Dies ist eine HTML Version eines Anhanges der Informationsfreiheitsanfrage 'Documents regarding endocrine disruptors DG TRADE'.






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.  
 
americanchemistry.com®                                  700 Second St., NE | Washington, DC | 20002 | (202) 249-7000                                                                       


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 
americanchemistry.com®                                  700 Second St., NE | Washington, DC  20002 | (202) 249.7000                                                                       


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 
americanchemistry.com®                                  700 Second St., NE | Washington, DC  20002 | (202) 249.7000                                                                       


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 
americanchemistry.com®                                  700 Second St., NE | Washington, DC  20002 | (202) 249.7000                                                                       


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. 
 
americanchemistry.com®                                  700 Second St., NE | Washington, DC  20002 | (202) 249.7000