Following a request from the European Commission, the EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS) was asked to deliver a scientific opinion on the safety of the use of polyvinyl alcohol-polyethylene glycol-graft-co-polymer (PVA-PEG graft co-polymer) as an instant-release film coating for food supplements.
PVA-PEG graft co-polymer is a synthetic, branched, graft co-polymer consisting of approximately 75 % PVA and 25 % PEG units. The co-polymer is primarily intended for use in aqueous instant-release film coatings in the preparation and formulation of food supplement products.
The polymer is currently approved for use for pharmaceutical applications in various countries including the EU.
The Panel noted that, although the co-polymer is currently not approved as a food additive in the EU, the individual constituents of the polymer, PVA and PEG, are both approved for use as film-coating agents in the EU for food supplement products.
The specifications proposed for PVA-PEG graft co-polymer are consistent with those for other food additives already approved film-coating agents for use in the EU, including PVA and PEG. However, the Panel noted that no specifications for the impurities ethylene glycol, diethylene glycol, 1,4-dioxane, ethylene oxide and ethylene glycol are included in the proposed specifications for polyvinyl alcohol-polyethylene glycol-graft-co-polymer by the applicant.
Following oral administration of a single dose of 1000 mg 14C-PVA-PEG graft co-polymer/kg bw to the rat, the compound was quantitatively excreted in the faeces within 168 hours. Excretion of the co-polymer in the urine, bile and via the in air exhaled carbon dioxide from the breakdown of 14C-PVA-PEG graft co-polymer, was negligible. The bioavailability of the co-polymer was calculated to be less than 1 %, indicating therefore virtually no absorption from the gastrointestinal tract. Overall, the Panel considered that absorption in humans is negligible.
The acute oral toxicity of PVA-PEG graft co-polymer in the rat was demonstrated to be low with the LD50 >2000 mg/kg bw.
In repeated dose oral toxicity studies no treatment related effects were reported following administration of PVA-PEG graft co-polymer to laboratory animals (rats, rabbits, dogs).
In a 3-month study in the rat no adverse effects related to the oral administration of the co-polymer at dosed up to 15000 mg/kg in the drinking water. From this study the no-observed-adverse-effect levels (NOAELs) were determined to be about 1600 mg/kg bw/day for the male and 2200 mg/kg bw/day for the female rat, the highest dose tested.
In a 9-month dog study, an increase in the mean absolute ovary weight was reported in all the female treated groups at daily oral dose up to 811 mg PVA-PEG copolymer/kg bw/day, when compared to controls. The mean ovary weight of the control group was below the historical control range and the ovary weights of the treated groups were well within the historical control values.
The Panel noted that in a 3-month study in the rat with oral doses up to 2200 mg/kg bw/day in females, no changes were recorded in the reproductive system even with histopathological examination. In addition no treatment-related findings in the combined fertility and pre- and postnatal toxicity test in rats were noted. Thus, the Panel concluded that the finding in the dog study was due to control and treated dogs being at different stage of the sexual cycle and their young age at the start of the study, and not directly related to the treatment. In agreement with the conclusion by the authors, the Panel considered the NOAEL to be about 800 mg/kg bw/day for both male and female dogs.
Negative results were obtained in in vitro and in vivo genotoxicity assays in both bacterial, as well as mammalian test systems indicating absence of any genotoxic effects.
No chronic toxicity/carcinogenicity studies were conducted with the co-polymer specifically, however no adverse effects following long-term consumption of PVA-PEG graft co-polymer are to be expected based on the absence of any substance-related adverse effects in the shorter term trials and the fact that the co-polymer is, virtually, not absorbed following oral exposure.
In two prenatal developmental toxicity studies, no consistent, substance-related developmental effects were observed following oral administration of the co-polymer to female rats or rabbits at dose levels of up to 1000 mg/kg bw/day during gestation. All external, soft tissue, and skeletal observations in fetuses of the co-polymer-treated groups that were identified to be significantly increased in comparison to the concurrent controls, were spontaneous findings and/or occurred without a dose-response relationship. Furthermore, administration of PVA-PEG graft co-polymer had no adverse effects on the maternal animals with respect to parameters of general toxicity and gestation.
In a combined fertility and pre- and postnatal toxicity study conducted with Wistar rats, no adverse effects were attributed to the oral administration of PVA-PEG graft co-polymer to the F0 males and females. Furthermore, F1 pups and parental animals also demonstrated no adverse effects that could be related to the exposure to the co-polymer in utero and during the lactation period.
The overall NOAELs for parental F0 and for pre- and postnatal developmental toxicity were determined to be 1000 mg PVA-PEG graft co-polymer/kg bw/day, the highest dose tested.
Data from the UK Food Standards Agency on the consumption of food supplements indicate that the use of food supplements among high consumers (97.5th percentile) ranged from 2 tablets/capsules per day in children (4-18 years old) to 7 tablets/capsules per day in adults. Based on the proposed coating level of 50 mg PVA-PEG graft co-polymer/tablet by the applicant, for high consumers an anticipated exposure of 100 mg PVA-PEG graft co-polymer/day for children and 350 mg PVA-PEG graft co-polymer/day for adults, corresponding to 4.3 mg/kg bw/day for children and to 5 mg/kg bw/day for adults, can be calculated. Assuming similar levels of use and intake data of PVA-PEG graft co-polymer from pharmaceuticals, the Panel calculated the combined intake from food supplements and pharmaceutical products to be respectively 8.6 mg/kg bw/day for children and 10 mg/kg bw/day for adults.
Considering that these estimates of intake were derived under the extremely conservative assumption that all food supplement products, as consumed on a daily basis, would be coated only with PVA-PEG graft co-polymer, these values are likely gross over-estimates of actual intakes of the co-polymer. Under these conservative assumptions, the consumption of PVA-PEG graft co-polymer from its use as a film-coating agent for food supplement products (i.e., 4.3 mg/kg bw/day for children and 5 mg/kg bw/day for adults) is approximately 190 to 160 times lower than the NOAEL of about 800 mg/kg bw/day (highest dose tested) derived from a 9-month feeding study in the dog.
Therefore, the Panel considered that the consumption of PVA-PEG graft co-polymer in film-coating formulations for food supplement tablets and/or capsules at the intended use level is not expected to present a risk to human health.
The Panel noted that vinyl acetate (VA) is a starting material used in the manufacturing process of PVA-PEG graft co-polymer and that the applicant proposed a residual level of unreacted VA of 20 mg/kg in the specifications. From the maximum residual levels of VA in PVA-PEG graft co-polymer (20 mg/kg), the Panel calculated for VA, Margins of Exposure (MOE) of 2.2x106 for adults and 2.5x106 for children. Therefore, the Panel considered that the presence of VA in PVA-PEG graft co-polymer up to 20 mg/kg would not be of safety concern.
The Panel concluded that given negligible absorption, the lack of genotoxic potential and the absence of effects at the highest doses tested in the subchronic and reproductive toxicity studies, there is no safety concern for the use of PVA-PEG graft co-polymer as a film coating at the proposed use levels.