in
styrene-butadiene, automobile
rubber (latex); also a exhaust;
flavoring agent for ice
cream and candy; use
of styrene in hobbies,
crafts and toys; use of
polystyrene containers
as package for food
Thiram High Yes Leaf-fungicide on fruit Food, workers At production Poorly Degraded to Not bioaccumulated No No, but the
and vegetables; also (wastewater) and metabolites metabolites
used in domestic area application whereunder MITC?? has
as antifungicide and ETU been found
antibacterial paint.

22
Substance Concern HPV Concerned use Human exposure Wildlife Soluble Persistent Bioaccumulation Mea- Observed in Remark
exposure Sured environment
Toxaphene High No Insecticide on grain, Food and workers At production, Poorly Persistent Highly accumulative Yes Yes in biota
fruit, vegetables, nuts; at production plant waste stage and and mother
as a piscicide and as and at application; application; long milk
veterinary for ticks and long boundary boundary
mites in livestock; in transport; found in transport
EU forbidden as plant mother milk
protection product
Tributyltin High Yes Used as molluscicides, Workers at At production, poorly Persistent Highly Yes Yes, in water, Little information
antifouling paints, production and waste stage and bioaccumulative sediment and available
wood preservatives, indirectly in food application biota
disinfectants and through use as
biocides for cooling pesticide (fish)
systems
Tri-n- High Metal No info No info No info Moderately Readily No bioaccumulation No No Little information
propyltin biodegradable available
Triphenyltin High Metal Fungicide on food Food (vegetables At production, poorly Persistent Highly Yes Yes in biota
crops and molluscicide and indirectly via waste stage and bioaccumulative (fish), water
on food crops fish) application and sediment
Vinclozolin High Yes Fungicide on fruit, Food, workers at At production, poorly Inherently No bioaccumulation yes Yes, in water
vegetables and production and waste stage and biodegradable
ornamental plants application application to metabolites
m1 and m2
which are also
inherently
biodegradable
Zineb High Yes Leaf fungicide on fruit Food, workers at At production, poorly Degraded to Not bioaccumulated no No, but the
and vegetable crops production and waste stage and metabolites metabolites
application application whereunder ETU has been
ETU found
Amitrole Medium Yes Herbicide, not directly Soil alongside Very good Rapidly Not bioaccumulated Yes, yes
on food crops, roads children, degraded to water
alongside roads workers metabolites
Nitrofen Medium Yes Herbicide on Food (not likely At production poorly Inherently Bioaccumulation no No
vegetables, Restricted because it is (wastewater) and biodegradable observed
in the EU: not to be forbidden) and application
used as plant exposure of
protection product workers at
production and
application

23
Substance Concern HPV Concerned use Human exposure Wildlife Soluble Persistent Bioaccumulation Mea- Observed in Remark
exposure Sured environment
Nonylphenol Medium Yes Used as raw materials Exposure through At production poorly Inherently Expected to yes Yes in water
for detergents, release from (wastewater) and biodegradable bioaccumulate and biota
emulsifiers, wetting polystyrene and at the waste
and dispersion agents PVC (nonylphenol) stage.
in paints, anti-oxidants, e.g. in baby bottles
pesticide and in PVC;
also used as
spermicides in
contraceptive foams;
biodegradation
products of APEOs
4 tert. Medium Yes Used as raw materials Exposure through At production poorly Inherently Expected to yes Yes in water
Octylphenol for detergents, release from (wastewater) and biodegradable bioaccumulate and biota
emulsifiers, wetting polystyrene and at the waste
and dispersion agents PVC (nonylphenol) stage.
in paints, anti-oxidants, e.g. in baby bottles
pesticide and in PVC;
also used as
spermicides in
contraceptive foams;
biodegradation
products of APEOs
4-nitro- Low Yes Intermediate (closed Only exposure At production poorly Inherently Not bioaccumulated hardly Hardly Very little
toluene system) in varnish through workers at (wastewater) biodegradable information
industry, production site available
pharmaceuticals and
fragrants
Tetrabutyltin Low Yes Intermediate for Workers at At production poorly Persistent - no no Check if there are
production of other production plant and waste stage only limited
organotins applications for
TetraBT

24
4. CONCLUSIONS AND RECOMMENDATIONS

4.1 Conclusions

In this study, a working list of 564 substances has been drawn up for which information on
endocrine disrupting effects has been gathered.
This study is carried out in four Steps, used to group the substances according to available
information on selected criteria.

STEP DESCRIPTION RESULTS

1. Review of existing lists and other sources of 564 substances

information

2. Selection of highly persistent and/or HPV 146 substances

substances

3. Preliminary evaluation of scientific evidence 66 substances

of ED-related effects (35 chemical groups)

4. Preliminary evaluation of exposure to humans 60 substances

and wildlife (29 chemical groups)

In Annex 10 an overview of all selection criteria on the substances is given. In Figure 4.1 an
overview is given of the results of all steps of the project and in table 4.1 the grouping of the
chemicals is given.

146 HPV and persistent chemicals are evaluated of which 66 (35 chemical groups) are to be
considered as category 1 chemicals (evidence for endocrine disruption in a living organism).

After a detailed evaluation, 60 substances (29 chemical groups) in category 1 are to be

considered as having high exposure concern. This group of 60 chemicals contains the
chemicals DDT, PCBs, organotins and dioxins as well as styrene, phthalates and some
pesticides. A number of 11 category 3 chemicals (no scientific basis for inclusion in list)
have been excluded from the list of which 553 substances remain. The candidate list contains
therefore 553 substances of which 60 substances are in Group I, 55 substances are in Group
II and 448 substances are in Group III.

The candidate list of 553 must not be considered as final. Based on new data other chemicals
may be added to the list in future. In other instances clear evidence may become available
that a substance on the list should be removed. The list should therefore be open to change:
additions and removals.

25
Figure 4.1 Schematic overview of the project steps and theresults

Inventory
STEP 1

Working list
564

STEP 2 Selection on HPV and/or highly

persistence

HPV and/or Highly Not HPV and not highly No data on

persistent persistent persistence
146 213 205
Group III Group III

STEP 3 Evaluation of ED-related effects

Evidence of Potential evidence No scientific basis for

endocrine effects of endocrine in inclusion in list or
66 effects no data
51 29
Group II

No data Excluded from

working list
18 11
Evaluation of exposure
STEP 4 concern to human and wildlife Group III

High exposure Medium exposure Low exposure

concern concern concern
60 4 2
Group I Group II Group III

26
Table 4.1. List of candidate substances summary of work to date

GROUP I
Selection criteria Number of substances Listing

Highly At least one study High concern in 60 See Annex 1.

persistent showing endocrine terms of human (29 chemical groups)
disruption in an and wildlife
And/or intact organism exposure
(Category 1)
HPV

GROUP II
Selection criteria Number of substances Listing

At least one study Medium 4 See Annex 1

showing endocrine concern in
Highly disruption in an terms of human
persistent intact organism and wildlife
(Category 1) exposure
And/or

HPV Potential for endocrine disruption 51

(Category 2)

GROUP III
Selection criteria Number of substances Listing

Highly At least one study Low concern in 2 See Annex 1

persistent showing endocrine terms of human
disruption in an and wildlife
And/or intact organism exposure
(Category 1)
HPV

No sufficient data (Category 3) 18*

Not HPV and not highly persistent 213

Not HPV and no data on persistence 205**

* Excluding 11 Substances that have been excluded from the candidate list because of data giving
no basis for inclusion in the list (Category 3)
** No Smiles notations were readily available for QSAR estimations on persistence.

27
4.2 Recommendations

This project is a first step into the overview of data and evaluation of substances associated
with endocrine disruption. Although an approach has been used that 146 selected chemicals
(HPV, persistent) are probably also the chemicals inherently related to high risk of exposure,
some notes have to be made to this approach. A substantial group of chemicals was not
selected in the group of 146, because no QSAR estimation on persistence could be made. For
these chemicals persistence is unknown. Another consideration must be made towards the
HPV criterion (>1000 tonnes/year). Substances that are produced in quantities smaller than
1000 tonnes per year with a moderate persistence might also present a high risk of exposure.

Recommendation 1: A follow-up has to be made to further evaluate the substances on the

candidate list of 553 chemicals.

A considerable number of 205 chemicals were not included in first selection, because Smiles
notations were not readily available. To complete the process for these substances Smiles
notations should be prepared and in a number of cases additional information, if necessary
by testing, should be provided.

At present there is no consensus yet on the methodology to assess endocrine disrupting

effects.

Recommendation 2: It is important that an agreement is reached on the effect parameters

indicating endocrine disruption

Recommendation 3: Standard tests have to be developed to identify endocrine disrupters

Recommendation 4: These tests should be applied with priority to category 1 substances with
evidence of endocrine disrupting activity. Risk assessments will also need to be reconsidered
when agreed test methods become available.

Recommendation 5: The database must be expanded with additional information on

endocrine disrupting activity.

There is a need to increase the reliability and significance of the data.

Recommendation 6: For the evaluation of endocrine disruption effects a comparison should

be made with the concentrations at which toxic effects (reproduction, mortality) occur.

Recommendation 7: Information is needed on the effects of endocrine disruption at a

population level

In the selected group of 146 HPV and persistent chemicals, 51 have been categorised as
category 2 chemicals due to a lack of sufficient information on endocrine disruption (e.g. in
vivo tests).

Recommendation 8: For category 2 substances information should be supplemented with

additional endocrine disruption data to reach a final categorisation (1 or 3).

Recommendation 9: The chemicals categorised as category 3 should be supplemented with

additional endocrine disruption data; with the option to exclude them from the list or
upgrade them to a category 2 or 1.

28
5 REFERENCES

BKH (2000), Background document on the project Identification of chemicals related to

endocrine disruption, Delft, The Netherlands.

COM (1999) 706 final, Communication from the Commission to the Council and the
European parliament, Community strategy for Endocrine Disrupters, a range of substances
suspected of interfering with the hormone systems of humans and wildlife.

Merck (1999), Merck index through online host.

Syracuse program, 1997. BIOWWIN Biodegradation Probability program version 3.6.

Worthing (1987) The Pesticide Manual, The British Crop Protection Council.

29