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Hcwh comments on

HCWH COMMENTS on the SCENIHR Preliminary Report: Safety
of Medical Devices Containing DEHP-plasticized PVC or Other
Plasticizers on Neonates and Other Groups Possibly at Risk

1. We applaud a number of statements made in this report.
a. We applaud the statement, (abstract p. 3, executive summary p. 4, text p. 44) that the potentially high exposure during medical treatments raises a concern, even in the absence of current clinical or epidemiological evidence, for harmful effects in humans. b. We applaud the recognition of the multiple vulnerable groups for which DEHP toxicity poses concern (neonates, male offspring, pregnant and lactating women, and patients undergoing treatment resulting in high levels of DEHP exposure): “Recent information on the exposure of the general population and especially of the vulnerable groups raised a concern on the potential toxicity of DEHP. Vulnerable groups are male infants, male offspring of pregnant and breastfeeding women undergoing certain medical procedures that may result in general in short-term exposure to relatively high levels of DEHP.”(p. 43) • patients receiving massive blood infusions due to traumas • patients receiving heart transplants or coronary artery bypass surgery • patients receiving enteral nutrition • neonates receiving exchange transfusions, ECMOs, Total Parenteral Nutrition, and other procedures in premature neonates (pp. 35-36.) “The EU risk assessment for DEHP (ECB 2006) identified the most critical effects as on the testes, fertility, development (anogenital distance), and kidney (repeated dose). The sensitivity for such endocrine effects is highest during gestation and the first month after birth when the most sensitive organs are developing. It has to be considered that there is the potential exposure for infants to other phthalates (chapter 3.5) that are toxic to reproduction, which may have via similar mechanisms of action as DEHP.” (p. 36) c. We commend the recognition of the cumulative effects from multiple exposures to other phthalates such as DBP, DIBP, which CAN create effect additivity to the toxic risks from DEHP: “Neonates may therefore be considered to be at risk for the adverse reproductive and developmental effects of DEHP. In addition, they may be exposed to other phthalates especially DBP and DIBP, and these phthalates may act additively with DEHP.” (p.43) “The focus of this opinion is on the possible risk for patients exposed to medical devices, but as there is a considerable exposure to plasticizers for the general public, this has been taken into account in the evaluation.” (p. 12) “Developing fetus and the neonate represent the most vulnerable phases of life particularly with regard to developmental and reproductive toxicity. In particular, neonates in the Neonatal Intensive Care Unit (NICU) environment, due to their small body size, thein physical condition and multiple medical device-related DEHP exposure (feeding tubes, infusion tubing systems, umbilical catheters, PVC blood bags, transfusion tubing systems, hemodialysis systems, cardiopulmonary bypass, continuous peritoneal dialysis, extracorporeal membrane oxygenation circuits or endotracheal tubes) combined with thein developmental vulnerability represent a population at particularly increased risk (CERHR 2005; FDA 2001; Health Canada 2002). “In fact, neonates receive higher doses, in terms of body weight, of DEHP than the general population (Calafat et al. 2004b; Green et al. 2005) and their daily dose to DEHP may increase up to 20 folds the tolerable daily intake (Jaeger et al. 2005). The combination of prenatal and postnatal exposures may exacerbate the reproductive hazard. Therefore a concern was raised about potential health effects of DEHP (CERHR 2005, ECB 2006).” (pp. 24-25) d. We commend the Committee for its finding that a Tolerable Daily Intake value for DEHP is not appropriate, given the potential high exposures during certain medical procedures and the very special group of patients involved. (p. 44) 2. However, we strongly criticize a number of sections and particular ‘editorialised’
sentences in this report. There are a number of places where the qualifying
statements or lack thereof show a consistent tendency either to imply that
alternative, non-PVC materials are a problem in comparison to the existing DEHP-
softened plastics or to omit an equally objective comment about alternative
plasticizers or DEHP-softened PVC devices. This tendency seems to amount to an
outright bias, which is also evident from the Committee’s interpretation of their
remit to exclude alternative plastic devices.

a. Firstly, we criticize the committee’s interpretation of their remit. The actual 2.1 Update of the scientific opinion adopted in September 2002 on DEHP plasticized medical devices. Taking into consideration recent scientific developments, the SCENIHR is requested to review and update, if appropriate, the scientific opinion adopted in September 2002 on “Medical Devices containing DEHP Plasticized PVC; neonates and other groups possibly at risk from DEHP toxicity”. In particular, the Scientific Committee is requested to evaluate: If DEHP in PVC plasticized medical devices is a cause for concern to neonates and children in paediatric care, in particular in relation to male fertility and tissue development, If there are other patient groups at risk, in particular in view of clinical procedures resulting in high exposure, If it is possible to establish Tolerable Intake Values of DEHP leaching from soft PVC as a basis for risk assessment for high risk patient groups, taking into account the route of exposure. 2.2 Medical devices containing alternative plasticizers: possible risk for certain uses or to certain patient groups. Since alternative DEHP free medical devices have been developed and are used to treat patients, the Scientific Committee is requested to evaluate the potential risks of currently available alternatives in relation to patient health, when used in medical devices. While the first sentence of item 2.2 is clearly referring to alternative plasticizers
(plasticizers other than DEHP), the second sentence refers to ‘currently available
alternatives’ – as in ‘alternative DEHP-free medical devices’ – which includes both
DEHP-free PVC devices which use other plasticizers; and non-PVC medical devices
which do not depend on plasticizers for their plasticity or flexible qualities
. These
non-PVC medical devices are already on the market, and provide a significant
alternative, because they do not pose the toxicity risks from DEHP or other plasticizer
leaching.
Moreover, the report makes explicit mention of these non-PVC alternatives: “A number of other substances are used as plasticizers in medical devices, and some
non-PVC based materials are also available as alternative to DEHP-PVC
.” (our
italics, p. 11)
b. Secondly, we strongly criticize the statement that no information on these “The results of this Call for Information and information available from other sources were used as a basis for the following evaluation on DEHP and its alternatives in PVC medical devices. Consequently in this report only the risks from DEHP and possible alternative plasticizers for which sufficient suitable information has been provided are considered.” (p. 11) “Possible alternative materials could not be evaluated in view of the lack of an analysis of the risks associated with these materials at that moment." (p. 11) “Although the published Call for Information included both alternative plasticizers and alternative materials, only the former was submitted.” (p. 43) During the call for information, Health Care Without Harm submitted the following information, including about alternative materials: • Phthalic acid esters in patients undergoing long-term haemodialysis, Kamil Sevela, Arnika Association, Health Care Without Harm, January 2005. (also the original Czech version of this article in Vnitr Lék 2005; 51(S2)). • Decrease in Anogenital Distance among Male Infants with Prenatal Phthalate Exposure, Shanna H. Swan et al, Environmental Health Perspectives, Volume 113 (8), August 2005 • Use of Di(2-ethylhexyl) Phthalate–Containing Medical Products and Urinary Levels of Mono(2-ethylhexyl) Phthalate in Neonatal Intensive Care Unit Infants, Ronald Green et al, Environmental Health Perspectives Volume 113 (9), September 2005 • Human Breast Milk Contamination with Phthalates and Alterations of Endogenous Reproductive Hormones in Infants Three Months of Age, Katharina M. Main et al, Environmental Health Perspectives Volume 114(2), February 2006 • Dibutylphthalat (DBP) in Arzneimitteln: ein bisher unterschätztes Risiko für Schwangere und Kleinkinder? Holger Martin Koch, Johannes Müller, Hans Drexler, Jürgen Angerer, Umweltmed Forsch Prax 10 (2) 144-146, 2005 • Exposure to Di-(2-Ethylhexyl) Phthalate Among Premature Neonates in a Neonatal Intensive Care Unit, Antonia M. Calafat, Larry L. Needham, Manori J. Silva and George Lambert, Pediatrics 2004;113;429-434 • Health Canada Expert Advisor Panel on DEHP in Medical Devices, Final Report 2002 • USA National Toxicology Program-Centre for Evaluation of Risks to Human Reprodution Expert Panel Update on the Reproductive and Developmental Toxicity of Di(2-ethylhexyl phthalate, NTP-CERHR-DEHP-05, November 2005 • Revised European Community Risk Reduction Strategy on DEHP, March 2006 • Alternatives to Polyvinyl Chloride (PVC) and Di(2-Ethylhexyl) Phthalate (DEHP) Medical Devices, Health Care Without Harm, Pub 3-05 22 March 2006. • Preventing Harm from Phthalates, Avoiding PVC in Hospitals, Karolina Ruzickova, Madeleine Cobbing, Mark Rossi, Thomas Belazzi, Health Care Without Harm, June 2004. We point out that a large number of alternative non-PVC medical devices are currently carrying the necessary ‘CE’ marking proving compliance with the European conformity assessment procedures, and therefore they have undergone the necessary testing for medical devices in accordance with the Medical Devices Directive. We therefore contest the statement that analysis of risks of these materials is lacking, particularly in view of the fact that the Committee was clearly able to obtain sufficient data to conduct customized risk assessments, as it were, for trimelitates, DOTP and citrates. (See for instance the articles included in the appendix to this comment). c. We criticize the discussion of blood bags, because it does not explicitly point out that the advantages of DEHP leaching into blood bags prolonging the longevity of blood storage is an exceptional case compared to most other existing DEHP-softened PVC medical devices, where the leaching is of great concern (p.13). d. We criticize the statement that the long-term effects of alternative materials, when used in medical devices, are not well known (p. 9). This wording implies that the long-term effects on human health of the use of DEHP-plasticized medical devices are known, when that is not the case (see point C above). There is no accompanying qualifying sentence which explicitly states that the same unknown applies to DEHP-plasticized medical devices. e. We criticize the qualifying sentence in the paragraph on page 13 that refers to the opportunities for alternative materials: “However, this probably can not be
achieved for all medical procedures”. It has never been argued that it is either
possible or necessary to use alternative materials for all medical procedures, nor
for all patients, given the existing range of alternative plastic devices. We find this
sentence shows the tendency to bias as noted in point 2 above, by attempting to
reduce the significance of the prior statement “It is possible to greatly reduce the
use of DEHP-PVC in hospital procedures as demonstrated in several hospitals around
Europe”.
f. We strongly criticize the final sentence in the 3rd paragraph of the Conclusion to 3.4.9 Newborns at Risk, which again shows a consistent bias against alternative
plastic medical devices, and for phthalate-plasticized PVC devices.
“Premature neonates in intensive care can receive even higher DEHP exposures
than adults relative to their body weight (up to 35 mg/kg bw over 10 day period).
This exposure may be even higher than the doses observed to induce reproductive
toxicity in animals. In effect, this means that there is no margin of exposure (MoE)
for certain procedures. However, this is justified by the beneficial effects of
these procedures
.” (p. 35)
The exposures can in no way be justified by the beneficial effects of those procedures if those procedures can be equally delivered by other devices which do not produce such high DEHP exposures. Another example of the bias against alternative plastic medical devices, and for
phthalate-plasticized PVC devices can be found on page 36.
“It should be noted that medical devices made from plasticized PVC provide many effective treatments.” The same can be but is NOT said of medical devices made from non-PVC plastics already on the European market, and in use in numerous European hospitals. g. Yet another example of the BIAS against alternative plastic medical devices, and
for phthalate-plasticized PVC devices can be found on page 42.
“However, these exposure levels from the use of certain medical procedures should be considered in the light of treatment needed.” The exposures should be considered in the light of the treatments possible with
non DEHP leaching medical devices
. If alternatives are available, the risk-benefit
balance of the exposures is altogether different.
h. The committee neglected to discuss two studies which have detected the non- monotonic dose response patterns in animal studies in relation to neurological and immunological systems. Given that the non-monotonic dose response patterns challenges the adequacy of safety testing done at higher doses, we find this omission disturbing. • Takano, H, R Yanagisawa, K-I Inoue, T Ichinose, K Sadakano, and T Yoshikawa. 2006. Di-(2-ehylhexyl) Phthalate Enhances Atopic Dermatitis-Like
Skin Lesions in Mice. Environmental Health Perspectives 114: 1266-1269.
• Andrade, AJM, SW Grande, CE Talsness, K Grote and I Chahoud. 2006. A
dose–response study following in utero and lactational exposure to di-(2-
ethylhexyl)-phthalate (DEHP): Non-monotonic dose–response and low dose
effects on rat brain aromatase activity. Toxicology 227: 185-192
The implications from these studies are that any level of exposure to DEHP via medical devices, for pregnant women are of major concern. 3. In conclusion, we find this long-awaited opinion disappointing. We do commend the
Committee on its recognitions of the toxicity dangers posed by DEHP in medical
devices. But the strand of biased implications and one-sided comments regarding
alternative non-PVC medical devices and ultimately the deliberate exclusion of
these, particularly when the enormous work undertaken to deliver risk-assessment
of other plasticizers is considered, leave this report sorely lacking in relevant
conclusions.

APPENDIX
Articles concerning leaching from non-pvc alternative plastics: 1. Trissel, Lawrence A; Xu, Quanyun A; Baker, Mary “Drug compatibility with new
polyolefin infusion solution containers” AMERICAN JOURNAL OF HEALTH-SYSTEM
PHARMAC
Y
ABSTRACT
Purpose. The compatibility of new polyolefin (VISIV) containers with
seven drugs that have exhibited sorption to polyvinyl chloride (PVC) containers and sets and an additional four drugs that have exhibited leaching of plasticizer or other polymer matrix components from PVC containers and sets was studied. Methods. For the sorption portion of the study, amiodarone hydrochloride,
carmustine, regular human insulin, lorazepam, nitroglycerin, sufentanil citrate, and
thiopental sodium and their respective reference standards were used. For the
leaching portion of the study, docetaxel, paclitaxel, tacrolimus, teniposide, and
diethylhexyl phthalate (DEHP) reference standard, were used. A 350-mL quantity of
each test admixture was prepared, and 100-mL aliquots were transferred into three
of the VISIV containers. The containers were stored at ambient temperature and
exposed to fluorescent light. Samples for analysis were taken initially and after 24
hours for all drugs except carmustine, which was evaluated for only 6 hours
because of its limited stability. High-performance liquid chromatography was used
to evaluate each test solution.
Results. Of the seven drugs subject to sorption to PVC, only insulin showed a
substantial loss in the VISIV containers. Carmustine exhibited a loss consistent with
the drug's known chemical stability. None of the drugs that are known to leach
plastic components, such as DEHP plasticizer, from PVC equipment exhibited any
leached components in the VISIV containers.
Conclusion. Of the drugs tested, only insulin exhibited sorption to the new VISIV
polyolefin containers. No leaching of plastic components, such as plasticizer, from
the containers was found with any of the surfactant-containing drugs.
2. Bagel-Boithias, S; Sautou-Miranda, V ; Bourdeaux, D ; Tramier, V ; Boyer, A;
Chopineau, J “Leaching of diethylhexyl phthalate from multilayer tubing into
etoposide infusion solutions” AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY

ABSTRACT
Purpose. The extent of leaching of diethylhexyl phthalate (DEHP) from
various polyvinyl chloride (PVC), polyethylene (PE), coextruded (PVC and PE), and triple-layered (PVC, ethyl vinyl acetate, and PE) i.v. extension tubing into etoposide infusion solutions was studied. Methods. Different lengths of tubing (25, 50, and 80 cm) were tested in two types
of experiments: (1) static, in which the etoposide solution was left in contact inside
the tubing for various times and then removed, and chromatography was used to
quantify the DEHP content of the effluate, and
(2) dynamic, in which infusion was simulated using syringe reservoirs, and three flow rates were tested to assess the effect of flow rate on the quantities of DEHP leached. Results. The static study showed that large quantities of DEHP were leached from
all tubing types except the PE tubing. The dynamic study confirmed that leaching
occurred, although the values were below the threshold limit of 5 mug/mL. The
values varied depending on flow rate, tubing length, and etoposide concentration.
The coextruded and triple-layered i.v. tubing did not provide the inertness and
safety they are intended to have, as DEHP not only leached out but did so in
quantities almost equivalent to those found with tubing made of PVC only.
Conclusion. DEHP leached rapidly from PVC, coextruded, and triple-layered i.v.
tubing into etoposide infusion solution. The quantity of DEHP found in the infusion
solution was influenced by the length of the tubing and concentration of etoposide.
3. “Extraction of Di-ethylhexyl-phthalate from perfusion lines of various material,
length and brand by lipid emulsions” JOURNAL OF PEDIATRIC GASTROENTEROLOGY
AND NUTRITION

ABSTRACT
Background: The plasticizer di-ethylhexyl-phthalate (DEHP) is extracted especially
by lipid emulsions from polyvinylchloride infusion systems. The aim of this study
was to systematically examine the extraction from perfusion lines commonly used
in our hospital for lipid emulsion infusions.
Methods: Perfusion lines made from polyvinylchloride of various lengths and
brands, polyethylene, polyvinylchloride/polyethylene (PVC/PE) and
polyvinylchloride/poly urethane (PVC/PU), were perfused with lipid emulsions
according to the circumstances of newborns on an intensive care unit, i.e. high
temperature, 24-hour duration and low quantities. Concentration of di-ethylhexyl-
phthalate was determined with gas chromatograph mass spectrometry.
Results: The lipid emulsions before perfusion had a contamination with DEHP of
0.82 mug/ml. Pure PVC lines of 1.5 m length leached between 74 mug/ml and 107
mug/ml. Sterilization of the lines did not influence DEHP extraction. After
perfusion of DEHP-free PVC lines and PVC-free lines, the emulsions had a
contamination with DEHP of 0.23 mug/ml and 0.11 mug/ml, respectively. PVC/PU
co-extruded lines leached 73 mug/ml. PVC/PE lines leached 41.6 mug/ml.
Conclusions: Lipid emulsions contain a production-inherent load of DEHP. Perfusion
through PVC-perfusion lines extracts a varying large amount of DEHP depending on
length and brand of the perfusion lines. Co-extruded PVC/PU and PVC/PE lines,
intended to avoid DEHP contamination, leach a similar amount of DEHP and thus do
not avoid the DEHP toxicity issue. The load accumulated by a baby on an intensive
care unit easily reaches several milligrams of DEHP per day. As its effect upon
biologic systems has been proven, and alternatives (PE or PU perfusion lines) are
available, PVC and PVC co-extruded perfusion lines should be abandoned for
infusions, especially in babies.

Source: http://ny.pvc.dk/billeder/SoftPVC/selecteddocuments/medicaldevices/SCENIHR.pdf

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