Although substitution is, in principle, a simple concept the practical application is more complex.  The UK Chemicals Stakeholder Forum has just published a new “Guide to Substitution” which provides a short, readable introduction to the key principles.

We have selected 12 lists covering a range of types and organisations and broadly related to Europe and the USA. The combined list has been compiled from the data contained in the governmental and NGO lists below, and is presented as a pdf document.

We hope that this list is useful to organisations who want to be aware of potential issues associated with the substances that they use (although we must stress the word “potential”, as the evidence for adverse effects is sparse for some of the identified substances).

Download the pdf document by clicking on this link.

More information on the individual lists that make up the document is priovided below.

California Proposition 65

California Proposition 65 consists of a list of chemicals known to the State of California to cause cancer or reproductive toxicity. The proposition was introduced as part of the Safe Drinking Water and Toxic Enforcement Act of 1986.

For more information on California Proposition 65 click here

ChemSec SIN List

The SIN (Substitute It Now) list is an NGO project to identify Substances of Very High Concern. The chemicals have been identified using REACH criteria. The SIN list aims to provide a list that businesses can use ahead of legislation to introduce safer alternatives to hazardous chemicals.

For more information on the ChemSec SIN List click here

Danish List of Undesirable Substances

The Danish List of Undesirable Substances (LOUS) produced by the Danish Environmental Protection Agency includes substances classified in the EU and substances that have not yet been classified. The List includes substances classified according to such effects as high acute and/or chronic toxicity; carcinogenicity; ability to cause heritable genetic damage; ability to impair fertility; ability to induce allergy; and environmental impact. The list also covers substances that present problems in the marine environment, waste disposal and groundwater. The fact that a substance is included on the LOUS does not signify that the Danish EPA has decided to recommend prohibition of that substance.#

For more information on the Danish List of Undesirable Substances click here

ECHA REACH Annex XIV Candidate List

The European Chemicals Agency (ECHA) administers the new European Chemicals Regulation (REACH). The substances included in the Annex XIV Candidate List have been identified as Substances of Very High Concern. These substances may have very serious and often irreversible effects on humans and the environment. Reasons for substance inclusion on the Candidate List include carcinogenicity, vPvB (very Persistent and very Bioaccumulative), PBT (Persistent, Bioaccumulative and Toxic), mutagenicity and toxicity for reproduction. Inclusion in the Candidate List is the first step in the REACH authorisation procedure and the inclusion of a substance in the List may have legal implications for manufacturers and users.

For more information on the ECHA REACH Annex XIV Candidate List click here

EU Water Framework Directive List of Priority Substances

The EU Water Framework Directive List of Priority Substances is contained in its Daughter Directive on Environmental Quality Standards. This identifies substances that have been shown to be of major concern for European Waters. Priority hazardous substance classification has been assigned to 11 substances which are of particular concern for inland, transitional, coastal and territorial waters. The discharge of these substances to EU watercourses will be phased out within the next 20 years. Candidate substances for inclusion on the Priority Substances list are considered by the Commission at regular intervals, so the list of Priority and Priory Hazardous Substances is very likely to expand over time.

For more information on the EU Water Framework Directive List of Priority Substances click here

OSPAR List of Chemicals of Concern

The Oslo & Paris Commission (OSPAR) is the secretariat appointed to administer the Oslo and Paris Conventions on the dumping or discharge of materials, primarily into the North Atlantic. The OSPAR list of Chemicals of Concern consists of PBT (Persistent, Bioaccumulative and Toxic) substances, or substances which produce an equivalent level of concern. The OSPAR Hazardous Substances Strategy aims to prevent marine pollution by reducing discharges and emissions in order to achieve near background values for naturally occurring substances and close to zero for man-made synthetic substances.

For more information on the OSPAR List of Chemicals of Concern click here

OSPAR List of Chemicals for Priority Action

The substances from the OSPAR List of Concern can subsequently be included in the OSPAR List of Chemicals for Priority Action following the preparation of a background document. The Background Document is used to assess the situation of the substance and the action necessary. Monitoring strategies have been prepared for hazardous substances, which describe the information needed in order to assess progress towards OSPAR target levels.

For more information on the OSPAR List of Chemicals for Priority Action click here

Stockholm Convention List of Persistent Organic Pollutants

The Stockholm Convention on Persistent Organic Pollutants (POPs) is intended to deal with the impact of organic substances which remain intact for long periods of time, become widely distributed, bioaccumulate and are toxic to humans and the environment. Persistent Organic Pollutants can cause specific effects on humans, including cancer, allergies and hypersensitivity, damage to the central and peripheral nervous systems, reproductive disorders and disruption of the immune system. Some POPs are also endocrine disrupters, which can damage the reproductive and immune systems of individuals and their offspring; they can also be toxic to reproduction, with developmental and carcinogenic effects. The Stockholm Convention List of Persistent Organic Pollutants includes substances classified as elimination, restriction and unintentional by-products. Only the elimination substances have been included in the Avoidance list.

For more information on the Stockholm Convention List of Persistent Organic Pollutants click here. Further information on the convention’s amendments can be found here

US EDSP Tier 1 Screening List

The US EPA Endocrine Disruptor Screening Program includes substances which may disrupt the endocrine system of humans and wildlife, producing developmental and reproductive problems. The Food Quality Protection Act in 1996 requires EPA to screen environmental contaminants for potential endocrine disrupting effects.

For more information on the US EDSP Tier 1 Screening List click here

US EPA Containment Candidate List CCL3

The US EPA Containment Candidate CCL3 list includes substances known or expected to occur in public water systems which do not currently fall under any national primary drinking water regulations, but which may require regulation under the Safe Drinking Water Act. The list includes pesticides, disinfection by-products, chemicals used in commerce, waterborne pathogens, pharmaceuticals, and biological toxins, among others. The CCL 3 list includes chemicals, chemical groups and microbiological contaminants.

For more information on the US EPA Containment Candidate List CCL3 click here

US VCCEP Pilot Programme List

The US Voluntary Children’s Chemical Evaluation Program is the section of the recent Chemical Right to Know Initiative that considers risks to children. The Chemical Right to Know Initiative aims to provide information on the effects of chemicals in order that citizens can make informed decisions in the marketplace. The VCCEP is currently being implemented as a trial before the final processes are determined and additional chemicals are selected. The trial consists of substances to which children have a high likelihood of exposure.

For more information on the US VCCEP Pilot Programme List click here

REACH Annex XVII

Annex XVII covers restrictions on substances which, from manufacture, use or placing on the market, pose unacceptable risk to human health or the environment. The decision about unacceptable risk will be based on a combination of both socioeconomic analysis and risk assessment, rather than just the latter. Inclusion of a substance in Annex XVII may lead to further restrictions and risk management measures, beyond those already in place, for manufacturers, importers, downstream users and distributors. The restrictions in Annex XVII are a consolidation of the restrictions contained in Directive 76/769/EC, which is an approximation of the marketing and use restrictions of particular dangerous substances and preparations by Member States.

For more information on REACH Annex XVII click here

The inchemicotox project has produced the following outputs, which will be described and demonstrated at the workshop:

1. Quality assured databases have been provided for the regulatory endpoints skin sensitisation and acute fish toxicity.

2. Robust QSARs have been developed for narcotic mechanisms of action for acute fish toxicity. QSAR Model Reporting Formats have been created. The use of grouping and read-across has been shown for the prediction of skin sensitisation.

3. The in vitro components of an Intelligent Testing Strategy have been identified. These are supported by methods to extrapolate information from in vitro data.

4. In chemico information has been created that supports assigning a compound to a reactive mechanism of action. The reactive mechanisms assist in grouping together compounds that act as skin sensitisers and help to identify non-narcotic compounds.

5. A tool has been created to guide users through assessing the information within an Intelligent Testing Strategy. This enables them to make evidence-based decisions to assess toxicity.

6. Intelligent Testing Strategies have been developed for fish acute toxicity and skin sensitisation to enable appropriate decisions for risk and hazard assessment. These strategies build on the components developed in this project and provide the user with a flexible solution to using non-test data.

The workshop will be of interest to colleagues from regulatory agencies, industry, consultancy and NGOs who need to use QSARs and other non-testing methods under REACH and other European chemicals directives.

Attendance at the workshop is free of charge, but places are limited. Please email me if you wish to attend. A detailed agenda, further background information, and a location map will be provided to all registrants in early August.

However, by necessity, these controls tend to be retrospective, being established only after a potential environmental impact has been identified.  Environmental impacts can be acute in nature and the incidence of the effect, although not necessarily its cause, are then usually relatively obvious.  The devastation of the Gyps vulture population in India from an unusual exposure to Diclofenac is a classic example. However, chronic impacts may be equally devastating but are usually much more difficult to discern.  For example the impact of tributyl tin antifoulants on dog whelks and of natural & synthetic oestrogens on male fish, were only identified because single research groups happened to be interested in, and were thus monitoring, affected populations.

This raises the question: what needs to be done in order to minimise the risks to biodiversity from such potential impacts?  The obvious solution would be to identify these potential impacts as early as possible, but this is not a simple task.

Comprehensive chemical monitoring of the environment is impractical in view of the very large number of potential determinands coupled with the size and complexity of the environment. It is also unnecessary since precautionary computer modelling techniques can predict likely worst case environmental distribution patterns. In addition, what we need to identify is any biological impact, NOT the level of exposure.

Pharmacovigilance has a long history in the patient health sector aimed at tackling a similar issue.  This encourages the reporting of adverse impacts (i.e. unexpected side effects) of pharmaceuticals to a central point.  This enables connections to be more readily identified and investigated.  Although, for many reasons, not an exact parallel, some form of ecovigilance reporting might be valuable in the early identification of unexpected impacts.

The establishment of global or even regional ecosystem surveillance monitoring programmes aimed simply at identifying acute impacts would be a daunting task in itself; however for chronic impacts, at the species level, such a task becomes impossible.

However, more value is potentially extractable from the large amounts of data that are being collected already for other purposes.  Biological monitoring studies of species, species assemblages and ecosystems are being undertaken all the time by a range of researchers in many parts of the world.  These may identify adverse or unexpected effects of unknown cause and such observations may (or may not) subsequently be included in reports or scientific publications.  However, even if the observations are reported they are, in effect, randomly distributed throughout the literature and there is currently no process, other than serendipity whereby connections might be made and restorative action initiated.  For example it took several years before it was recognised that amphibian populations in many parts of the world were in decline or that honey bee populations were under pressure.

Such an ecovigilance system need not be either onerous or expensive, but could nevertheless be extremely valuable in identifying chronic impacts caused by low level contamination of the environment by biologically active substances.  It would require a central reporting locus to be established whose role would be to maintain a simple on-line database of reported adverse effects.  This body would not necessarily undertake any research itself, but would be widely advertised as an archive of potential impacts and a source for researchers to use.  In this way identification of similar biological impacts of unknown cause could be facilitated by adding value to information that was already being generated.

Ultimately a data collection system covering the global environment would be a desirable outcome; however the European Union is now sufficiently large for an EU system to be viable on its own, at least initially.  A good starting point might be to begin with the large amount of biological monitoring data that will be generated as part of the implementation of the Water Framework Directive.

There are various stages at which water sustainability becomes important and can have an impact on operations. There are also issues of cost saving, since water usually has to be paid for. The stages that are of greatest interest are:

1. Sourcing of raw materials, particularly crops, and developing ways of determining the most water efficient and sustainable sources.

2. Recycling water in processing, from washing crops, through to bottling, canning and general washing and rinsing. This is also linked into concerns about introducing potential contaminants, as was the case with the pre-washed salad industry.

ILSI Europe was active in starting this process by publishing a report on Considering Water Quality for Use in the Food Industry. More recently ILSI has examined water use in agriculture, initially focussing on oil crops, and has developed an approach to compare the water sustainability of various crop sources. The process begins with where the crop is grown, and needs to consider whether green or blue water is used and to what extent. ILSI has prepared a report which discusses ways of achieving more recycling, co-authored by John, who chairs their Expert Group on Sustainable Water Management for Crops. The key is to make the exercise as cost-effective as possible – some academic groups have recommended relatively complex approaches, but these may obscure rather than solve the problem.

In some cases the traditional approach of deriving an EQS from ecotoxicology test data and applying an assessment factor to derive an acceptable level in the environment may be inappropriate, especially in cases where the available test data are uncertain and the observed effects may not necessarily be due to chemical toxicity. The derivation of an EQS for iron may be such a case, and previous UK efforts to derive a PNEC from ecotoxicity test data and an assessment factor resulted in a PNEC which was below ambient background levels in unimpacted areas. There is a large body of field monitoring data in the UK for both ecological quality and water quality, and we have been analysing this to assess the effects of iron on freshwater ecosystems. The approaches employed require a large body of monitoring data, and the identification of effect thresholds requires that there are impacts on the local ecology at some of the sites due to the substance of interest (Figure 1). The possible standards which we have recently developed for iron (Figure 2) for the Environment Agency of England and Wales have the potential to align acceptable levels of iron in the environment with established levels of ecological quality under the WFD. This has never been possible before, and may allow a much greater degree of integration of chemical and ecological criteria for freshwater in the future.

Figure 1. Illustration of the interpretation of combined chemical and ecological field data.

Figure 2. Ecological quality as a function of iron exposure (click to enlarge and for more info)

This shift is not surprising given the amount of research already invested into endocrine disrupting effects, and in particular the inclusion of endocrine disruption as a hazard based cut-off criterion for the approval of active substances in the revised regulations regarding the authorisation of plant protection products (Regulation (EC) No 1107/2009). However, the fundamental scientific criteria necessary to define endocrine disrupting properties are not defined yet. The new regulation specifies that the Commission shall present a draft of the measures concerning specific scientific criteria for the assessment of endocrine disrupting properties to be adopted by 14 December 2013.

In the meantime various organisations have organised workshops to develop such criteria and make recommendations. ECETOC presented an initial proposal at a workshop of invited regulatory, academic and industry scientists (Barcelona; June 29-30, 2009) to evaluate the approach as a concept for identifying endocrine disrupting properties within a regulatory context (ECETOC 2009a, b). wca environment were contracted to help refine the guidance following input from the workshop and prepare the guidance for publication in the open literature. The ECETOC task force presented the refined guidance for the assessment of ED in wildlife at SETAC, which was well received. This presentation was followed by the joint views developed by the German Umweltbundesamt and the Fraunhofer Institute. Although there were differences in their approach compared to that presented by ECETOC, there were also some important common elements. Specifically, these included waiving the cut-off criterion for active substances with intended endocrine mode of actions (such as insect growth regulators), the requirement to link any adverse effects on apical endpoints (such as reproduction) to a mechanistic understanding of endocrine disruption, as well as the need to consider the potency and specificity of endocrine effects.

We also presented a poster at SETAC on a practical weight of evidence evaluation for endocrine disrupting properties of plant protection products, which can be used within a framework such as that proposed by ECETOC. The WoE evaluation consists of four evaluation steps: a) Study reliability & quality of work undertaken, b) Study relevance & endpoint relevance to endocrine disruption, c) Study significance & based on the earlier assessments made for reliability and relevance, and d) Balance of the weight of evidence, coherence and gap assessment.

The German Bundesinstitut für Risikobewertung (BfR; Federal Institute for Risk Assessment) has also been active in this field and has developed a draft concept paper on “The development of a stepwise procedure for the assessment of substances with endocrine disrupting properties according to the Plant Protection Products Regulation (Regulation (EC) No 1107/2009)” based on the results of a workshop held in Berlin in 2009. BfR provided this paper as a first input for the development of a harmonised European guidance document for use by Member State authorities and EC peer review groups.

This is a developing area and the criteria that are ultimately endorsed by the EU Parliament can have serious impacts on the registration, use, trade and transport of active substances in plant protection products and it is therefore critical that these issues are addressed in a scientifically sound way. Based on the proposed revisions to the regulations concerning biocidal products [COM(2009) 267 final from 12.6.2009], the same measures addressed under Regulation (EC) No 1907/2006 concerning specific scientific criteria for the assessment of endocrine disrupting properties should be applied as cut off criteria for the approval of biocidal active substances and their products. It is therefore also important that any guidance developed is applicable under various pieces of EC legislation (chemicals under REACH, as well as active substances in pesticides and biocides).

The chapter includes sections on the whole life cycle of pharmaceuticals: Stakeholders, Greener Drug Design, Sustainability issues in R&D, manufacturing, sales & distribution and finally product use and disposal.  The chapter concludes with a summary of the current position and the immediate research needs.

In the last 20 years since Richardson and Bowron (1985) produced their seminal publication, we have learnt a great deal about the potential impact of pharmaceutical residues in the environment. We recognise that many pharmaceuticals can be found at ng l^-1 concentrations in the environment, (with some at concentrations in the low µg l^-1) primarily as a direct consequence of therapeutic use by patients leading to constant input from multiple sources. The impact on human health appears to be insignificant, as does the acute impact on ecosystems. At present long term impacts on ecosystems caused by some pharmaceuticals cannot be ruled out, although increasingly the evidence from chronic studies does not indicate that these are widespread (Boxall et al. 2008).

Nevertheless the research pharmaceutical companies take their stewardship responsibilities seriously and are continuing to pursue research to reduce the uncertainties further. There are a number of areas where further investigations would be helpful, as described below.

A very large amount of information on pharmacokinetics and mammalian toxicology is produced during the development of any new medicine. Initial studies (Owen et al. 2007) have shown that such information could be valuable in developing intelligent ecological testing strategies but much more work is needed to investigate and validate this approach.

It is known that some pharmaceuticals are removed from wastewater by biological treatment plants; some are partially removed whilst others pass straight through. However, it is not known whether the pharmaceuticals are degraded or simply adsorbed onto the sewage sludge and, if the latter is the dominant mechanism, whether the adsorbed material can be desorbed. It has also been observed that removal efficiencies can vary dramatically, even with the same plant configuration, which raises the question as to whether all existing biological treatment plants could be tuned for maximum removal efficiency.

Most pharmaceutical compounds are not ‘readily degradable’ but few of them could be classified as completely persistent. Most of them appear to degrade slowly in the environment via a variety of biotic and abiotic mechanisms. Further studies in this area, especially if the mechanism could be linked to structure, would enable improved prediction of actual environmental concentrations to be undertaken and could potentially provide valuable information during the lead identification and optimisation stages in drug design.

“We will end the testing of household products on animals and work to reduce the use of animals in scientific research.”

Not surprisingly this has already been warmly welcomed by BUAV who have been actively campaigning for such action for several years.  However, if the UK acts unilaterally, such action may cause difficulties for those companies that need to comply with the European Union REACH Regulation where animal testing is required unless a suitable non animal alternative method exists.

There is no exemption in REACH for substances used in household products.