REVIEWS

PVC as pharmaceutical packaging material

A literature survey with special emphasis on plasticized PVC bags

A.A. Van Dooren

Introduction other substances, leading to a great variety of

Partly because of recent discoveries of traces of
dioxins in the milk of cows meadowing in the
vicinity of solid-waste incinerators, the use of
polyvinyl chloride (PVC) as a packaging material
has recently been severely questioned in the
Netherlands [1]. This has, for instance, led to
m a r k i n g by environmentalists of food packed in
PVC in several Dutch shops, as well as to a flow
of negative publicity, and the withdrawal of PVC
packaging for food by one of the leading Dutch
supermarkets.
PVC is used as a widespread packaging ma-
terial in pharmacy. Thus, it is likely that the
pharmacist will be confronted more and more
with questions about PVC from the lay public,
hospital staff etc.
This article gives the main facts about (medical
grade) PVC, w i t h emphasis on fluid containers.
The information m a y be used by the pharmacist
in order to fulfil his role as a pharmaceutical ad-
viser.
Occurrence of PVC
The first patent on PVC dates back as early as
1913 [2], and since its first industrial manufac-
ture in 1931, PVC has gained widespread appli-
cation as a universal plastic. Indeed, without
PVC modern lifestyle would have been very dif-
ferent. Its common use is due to a great variety
of suitable properties, such as:
- o p t i m u m versatility in designing character-
istics;
- high-frequency weldability;
- ability to be combined with a wide range of
flexibilities, appearances etc.;
- relatively low m a n u f a c t u r i n g costs [3];
- low oxygen and C02 permeability (compared
with polyolefins) (Table 1);
- predictable and long-term stability;
- being tasteless and practically odourless.
PVC demand amounts to approximately 4.1 mil-
lion tons per a n n u m in Western Europe, of which
5% is used in the Netherlands [4 5]. Approxi-
mately 2.8% of PVC sales are for medical use [6].
PVC has earned its place in health care be-
cause of its versatility, sterilizability, safety, ap-
pearance and favourable cost/performance ratio.
It cannot only be applied in various durables,
like renal dialysis units, oxygen tents, contact
lenses, protheses and heart valves, but also in
disposables, such as tablet strips and blisters,
sets and tubing, container bags (blood bags, in-
fusion bags, nutrition bags, drain bags and di-
alysis bags) and catheters and other components.
PVC production
The production of PVC can be subdivided into
the following processes:
- production of vinyl chloride monomer (VCM);
- polymerization of VCM into PVC;
-compounding of basic material, including
granulation;
- formation of end-product.
Production of V C M
VCM is made from chlorine and ethene (eth-
ylene) through the pyrolysis of the intermediate
1,2-dichloro-ethane (ethylene dichloride) (EDC).

Van Dooren AA. PVC as pharmaceutical packaging material. A literature survey with
special emphasis on plasticized PVC bags. Pharm Weekbl [Sci] 1991;13(3):109-18.

Abstract
In this report the state of the art with respect to PVC as pharmaceutical packaging
material is described. A general introduction into the applications of PVC is followed by a
description of its production process. The metabolic effects of the monomer of PVC, vinyl
chloride and of the most commonly used plasticizer diethylhexylphthalate are mentioned.
Special attention is given to the pharmaceutical properties of plasticized PVC bags in
Keywords comparison to other plastics and the environmental aspects of waste PVC disposal. Although
Chemistry there are emotional and political queries regarding the future use of PVC as a
Consumer product safety (pharmaceutical) packaging material, we conclude that there is no scientific justification for
Drug packaging a total or partial ban of PVC. PVC will remain a fact of life as a cheap, versatile,
Environmental pollution high-performance and well-investigated plastic material for medical and pharmaceutical
Plasticizers applications, to be replaced by newer plastics only for certain well-defined indications where
Polyvinyls the requirements of the plastic to be used are so specific that it will economically and
technically be justified to use another polymer. Community and hospital pharmacists have
Dr. A.A. Van Dooren: Medistad to be prepared for a role in intake of waste plastic disposables, probably against deposit
Holland BV, P.O. Box 99, money, in order to fulfil the logistics needed for recycling.
1670 AB Medemblik, the
Netherlands. Accepted 10 January 1991.

13(3) 1991 Pharmaceutisch Weekblad Scientific edition 109

 Ethene, the basic raw material for nearly all
polymers, is obtained through the cracking of
natural oil or gas, which are fundamentally
scarce resources. Total polymer production ac-
counts for approximately 4% of the use of these
resources.
Polyolefins are for nearly 100% dependent on
oil or gas, whilst PVC is for less than half of its
weight, since it contains 57% of chlorine. Chlor-
ine is not scarce. It is obtained through the elec-
trolysis of brine (NaC1), either with the help of a
transport medium (mercury) or increasingly
through diaphragm and membrane processes. A
discussion of chlorine chemistry falls beyond the
scope of this article.
About one third of the chlorine production is
used for the manufacture of PVC. Other import-
ant uses are in bleaching paper, in solvents and
titanium dioxide production [Nisbet A, unpub-
lished observations]. Chlorine production con-
curs with the formation of sodium hydroxide,
which is one of the basic materials for the manu-
facture of glass, aluminium, detergents, textiles
and paper [Nisbet A, unpublished observations.]
Polymerization of VCM
The most common polymerization process of vi-
nyl chloride monomer into PVC is an exothermal
reaction resulting from applying high pressure
at slightly elevated temperatures to a suspension
of VCM particles in the presence of an initiator,
surface-active agent and protective colloid. By
means of this so-called 'suspension' process, ac-
counting for over 90% of all PVC production, a
white powder is formed with a particle size of 100
to 200 #m.
Compounding of basic material
In the compounding phase the powdered poly-
mer is prepared for further processing by the ad-
dition of auxiliaries. During tubular extrusion,
the PVC powder and additives are molten (160-
200~ plasticized and homogenized in a cylin-
der by the action of a screw. Cooling is done with
filtered cold air.
It is the preferred method for the production of
tubings and extruded foil for use in, e.g., infusion
bags. Due to the high reaction temperature the
product is internally sterile, practically free of
particulate matter and free of pyrogens.
PVC foils as used in, e.g., blood bags or urine
drain bags are made by calandering or flat-die
extrusion. The product is normally neither ster-
ile nor pyrogen free, and contains more particu-

Table 1
Comparison of various sterile fluid container materials

Glass PVC Polypropylene Polyethylene

Volume range 1 ml-1 1 20 ml-100 1 100 ml-3 1 100 ml-1 l

Weight per emtpy container
(0,5 l) (g) 250 32 25 not available
as empty
container
Density (kg/m 8) 2.4-2.8 1.25 0.89 0.92
Hardness (shore D) 28 70 5O
Water permeability g/m 2 (24 h,
0.040 mm) 11 1.5 2.5
(over-
wrapping
needed)
Oxygen permeability g/m 2
(24 h, 0.0"40 mm) < 1 900 1,500 3,200
C02 permeability g/m ~ (24 h,
0.040 mm) < 1 10,000 9,000 17,000
Energy contents (MJ/kg) 10 53 73 69
Reusability yes no no no
Microporosity excellent good fair excellent
Cracking risk yes no yes a t ~ 10~ no
Resistance against cold good moderate poor good
Clarity excellent good fair fair
Particulate matter present practically flee practically flee practically flee
(rubber)
Autoclavability (~
(steam/water) 121 121 121 ~ 108
Aeration necessary (during
infusion) yes no no no
Pressure infusion possible no yes no no
Multicontainer systems
possible no yes no no
Possibility for hospital filling
of sterile fluids yes yes yes no

110 Pharmaceutisch Weekblad Scientific edition 13(3) 1991

 late matter than the extruded tubular foil. On - it is possible to incorporate a wide variety of
the other hand, it is valued for its uniform thick- substances into its microstructure. Because of
ness. this, the properties of PVC can be varied
enormously, which is one of the principal
Formation of the end-product reasons for its large variety of applications.
Medical PVC bags are made of extruded or cal- The Dutch and European Pharmacopoeias give a
endered foil by means of radiofrequency welding. positive listing of acceptable PVC additives for
This welding technique in which material is blood and infusion bags [14].
brought in a high-frequency alternating current The main additives are:
field (27.12 MHz), is only suitable for polar - t h e r m a l stabilizers, which are able to scav-
plastics like PVC or ethylene vinyl acetate enge HC1 formed during decomposition (cal-
(EVA) but not for, e.g., polyolefines, which can cium or zinc stearate, epoxidized linseed or
only be welded by thermosealing processes. The soya oil). Lead-based or cadmium-based stabil-
thermosealing process is not suitable for multi- izers are not permitted in medical-grade PVC
port designs due to microporosity along the seals, [14];
particularly in connections between tubings and -lubricants, like stearates and amide waxes
a flat surface. (the latter ones also having antiblocking
Tubings can be welded into PVC bags by the properties);
same high-frequency welding process. Connec- -colouring agents. The Dutch Pharmacopoeia
tors or joints, but also infusion sets, are mounted excludes colouring agents for blood bags [14].
by adhesion. The adhesives mainly used in prac- For infusion bags, tinted material (containing
tice are cyclohexanone and tetrahydrofurane. several ppm's of, e.g., ultramarine blue) is still
in use, without any advantage other than
Vinyl chloride m o n o m e r better appearance;
After initial reports concerning its carcinogen- - plasticizers, when a flexible PVC compound is
icity in animals [7 8], VCM was soon suspected of needed. The percentage can vary from 5 to
being carcinogenic in man as well, particularly even 70%. The Dutch Pharmacopoeia allows a
in operators exposed to high air VCM levels in percentage of not more than 40% diethylhexyl-
PVC production plants [9]. Nowadays, there is a phthalate (DEHP) for blood bags [14].
general consensus that VCM leads to a rare but The maximum amount of additives in PVC is
lethal form of cancer called liver angiosarcoma much higher than allowed for polyolefin ma-
[10]. terials. The Dutch Pharmacopoeia stipulates
In humans, VCM is metabolized into chloro- that low-density polyethylene (LDPE) should not
ethylene oxide [11] which is believed to be the contain additives, whilst high-density polyethyl-
most potent mutagenic metabolite [12]. Since ene (HDPE) and polypropylene (PP) containers
macromolecular adduct formation, detoxification for parenteral preparations may contain small
and excretion are in competition with each other, amounts of antioxidants and lubricants [16].
the carcinogenic action of VCM is thought to be
largely dose-dependent [10]. Plasticizers
Since 1974, the PVC industry has jointly taken The list of proposed plasticizers includes:
measures to reduce the risks of VCM intake to - phthalic acid esters, e.g. di-n-octyl phthalate
their operators and plant neighbours, by means (D-n-OP), diethylhexyl phthalate (DEHP), di-
of automated production, closed reaction vessels nonyl phthalate (DNP), didecyl phthalate
and better cleaning procedures. An average ex- (DDP);
posure to VCM not exceeding 5 ppm is now - a d i p i c acid esters, e.g. diethylhexyl adipate
judged to give no increase in cancer incidence (DEHA);
[13]. The European and Dutch Pharmacopoeias - c i t r i c acid esters, e.g. acetyltributyl citrate
require a maximum VCM concentration of 1 ppm (ATBC);
in virgin PVC powder [14]. Modern 'medical - esters of the trimellitate type such as tri-(2-
grade' PVC is believed to contain less than ethylhexyl)trimellitate (TOTM).
10 ppb VCM, which is below the current analyti- The only plasticizer mentioned explicitly in the
cal detection level (20 ppb) [15]. Dutch Pharmacopoeia monograph for blood bags
Although it cannot be maintained that current is DEHP [14].
VCM levels pose a toxicological problem, it TOTM is a newer plasticizer, which does not
should be stated that the theoretical zero ppm have a similar inhibitory effect on erythrocyte
level has not yet been reached. We believe that deterioration as compared to DEHP [17 18]. On
a further reduction should be strived for, even the other hand, it is stated that it migrates from
though this might require a substantial econ- the PVC matrix to a lesser extent [19] and is able
omic effort. to increase platelet survival from 3 to 5 days [20],
probably due to a better gas exchange [21].
Additives Meanwhile DEHP-containing PVC bags with
PVC is mixed with additives for the following better gas exchange properties have been de-
reasons: scribed [22].
- a t the extrusion temperature, 160-200~ DEHP is probably one of the best studied
autocatatytic degradation of PVC may occur. substances in the world. It is estimated that over
Antioxidants and organometallic stabilizers 3,000 scientific papers on its biological activity
may be added in order to prevent this decom- have appeared to date, amongst them very com-
position; prehensive review studies [23-31].

13(3) 1991 Pharmaceutisch Weekblad Scientific edition 111

 Although the aqueous solubility of DEHP is
low (<0.04 mg/ml at 20~ [27 32], it is not co-
valently bound in the PVC matrix and may
therefore migrate out of the plastic [18], es-
pecially in the presence of solubilizing lipids,
lipoproteins and albumin. The migration de-
pends on temperature [29], storage time and
nature of the solution, like anticoagulant in
blood bags [33].
Since 1970, it has been known that DEHP is
present in blood stored in PVC bags [34 35].
Various extraction rates have been reported,
such as 0.25+_0.03 mg/100 ml blood/day at 4~
[36], 1 rag/unit blood/day or 6 mg/unit platelet
concentrate/day (room temperature) [37], 10-
50 rag/1 plasma in vitro [34], or 11.5 mg/100 ml
plasma [38].
DEHP interacts with the red-cell membrane
[17 18] and improves the survival time of eryth-
rocytes and their osmotic fragility and flexibility
after prolonged storage, both in vitro [39 40] and
in vivo [41]. It has little effect on platelet function
or survival [42].
Although existing data should be viewed with
care due to poor DEHP stability in water to arti-
facts contributed by phthalate-solubilizer inter-
actions, environmentally present DEHP or to
analytical problems [26 38 43], DEHP was de-
tected in organs of deceased humans, in doses as
high as 25 mg/kg spleen to 91.5 mg/kg lung [34],
and was shown to have a significant effect on
various biological responses [44].
DEHP metabolism takes place very rapidly in
mammals [26 45]. More than half of the perfused
doses of DEHP are eliminated in the urine with-
in 8 h [37], and liver, kidney and gastro-intes-
tinal tract probably accumulate phthalate esters
as a mechanism of excretion and may therefore
inappropriately be labelled as repositories [26].
The main metabolite of DEHP is the monoester
MEHP [37]. In rodents, further metabolism takes
place through oxidation of the end site of the
aliphatic chain [46] and successive oxidation to
ketone and carboxylic acid bodies [26 47]. In pri-
mates and man, primarily glucuronide conju-
gates of MEHP are formed [37].
The acute toxicity of DEHP is low. LD50 values
of 30-50 g/kg bodyweight are generally reported
[24 25 29]. However, the main metabolite MEHP
has a far greater acute toxicity [23 48].
In chronic toxicity testing, no-effect doses
of about 60 m g . k g - l - d -1 during i year to
200 m g . k g - l - d -1 in rats were reported [23 48].
DEHP is regarded to be hepatotoxic in rats [49],
leading to hepatomegaly and enhanced enzyme
activity [50]. Also, in rhesus monkeys after blood
transfusion hepatic changes were found [51],
although the number of animals in this study
was too small to draw definite conclusions.
Microscopically, a proliferation of peroxisomes
could be detected [52]. These peroxisomes are in-
volved in cell respiratory phenomena which
generate H202, in gluconeogenesis, lipid metab-
olism and thrombogenesis [29].
In 1982, it was found that DEHP is carcino-
genic in mice and rats after feeding them for
2 years with high doses (3,000-12,000 ppm/day)
[53 54]. However, the doses in these rodent
112 Pharmaceutisch Weekblad Scientific edition
studies were extremely high and it can be ques-
tioned whether the animals under trial had a
normal metabolic response. Since, moreover, the
metabolism in rats is very different from that in
primates, as mentioned above, it is now gener-
ally agreed that it is not justified to simply ex-
trapolate rodent findings to humans [29 30 47].
Mutagenicity of phthalate esters was also
studied [29]. Although it was found that MEHP
in vitro induces chromosomal aberrations in
hamster embryo cells [55], the majority of in vivo
tests report negative results with both DEHP
and MEHP [29].
The toxicity of DEHP to the reproductive
system was tested as well. It can be concluded
that testicular atrophy is observed in all
species, particularly in rodents at doses of
100 mg. kg -1. d -1, whilst teratogenic effects are
only observed after high doses of DEHP (above
100 m g . k g - l . d -1) administered orally. MEHP
appears to have no teratogenic effect [56-59].
Where does this abundance of data lead to in
terms of risks in the case of human exposure? If
we estimate the average content of DEHP in
whole blood (21 days at 4~ at 100 mg/1, a 70 kg
adult being given 2 units of blood would receive
1.5 mg/kg of DEHP. If a haemodialysis session
releases 200 mg of DEHP (from perfusion
tubings) an adult undergoing 3 sessions per week
would receive a dose of 8.5 mg. kg -1 each week
(440 mg. kg -1 a year) [29]. Taking a safety factor
of 100 when extrapolating animal results to
man, an adult receiving 1 1 of blood is at the limit
of the doses capable of inducing toxic effects and
a haemodialysis patient would be exposed to a
dose even above this limit'[29].
In view of the species differences mentioned,
and the many individual factors and experimen-
tal conditions noted to affect results on DEHP
bioactivity, benefits and risks should be accu-
rately weighed here [31]. Up till now, no human
impairment or death has been reported in con-
nection with DEHP intake.
In fact, in June 1989, the European Pharmaco-
poeia Committee concluded that the incidence of
liver tumours in rodents should be seen as a
species-specific characteristic and that there is
sufficient safety margin between the dose caus-
ing toxic effects in animals and the dose to which
humans may be exposed. It was therefore stated
that, although research into plasticizer-free
plastics should continue, there is no fundamental
reason not to use medical accessories containing
DEHP [60].
Pharmaceutical properties of plasticized
PVC bags
Plasticized PVC containers possess a number
of advantages which make PVC still a widely
used material suitable for pharmaceutical pack-
aging. The main ones are:
- its ability to undergo high-frequency welding
(which leads to essentially leakage-free prod-
ucts and nearly indefinite design possibilities);
- its ability to be steam-sterilized at 121~
- its favourable cost/performance ratio;
- its low weight leading to low storage and dis-
tribution costs;
13(3) 1991
 -its strength (resistance to breakage) and like dynamic headspace gas chromatography-
transparency; mass spectrometry [72], it was even found that
- its flexibility (no need for aeration during in- caprolactam monomer from overwrapping
fusion or transfusion; possibility to give in- layers containing polyamide, can be traced in
fusion under pressure); an infusion solution [71]. The presence of
- its low energy content and low use of scarce plasticizers in infusion solutions can be as-
raw materials; sayed by means of gas chromatography [73].
- its favourable effect on erythrocyte survival - Physical properties of the plastic can be modi-
[61]; fied by drug action. Examples of such drugs
- its low acute toxicity as measured according are fat emulsions used in total parenteral nu-
to the USP [62]; trition and surfactants like polysorbate [65]
- the extensive knowledge about its pharma- and Cremophor| [70].
ceutical properties. The major part of the information on d r u g -
In Table 1, a comparison is made between Vari- plastic interactions pertains to PVC infusion con-
ous container materials. When using PVC con- tainers. This undoubtedly is due to the fact that
tainers for large-volume parenterals, the follow- such containers were the first flexible containers
ing aspects should be considered. to be commercially available, but also because of
the complex nature of the PVC matrix in which
Evaporation of water a number of components are necessarily present
PVC is permeable to water, thus causing an in- [14].
crease in concentration of infusion solutions However, even polyolefin container materials,
upon storage. Evaporation can be decreased by which essentially contain fewer components,
storing bags in a carton or, better still, by over- may give rise to leaching. Arbin [71] found that
wrapping the infusion bags w i t h polyethylene polypropylene releases many volatile low-mol-
(PE) or laminate foils [63]. It is advisable to over- ecular-weight oligomers, whilst polyethylene re-
wrap PVC infusion bags before autoclaving (al- leases more high-molecular weight oligomers.
though special, more expensive overwrap ma- In sum, it can be stated that the number of
terials are then needed), because of increased 'suspect' drugs and the clinical relevance of the
safety (leakage and easier detection of pinholes incompatibilities found are small [70]. If, how-
which could give rise to non-sterility), or when ever, an incompatibility is to be expected, vari-
bags with a sterile outer side are needed (e.g. in ous alternatives are open to the pharmacist to
operating theatres). circumvent this problem, like titration of the
When overwraps are used, the water evapor- patient, decreasing the drug concentration, in-
ation rate can be reduced to a level of approxi- creasing the rate of administration, or a change
mately 1% per annum at ambient room tempera- of formulation or of plastic material. The choice
ture, which leads to an acceptable stability of the alternative should be based upon a c o st-
period of 3 years. If necessary, concentrations benefit analysis [70].
can be slightly adapted during manufacture.
Sterilization
Compatibilities If PVC bags are to be steam-sterilized without
Since the classic studies by Moorhatch and containing fluid, the use of internally ribbed or
Chiou [64-67] the possibility of drug-plastic embossed films is required to prevent sticking of
interactions has been generally acknowledged the surface. After steam sterilization of filled in-
and summarized in many good survey articles fusion bags, the pH of the aqueous solution is de-
[68-70]. The pharmacist should be aware of the creased. The acidic impurities were found to be
following possible complications. formic acid and acetic acid, very likely decompo-
- Migration of drugs into plastic (sorption) may sition products from PVC oxidation during auto-
lead to subtherapeutic drug concentrations. claving [74].
Well-known examples are insulin, vitamin A PVC is rather sensitive to gamma irridiation.
acetate, diazepam and nitroglycerin. A tabu- It becomes light or dark brown in colour due to
lation of 'suspect' drugs is given by Wang and the formation of a chain of conjugated double
Chien [69]. Influencing factors are drug con- bonds initiated by free radicals formed by oxi-
centration, partition coefficient and lipophil- dation, also leading to the release of hydrochloric
icity, pH, excipients, temperature, structure of acid. Care has to be taken to control the radi-
the plastic, the volume/surface area ratio, ation dose. Special gamma-resistant PVC com-
storage time and, possibly, the rate of admin- pounds are commercially available.
istration [70]. Sterilization of medical disposables by ethyl-
- L e a k a g e of plastic components into the sol- ene oxide is a common procedure, although it
ution sometimes leads to undesirable reac- should be remembered that ethylene oxide is not
tions. Leakage of PVC plasticizer into a sol- only toxic to micro-organisms, but also to
ution is a well-known example, as mentioned mammals [75]. 5% Of all patients react allergi-
above. Apart from the composition of the cally to ethylene oxide, therefore the concen-
plastic, influencing factors are storage time, tration of ethylene oxide in the vicinity of the
pH, temperature, contact area and nature of sterilizator is bound to strict limits (5 ppm/
the stored solution. It appears that different 15 rain) [76].
supplies of PVC material give rise to different PVC, once gamma-irradiated, should not be
leachates, as was shown by Arbin [71]. resterilized with ethylene oxide. The hydro-
- B y means of various analytical techniques, chloric acid released during ionization may react

13(3) 1991 Pharmaceutisch Weekblad Scientific edition 113

 with ethylene oxide to form ethylene chlor-
hydrin, a toxic substance which is very difficult
to remove [19].
Waste disposal
Finally, all plastics end up in the solid-waste
stream. However, they form only a minor part of
this stream. In the Netherlands, total plastic
waste amounts to 663,000 tons per annum, of
which 13% (86,000 tons) consist of PVC [77]. The
amount of Dutch hospital waste is estimated to
be 115,000 tons, of which 15% (16,500 tons/
annum) are plastics. The percentage of PVC in
hospital waste is unknown [77].
Municipal waste, including hospital waste, is
disposed of via different methods:
- landfill disposal;
- incineration;
- recycling.
Landfill disposal
In the Netherlands, approximately 68% of mu-
nicipal waste is still disposed of via landfill [77].
Landfill disposal of municipal waste is generally
not dangerous, but the formation of landfill gas
and the leaking of degradation products into
ground water should be considered. It is known
that under certain conditions plasticizers may
leak out of deposited PVC material, and
although these are in principle easily degradable
by micro-organisms it is not yet fully understood
whether bacterial degradation actually takes
place under the conditions of decomposition.
A relationship between PVC and VCM traces
in landfill gas has not been established (the main
source of VCM is thought to be chlorine-
cOntaining solvents) [78].
The main problem of landfill disposal is the in-
creasing shortage of landfill sites. Thus, it is un-
derstandable that governments are striving to
decrease waste disposal by this means [79]. Land-
fill deposition is not the method of choice for the
disposal of hospital waste.
Waste incineration
Two major problems are attributed to inciner-
ation of PVC: emission of hydrochloric acid and
dioxine formation.
Emission of hydrochloric acid. Upon inciner-
ation, PVC releases hydrochloric acid which is a
component of acid rain, attributing to the well-
known forest death. HC1 formation due to incin-
eration of waste contributes for only a minor part
(0.35%) to the total acid emission responsible for
acid rain formation. 50-70% Of the HC1 emission
caused by incineration of waste is due to PVC
[79], the remainder being caused by burning
paper (bleached with HC1), vegetables and other
so-called natural material (wood, NaC1 in
kitchen waste). Total HC1 emissions in offgases
from incinerators are in the region of 800-
900 mg/m 3 [80]. Without any PVC this amount
would drop to 300-450 mg/m 8. The future (1995)
Dutch norm for maximum HC1 emission is
50 mg/m ~ [80]. Thus, it should be concluded that
wet scrubbing of offgas to remove HC1 is necess-
ary with or without any PVC in the waste.
A debate is still going on whether it is useful to
114 Pharmaceutisch Weekblad Scientific edition
Figure 1
Structures of dibenzodioxin (left) and dibenzofurane
(right)
reuse the NaC1 formed by scrubbing [81] but in
theory the chlorine cycle is completely closed, as
is shown in the German Iserlohn incineration
plant [82].
Dioxin formation. Since 10 July 1976, the day
of the Seveso disaster, the word 'dioxin' has been
added to the general vocabulary as a symbol of
terror and catastrophy. Dioxin is a collective
term for as many as 210 different substances,
with structures based on dibenzodioxin and di-
benzofurane moieties (Fig. 1). The toxicity of
these substances varies greatly, the most toxic
isomer being 2,3,7,8-tetrachlorodibenzopara-
dioxin (TCDD) (Fig. 2).
The substance in Figure 2 is extremely toxic,
but the acute toxicity is species-specific. The
most sensitive animal is the guinea-pig (oral
LD50 0.6-2.9 /xg/kg). The oral LD50 for the
monkey is 70/~g/kg [83]. In humans acute skin
irritation (chloracne) and eye irritation were re-
ported after the Seveso disaster [83]. Dioxins are
not metabolized appreciably by bio-organisms,
(except maybe by the cow) [83]; they appear to ac-
cumulate in adipose tissues and can be excreted
through breastmilk.
Both dibenzodioxins and dibenzofuranes are
teratogenic, but they appear to have no signifi-
cant mutagenic activity in vitro [83]. In rats,
TCDD is carcinogenic at doses of 0.1 ng-kg -1. d -1
It is a tumour promotor rather than a tumour in-
itiator. The no-observed-adverse-effect level
(NOAEL) is 0.001 ~ g . k g - l . d -~ and using a
safety margin of 100-250 when extrapolating
animal data to humans, a virtually safe dosis of
1-10 pg. kg -1- d -1 for humans is reached [83].
Dioxins are regarded to be side products of in-
complete combustion [84]. Phenolic non-chlori-
nated precursors can be formed by pyrolysis from
e.g. lignin [85]. Chlorination of these precursors
may follow in the cooling phase (400-200~
after their adsorption to fly-ash particles, in the
presence of heavy metals, like copper [80 86].
For this so-called "de novo synthesis' the pres-
ence of oxygen is essential; water has an antag-
onistic effect [84]. Clearly, PVC may act as a
source of chlorine necessary for the de novo syn-
Figure 2
Structure of 2,3, 7,8-tetrachlorodibenzoparadioxin
13(3) 1991
 thesis. An assessment of the available literature less t h a n t h a t of the virgin material. Pharmaco-
on the influence of the PVC content of waste on poeial standards currently prevent the use of
dioxin formation during incineration leads to the PVC regenerates for pharmaceutical purposes.
following considerations. F u r t h e r problems in recycling include [88]:
- Waste incineration contributes for about 25% - cleanliness of the material and possibilities of
of total air dioxin concentration [80]. In the demixing various waste components, without
vicinity of incinerators, this percentage is leading to pollution of the environment;
probably higher. Other sources, like cigarette - regenerates should lead to products acceptably
burning, traffic offgases, household open fires fit for use;
and barbecueing, may also lead to dioxin - at the moment, recycling is still only rarely
emission. economical. It can be expected t h a t this will
- There is a non-quantifiable probability t h a t a change rapidly in the near future [77].
decrease of chlorine-containing sources in the Approximately 90-95% of scrap in the medical
waste would lead to a decrease of dioxin for- plastic processing industry is already recycled in-
mation. house or by specialized recycling companies,
- Addition of PVC to the waste does not decrease although not for medical purposes [88].
the incineration temperature. Possibilities to recycle empty infusion bags,
- Under experimental conditions, the burning of tablet strips or sets are still hampered by dif-
pure PVC does not lead to dioxin formation, ficulties in separating, e.g., metal or rubber com-
not even at low temperatures. For the de novo ponents and in disinfecting and drying the prod-
synthesis m o r e factors should be present. ucts to make t h e m suitable for processing, but as
- Normal dioxin emissions are in the nanogram soon as these problems have been overcome it
range. Even without any PVC the chlorine can well be envisaged t h a t such articles could be
content of waste (approximately 0.7%) pre- charged with mandatory deposit money to en-
sents an enormous excess to the amounts of sure separate collection [77]. Research is on its
chlorine needed for dioxin formation [77 87 way into new techniques to separate waste com-
88]. ponents and to recycling processes, such as py-
- The analysis of dioxins, especially the step of rolysis (heating at 600-900~ without oxygen),
sample preparation, is difficult. Analytical re- hydrogenation (with hydrogen gas under elev-
sults should be viewed with caution, taking ated pressure at temperatures of 300-500 ~C) and
into account accuracy and confidentiality in- fuelling of plastics for energy recycling [88].
tervals [89]. Studies on the relationship be-
tween PVC content of waste and dioxin C o n c l u s i o n s

emission present conflicting results. In vari- Since the beginning of the seventies, PVC has
ous studies, both under experimental and had to face various severe threats shaking the
practical conditions, no relationship could be roots of its existence: firstly, the vinylchloride
established [86 90-93], but a recent Dutch carcinogenicity, secondly, plasticizer leakage
study showed a positive relation [80]. This and toxicity and nowadays, the environmental
latter test was carried out in a relatively old issues. Close scrutiny of the available literature
incinerator and the conditions were not opti- leads to the conclusion t h a t there is no scientific
mal [77]. justification for any complete or partial ban of
In conclusion, it must be stated t h a t the avail- PVC. The problems of VCM exposure for workers
able literature data is contradictory and t h a t in polymerization plants and for patients have
further research is necessary. A general consen- been largely solved by processing measurements
sus in the literature can be found in the desig- and strict standards for m a x i m u m levels in medi-
nation of priority steps to be t a k e n in order to de- cal grade PVC. Furthermore, there is no proof
crease dioxin emissions by waste incineration, t h a t the plasticizer D E H P is toxic or carcino-
which pertain to improvement of combustion genic to humans, whilst its beneficial effects on
conditions [77]: red blood cell survival is a valued property. The
- incineration under homogeneous, undisturbed total PVC content of solid waste is only a minor
process conditions; fraction, although PVC does account for the
- m i n i m u m furnace t e m p e r a t u r e 800-850~ main part of the hydrochloric acid formation
- avoidance of overload (slow addition of waste after incineration of municipal waste. However,
to maintain combustion temperature); without PVC in the waste this HC1 emission is
- offgas scrubbing to scavenge dioxins; still above acceptable m a x i m u m levels, and
- recombustion or removal of fly-ash [87]. sequestering HC1 by means of wet scrubbing is a
more logical step towards diminishing its
Recycling emission t h a n a ban of PVC. Neither has it been
Recycling of waste will become one of the great proven t h a t PVC would have any effect on the
challenges of the coming era. The Dutch govern- formation of dioxins during incineration. The
ment aims at an increase of the recycling per- existing literature is conflicting, but it can gen-
centage of plastic waste from 10% (in 1986) to erally be agreed t h a t good incineration cir-
37% (in the year 2000) [79]. cumstances have a better effect on the decrease
Recycling is a means of reducing waste of dioxin emissions t h a n the removal of PVC
streams: it leads to an effective reuse of ma- from the waste.
terials and it can save natural resources [77]. All It might even be contended t h a t in the long
thermoplastics including PVC can be recycled, term, after the problem of acid scrubbing and
although the quality of the regenerates is always preventing the 'de novo synthesis' of dioxins has

13(3) 1991 Pharmaceutisch Weekblad Scientific edition 115

 b e e n solved, P V C h a s a m o r e positive effect on
e n v i r o n m e n t a l e m i s s i o n s t h a n polyolefins, since
it n o t o n l y r e l e a s e s less c a r b o n m o n o x i d e a n d
n i t r o g e n oxide, b u t also less c a r b o n dioxide.
T h u s , P V C h a s less i n f l u e n c e o n t h e causes of t h e
' g r e e n h o u s e ' effect!
W e b e l i e v e t h a t PVC will r e m a i n a cheap, ver-
s a t i l e a n d w e l l - s t u d i e d p l a s t i c w h i c h will keep its
place i n p h a r m a c y as a disposable p a c k a g i n g ma-
t e r i a l . T h a t does n o t m e a n t h a t r e s e a r c h on n e w
plastic materials should not continue, although
it will t a k e a long t i m e before t h e a d v a n t a g e s
a n d d i s a d v a n t a g e s of such n e w c o m p o u n d s will
be k n o w n to t h e s a m e e x t e n t t h a t a t p r e s e n t is
k n o w n of PVC [94-96]. I n t h e n e a r f u t u r e , u s e of
n e w plastics will r e m a i n l i m i t e d to c e r t a i n
h i g h l y specialized a r e a s [3]. O n t h e o t h e r h a n d ,
b o t h t h e p h a r m a c e u t i c a l i n d u s t r y a n d t h e com-
m u n i t y a n d h o s p i t a l p h a r m a c i s t s will become
more a n d more i n v o l v e d i n t h e logistics of recyc-
l i n g waste, i n c l u d i n g w a s t e - P V C . P h a r m a c i s t s
will h a v e to face a n e w t a s k : t h e collection of
w a s t e i n c l u d i n g PVC disposables, p r o b a b l y
a g a i n s t deposit m o n e y , i n order to i m p r o v e recyc-
l i n g logistics.
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