EndocrineDisruptors 2011 8-9 February 2011 - Zurich, Switzerland
MANAGING A SUBSTANCE IN THE MARKETPLACE WHEN THE RULES ARE UNCLEAR
'A CASE STUDY OF A THYROID-ACTIVE CHEMICAL'
by
Paul Ashford, Caleb Management Services Ltd.
The Old Dairy, Woodend, Cromhall, Wotton-under-Edge, Gloucestershire, GL 12 BAA, UK Tel. +44-1454-269330; Fax. +44-1454-269197; E-mail: [email protected]; Keywords: REACH , thyroid, equivalent concern , reversible, proactive
BIOGRAPHICAL NOTES
Paul Ashford is Managing Director of Caleb Management Services which he founded in
1994 following a fifteen year career within BP Chemicals that encompassed product
development, process development, technology licensing, business development and
business management functions. Building on credentials established in the Montreal
Protocol arena, Paul has been a long-standing advisor to regulators and industry groups
on a number of critical regulatory issues in the chemical sector. He has managed issues
on the chemical/regulatory interface for over 20 years.
Summary
When the authorities within the European Union confirmed, in the late 19908, that the thyroid should be treated as
part of the endocrine system for regulatory purposes , it created a high level of uncertainty for a number of thyroid­
active chemicals, even though their effects , being often reversible , were well understood and risks already managed.
The emergence of unofficial 'lists' around the REACH process have only served to raise ,the stakes still further. This
paper explores how the manufacturers of one such substance took a proactive stance from the outset and asks
whether the strategy has helped the regulatory treatment of that substance in the meantime or not.
Resorcinol - the management of a thyroid active substance prior to 1999
Resorcinol (1,3-Benzenediol) has been used as an industrial and pharmaceutical chemical since the mid-19
century. The current scope of applications includes:
th
• Adhesion promoter in tyre and other rubber reinforcing applications
• Base for adhesives used in the structural wood sector
• Intermediate for ' a number of other products including UV stabilisers, flame retardants , agricultural
chemicals and industrial dyes
• Ingredient for hair dye formulations
• Component of certain topical ointments used for skin ulcers
The chemical is not currently manufactured in Europe following the closure of the Hoechst facility in the early 1990s,
so the EU industrial base is reliant on imports to meet its needs. The three major global producers are INDSPEC (a
subsidiary of Occidental Petroleum) who specialise in resorcinol chemistry, Sumitomo and Mitsui. There are also
other manufacturers in India and China. Consumption inside Europe is well in excess of 10,000 tonnes per year,
with the majority going into the tyre industry. Hair dyes and topical ointments account for considerably less than 5%
of the demand, but, unsurprisingly, have been the focus of more attention from a health and safety perspective than
other, larger uses. This interest has arisen from the reversible thyroid activity related to the substance.
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Endocrine Oisruptors 2011 8-9 February 2011 - Zurich, Switzerland
The mechanism for thyroid activity arising from resorcinol has been well understood for many decades. Resorcinol
exhibits a mild dose-related reversible effect on the thyroid through a mechanism of thyroperoxidase inhibition. This '
was first seen in human cases in the late 1800s and early 1900s, when the use of high levels of resorcinol was
common-place in topical ointments used to treat skin ulcers. As with phenol , resorcinol was ,understood to have
significant antiseptic properties and promoted more rapid healing . It was therefore a 'favourite' amongst
independent pharmacists of the day, who usually prepared their own (unregulated) formulations. It was not
uncommon for free resorcinol levels to exceed 25%, or even 50% in occasional cases .
One of the aspects of the skin lesions created by ulcers is that they provide direct access to the blood stream. The
consequence of this was that resorcinol could get direct access to the thyroid, resulting in the formation of goiters
which would persist for the duration of the ulcer treatment but would disappear again once the exposure to the
topical ointment was ceased. Such medical records were relatively common-place , leading the profession to make
th
cause-and-effect linkage by the middle of the 20 century. As a result, the Pharmacopoeia entry was revised in the
1950s to limit resorcinol content in these ointments to less than 5%. Not surprisingly, the flow of medical case
records began to dry up allowing the profession to conclude that the issue had been dealt with appropriately. In fact,
a comprehensive epidemiologic review of all available data indicate that beyond these medical case reports , no
causal link has been established between resorcinol and thyroid disease in human populations. Occupational
epidemiology studies have not provided any evidence that potential exposures to concentrations of resorcinol
higher than found in the general environment cause thyroid dysfunction ((Lynch, BS et al. 2002)
Similar limits for free resorcinol in hair dyes were also introduced under the Cosmetics Directive , although the
exposure scenarios here are rather different, since there is rarely any exposure to broken skin . Even in such
instances, the exposure is certainly not systematic, in the way that is prevalent when treating ulcers. Accordingly,
the risks of thyroid interaction from the use of resorcinol in hair dyes are seen as negligible.
Apart from the potential of interaction with the thyroid , resorcinol is a relatively benign substance. According to
Council Directive 67/548/EEC , resorcinol is classified as irritating to the, skin and eyes as well as a skin sensitizer.
The substance was therefore historically considered by most of the European Regulatory community as being a
substance of low regulatory concern. It therefore did not figure on any priority lists being put forward under the
Existing Substance Risk Assessment Programme developed within the EU during the 1990s. However, all that was
about to change!
New challenges and uncertainties created by the European Union's ED Strategy
In the late 1990s, the European Commission, in preparation for the launch of its strategy on Endrocrine Disrupters ,
had been reviewing its regulatory definition of the endrocrine system . Unbeknown to the resorcinol industry, this
initiative had included discussions about the inclusion of the thyroid within that definition. Whilst it is clear that this
was a perfectly legitimate debate to have had , its implication on thyroid-active chem icals , such as resorcinol, was
completely unrecognised by the industry at that time. The consequence was that, by the time the implications were
apparent the debate was already over.
Although the global resorcinol industry had already expressed interest in participating in the voluntary high
production volume (HPV) programmes to characterise resorcinol more formally, the emergence of a concern for
thyroid-active substances in Europe provided a further jolt. Accordingly, a Resorcinol Task Force (RTF) was formed
in 1999 to provide a vehicle to address the implications of these developments and to assess the potential for the
provi$ion of additional data into the discussion. Its primary objectives were:
1. To provide information on the uses of resorcinol and any likely health and environmental issues arising
2. To seek to fill data gaps in the toxicological and epidemiological data sets (especially for US HPV Challenge
& the OECD ICCA SIDS Programmes)
3. To assist regulators in assessing the overall risks to human health and the environment posed by resorcinol
Caleb, because of its involvement in one of the major downstream uses (resin manufacture) was asked to act as
manager for the Task Force. This decision was also reinforced by the fact that the company was already based in
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Endocrine Oisruptors 2011
8-9 February 2011 - Zurich, Switzerland
Europe and had existing contacts in the EU regulatory community although , it must be said , not in the emerging
area of EDs.
And so the odyssey began! The initial challenge was dealing with the outputs from the first BKH Report which had
been tasked to identify all of the substances for which there was any evidence of interaction with the endocrine
system . Not surprisingly, resorcinol showed up, along with 552 others , and was included on the candidate list for
further evaluation. This evaluation took the form of a legal assessment of the regulatory situation and confirmed that
resorcinol was one of only 9 industrial HPV chemicals for which no other regulatory governance was either in place
or pending. In a strange way, resorcinol had become a victim of its low regulatory concern status. It would have
been far less conspicuous had it been otherwise regulated or the subject of an on -going risk assessment. The
diagram below appeared in the 2004 Commission Staff Working Document on ED Strategy [SEC(2004)1372] and
illustrates the predicament well.
Annex 1: Figure outlining the grouping of substa nces for furtbel' evaluation
Figul"e 1 . E::to.bli:hment of 0. pl"iol"ity
li:t of : ub::to.nce:: fO l" fur ther
evo.luo.tion .
HPV o.nd/ or highly per:: i: tcnt wit h
evidence (66} 01" ,e v,idencc of
pot en:tio.l ED (52)
118
I
HPVand/ of'
pe r::i:tent and/ Ol"
expo:ure expcet c d'
204
435 =ub:tQf\OC:
Not HPV Qnd (not
pCI":: i:tcn,t o.nd/ or
cxpO::'UI"C
cxpcctod)
Mixture:: o.ncIJor
polymer: . double input:
o.nd gr oup name::
59
112
Sub:tanoc:
wit h cwidcmee
of ED or
e vidence of
potent iQlI ,EO
cahel"
r cgulOot,e d or
under review
,in ex i: ting
Iegi: IOot,ion
109
Sub:tanec: w,it'ft
cvidcncc of ,EO
01" e vidence of
poTcntio.l ED and
c it her not
r c::trie'ted or
not bcing
o.ddr c::::cd in
ex i:ting'
Community
legi: IOotion
9
HPV = High P'rodtICtfon Volume
ED
= Endocl"ine Disrllpt ion
E¥id'e nc'e of ED
94
(Expo::ur-e conce,.,,:
High 84 * ,
Medium 5,
Low 4)
Evidence of
potent"QI E:C
53
No :cient,if ic bOo:i:
,, 19) 01" ,i'n :ufflieiGnt
dQto. for inc lli:l:ion
in li.::t (3S)
57
(Annex III, Tablle
5 &: 4)
* Synt het ic drug Mestl"'QrIOl
excluded
Adr-e::ed' in c xi::ting
CommU\ity Ilcgi: latlion.
129
(Anncx III, T o.ble 2 &. 3)
Not ,Q,drc:=:cd lin ex i:ting
Community legi::IOotion
18
{Annex m , Tab'le 1}
In 2001, the Commission engaged a consultant (WRc pic) to carry out a more in-depth desk study of the nine
chemicals identified by the screening process - the '9 +3' List. This project involved a level of informal consultation
with the industries involved. RTF took a leading role for the resorcinol industry and was able to provide substantial
information as a result of its own literature review conducted in 2000. One of the challenges for resorcinol , and other
substances like it, is that there is generally no shortage of data from 100+ years of study. The real challenge is to
assess the quality of that data and to identify which of the sources has relevance to a 21 st century risk assessment.
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In its work, the Task Force had already identified some key data gaps - particularly in respect to reproductive
toxicity and chronic aquatic studies . It was therefore able to communicate to WRc its plans to fill these data gaps
and, in particular, its plans to address the thyroid end-points.
The WRc Report was presented back to the Commission and formed a significant part of the input to the 2004
Commission Staff Working Document [SEC(2004)1372]. Extracts from that text showed that the WRc Report had
gone a considerable way to alleviating fears about any serious risk to human health or the environment resulting
from resorcinol (see below):
For substances where
tlll"ough epoxy lining of food and
tll1'ough phal111aceutical products)
consumers. including children, from
there is a potential for consumer exposure (BADGE
drink cans and 4-chloro-3-methylphenol and resorcinol
the data indicates that there is evidently no risk to
current exposure pattems.
In dealing specifically with reproductive toxicity, the Commission noted that:
. However, there is uncertainty with clata_ for 4-chlol'o-3 -methylphenol.
2A-dichlorophenol. 4-11itrotoluene and resorcinoe since although data on
reproduction and development1..l endpoints is available. a definitive multi­
generational reproduction study has not been conducted .
.. .. however, it added in a footnote that:
The Resorcinol Task Force has already fonnulated a comprehensive test programme to address the
main uncertainties and/or gaps related with the potential adverse effects of the exposure to resorcinol
The Resorcinol Task Force duly delivered on its commitment to perform a two generation reprotoxicity study with
focus on thyroid end-points and in its overall data-gap filling activities spent just under € 1 million in direct study
costs plus another € 350,000 in assessing existing studies and upgrading the IUCLID dossier.
Since resorcinol is very water soluble, it was always understood that the most likely route of human and
environmental exposure would arise from the aqueous compartment. In addition, there existed several poorly
researched papers from the mid-1970s , that associated goitrogenic activities in some rural populations with
drinking water taken from watersheds containing large sedimentary deposits (coal, shale) , where resorcinol occurs
naturally. These papers consistently failed to take into account the socioeconomic status of the inhabitants and the
impact that issues such as diet had on the thyroid, as well as overlooked the presence in the drinking water of other
substances such as organic disulfides and phthalates, which also effect thyroid function. Nonetheless, it was felt
that the potential impact of resorcinol in drinking water should be addressed , bearing in mind that this would be the
most likely exposure route in practice.
The findings of the two-generation reprotox study demonstrated conclusively that neither the thyroid gland, nor any
of the reproductive endpoints evaluated , were adversely affected by high daily resorcinol doses ingested via
drinking water. The observed results supported the interpretation that resorcinol would typically be screened out in
the first-pass through the liver. This was also consistent with the known rapid metabolism of the substance. These
findings were reported back to the Commission in 2005 and no further mention was made of resorcinol in the
second Commission Staff Working Document [SEC(2007)1635] published in late 2007.
In parallel with this targeted assessment of thyroid activity, the global community was also involved in resorcinol
assessments. INDSPEC made a submission under the US HPV Challenge Program in 2005, which made publicly
available the data set then assembled by the Task Force. In addition, the International Programme for Chemical
Safety (IPCS - A joint activity between the United Nations Environment Programme, the World Health Organisation
and the International Labou r Organisation) commissioned and published a Concise International Chemical
Assessment Document (CICAD) for resorcinol. The CICAD provided summaries of the relevant scientific data
concerning the effect of resorcinol upon human health and the environment and reflected the collective views of an
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international group of experts. After review of the available studies , these experts developed a risk characterisation
based, not on thyroid effects, but on other end-points, since these were now seen to be of more significance to
humans, even though the substance continued to be seen as of low regulatory concern.
A similar experience took place under the OECD SIDS Programme where a SIDS Initial Assessment Report (SIAR)
was peer-reviewed by the regulatory communities of the OECD countries and resulted in resorcinol being
considered as a 'low priority for further work' based on the same information that was available to the CICAD review
team .ln conclusion , it was shown and recognized that any risk of resorcinol can be managed with sufficient certainty.
The treatment of Endocrine Disrupters
un~er
REACH
The resorcinol industry could be forgiven for thinking that it had successfully addressed the question of the impact
of resorcinol on the thyroid through known exposure routes , since no regulators were now identifying this as a
significant health factor in practice. Of course, it had never been questioned that resorcinol had a mild reversible
effect on the thyroid through direct exposure via the bloodstream , but this had been addressed through
pharmaceutical and cosmetic industry controls long before the issue of endocrine disruption had really emerged.
Understandably, the Resorcinol Task Force was watching closely as those entrusted with the development of
REACH began to address the thorny subject of EDs. The wider industry had been arguing for some time that
endocrine disruption was not a health-based end -point, but was a mode of action. This fact had also brought the
European Commission into some difficulty because it could not produce a legally defendable definition of what an
endocrine disruptor was. There was a sense that 'we would know one when we saw one'. The Member States were
also split over the subject of the treatment of EDs. Since this was not the only hazard end-point that was under
discussion (agreement could not be reached either on consi'stent PBT definitions) , it began to become politically
prudent to introduce a new clause within REACH to capture these uncertain areas. This clause would put the
burden of proof back with the Member States (and indeed the Commission, on a case-by-case basis) and would
ask proponents of inclusion in Annex IV (Substances of Very High Concern) to provide support through the
introduction of an Annex XV dossier. This clause became known as Article 57(f) and the final text reads as follows:
Article 57
Substance to be included in Annex XIV
The
~
11 wing substances may be included in Annex XN in
accordance with the pro-cedure laid down in Article 58:
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The text highlighted in red is the key to determining the fate of those substances in the same predicament as
resorcinol. During the stages of negotiation of this text, there was a considerable debate between DG Environment
(as it was then) and DG Enterprise on whether the word 'irreversible' should have been included before the word
'effects' in the clause . Of course, this would have made a massive difference to the resorcinol case and it would
have been fairly straight-forward to argue that Article 57(f) does not apply. However, resorcinol is currently left in a
position where the effects to human health and the environment are relatively low level , but the final verdict on
whether they are sufficiently low level depends on two factors :
1. The determination of criteria for assessing compliance with the text (still on-going in ECHA)
and/or
2. The decision of a Member State or Commission sponsor to prepare an Annex XV dossier (which they are
unlikely to do if they see the effects as low level)
The problem for the resorcinol industry and industries like it, is that the impression given by the text is that
endocrine disruptors are all sources of 'serious effects' when , in fact this is not what the text says. The lack of
further elaboration of the meaning of the text in appropriate guidance has left the interpretation open to others. We
have seen the emergence of such initiatives as the SIN List and the European Trade Union List of potential SVHCs
which are in danger of becoming de facto black lists, even before any regulatory decisions have been made.
Interestingly, the SIN List, which is seen as the more rigorous of the two lists , does not contain resorcinol , so there
is even an inconsistency between the lists themselves at present. The Resorcinol Task Force continues to work
with such organisations to assist in improving the understanding of the findings highlighted in this paper. However,
there is always a risk that the momentum to proliferate such lists, often with less rigour, could make the situation
impossible to manage in future.
The industry remains clear that the data it has put together reinforces the fact that resorcinol is a chemical of low
regulatory concern and hopes that the criteria used for the interpretation of Article 57(f) will substantiate that
resorcinol does not represent a risk of 'serious effects to human health or the environment'.
Conclusions
The following conclusions can be drawn from this review:
1. Even with a ten year investment in data generation and interpretation , the future regulatory treatment of a
typical chemical impacted by Article 57(f) cannot be guaranteed at this time , despite little, or no evidence of
potential 'serious effects to human health or the environment'
2. The lack of criteria against which to assess chemicals under Article 57(f) needs to be filled rapidly if the
wider potential SVHC listings are not going to be a determining factor
3. The industry continues to have faith in the regulatory community to reach the right decisions in assessing
hazard and risk
4. There is no way in which this particular industry would have been able to make its case as stridently as it
now can unless the data gaps had been appropriately filled
Paul Ashford - Caleb Management Services Limited - December 2010
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Disclaimer
The interpretations, views and opinions expressed in this paper are those of the authors and are not intended to
reflect any confirmed opinions from the regulators or of any court of law that may subsequently rule on the REACH
text. Readers acting on the information contained in this paper do so entirely at their own risk and Caleb
Management Services accepts no liability whatsoever, whether express or implied, for any loss or damages arising
from such action.
This position is entirely consistent with the uncertain status of the legislation itself in the absence of final Guidance
documentation in some areas and relevant legal rulings.
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