Opinion of the Scientific Panel on Food - EFSA

Transcript

The EFSA Journal (2006) 414, 1-22
Opinion of the Scientific Panel on Food Additives, Flavourings, Processing
Aids and Materials in Contact with Food
on a request from the Commission related to an application on
the use of polyethylene glycol (PEG) as a film coating agent for use in food
supplement products
QUESTION N° EFSA-Q-2005-277
Adopted on 28 November 2006
SUMMARY
The Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact
with Food has been asked to evaluate the safety in use of polyethylene glycol as a film coating
agent for use in food supplement products.
Polyethylene glycols are addition polymers of ethylene oxide and water identified by a number
approximating to their corresponding molecular weight. The present application is being
submitted for six grades of polyethylene glycol (i.e. PEG 400, PEG 3000, PEG 3350, PEG
4000, PEG 6000, and PEG 8000).
The extent of polyethylene glycol absorption appears to be dependent on the molecular weight
of the specific polymer, such that more complete absorption has been reported for the lower
weight polyethylene glycols, while absorption is much more limited in the case of the higher
molecular weight polyethylene glycols.
Several pre-GLP oral and non-oral, short and long-term animal toxicity studies, as well as a
more recent 90-day GLP-compliant animal toxicity study, and a number of mutagenicity tests
and human clinical trials have been reported for polyethylene glycols. Together the outcomes
of these studies give no reason for concern. The Panel noted that PEG 6000 and PEG 8000
were not included in the carcinogencity studies but given their lower level of absorption than
the lower molecular weight PEGs this is not considered a matter of concern.
Intake estimates based on the applicant’s proposed use levels of polyethylene glycol as a food
additive and on conservative assumptions lead to a calculated intake estimate up to 120 mg/day,
amounting to 2 mg/kg bw/day assuming 60 kg bw.
Additional exposure to polyethylene glycol may also occur from use of pharmaceutical
products both tablets and capsules, for which coating with polyethylene glycol-containing films
has been approved. Assuming similar levels of use and intake of pharmaceutical products and
food supplements per day the combined intake from food supplements and pharmaceutical
products would be about 4 mg/kg bw/day.
Limited additional exposure in the EU could occur from the approved use of polyethylene
glycol 6000 as a carrier for sweeteners, as well as from the use of the PEG in food contact
materials.
http://www.efsa.eu.int/science/afc/afc_opinions/catindex_en.html
Polyethylene glycol (PEG)
The EFSA Journal (2006) 414, 2 of 22
The estimated daily intakes of the polyethylene glycols from the use as a coating agent for food
supplements are below the ADI of 0-10 mg/kg body weight allocated by JECFA and the group
TDI of 5 mg/kg body weight established by the SCF for the polyethylene glycols.
Therefore, overall the data support the conclusion that consumption of polyethylene glycols
(PEG 400, PEG 3000, PEG 3350, PEG 4000, PEG 6000, and PEG 8000) through use as
plasticizers in film-coating formulations for food supplement tablets and/or capsules at the
intended use level are not of safety concern.
KEY WORDS
Polyethylene glycol, food additive, CAS Registry Number 025322-68-3.
BACKGROUND
Polyethylene glycols are synthetic polymers identified by a number approximating to their
corresponding molecular weight. They are used in the pharmaceutical industry as a coating
agent for tablets and capsules in many countries throughout the world. Colorcon, a US-based
company, has requested the use of PEG as a film coating agent for food supplement products.
Such a use falls under Directive 95/2/EC on food additives other than colours and sweeteners.
PEG 6000 has been previously evaluated for safety by the Scientific Committee for Food in
December 1994 for its use as an excipient in sweetener based tablets used for the preparation of
sodas and PEG 6000 is currently permitted as a carrier/carrier solvent for sweeteners as laid
down in European Parliament and Council Directive 95/2/EC (as amended) (European
Parliament and Council Directive, 1995 and 1998).
The Joint FAO/WHO Expert Committee on Food Additives (JECFA) has evaluated
polyethylene glycols (200 or 9500) as carrier solvents and excipients in 1979 at which time
they allocated an Acceptable Daily Intake of 10 mg/kg body weight.
TERMS OF REFERENCE
The Commission asks EFSA to issue an opinion on the safety in use of polyethylene glycol as a
film coating agent for use in food supplement products.
ASSESSMENT
Chemistry
Polyethylene glycols are addition polymers of ethylene oxide and water identified by a number
approximating to their corresponding molecular weight. The present application is being
submitted for six grades of polyethylene glycol (i.e. PEG 400, PEG 3000, PEG 3350, PEG
4000, PEG 6000, and PEG 8000).
The following formula applies: HOCH2(CH2OCH2)nCH2OH where n equals the average
number of oxyethylene groups. The CAS Registry Number is 025322-68-3.
The structural formula of PEG is:
Depending on the number of oxyethylene groups, the molecular weight ranges from 200 to
approximately 9500 (FCC, 2003).
Manufacturing Process
Polyethylene glycols are formed via an addition reaction of ethylene oxide and water,
conducted under pressurized conditions, in the presence of a basic catalyst. Once the desired
molecular weight has been attained, the reaction is terminated by neutralizing the catalyst with
acid such as lactic acid (Henning, 2002)
Specifications
Proposed specifications for all six polyethylene glycols are based on those established for
polyethylene glycol 6000 in Commission Directive 2003/95/EC (Commission of the European
Communities, 2003).
A monograph describing the specifications for the use of pharmaceutical grades of
polyethylene glycol is included in the European Pharmacopoeia (2005).
Several of the specification parameters (i.e. description, assay, molecular weight, hydroxyl
value, melting point range, solubility, and viscosity) vary depending on the particular grade of
polyethylene glycol, as characterised by the molecular weight.
Analysis results of several non-consecutive batches for each of the six grades of polyethylene
glycol are provided by the applicant and confirm that the method of production yields a
consistent product meeting the product specifications provided.
Polyethylene glycol can be purchased with or without added BHT. The BHT level of use in the
polyethylene glycol is approximately 100 mg/kg. The applicant estimates that exposure to BHT
from the consumption of PEG coated products would not exceed 0.000167 mg/kg bw/day,
which is well below the JECFA and SCF ADI of 0.3 mg/kg bw/day and 0.05 mg/kg bw/day
respectively.
The primary impurities result from the manufacturing process and include mono- and
diethylene glycol, as well as unreacted ethylene oxide (not more than 0.2 mg/kg) and 1,4dioxane, a by-product of ethoxylation.
The International Agency for research on Cancer (IARC) has evaluated 1,4-dioxane in the past
and assigned a group 2B classification (i.e. the compound is possibly carcinogenic to
human)(IARC, 1999). In 2002 the Scientific Committee for Food (SCF) published an opinion
on 1,4-dioxane, as well as on mono- and diethylene glycol in currently permitted food additives
and in proposed use of ethyl hydroxyethyl cellulose (EHEC) in gluten-free bread (SCF, 2002a).
With regard to 1,4-dioxane, the SCF concluded that a threshold approach could be used in
determining acceptable levels of exposure, as 1,4-dioxane was demonstrated to exert its
carcinogenic effects by non-genotoxic mechanisms. Analysis of the polyethylene glycols
prepared by the applicant confirm 1,4-dioxane levels of less than the specification limit of not
more than 10 mg/kg as adopted for the polymers by JECFA (JECFA, 1992).
The SCF has in the past expressed concern regarding the exposure to residual levels of ethylene
oxide in food additives and recommended that specifications of food additives manufactured
using ethylene oxide should be revised to restrict ethylene oxide as an impurity to below its
current limit of detection (SCF, 2002b). The level for the residual levels of ethylene oxide of
1.0 mg/kg originally established for residual ethylene oxide in polyethylene glycol 6000
(Commission of the European Communities, 2003), was reduced to 0.2 mg/kg. Accordingly the
applicant has set a specification parameter of not more than 0.2 mg/kg for ethylene oxide in the
polyethylene glycols.
The polyethylene glycols contain the glycol monomer and dimer at levels below those accepted
by JECFA (i.e. not more than 0.25 %)(JECFA, 1992). For the mono- and diethylene glycols,
the group tolerable daily intake (TDI) of 0.5 mg/kg bw initially established by the SCF in 1986
(SCF, 1986) was maintained at the 2002 evaluation (SCF, 2002a). The applicant estimates that
the intake of mono- and diethylene glycols from the proposed uses of polyethylene glycol is
more than 100 fold below this TDI.
Methods of analysis in foods
Polyethylene glycol is used as part of a tablet coating formulation and as such is not added
directly into the tablet core. The weight-difference method is a common approach used to
assess the quantity of film coating applied to a tablet. Essentially the film weight is determined
by substracting the mean weight of the uncoated tablet from that of the coated tablet. Since
polyethylene glycol is an integral part of the formulated coating system, the film weight
addition will comprise all components of the coating formulation, including that of
polyethylene glycol.
Reaction and fate in foods, stability
Polyethylene glycols are reported to be stable in air and solution, and do not hydrolyze or
deteriorate upon storage (Merck, 2001). Polyethylene glycols are not conducive to mould
growth and do not become rancid (Merck, 2001; Rowe et al., 2003).
Stability data for 3 batches of polyethylene glycol 3350, a representative mid-range molecular
weight grade of polyethylene glycol were provided by the applicant and demonstrated that for
the duration of an 18-month storage period at temperatures ranging between 25 and 40 oC, all
parameters evaluated were within the limits of the specifications of polyethylene glycol 3350.
The applicant indicates that there are no known specific incompatibilities with typical food
supplement active ingredients and polyethylene glycol. The applicant also indicates that
polyethylene glycol is not expected to react with other components of food supplements or in
the gastrointestinal tract. General reactions of PEG described in the Handbook of
Pharmaceutical Excipients require extreme conditions not relevant for the proposed use (Rowe
et al., 2003).
Case of need and proposed uses
Polyethylene glycols are intended for use as plasticizers in aqueous film coatings used in the
preparation and formulation of food supplement products.
The applicant indicates that a food supplement tablet would typically be coated such that the
aqueous film coating formulation would provide a 4.0% weight gain to the overall weight of
the tablet/capsule. Depending on the particular coating formulation, polyethylene glycols are
expected to comprise up to approximately 25.0 % of the weight of the formulation, and
therefore may constitute up to 1.0 % of the weight of the tablet/capsule. The applicant also
indicates that polyethylene glycol 400, for example, is typically present in a film coating
preparation at levels of only 8.0 %, and consequently would only consitute 0.32 % of a
tablet/capsule weight.
Exposure
An estimate of consumption was made by the Panel based on the assumption that individuals
will not normally exceed six capsules per day and that extreme consumers will not take more
than double this amount, in line with previous opinions on food supplements (EFSA, 2004).
The applicant indicates the use of 500 mg, 750 mg and 1000 mg tablets/capsules containing 4%
of their weight as a PEG formulation containing 25% PEG, and thus containing respectively 5,
7.5 and 10 mg PEG. On this basis, using the maximum usage levels of polyethylene glycol,
intake would be around 120 mg per day amounting to 2 mg/kg bw/day. This assumes that an
individual of 60 kg may ingest on a daily basis twelve supplements as capsules containing 10
mg PEG each.
The UK Foods standards Agency provided information on the consumption data of food
supplements in different population groups (Henderson et al, 2002), young persons, 4-18 years,
(Gregory, 2000) and toddlers aged 1.5 to 4.5 years (Gregory, 1995). The 97.5th percentile of
estimated intake in consumers was 70 mg/day for adults (deriving from 7 capsules a day) and
20 mg/day for young people (deriving from 2 capsules a day).
These estimates pertain to users of dietary supplement products only.
has been approved.
Assuming similar levels of use and intake of pharmaceutical products and supplements per day
the combined intake from food supplements and pharmaceutical products would be twice as
high as estimated for the intake of supplements only and amount to 4 mg/kg bw/day.
Limited additional intake in the EU could occur from the approved use of polyethylene glycol
6000 as carrier for sweeteners, as well as from use of PEG in food contact materials.
Existing authorisations and evaluations
In addition to its use as a tablet/capsule coating agent, polyethylene glycol is also used in
various type of approved medical products, such as laxatives and ophthalmic products.
Polyethylene glycols were evaluated by the Joint FAO/WHO Expert Committee on Food
Additives (JECFA) in 1979 at the 23rd meeting (JECFA, 1980a,b). Based on toxicological data
provided, the Committee allocated an Acceptable Daily Intake (ADI) of 0-10 mg/kg bw/day.
Specifications prepared for the use of polyethylene glycol as a carrier solvent and excipient
were subsequently adopted at the 31st meeting (JECFA, 1992).
The evaluation by JECFA included PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000, PEG
1500, PEG 1540, PEG 4000, PEG 6000, PEG 9000 and PEG 10000. The JECFA concluded
that the acute and short-term studies cover a wide range of animal species and that PEGs have
essentially similar toxicity, with toxicity being inverse to molecular weight. The estimate of the
ADI of 0-10 mg/kg bw/day was based on the observation that in the rat 20 g/kg diet of PEG
400 equivalent to 1000 mg/kg bw/day was the level causing no adverse effect. Higher levels of
PEG produced small, non-specific effects upon growth or minor cloudy swelling of the liver
(Smyth et al., 1955; JECFA, 1980b).
In 1978 the SCF included polyethylene glycol (PEG 300-4000) in the list of substances which
were considered toxicologically acceptable for use in the manufacture of regenerated cellulose
film, with a TDI of 5 mg/kg bw as the sum of these substances (SCF, 1978).
PEG 6000 has been evaluated for safety by the SCF for its use as an excipient in sweetener
based tablets used for the preparation of sodas. The SCF opinion indicates that these tablets
notably contain around 3% of PEG 6000 and are designed to produce when dissolved in water a
soda-type beverage. The SCF concluded that, given its low absorption, the absence of known
toxic manifestations and the limited exposure which could results from the recommended use,
PEG 6000 may be considered as acceptable for the limited requested use (SCF, 1997).
According to Directive 98/72/EC polyethylene glycol 6000 is approved for use only as a carrier
for sweeteners (European parliament and Council of the European Union, 1998). No other
grades or uses are approved for use in food in the EU.
In the US polyethylene glycols with a mean molecular weight of 200 to 9500 are permitted for
use as a direct, multipurpose food additive (Federal Register, 2005).
Additionally, polyethylene glycols can be used in numerous pharmaceutical and dietary
supplement products in the US for oral administration. Maximum amounts of the polyethylene
glycols permitted for use in approved drug products for oral administration as listed in the US
Food and Drug Administration (FDA) Inactive Ingredient database (FDA, 2005) are for PEG
400, 3350, 4000, 6000 and 8000 respectively 960.48, 76.92, 449.6, 450 and 100 mg per dosage
form.
Polyethylene glycols are widely used in approved drug products in various countries in the Asia
Pacific region. In Japan, the Japanese Pharmaceutical Excipients Directory (JPED) specifies a
highest maximum permitted amount of 2.31 g/day for orally administered polyethylene glycol
400, 604.8 mg/day for PEG 4000, and 750 mg/day for PEG 6000.
Polyethylene glycols are approved in pharmaceutical products at various levels in China, India,
Pakistan, Indonesia, Malaysia, Philippines, Korea, Taiwan, Australia, and many other
countries. Additionally, in Taiwan polyethylene glycols also are approved for various food
uses.
The draft Codex alimentarius General Standard for Food Additives (GSFA) lists polyethylene
glycol for use in five food categories (Codex alimentarius, 2004).The maximum use levels for
polyethylene glycol for these five food categories are as follows: chewing gum (20,000 mg/kg),
table-top sweeteners, including those containing high-intensity sweeteners (10,000 mg/kg),
food supplements (70,000 mg/kg), water-based flavoured drinks, including sport or electrolyte
drinks and particulated drinks (1,000 mg/kg) and surface treated fresh fruit (Good
Manufacturing Practice).
Polyethylene glycol is permitted for use as an adjuvant, antifoaming agent, emulsifier, flavour
enhancer, glazing agent, release agent, stabilizer, and thickener.
TOXICOLOGICAL DATA
Absorption, Bioavailability and Metabolism
Several animal studies on the absorption, bioavailability, metabolism and urinary and faecal
excretion of different polyethylene glycols have been reported (Shaffer and Critchfield, 1947;
Shaffer et al., 1948; Shaffer et al., 1950; Stahl et al., 1991; Carpenter et al., 1971; Kim, 1996;
Krugliak et al., 1989; Roy et al., 1987)
Generally these studies demonstrate that the extent of polyethylene glycol absorption appears to
be dependent on the molecular weight of the specific polymer, such that more complete
absorption has been reported for the lower weight polyethylene glycols like polyethylene glycol
400, while absorption is much more limited in the case of the heavier polyethylene glycols like
polyethylene glycol 4000 and 6000.
Once absorbed, polyethylene glycols are excreted in urine by glomerular filtration without
tubular reabsorption (Shaffer et al., 1948).
In addition several human studies reported on the bioavailability, absorption, metabolism and
excretion characteristics of polyethylene glycols (Shaffer et al. 1950; Delahunty and Hollander,
1986; Chadwick et al., 1977; Shaffer and Critchfield, 1947; DiPiro et al., 1986; Schiller et al.,
1997; Almer et al., 1993; Parlesak et al., 1994).
All together these human studies also reveal that the potential for and degree of absorption
following oral administration of the polyethylene glycol polymers is dependent on the
molecular weight of the compound.
For lower molecular weight polymers, urinary recovery, indicative of systemic absorption of
the polymers, accounted for approximately 20 to 36% of the administered dose in animals
(Shaffer et al., 1950) and as much as 60% in healthy humans (Shaffer et al., 1950; Chadwick et
al., 1977; Delahunty and Hollander, 1986; Oliva et al., 1994; Parlesak et al., 1994; Eaton et al.,
1995). In contrast, higher molecular weight polyethylene glycols exhibited lower absorption in
humans (Shaffer and Critchfield, 1947; DiPiro et al., 1986; Parlesak et al., 1994; Schiller et al.,
1997). Although the metabolic fate of the absorbed polyethylene glycols has not been fully
elucidated, incomplete urinary excretion of the lower molecular weight compounds following
intravenous administration was suggested to be indicative of possible degradation prior to
elimination. In vitro oxidation of the polymers to carboxylic acids was determined to be the
most likely metabolic pathway (Friman et al., 1993).
However, Chadwick et al. (1977) reported almost complete (>90%) recovery of 10 g of
polyethylene glycol 400 in the urine and faeces following oral exposure of 4 human volunteers
and a 4-day collection period. Ultimately, unchanged polyethylene glycols and/or their
metabolites are excreted via glomerular filtration in the urine or alternatively are secreted into
bile and eliminated via the faeces together with the unabsorbed portion of the ingested
polymers.
As demonstrated in rat perfusion studies, polyethylene glycol polymers can permeate the
intestinal epithelium via aqueous channels (Krugliak et al., 1989; Kim, 1996).
Acute Oral Toxicity
Acute toxicity studies were conducted in several species including rats, mice, guinea pigs, and
rabbits to determine oral LD50 values for polyethylene glycols characterized by molecular
weights of 200 to 9,000. In rats, oral LD50 values were reported to range from greater than 5 to
greater than 50.0 g/kg body weight (Smyth et al., 1941; Union Carbide, 1965; Huntingdon,
2003). Similarly, in mice LD50 values greater than 30.0 g/kg body weight were reported for the
polyethylene glycols (Smyth et al., 1941; Union Carbide, 1965). Overall, the results
demonstrate that the acute toxicity of polyethylene glycols (200 to 9,000) in several different
laboratory animals is low. Furthermore, oral toxicity of polyethylene glycol appears to decrease
with increasing molecular weight (Smyth et al., 1950).
Short-term and chronic toxicity
Several oral and non-oral, short and long-term animal toxicity studies, including a 90-day GLPcompliant animal toxicity study, have been reported.
Overall, no consistent adverse effects have been shown to be associated with polyethylene
glycol compounds of variable molecular weights, administered orally to various laboratory
animals including rabbits, rats, dogs, and monkeys.
Isolated occurrences of non-neoplastic renal effects were reported in some of the short-term
studies (Smyth et al., 1942, 1945, 1950, 1955; Prentice and Majeed, 1978; Hermansky et al.,
1995), but in none of the long-term toxicity studies (Smyth et al., 1947, 1955; Weil and Smyth,
1956) in which the polyethylene glycol compounds were provided orally.
Accumulation of calcium oxalate crystals resulting from the potential metabolism of
polyethylene glycol to ethylene glycol, which is subsequently excreted as oxalic acid, was
suggested as a possible mechanism for the apparent kidney effects (Prentice and Majeed, 1978;
Hermansky et al., 1995). However, reports of adverse kidney effects were not consistently
associated with crystal formation in the renal organs and in animals ethylene glycol has not
been detected as a metabolite of polyethylene glycol (Shaffer et al., 1950).
In a more recent subchronic toxicity study, designed to specifically examine potential renal
toxicity, 28-day old Fisher 344 rats (10/group/sex) were administered polyethylene glycol 400
at dose levels of 0 (control),1.0, 2.5, or 5 mL/kg body weight/day (approximately 1.1, 2.8, and
5.6 g/kg body weight/day, respectively) via oral gavage 5 days per week for a period of 13
weeks (total of 65 doses) (Hermansky et al., 1995). Clinical signs of toxicity were limited to a
transient passage of unformed stools, reported 1 day following initial polyethylene glycol 400
administration in both sexes at the high-dose level (5.6 g/kg body weight/day) and disappearing
in the first week of treatment. Loose faeces formation was reported to reoccur toward study
completion in 70% of males and 61% of females at the high dose level, as well as in 20% of
mid-dose males (2.8 g/kg body weight/day). Throughout the study and recovery periods, body
weights of high-dose animals were slightly decreased compared to controls. Food consumption
of treated males in the mid- and high-dose groups was slightly reduced (2 to 8%), while a doserelated increase in water consumption was observed during dosing in both males and females.
The loose faeces, and reduced food consumption and body weights were attributed to the
relatively large dose of the compound administered and not to a direct compound-related toxic
effect per se.
Haematological and clinical chemistry indices, including serum calcium concentrations,
evaluated immediately following treatment were unaffected; however, urinalysis revealed
several variations.
Dose-dependent increases were reported in N-acetyl-β-D-glucosamidase (NAG) activity,
osmolality, and specific gravity at every dose level of treated males; however, in the low-dose
group only the variation in specific gravity was statistically significant. In females, increases in
urinary osmolality and specific gravity also were noted in all test groups, but only the increase
in specific gravity in the high-dose group reached levels of statistical significance. Urine pH
and concentrations of protein and bilirubin were decreased and increased, respectively, in all
males. Levels of red and white blood cells were slightly elevated in high-dose males. In female
mid- and high-dose groups urine pH also was decreased and protein concentration increased.
Following the recovery period, no differences were reported in haematology, clinical
chemistry, or urinalysis compared to control values.
Statistically significant organ weight variations at 13-week scheduled necropsy included
increases of 2%, 4% and 4% in relative kidney weights in males at the low- (1.1 g/kg body
weight/day), and mid- and high-dose levels (2.8 and 5.6 g/kg body weight/day), respectively. In
females, relative kidney weights also were elevated in the mid- and high-dose groups, albeit not
at levels of statistical significance. The increase persisted into the recovery period, at which
point the difference became statistically significant. Additionally, in males relative brain and
testes weights were increased by 8 and 6% in animals treated at the high-dose level; these
variations, however, were secondary changes attributed to the decrease noted in final body
weights. Both gross and microscopic examinations were unremarkable and more specifically no
histopathological lesions were observed in the renal organs. However, based on the variability
observed in several of the urinary parameters examined, accompanied by the relative kidney
weight changes in males, the authors determined the no-adverse-effect-level (NOAEL) to be at
1.0 and 2.5 mL/kg body weight/day (1.1 and 2.8 g/kg body weight/day, respectively) in males
and females, respectively.
There are also several non-oral subchronic toxicity studies with polyethylene glycols, but given
the fact that non-oral routes of exposure are less relevant for the exposure to polyethylene
glycol via food they are not included in this opinion.
Reproductive and developmental toxicity
No published, peer-reviewed studies were available for the assessment of the potential
teratogenicity, or reproductive and/or developmental toxicities of the polyethylene glycols. The
applicant indicates that several study abstracts were identified as well as a summary of an U.S.
Army laboratory report, which overall demonstrated absence of such adverse effects associated
with exposure to the polyethylene glycols.
Polyethylene glycol 200 was reported to induce slight teratogenic effects in mice, but not in rats
(Vannier et al., 1989; abstract only). Daily doses of 0.5 or 0.7 mL (approximately 0.6 and 0.8 g,
respectively) undiluted polymer per animal were administered to CD-1 female mice on
gestation days 6 to 17, equivalent to doses of about 0.1 g/kg bw/day. Dams were killed on day
18 and fetuses removed and examined for skeletal malformations. With the exception of a
single death on the day of study termination in the high-dose group, no other symptoms of
maternal toxicity were observed. Compared to controls, fetal loss and body weights were lower
in the treated groups. Malformations affecting the skull, paws, and thoracic skeleton were
identified. The effects were reported to be dose-dependent.
These slight teratogenic effects observed in mice following polyethylene glycol 200 treatment
(Vannier et al., 1989; Spezia et al., 1992) were not observed in studies performed with rats and
rabbits exposed to polyethylene glycols 200 or 400 at dose levels from 1 to 10 g/kg bw/day
(Starke and Pellerin, 1981; Spezia et al., 1992; Gupta et al., 1996a,b). In rat whole embryo
cultures, teratogenic effects were only observed in the presence of mouse S9-mix for metabolic
activation and not in the presence of rat, human, rabbit or hamster S9-mix. The effects in mice
were therefore considered to be species-specific.
Mutagenicity
Mortelmans et al., (1986) and Gerber (1982) evaluated the potential mutagenicity of
polyethylene glycol 200 in several strains of Salmonella typhimurium including TA98, TA100,
TA1535, and TA1537. Polyethylene glycol 200, tested negative in the absence and presence of
metabolic activation.
Likewise, negative results for mutagenic activity were obtained for polyethylene glycol 3000
evaluated in a battery of S. typhimurium strains (i.e., TA1535, TA1537, TA98, and TA100) and
Escherichia coli WP2uvrA/pKM101 (CM891) at concentrations of up to 5,000 µg/plate with
and without metabolic activation (Huntingdon, 2002).
Sister chromatid exchange (SCE) was examined in CHO cells exposed to polyethylene glycol
400 for 5 hours in the absence of metabolic activation and for 2 hour in the presence of
metabolic activation (CIR, 1993). Compared to control values, significantly elevated SCE
frequency was noted only at 0.5% polyethylene glycol 400, with metabolic activation, but not
at 1 %.
Similarly, in an unscheduled DNA synthesis (UDS) assay in rat hepatocytes incubated with
polyethylene glycol 400, increased UDS activity was apparent in the nuclei and DNA, but only
at the higher concentration were levels of statistical significance attained (CIR,
1993).Furthermore, no significant elevations in UDS frequency and no dose-dependency were
identified.
Thus although some positive results were obtained in the SCE and UDS assays, no doseresponses were established.
Chinese hamster epithelial cells (CHEL), which are reported to retain metabolic capabilities to
activate promutagens and procarcinogens, were incubated with polyethylene glycol 200 and
400 at concentrations of 2.0 to 8.0 mM and up to 7.0 mM, respectively (Biondi et al., 2002). A
significant increase in the percentage of cells with chromosome aberrations was observed with
polyethylene glycol 200, but not with polyethylene glycol 400. In a subsequent assay
performed to verify the absence of genotoxicity observed in CHEL cells exposed to
polyethylene glycol 400, CHO cells were exposed to the polymer at concentrations ranging
between 17 and 35 mM, in the presence and absence of metabolic activation. Clastogenic
effects, as evidenced by statistically significant increases in the frequency of aberrant cells,
were reported with metabolic activation, and at concentrations of 25 and 35 mM at moderate
cytotoxicity but without a clear dose-reponse. Furthermore the value of the study is limited
because it is poorly reported.
A sex-linked recessive lethal test was used to investigate the potential mutagenicity of
polyethylene glycol 200 in Drosophila melanogaster (Crook et al., 1981). Polyethylene glycol
200 did not induce a significant increase in mutations at any of the concentrations evaluated.
Of the polyethylene glycols of greater molecular weight, polyethylene glycol 6000 was
evaluated in vitro in the L5178Y/tk+/- mouse lymphoma assay (Wangenheim and Bolcsfoldi,
1988), a study which was subsequently reviewed by the U.S. Environmental Protection Agency
(EPA) (Mitchell et al., 1997). Polyethylene glycol 6000 was reported to produce a noncytotoxic
negative response at 50 to 125 mg/mL in the absence of metabolic activation. However, at the
highest concentration tested (150 mg/mL), polyethylene glycol induced a 2.3-fold increase in
mutation frequency and a reduction in the growth rate. Since the growth rate was not reduced to
levels below 10 to 20% of growth observed at the other concentrations, the overall evaluation
of the U.S. EPA with respect to potential polyethylene glycol 6000-related mutagenicity was
inconclusive. However, the panel did its own evaluation of the study and considers the weak
positive effect at the highest toxic dose of PEG 6000 not toxicologically relevant.
Carcinogenicity
None of the chronic oral toxicity studies in which polyethylene glycols 200 to 4000
administered at up to 1 g/kg body weight/day for up to 2 years to Wistar rats (Smyth et al.,
1947), at up to 4 g/kg bw/day to Sherman rats (Smyth et al., 1955), or at up to 2 g/kg bw/day to
rats (strain not specified)(Weil and Smyth, 1956) produced any dose-dependent compoundrelated adverse effects and did not reveal any gross or microscopic kidney variations (Smyth et
al., 1947, 1955; Weil and Smyth, 1956), including no incidences of neoplasms or other
pathological abnormalities in comparison to untreated control groups.
Collectively, the results of the longer term studies (90 days up to 2 years) conducted with the
polyethylene glycol 400, 1540 and 4000 polymers (Smyth et al., 1947 and 1955; Weil and
Smyth, 1956) demonstrate the absence of any compound-related toxicities, and further support
the hypothesis that some of the adverse effects observed with the heavier polyethylene glycol
1500 and 4000 polymers in the 1942 Smyth et al. subchronic study, but not at similar or higher
dose levels in subsequent short-term studies (Smyth et al., 1950, 1955), may have been the
result of inadequate production methods, which may have introduced unidentified by-products
or contaminants with unknown toxicities.
Berenblum and Haran (1955) conducted a study to assess the effect of polyethylene glycol 400
and croton oil on forestomach carcinogenesis in male Swiss mice. Several treatment groups
were included in this study, one of which consisted of weekly administration of 0.3 mL
(approximately 0.34 g) polyethylene glycol 400 via oral gavage for a period of 30 weeks.
Following the treatment period no occurrences of forestomach tumours were reported.
In a non-oral toxicity study assessing the carcinogenic properties of various rubber additives,
polyethylene glycol 400 was used as the solvent and was provided to the solvent control group
(Boyland et al., 1968). The solvent control group consisted of 24 male CB rats. Rats were
administered weekly 0.25 mL polyethylene glycol 400 (approximately 0.28 g) via
intraperitoneal injection for a period of 6 months. Therefore, in total rats were exposed to
approximately 30 g polyethylene glycol 400/kg body weight. Animals were examined daily for
clinical signs of toxicity for up to 2 years. No intraperitoneal tumours were identified in the
polyethylene glycol-control group and only a single incidence of hepatoma was identified in a
22- to 24-month old rat.
Furthermore, polyethylene glycol was identified to possess anticarcinogenic properties when
administered during the promotion phase following initiation with various chemical
carcinogens. These studies are however not considered relevant for judging the safety of
polyethylene glycol.
Human data
Given the prevalent use of the polyethylene glycols for various medical applications, several
reports of adverse events possibly associated with the exposure to the polymers have been
documented in the published literature (Bruns et al., 1982; Sturgill et al. 1982; McCabe et al.,
1959; Mutter et al., 2002; Laine et al. 1995; Erickson et al. 1996; Franga and Harris, 2000).
Several case reports have indicated potential for nephrotoxicity in patients receiving continuous
infusions of polyethylene glycol 400, used as a diluent in hospital intravenous preparation, for
extended periods of time (McCabe et al., 1959; Laine et al., 1995; Erickson et al., 1996; Mutter
et al., 2002), as well as in burn victims treated with topical polyethylene glycol-based creams
(Bruns et al., 1982; Sturgill et al., 1982). However, the route of administration (intravenous
instead of oral), at doses greatly exceeding those expected from the consumption of any of the
polyethylene glycols as coating agents, or following topical application to open wounds
covering large areas of the body, is not reflective of the exposure following absorption from
orally administered doses and, therefore, is not considered to be predictive of oral toxicity.
In addition, the subjects of these case reports were often diseased, received several different
medications simultaneously, and were administered polyethylene glycol at levels considerably
higher than those expected from the use of the polymers as tablet-coating agents. Therefore
these studies are not considered to be reflective of typical use conditions associated with the
application of the polyethylene glycols in tablet formulations, and, therefore, not relevant for
the present overall safety assessment of the polymers.
Clinical Trials
Several studies were conducted to assess the safety and efficacy of polyethylene glycols 3350
and 4000 as osmotic laxatives in adults and children (DiPalma et al., 2000; Cleveland et al.,
2001; Chaussade and Minic, 2003; Pashankar et al., 2003). Mixtures of polyethylene glycols
3350 or 4000 in combination with electrolytes are used to cleanse the bowel prior to
colonoscopy, radiological procedures, or surgery (Sweetman, 2002). On a longer-term basis,
similar preparations may be used as routine laxatives (Sweetman, 2002).
In a double-blind, randomized, parallel-group study, polyethylene glycol 3350 in an isoosmotic solution (i.e., with electrolytes) and polyethylene glycol 4000 in hypo-osmotic solution
(i.e., without electrolytes) were provided at a standard or maximum daily dose level for a
period of 1 month to groups of male and female patients presenting with constipation
(Chaussade and Minic, 2003). In total 266 patients were included in the study, of which 211
completed the trial. Reasons for early termination included adverse events, treatment failure,
other reasons (not specified by the authors) and loss to follow-up. Patients were randomized to
one of the following 4 treatment groups: 5.9 or 11.8 g polyethylene glycol 3350, or 10 or 20 g
of polyethylene glycol 4000.
Polyethylene glycol 3350 and 4000 were provided in sachets containing 5.9 and 11.9 g,
respectively, and were diluted with water prior to consumption. Patients were examined
clinically at week 0 to establish baseline levels and at weeks 2 and 4 thereafter. At both
timepoints of examination, stool frequency was significantly increased in all groups and stool
consistency was significantly improved compared to baseline levels. Additionally, in
comparison to baseline levels, percentage of patients with semi-liquid to liquid stool
consistency was elevated at weeks 2 and 4 in all groups, with the exception of the group
consuming 5.9 g of polyethylene glycol 3350. All test compounds were well tolerated and no
differences were observed between treatment groups. No deaths or serious adverse effects were
reported throughout the study period. In each test group, approximately 50 to 60% of the
participants reported at least one adverse event, the majority of which were described as
gastrointestinal disturbances. Incidences of diarrhoea and liquid stools, which occurred at least
on one occasion in 69 subjects and were more prevalent at the higher dose levels, were
probably or possibly attributed to compound ingestion. Distension, flatulence, and abdominal
pain were among the other gastrointestinal problems reported as possibly or probably
compound-related.
DiPalma et al., (2000) reported no significant adverse events and no variations in the laboratory
results [i.e., blood chemistry, complete blood count (CBC), and urinalysis] following
consumption of 17 g polyethylene glycol 3350/day without electrolytes dissolved in water for a
period of 14 days. A total of 135 constipated but otherwise healthy adult subjects participated
in this placebo-controlled, randomized, parallel trial. In comparison to the dextrose placebo
group, an improvement in bowel movements and significantly less cramping (12% vs. 22.6%)
and gas (24% vs. 40.2%) was reported in the test group.
The safety and efficacy of polyethylene glycol 3350 without electrolytes was confirmed in
another 14-day, double crossover trial involving a group of 23 (22F, 1M) patients with a history
of constipation (Cleveland et al., 2001). During the test period subjects consumed daily 17 g
polyethylene glycol 3350 in 250 mL flavoured water, while the placebo solution consisted of
flavouring only. By the second week of treatment a significant improvement in bowel
movements was observed. Cramping, flatulence, and rectal irritation were relatively mild
during polyethylene glycol 3350 treatment and less severe than during the placebo phase.
Diarrhoea was reported by 3 patients while consuming polyethylene glycol 3350, while nausea
and impaction were reported by individuals during both the test and placebo periods. Blood
chemistry, complete blood counts (CBC), and urinalysis did not reveal any clinically significant
variations.
Polyethylene glycol 3350 was used in a prospective observational study in children presenting
with chronic constipation (Pashankar et al., 2003). Children 2 to 17 years of age receiving
polyethylene glycol 3350 daily for at least 3 months were enrolled in this study. In total 83
children (48M, 35F) participated in the study and the mean study duration was reported to be
8.7 months. Polyethylene glycol 3350 without electrolytes was provided as a powder and was
initially prescribed at a dose level of 0.8 g/kg body weight. Prior to ingestion, 17 g of the
powder were dissolved in water or other beverage and provided in 2 divided doses.
Subsequently, doses were adjusted depending on the symptoms such that the mean daily dose
consumed was 0.75 g/kg body weight (0.2 to 1.8 g/kg body weight). At the time of evaluation
parents and children were interviewed, and information pertaining to the occurrence of any
adverse effects and tolerability of the laxative treatment were recorded. Additionally, blood
samples were collected for evaluation of several haematology and clinical chemistry
parameters. Blood tests were repeated within 8 weeks in cases where results deviated by more
than 1 point from the age- and sex-specific reference range established for the hospital.
Polyethylene glycol 3350 was well accepted and was associated with an improvement in
symptoms in 91% of subjects. Clinically adverse effects consisting of watery stools (10%),
bloating or flatulence (6%), and abdominal pain (2%), were generally minor and acceptable,
and did not result in any early withdrawals from therapy. Laboratory results revealed a slight
increase in levels of alanine aminotransferase (ALT) in 9 patients and of aspartate
aminotransferae (AST) levels in 3 patients. Of the 9 individuals exhibiting elevated ALT levels,
8 had levels remeasured within 8 weeks, 7 of whom continued to received polyethylene glycol
3350. At retesting, levels were reported to fall within the reference range for all but 1 of the 8
patients. Similarly, AST values returned to normal when re-examined in the 3 individuals
initially showing increases in AST levels. The dosages administered and the duration of
polyethylene glycol 3350-treatment in children with the slight variations in the enzymes were
comparable to others with unremarkable laboratory results. As no signs or symptoms of liver
disease were observed in this group of children, the fluctuations were deemed to be clinically
insignificant and not related to the consumption of polyethylene glycol 3350.
DISCUSSION
Polyethylene glycols are synthetic addition polymers prepared via an addition reaction of
ethylene oxide and water in the presence of a catalyst. Several of the physico-chemical
properties of the polyethylene glycols and thus the proposed specifications vary depending on
the molecular weight of the particular polymer.
The present application is being submitted for six grades of polyethylene glycol (i.e. PEG 400,
PEG 3000, PEG 3350, PEG 4000, PEG 6000, and PEG 8000).
Generally, however, specifications proposed by the applicant were in accordance with those
adopted for polyethylene glycol 6000, which is presently approved for use in the European
Union in food as a carrier for sweeteners.
Several oral and non-oral, short and long-term animal toxicity studies, including a 90-day GLPcompliant animal toxicity study, as well as a number of mutagenicity tests and human clinical
trials have been reported.
In particular, while following oral administration of the low molecular weight polyethylene
glycols (i.e., polyethylene glycol 400) urinary recovery was reported to be approximately 20 to
30% of the administered dose in rats and as much as 60% in healthy humans, high molecular
weight polyethylene glycols exhibited lower absorption in humans. Ultimately, unchanged
polyethylene glycols and/or their metabolites are excreted via glomerular filtration in the urine
or alternatively are secreted into bile and eliminated via the faeces.
Overall, no consistent adverse effects have been shown to be associated with polyethylene
glycol compounds of variable molecular weights, administered orally to various laboratory
animals including rabbits, rats, dogs, and monkeys. Isolated occurrences of non-neoplastic renal
effects were reported in some of the short-, but none of the long-term toxicity studies in which
the polyethylene glycol compounds were administered orally.
None of the chronic oral toxicity studies in which polyethylene glycols 200 to 4000 were
administered at up to 4 g/kg body weight/day for up to 2 years produced any dose-dependent
compound-related adverse effects and did not reveal any gross or microscopic kidney
variations, including no urinary tract tumours in one oral and non-oral carcinogenicity study.
The Panel noted that PEG 6000 and PEG 8000 were not included in the carcinogencity studies
but given its lower level of absorption than the lower molecular weight PEGs this is not
considered a matter of concern.
The Panel concludes that the data available from several in vitro mutagenicity and genotoxicity
studies, performed in both prokaryotic and eukaryotic test systems do not give rise to safety
concerns with respect to genotoxicity of polyethylene glycols. The slight teratogenic effects
observed in mice following polyethylene glycol 200 treatment were deemed to be speciesspecific and were not observed in studies performed with rats and rabbits exposed to
polyethylene glycols 200 or 400 at doses up to 10 g/kg bw/day.
The pharmaceutical application of the higher molecular weight polymers, in particular
polyethylene glycol 3350 and 4000, as laxatives for long term use, has prompted investigation
of their safety and effectiveness in several clinical studies. In both children and adults daily oral
doses of up to 20 g consumed for periods of up to 9 months, were generally well tolerated. Side
effects reported at these dose levels were limited to gastrointestinal disturbances such as
diarrhoea, flatulence and abdominal discomforts. None of the clinical chemistry and urinalysis
results varied significantly from baseline evaluations.
amounting to 2 mg/kg bw/day, assuming 60 kg bw.
has been approved. Assuming similar levels of use and intake of pharmaceutical products and
food supplements per day the combined intake from food supplements and pharmaceutical
products would be about 4 mg/kg bw/day.
Limited additional exposure in the EU could occur from the approved use of polyethylene
glycol 6000 as a carrier for sweeteners, as well as from the use of the PEG in food contact
materials.
CONCLUSIONS
The applicant requests the authorisation of polyethylene glycols for use as plasticizers in
aqueous film coatings for use in the preparation and formulation of food supplement products.
Several pre-GLP oral and non-oral, short and long-term animal toxicity studies, as well as a
more recent 90-day GLP-compliant animal toxicity study, and a number of mutagenicity tests
and human clinical trials have been reported. Together the outcomes of these studies give no
reason for concern. The Panel noted that PEG 6000 and PEG 8000 was not included in the
carcinogencity studies but given their lower level of absorption than the lower molecular
weight PEGs this is not considered a matter of concern.
amounting to 2 mg/kg bw/day assuming 60 kg bw.
Assuming similar levels of use and intake of pharmaceutical products and food supplements per
day the combined intake from food supplements and pharmaceutical products would be about 4
mg/kg body weight.
The estimated daily intakes of the polyethylene glycols from the use as a coating agent for food
supplements are below the ADI of 0-10 mg/kg body weight allocated by JECFA and the group
TDI of 5 mg/kg body weight established by the SCF for the polyethylene glycols.
Therefore, overall the data support the conclusion that consumption of polyethylene glycols
(PEG 400, PEG 3000, PEG 3350, PEG 4000, PEG 6000, and PEG 8000) through use as
plasticizers in film-coating formulations for food supplement tablets and/or capsules at the
intended use level are not of safety concern.
DOCUMENTATION PROVIDED TO EFSA
Application for the approval of polyethylene glycol (PEG) for use as a film coating agent for
food supplement products. Dossier provided by Cantox on behalf of the applicant Colorcon.
REFERENCES
List of References
Almer, S., Franzen, L., Olaison, G., Smedh, K., Strom, M. Increased absorption of polyethylene
glycol 600 deposited in the colon in active ulcerative colitis. Gut 34, 509-513, 1993.
Berenblum, I., Haran, N. The influence of croton oil and of polyethylene glycol-400 on
carcinogenesis in the forestomach of the mouse. Cancer Res 15, 510-516, 1955.
Biondi, O., Motta, S., Mosesso, P. Low molecular weight polyethylene glycol induces
chromosome aberrations in Chinese hamster cells cultured in vitro. Mutagenesis 17,
261-264, 2002.
Boyland, E., Carter, R.L., Gorrod, J.W., Roe, F.J. Carcinogenic properties of certain rubber
additives. Eur J Cancer 4, 233-239, 1968.
Bruns, D.E., Herold, D.A., Rodeheaver, G.T., Edlich, R.F. Polyethylene glycol intoxication in
burn patients. Burns 9, 49-52, 1982.
Carpenter, C.P., Woodside, M.D., Kinkead, E.R., King, J.M., Sullivan, J.L. Response of dogs
to repeated intravenous injection of polyethylene glycol 4000 with notes on excretion and
sensitization. Toxicol Appl Pharmacol 18, 35-40, 1971.
Chadwick, V.S., Phillips, S.F., Hofmann, A.F. Measurements of intestinal permeability using
low molecular weight polyethylene glycols (PEG 400). Gastroenterology 73, 241-246, 1977.
Chaussade, S., Minic, M. Comparison of efficacy and safety of two doses of two different
polyethylene glycol-based laxatives in the treatment of constipation. Aliment Pharmacol Ther
17, 165-172, 2003.
CIR (Cosmetic Ingredient Review). Final report on the safety assessment of polyethylene
glycols (PEGs) –6, -8, -32, -75, -150, -14M, -20M. J Am Coll Toxicol 12, 429-457, 1993.
Cleveland, M., Flavin, D.P., Ruben, R.A., Epstein, R.M., Clark, G.E. New polyethylene glycol
laxative for treatment of constipation in adults: A randomized, double-blind, placebocontrolled
study. South Med J 94, 478-481, 2001.
Codex Alimentarius Commission. Food and Agriculture Organization of the United Nations
(FAO)/World Health Organization (WHO), Rome, 2004. [CX/FAC 05/37/6, Nov., 2004].
Available from:
ftp://ftp.fao.org/codex/ccfac37/fa37_06e.pdf.
Commission of the European Communities. Commission Directive 2003/95/EC of 27 October
2003 amending Directive 96/77/EC laying down specific purity criteria on food additives other
than colours and sweeteners. Off J Eur Union 46, 71-77, 2003.
Crook, J.W., Hott, P., Weimer, J.T., Farrand, R.L., Cooper, A.E. The Acute Toxicity of
Polyethylene Glycol 200 in Laboratory Animals. Army Armament Research and
Development Command, Aberdeen Proving Ground, Maryland. Chemical Systems Lab., 1981.
[ADA106519/2 ; ARSCL-TF-81058].
Delahunty, T., Hollander, D. New liquid-chromatographic method for measuring polyethylene
glycol in urine. Clin Chem 32, 351-353, 1986.
DiPalma, J.A., DeRidder, P.H., Orlando, R.C ., Kolts, B.E., Cleveland, M.B. A randomized,
placebo-controlled, multicenter study of the safety and efficacy of a new polyethylene glycol
laxative. Am J Gastroenterol 95, 446-450, 2000.
DiPiro, J.T., Michael, K.A., Clark, B.A., Dickson, P., Vallner, J.J., Bowden, T.A. (Jr.),
Tedesco, F.J. Absorption of polyethylene glycol after administration of a PEG-lavage solution.
Clin Pharm 5, 153-155, 1986.
EFSA (2004) Opinion of the Scientific panel on Food Additives, Flavourings, processing Aids
and Materials in Contact with Food on a request from the Commision related to Pullulan PI-20
for use as a new food additive. The EFSA Journal (2004) 85, 1-31.
http://www.efsa.europa.eu/en/science/afc/afc_opinions/629.html
Eaton, K.K., Howard, M., McLaren Howard, J.M.H. Gut permeability measured by
polyethylene glycol absorption in abnormal gut fermentation as compared with food
intolerance. J R Soc Med 88, 63-66, 1995.
Erickson, T.B., Aks, S.E., Zabaneh, R., Reid, R. Acute renal toxicity after ingestion of Lava
light liquid. Ann Emerg Med 27, 781-784, 1996.
European Parliament and Council of the European Union. Directive No. 95/2/EC of 20
February 1995 on food additives other than colours and sweeteners [amended to 1998]. Off J
Eur Communities 38, 1-40, 1995.
European Parliament and Council of the European Union. Directive 98/72/EC of the European
Parliament and of the Council of 15 October 1998 amending Directive 95/2/EC on food
additives other than colours and sweeteners. Off J Eur Communities 41, 18-30, 1998.
European Pharmacopoeia (2005).
www.pheur.org
FCC. Polyethylene glycols. In: Food Chemicals Codex, 5th Ed. National Academy Press
(NAP), Washington, DC, 2003, pp. 340-342.
FDA. Polyethylene glycol. In: FDA/CDER. Inactive Ingredient Search for Approved Drug
Products. Center for Drug Evaluation and Research (CDER), Office of Generic Drugs, U.S.
Food and Drug Administration, Inactive Ingredient Database, 2005. Available from:
http://www.accessdata.fda.gov/scripts/cder/iig/
Federal Register 21CFR172-- PART 172_FOOD ADDITIVES PERMITTED FOR DIRECT
ADDITION TO FOOD FOR HUMAN, Sec. 172.820 Polyethylene glycol, 2005.
http://www.access.gpo.gov/nara/cfr/waisidx_06/21cfrv3_06.html
Franga, D.L., Harris, J.A. Polyethylene glycol-induced pancreatitis. Gastrointest Endosc 52,
789-791, 2000.
Friman, S., Egestad, B., Sjövall, J., Svanvik, J. Hepatic excretion and metabolism of
polyethylene glycols and mannitol in the cat. J Hepatol 17, 48-55, 1993.
Gerber, B.V. Unpublished Preliminary Experiments. U.S. Army ARRADCOM Chemical
Systems Laboratory, Private Communication, 1982.
Gregory J., National diet and nutrition survey children aged 1 1/2 to 4 1/2 years Vol. 1 Report
of the diet and nutrition survey, HMSO, 1995.
Gregory, J. National diet and nutrition survey young people aged 4-18 years Vol. 1 Report of
the diet and nutrition survey, UK Stationery Office, 2000.
Gupta, U., Beaulieu, J., Chapin Hopper, J., Hagler, A.R., Hills-Perry, P. Teratogenic evaluation
of alternative vehicles: PEG 400, cremophor, carboxymethylcellulose: Comparison with
methylcellulose. Teratology 53, 111, 1996a. [Abstract No. P32].
Gupta, U., Beaulieu, J., Hills-Perry, P. Developmental toxicity testing of alternative vehicles:
PEG 400, cremophor and carboxymethylcellulose: Comparison with methylcellulose.
Toxicologist 30, 192, 1996b. [Abstract No. 980].
Henderson, L, Gregory, J., Swan G. (2002) National Diet and Nutrition Survey: adults aged
19-64 years. Volume 1: types and quantities of foods consumed, The Stationary Office.
Henning, T. Polyethylene glycols (PEGs) and the pharmaceutical industry. Fine, Specialty &
Performance
Chemicals.
PharmaChem,
June,
57-59,
2002.
Available
from:http://www.clariant.de/C125691A003596E5/vwWebDownloadsWT/Polyethylene_glycols
_(PEGs)_and_the_pharmaceutical_industry.pdf.
Hermansky, S.J., Neptun, D.A., Loughran, K.A., Leung, H.W. Effects of polyethylene glycol
400 (PEG 400) following 13 weeks of gavage treatment in Fischer-344 rats. Food Chem
Toxicol 33, 139-149, 1995.
Huntingdon. PEG 3000. Bacterial Reverse Mutation Test. Huntigdon Life Sciences Ltd. Study
No. CNO 009/024608, 2002.
Huntingdon. PEG 3000: A Single-Dose Oral Toxicity Study in Rats. Huntigdon Life Sciences Ltd.
Study No.: 02-2790, 2003.
IARC. 1,4-Dioxane. In: Re-Evaluation of Some Organic Chemicals, Hydrazine and Hydrogen
Peroxide. International Agency for Research on Cancer (IARC), Lyon, France, IARC
Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 71, Part 2, 1999, pp.
589-602.
JECFA. Polyethylene glycols. In: Evaluation of Certain Food Additives, 23rd JECFA Session,
Apr. 2-11, 1979, Geneva. Joint FAO/WHO Expert Committe on Food Additives (JECFA)/Food
and Agriculture Organization of the United Nations (FAO). World Health Organization
(WHO), Geneva, WHO Technical Report Series, No. 648, 1980a, pp. 17-18. Available from:
http://whqlibdoc.who.int/trs/WHO_TRS_648.pdf.
JECFA. Polyethylene glycols. In: Toxicological Evaluation of Certain Food Additives, 23rd
JECFA Session, Apr. 2-11, 1979, Geneva. Joint FAO/WHO Expert Committe on Food
Additives. World Health Organization (WHO); Geneva, WHO Food Additives Series, No. 14,
1980b, pp. 76-83.
available from: http://www.inchem.org/documents/jecfa/jecmono/v14je19.htm .
JECFA. Polyethylene glycols. In: Compendium of Food Additives Specification, Volume 2.
Combined Specifications from 1st Through the 37th Meetings 1956-1990. Joint FAO/WHO
Expert Committee on Food Additives (JECFA), World Health Organization (WHO). Food and
Agriculture Organization of the United Nations (FAO), Rome. FAO Food and Nutrition Paper,
No. 52, 1992, pp. 1105-1115. Available from:
http://www.fao.org/WAICENT/FAOINFO/ECONOMIC/ESN/jecfa/database/cover.htm.
Kim, M. Absorption of polyethylene glycol oligomers (330-1122 Da) is greater in the jejunum
than in the ileum of rats. J Nutr 126, 2172-2178, 1996.
Krugliak, P., Hollander, D., Ma, T.Y., Tran, D., Dadufalza, V.D., Katz, K.D., Le, K.
Mechanisms of polyethylene glycol 400 permeability in perfused rat intestine.
Gastroenterology 97, 1164-1170, 1989.
Laine, G.A., Hossain, S.M., Solis, R.T., Adams, S.C. Polyethylene glycol nephrotoxicity
secondary to prolonged high-dose intravenous lorazepam. Ann Pharmacother 29, 1110-1114,
1995.
McCabe, W.R., Gee Jackson, G., Grieble, H.G. Treatment of chronic pyelonephritis. A.M.A.
Arch Intern Med 104, 710-719, 1959.
Merck. Polyethylene glycol. In: Merck Index: An Encyclopedia of Chemicals, Drugs, and
Biologicals, 13th Ed. Merck & Co., Inc., Whitehouse Station, New Jersey, 2001, pp. 1358-1359
[Abstract No. 7651].
Mitchell, A.D., Auletta, A.E., Clive, D., Kirby, P.E., Moore, M.M., Myhr, B.C. The
L5178Y/tk+/- mouse lymphoma specific gene and chromosomal mutation assay. A phase III
report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutat Res 394, 177303, 1997.
Mortelmans, K., Haworth, S., Lawlor, T., Speck, W., Tainer, B., Zeiger, E. Salmonella
mutagenicity tests: II. Results from the testing of 270 chemicals [Polyethylene glycol]. Environ
Mutagen 8, 1-26, 36 & 101, 1986.
Mutter, W.P., Maynard, S.E., Brown, R.S. Acute renal failure after high dose intravenous
lorazepam therapy: Delayed polyethylene glycol toxicity as a cause of rapidly reversible anuria.
J Am Soc Nephrol 13, 757, 2002 [Abstract No. PUB428].
Oliva, A., Armas, H., Fariña, J.B. HPLC determination of polyethylene glycol 400 in urine:
Oligomeric profile in healthy and celiac disease subjects. Clin Chem 40, 1571-1574, 1994.
Parlesak, A., Bode, J.C., Bode, C. Parallel determination of gut permeability in man with
M(r)400, M(r)1500, M(r)4000 and M(r)10000 polyethylene glycol. Eur J Clin Chem Clin
Biochem 32, 813-820, 1994.
Pashankar, D.S., Loening-Baucke, V., Bishop, W.P. Safety of polyethylene glycol 3350 for the
treatment of chronic constipation in children. Arch Pediatr Adolesc Med 157, 661-664, 2003.
Prentice, D.E., Majeed, S.K. Oral toxicity of polyethylene glycol (PEG 200) in monkeys and
rats. Toxicol Lett 2, 119-122, 1978.
Rowe, R.C., Sheskey, P.J., Weller, P.J. (Eds.). Polyethylene glycol. In: Handbook of
Pharmaceutical Excipients, 4th Ed.. Pharmaceutical Press, London,
England/Washington, DC, 2003, pp. 454-459.
Roy, A.B., Curtis, C.G., Powell, G.M. The metabolic sulphation of polyethylene glycols by
isolated perfused rat and guinea-pig livers. Xenobiotica 17, 725-732, 1987.
SCF. (1978) Report of the Scientific Committee for Food on the Positive List of Substances to
be Authorized in the Manufacture of Regenerated Cellulose Films Intended to Come Into
Contact with Foodstuffs (Opinion Expressed on 28th September 1978). Commission of the
Europe Communities, Scientific Committee for Food (SCF); Brussels, Belgium, Reports of the
Scientific Committee for Food, 6th Series, 1978. Available from:
http://www.europa.eu.int/comm/food/fs/sc/scf/reports_en.html
http://www.europa.eu.int/comm/food/fs/sc/scf/reports/scf_reports_06.pdf.
SCF. (1986) Report of the Scientific Committee for Food Concerning Certain Monomers and
Other Starting Substances to be Used in the Manufacturing of Plastic Materials and Articles
Intended to Come Into Contact With Foodstuff (Opinion Expressed 14th December 1984).
Commission of the Europe Communities, Scientific Committee for Food (SCF), Brussels,
Belgium, Reports of the Scientific Committee for Food, 17th Series , 1986.
available from: http://www.europa.eu.int/comm/food/fs/sc/scf/reports/scf_reports_17.pdf.
SCF (1997) Food Science and techniques. Reports of the Scientific Committee for Food
(Thirty-sixth series) Directorate- General Industry pp 35-36.
available from: http://ec.europa.eu/food/fs/sc/scf/reports/scf_reports_36.pdf
SCF. (2002a) Opinion of the Scientific Committee on Food on Impurities of 1,4-Dioxane, 2Chloroethanol and Mono- and Diethylene Glycol in Currently Permitted Food Additives and in
Proposed use of Ethyl Hydroxyethyl Cellulose in Gluten-Free Bread (Expressed on 4
December 2002). Scientific Committee for Food (SCF), Brussels, Belgium, 2002a.
[SCF/CS/ADD/EMU/198 Final].
available from: http://europa.eu.int/comm/food/fs/sc/scf/out156_en.pdf.
SCF. (2002b) Opinion of the Scientific Committee for Food on Impurities of Ethylene Oxide in
Food Additives (Expressed on 17 April 2002). Scientific Committee for Food (SCF), Brussels,
Belgium, 2002b. [SCF/CS/ADD/EMU/186 Final].
available from: http://europa.eu.int/comm/food/fs/sc/scf/out127_en.pdf.
Schiller, L.R., Santa Ana, C.A., Porter, J., Fordtran, J.S. Validation of polyethylene glycol 3350
as a poorly absorbable marker for intestinal perfusion studies. Dig Dis Sci 42, 1-5, 1997.
Shaffer, C.B., Critchfield, F.H. The absorption and excretion of the solid polyethylene glycols
(“Carbowax” compounds). J Am Pharm Assoc Sci Ed 36, 152-157, 1947.
Shaffer, C.B., Critchfield, F.H., Carpenter, C.P. Renal excretion and volume distribution of
some polyethylene glycols in dogs. Am J Physiol 152, 93-99, 1948.
Shaffer, C.B., Critchfield, F.H., Nair, J.H. The absorption and excretion of a liquid
polyethylene glycol. J Am Pharm Assoc Sci Ed 39, 340-344, 1950.
Smyth, H.F. (Jr.), Seaton, J., Fischer, L. The single dose toxicity of some glycols and
derivatives. J Ind Hyg Toxicol 23, 259-268, 1941. (Cited In: JECFA, 1980b).
Smyth, H.F., Carpenter, C.P., Shaffer, C.B., Seaton, J., Fischer, L. Some pharmacological
properties of polyethylene glycols of high molecular weight (“Carbowax” compounds). J Ind
Hyg Toxicol 24, 281-284, 1942.
Smyth, H.F. (Jr.), Carpenter, C.P., Shaffer, C.B. The subacute toxicity and irritation of
polyethylene glycols of approximate molecular weights of 200, 300, and 400. J Am
Pharm Assoc 34, 172-174, 1945.
Smyth, H.F. (Jr.), Carpenter, C.P, Shaffer, C.B. The toxicity of high molecular weight
polyethylene glycols: Chronic oral and parenteral administration. J Am Pharm Assoc Sci Ed 36,
157-160, 1947.
Smyth, H.F. (Jr.), Carpenter, C.P., Weil, C.S. The toxicology of the polyethylene glycols. J Am
Pharm Assoc 39, 349-354, 1950.
Smyth, H.F. (Jr.), Carpenter, C.P., Weil, C.S. The chronic oral toxicity of the polyethylene
glycols. J Am Pharm Assoc Sci Ed 44, 27-30, 1955.
Spezia, F., Julien, P., Fournex, R., Vannier, B. In vitro dysmorphogenic effect of PEG 200 on
rat whole-embryo cultures in relation to the species origin of the metabolic activating system
used. Teratology 46, 28A, 1992.
Stahl, G.E., Fayer, J.C., Ling, S.C., Watkins J.B. Comparison of nonabsorbable markers Poly
R-478 and (sup 1sup 4C)PEG-4,000 for use in developmental absorption studies. J Pediatr
Gastroenterol Nutr 12, 485-493, 1991.
Starke, W.C., Pellerin, R.J. Oral Toxicology and Teratogenicity of Polyethylene Glycol 200 and
N-Butyl Mercaptan in Rats. U.S. Army, Chemical Systems Laboratory Tech. Rept. Report
ARCSL-TR-81029, 1981.
Sturgill, B.C., Herold, D.A., Bruns, D.E. Renal tubular necrosis in burn patients treated with
topical polyethylene glycol. Lab Invest 46, 81A, 1982.
Sweetman, S.C. (Ed.).(2002) Macrogols. In: Martindale: The Complete Drug Reference, 33rd
Ed. Pharmaceutical Press, London, Englpp 1630-1631.
Union Carbide. Unpublished data, 1965. Cited in JECFA 1980b.
Vannier, B., Bremaud, R., Benicourt, M., Julien, P. 1989 Teratogenic effects of polyethylene
glycol 200 in the mouse but not in the rat. Teratology 40, 302A [Abstract].
Wangenheim, J., Bolcsfoldi G (1988) Mouse lymphoma L5178Y thymidine kinase locus assay
of 50 compounds. Mutagenesis 3, 193-205.
Weil, C.S., Smyth, H.F. (Jr.). Unpublished Data (Special Report). Institute of Industrial
Research, University of Pittsburgh, 1956. Cited In: JECFA, 1980b.
SCIENTIFIC PANEL MEMBERS
Fernando Aguilar, Herman Autrup, Sue Barlow, Laurence Castle, Riccardo Crebelli, Wolfgang
Dekant, Karl-Heinz Engel, Natalie Gontard, David Gott, Sandro Grilli, Rainer Gürtler, John
Chr. Larsen, Catherine Leclercq, Jean-Charles Leblanc, F. Xavier Malcata, Wim Mennes,
Maria Rosaria Milana, Iona Pratt, Ivonne Rietjens, Paul Tobback, Fidel Toldrá.

Opinion of the Scientific Panel on Food - EFSA

Transcript

Documenti analoghi

Safety assessment on polyethylene glycols (PEGs) - Beauty

What is an electronic cigarette? And a shisha-pen?

fizeau interferometer

Volume 14, No. 1

Minutes of the Plenary Meeting of the FEEDAP Panel

SCF_LAB: the Satellite/Lunar/GNSS laser ranging and altimetry

Risk assessment related to the use of aluminum in cosmetic

application/pdf

1 29 October 2015 Mr. Vytenis Andriukaitis European Commissioner