opinion of the scientific panel on food additives, flavourings

The EFSA Journal (2006) 414, 1-22

http://www.efsa.eu.int/science/afc/afc_opinions/catindex_en.html

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.

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 1,4-dioxane, 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. 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 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 GLP-compliant 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 dose-related 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 dose-responses 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 compound-related 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 iso-osmotic 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 GLP-compliant 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 species-specific 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. 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. 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.


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. 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.


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opinion of the scientific panel on food additives, flavourings

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