THE ISSUE
There have been concerns over possible health effects of di(2-ethylhexyl)phthalate (DEHP) for many years but public awareness was relatively limited until two years ago, when advocacy groups such as Green Peace and Health Care Without Harm brought media attention to these concerns. The initial focus then on possible carcinogenic effects of products containing DEHP has turned out not to be the most important issue. Instead, other potential effects seen largely in animal studies and particularly related to possible reproductive problems now appear of more concern. The possibility that such effects might occur in susceptible humans requires rigorous study. If such effects appear to be a significant risk in any human population this could require regulation of use of the product by Health Canada (HC). Therefore, the Expert Advisory Panel was formed to advise HC on the scientific evidence for any risk and possible actions which would reduce or eliminate exposure, and therefore any possible risks.
THE PANEL
Selected by HC, the members represented a broad range of expertise on the use of DEHP, the science related to its potential effects and clinical practice with DEHP containing products. Covering areas such as transfusion practice, intravenous therapy and drug administration, the range of expertise included clinical practice in medicine, nursing, neonatology, family practice, pharmacy, and poison information. In addition, there was an expert on blood products' uses, and one member, a toxicologist and specialist in risk assessment, was nominated by the plastic industry*. HC representatives included a toxicologist with specific knowledge on substances used in medical devices.
PANEL MEMBERSHIP LIST
Dr. Robin Walker (Chair) Children's Hospital of Eastern Ontario
Dr. Donald Branch Canadian Blood Services/The Toronto Hospital
Zorina Flaman, Registered Nurse at the Hospital for Sick Children Ontario
Regional Pois on Information Centre and Medical Information Centre
Dr. Gail Rock Canadian Hematology Society
Dr. Natalie Dayneka Pharmacy, Children's Hospital of Eastern Ontario
Dr. Ron Brecher* GlobalTox International Consultants Inc.
Dr. Mindy Goldman Héma-Québec
Dr. Kapil Khatter College of Family Physicians of Canada
HEALTH CANADA REPRESENTATIVES
Dr. R. Peterson
Ms. B. Pieterson
Dr. I. Hinberg
Dr. W. Freeland
Dr. B. Foster
Ms. H. Shahbazian
Ms. M. Davis
TERMS OF REFERENCE
The Therapeutic Products Directorate (TPD) Expert Advisory Panel on Di(2-ethylhexyl) phthalate (DEHP) in medical devices (EAP-DEHP) has been established to review the methodology and conclusions of the Exposure and Toxicity Report prepared by the Medical Devices Bureau (MDB), review and comment on the proposed risk management options, and advise the Directorate in developing position statement on DEHP in medical devices. Decision-making responsibility remains with Health Canada.
1. MANDATE
The Panel will fulfil its mandate by reviewing documentation provided by the TPD and advising on specific questions regarding the methodology and conclusions of the MDB report and other scientific or medical issues identified by the Directorate relating to these products.
2. REPORTING STRUCTURE
The Panel reports to the Director General, TPP, who acts as the Executive Secretary to the Panel. The TPD provides secretariat support to the Panel.
3. MEMBERSHIP / PARTICIPATION / QUALIFICATIONS
The Panel members will be selected for their expertise and knowledge pertinent to the mandate of the Panel. The Director General will select members and appoint a Chair.
The membership of the Panel as a whole will cover areas of expertise and knowledge such as: reproductive toxicology, paediatrics, neonatology, haematology, pharmacokinetics, biostatistics, epidemiology, public health and risk assessment. Members will serve on the Panel as knowledgeable individuals in their own right and in the best interests of Canadians.
Health Canada staff will not serve as members of the Panel, but will provide Secretariat support and respond to questions and provide information at the call of the Chair.
4. PROPOSED TENURE
The Panel has a finite term and once the mandate is fulfilled the Panel will be disbanded. The members will be appointed for the duration of the Panel. An individual may withdraw from service on the Panel at any time upon written notification to the Director General.
In the future, members might be invited to participate in other Health Canada Expert Advisory Committees to provide advice on issues for which their expertise would be suitable.
5. SECURITY CLEARANCE, CONDUCT AND CONFLICT OF INTEREST
Documents leaving Health Canada must be securely stored at all times. Information must be returned to Health Canada, including electronic and word processing records.
Panel members are expected to conduct themselves in an appropriate manner, i.e. the use of their positions cannot be reasonably construed to be for their private gain, or that of any other persons or organization. They must refrain from any conflict of interest and, indeed, its very appearance.
In situations where conflict of interest, or the appearance thereof arises in the course of the work of the Panel, the individual involved must declare its existence. A decision to disqualify the individual from participation in the discussion will be made by the Chair in consultation with the Director General, according to the circumstances or specific situation.
Guidance on conflict of interest will be provided to potential members when discussing the appointment. Before appointment, all potential Panel members will be required to submit conflict of interest declarations to disclose to the Directorate any circumstance that may place, or be seen to place, the member in a real, apparent or potential conflict of interest. It will be incumbent upon the member to update their disclosure should their personal situation change.
All members must protect and maintain as confidential any trade secret or privileged information divulged during the work of the Panel. Members may only discuss this information with persons on the Panel or Therapeutic Products Directorate staff; they must not divulge information obtained from the work of the Panel, including presentations made to it and the Panel's deliberations, until such time as this information has been officially released for public distribution.
6. COMPENSATION
Members will be compensated for travel expenses according to federal government policy. Honoraria may be paid to persons outside the Government of Canada for the performance of a service. The per diem rate for honoraria will be set by the Therapeutic Products Directorate. Specific contractual arrangements will be made should additional work be offered or assigned to committee members.
7. MANAGEMENT AND ADMINISTRATION
The specific question(s) for Panel discussion will be determined by the Therapeutic Products Directorate staff. The agenda will be developed by the Executive Secretary, or designate, of the Panel in collaboration with the Chair. Prior to meeting, members will receive an agenda, briefing materials and other documentation as far as possible but at least seven days in advance of meeting(s). The meeting(s) will be held in the National Capital Region or by teleconference if the need arises. Panel members will be expected to demonstrate fairness and a commitment to in-depth examination of the matter under review.
Minutes of the meeting(s) will be circulated to members after approval by the Chair. The minutes will be kept to the minimum detail required to effectively summarize the proceedings. There will be no attribution. There will be no other recording of meetings.
Decisions of the Panel will be reached by consensus, and will be recommendations to the Director General, Therapeutic Products Directorate. Reasons for lack of consensus, if any, must be clearly identified and substantiated. If appropriate, with respect to further study of the issue, a proposal for resolution may also be made.
METHODOLOGY
The Panel was provided with the following MDB report:
Prior to the first meeting, Panel members were advised to search the literature for additional information pertaining to their fields as well as to provide answers to specific questions presented to the panel by HC. Each Panel member brought to the meeting references or papers pertinent to the discussion. HC obtained copies of any further literature requested by the panelists during their discussion. Additional reports requested by the Panel or other information have been provided to the members subsequent to the EAP meeting. These include numbers 9-13 from the above list (information from these reports has been incorporated into the following report, including where appropriate in the Panel's recommendations.) The Panel initiated discussion around a framework of questions suggested by HC but was free to explore all aspects of the topic under discussion as will be seen in the following report. However, in making its recommendations, the Panel was fully aware these are merely advisory to HC. HC, in its capacity as regulator has the responsibility of decision-making. In the presence of certain or possible risks, HC, in its capacity as regulator, will err on the side of caution. HC will also balance decisions according to the known risks, and the consequences of proceeding with or without regulation.
Panel Chair Dr. Robin Walker prepared the report with the assistance of selected Panel members. This method was utilized to ensure no conflict of interest nor perception of conflict of interest was perceived in the writing of the report. However, all members of the Panel were invited to comment on the report; thus the report's text and recommendations were subjected to the approval of the entire Panel. Although the toxicity of DEHP and other similar phthalates has been extensively studied, there remain significant gaps, in particular an almost complete absence of data on effects in humans. Thus, the Panel reached a consensus by collaborating to interpret the scientific evidence available. In addition, the Panel utilized the expert knowledge of its members in formulating the report. Definitive recommendations were achieved in several areas. These were accompanied by an explanation to HC attempting to give a clear sense of how such recommendations have been arrived at by the EAP.
Finally, two Panel members (Chair Dr Robin Walker and toxicologist Dr Ron Brecher) attended a meeting between the HC Medical Devices Bureau and the Vinyl Council of Canada (a member of the Canadian Plastic Industry Association), the Phthalate Esters Panel and the American Chemistry Council on 2001 December 14th. At this meeting, they heard several presentations of new and recent studies and discussed their findings. These studies re-assess certain aspects of the toxicity of DEHP in rodents and refine NOAEL values. The studies provide some reassurance that the rodent NOAEL for both parenteral and oral exposures may be somewhat higher than thought previously and also fill in some important data gaps. In addition, the Panel representatives heard about plans for additional studies intended to fill remaining data gaps. However, primate data are not currently available, and the possibility of adverse effects from high exposures in potentially sensitive humans cannot be ruled out at this time. Therefore the Panel believes that the following recommendations represent the most prudent approach at the present time and until more human data become available.
SAFETY PROFILE AND POSSIBLE TOXICITY OF DEHP,RELEVANCE OF MECHANISMS OF ACTION, AND ENVIRONMENTAL ISSUES
There are essentially no data to confirm toxicity of DEHP or its metabolites in humans; indeed DEHP has been used in the plastic used to produce blood bags for several decades without reports of disease or unexplained "abnormalities" in humans. Such limited studies as exist are clearly inadequate in design and outcomes to demonstrate cause-effect relationships between DEHP exposure and toxicity. Therefore evaluation of risk to humans can only be extrapolated from animal data. Such extrapolations are questionable (without the incorporation of quantitative data on interspecies differences or human variability in toxicokinetics and toxicodynamics into the toxicity assessment) since there are significant species differences in metabolism that may completely alter the effect of a substance between experimental animal models and the human. This means that confirmed toxicity in an animal species may not occur at all in the human; or conversely a substance that appears safe in animals may ultimately demonstrate significant toxicity in humans. Only good quality and extensive human data can reliably confirm or refute a concern about toxicity.
This is particularly important for DEHP in the case of carcinogenicity. DEHP induces liver tumours in rats and mice when administered at high doses in their diet. The International Agency for Research on Cancer, however, has concluded that the mechanism by which this occurs in rodents is NOT relevant to humans. The Panel accepts the IARC conclusions and recommends that at this time the cancer endpoint not be considered in making recommendations about DEHP in medical devices.
Conversely, although there are also no data on the reproductive and developmental toxicity of DEHP or its metabolites in the human, the mechanism by which developmental and testicular toxicity in particular occur in rodents appears relevant to humans. It is not possible to assess the degree of risk based on rodent data because a) dose and, in most cases, the route of exposure (oral in the animal experiments) are different from in the human, and b) although qualitatively similar, there are several major differences between the metabolism of DEHP in rats and primates. Therefore it is not possible to even estimate the NOAEL (noobservable-adverse-effect level) of DEHP in humans from the animal data or even to be certain that such toxicity can occur. Nevertheless the Panel concluded that the animal data must be taken to indicate at least the theoretical possibility of developmental and testicular toxicity, particularly in the young human with high exposure levels.
Our conclusions are therefore contrary to the June 1999 review and consensus statement of the American Council on Science and Health, which states that "DEHP, as used in medical devices, is not harmful to humans even under chronic or higher-than-average conditions of exposure". On the other hand, our conclusions are very similar to those of the October 2000 NTP-CERHR Expert Panel report. The October 2000 panel and our Panel both concluded that the risk of developmental and reproductive problems in the general adult population is small; but the risk to infants, toddlers, critically ill children and during pregnancy and lactation may be more significant. Thus our Panel will make recommendations in the following report that relate to those likely to be at highest risk of this theoretical possibility, namely (in approximate order starting from the highest theoretical risk), newborns, infants, toddlers and children with critical illnesses, those sub-populations exposed to relatively high 'doses' of DEHP and the developing fetus. We will also make recommendations that alternatives to DEHP should be assured to have a safety profile at least as good as DEHP before being introduced into medical devices to replace DEHP.
Finally, the Panel also briefly considered the impact of DEHP on the environment. DEHP is recognized as a toxic substance in the Canadian Environmental Protection Act (CEPA). However, the CEPA Assessment Report found insufficient information to determine whether DEHP is having a harmful effect on the environment. Indeed it concluded that DEHP "is not entering the environment in a quantity or concentration or under conditions that constitute a danger to the environment on which human life depends." As a result the CEPA Strategic Options Report of Stakeholder Consultations on DEHP affirmed that "it would not be advisable that Environment Canada and Health Canada proceed with further risk management actions at this time." For the purposes of this report, the Panel recognizes that the environmental impact of DEHP, while an important issue, falls outside our terms of reference. However, the Panel considers the possible environmental impact of any substance entering the environment to be worthy of study and it is clear that our recommendations would not increase and would potentially decrease entry of DEHP into the environment.
THE QUESTIONS PRESENTED TO THE PANEL
1. CLINICAL PRACTICE
Does the Expert Advisory Panel have information on current clinical practices for the following medical procedures:
(1) Extracorporeal membrane oxygenation (ECMO) procedures: The MDB report discusses a study suggesting that ECMO using heparin-coated tubing would expose the patient to little or no DEHP. The use of this tubing appears to be the current standard of practice in the US but not in Canada. Heparincoated ECMO circuits are commercially available. How common is their use?
ECMO is a relatively infrequent technology intensive procedure used particularly in newborns and infants. Scientific data on its efficacy is limited -- the only randomized newborn ECMO trial to date, conducted in Britain, gave equivocal results. The trial investigators interpreted the results as showing efficacy of ECMO when used for certain newborn illnesses. However, the management of the intervention and control groups was very different in respects other than ECMO use, diluting the significance of the findings. Data on ECMO in infants beyond the newborn period is even more limited. Thus the panel recognized that further study on the use of ECMO itself is required.
When utilized the procedure uses apparatus similar to the heart-lung machine to 'rescue' babies in lung failure. Treatment is usually necessary for several days and sometimes for weeks. The panel believes that there are only two funded Canadian centres for ECMO; Montreal Children's Hospital treats about 10-15 patients/year and the Royal Alexandria Hospital in Edmonton treats about 20-30/year. The Children's Hospital of Eastern Ontario (CHEO) in Ottawa and the Hospital for Sick Children in Toronto, among others, also use the procedure but only infrequently and usually on infants beyond the newborn period. Numbers treated by ECMO appear to be declining in all North American centres as other less invasive treatments are developed for these infants.
Although fewer than 40 babies per year may be receiving ECMO in Canada, there are many complications and each baby could possibly use many kits in the course of one treatment. Even so, the cost of suggesting replacement of DEHP kits with alternate products might still be reasonable; the number of procedures per capita is limited and only a small number of babies are exposed to DEHP through ECMO. Therefore, the panel felt that the cost of alternate materials for this procedure should not be a major consideration.
The sets currently used in the US consist of heparin-coated (DEHP-containing) PVC tubing and non-PVC filters. The use of heparin-coated tubing for ECMO is popular because of its clinical benefits. Hemorrhagic disorders due to systemic heparinization are frequent during ECMO. There is evidence that the use of heparin-coated tubing for ECMO improves the safety of this procedure by greatly reducing the thrombogenicity of the extracorporeal circuit (effect on platelets, etc.) and, therefore, reducing the need for systemic heparinization in an extracorporeal life support system. Thus, reduced postoperative blood loss and, as a result fewer transfusions, are the main benefits of heparin-coated equipment allowing for perfusion with low systemic heparinization. The expert members have been informed that heparin-coated tubing is commonly being used in Canada for this procedure.
[Another factor to be considered is the use of different filters in the process, which could make a difference in the amount of DEHP exposure. Different filters may cause significant levels of hemolysis. However, the Panel is not aware of any reports that the rate of DEHP leaching or the level of DEHP exposure increases because of hemolysis. There could be an indirect effect if kits with filters that cause significantly higher levels of hemolysis are likely to be changed more frequently. The number of kits used per day is also partially dependant on how often the filters clog up. Usually one kit is needed per day on average. It is possible that more frequent changing of filters increases the patient's exposure to DEHP because the release of DEHP from PVC tubing is non-linear with time, with much more DEHP being released in the first 6-12 hours than in the next 12. The Panel knows of no additional information on the impact of different filters at this time.]
RECOMMENDATION 1
While it is not within the Panel's mandate to determine whether or not ECMO is an effective treatment, it does recommend that alternate products that are already available, (i.e., heparin-coated tubing,) should be utilized for all ECMO procedures in newborns and infants.
(2) IV infusion of drugs: Drugs such as Taxol and Cyclosporine that extract large amounts of DEHP from PVC should be prepared in non-PVC containers and administered through non-PVC tubing. Is this currently the standard practice in Canada?
Currently, PVC tubing is routinely used for administration of most drugs (including lipophilic drugs) in Canada to patients of all ages (adults and infants). When non-PVC is recommended by the drug manufacturer as with some newer drugs and chemotherapy agents, healthcare professionals strictly adhere to the instructions. However the situation is different with the older drugs, as there is no warning on the label.
Different procedures are used in the preparation, storage and administration processes of drugs that could affect the amount of exposure to DEHP. Some of the issues include:
A recent letter to health care professionals from a drug manufacturer states:
"An expert panel recently concluded that, based on data from animal studies, there was concern that exposure to DEHP may adversely affect male reproductive tract development during fetal, infant, and toddler stages of development if the exposure in these immature stages is several fold higher than in adults, a situation that might be associated with intensive medical procedures such as those used in critically ill infants. Although a no-observable-adverse-effect level (NOAEL) by the oral route was identified for sexually mature rats (3.7-14 mg/kg per day), a NOAEL was not identified for rats in the postnatal stage. The maximum anticipated exposure to DEHP following Cordarone I.V. administration under conditions of pediatric administration was calculated to be about 1.9 mg/kg per day for a 3-kg infant, which produces a safety margin of between about twofold and sevenfold." Wyeth-Ayerst Pharmaceuticals, Letter to Health Care Professionals, 2001 June 08.
[This particular concern about the leaching of DEHP into Cordarone IV preparations was due to the presence of the surfactant, Tween 80. All IV drug products that contain not just Tween 80 but any other surfactant are of concern because of the possibility that the surfactant will leach out large amounts of DEHP.]
RECOMMENDATION 2
Tubing and storage bags used for administration of lipophilic drugs or drugs which contain surfactants (i.e., lipophilic drug formulations) should not contain DEHP, or strategies to decrease DEHP exposure should be employed, particularly when administering these drugs to infants and children. (Also see later recommendations on labeling.)
(3) Total parenteral nutrition therapy (TPN): It is the standard practice in the US to use DEHP-free containers to mix and store TPN solutions that contain lipids. Polyethylene syringes are generally used for premature and newborn infants. Although commercial PVC-free infusion sets are available for this procedure, infusion lines made of PVC are almost always used. Is this the practice in Canada?
TPN treatment can last up to a year in some circumstances. In most cases in Canada, the syringes used are polyethylene or polypropylene and the tubing is still PVC. If manufacture and storage of TPN were to be done in DEHP free material as well, cost would be a factor because very large quantities of tubing are used. Information pertaining to IV tubing and alternatives was to have been discussed at a meeting on June 18 between manufacturers and Health Canada's Plasticizer Working Group but this meeting has been postponed (see above.) However, the Panel has received information from manufacturers indicating that DEHP-alternatives are available for this application although they are presently significantly more costly than DEHP-containing products.
Patient age is also a factor in these recommendations. Newborns, particularly prematures, are potentially more susceptible to toxicity of any substance and are known to develop liver damage with cholestatic jaundice during prolonged treatment with TPN. There is no current data on any relationship of such damage to DEHP exposure in the MDB report or in the medical literature. In adults, cholestatic complications are apparently much less frequent during TPN treatment. These observations support the concerns in Section 2.7.3 of the MDB report that since infants do not have mature glucuronidation pathways until they are 3 months old, high levels of DEHP may increase the risk of cholestasis.
The use of heparin was discussed, as it slows the leaching of DEHP when used to coat tubing; in solution however it may actually increase breakdown of DEHP to Mono(2-ethylhexyl)phthalate (MEHP) by lipases. (Heparin added to blood may have this effect. Heparin-coated tubing may not because of the lower circulating concentration of heparin.) Cost associated with this is variable since different hospitals use different suppliers and obtain different prices for the tubing.
Coating DEHP-containing tubing with other inert polymers (e.g., polyethylene) or other materials may prevent the release of DEHP while retaining the desirable properties of the tubing. Polyethylene-coated DEHP tubing is commercially available. Again there is an increased cost for such tubing.
Several companies market DEHP-free tubing in the US and this is also available in Canada. As an example, recent correspondence from a manufacturer states the following:
"We have several products in both the intravenous and neonatal areas that incorporate non-DEHP tubing. The cost of intravenous sets that are non-DEHP is incrementally greater than DEHP containing products: approximately 10 to 12% more. There has been a limited market for non-DEHP sets for long term TPN for several years; our first inquiry was probably 12 years ago. However, it is not generally requested from users at the present time. For the neonate, we have a line of silicone feeding tubes, umbilical catheters and urinary drainage catheters. These are significantly more expensive than regular PVC or polyurethane: approximately $20 vs. $2.50. However, we do find a market for them despite the price difference due to longer dwell times." McLean Medical, 2001.
RECOMMENDATION 3
As alternative products are already available (albeit at significantly elevated cost), the Panel recommends that total parenteral nutrition solutions be administered to newborns and infants only via products which do not contain DEHP.
(4) Are there other ways of reducing the release of DEHP from medical devices? Several factors were discussed that could have an effect of lowering DEHP exposure. They were:
(5) Do we have sufficient information to determine whether the solutions proposed in the answer to Question 4 above are practical, safe and effective?
For many products, the relatively small population of Canada may seem to make marketing of low volume products not profitable; non-DEHP products are presently somewhat of a "niche" product. However, restriction of the use of DEHP-containing products for certain applications and populations may encourage manufacturers to develop and market alternatives. Nevertheless, the Panel recognizes the obvious cost of developing and changing product lines.
Research into the importance of the percentage of DEHP in the plastic and the possibility of changing the manufacturing process to reduce this concentration would be an alternative approach. It would be valuable to know if such changes would reduce the amount of DEHP available to leach out while still preserving the useful properties of the plasticizer. Such reductions might reduce DEHP exposure of patients as well as passage into the environment. (The Panel notes that current data suggest most environmental exposure comes from food, air and soil rather than from medical devices.) Unfortunately, since the amount of plasticizer used is generally selected by the manufacturer based on the mechanical properties needed for a given application reductions may not be possible. This is why the DEHP content in PVC-containing medical devices varies from < 25% to about 80%. Moreover, although reducing DEHP in medical products may appear worthy of study, an HC study on diisononylphthalate (DINP) in toys did not show good correlation between DINP content and exposure. Nevertheless, further study of DEHP content and leaching rates appears warranted.
New plastics used in Europe and alternatives already available in the US could be considered for use in Canada. Ethylene vinyl acetate, polyethylene, polypropylene, polyurethane, and silicone have been approved for use in a wide variety of medical applications. There are also reasonable safety data on medical PVCs made with tri-2 (ethylhexyl) trimellitate - TEHTM -- and butyryl-tri-n-hexyl-citrate - BTHC -- which are already used in some commercial platelet and plasma bags, as well as some studies using TOTM (see above.) However, the European Commission's Scientific Committee on Toxicity, Ecotoxicity and the Environment considers safety data for some other citrates and adipates inadequate. Tickner's paper for the Health Care Without Harm campaign also confirms the availability of alternatives for many applications, although commenting little on their safety. The exception is that there are few reports in the literature of active research into an alternative to DEHP as a blood bag plasticizer, where it would be necessary to overcome the current disadvantage to such alternatives in terms of storage time. However, the Panel is aware of much work done by manufacturers to assess a variety of substitutes and there are FDA approved "alternatives" to DEHP-containing blood bags, e.g. PVC bags plasticized with TEHTM; however, they do not preserve blood for 42 days as effectively as the DEHP-containing blood bags. Tickner notes that a manufacturer that found and marketed an alternative which matched DEHP's storage times would be "at a unique market advantage". For currently unapproved alternatives to DEHP, HC has informed the Panel that for medical devices the licensing procedure is not long, figuratively, when compared to drugs. The average time for approval is about 100 days. I.e., if a product is recommended, then it can be brought in fairly quickly.
The Panel is cognizant of the need in making any recommendation to consider many factors such as cost vs. practicality, and safety vs. effectiveness. There are inevitable trade-offs to be considered when there is not enough data at this time to answer all concerns in a definitive manner. Information on proposed alternatives (plasticizers), their safety, and their toxicity profiles is also important and for many proposed alternatives such information is limited.
RECOMMENDATION 4
Research into further methods for reducing release of DEHP from products containing this plasticizer as well as into alternatives to DEHP-containing products should be urgently encouraged.
2. RISK ASSESSMENT
"Health Canada's risk management of DEHP in medical devices will need to take into account both the risks and benefits associated with the use of the compound. Studies have shown that the use of DEHP as a plasticizer for blood storage bags, for example, has a clear advantage in that it prolongs the storage time of whole blood, perhaps by stabilizing the erythrocyte membrane. In addition, DEHP-containing PVC has many physical properties that make it highly suitable for fabricating medical bags and tubing. It is easily shaped, flexible, strong, optically clear, suitable for use at a wide range of temperatures, and easily sterilized. The reports cited (# 6 & 7 in listing under "Methodology") summarize the data available on the safety and effectiveness of alternatives to DEHP such as ethylene vinyl acetate, polyethylene, polypropylene, polyurethane, and silicone, and PVC softened with alternative plasticizers such as citrates. Some alternatives lack a number of the benefits of PVC plasticized with DEHP, while others are much more expensive. There is also inadequate safety data for a number of the alternatives such as PVC plasticized with citrates and adipates. They may expose patients to hazards not present with devices made with DEHP. These factors must be taken into account in reviewing the acceptability of DEHP-containing medical devices for specific medical treatments." (Expert Advisory Panel on DEHP in Medical Devices Record of Proceedings, July 20, 2001.)
(1) Does the report accurately identify the sub-populations that have the highest long-term or short exposures to DEHP?
The Panel was satisfied that the MDB report does identify sub-populations with the highest exposures. The panel summarized the sub-populations of greatest concern as being:
In all the above except for hemodialysis, the patient's short-term potential exposure to DEHP is high. Hemodialysis was not identified in the MDB report as a population of concern but may be the highest source of chronic medical exposure (as opposed to the other situations above which are all short-term high level exposures.) These patients also have renal insufficiency which may have implications for their ability to eliminate substances from the body. Finally, reduced cardiac output has been described in hemodialysis patients, a finding consistent with in-vitro studies of MEHP showing reversible negative inotropic effects on myocardial tissue (although other causes seem more likely to be responsible for this effect than DEHP/MEHP exposure.) The Panel does not have information to allow a definitive conclusion on risk of such chronic exposure in this population but does wish to identify this population as one in which the exposure is sufficient to be of possible concern and requires further investigation.
Patients receiving certain IV therapies, particularly those on TPN and those receiving lipophilic drug formulations, etc. - see Recommendations 2 & 3
(NB: Infusion of IV solutions such as normal saline, glucose solutions and Ringer's lactate were not identified as a significant source of DEHP exposure in the MDB Report)
Oxygen Therapy patients (theoretical risk only - no reliable data on levels of exposure)
(2) Does the report correctly identify the sub-populations who may be at an increased risk for the adverse effects of DEHP?
The Panel felt most sub-populations at greatest risk are identified, particularly the youngest infants and children, but that some additional populations should be considered where reproductive or hepatotoxic effects are potentially significant:
RECOMMENDATION 5
The sub-populations to be considered at greatest risk should include the following:
Sub-populations that should be considered to be at possible but presently undetermined risk include:
(3) Is the panel aware of important medical exposures that have not yet been reported in the scientific literature?
The Panel described several procedures that may put a patient at increased risk of exposure to DEHP which were either not mentioned or not fully described in the MDB report, and which they thought needed attention in future deliberations. They are listed below:
RECOMMENDATION 6
The highest priorities for further study in the Panel's opinion include: ECMO, hemodialysis, intrauterine transfusions, TPN, oxygen therapy, IV therapy, particularly using blood products, IVIg, etc. and enteral feeding. In view of the limited data available for many of the above applications, the Panel's further recommendations are limited to IV delivery products, preparatory or storage products.
(4) What other factors need to be taken into account in reviewing the acceptability of DEHP-containing medical devices for specific medical treatments?
Among the other factors that need to be considered and for which there remain limited data, the following are of potential significance:
(5) What level of concern would justify the replacement of DEHP-containing devices by an alternative for certain medical procedures?
The panel agreed by consensus to change the wording of this question as follows:
What types of findings would justify the replacement of DEHP-containing devices by an alternative for certain medical procedures?
There are few human data to substantiate the concerns of potential toxicity but the Panel is aware of in vitro data on isolated human heart tissue showing direct toxic effects of phthalates (Blood 1988; 72: 1438-9 [Letter]), as well as a few anecdotal reports of adverse effects in humans. These observations do not demonstrate a cause-effect relationship between DEHP exposure and adverse effects in humans. The Panel does consider that the mechanisms of certain known effects of DEHP and its metabolites in animals could certainly be operative in humans also. Concern is highest in humans where the susceptibility of the patient and exposure are both high. In these situations alternate procedures are probably justified now as a prudent cautionary measure even without clear evidence of human toxicity; alternate products are already available for some procedures (e.g., heparin-coated tubing for ECMO, non-PVC sets adaptable for neonatal TPN, etc.) although they are more costly than current products. Highly exposed persons who are not as susceptible are slightly less of a concern, but may also merit consideration by HC of the need for alternate procedures. As noted previously, plasticizers intended to be used as alternates to DEHP should be shown to have a safety profile at least as good as DEHP before adoption for use in medical devices.
RECOMMENDATION 7
Alternate measures are immediately justifiable and should be introduced as quickly as possible to protect those sub-populations at greatest risk, namely the fetus, newborns, infants and young children receiving transfusions, ECMO, cardiopulmonary bypass, exchange transfusion, hemodialysis, TPN and lipophilic drug formulations.
(6) Are the benefits of DEHP in prolonging the storage time of whole blood significant enough to shift the risk-benefit ratio in favor of using bags with DEHP?
There is a significant known reduction in the duration of time that red cells can be kept if DEHP is not used. Currently CPDA1 is no longer the primary anti-coagulant in Canada; CP2D is used both by Héma Quebec and in the rest of the country. Whole blood is collected into this solution, centrifuged, the plasma removed, and an additive solution AS3 is used to re-suspend the red cells. DEHP appears to stabilize the cell membrane and prevent hemolysis, thus permitting an up to 42 day storage time.
Changing plasticizers or any other element in the blood bags would require having two separate blood supplies, i.e., separate inventories for certain patient populations. CBS does already have several different blood supplies in inventory at any time (e.g., they do not usually use CP2D for neonatal transfusions.) Further diversification of inventories might however create new inventory management problems. It is clearly more convenient to have as few different blood bags as feasible with a separate procedure at the end of processing for different recipients, i.e., to reduce exposure for at-risk populations.
Current pediatric transfusion practices use DEHP stored RBCs up to 42 days depending on volumes1. Therefore the Panel must express caution in any recommendation that would lead to only short-term storage. For example, recent data shows that even with an improved additive solution (EAS-61), red cells stored in polyolefin blood bags had higher hemolysis and lower RBC ATP concentrations than those stored in PVC bags after 6 weeks2. However, it should be noted that the majority of blood that is transfused in this country is not older than 21 days. Extending the shelf life to 42 days has resulted in only a very minor change in utilization. Therefore removing DEHP from all blood bags might result in an increase in blood donation requirements for the Canadian blood system but the magnitude of this effect, if any, is unknown.
1 International Forum Vox Sanguinis 2001; 80:122-133
A change in plasticizer might also change survival in vivo of transfused red cells. Ethics Board approval of in vivo studies using radiolabeled red cells might be difficult in the absence of evidence of harm to humans from the current plasticizer. Given the difficulty already in keeping up with demands on the system the Panel cannot at this time recommend a change which would shorten current storage times in the absence of clear data showing toxicity in humans. (Indeed, DEHP-containing blood bags have been used for many decades without evidence of harm to humans.)
The Panel sees a need for additional research on blood product storage times and the impact of alternate products on this factor. However, it also believes continued use of DEHP in blood bags is currently justified in view of the importance of storage time to the viability of the system and the lack of evidence based on human data to confirm harm.
RECOMMENDATION 8
DEHP should continue to be used in blood bags until an alternative which allows acceptable storage times becomes available or failing this, until human data confirms harm from this practice. For susceptible populations, the Panel encourages an exploration of special systems and procedures to reduce exposure to DEHP and its metabolites from use of blood products.
3. RISK MANAGEMENT OPTIONS
An important part of the mandate of this Panel has been to review and make recommendations on possible risk management options relating to the use of DEHP in medical devices.
In addition to an assessment of the potential adverse health effects caused by exposure to DEHP in medical devices, careful consideration needs to be given to the availability of safe and effective alternatives in sufficient volume and at a reasonable cost. The imp act that banning DEHP is likely to have on the health care delivery system in the short term and the long term, includes the significantly higher cost of alternatives for a number of common medical procedures. The need to develop new protocols for other procedures also has to be taken into account. The long-term costs cannot be accurately estimated as market forces are likely to dramatically lower the costs of alternative products if used more frequently.
NB: The Panel had hoped that information would be forthcoming from the manufacturing sector on the availability and costs of possible alternatives to DEHP through a presentation sponsored by the Canadian Plastics Industry Association (CPIA) and the Vinyl Council on alternatives to DEHP-plasticized PVC. Unfortunately however this presentation has been postponed indefinitely. In the meantime the Panel was able to obtain much information on alternatives from several manufacturers following a request by MDB to MEDEC, the Canadian medical device industry trade association.
The options considered by the Panel included the following possibilities:
_3.1. Status quo
(1) Are there other factors that need to be taken into account in considering this option?
(2) Do the health and safety issues justify this option?
2 Vox Sanguinis 2001; 81:161-166.
(3) Is this option practical?
The Panel quickly came to the conclusion that the status quo is not an acceptable option. The level of concern, even though the concerns are based entirely on data derived from animal research, is nevertheless too high to recognize status quo as an option.
_3.2. Phasing Out the Use of DEHP in Medical Devices
(1) Are there other factors that need to be taken into account in considering this option?
(2) Do the health and safety issues justify this option?
(3) Is this option practical?
(4) Do the available data on the risks and benefits justify the regulator mandating the discontinuance or phasing out the use of DEHP in medical devices?
In any situation where there is a perception of risk, it appears preferable to the Panel to obtain data on the possible risk and if found plausible as a risk to humans use an alternate approach, assuming the alternate approach has been shown to have a safety profile at least as good as the current approach and not to introduce new risks . In this case, the panel recognizes the benefit that would be perceived by many to be present if one were to phase out this substance of uncertain risk. However, there remain no data to substantiate any risk in humans at this time. Moreover, the few alternatives available and the limited data on their safety suggest that complete phasing out of the use of DEHP is at this time impractical.
_3.3. Restricting the Use of DEHP
HC has taken this approach in certain other areas of concern where scientific evidence does not support a complete phasing out of the substance; for example, its risk management of dental amalgam. HC recommends restricting the use of dental amalgam in young children, pregnant women and other groups considered to be more vulnerable than the general population.
(1) Do the available data justify restricting the use of devices that contain DEHP to certain procedures or certain patients?
(2) Is this option practical?
The Panel believes that the concerns about possible ill effects of DEHP are indeed sufficient to restrict use of the product for certain populations and uses. The Panel worked from the principle that the highest risk will be to:
1.the most susceptible populations. For example, animal and in-vitro studies suggest the possibility of testicular effects (in males) and cardiac effects. Newborns have increased susceptibility to a broad range of substances so would be expected to be at greatest risk of DEHP-related toxicity if this were to occur in humans. These concerns are also relevant to potential exposure of the fetus via the placenta in pregnancy or of newborns through lactation. Pre-pubertal males would be potentially susceptible to the testicular effects beyond the newborn period. Even certain adults might have increased susceptibility, e.g., heart transplant recipients to the potential cardiac effects.
2. for uses where exposure is high or long-term. Thus, even a population with presumed lower susceptibility such as adults might be considered at theoretical risk of the above toxicities demonstrated in animal/in-vitro models if exposure may be either very high, e.g., during cardiac procedures or during multiple transfusions for trauma, or long-term, e.g., during hemodialysis (where impaired renal function may also impede clearance of metabolites.)
Therefore the Panel makes the following recommendation on areas where DEHP use should be restricted.
RECOMMENDATION 9
DEHP containing devices should not be used in the following circumstances (i.e., only devices containing an alternative to DEHP should be used in these situations):
These procedure changes are the most practical answer at this time based on the limited data available, and should be addressed through Clinical Practice Guidelines by such national professional organizations as the Canadian Pediatric Society, the Canadian Pharmacists Association, etc. (see below)
_3.4. Labeling
HC often uses this approach to manage risks. The Medical Devices Regulations require the label of a medical device to include "directions for use," which are defined as "full information as to the procedures recommended for achieving the optimum performance of the device, and includes cautions, warnings, contra-indications and possible adverse effects."
(1) Can the risks of DEHP exposure from medical procedures be managed through the use of warning labels?
(2) What information would be needed to ensure that health care providers are fully informed of the risks and the availability of alternative products?
(3) Should there be special warning labels on specific medical devices stating that they are not recommended for use in medical procedures associated with high DEHP exposures? For example, should uncoated DEHP tubing have a warning that it is unsuitable for use in ECMO procedures?
(4) How effective would warnings in the labeling be?
It is important to distinguish between disclosure labels versus warning labels. The Panel sees no disadvantage to disclosure labeling included on the product monograph and on the product if possible, or on the box for tubing. Therefore, although not all uses of DEHP can be avoided at the present time, the Panel believes that it is appropriate that labeling of products always indicate that DEHP is present in a particular product. However, it was also agreed that supplementary warning labels are not necessary or appropriate at this time. Indeed, if these were to cause a delay in the use of a product during an emergency situation they could be harmful to a patient's interests, an unacceptable effect given that the human data are insufficient to support such warnings. To supplement the use of disclosure labeling, the Panel recommends that the indications of use (risk communications) should be captured in the clinical practice guidelines (see below).
RECOMMENDATION 10
The Panel recommends that labeling of products always indicate that DEHP is present in a particular product. To supplement the use of disclosure labeling, the Panel recommends that the indications of use (risk communications) should be captured in the clinical practice guidelines recommended below.
_3.5. Informed Consent
It is generally accepted that patients are entitled to receive sufficient information to make an informed choice regarding a medical procedure, including information on the risks and benefits of the procedure and suitable alternatives.
(1) Can the risks of DEHP exposure from medical procedures be managed through informed consent?
The Panel fully supports the important principle of informed consent to procedures and treatments and would certainly support this prior to use of DEHP containing products if in the future new data confirm risk to humans. However, it is often difficult even with a great deal of time to give a patient enough information to make a fully informed consent to treatments involving complex issues and incomplete or conflicting information. Time becomes a major concern in situations requiring urgent treatment, as is relevant to many of the uses noted above. If a patient informed of presently unsubstantiated risks to humans opts against use of DEHP containing systems, there may not be a reasonable alternative to be presented to the patient at this time. If this were to delay emergency treatment the patient would in fact be harmed by such an attempt to 'do the right thing'. Therefore, the Panel considers informed consent to be not presently a viable option in the absence of demonstrated risk to humans, and with alternative products proven safe and efficacious not available at this time for many uses.
(2) What measures would be needed to ensure that all patients are fully informed of the risks and the availability of alternative products? What information should be provided? Should special advice be given to patients who are most vulnerable, or to all patients undergoing procedures associated with the higher exposures?
The approach on this issue should be a precautionary one. Where there is a demonstrated risk a patient should always be informed of all risks. In the case of DEHP the Panel finds that risk to humans remains uncertain .Thus our concerns are largely based on animal data and in-vitro studies on human myocardial tissue. If the same is true for alternatives to DEHP the same approach is appropriate (i.e., request informed consent only where human data shows risk.) However, the Panel does believe that alternatives should not in general be introduced unless there is human data on safety and efficacy, so as to avoid a similar problem in the future with DEHP alternatives.
In the meantime, health care professionals need to be made aware of this issue so that if further human data become available in the future they will be in a position to request informed consent as and when that might be appropriate. The Panel believes this is more appropriate than a warning to the patient at the present time. If evidence based on human data demonstrating adverse effects of DEHP becomes available in the future, HC may then wish to seek the advice of a bioethicist on the best approach to informing the patient.
_3.6. Clinical Practice Guidelines
(1) Should Health Canada recommend that health professionals develop clinical practice guidelines for the use of DEHP in certain medical procedures?
Clinical practice guidelines are needed to reduce DEHP exposure for high susceptibility high exposure populations. They should also be developed to reduce exposure to DEHP from use of DEHP containing devices for certain intermediate-risk populations as a supplementary approach to disclosure labeling as recommended above, for example, lactating mothers, etc. Guidelines are seen as having a potential impact towards reducing exposure where it cannot be eliminated completely by educating drug manufacturers, pharmacists, nurses and other clinicians, etc. Awareness of this information is of paramount importance, and a mechanism for effectively communicating it to practitioners is a major issue. While it is the responsibility of clinicians to be up-to-date on new clinical practice guidelines and to follow such advice accordingly, it is the role of national professional organizations to produce and disseminate such guidelines. It was felt that ECMO and cardiac surgery procedures (especially in neonates) would definitely require clinical practice guidelines. Routine use of heparin-coated devices for example would significantly reduce exposure to DEHP. Guidelines to reduce DEHP exposure during TPN administration in newborns would also be valuable. Other situations where guidelines would be useful include double volume exchange transfusions in newborns; some adults such as heart transplant patients, hemodialysis patients, pregnant or lactating women, and in pre-pubertal males; and for the administration of lipophilic drug formulations. Finally there are some situations where the risk of DEHP exposure needs further study but which might then benefit from appropriate guidelines, for example, adult trauma patients from populations with potential increased susceptibility to DEHP effects.
RECOMMENDATION 11
Health Canada should encourage national professional organizations to develop clinical practice guidelines to reduce DEHP exposure for potentially sensitive populations (Recommendation 5) and high exposure uses.
_3.7. Other Considerations and Options
Does the Panel have any other recommendations for risk management?
The Panel agreed another option was essential to be added to the above list -- further research into this issue, both on potential risks and possible solutions.
The Panel notes that there are very limited human data on this issue. Given the significant concerns arising from animal studies, research to ascertain the real level of risk in humans is urgently needed. Furthermore, the safety and efficacy of alternatives need to be studied to be certain of their appropriateness for future long-term use. DEHP and any alternatives that are considered should be evaluated on an even playing field - for example, all should be shown to be safe and efficacious in humans in order to be used in the future. HC and Environment Canada have announced they are exploring the feasibility of developing a national longitudinal cohort study to evaluate the effects of exposures to toxics in the physical environment on child health and development (Bureau of Reproductive and Child Health.) A US consortium has already begun work on a similar study and has invited Canada to partner with them (National Institute of Child Health and Development, Centers for Disease Control and Prevention, and US Environmental Protection Agency.) HC may wish to define what kind of evidence is needed to make a decision on a product's use in humans. For example, if a product is found that has no effects in rodents and no effects in primates, does that make it acceptable for use in humans even in the absence of human data? According to the Medical Devices Regulations, this would depend on classification of the medical devices. A manufacturer would have to submit detailed clinical trial results for Class IV devices. The problem here is that theoretically a product with no effects in rodents and primates could still eventually be found to be toxic in humans. Randomized trials represent the best evidence of safety and efficacy but in the case of DEHP may not be feasible because the product is in use now - for example, what product/s could be used for a control group? Guidelines in decision making for use of products where human data are lacking would be very valuable in reducing the potential for harm from such products in the future.
HC has requested input on Canadian application of the precautionary principle3, 4. Dr Graham Chance has recently written in a Canadian journal on the application of this principle to childhood risks from environmental exposures5. In his article he restates a recent version of the principle from a US publication6, as follows: "When an activity raises threats of harm in human health or environment, precautionary measures should be taken even if some cause and effect relationships are not fully established scientifically.
3 A Canadian Perspective on the Precautionary Principle: Discussion Document. Ottawa: Government of Canada, September 2001.
4 A Canadian Perspective on the Precautionary Principle: Proposed Guiding Principles. Ottawa: Government of Canada, September 2001.
5 Chance G. Environmental contaminants and children's health: Cause for concern, time for action. Paediatr Ch Health 2001; 6:731-743.
6 Raffensberger C, Tickner T, eds. Protecting Public Health and the Environment: Implicating the Precautionary Principle. Washington: Island Press, 1999:353-4.
In this context the proponent of an activity, rather than the public, should bear the burden of proof. The process of applying the Precautionary Principle should be open, informed, and democratic and must include potentially affected parties. It must also involve an examination of the full range of alternatives, including no action."
The Panel would support HC in enunciating a clear precautionary principle regarding the regulation of all medical devices, even where human data are incomplete or inconclusive. An example of the type of guideline the Panel suggests might read something like:
"Products/devices should be demonstrated to have benefits that clearly outweigh risks to patients, including those potentially sensitive to substances or exposed to high levels of substances in the device; or at least be free of adverse effects in [specified] animals at [specified] levels." The principle should include a statement on its application to risk in children such as: "Potentially sensitive populations include newborns, infants and children. The risk-benefit estimation of all medical products/devices therefore must always take into account the disproportionate risk to newborns, infants and children."
This statement echoes a White House Executive Order issued in 1997 that directed all US federal regulatory agencies to ensure their policies, programs & standards address the disproportionate health risks suffered by children7. In this respect it should be noted that the American Medical Association House of Delegates passed a resolution in October 2001 containing recommendations consistent with those in this report8. The resolution urges that DEHP-containing products be phased out of use in Neonatal Intensive Care Units (NICUs) and replaced by non-DEHP alternatives; that there be further study of the use of PVC products containing DEHP in NICUs; and that medical device manufacturers continue developing PVC-free and DEHP-free medical devices while phasing out production of those that contain PVC and/or DEHP.
RECOMMENDATION 12
The Panel recommends that Health Canada support and facilitate by any means possible the conduct of research to define the real level of risk to humans from DEHP exposure, as well as the safety and efficacy of alternative products. The Panel further recommends that Health Canada develop clear guidelines governing the approval of products for human use where human data are lacking.
Summary
The Panel concluded deliberations of these questions by noting that these recommendations are not mutually exclusive solutions, but merely a list of possible choices to aid HC's decision-making in the absence of good human data. The Panel felt the need to examine as many options as possible. In the final analysis, they hope these recommendations will assist HC in developing not only an approach to the use of this particular substance but also a combined and comprehensive approach to address future decisions on substances for which human data may not yet be complete or available.
Respectfully submitted: C Robin Walker, MB, ChB, FRCPC, FAAP, Chair, Expert Advisory Committee on DEHP in Medical Devices. 2001 January 11.
7 The White House. Protection of Children from Environmental Health Risks and Safety Risks. April 21st,7 1997.
8 American Medical Association House of Delegates. Resolution: 506 (I-01). October 22nd, 2001.
Acknowledgments: The Chair wishes to acknowledge gratefully the broad-ranging contributions and expertise of all Panel members; the support of Health Canada, particularly Ms. H. Shahbazian without whose administrative assistance this report could not have been concluded; and the expertise of Dr. I. Hinberg who contributed greatly to the Panel's deliberations.
SUMMARY OF RECOMMENDATIONS
1. While it is not within the Panel's mandate to determine whether or not ECMO is an effective treatment, it does recommend that alternate products that are already available, (i.e., heparincoated tubing,) should be utilized for all ECMO procedures in newborns and infants.
2. Tubing and storage bags used for administration of lipophilic drugs or drugs which contain surfactants (i.e., lipophilic drug formulations) should not contain DEHP, or strategies to decrease DEHP exposure should be employed, particularly when administering these drugs to infants and children. (Also see later recommendations on labeling.)
3. As alternative products are already available (albeit at significantly elevated cost), the Panel recommends that total parenteral nutrition solutions be administered to newborns and infants only via products which do not contain DEHP.
4. Research into further methods for reducing release of DEHP from products containing this plasticizer as well as into alternatives to DEHP-containing products should be urgently encouraged.
5. The sub-populations to be considered at greatest risk should include the following:
6. The highest priorities for further study in the Panel's opinion include: ECMO, hemodialysis, intrauterine transfusions, TPN, oxygen therapy, IV therapy, particularly using blood products, IVIg, etc. and enteral feeding. In view of the limited data available for many of the above applications, the Panel's further recommendations are limited to IV delivery products, preparatory or storage products.
7. Alternate measures are immediately justifiable and should be introduced as quickly as possible to protect those sub-populations at greatest risk, namely the fetus, newborns, infants and young children receiving transfusions, ECMO, cardio-pulmonary by-pass, exchange transfusion, hemodialysis, TPN and lipophilic drug formulations.
8. DEHP should continue to be used in blood bags until an alternative which allows acceptable storage times becomes available or failing this, until human data confirms harm from this practice. For susceptible populations, the Panel encourages an exploration of special systems and procedures to reduce exposure to DEHP and its metabolites from use of blood products.
9. DEHP containing devices should not be used in the following circumstances (i.e., only devices containing an alternative to DEHP should be used in these situations):
10. The Panel recommends that labeling of products always indicate that DEHP is present in a particular product. To supplement the use of disclosure labeling, the Panel recommends that the indications of use (risk communications) should be captured in the clinical practice guidelines recommended below.
11. Health Canada should encourage national professional organizations to develop clinical practice guidelines to reduce DEHP exposure for potentially sensitive populations (Recommendation 5) and high exposure uses.
12. The Panel recommends that Health Canada support and facilitate by any means possible the conduct of research to define the real level of risk to humans from DEHP exposure, as well as the safety and efficacy of alternative products. The Panel further recommends that Health Canada develop clear guidelines governing the approval of products for human use where human data are lacking.
source: http://www.hc-sc.gc.ca/hpb-dgps/therapeut/htmleng/advcomm_eapdehp.html 24jan02
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