Ref. Ares(2016)394896 - 25/01/2016
Ref. Ares(2017)676538 - 07/02/2017
January 24, 2016
Submitted via e-mail to EU TBT Enquiry Point
ACC Comments on G/TBT/EU/N/325
To whom it may Concern:
The American Chemistry Council (ACC)1 appreciates the opportunity to provide the following
comments on WTO TBT notification G/TBT/EU/N/325. These comments express concerns
regarding the recent harmonized classification decision for dicyclohexyl phthalate (DCHP, CAS
number: 84-61-7; EC number 201-545-9) communicated to the WTO by the European
Commission as part of the draft proposal for a ninth adaptation to the technical progress of
Regulation (EC) 1272/2008 on classification, labelling and packaging of substances and mixtures
(the CLP Regulation). This communication aims to amend Annex VI to the CLP Regulation to
include a new harmonized classification for DCHP as Reproductive Agent Category 1B, on the
basis of developmental effects. DCHP is a phthalate ester with two cyclohexyl rings and is
structurally distinct from those phthalate esters having linear or branched alkyl side chains with
low or high molecular weight. It is used to make PVC plastisols, PVC and rubber compounds,
used in sealant manufacture, and in the formulation of organic peroxide catalysts (phlegmatizer
and dispersing agent).
The revised DCHP classification for developmental effects is not supported by the scientific
data. As detailed below, clear and sufficiently convincing evidence of an adverse effect on
sexual function and fertility or on development following exposure to DCHP has not been
demonstrated, despite this being a clear requirement for ascribing a category 1B classification
according to CLP Regulation. Therefore classification of DCHP as Category 1B according to
CLP is not scientifically supportable. Considering the classification considerations for
reproductive toxicity are consistent between CLP and the international UN Globally Harmonised
System (GHS) for classification, classification of DCHP as Category 1B is also not scientifically
supportable under GHS. No classification or at most classification as a Category 2 (“some
evidence”) reproductive agent would be consistent with the scientific data and balanced
interpretation versus the CLP and UN GHS criteria.
1The American Chemistry Council (ACC) represents the leading companies engaged in the business of chemistry.
ACC members apply the science of chemistry to make innovative products and services that make people's lives
better, healthier and safer. ACC is committed to improved environmental, health and safety performance through
Responsible Care®, common sense advocacy designed to address major public policy issues, and health and
environmental research and product testing. The business of chemistry is a $804 billion enterprise and a key
element of the U.S. economy. It is one of the nation‟s largest exporters, accounting for twelve cents out of every
dollar in U.S. exports.
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The significance of this proposed classification with regard to international trade is that, because
it not based on a robust weight of evidence scientific evaluation, it could lead to inconsistent and
very different regulatory conclusions in different regions leading to the disruption of trade of
articles made with DCHP and thereby constitute a barrier to trade. For example there is a
significant difference between the treatment of Category 1B reproductive agents and Category 2
under the EU REACH regulation, with Category 1B reproductive agents qualifying for the
REACH Candidate List as “Substances of Very High Concern”, with subsequent proposals for
phase out subject to specific time limited approvals (the REACH Authorisation process). In
addition it also means that articles made outside the EU containing DCHP and exported to the
EU will be subject to notification requirements under REACH. EU regulations also ban the use
of Category 1B substances in articles such as toys, electrical and electronic equipment and
medical devices with the associated implications of unjustified restriction in the trade of such
articles. So such articles containing DCHP will be subject to bans with the associated impact on
trade. If this non-robust weight of evidence scientific evaluation approach is more broadly
applied in the classification process, this could result in very broad impacts on trade. For
example agricultural produce can also be impacted by such scientifically unjustified
classifications, since crop protection agents which may be present as residues and which if
classified as Category 1B reproductive agents are considered as endocrine disruptors under EU
regulation, with the result that international trade of such produce could be impacted through
restrictions and bans. In view of these potential trade impacts of a Category 1B classification
under the CLP and/or GHS, it essential that robust scientific standards of evaluation are
rigorously applied.
Detailed information on the lack of sufficient scientific evidence to support a Category 1B
Classification for DCHP
According to the RAC report (Feb 2015), the DCHP Category 1B classification for
development is based on observations of reduced anogenital distance and mammae/nipple
retention in males; and recorded effects on male reproductive organs (testicular atrophy,
reduced testicular spermatid head count and decreased weight of the prostate and of the
levator ani/bulbocavernosus).
When considered in the light of the entire database, the
significance of these findings is low and therefore does not warrant classification.
o The CLP refers to this aspect as follows: “If, in some reproductive toxicity
studies in experimental animals the only effects recorded are considered to be of
low or minimal toxicological significance, classification may not necessarily be
the outcome.”
o In principle, classification of Category 1B on the basis of reduced anogenital
distance and mammae/nipple retention is not supportable as these are not
evidence of adverse effects but rather biological markers which have been shown
in many cases to be reversible. As defined by the WHO/IPCS (2004), an adverse
effect includes a change that results in impairment of functional capacity.
o A link between reduced anogenital distance and mammae/nipple retention with
impairment in reproductive functional capacity has not been established in rodents
or humans. Therefore, a reduction in male anogenital distance and retained
mammae/nipples in the absence of observed impairment of reproductive function
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cannot be considered “clear evidence of an adverse effect” and therefore cannot
lead to Category 1B classification.
While effects on reproductive organs were noted in some studies for DCHP,
the
toxicological significance of these reported findings is questionable as they are not
dose responsive, consistently observed, and/or reliably reported in the database.
o For example, it cannot be agreed that observations of testicular atrophy are
reliable in a study (Ayodogan Ahbab, 2013) the dossier submitter described as
„not so well reported‟.
This study failed to report several important parameters which are key for
understanding if the observed effects are chemical specific (e.g. clinical
signs, litter size, sex ratio, live birth index etc.).
The study also had gross errors in the reporting of organ weight outcomes
where, for example, the testes are reported to weigh more than the entire
animal; and questionable statistics (e.g. small standard errors were
calculated for endpoints with large variation in reported values).
o Deficiencies in study design impact the quality and reliability of the evidence and
should not be overlooked in assessments. The CLP refers to this aspect of study
quality consideration as follows: “if deficiencies in the study make the quality of
the evidence less convincing, Category 2 classification could be the more
appropriate classification.”
o The reported occurrence of reduced testicular spermatid head counts (Hoshino et
al. 2005) is also of questionable significance.
This observation was found in only one of the two generations of animals
examined; was not accompanied by a change in sperm motility
morphology, or number; and did not lead to any deficit in the ability of
these males to reproduce.
This finding was also not reported in other studies examining DCHP
effects on sperm (Ahbab Ayodogan, 2013). The identified decreased
weight of the prostate and levator ani/bulbocavernosus were also not dose
dependent nor consistently reproduced in the database as they were only
reported in one study (Yamasaki et al. 2009).
Consistency and toxicological significance of observations impacts the weight of the
evidence and should be considered in a classification determination. For DCHP, the above
observations are of low toxicological significance and therefore do not provide clear and
sufficiently convincing evidence to warrant classification as category 1B.
The RAC report aims to establish additional support for a Category 1B developmental
classification for DCHP through discussion of the toxicological data for a group of
substances termed „transitional phthalates‟ which have a harmonised classification of
developmental toxicants in Repro 1B. The CLP (and UN GHS) refers to and accepts
consideration of data on chemically related substances in a classification decision,
however if these considerations are to be important to classification both structural and
biological similarity need to be supported.
o The database for DCHP does not sufficiently support similarity in either of these
categories. DCHP has a cyclical sidechain structure whereas the comparative
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class of „transitional phthalates‟ have linear and/or branched sidechains of varying
length, making DCHP structurally distinct. This is of particular importance as the
effects on the male reproductive tract caused by certain phthalates are
hypothesized to be due to the carbon backbone lengths of the linear and/or
branched monoester side chain (Fabjen et al. 2006).
o The „transitional phthalates‟ referenced in the RAC opinion induce toxicological
effects that are much more prevalent, consistent and severe compared to those
effects observed for DCHP, making DCHP biologically distinct. For example, the
Low Molecular Weight phthalate DBP (classified as Category 1B) displays areola
mammae/nipple retention and decreased male anogenital distance in addition to a
number of adverse developmental effects such as a high incidence of hypospadias,
underdeveloped or absent epididymis and atrophy of seminiferous tubules.
o The structural and biological distinctions were recognised during the RAC
discussion. However, despite this, both substances will now be classified as 1B.
Having both substances classified as Category 1B is not in line with the scientific
data or the principle of proportionate decision-making.
In conclusion, the reporting of the hazard data for DCHP in the RAC report is
misrepresentative of what should be objectively and reasonably concluded from the
database.
Observations were considered significant without regard to their dose-responsiveness or
reoccurrence in the larger dataset, both of which are key principles for evaluating the
toxicological relevance of an outcome.
Negative data were not given equal weight with more weight being given to positive
unreliable outcomes than high quality negative outcomes.
A lack of a structured and transparent approach to data assessment results in an
appearance of greater certainty and weight in support of a hazard than the database
scientifically warrants.
A need for improved transparency and standardization to data assessment is exemplified
best by the disparity in the basis for the decision captured in the final CLH report (dated
February 4, 2015). In the opening scientific justification for the proposal, the basis for the
classification decision is summarized as follows: “
Most pronounced signs seen were
areole mammae/nipple retention and decreased anogenital distance, but also a
malformation (hypospadias) was noted”. This is inconsistent with the conclusion section
at the close of the document which reads: “
Effects on the anogenital distance as well as
on the occurrence of mammae/nipple retention in male pups were recorded in multiple
studies and the findings were considered to be specific and not secondary non-specific
consequences. Effect on male reproductive organs was also recorded (testicular atrophy,
reduced testicular spermatid head count and decreased weight of the prostate and of the
levator ani/bulbocavernosus) and these findings are considered to be specific and not
secondary non-specific consequences.” Based on these statements, the introduction of
the document reflects a classification basis of AGD, nipple retention, and hypospadias
whereas the concluding section reflects a classification basis of AGD, nipple retention,
and histology effects on male reproductive organs. Therefore it is unclear what data
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actually provide the basis for the decision and what level of evidence is considered by the
RAC as necessary for a classification decision.
To conclude on a classification determination, there is a need to take into account the evidence
for each substance in a robust weight of evidence approach and develop regulatory decisions that
are commensurate and proportionate with the data (as stated in section 3.7.2.3 of the CLP
regulation). Such an approach should result in the minimization of potential conflicts of interest,
whether these are commercial, political, institutional or personal. This is particularly important
when decisions such as a classification can trigger further regulatory measures, e.g. potential
candidate listing, with clear socio-economic implications for industry and society. As detailed
above, such a robust and transparent weight of evidence evaluation approach has not been
carried out in the case of DCHP resulting in a scientifically unjustified classification.
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